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DOI 10.3310/hta25600
Amoxicillin duration and dose for
community-acquired pneumonia
in children: the CAP-IT factorial
non-inferiority RCT
Sam Barratt, Julia A Bielicki, David Dunn, Saul N Faust, Adam Finn,
Lynda Harper, Pauline Jackson, Mark D Lyttle, Colin VE Powell,
Louise Rogers, Damian Roland, Wolfgang Stöhr, Kate Sturgeon,
Elia Vitale, Mandy Wan, Diana M Gibb and Mike Sharland
on behalf of the CAP-IT Trial Team and the PERUKI and GAPRUKI Networks
Health Technology Assessment
Volume 25 • Issue 60 • November 2021
ISSN 1366-5278
Amoxicillin duration and dose for community-
acquired pneumonia in children: the CAP-IT
factorial non-inferiority RCT
Sam Barratt ,
1
Julia A Bielicki ,
2
David Dunn ,
1
Saul N Faust ,
3
Adam Finn ,
4
Lynda Harper ,
1
†
Pauline Jackson ,
5
Mark D Lyttle ,
5,6
Colin VE Powell ,
7,8
Louise Rogers ,
9
Damian Roland ,
10,11
Wolfgang Stöhr ,
1
Kate Sturgeon ,
1
Elia Vitale ,
2
Mandy Wan ,
12
Diana M Gibb
1
and Mike Sharland
2
* on behalf
of the CAP-IT Trial Team and the PERUKI and
GAPRUKI Networks
1
MRC Clinical Trials Unit, University College London, London, UK
2
Paediatric Infectious Diseases Research Group, Institute for Infection and Immunity,
St George’s University of London, London, UK
3
NIHR Southampton Clinical Research Facility and Biomedical Research Centre,
University of Southampton, University Hospital Southampton NHS Foundation
Trust, Southampton, UK
4
Bristol Children’s Vaccine Centre, School of Population Health Sciences/School of
Cellular and Molecular Medicine, University of Bristol, Bristol, UK
5
Emergency Department, Bristol Royal Hospital for Children, Bristol, UK
6
Faculty of Health and Applied Sciences, University of the West of England, Bristol, UK
7
Paediatric Emergency Medicine Department, Sidra Medicine, Doha, The State of Qatar
8
School of Medicine, Cardiff University, Cardiff, UK
9
Research and Development Nursing Team, Birmingham Women’s and Children’s
NHS Foundation Trust, Birmingham, UK
10
Paediatric Emergency Medicine Leicester Academic (PEMLA) Group, University
Hospitals of Leicester NHS Trust, Leicester, UK
11
SAPPHIRE Group, Health Sciences, Leicester University, Leicester, UK
12
Evelina Pharmacy, Guy’s and St Thomas’NHS Foundation Trust, London, UK
*Corresponding author
†In memoriam
Declared competing interests of authors: David Dunn reports grants from the National Institute for
Health Research during the conduct of the study (RP-PG-1212-20006). Saul N Faust reports personal
fees or grants from AstraZeneca plc (Cambridge, UK)/Medimmune (Gaithersburg, MA, USA), Sanofi SA
(Paris, France), Pfizer Inc. (New York, NY, USA), Seqirus UK Ltd (Maidenhead, UK), Sandoz (Holzkirchen,
Germany), Merck KGAA (Darmstadt, Germany), GlaxoSmithKline plc (Brentford, UK) and Johnson & Johnson
(Brunswick, NJ, USA) outside the submitted work. In addition, Saul N Faust received grants for contract
commercial clinical trials, which were paid to Saul N Faust’s institution (with no personal payment of any
kind). Last, Saul N Faust is a member of the Health Technology Assessment Commissioning Committee
(2017–22). Adam Finn reports grants from GlaxoSmithKline plc, Pfizer Inc., Novavax (Gaithersburg, MA,
USA), Sanofi Pasteur (Lyon, France), VBI Vaccines Inc. (Cambridge, MA, USA), Janssen Pharmaceuticals
(Beerse, Belgium), Valneva SE (Saint-Herblain, France) and JITSUVAX outside the submitted work.
Published November 2021
DOI: 10.3310/hta25600
This report should be referenced as follows:
Barratt S, Bielicki JA, Dunn D, Faust SN, Finn A, Harper L, et al. Amoxicillin duration and dose
for community-acquired pneumonia in children: the CAP-IT factorial non-inferiority RCT.
Health Technol Assess 2021;25(60).
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Abstract
Amoxicillin duration and dose for community-acquired
pneumonia in children: the CAP-IT factorial
non-inferiority RCT
Sam Barratt ,
1
Julia A Bielicki ,
2
David Dunn ,
1
Saul N Faust ,
3
Adam Finn ,
4
Lynda Harper ,
1
†
Pauline Jackson ,
5
Mark D Lyttle ,
5,6
Colin VE Powell ,
7,8
Louise Rogers ,
9
Damian Roland ,
10,11
Wolfgang Stöhr ,
1
Kate Sturgeon ,
1
Elia Vitale ,
2
Mandy Wan ,
12
Diana M Gibb
1
and Mike Sharland
2
* on behalf of the CAP-IT Trial
Team and the PERUKI and GAPRUKI Networks
1
MRC Clinical Trials Unit, University College London, London, UK
2
Paediatric Infectious Diseases Research Group, Institute for Infection and Immunity, St George’s
University of London, London, UK
3
NIHR Southampton Clinical Research Facility and Biomedical Research Centre, University of
Southampton, University Hospital Southampton NHS Foundation Trust, Southampton, UK
4
Bristol Children’s Vaccine Centre, School of Population Health Sciences/School of Cellular and
Molecular Medicine, University of Bristol, Bristol, UK
5
Emergency Department, Bristol Royal Hospital for Children, Bristol, UK
6
Faculty of Health and Applied Sciences, University of the West of England, Bristol, UK
7
Paediatric Emergency Medicine Department, Sidra Medicine, Doha, The State of Qatar
8
School of Medicine, Cardiff University, Cardiff, UK
9
Research and Development Nursing Team, Birmingham Women’s and Children’s NHS Foundation
Trust, Birmingham, UK
10
Paediatric Emergency Medicine Leicester Academic (PEMLA) Group, University Hospitals of Leicester
NHS Trust, Leicester, UK
11
SAPPHIRE Group, Health Sciences, Leicester University, Leicester, UK
12
Evelina Pharmacy, Guy’s and St Thomas’NHS Foundation Trust, London, UK
*Corresponding author msharland@sgul.ac.uk
†In memoriam
Background: Data are limited regarding the optimal dose and duration of amoxicillin treatment for
community-acquired pneumonia in children.
Objectives: To determine the efficacy, safety and impact on antimicrobial resistance of shorter (3-day)
and longer (7-day) treatment with amoxicillin at both a lower and a higher dose at hospital discharge in
children with uncomplicated community-acquired pneumonia.
Design: A multicentre randomised double-blind 2 × 2 factorial non-inferiority trial in secondary care in
the UK and Ireland.
Setting: Paediatric emergency departments, paediatric assessment/observation units and inpatient wards.
Participants: Children aged >6 months, weighing 6–24 kg, with a clinical diagnosis of community-acquired
pneumonia, in whom treatment with amoxicillin as the sole antibiotic was planned on discharge.
DOI: 10.3310/hta25600 Health Technology Assessment 2021 Vol. 25 No. 60
Copyright © 2021 Barratt et al. This work was produced by Barratt et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social
Care. This is an Open Access publication distributed under the terms of the Creative Commons Attribution CC BY 4.0 licence, which permits unrestricted use, distribution,
reproduction and adaption in any medium and for any purpose provided that it is properly attributed. See: https://creativecommons.org/licenses/by/4.0/. For attribution the
title, original author(s), the publication source –NIHR Journals Library, and the DOI of the publication must be cited.
vii
Interventions: Oral amoxicillin syrup at a dose of 35–50 mg/kg/day compared with a dose of
70–90 mg/kg/day, and 3 compared with 7 days’duration. Children were randomised simultaneously
to each of the two factorial arms in a 1 : 1 ratio.
Main outcome measures: The primary outcome was clinically indicated systemic antibacterial treatment
prescribed for respiratory tract infection (including community-acquired pneumonia), other than trial
medication, up to 28 days after randomisation. Secondary outcomes included severity and duration of
parent/guardian-reported community-acquired pneumonia symptoms, drug-related adverse events
(including thrush, skin rashes and diarrhoea), antimicrobial resistance and adherence to trial medication.
Results: A total of 824 children were recruited from 29 hospitals. Ten participants received no trial
medication and were excluded. Participants [median age 2.5 (interquartile range 1.6–2.7) years; 52%
male] were randomised to either 3 (n=413) or 7 days (n=401) of trial medication at either lower
(n=410) or higher (n=404) doses. There were 51 (12.5%) and 49 (12.5%) primary end points in the
3- and 7-day arms, respectively (difference 0.1%, 90% confidence interval –3.8% to 3.9%) and 51 (12.6%)
and 49 (12.4%) primary end points in the low- and high-dose arms, respectively (difference 0.2%, 90%
confidence interval –3.7% to 4.0%), both demonstrating non-inferiority. Resolution of cough was faster
in the 7-day arm than in the 3-day arm for cough (10 days vs. 12 days) (p=0.040), with no difference
in time to resolution of other symptoms. The type and frequency of adverse events and rate of
colonisation by penicillin-non-susceptible pneumococci were comparable between arms.
Limitations: End-of-treatment swabs were not taken, and 28-day swabs were collected in only 53% of
children.We focused on phenotypic penicillin resistance testing in pneumococci in the nasopharynx, which
does not describe the global impact on the microflora. Although 21% of children did not attend the final
28-day visit, we obtained data from general practitioners for the primary end point on all but 3% of children.
Conclusions: Antibiotic retreatment, adverse events and nasopharyngeal colonisation by penicillin-non-
susceptible pneumococci were similar with the higher and lower amoxicillin doses and the 3- and 7-day
treatments. Time to resolution of cough and sleep disturbance was slightly longer in children taking
3 days’amoxicillin, but time to resolution of all other symptoms was similar in both arms.
Future work: Antimicrobial resistance genotypic studies are ongoing, including whole-genome
sequencing and shotgun metagenomics, to fully characterise the effect of amoxicillin dose and duration
on antimicrobial resistance. The analysis of a randomised substudy comparing parental electronic and
paper diary entry is also ongoing.
Trial registration: Current Controlled Trials ISRCTN76888927, EudraCT 2016-000809-36 and
CTA 00316/0246/001-0006.
Funding: This project was funded by the National Institute for Health Research (NIHR) Health
Technology Assessment programme and will be published in full in Health Technology Assessment;
Vol. 25, No. 60. See the NIHR Journals Library website for further project information.
ABSTRACT
NIHR Journals Library www.journalslibrary.nihr.ac.uk
viii
Contents
List of tables xiii
List of figures xv
List of boxes xvii
List of abbreviations xix
Plain English summary xxi
Scientific summary xxiii
Chapter 1 Introduction 1
Background 1
What are the current challenges in the management of childhood community-
acquired pneumonia? 1
What are the current management recommendations for childhood community-
acquired pneumonia? 2
What are the current dose recommendations? 2
What are the current duration recommendations? 2
What is the impact of antimicrobial resistance in childhood community-acquired
pneumonia? 3
Trial rationale 3
Objectives 4
Chapter 2 Methods 5
Trial design 5
Trial setting 6
Participants 6
Recruitment pathways 7
Inclusion criteria 7
Exclusion criteria 7
Changes to selection criteria 7
Interventions 8
Drug substitutions and discontinuations of trial treatment 9
Trial assessments and follow-up 9
Enrolment and randomisation 9
Follow-up 11
Data collection and handling 11
Randomisation 11
Blinding 12
Outcomes 12
Primary outcome 12
Secondary outcomes 13
Sample size 14
Statistical methods 14
Analysis principles 14
Primary outcome 15
DOI: 10.3310/hta25600 Health Technology Assessment 2021 Vol. 25 No. 60
Copyright © 2021 Barratt et al. This work was produced by Barratt et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social
Care. This is an Open Access publication distributed under the terms of the Creative Commons Attribution CC BY 4.0 licence, which permits unrestricted use, distribution,
reproduction and adaption in any medium and for any purpose provided that it is properly attributed. See: https://creativecommons.org/licenses/by/4.0/. For attribution the
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ix
Sensitivity analyses 15
Subgroup analyses 15
Community-acquired pneumonia symptoms 15
Clinical adverse events 16
Antimicrobial resistance 16
Interim analyses 16
Patient and public involvement 16
Protocol amendments 17
Chapter 3 Results 19
Participant flow 19
Baseline 21
Patient characteristics 21
Medical history 21
Vital parameters and clinical signs 21
Chest examination 23
Parent/guardian-reported community-acquired pneumonia symptoms 24
Clinical investigations 25
Prior antibiotic exposure 26
Other medical interventions in exposed group 26
Follow-up 27
Adherence 29
Primary outcome 31
End-Point Review Committee results 31
Analysis of primary end point 33
Interaction effects 33
Primary end-point sensitivity analyses 34
All systemic antibacterial treatments 34
Treatment events for community-acquired pneumonia/chest infection 36
All treatment events for community-acquired pneumonia/chest infection 36
Only treatment events started after the first 3 days (duration randomisation) 37
On-treatment analyses 37
Subgroup analyses 37
Participants with severe community-acquired pneumonia 37
Seasonal effect 38
Streptococcus pneumoniae carriage and resistance 39
Availability of nasopharyngeal culture results 39
Streptococcus pneumoniae carriage 39
Streptococcus pneumoniae penicillin non-susceptibility 39
Streptococcus pneumoniae amoxicillin resistance/non-susceptibility 40
Community-acquired pneumonia symptoms 40
Time to resolution of community-acquired pneumonia symptoms: overall 42
Time to resolution of community-acquired pneumonia symptoms: dose randomisation 42
Time to resolution of community-acquired pneumonia symptoms: duration randomisation 42
Sensitivity analysis for duration randomisation 43
Adverse events 43
Serious adverse events 43
Specified clinical adverse events (diarrhoea, thrush and skin rash) 45
Health-care services 47
Daily activities and child care 48
Chapter 4 Discussion 49
Limitations 49
CONTENTS
NIHR Journals Library www.journalslibrary.nihr.ac.uk
x
Generalisability 49
Interpretation 50
Implications 51
Chapter 5 Conclusions 53
Acknowledgements 55
References 59
Appendix 1 Details of main protocol amendment: joint analysis of paediatric
emergency department and ward groups 67
Appendix 2 Community-acquired pneumonia symptoms at trial entry by strata 69
Appendix 3 On-treatment analysis of the primary end point 71
DOI: 10.3310/hta25600 Health Technology Assessment 2021 Vol. 25 No. 60
Copyright © 2021 Barratt et al. This work was produced by Barratt et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social
Care. This is an Open Access publication distributed under the terms of the Creative Commons Attribution CC BY 4.0 licence, which permits unrestricted use, distribution,
reproduction and adaption in any medium and for any purpose provided that it is properly attributed. See: https://creativecommons.org/licenses/by/4.0/. For attribution the
title, original author(s), the publication source –NIHR Journals Library, and the DOI of the publication must be cited.
xi
List of tables
TABLE 1 Weight bands used for dosing of CAP-IT IMP 8
TABLE 2 The CAP-IT assessment schedule 10
TABLE 3 Ineligible patients 19
TABLE 4 Randomisation outcomes: analysis population 20
TABLE 5 Patient characteristics 21
TABLE 6 Medical history 22
TABLE 7 Vital parameters and clinical signs at presentation by randomisation status 22
TABLE 8 Chest examination at presentation by randomisation status 23
TABLE 9 Baseline radiographic findings in participants who had chest
radiography performed 25
TABLE 10 Baseline respiratory sample virology assessment results 26
TABLE 11 Prior exposure with antibiotics 27
TABLE 12 Final visit and follow-up data completeness 28
TABLE 13 Participant follow-up rate 28
TABLE 14 Parent/guardian diary completion rate 29
TABLE 15 Adherence to trial medication by randomisation arm 30
TABLE 16 Reasons for starting non-trial systemic antibacterials, as adjudicated by
the ERC 31
TABLE 17 End-Point Review Committee primary end-point adjudication results 32
TABLE 18 Abnormalities at presentation considered for subgroup analysis for
severe CAP 37
TABLE 19 Availability of nasopharyngeal culture results 39
TABLE 20 Streptococcus pneumoniae carriage 40
TABLE 21 Penicillin and amoxicillin resistance/non-susceptibility in all participants
with a culture result, either negative or positive for S. pneumoniae 41
TABLE 22 Summary of SAEs 43
TABLE 23 Serious adverse event details 44
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Care. This is an Open Access publication distributed under the terms of the Creative Commons Attribution CC BY 4.0 licence, which permits unrestricted use, distribution,
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title, original author(s), the publication source –NIHR Journals Library, and the DOI of the publication must be cited.
xiii
TABLE 24 Prevalence of diarrhoea, oral thrush and skin rash after baseline 46
TABLE 25 Health-care service utilisation 47
TABLE 26 Daily activities and child care 48
TABLE 27 Community-acquired pneumonia symptoms at trial entry by stratum 69
LIST OF TABLES
NIHR Journals Library www.journalslibrary.nihr.ac.uk
xiv
List of figures
FIGURE 1 The CAP-IT schema 5
FIGURE 2 Treatment arms 9
FIGURE 3 A CONSORT (Consolidated Standards of Reporting Trials) flow diagram 20
FIGURE 4 Symptoms at trial entry 24
FIGURE 5 Clinical symptoms (i.e. fever, cough, phlegm and breathing fast) at trial
entry, by group 24
FIGURE 6 Clinical symptoms (i.e. wheeze, sleep disturbance, vomiting, eating less and
abnormal activity) at trial entry, by group 25
FIGURE 7 Kaplan–Meier curve for primary end point: dose randomisation 33
FIGURE 8 Kaplan–Meier curve for primary end point: duration randomisation 34
FIGURE 9 Kaplan–Meier curve for analysis of interaction between the two
randomisations 34
FIGURE 10 Kaplan–Meier curve for analysis of interaction between pre-exposure
with antibiotics and dose randomisation 35
FIGURE 11 Kaplan–Meier curve for analysis of interaction between pre-exposure
with antibiotics and duration randomisation 35
FIGURE 12 Forest plot summarising sensitivity and subgroup analyses outcomes in
terms of difference in proportions of retreatment by day 28 for the dose randomisation 36
FIGURE 13 Forest plot summarising sensitivity and subgroup analyses outcomes in
terms of difference in proportions of retreatment by day 28 for the duration
randomisation 36
FIGURE 14 Kaplan–Meier curve for severe CAP subgroup primary analysis for
duration randomisation 38
FIGURE 15 Kaplan–Meier curve for severe CAP subgroup primary analysis for
dose randomisation 38
FIGURE 16 Availability of symptom data over time, by data source 41
FIGURE 17 Kaplan–Meier curves for time to symptom resolution across all
randomisation arms 42
FIGURE 18 Kaplan–Meier curve for time to resolution of cough in the duration
treatment arms 42
DOI: 10.3310/hta25600 Health Technology Assessment 2021 Vol. 25 No. 60
Copyright © 2021 Barratt et al. This work was produced by Barratt et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social
Care. This is an Open Access publication distributed under the terms of the Creative Commons Attribution CC BY 4.0 licence, which permits unrestricted use, distribution,
reproduction and adaption in any medium and for any purpose provided that it is properly attributed. See: https://creativecommons.org/licenses/by/4.0/. For attribution the
title, original author(s), the publication source –NIHR Journals Library, and the DOI of the publication must be cited.
xv
FIGURE 19 Kaplan–Meier curve for time to resolution of sleep disturbed by cough in
the duration treatment arms 43
FIGURE 20 Skin rash severity during treatment period: duration randomisation 47
FIGURE 21 Dose randomisation: participants who took at least 80% of all trial
medication, including placebo 71
FIGURE 22 Dose randomisation: participants who took at least 80% of active
trial drug 71
FIGURE 23 Duration randomisation: participants who took at least 80% of all trial
medication, including placebo 72
FIGURE 24 Duration randomisation: participants who took at least 80% of active
trial drug 72
LIST OF FIGURES
NIHR Journals Library www.journalslibrary.nihr.ac.uk
xvi
List of boxes
BOX 1 Definition of clinical diagnosis of CAP 7
DOI: 10.3310/hta25600 Health Technology Assessment 2021 Vol. 25 No. 60
Copyright © 2021 Barratt et al. This work was produced by Barratt et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social
Care. This is an Open Access publication distributed under the terms of the Creative Commons Attribution CC BY 4.0 licence, which permits unrestricted use, distribution,
reproduction and adaption in any medium and for any purpose provided that it is properly attributed. See: https://creativecommons.org/licenses/by/4.0/. For attribution the
title, original author(s), the publication source –NIHR Journals Library, and the DOI of the publication must be cited.
xvii
List of abbreviations
AE adverse event
BNFc British National Formulary for
Children
BTS British Thoracic Society
CAP community-acquired pneumonia
CAP-IT Community-Acquired Pneumonia:
a protocol for a randomIsed
controlled Trial
CI confidence interval
ED emergency department
ERC End-Point Review Committee
GP general practitioner
ID identification
IDMC Independent Data Monitoring
Committee
IMP investigational medicinal product
IQR interquartile range
ITT intention to treat
MIC minimal inhibitory concentration
PCV pneumococcal conjugate vaccine
PED paediatric emergency department
PPI patient and public involvement
RCT randomised controlled trial
SAE serious adverse event
SAP statistical analysis plan
SAR serious adverse reaction
T>MIC time spent above the minimum
inhibitory concentration
TSC Trial Steering Committee
WHO World Health Organization
DOI: 10.3310/hta25600 Health Technology Assessment 2021 Vol. 25 No. 60
Copyright © 2021 Barratt et al. This work was produced by Barratt et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social
Care. This is an Open Access publication distributed under the terms of the Creative Commons Attribution CC BY 4.0 licence, which permits unrestricted use, distribution,
reproduction and adaption in any medium and for any purpose provided that it is properly attributed. See: https://creativecommons.org/licenses/by/4.0/. For attribution the
title, original author(s), the publication source –NIHR Journals Library, and the DOI of the publication must be cited.
xix
Plain English summary
Pneumonia (an acute lung infection) is a common diagnosis in young children worldwide. To cure
this, some children are given antibiotics, but we do not currently know the best amount (dose) to
give and the ideal number of days (duration) of treatment.
Taking antibiotics causes changes in bacteria, making them more resistant to treatment. This may be
affected by the dose and duration, and is important because resistant bacteria are harder to treat and
could spread to other people.
Amoxicillin is the most common antibiotic treatment for children with pneumonia. CAP-IT (Community-
Acquired Pneumonia: a protocol for a randomIsed controlled Trial) tested if lower doses and shorter
durations of amoxicillin are as good as higher doses and longer durations, and whether or not these
affect the presence of resistant bacteria.
In total, 824 children in the UK and Ireland with pneumonia participated. They received either high- or
low-dose amoxicillin for 3 or 7 days following discharge from hospital. To ensure that neither doctors
nor parents were influenced by knowing which group a child was in, we included dummy drugs (placebo).
We measured how often children were given more antibiotics for respiratory infections in the 4 weeks
after starting the trial medicine. To check for resistant bacteria, a nose swab was collected before
starting treatment and again after 4 weeks.
One in every eight participating children was given additional antibiotics. We found no important
difference in this proportion between 3 days and 7 days of amoxicillin treatment, or between lower
or higher doses. Although children’s coughs took slightly longer to go away when they received only
3 days of antibiotics, rash was reported slightly more often in children taking 7 days of antibiotics.
There was no effect of dose of amoxicillin on any of the symptom measurements. No effect of duration
of treatment or dose was observed for antibiotic resistance in bacteria living in the nose and throat.
DOI: 10.3310/hta25600 Health Technology Assessment 2021 Vol. 25 No. 60
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xxi
Scientific summary
Background
Antibiotics are among the most frequently prescribed medicines for children worldwide, and the most
common indication is acute respiratory tract infection. Community-acquired pneumonia (CAP) accounts
for a substantial proportion. Although the majority of pneumonia deaths occur in low- and middle-income
countries, CAP is a major cause of morbidity in Europe and North America.
According to current guidance, including guidance from the British National Formulary for Children
(BNFc) and the British Thoracic Society (BTS) in the UK, amoxicillin is the recommended treatment
for childhood CAP. Twice-daily dosing is widely recommended internationally, but the BNFc currently
recommends amoxicillin (250 mg) three times daily for children aged 1–5 years, with a total daily
dose similar to countries using twice-daily dosing. Owing to this age-banded dose selection, there
is considerable variability in the effective total daily dose for treated children in the UK. In terms
of duration, the 2019 National Institute for Health and Care Excellence treatment guidelines for
childhood pneumonia recommend a 5-day course be prescribed, European and World Health
Organization guidance has suggested that a 3- to 5-day course be prescribed and the BTS recognises
that there are no robust data to inform duration. Overall, there is insufficient evidence to inform
optimal amoxicillin dose or duration for childhood CAP.
Streptococcus pneumoniae is the bacterial pathogen most commonly associated with childhood CAP. The
pneumococcal conjugate vaccination (PCV13) covers 13 serotypes of S. pneumoniae and was introduced
in the UK in 2010, with an uptake of nearly 95%. Despite this, there has not been a significant reduction
in CAP-related hospital admissions in young children. S. pneumoniae resistance to penicillin in the UK is
relatively rare and generally low level, reported to be identified in approximately 15% of respiratory
isolates and 4–6% of blood culture isolates. To the best of our knowledge, there are virtually no data on
the impact of duration and dose of antibiotic treatment on colonisation with resistant bacteria in children,
but the relationship is likely to be dynamic and highly complex.
Although there is clear agreement that amoxicillin should be used as the first-line agent in children
requiring antibiotic treatment, there are insufficient data on the impact of amoxicillin dose and duration
on clinical cure, drug toxicity and resistance to key bacteria, including S. pneumoniae.
Objectives
The main objective CAP-IT (Community-Acquired Pneumonia: a protocol for a randomIsed controlled
Trial) was to determine the following for young children with uncomplicated CAP treated after
discharge from hospital if:
la 3-day course of amoxicillin is non-inferior to a 7-day course, determined by receipt of a clinically
indicated systemic antibiotic other than trial medication for respiratory tract infection (including CAP)
in the 4 weeks after randomisation up to day 28
llower-dose amoxicillin is non-inferior to higher-dose amoxicillin under the same conditions.
Secondary objectives were to evaluate the impact of lower-dose and shorter-duration amoxicillin on
antimicrobial resistance, severity and duration of parent/guardian-reported CAP symptoms and
specified clinical adverse events (AEs) (i.e. rash and diarrhoea).
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xxiii
Methods
Trial design
CAP-IT was a multicentre clinical trial with a target sample size of 800 participants conducted in
hospitals in the UK and Ireland. It was a randomised, double-blind, placebo-controlled, 2 × 2 factorial,
non-inferiority trial that evaluated amoxicillin dose and duration in young children with CAP.
Eligibility and recruitment
Patients presenting to 28 UK NHS hospitals and one children’s hospital in Ireland were recruited in
emergency departments (EDs), assessment/observation units and inpatient wards.
Participants
Children were eligible if they had a diagnosis of uncomplicated CAP, were aged >6 months, weighed
6–24 kg and treatment with amoxicillin as the sole antibiotic was planned on discharge. CAP diagnosis
was defined as cough within the previous 96 hours, fever (≥38 °C) in the previous 48 hours and respiratory
distress and/or focal chest signs. Children could have received either no antibiotics or <48 hours of
beta-lactam antibiotics prior to randomisation.
Children were excluded for any severe underlying chronic disease with an increased risk of complicated
CAP (including sickle cell anaemia, immunodeficiency, chronic lung disease and cystic fibrosis), documented
penicillin allergy or other contraindication to amoxicillin, diagnosis of complicated pneumonia (i.e. shock,
hypotension, altered mental state, ventilatory support, empyema, pneumothorax or pulmonary abscess)
or bilateral wheezing without focal chest signs.
Interventions
Amoxicillin suspension was orally administered by parents/guardians twice daily. All children were
weighed during eligibility screening to determine dose volume according to seven weight bands.
Children were randomised to receive either a lower (35–50 mg/kg/day) or a higher (70–90 mg/kg/day)
dose, and to receive either 3 or 7 days of amoxicillin at the point of discharge from hospital.
Randomisation and blinding
Patients underwent two simultaneous factorial 1 : 1 randomisations (dose and duration), resulting in
their allocation to one of the four amoxicillin regimens (low dose, short duration; low dose, long
duration; high dose, short duration; or high dose, long duration) using computer-generated random
permuted blocks of size eight, stratified according to whether or not they had received non-trial
antibiotics in hospital before being enrolled. Initially, stratification was by paediatric ED or ward group,
reflecting whether participants were admitted to inpatient wards or observation units or discharged
directly from the ED. Following an amendment for the joint analysis of these groups, stratification
was effectively based on whether or not participants had received in-hospital antibiotics prior to
randomisation. Blinded investigational medicinal product (IMP) labels were applied to each treatment pack
and participants were randomised by dispensing the next sequentially numbered pack in the active block.
All treating clinicians, parents/guardians and outcome assessors were blinded to the allocated treatment.
Dose blinding was achieved by using otherwise identical amoxicillin products of two different strengths
(125 mg/5 ml and 250 mg/5 ml). A placebo manufactured to match oral amoxicillin suspension was used
to blind the duration. One brand of amoxicillin was used for the first 3 days, followed by either a second
brand of amoxicillin or placebo for days 4–7. Parents were informed to expect a taste change between
bottles, but they did not know whether this was because of placebo or alternative amoxicillin.
Outcomes
The primary outcome for CAP-IT was defined as any clinically indicated systemic antibacterial treatment
prescribed for respiratory tract infection (including CAP) other than trial medication within 4 weeks of
randomisation (including if prescribed at the final follow-up visit at day 28). An expert clinician End-Point
Review Committee (ERC) adjudicated the main clinical indication for all reported primary outcomes.
SCIENTIFIC SUMMARY
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xxiv
Secondary outcomes included phenotypic resistance to penicillin at day 28 measured in nasopharyngeal
S. pneumoniae isolates, severity and duration of parent/guardian-reported CAP symptoms (including fever,
cough, phlegm, fast breathing, wheeze, disturbed sleep, eating/drinking less, interference with normal
activity and vomiting), adherence to trial medication, the occurrence of specified clinical AEs (including
skin rash, thrush and diarrhoea) and serious adverse events (SAEs).
Data collection
Data on primary and secondary end points were collected on paper case report forms by site staff at
trial entry, via telephone contact at days 3, 7, 14 and 21 and at a final face-to-face visit on day 28.
In the case of children who did not attend the final face-to-face visit, consent was obtained for the trial
team to contact their general practitioner (GP) to ascertain whether or not they had received a further
course of antibiotics for any respiratory illness. In addition, parents/guardians completed a daily diary
from day 1 to day 14.
Sample size
The sample size was calculated assuming a 15% event rate, an 8% non-inferiority margin (on a risk
difference scale) assessed against a two-sided 90% confidence interval (CI), 90% power and 15% loss
to follow-up, resulting in a sample size of 800 children.
Statistical methods
Statistical analyses were performed according to a modified intention-to-treat (ITT) principle, including
all patients enrolled and analysed according to the group to which they were randomised. The one
modification to the strict ITT principle was the exclusion of randomised patients who did not take any
IMP from all statistical analyses.
The primary outcome was compared between the randomised groups using time-to-event methods,
analysing time from enrolment to the first occurrence of the primary end point. Participants with
incomplete primary outcome data were censored at the time of their last contact (including contact
with their GP). Kaplan–Meier estimates were used to derive the risk difference between the randomised
groups for the primary end point at day 28.
Four predefined sensitivity analyses for the primary outcome were performed: (1) including all systemic
antibacterial treatments regardless of reason or indication; (2) limiting to end points where either CAP
or chest infection (rather than respiratory tract infection generally) was adjudicated as the reason for
treatment; (3) as the second analysis, but also including end points where the clinical indication was judged
as ‘unlikely’by the ERC; and (4) for the duration comparison only, disregarding prescriptions occurring
within 3 days of randomisation because these cannot, by definition, be related to this randomisation.
Two predefined subgroup/stratified analyses were performed: (1) including participants at the higher
end of the severity spectrum only, defined as two or more abnormalities at presentation [i.e. a raised
respiratory rate (>37 breaths/minute for children aged 1–2 years; >28 breaths/minute for children
aged 3–5 years), oxygen saturation <92% in room air, presence of chest retractions]; and (2) a
stratification by calendar time, based on Public Health England reports of circulating viruses/bacteria
in the winter seasons spanned by CAP-IT.
Results
Primary end point
Of 814 participants in the analysis population, 100 (12.5%, 90% CI 10.7% to 14.6%) met the primary
end point [51 (12.6%) participants in the lower-dose arm and 49 (12.4%) participants in the higher-
dose arm (difference 0.2%, 90% CI –3.7% to 4.0%); 51 (12.5%) participants in the shorter-duration
arm and 49 (12.5%) participants in the longer-duration arm (difference 0.1%, 90% CI –3.8% to 3.9%)].
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xxv
For both comparisons, the upper 90% confidence limit was less than the non-inferiority margin of 8%,
indicating non-inferiority of lower to higher dose and shorter to longer duration. There was no evidence
of an interaction between the two randomisation arms or between the individual randomisation arms and
pre-treatment with antibiotics.
All four of the sensitivity analyses supported the primary analysis, demonstrating non-inferiority for
the dose and duration comparisons.
Community-acquired pneumonia symptoms
There was no evidence for a difference between the lower- and higher-dose groups in time to resolution
of any of the nine parent/guardian-reported symptoms (p>0.05).
There was evidence of a faster time to resolution of cough in the longer-duration group (median
10 days) than in the shorter-duration group (median 12 days) (p=0.040). A similar difference was
also observed for sleep disturbed by cough (p=0.026). There was no significant difference between
the duration groups in time to resolution of the other seven symptoms (p>0.05).
Adverse events
A SAE was experienced by 43 of 814 (5.3%) participants. One participant (0.1%) experienced a serious
adverse reaction and no participants experienced a suspected unexpected adverse reaction. The proportion
of participants who experienced a SAE was similar in the different dose and duration groups.
There was no difference in the time to onset or severity of diarrhoea or thrush for either the dose
or duration randomisation. The proportion of participants who reported skin rash after baseline
was slightly higher in the longer-duration arm (106/387, 27.4%) than in the shorter-duration arm
(87/404, 21.5%; p=0.055).
Limitations
Limitations of the trial were that end-of-treatment swabs were not taken and 28-day swabs were
collected in only 53% of children. In addition, we focused on phenotypic penicillin resistance testing in
pneumococci in the nasopharynx, which does not describe the global affect on the microflora. Although
21% of children did not attend the final 28-day visit, we obtained data from general practitioners for
the primary end point on all but 3% of children.
Conclusions
In summary, we found a 3-day treatment course of amoxicillin to be non-inferior to a 7-day course of
amoxicillin, and a lower daily dose of amoxicillin to be non-inferior to a higher daily dose of amoxicillin,
in terms of antibiotic retreatment for respiratory tract infection within 28 days. Time to resolution
of parent/guardian-reported symptoms was similar in randomisation arms, except that mild cough
lasted, on average, 2 days longer in participants in the shorter-duration arm than in participants in the
longer-duration arm. AE rates and health-care services use within the 28-day follow-up period and
penicillin non-susceptible pneumococcal colonisation rates at 28 days were similar in all dose and
duration randomisation groups. No penicillin-resistant pneumococci were identified in samples from
CAP-IT participants. Based on these findings, 3 days could be considered for the duration of amoxicillin
treatment for children with uncomplicated pneumonia treated in the ambulatory setting. Current
BNFc age-banded dosing in the UK results in a wide range of total daily doses, spanning both the
lower and higher doses investigated in CAP-IT.
SCIENTIFIC SUMMARY
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xxvi
Future work
Antimicrobial resistance genotypic studies are ongoing, including whole-genome sequencing and shotgun
metagenomics, to fully characterise the effect of amoxicillin dose and duration on antimicrobial resistance.
The analysis of a randomised substudy comparing parental electronic and paper diary entry is also ongoing.
Trial registration
This trial is registered as ISRCTN76888927, EudraCT 2016-000809-36 and CTA 00316/0246/001-0006.
Funding
This project was funded by the National Institute for Health Research (NIHR) Health Technology
Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 60.
See the NIHR Journals Library website for further project information.
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xxvii
Chapter 1 Introduction
This chapter includes material that has been adapted from the trial protocol, which has been
published in BMJ Open.1This is an Open Access article distributed in accordance with the terms
of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix,
adapt and build upon this work, for commercial use, provided the original work is properly cited.
See: https://creativecommons.org/licenses/by/4.0/. The text below includes minor additions and formatting
changes to the original text.
Background
Antibiotics are among the most frequently prescribed medicines for children worldwide.2,3 In the UK,
Italy and the Netherlands, almost 50% of children have received antibiotics by their second birthday.
Annually, it is estimated that 30% of children aged 2–11 years receive antibiotics.3
Of the possible indications in children aged <5 years, the most common are acute respiratory tract
infections, including community-acquired pneumonia (CAP).4–6CAP is one of the most common serious
bacterial childhood infections. Although the majority of pneumonia deaths occur in low- and middle-
income countries, CAP is a major cause of morbidity in Europe and North America.5,7 In the UK, 62%
of all antibiotics prescribed for community-acquired infections are for CAP.8In the USA, respiratory
symptoms, fever or cough are responsible for one-third of all childhood medical visits, and 7–15% of
these children will be diagnosed with CAP.9,10
Emergency department (ED) attendances and hospital admissions of children with respiratory complaints
have increased in recent decades, mostly in preschool children.9,11,12 According to Hospital Episode
Statistics,13 children aged 0–4 years accounted for around 2.11 million ED attendances in 2017–18.
More than 11,000 children aged <15 years were admitted to hospitals in England with a diagnosis
of bacterial pneumonia in 2008, and 9000 1- to 4-year-old inpatients with non-influenza pneumonia
were recorded in 2012/13.13,14
The bacterial pathogen most commonly associated with childhood CAP is Streptococcus pneumoniae,
including in countries where pneumococcal conjugate vaccine (PCV) is routinely administered.7,15–17
In 2010, PCV13 (which covers 13 S. pneumoniae serotypes) was introduced in the UK, with almost
95% uptake in young children.18,19 However, despite an observed impact on invasive pneumococcal
disease, a decrease in CAP-related hospital admissions in young children has not been observed.11,14,20,21
What are the current challenges in the management of childhood
community-acquired pneumonia?
There is no test capable of accurately distinguishing between bacterial and viral CAP.22 Interobserver
agreement for chest radigoraphic findings is poor, casting doubt on the usefulness of chest radiographs
for identifying bacterial CAP, and culturing of microbiological samples, such as sputum, has low diagnostic
value and samples are often difficult to take from young children.23–25 Diagnosis of bacterial CAP presents
a challenge for treating clinicians, who rely largely on clinical criteria.22 Children presenting with fever,
raised respiratory rate, focal chest signs and other respiratory signs and symptoms (such as cough) are
commonly ascribed a diagnosis of bacterial CAP,10,26–28 whereas wheezing is associated with the absence
of radiographic pneumonia and failure to detect bacteria in clinical samples.26,29 If bacterial CAP is
considered the likely diagnosis, treatment with antibiotics is instituted.10,30 This diagnostic challenge is
particularly problematic in secondary care, where the proportion of children presenting with serious
bacterial infections is higher than in primary practice.31,32
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1
A further challenge for clinicians is severity assessment. Available validated predictive scoring systems
for CAP severity include the Pneumonia Severity Index and the CURB-65 (confusion, urea, respiratory
rate, blood pressure, and 65 years of age or older) score, but these are not applicable to children.33,34
Pneumonia mortality risk scores for children have been developed in low-resource settings, but do
not differentiate between viral and bacterial pneumonia.35,36 Low oxygen saturation in room air is
included as one component in these risk scores, and is an important factor for differentiating between
non-severe and severe pneumonia.37–39
Finally, assessing the efficacy of childhood CAP treatment is complex. Key measures in studies assessing
efficacy early in the treatment course include lack of improvement or worsening of clinical symptoms
and signs, such as respiratory rate and oxygen saturation.40 According to British Thoracic Society (BTS)
guidance, such criteria should trigger clinical review of children treated with oral antibiotics for CAP,22
including where the following features are present at 48 hours: (1) persistent high fever, (2) increasing or
persistently increased effort of breathing and (3) persistent or increasing oxygen requirement to maintain
saturations ≥92%.22 Approximately 15% of children with CAP receive further antibiotics within 28 days
of starting treatment because of symptoms that concern parents.41–44 However, only half of children
show recovery from symptoms of acute respiratory illness by day 9 or 10, and 90% of children recover
by 3.5 weeks after symptom onset.45–47
What are the current management recommendations for childhood
community-acquired pneumonia?
Amoxicillin is the drug of choice for the treatment of childhood CAP according to the British National
Formulary for Children (BNFc) and BTS and National Institute for Health and Care Excellence guidelines,
as well as several international guidelines,22,48–51 as it can effectively target and treat S. pneumoniae
in the absence of high-level penicillin resistance. As a result, amoxicillin accounts for a very high
proportion of overall oral antibiotic use among young children in many settings. Despite this, there is
insufficient evidence to inform optimal treatment dose or duration.
What are the current dose recommendations?
Antibiotic dose selection should be driven by pharmacokinetic/pharmacodynamic considerations.The key
pharmacokinetic/pharmacodynamic parameter for beta-lactams (including amoxicillin) is time spent above
the minimum inhibitory concentration (T >MIC) (mainly focused here on pneumococcus). The recommended
T>MIC is 40–50% of the dosing interval; however, the exact relationship between blood pharmacokinetics
and concentrations of amoxicillin in the lungs is unclear.48,52 The half-life of oral amoxicillin is about
1.0–1.5 hours and, on this basis, a three times daily regimen has been widely recommended.53 However,
there are few data to inform whether or not three times daily dosing is likely to achieve pharmacokinetic/
pharmacodynamic parameters better than twice-daily dosing. The available data suggest that, in the case
of total amoxicillin doses of 25–50 mg/kg/day, twice-daily dosing should be sufficient to achieve adequate
T>MIC53 and a Brazilian group recently demonstrated non-inferiority of twice-daily dosing compared
with thrice-daily dosing in childhood CAP.54 Together with a likely improvement in adherence to less
frequent administration, twice-daily dosing is, therefore, widely recommended.48–50,52 Currently, the BNFc
recommends amoxicillin (250 mg) thrice daily for children aged 1–5 years with CAP, resulting in highly
variable dosing, between approximately 40 mg/kg/day and 80 mg/kg/day, depending on the weight of the
child.55 Therefore, alternative strategies, such as weight-banded dosing, may be more appropriate.56
Furthermore, much higher daily doses of amoxicillin, up to 200 mg/kg/day, are recommended for the
treatment of severe infections.55
What are the current duration recommendations?
Several large randomised controlled trials (RCTs) have found shorter treatment courses in childhood
CAP to be effective in low- and middle-income settings in terms of clinical cure, treatment failure and
relapse rate.57,58 However, these trials enrolled children with symptoms indicative of a viral infection
not requiring antibiotics, and generalisability to the UK has, therefore, been questioned.22
INTRODUCTION
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2
The BTS recognises that there are no robust data to inform guidance on duration of antibiotic treatment
in childhood CAP.22 The BNFc guidance relevant at the start of this trial recommended a 7-day course,
whereas European and World Health Organization (WHO) guidance suggests a 3- to 5-day course.48,55
In 2019, the National Institute for Health and Care Excellence published guidance recommending stopping
amoxicillin treatment after 5 days (250 mg thrice daily) for children aged 1–4 years, unless microbiological
results suggest that a longer course length is needed or the patient is not clinically stable.51
What is the impact of antimicrobial resistance in childhood community-
acquired pneumonia?
In the UK, the rates of penicillin non-susceptibility of S. pneumoniae are relatively low, at approximately
15% for respiratory samples (mainly from adults) and 4–6% for blood culture isolates.59 Penicillin
resistance [i.e. minimal inhibitory concentration (MIC) >2μg/ml] has not been observed in blood
culture isolates and has been found in <1% of respiratory S. pneumoniae isolates in the UK since
2010.59 However, some worrying trends are observed in resistance of gut bacteria, and this situation
will be exacerbated in a setting where antibiotics are used injudiciously.60
The relationship between MIC (an in vitro phenomenon) and clinical outcome in CAP is complex,
and data on the level of S. pneumoniae antimicrobial resistance that reduces amoxicillin effectiveness
are limited. Harmonisation of European breakpoints (i.e. the MIC at which an isolate is considered
susceptible, intermediate or resistant) attempts to provide a link between clinical impact and in vitro
observation of resistance.61 Clinical breakpoints are determined based on a variety of data, in addition
to efficacy studies. This includes pharmacokinetic/pharmacodynamic data, which for penicillin usually
take T >MIC of 40% as the key exposure measure.
Children have high rates of bacterial colonisation, which often represents an increased level of carriage
of resistant organisms62,63 These may be passed on to others in the community, especially within child-
care settings.64,65 Interventions to maintain a low level of antimicrobial resistance among colonising
bacteria may, therefore, have population implications.
The limited existing data on the specific impact of duration and dose of antibiotic treatment on
subsequent colonisation with resistant bacteria in vivo suggest a complex and dynamic relationship.62–73
Experimental models suggest that insufficiently high dosing could promote selection of resistant
pathogens. In addition, although most of the effect on bacterial load is achieved early during antibiotic
exposure, resistant isolates emerge after 4 or 5 days.74–78 RCTs assessing the effect of antibiotic
duration and dose have been called for, as they will probably provide the strongest evidence for the
relationship between antibiotic exposure and colonisation with resistant bacteria.79 One such RCT
found that higher-dose shorter-duration amoxicillin therapy for childhood CAP led to less colonisation
with resistant bacteria after 4 weeks, and was associated with better treatment adherence.72 However,
mathematical modelling indicates that this may come at the price of selecting isolates with higher
levels of resistance, and clinical efficacy was not addressed in the trial.72,78
Trial rationale
Despite the reduction in incidence of invasive pneumococcal disease since the introduction of the
conjugate vaccine,20 CAP remains one of the most commonly identified and treated childhood
infections in the UK. Although there is clear agreement that amoxicillin should be the first-line
treatment, there are insufficient data to inform selection of dose and duration, and the impact that
different regimens have on antimicrobial resistance is unknown.
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3
Effectiveness and resistance-outcome data pertaining to dose and duration of amoxicillin could inform
antimicrobial stewardship strategies in the large group of children with a high likelihood of bacterial
CAP targeted by CAP-IT (Community-Acquired Pneumonia: a protocol for a randomIsed controlled
Trial). A better understanding of the relationship between dose and duration of antibiotic treatment,
and the impact on clinical outcomes and antimicrobial resistance, would make it possible to formulate
improved evidence-based treatment recommendations for childhood CAP.
Objectives
The main objective of CAP-IT was to determine the following for young children with uncomplicated
CAP treated after discharge from hospital if:
la 3-day course of amoxicillin is non-inferior to a 7-day course, determined by receipt of a clinically
indicated systemic antibiotic other than trial medication for respiratory tract infection (including CAP)
in the 4 weeks after randomisation up to day 28
llower-dose amoxicillin is non-inferior to higher-dose amoxicillin under the same conditions.
Secondary objectives were to evaluate the impact of lower-dose and shorter-duration amoxicillin on
antimicrobial resistance, severity and duration of parent/guardian-reported CAP symptoms and
specified clinical adverse events (AEs).
INTRODUCTION
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4
Chapter 2 Methods
Trial design
The CAP-IT study was a multicentre clinical trial with a target sample size of 800 participants in
the UK and Ireland. In design, it was a randomised double-blind placebo-controlled 2 × 2 factorial
non-inferiority trial of amoxicillin dose and duration in young children with CAP (Figure 1).
Children aged >
6 months and weighing 6–24
kg with CAP
presenting to participating hospitals
Eligibility assessment to identify potential participants
Clinical diagnosis of CAP and oral amoxicillin treatment planned on discharge
Treatment with beta-lactam antibiotic ≤
48 hours as outpatient or inpatient
Written informed consent
Nasopharyngeal swab
Concurrently randomise to:
Face-to-face follow-up at day 28 with nasopharyngeal swab
Telephone follow-up at days 3, 7, 14 and 21
Amoxicillin dose:
• 35–50
mg/kg/day in two doses (low)
• 70–90
mg/kg/day in two doses (high)
Amoxicillin duration
• 3-day active
• 4-day placebo (short)
• 7-day active (long)
Low dose
Short duration
Low dose
Long duration
High dose
Short duration
High dose
Long duration
Follow-up Allocation Screening/enrolment
FIGURE 1 The CAP-IT schema.
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5
Trial setting
Participants were recruited from 28 UK NHS hospitals and one children’s hospital in Ireland:
1. Alder Hey Children’s Hospital NHS Foundation Trust (Liverpool, UK)
2. Barts Health NHS Trust (London, UK)
3. Birmingham Women’s and Children’s NHS Foundation Trust (Birmingham, UK)
4. Brighton and Sussex University Hospitals NHS Trust (Brighton, UK)
5. Chelsea and Westminster Hospital NHS Foundation Trust (London, UK)
6. Children’s Health Ireland (Dublin, Ireland)
7. City Hospitals Sunderland NHS Foundation Trust (Sunderland, UK)
8. Countess of Chester Hospital NHS Foundation Trust (Chester, UK)
9. County Durham and Darlington NHS Foundation Trust (Darlington, UK)
10. Guy’s and St Thomas’NHS Foundation Trust (London, UK)
11. Hull and East Yorkshire Teaching Hospitals NHS Trust (Hull, UK)
12. Imperial College Healthcare NHS Trust (London, UK)
13. King’s College Hospital NHS Foundation Trust (London, UK)
14. The Leeds Teaching Hospitals NHS Trust (Leeds, UK)
15. Manchester University NHS Foundation Trust (Manchester, UK)
16. Nottingham University Hospitals NHS Trust (Nottingham, UK)
17. Oxford University Hospitals NHS Foundation Trust (Oxford, UK)
18. Southport and Ormskirk Hospital NHS Trust (Southport, UK)
19. Royal Hospital for Children (Glasgow, UK)
20. Sheffield Children’s NHS Foundation Trust (Sheffield, UK)
21. South Tees Hospitals NHS Foundation Trust (Middlesbrough, UK)
22. St George’s University Hospitals NHS Foundation Trust (London, UK)
23. University Hospitals Bristol and Weston NHS Foundation Trust (Bristol, UK)
24. University Hospitals of Derby and Burton NHS Foundation Trust (Derby, UK)
25. University Hospitals of Leicester NHS Trust (Leicester, UK)
26. University Hospitals Lewisham (London, UK)
27. University Hospital Southampton NHS Foundation Trust (Southampton, UK)
28. University Hospital of Wales (Cardiff, UK).
Participating sites were tertiary or secondary hospitals with paediatric emergency departments (PEDs)
and inpatient facilities, and were selected in collaboration with Paediatric Emergency Research in the
UK & Ireland80 on the basis of clinical and research infrastructure, experience in clinical research and
likely eligible population size.
Participants
Patients presenting to participating hospitals were identified in PEDs, assessment/observation units or
inpatient wards. Potential participants were screened as early as possible during the initial clinical
assessment. Informed consent was sought from a parent/guardian once eligibility had been confirmed,
but only after full explanation of the trial aims, methods and potential risks and benefits. Discussions
regarding the trial took place between families and clinical teams when the child’s clinical condition
was stable, to minimise distress. Extensive information and recruitment materials were available for
recruiting sites, including printed and video materials [accessible at URL: www.capitstudy.org.uk
(accessed 29 July 2021)]. CAP-IT information film was designed to assist research teams in the
recruitment process and provided information to parents/guardians about the purpose of the trial, the
use of placebo and trial procedures. Parents/guardians could watch the film in their own time while in
hospital, and research teams reported that the film was a useful tool during the recruitment process.
METHODS
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6
The film was made with input from the trial patient and public involvement (PPI) representative and
featured a site principal investigator and research nurse, as well as graphics to aid explanation of trial
procedures. [It can be viewed at https://vimeo.com/217849985 (accessed 29 July 2021).] Families were
able to decline participation in the trial at any time without providing a reason and without incurring
any penalty or affecting clinical management.
Recruitment pathways
Children were recruited through two different pathways based on whether they received any inpatient
antibiotic treatment (ward group) or not (PED group). Children in either group may have had up to
48 hours of oral or parenteral beta-lactam treatment before enrolment. The PED group contained
children who had not received any in-hospital antibiotic treatment (but may have had up to 48 hours
of beta-lactam antibiotics in the community), whereas the ward group contained children who received
any in-hospital oral or intravenous beta-lactam therapy prior to randomisation. Children in the latter
group may have received beta-lactam treatment in the community first and subsequently in hospital,
without interruption, for a total of <48 hours.
Inclusion criteria
Children were eligible if they had a clinical diagnosis of uncomplicated CAP, were aged >6 months
and weighed 6–24 kg, and treatment with amoxicillin as the sole antibiotic was planned on discharge.
Box 1 shows the clinical criteria required for a diagnosis of CAP in CAP-IT.
Exclusion criteria
Children were excluded if they had received ≥48 hours of beta-lactam antibiotics or any non-beta-
lactam agents, or if they had severe underlying chronic disease with increased risk of complicated CAP
(including sickle cell anaemia, immunodeficiency, chronic lung disease and cystic fibrosis), documented
penicillin allergy or other contraindication to amoxicillin, complicated pneumonia (including shock,
hypotension, altered mental state, ventilatory support, empyema, pneumothorax and pulmonary abscess)
or bilateral wheezing without focal chest signs.
Changes to selection criteria
During the trial enrolment period, eligibility criteria were modified based on emerging data to better
reflect clinical management and facilitate inclusion of all children to whom the results of the trial may
be of relevance.
Age and weight criteria were amended from ‘age from 1 to 5 years (up to their 6th birthday)’in
protocol v2.0 to ‘greater than 6 months and weighing 6–24 kg’in protocol v3.0. Children recruited to
protocol v2.0 were excluded if they were receiving systemic antibiotic treatment at presentation.
This was modified in protocol v3.0 for the PED group and in protocol v4.0 for the ward group, such
that children were eligible if they had received ≤48 hours’systemic antibiotic treatment at trial entry,
as per section 2.3 of the protocol.
BOX 1 Definition of clinical diagnosis of CAP
Clinical diagnosis of CAP is defined as:
lcough (reported by parents/guardians within 96 hours before presentation)
ltemperature ≥38 °C measured by any method or likely fever within 48 hours before presentation
lsigns of laboured/difficult breathing or focal chest signs (i.e. one or more of nasal flaring, chest
retractions, abdominal breathing, focal dullness to percussion, focal reduced breath sounds, crackles
with asymmetry or lobar pneumonia on chest radiograph).
DOI: 10.3310/hta25600 Health Technology Assessment 2021 Vol. 25 No. 60
Copyright © 2021 Barratt et al. This work was produced by Barratt et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social
Care. This is an Open Access publication distributed under the terms of the Creative Commons Attribution CC BY 4.0 licence, which permits unrestricted use, distribution,
reproduction and adaption in any medium and for any purpose provided that it is properly attributed. See: https://creativecommons.org/licenses/by/4.0/. For attribution the
title, original author(s), the publication source –NIHR Journals Library, and the DOI of the publication must be cited.
7
Children in the ward group were excluded in protocol v2.0 if they had ‘current oxygen requirement’or
‘current age-specific tachypnoea’; however, these criteria were removed in protocol v3.0 and replaced
with the inclusion criterion ‘child is considered fit for discharge at randomisation’.
The CAP diagnostic criterion relating to fever changed from ‘temperature ≥38 °C measured by any
method OR history of fever in last 24 hours reported by parents/guardians’in protocol v2.0 to
‘temperature ≥38 °C measured by any method OR likely fever in last 48 hours’in protocol v3.0 to
account for the accompanying parent/guardian not measuring temperature in the preceding 24 hours.
Interventions
The investigational medicinal product (IMP) for treatment at home was provided as a powder to be
suspended on the day of randomisation. Children received oral amoxicillin suspension twice daily,
commencing on the day of randomisation. All children were weighed during eligibility screening and
was used to determine dose volume according to seven weight bands (Table 1).
Participants were randomised to receive either a lower (35–50 mg/kg/day) or a higher (70–90 mg/kg/day)
dose, concealment of which was achieved by using amoxicillin products of two different strengths
(125 mg/5 ml and 250 mg/5 ml). Therefore, children in each dose arm in the same weight band were
administered the same volume of suspension .
Participants were simultaneously randomised to receive either 3 or 7 days of amoxicillin treatment at
home. A placebo manufactured to match the characteristics of oral amoxicillin suspension was used
to blind parents/guardians and clinical staff to the duration allocation. Both active drug and placebo
formed a yellow-coloured similar-tasting suspension. However, because of difficulties in exactly taste-
matching the placebo suspension to amoxicillin, one brand of amoxicillin was used for the first 3 days
of treatment followed by a second brand for days 4–7 when duration of treatment was 7 days. Parents
were instructed to expect a taste change between bottles, but they did not know whether this was
due to moving to placebo or to a new brand of amoxicillin. Allocated treatment duration to be given
after discharge from hospital was fixed at 3 or 7 days independently of any antibiotics received before
randomisation, with up to 48 hours of oral or parenteral beta-lactam treatment permitted before enrolment.
This resulted in four treatment arms, as shown in Figure 2.
The hypothesis is that higher doses of amoxicillin given for a longer duration are non-inferior to lower
doses of amoxicillin given for a shorter duration for the treatment of children attending hospital with
CAP in terms of antibiotic retreatment.
TABLE 1 Weight bands used for dosing of CAP-IT IMP
Weight range (kg) Dosing intructions
≤6.4 4.5 ml twice a day
6.5–8.4 6 ml twice a day
8.5–10.4 7.5 ml twice a day
10.5–13.4 9.5 ml twice a day
13.5–16.9 12 ml twice a day
17.0–20.9 15 ml twice a day
21.0–24.0 16.5 ml twice a day
METHODS
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8
The objective is to conduct a RCT in children attending hospital with CAP comparing higher and lower
doses of amoxicillin given for 3 or 7 days.
Drug substitutions and discontinuations of trial treatment
Substitution of an alternative amoxicillin formulation or another antibiotic was permitted where tolerability
issues could not be overcome by improving acceptability (e.g. by mixing the suspension with formula milk,
other liquids or foods) or where a clinical need for continued treatment persisted. In situations of toxicity,
for example if an allergic reaction to penicillin was suspected, substitution with an alternative class of
antibiotic was permitted.
Discontinuation of trial treatment was permitted if, on clinical review, a change in the child’s condition
justified discontinuation or modification of trial treatment, if use of a medication with a known major
or moderate drug interaction with amoxicillin was essential for the child’s management or if the
parent/guardian withdrew consent for treatment.
In situations where retreatment was deemed necessary, the choice of antibiotic was left to the
treating clinician.
Trial assessments and follow-up
Participants were screened as described in Participants, and, following receipt of informed consent,
randomisation was performed at the point of discharge from hospital. Following randomisation,
all participants were followed up for 29 days for evaluation of the primary and secondary end points
described in Outcomes. The timing and frequency of assessments are summarised in the trial schedule
(Table 2) and described below.
Enrolment and randomisation
Following identification, screening and informed consent of eligible patients, baseline information
was obtained through interview with the parent/guardian. This included demographic information,
such as sex and ethnicity, medical history, including review and duration of symptoms (e.g. cough,
temperature and respiratory symptoms), underlying diseases and antibiotic exposure in the preceding
3 months. Details of the physical examination, including weight and vital parameters (e.g. temperature,
respiratory rate, heart rate and oxygen saturation in room air), were recorded and a baseline
nasopharyngeal swab was obtained.
d0 d3 d7
Trial medication – amoxicillin 125
mg/5
ml
Trial medication – amoxicillin 125
mg/5
ml
Trial medication – amoxicillin 250
mg/5
ml
Trial medication – amoxicillin 250
mg/5
ml
Trial medication – amoxicillin 125
mg/5
ml
Trial medication – placebo
Trial medication – amoxicillin 250
mg/5
ml
Trial medication – placebo
Longer/lower dose
7 days at
35–50
mg/kg/day
Shorter/lower dose
3 days at
35–50
mg/kg/day
Longer/higher dose
7 days at
70–90
mg/kg/day
Shorter/higher dose
3 days at
70–90
mg/kg/day
FIGURE 2 Treatment arms.
DOI: 10.3310/hta25600 Health Technology Assessment 2021 Vol. 25 No. 60
Copyright © 2021 Barratt et al. This work was produced by Barratt et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social
Care. This is an Open Access publication distributed under the terms of the Creative Commons Attribution CC BY 4.0 licence, which permits unrestricted use, distribution,
reproduction and adaption in any medium and for any purpose provided that it is properly attributed. See: https://creativecommons.org/licenses/by/4.0/. For attribution the
title, original author(s), the publication source –NIHR Journals Library, and the DOI of the publication must be cited.
9
TABLE 2 The CAP-IT assessment schedule
Assessment
Pre randomisation:a
≤48 hours before
randomisation
Days in trial
Day 0
(randomisation) Day 3
Days
7–9
(week 1)
Days
14–16
(week 2)
Days
21–23
(week 3)
Days
28–30
(week 4)
Any
acute
event
Trial participation
Parent/guardian
information
sheetb
✗✗
Informed consent ✗
Drug supply
dispensing
✗
Adherence
questionnaire
✗✗ (✗)
Adherence
review (returned
medication)
✗
Clinical assessment
Medical historyb(✗)✗
Physical
examinationb
(✗)✗✗✗
Symptom reviewb(✗)✗ ✗✗✗✗✗✗
EQ-5D ✗✗✗ ✗✗
Use of health
services
✗ ✗✗✗✗✗
Laboratory assessment
Nasopharyngeal
swabc
(✗)✗✗(✗)
Haematology (✗)(✗)(✗)(✗)
Biochemistry (✗)(✗)(✗)(✗)
Virology (✗)(✗)(✗)(✗)
Radiological assessment
Chest
radiography
(✗)(✗)(✗)
Parent-completed diary
Symptom diary ✗✗ ✗
Ancillary subgroup studies
Stool samplec✗✗ ✗ ✗
EQ-5D, EuroQol-5 Dimensions.
a Assessments in this column were undertaken only for potential participants receiving inpatient antibiotic treatment.
b May be carried out any time before enrolment discussion.
c Taken before starting antibiotics, where possible.
Notes
Dark-purple shading indicates face-to-face assessment, light-purple shading indicates telephone assessment and aqua
shading indicates telephone or face-to-face assessment.
(✗) indicates tests that may be carried out if the child’s condition requires it or allows it, but are not mandatory.
METHODS
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10
No additional tests were mandated, but results were collected if tests were performed as part
of clinical care, including haematology tests (e.g. haemoglobin, platelet count, leucocyte count,
neutrophil count and lymphocyte count), biochemistry tests (e.g. C-reactive protein, procalcitonin
and electrolytes), virology [rapid testing for respiratory syncytial virus and influenza A/B (any method)]
and chest radiography.
Parents/guardians were provided with trial materials, including a symptom diary, participant information
sheet, IMP administration instructions and contact details for the trial team. The symptom diary collected
data pertinent to the primary and secondary outcomes and was completed by parents for 14 days
following randomisation.
Follow-up
Telephone contact was made with participants on days 3, 7–9, 14–16 and 21–23, with a face-to face
visit within 2 days of day 28. At these contacts, primary and secondary end points were reviewed,
including additional antibiotic treatment, clinical signs and symptoms, adverse treatment effects and
IMP adherence. During face-to-face visits (final or unscheduled) a nasopharyngeal swab was collected,
and, if CAP symptoms were ongoing, physical examination findings and physiological parameters were
collected. If a hospitable face-to-face visit was not possible for final follow-up, it was attempted by
telephone or as a home visit. If this failed, despite reasonable efforts, primary end-point data were
sought through contact with the general practitioner (GP) where consent had been given to do so.
If participants required acute clinical assessment for ongoing/re-emerging symptoms during the follow-up
period, the treating clinician’s judgement determined if investigations, treatment or hospitalisation
was required. On premature discontinuation of IMP, irrespective of reason, parents/guardians were
encouraged to remain in follow-up. However, parent/guardian decisions were respected, and if follow-up
was stopped prematurely, then data and samples already collected were included in the analysis unless
parents/guardians requested otherwise.
Data collection and handling
Data were recorded on paper case report forms and entered onto the CAP-IT database by clinical or
research staff at each site. Staff with data entry responsibilities completed standardised database
training before being granted access to the database. Data were exported into Stata®(v15.1) (StataCorp LP,
College Station, TX, USA) for analysis.
Randomisation
Eligibility was confirmed by CAP-IT site investigators through completion of an eligibility checklist.
Patients were randomised simultaneously to each of the two factorial randomisations in a 1 : 1 ratio.
Randomisation was stratified by group (PED and ward) according to whether or not they had received
any non-trial antibiotics in hospital before being enrolled.
A computer-generated randomisation list was produced by the trial statistician based on random
permuted blocks of eight. Each block contained an equal number of the four possible combinations of
dose and duration in random order. The IMP supplier packaged the trial medication into kits that were
grouped into blocks of eight, in accordance with to the randomisation list specification. Blinded IMP
labels were applied to each kit, which contained the kit identifications (IDs). Kit IDs were made up of
four numerical digits, the first three of which represented the block ID and fourth specified the kit ID
within the block. Blinded randomised blocks of IMP were delivered to trial sites and participants were
randomised by dispensing the next sequentially numbered kit within the active block.
DOI: 10.3310/hta25600 Health Technology Assessment 2021 Vol. 25 No. 60
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11
Blinding
All treating clinicians, parents/guardians and outcome assessors [including End-Point Review
Committee (ERC) members] were blinded to the allocated treatment. The use of placebo, as well
as the permuted block randomisation strategy and blinded drug kits, ensured that parents and
clinic staff remained blinded to amoxicillin duration and dose.
Access to the randomisation list was restricted to trial statisticians and IMP repackagers, and
unblinded data were reviewed confidentially only by the Independent Data Monitoring Committee
(IDMC) (annually) and trial statisticians. The Trial Management Team remained blinded until after
the trial end and completion of the statistical analysis in accordance with the prespecified statistical
analysis plan (SAP).
Unblinding was possible in situations where a treating clinician deemed it necessary, for example in
the case of a significant overdose. This could be performed using an emergency unblinding system
accessible through the CAP-IT website. Only the treating clinician would then be informed of the
child’s allocation, maintaining the blinding of the trial team.
Outcomes
Primary outcome
The primary outcome for CAP-IT was defined as any clinically indicated systemic antibacterial treatment
prescribed for respiratory tract infection (including CAP) other than trial medication up to and at week 4
final follow-up (i.e. day 28). Prescription of non-trial medication when the primary reason was (1) illness
other than respiratory tract infection, (2) intolerance of or adverse reaction to IMP, (3) parental
preference or (4) administrative error did not constitute a primary end point.
An ERC, comprising doctors independent of the Trial Management Group and blinded to randomised
allocations, reviewed all cases of a participant being prescribed non-trial systemic antibacterial
treatment. The main role of the ERC was to adjudicate, based on all available data, whether or not the
primary outcome was met. The ERC classified non-trial systemic antibacterial treatment as being for
respiratory tract infection with likelihoods of ‘definitely/probably’,‘possibly’,‘unlikely’or ‘too little
information’. Those infections categorised as ‘CAP’,‘chest infection’or ‘other respiratory tract infection’
with a treatment likelihood assessment of ‘definitely/probably’or ‘possibly’were regarded as fulfilling
the primary end point.
Information on additional antibacterial treatments was collected from parents through follow-up
telephone contact with parents on days 3, 7, 14 and 21, at the final visit contact and finally through
a daily diary completed by parents on days 1–14.
During enrolment, parents were asked to provide consent for the research teams to contact their child’s
general practice to collect information regarding antibacterial treatment given during the follow-up
period. This additional information supported the ERC in accurately adjudicating events. In addition, this
allowed the collection of primary outcome data where contact with participants had been lost prior to
completion of the follow-up period.
Changes to primary end point
The primary end-point definition was clarified in protocol v3.0 to specify that ‘systemic antibacterial’
treatments should avoid inclusion of topical antibiotics, which were not of interest. In protocol v4.0,
the primary end point was refined further, resulting in the definition in Primary outcome. This definition
specified that the systemic antibacterial must be clinically indicated and prescribed for a respiratory
tract infection (including CAP), as adjudicated by the ERC.
METHODS
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Secondary outcomes
Secondary outcomes included measures of morbidity, antimicrobial resistance and trial
medication adherence.
Morbidity
Morbidity secondary outcomes included severity and duration of parent/guardian-reported CAP
symptoms and specified clinical AEs.
The following CAP symptoms were elicited at baseline, in follow-up telephone calls at days 4, 8,
15 and 22 and at the final visit, as well as at unscheduled visits: cough, wet cough (i.e. phlegm),
breathing faster (i.e. shortness of breath), wheeze, sleep disturbed by cough, vomiting (including
after cough), eating/drinking less and interference with normal activity. Parents/guardians were
asked to grade each symptom using the following five categories: (1) not present, (2) slight/little,
(3) moderate, (4) bad and (5) severe/very bad. Date of start and resolution were also elicited.
Symptoms and their severity (using the same categories) were obtained daily on the symptom
diary for 14 days from randomisation.
Information about diarrhoea, skin rash and thrush was collected and graded in the same way as
CAP symptoms. In addition, AEs related to the stopping of trial medication or the start of non-trial
antibiotics were recorded.
Other AEs meeting the criteria for seriousness [i.e. serious adverse events (SAEs)] were reported
within 24 hours of research sites becoming aware of the event. SAEs were classified by system
organ class and lower-level term in accordance with the Medical Dictionary for Regulatory Activities
(MedDRA®; version 21.1) and were graded using the Division of Aids (DAIDS) Table for Grading the
Severity of Adult and Paediatric Adverse Events.81
Antimicrobial resistance
The antimicrobial resistance secondary end point was defined as phenotypic resistance to penicillin
at week 4 measured in S. pneumoniae isolates colonising the nasopharynx. Carriage and resistance
of S. pneumoniae isolates were assessed by analysis of nasopharyngeal samples, collected from
participants at baseline, at the final visit (i.e. day 29) and at any unscheduled visits during the
follow-up period.
Phenotypic penicillin susceptibility was determined for S. pneumoniae isolates by microbroth dilution
across a dilution range for penicillin of 0.016–16 mg/l and interpreted in accordance with EUCAST
(European Committee on Antimicrobial Susceptibility Testing) clinical break-point tables v10.0 for
benzylpenicillin and S. pneumoniae (infections other than meningitis) [i.e. sensitive (MIC ≤0.064 mg/l),
non-susceptible (MIC 0.125–2 mg/l) or resistant (MIC >2 mg/l)].82 The same approach was taken for
amoxicillin susceptibility testing [isolates with MIC ≤0.5 mg/l were sensitive and isolates with MIC
>1 mg/l were resistant). S. pneumoniae ATCC®49619™(ATCC, Manassas, VA, USA) was used for
quality control.82
Adherence
Data on IMP adherence were elicited during follow-up telephone calls, at the final visit (where follow-up
telephone calls were not performed) and at unscheduled visits. At each time point, parents/guardians
were asked if IMP had been stopped early, and, if so, the date of the last dose taken and for which
of the following reasons: CAP improved/cured, CAP worsened/not improving or gagging/spitting out/
refusing. In addition, parents/guardians were asked how many doses of each bottle were either missed
or were less than the full prescribed volume.
DOI: 10.3310/hta25600 Health Technology Assessment 2021 Vol. 25 No. 60
Copyright © 2021 Barratt et al. This work was produced by Barratt et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social
Care. This is an Open Access publication distributed under the terms of the Creative Commons Attribution CC BY 4.0 licence, which permits unrestricted use, distribution,
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13
Sample size
The sample size was based on demonstrating non-inferiority for the primary efficacy end point for each
of the duration and dose randomisations. Although inflation factors have been advocated for factorial
trials to account for interaction between the interventions, or a reduction in the number of events, this
is not necessary if either randomised intervention (dose or duration) has a null effect (i.e. the underlying
hypothesis with a non-inferiority design), as marginal analyses can then be conducted.
The expected antibiotic retreatment rate was originally assumed to be 5%. However, data emerging
during the enrolment phase suggested that the primary outcome event rate was considerably higher,
at approximately 15%. This necessitated a change in the non-inferiority margin, which was increased
from 4% to 8%. This is still lower than the European Medicines Agency’s recommendation of a 10%
non-inferiority margin for adult CAP trials.83 Assuming a 15% event rate, 8% non-inferiority margin
(on a risk difference scale) assessed against a two-sided 90% confidence interval (CI) and 15% loss to
follow-up, the sample size was calculated as 800 children to achieve 90% power.
Statistical methods
Analysis principles
The primary analysis adopted a modified intention-to-treat (ITT) principle, that is it included all patients
enrolled and analysed in accordance with the group to which they were randomised, regardless of
treatment actually received. One modification to the strict ITT principle prespecified in the trial SAP was
the exclusion of randomised patients who did not take any IMP. Owing to the blinded nature of the trial, the
risk of introducing bias by exclusion of these patients was considered minimal. A secondary on-treatment
analysis was performed that excluded ‘non-adherent’participants, defined as having taken <80% of
scheduled trial medication, based on (1) all trial medication including placebo and (2) active drug only.
In the primary and secondary analyses, the main effect for each randomisation was estimated by
collapsing across levels of the other randomisation factor, supplemented by tests for interaction
between the two randomisations and with previous systemic antibacterial exposure. Interaction was
assessed on an additive scale.
For continuous variables, the mean (with standard deviation) or median [with interquartile range (IQR)]
of absolute values and of changes in absolute values from baseline were reported by scheduled
telephone calls/visits and by randomised group.
For binary and categorical variables, differences between groups at particular time points were tested
using chi-squared tests (or exact tests, if appropriate). For ordered variables, differences between
groups at particular time points were tested using rank tests.
For time-to-event outcomes, the time from baseline to the event date was used, applying Kaplan–Meier
estimation. Where participants did not experience an event, data were censored at the date of last review
of that event. Differences between groups were tested using a log-rank test.
Formal statistical adjustment for multiple comparisons (particularly pertinent for some of the secondary
end points) were not applied, and significance tests should be interpreted in the context of the total
number of related comparisons performed.
The primary end point was analysed within a non-inferiority framework, where significance testing has
no clear role (with emphasis instead on CIs). Secondary outcomes were analysed within a superiority
framework (i.e. assessing the null hypothesis of no difference). All estimates, including differences
between randomised groups, are presented with two-sided 90% CIs (rather than the more conventional
95%) to achieve consistency with the reporting of the primary end point.
METHODS
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14
Primary outcome
The proportion of children meeting the primary end point was obtained from the cumulative incidence
at day 28, as estimated by Kaplan–Meier methods (i.e. accounting for the differential follow-up times).
Participants with incomplete primary outcome data (e.g. as a result of a missed final visit) were censored
at the time of their last contact. In the case of participants who missed the final visit but whose GP
confirmed that no additional antibacterials were prescribed during the follow-up period, day 28 was used
as the censoring date.
Kaplan–Meier estimates were used to derive the risk difference between the randomised groups for
the primary end point, and standard errors and CIs for the risk difference were derived from the
estimated standard errors of the individual survival functions.
Lower-dose treatment and shorter-duration treatment were considered ‘non-inferior’to higher-dose
treatment and longer-duration treatment, respectively, if the upper limit of the two-sided 90% CI for
the difference in the proportion of children with the primary end point at day 28 was less than the
non-inferiority margin of 8%. Although the non-inferiority margin was important to the design of the
trial, it is less relevant to its interpretation, which should be based on observed estimates and CIs.
Sensitivity analyses
As described in Primary outcome, the primary analysis included only end points confirmed by the ERC
as clinically indicated antibacterial treatment for respiratory tract infection (including CAP). To improve
confidence in the primary analysis, the following sensitivity analyses were performed for the primary
end point:
lincluding all systemic antibacterial treatments other than trial medication regardless of reason
and indication
lincluding only ERC-adjudicated clinically indicated systemic antibacterial treatment where either
CAP or ‘chest infection’was specified as the reason for this treatment (rather than any respiratory
tract infection)
las above, but also including, as an end point, all systemic antibacterial treatments for CAP or ‘chest
infection’where the clinical indication was ‘unlikely’, as adjudicated by the ERC
ldisregarding systemic antibacterial prescriptions occurring within the first 3 days from randomisation,
as these events cannot be related to the treatment duration randomisation, to allow comparison of
shorter and longer treatment.
Subgroup analyses
Two subgroup analyses were performed. The first considered severity of CAP at enrolment to provide
reassurance that a potential null effect was not due to dilution arising from inclusion of children with
mild disease. The main efficacy analysis was repeated, but included only participants with severe CAP,
defined as two or more of the following abnormal signs/symptoms at enrolment: raised respiratory
rate (>37 breaths/minute for children aged 1–2 years; >28 breaths/minute for children aged 3–5 years),
oxygen saturation <92% in room air and presence of chest retractions.
The second subgroup analysis considered the potential for seasonal changes in infections, by including
only primary end points occurring in the two winter seasons spanned by CAP-IT. This was based on
Public Health England reports of circulating viruses/bacteria in the winter seasons spanned by CAP-IT.
Community-acquired pneumonia symptoms
The severity of the symptoms (detailed in Morbidity) were reviewed by the number (%) of symptoms in
each severity category at each scheduled contact visit and analysed as described for ordered outcomes
in Analysis principles.
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15
Duration of a symptom was measured as time from baseline to resolution, defined as the first day the
symptom was reported as not present. This was analysed as a time-to-event outcome, as specified in
Analysis principles. Where a symptom was not present at enrolment, participants were excluded from
the analysis of that symptom.
Clinical adverse events
Solicited clinical AEs, specified in Morbidity, were analysed overall and by randomised arm. Analysis
considered total number of events, number of participants with at least one event, the number of
participants with at least one new event and event severity. These variables were analysed as
described for binary outcomes in Analysis principles.
In addition, the number of participants experiencing at least one SAE were compared as a binary outcome
(see Analysis principles).
Antimicrobial resistance
Descriptive analyses of baseline samples were analysed as follows: proportion of samples with positive
S. pneumoniae culture, frequency distribution of broth microdilution MIC values and proportion of
samples classified as S –susceptible, standard dosing regimen; I –intermediate, increased exposure;
and R –resistant (see Secondary outcomes).
S. pneumoniae carriage, determined by tabulation of the proportion of samples with positive
S. pneumoniae culture at the final visit by randomisation group, was compared using tests for binary
variables, as described in Secondary outcomes.S. pneumoniae culture results at the final visit were
cross-tabulated with baseline culture results (including missing values).
For the antimicrobial resistance analysis, a descriptive analysis of the proportion of samples with
resistance to penicillin (S –susceptible/I –intermediate/R –resistant categorisation) at the final visit
was performed using both cut-off points (penicillin and amoxicillin) described in Secondary outcomes.
This analysis was repeated, first, including only samples with a positive S. pneumoniae culture result
and, second, including all samples. Randomised groups were compared by tests for binary variables,
and cross-tabulation of penicillin resistance at the final visit compared with penicillin resistance at
baseline was performed as a descriptive analysis.
Finally, the change in broth microdilution MIC (in patients for whom this was measured at both the
baseline and the final visit) was analysed with randomisation group as factors and after adjusting for
baseline MIC.
Interim analyses
The trial was reviewed by the CAP-IT IDMC. They met three times over the course of the trial: once
at a joint meeting with the Trial Steering Committee (TSC) in June 2017 and twice in strict confidence
in January 2018 and January 2019. The IDMC reviewed unblinded safety and efficacy data and made
recommendations through correspondence to the TSC following each meeting.
Patient and public involvement
Parents of young children were involved during the development and delivery of CAP-IT. A PPI
representative was a member of the TSC, contributing at meetings and in an ad hoc fashion when
required. When considering the research question, the trial team were advised by parents that shorter
antibiotic courses would be welcomed if equally effective, because of difficulties in giving medicine
(due to palatability or challenges with day care and daytime doses). For the same reasons, parents
METHODS
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16
supported the twice-daily dosing of the CAP-IT. Multiple PPI representatives reviewed and provided
input on the patient information materials, including the CAP-IT information film, to ensure that they
were clear, easy to understand and not off-putting to parents, while still providing sufficient detail to
allow informed consent. Valuable input was provided from the PPI representative on the CAP-IT TSC
on the plan for dissemination of the CAP-IT results.
Protocol amendments
The CAP-IT protocol v.2.0 was active when recruitment to CAP-IT commenced in January 2017. Two
protocol amendments were completed subsequently, with version 3 implemented in September 2017 and
version 4 in December 2018. Amendments were largely in relation to selection criteria (see Exclusion
criteria) and the SAP (to which three significant updates were made on the basis of accumulating trial
data). First, a stratified analysis was originally planned based on the PED and ward groups. This was
changed to a joint analysis in protocol version 3 because of significant clinical overlap (see Appendix 1
for more details) Second, the primary end-point definition was made more specific in protocol version 3
and further refined in version 4 (see Changes to primary end point). Finally, the non-inferiority margin was
adjusted, as the primary end-point event rate had been substantially underestimated. The trial and all
substantial amendments were approved by the London –West London & GTAC Research Ethics
Committee (reference 16/LO/0831).
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17
Chapter 3 Results
Participant flow
Between 1 February 2017 and 23 April 2019, a total of 2642 children were assessed for eligibility and
824 were randomised. Ten patients were randomised but received no trial medication (owing to, for
example, a change of mind by parent/guardian or administrative error) and were, therefore, excluded
from the analysis, resulting in an analysis population of 814 patients.
A total of 591 participants had no pre-treatment antibiotic at trial entry. A total of 223 (mainly
following admission to assessment units of wards) had received beta-lactam antibiotic pre-treatment
for no more than 48 hours. The final follow-up visit occurred on 21 May 2019, which was considered
the trial end date.
Six participants were randomised in error but were included in the analysis in accordance with the ITT
principle. Of these participants, five did not have all the required symptoms to fulfil the criteria for
CAP diagnosis (see Box 1). One patient did not have a cough reported in the previous 96 hours at
presentation, two patients did not have a reported fever in the previous 48 hours at presentation and
two patients lacked documentation of signs of laboured/difficult breathing and/or focal chest signs at
presentation. In one of the final two patients, chest radiography was suggestive of lobar pneumonia,
prior to this being added to the inclusion criteria as part of protocol version 4.0, and in the other
participant pneumonia was diagnosed on chest radiography, but was documented as patchy infiltrate,
which did not fulfil the inclusion criteria. The final patient randomised in error received an antibiotic
other than a beta-lactam (clarithromycin) before discharge (Table 3).
Participants were well distributed between arms, with 208 (25.6%) participants receiving 3 days of
lower-dose treatment, 202 (24.8%) participants receiving 7 days of lower-dose treatment, 205 (25.2%)
participants receiving 3 days of higher-dose treatment and 199 (24.4%) participants receiving 7 days of
higher-dose treatment (Figure 3 and Table 4).
TABLE 3 Ineligible patients
Reason for ineligibility
Treatment arm, n(%)
Total (N=814),
n(%)
Lower dose
(N=410)
Higher dose
(N=404)
Shorter duration
(N=413)
Longer duration
(N=401)
Known violation of any
inclusion/exclusion
criterion
1 (0.2) 5 (1.2) 4 (1.0) 2 (0.5) 6 (0.7)
No presence of cough 0 1 0 1 1
No presence of fever 0 2 2 0 2
No presence of CAP
signs
022 0 2
Pre-treatment with
non-beta-lactams
100 1 1
Excluded from analysis 0 0 0 0 0
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19
Assessed for eligibility
(n
=
2642)
Underwent randomisation
(n
=
824)
Included in the analysis
(n
=
410)
Included in the analysis
(n
=
404)
Included in the analysis
(n
=
413)
Included in the analysis
(n
=
401)
Not enrolled
(n
=
1818)
• Discharged on antibiotic
other than amoxicillin,
n
=
334
• Failed ward group criteria,a
n
=
671
• Language barrier, n
=
148
• Eligible but not enrolled
(parents’ decision), n
=
665
Assigned to lower dose
(n
=
412)
• Did not take trial
medication,b n
=
2
Primary end-point status
fully characterised
(n
=
401)
• Withdrew or were lost to
follow-up,c n
=
9
Assigned to higher dose
(n
=
412)
• Did not take trial
medication,b n
=
8
Primary end-point status
fully characterised
(n
=
388)
• Withdrew or were lost to
follow-up,c n
=
16
Assigned to shorter duration
(n
=
416)
• Did not take trial
medication,b n
=
3
Primary end-point status
fully characterised
(n
=
401)
• Withdrew or were lost to
follow-up,c n
=
12
Assigned to longer duration
(n
=
408)
• Did not take trial
medication,b n
=
7
Primary end-point status
fully characterised
(n
=
388)
• Withdrew or were lost to
follow-up,c n
=
13
FIGURE 3 A CONSORT (Consolidated Standards of Reporting Trials) flow diagram. a, Inpatient stay >48 hours and
treated with non-beta-lactam antibiotics as inpatients; b, these children have been excluded from all analyses; and
c, follow-up included up to time of withdrawal or no further contact.
TABLE 4 Randomisation outcomes: analysis population
Outcome
Treatment arm, n(%)
Total (N=814), n(%)PED (N=591) Ward (N=223)
Randomisation arm
Lower dose plus shorter duration 153 (25.9) 55 (24.7) 208 (25.6)
Lower dose plus longer duration 150 (25.4) 52 (23.3) 202 (24.8)
Higher dose plus shorter duration 146 (24.7) 59 (26.5) 205 (25.2)
Higher dose plus longer duration 142 (24.0) 57 (25.6) 199 (24.4)
Dose randomisation
Lower 303 (51.3) 107 (48.0) 410 (50.4)
Higher 288 (48.7) 116 (52.0) 404 (49.6)
Duration randomisation
Shorter 299 (50.6) 114 (51.1) 413 (50.7)
Longer 292 (49.4) 109 (48.9) 401 (49.3)
RESULTS
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20
Baseline
Patient characteristics
Baseline patient characteristics were well balanced between the randomisation groups (see Table 4).
The median age of participants was 2.5 (IQR 1.6–3.7) years, with a minimum and maximum age of
0.5 and 8.8 years, respectively, and 52% were male (Table 5).
Medical history
One-third of participants (30.7%) reported an underlying diagnosis of asthma or use of an asthma
inhaler within the past month. The second most common comorbidity (affecting 20% of participants)
was eczema, followed by food or drug allergies (9.6%) and hay fever (9.1%). Routine vaccinations had
been received by 95% of participants; the remaining 5% either had not had routine vaccinations (3.2%),
or were of unknown vaccination status or had been vaccinated outside the UK (1.8%).
Vital parameters and clinical signs
Participant vital parameters were measured at presentation and were similar between randomisation
groups (Table 6). The median temperature was 38.1 °C (IQR 37.2–38.8 °C) and median oxygen
saturation was 96% (IQR 95–98%). The median number of days for which a child had a cough at
presentation was 4 (IQR 2–7) days, and the median number of days for which a child had a
temperature was 3 (IQR 1–4) days. The median weight was 13.5 (IQR 11.2–16.4) kg.
The most common baseline clinical signs were coryza [affecting 599/814 (73.6%) participants] and
chest retractions [affecting 483/814 (59.3%) participants] (Table 7). Other baseline clinical signs were
less common (enlarged tonsils or pharyngitis, 22.5%; pallor, 20.9%; nasal flaring, 9.3%, inflamed/bulging
tympanic membrane or middle ear effusion, 9%; and stridor, 1.2%).
Multiple vital parameters and clinical signs differed at presentation between the children previously
exposed and unexposed to antibiotics (see Table 7).
TABLE 5 Patient characteristics
Characteristic
Treatment arm
Total
(N=814)
Lower dose
(N=410)
Higher dose
(N=404)
Shorter duration
(N=413)
Longer duration
(N=401)
Age (years)
Median (IQR) 2.5 (1.6–3.7) 2.4 (1.6–3.7) 2.5 (1.7–3.7) 2.5 (1.5–3.7) 2.5 (1.6–3.7)
Minimum, maximum 0.5, 8.8 0.5, 8.5 0.5, 8.5 0.5, 8.8 0.5, 8.8
Sex, n(%)
Male 210 (51) 211 (52) 217 (53) 204 (51) 421 (52)
Female 200 (49) 193 (48) 196 (47) 197 (49) 393 (48)
Ethnicity, n(%)
White 275 (67) 279 (69) 283 (69) 271 (68) 554 (68)
Asian or British Asian 55 (13) 51 (13) 53 (13) 53 (13) 106 (13)
Black or black British 40 (10) 36 (9) 40 (10) 36 (9) 76 (9)
Other 40 (10) 38 (9) 37 (9) 41 (10) 78 (10)
Number (%) of
households with smokers
69 (17) 62 (16) 61 (15) 70 (18) 131 (16)
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21
TABLE 6 Medical history
Medical history
Treatment arm, n(%)
Total (N=814),
n(%)
Lower dose
(N=410)
Higher dose
(N=404)
Shorter duration
(N=413)
Longer duration
(N=401)
Asthma or inhaler use
within past month
119 (29) 136 (34) 125 (30) 130 (32) 255 (31)
Hay fever 34 (8) 40 (10) 37 (9) 37 (9) 74 (9)
Food or drug allergy 38 (9) 40 (10) 37 (9) 41 (10) 78 (10)
Eczema 84 (20) 79 (20) 78 (19) 85 (21) 163 (20)
Prematurity 43 (10) 43 (11) 51 (12) 35 (9) 86 (11)
Routine vaccinations?
Yes 388 (95) 385 (95) 394 (95) 379 (95) 773 (95)
No 14 (3) 12 (3) 15 (4) 11 (3) 26 (3)
Not sure
(or vaccinated
outside UK)
8 (2) 7 (2) 4 (1) 11 (3) 15 (2)
Other underlying
disease
37 (9) 19 (5) 21 (5) 35 (9) 56 (7)
TABLE 7 Vital parameters and clinical signs at presentation by randomisation status
Parameter/clinical
sign
Treatment arm
Total (N=814)
Lower dose
(N=410)
Higher dose
(N=404)
Shorter duration
(N=413)
Longer duration
(N=401)
Weight (kg), median
(IQR)
13.6 (11.2–16.8) 13.3 (11.1–16.2) 13.8 (11.5–16.4) 13.2 (10.9–16.4) 13.5 (11.2–16.4)
Temperature (°C),
median (IQR)
38.1 (37.3–38.9) 38.0 (37.2–38.6) 38.0 (37.1–38.7) 38.1 (37.3–38.8) 38.1 (37.2–38.8)
Temperature ≥38 °C,
n(%)
227 (55) 214 (53) 221 (54) 220 (55) 441 (54)
Heart rate (b.p.m.),
median (IQR)
146 (131–160) 143 (130–158) 144 (131–158) 146 (130–162) 145 (130–160)
Abnormal heart rate,a
n(%)
307 (75) 271 (67) 282 (68) 296 (74) 578 (71)
Respiratory rate
(breaths/minute),
median (IQR)
37 (30–44) 38 (32–44) 36 (30–43) 38 (32–45) 37 (30–44)
Abnormal respiratory
rate,bn(%)
270 (66) 258 (64) 262 (64) 266 (67) 528 (65)
Oxygen saturation
(%), median (IQR)
96 (95–98) 96 (95–98) 96 (95–98) 96 (95–98) 96 (95–98)
Abnormal oxygen
saturation,cn(%)
18 (4) 25 (6) 18 (4) 25 (6) 43 (5)
Nasal flaring, n(%) 33 (8) 42 (10) 35 (9) 40 (10) 75 (9)
Chest retractions,
n(%)
239 (58) 244 (60) 239 (58) 244 (61) 483 (59)
Pallor, n(%) 82 (20) 87 (22) 93 (23) 76 (19) 169 (21)
RESULTS
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Chest examination
Chest examination findings at presentation were reported as absent, bilateral or unilateral. Unilateral
findings were present in 691 (85%) participants overall, featuring as crackles/crepitations in 562
(71%) participants, reduced breath sounds in 336 (44%) participants, bronchial breathing in 103 (15%)
participants and dullness to percussion in 59 (13%) participants. The proportions of the four chest
examination variables were very similar among the randomisation arms (Table 8).
TABLE 7 Vital parameters and clinical signs at presentation by randomisation status (continued)
Parameter/clinical
sign
Treatment arm
Total (N=814)
Lower dose
(N=410)
Higher dose
(N=404)
Shorter duration
(N=413)
Longer duration
(N=401)
Stridor, n(%) 4 (1) 6 (1) 5 (1) 5 (1) 10 (1)
Inflamed/bulging
tympanic membrane
or middle ear
effusion, n(%)
37 (9) 35 (9) 39 (10) 33 (8) 72 (9)
Coryza, n(%) 291 (71) 308 (76) 304 (74) 295 (74) 599 (74)
Enlarged tonsils or
pharyngitis, n(%)
95 (24) 86 (22) 92 (22) 89 (23) 181 (23)
b.p.m., beats per minute.
a Abnormal respiratory rate: >37 breaths/minute for children aged 1–2 years and >28 breaths/minute for children
aged ≥3 years.
b Abnormal heart rate: >140 b.p.m. for children aged 1–2 years and >120 b.p.m. for children aged ≥3 years.
c Abnormal oxygen saturation: <92%.
TABLE 8 Chest examination at presentation by randomisation status
Chest examination
finding
Treatment arm, n(%)
Total (N=814),
n(%)
Lower dose
(N=410)
Higher dose
(N=404)
Shorter duration
(N=413)
Longer duration
(N=401)
Dullness to percussion
Absent 194 (86) 186 (86) 198 (86) 182 (86) 380 (86)
Unilateral 32 (14) 27 (13) 31 (13) 28 (13) 59 (13)
Bilateral 0 (0) 3 (1) 1 (<1) 2 (1) 3 (1)
Bronchial breathing
Absent 283 (82) 263 (82) 276 (83) 270 (81) 546 (82)
Unilateral 53 (15) 50 (16) 49 (15) 54 (16) 103 (15)
Bilateral 10 (3) 7 (2) 8 (2) 9 (3) 17 (3)
Reduced breath sounds
Absent 202 (52) 187 (49) 202 (51) 187 (50) 389 (50)
Unilateral 168 (43) 168 (44) 174 (44) 162 (43) 336 (44)
Bilateral 20 (5) 26 (7) 20 (5) 26 (7) 46 (6)
Crackles/crepitations
Absent 69 (17) 65 (17) 71 (18) 63 (16) 134 (17)
Unilateral 287 (71) 275 (70) 290 (72) 272 (69) 562 (71)
Bilateral 48 (12) 52 (13) 42 (10) 58 (15) 100 (13)
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Parent/guardian-reported community-acquired pneumonia symptoms
Parent/guardian-reported symptom severity at trial entry is shown in Figure 4. The most common clinical
symptom was cough, reported by 96.5% of participants. Fever and fast breathing were reported for
79.6% and 83.5% of participants, respectively, and the least common symptoms at baseline were
vomiting and wheeze, reported in 41.1% and 51.8% of participants, respectively. Sleep disturbance,
eating less and interference with normal activity were reported in between 80% and 90% of participants.
Clinical symptoms in patients who received in-hospital antibiotics prior to trial entry (i.e. the ward group)
were reported by parents/guardians at presentation (pre trial) and at baseline (trial entry). Figures 5 and 6
show parent/guardian-reported clinical symptom severity both pre trial and at trial entry for the ward
group and at trial entry only for the PED group. For the ward group, the proportion of participants with
presence of symptoms at any level of severity decreased between pre trial and trial entry for all
symptoms except wet cough (phlegm). The greatest proportional decrease was for fever, for which the
proportion of participants with a severity of slight/little or greater decreased from 87.9% to 50.2%.
0
10
20
30
40
50
Percentage
60
70
80
90
100
Fever
Cough
Phlegm
Breathing fast
Wheeze
Sleep disturbance
Vomiting
Eating less
Abnormal activity
Severe/very bad
Bad
Moderate
Slight/little
Not present
20
3
13
42
33
17
28
21
30
16
27
29
22
Symptom
9
18
22
48
15
18
25
26
8
12
17
59
11
26
31
24 22
32
24 Symptom severity
14
13
27
30
FIGURE 4 Symptoms at trial entry.
0
10
20
30
40
50
Percentage
60
70
80
90
100
Ward: per trial
Ward: trial entry
PED: trial entry
Severe/very bad
Bad
Moderate
Slight/little
Not present
Ward: per trial
Ward: trial entry
PED: trial entry
Ward: per trial
Ward: trial entry
PED: trial entry
Ward: per trial
Ward: trial entry
PED: trial entry
Fever Cough Phlegm Breathing fast
31
30
10
12
50
14
19
12
36
30
12
93
7
43
37
26
43
20
62
10
42
35
17
29
14
35 32
20
29
16 17
27
21
29
6
14
27
35
16
23
31
26
13
26
31
24
Symptom severity
FIGURE 5 Clinical symptoms (i.e. fever, cough, phlegm and breathing fast) at trial entry, by group.
RESULTS
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24
Community-acquired pneumonia symptoms at trial entry, by stratum, are shown in Appendix 2,Table 27.
Clinical investigations
Clinical investigations, including chest radiography, haematology assessment, biochemistry assessment,
blood culture and respiratory samples, were not mandatory in CAP-IT. However, if any of these
investigations were undertaken, results were reported.
Chest radiography was the most common investigation and was undertaken in 391 (48%) participants
(Table 9). Haematological and biochemical assessments were undertaken in 81 (10%) and 82 (10.1%)
participants, respectively, while blood cultures and respiratory specimens were obtained in 41 (5%) and
46 (5.7%) participants, respectively.
0
10
20
30
40
50
Percentage
60
70
80
90
100
Ward: per trial
Ward: trial entry
PED: trial entry
Severe/very bad
Bad
Moderate
Slight/little
Not present
Ward: per trial
Ward: trial entry
PED: trial entry
Ward: per trial
Ward: trial entry
PED: trial entry
Ward: per trial
Ward: trial entry
PED: trial entry
Ward: per trial
Ward: trial entry
PED: trial entry
Wheeze Sleep disturbance Vomiting Abnormal activityEating less
23
9
17
23
49 48
22
19
9
32
23
15
17
25
25
25
19
29
26
16
11
50
17
22
87
8
14
70
55
19
14
8
27
38
16
613
30
30
18
27
31
24
11 7
14
30
38
18
28
26
22
10
23
34
24
20
12
38
Symptom severity
FIGURE 6 Clinical symptoms (i.e. wheeze, sleep disturbance, vomiting, eating less and abnormal activity) at trial entry, by group.
TABLE 9 Baseline radiographic findings in participants who had chest radiography performed
Result of chest
radiography
Treatment arm, n(%)
Total (N=391),
n(%)
Lower dose
(N=192)
Higher dose
(N=199)
Shorter duration
(N=196)
Longer duration
(N=195)
Suggestive of
pneumonia: lobar
infiltrate
65 (33.9) 69 (34.7) 64 (32.7) 70 (35.9) 134 (34.3)
Suggestive of
pneumonia: patchy
infiltrate
72 (37.5) 82 (41.2) 84 (42.9) 70 (35.9) 154 (39.4)
Unsure if suggestive
of pneumonia
21 (10.9) 16 (8.0) 15 (7.7) 22 (11.3) 37 (9.5)
Other diagnosis 7 (3.6) 5 (2.5) 6 (3.1) 6 (3.1) 12 (3.1)
No finding/not
suggestive of
pneumonia
27 (14.1) 27 (13.6) 27 (13.8) 27 (13.8) 54 (13.8)
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Of the 46 respiratory samples taken, 44 samples underwent virology assessment and 11 samples
underwent bacteriology assessment (Table 10). All 11 of the respiratory samples subjected to
bacteriological assessment showed no significant growth.
Finally, of the 40 blood samples taken for culture, 37 (93%) returned a negative result. The three positive
results were considered probably due to contamination, with two identifying as coagulase-negative
staphylococci and one identifying as Gram-positive cocci (not further differentiated).
Prior antibiotic exposure
A total of 242 (29.7%) children received antibiotics for up to 48 hours prior to enrolment, of whom
241 received beta-lactam antibiotics and one received a macrolide. Amoxicillin was the most common
antibiotic taken prior to trial entry (209/242, 86.4%), followed by co-amoxiclav (20/242, 8.3%). In children
receiving antibiotics prior to enrolment, the median number of doses was 2 (IQR 1–3). More than half of
children (55%) were enrolled within 12 hours of commencing antibiotic treatment, with 24.8% enrolled
within 12–24 hours, 12.4% within 24–36 hours and 7.9% within 36–48 hours (Table 11).
Other medical interventions in exposed group
In addition, 54.3% of children in the ward group received supportive measures, including oxygen (49.3%),
nasogastric feeds or fluids (2.7%), parenteral fluids (8.5%) and chest physiotherapy (2.7%). Finally, 82.1%
of children in the ward group received pharmacological treatment other than antibiotics in hospital,
including salbutamol inhalers (58.3%), paracetamol (52.1%), steroids (22.9%), ibuprofen (15.7%) and
ipratropium bromide (8.3%).
TABLE 10 Baseline respiratory sample virology assessment results
Assessment result
Treatment arm, n(%)
Total (N=44),
n(%)
Lower dose
(N=19)
Higher dose
(N=25)
Shorter duration
(N=24)
Longer duration
(N=20)
Type of respiratory sample for virology
Nasopharyngeal 13 (68) 21 (84) 20 (83) 14 (70) 34 (77)
Oropharyngeal 6 (32) 4 (16) 4 (17) 6 (30) 10 (23)
Respiratory sample for virology: result
Rhinovirus 5 (26) 7 (28) 6 (25) 6 (30) 12 (27)
Influenza A/B 1 (5) 1 (4) 0 (0) 2 (10) 2 (5)
Adenovirus 0 (0) 1 (4) 1 (4) 0 (0) 1 (2)
Rhinovirus plus
adenovirus
2 (11) 1 (4) 2 (8) 1 (5) 3 (7)
Rhinovirus plus
enterovirus
4 (21) 5 (20) 5 (21) 4 (20) 9 (20)
Rhinovirus plus
enterovirus plus
adenovirus
0 (0) 1 (4) 0 (0) 1 (5) 1 (2)
Rhinovirus plus
enterovirus plus
coronavirus
1 (5) 0 (0) 1 (4) 0 (0) 1 (2)
Human metapneumovirus 1 (5) 2 (8) 2 (8) 1 (5) 3 (7)
No viral isolate present 5 (26) 7 (28) 7 (29) 5 (25) 12 (27)
RESULTS
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26
Follow-up
Of the 814 patients included in the analysis, 642 (79%) completed the final assessment. Where possible,
this final assessment was carried out face to face at hospital or at home, but if this proved impossible
(e.g. if parents/guardians were unable to attend an appointment), then the assessment was completed
by telephone. Overall, 25% of final assessments were performed by telephone, 74% were performed
in hospital and 1% were performed at home. In 172 (21%) participants, the final assessment was not
conducted with the family. Of these 172 participants, 11 had withdrawn consent and a further 161
could not be contacted. However, 150 of these participants (87%) had provided consent for collection of
the primary outcome via hospital and GP records, and primary outcome data were successfully collected
in 144 of these participants. This ensured that primary outcome data were available for 786 (97%)
participants, and only 28 participants (3%) were considered withdrawn or lost to follow-up (Table 12).
TABLE 11 Prior exposure with antibiotics
Prior exposure
Treatment arm
Total (N=814)
Lower dose
(N=410)
Higher dose
(N=404)
Shorter duration
(N=413)
Longer duration
(N=401)
Any systemic antibiotic in last 3 months, n(%)
Yes 64 (16) 65 (16) 66 (16) 63 (16) 129 (16)
No 346 (84) 339 (84) 347 (84) 338 (84) 685 (84)
Antibiotics received in last 48 hours?, n(%)
Yes 119 (29) 123 (30) 123 (30) 119 (30) 242 (30)
No 291 (71) 281 (70) 290 (70) 282 (70) 572 (70)
Class of prior antibiotic, n(%)
Beta-lactam 118 (99) 123 (100) 123 (100) 118 (99) 241 (100)
Macrolide 1 (1) 0 (0) 0 (0) 1 (1) 1 (<1)
Prior antibiotic, n(%)
Amoxicillin 103 (87) 106 (86) 104 (85) 105 (88) 209 (86)
Benzylpenicillin 1 (1) 2 (2) 1 (1) 2 (2) 3 (1)
Ceftriaxone 2 (2) 4 (3) 3 (2) 3 (3) 6 (2)
Cefuroxime 2 (2) 0 (0) 2 (2) 0 (0) 2 (1)
Clarithromycin 1 (1) 0 (0) 0 (0) 1 (1) 1 (<1)
Co-amoxiclav 9 (8) 11 (9) 13 (11) 7 (6) 20 (8)
Phenoxymethylpenicillin 1 (1) 0 (0) 0 (0) 1 (1) 1 (<1)
Number of prior antibiotic
doses, median (IQR)
2(1–3) 2 (1–3) 2 (1–3) 2 (1–3) 2 (1–3)
Prior antibiotic: route, n(%)
Intravenous 15 (13) 10 (8) 17 (14) 8 (7) 100 (41)
Oral 103 (87) 110 (89) 106 (86) 107 (90) 85 (35)
Intravenous plus oral 1 (1) 3 (2) 0 (0) 4 (3) 28 (12)
Duration (hours) of prior antibiotic treatment, n(%)
<12 67 (56) 66 (54) 68 (55) 65 (55) 133 (55)
12–24 27 (23) 33 (27) 33 (27) 27 (23) 60 (25)
24–36 13 (11) 17 (14) 13 (11) 17 (14) 30 (12)
36–48 12 (10) 7 (6) 9 (7) 10 (8) 19 (8)
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27
Follow-up data were also collected by telephone at days 3, 7, 14 and 21 (Table 13). Follow-up rates were
88% at day 3, 75% at day 14 and 76% at day 21. A total of 443 (54%) parents/guardians of participants
completed all telephone calls and the final visit, with 153 (19%) parents/guardians of participants missing
one follow-up visit, 95 (12%) parents/guardians of participants missing two follow-up visits, 51 (6%)
parents/guardians of participants missing three follow-up visits and 48 (6%) parents/guardians of
participants missing four follow-up visits. Twenty-four (3%) parents/guardians of participants missed all
telephone calls and visits.
TABLE 12 Final visit and follow-up data completeness
Final visit and
follow-up data
Treatment arm, n(%)
Total (N=814),
n(%)
Lower dose
(N=410)
Higher dose
(N=404)
Shorter duration
(N=413)
Longer duration
(N=401)
Attendance
Final visit completed 329 (80) 313 (77) 315 (76) 327 (82) 642 (79)
Previously withdrawn 8 (2) 3 (1) 6 (1) 5 (1) 11 (1)
Not withdrawn but
not completed
73 (18) 88 (22) 92 (22) 69 (17) 161 (20)
Where/how did final visit take place?
Hospital 242 (74) 236 (75) 231 (73) 247 (76) 478 (74)
Home 3 (1) 3 (1) 3 (1) 3 (1) 6 (1)
Telephone call 84 (26) 74 (24) 81 (26) 77 (24) 158 (25)
Consent for further data collection?
Yes 71 (88) 79 (87) 87 (89) 63 (85) 150 (87)
No 10 (12) 12 (13) 11 (11) 11 (15) 22 (13)
Day 28 data received from GP?
Yes 70 (99) 74 (94) 84 (97) 60 (95) 144 (96)
No 1 (1) 5 (6) 3 (3) 3 (5) 6 (4)
Final visit status
Completed 329 (80) 313 (77) 315 (76) 327 (82) 642 (79)
Not completed, but
GP data received
70 (17) 74 (18) 84 (20) 60 (15) 144 (18)
Withdrawn/lost 11 (3) 17 (4) 14 (3) 14 (3) 28 (3)
TABLE 13 Participant follow-up rate
Follow-up
Treatment arm, n(%)
Total (N=814),
n(%)
Lower dose
(N=410)
Higher dose
(N=404)
Shorter duration
(N=413)
Longer duration
(N=401)
Trial entry 410 (100) 404 (100) 413 (100) 401 (100) 814 (100)
Day 3 355 (87) 360 (89) 365 (88) 350 (87) 715 (88)
Day 7 332 (81) 343 (85) 342 (83) 333 (83) 675 (83)
Day 14 314 (77) 299 (74) 307 (74) 306 (76) 613 (75)
Day 21 315 (77) 302 (75) 303 (73) 314 (78) 617 (76)
Final visit (day 28) 329 (80) 313 (77) 315 (76) 327 (82) 642 (79)
RESULTS
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28
A symptom diary was to be completed daily by parents/guardians for the first 14 days after trial entry.
Completed diary data were available for 406 (49.9%) participants and no diary data were available
for 227 (27.9%) participants. Parents/guardians were assigned to complete symptom diaries either
electronically (42.5%) or on paper (57.5%) using pseudorandomisation. Summary data on diary completion
are presented in Table 14.
Adherence
A total of 240 (29.5%) participants deviated from the prescribed IMP regimen for reasons including taking
fewer doses or a lower volume, taking too many doses or a greater volume, or deviation in timing (Table 15).
For dose randomisation, there was no evidence of an overall difference in adherence deviation between
the two arms (p=0.21). However, a greater proportion of participants in the lower-dose arm (7.3%)
than in the higher-dose arm (4%) did not take bottle B/C as prescribed (p=0.038).
For duration randomisation, 134 (32.4%) participants in the shorter-duration arm deviated, compared
with 106 (26.4%) participants in the longer-duration arm (p=0.06). A greater proportion of participants in
the shorter-duration arm (13.3%) than in the longer-duration arm (9.4%) did not complete trial treatment
(p=0.015) (see Table 15).
TABLE 14 Parent/guardian diary completion rate
Diary completion
Treatment arm, n(%)
Total (N=814),
n(%)
Lower dose
(N=410)
Higher dose
(N=404)
Shorter duration
(N=413)
Longer duration
(N=401)
Diary status
Completed: all days 201 (49.0) 205 (50.7) 212 (51.3) 194 (48.4) 406 (49.9)
Completed: partly 97 (23.7) 84 (20.8) 79 (19.1) 102 (25.4) 181 (22.2)
No diary data available 112 (27.3) 115 (28.5) 122 (29.5) 105 (26.2) 227 (27.9)
Number of days completed
None 112 (27.3) 115 (28.5) 122 (29.5) 105 (26.2) 227 (27.9)
1–4 26 (6.3) 11 (2.7) 14 (3.4) 23 (5.7) 37 (4.5)
5–8 27 (6.6) 32 (7.9) 33 (8.0) 26 (6.5) 59 (7.2)
9–12 44 (10.7) 41 (10.1) 32 (7.7) 53 (13.2) 85 (10.4)
13 201 (49.0) 205 (50.7) 212 (51.3) 194 (48.4) 406 (49.9)
No diary data: reason
Withdrawal 7 (6.3) 2 (1.7) 5 (4.1) 4 (3.8) 9 (4.0)
Paper: no final visit 40 (35.7) 48 (41.7) 49 (40.2) 39 (37.1) 88 (38.8)
Paper: final visit as
telephone call
23 (20.5) 18 (15.7) 17 (13.9) 24 (22.9) 41 (18.1)
Lost/forgot 21 (18.8) 19 (16.5) 24 (19.7) 16 (15.2) 40 (17.6)
Technical/password issue 8 (7.1) 13 (11.3) 11 (9.0) 10 (9.5) 21 (9.3)
No time 4 (3.6) 6 (5.2) 6 (4.9) 4 (3.8) 10 (4.4)
Site error 0 (0.0) 1 (0.9) 1 (0.8) 0 (0.0) 1 (0.4)
Unknown 9 (8.0) 8 (7.0) 9 (7.4) 8 (7.6) 17 (7.5)
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29
TABLE 15 Adherence to trial medication by randomisation arm
Adherence to trial medication
Treatment arm, n(%)
p-value
Treatment arm, n(%)
p-value Total (N=814), n(%)
Lower dose
(N=410)
Higher dose
(N=404)
Shorter duration
(N=413)
Longer duration
(N=401)
Early cessation of trial treatment
Trial treatment completed 355 (86.6) 366 (90.6) 0.10 358 (86.7) 363 (90.5) 0.015 721 (88.6)
Early cessation for clinical improvement 7 (1.7) 1 (0.2) 5 (1.2) 3 (0.7) 8 (1.0)
Early cessation for clinical deterioration 16 (3.9) 11 (2.7) 10 (2.4) 17 (4.2) 27 (3.3)
Early cessation for other reason 32 (7.8) 26 (6.4) 40 (9.7) 18 (4.5) 58 (7.1)
Day of last dose of trial medication
Day 0 or 1 11 (20) 4 (11) 0.62 9 (16) 6 (16) 0.61 15 (16)
Day 2 or 3 17 (31) 15 (39) 16 (29) 16 (42) 32 (34)
Day 4 or 5 22 (40) 15 (39) 24 (44) 13 (34) 37 (40)
Day 6 or after 5 (9) 4 (11) 6 (11) 3 (8) 9 (10)
Bottles received
Taken bottle A but not bottles B/C 30 (7.3) 16 (4.0) 0.038 21 (5.1) 25 (6.2) 0.48 46 (5.7)
Taken bottle A and bottles B/C 380 (92.7) 388 (96.0) 392 (94.9) 376 (93.8) 768 (94.3)
Overall: fewer doses taken than scheduled
Yes 86 (21.0) 77 (19.1) 0.49 85 (20.6) 78 (19.5) 0.69 163 (20.0)
No 324 (79.0) 327 (80.9) 328 (79.4) 323 (80.5) 651 (80.0)
Overall: fewer doses or less volume taken than scheduled
Yes 104 (25.4) 95 (23.5) 0.54 113 (27.4) 86 (21.4) 0.050 199 (24.4)
No 306 (74.6) 309 (76.5) 300 (72.6) 315 (78.6) 615 (75.6)
Overall: any deviation (including too many doses/volume or timing deviations)
Yes 128 (31.2) 107 (26.5) 0.14 133 (32.2) 102 (25.4) 0.033 235 (28.9)
No 282 (68.8) 297 (73.5) 280 (67.8) 299 (74.6) 579 (71.1)
RESULTS
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30
Primary outcome
End-Point Review Committee results
There were 143 events of non-trial systemic antibacterial treatment in 139 participants (four participants
had two events). All events were adjudicated by the ERC (see Chapter 2,Primary outcome) and reasons
for starting new non-trial antibacterials are given in Table 16. Of 139 participants, 100 (71.9%) met
the criteria for a primary end point (see Table 16). Among the 100 participants who had an event that
met the criteria for a primary end point, ‘CAP/chest infection’was the most common reason for
treatment, accounting for 76 (76%) events (see Table 16). The ERC adjudicated 38% of the events as
definitely/probably clinically indicated and 62% of the events as possibly indicated (Table 17).
TABLE 16 Reasons for starting non-trial systemic antibacterials, as adjudicated by the ERC
Reason
Treatment arm (n)
Total (N)
(N=139)
Lower dose
(N=74)
Higher dose
(N=65)
Shorter duration
(N=73)
Longer duration
(N=66)
CAP/chest infection 38 40 40 38 78
Other respiratory tract infection 19 12 18 13 31
Otitis media 7 3 6 4 10
URTI 7 2 4 5 9
Tonsillitis 3 5 5 3 8
Othera22 3 1 4
Other bacterial infection 8 7 9 6 15
Skin infection 2 2 3 1 4
Urinary tract infection 2 2 3 1 4
Cellulitis 1 2 2 1 3
Scarlet fever 1 1 0 2 2
Nail infection 1 0 0 1 1
Salmonella gastroenteritis 1 0 1 0 1
Other illness/injury 4 2 3 3 6
Appendicitis 1 0 1 0 1
Asthma 0 1 0 1 1
Bronchospasm/asthma 1 0 1 0 1
Dental abscess 0 1 1 0 1
Lymphadenitis 1 0 0 1 1
Prophylaxis 1 0 0 1 1
Intolerance to IMP/AE 3 5 5 3 8
Vomiting 1 4 4 1 5
Diarrhoea 1 0 0 1 1
Rash 0 1 0 1 1
Refusing IMP 1 0 1 0 1
Parental preference 3 0 0 3 3
Pharmacy/administration error 1 1 2 0 2
URTI, upper respiratory tract infection.
a Bronchiolitis, n=1; cough, n=2; scarlet fever and tonsillitis, n=1.
Note
Four patients had two events.
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31
TABLE 17 End-Point Review Committee primary end-point adjudication results
Primary end-point adjudication result
Treatment arm
TotalLower dose Higher dose
Shorter
duration
Longer
duration
Patients who started systemic non-trial antibacterials
N74 65 73 66 139
Patients who had a primary end point, n(%)
Yes 51 (69) 49 (75) 51 (70) 49 (74) 100 (712)
No 23 (31) 16 (25) 22 (30) 17 (26) 39 (28)
Events that met the criteria for primary end point
N51 49 51 49 100
Primary reason for starting new antibacterials, n(%)
CAP/chest infection 37 (73) 39 (80) 39 (76) 37 (76) 76 (76)
Otitis media 5 (10) 3 (6) 4 (8) 4 (8) 8 (8)
Tonsillitis 3 (6) 5 (10) 5 (10) 3 (6) 8 (8)
URTI 5 (10) 2 (4) 3 (6) 4 (8) 7 (7)
Other respiratory tract infection 1 (2) 0 (0) 0 (0) 1 (2) 1 (1)
Clinical indication, n(%)
Definitely/probably 19 (37) 19 (39) 19 (37) 19 (39) 38 (38)
Possibly 32 (63) 30 (61) 32 (63) 30 (61) 62 (62)
First new antibiotic, n(%)
Amoxicillin 25 (49) 24 (49) 23 (45) 26 (53) 49 (49)
Amoxicillin (i.v.) 0 (0) 1 (2) 1 (2) 0 (0) 1 (1)
Azithromycin 3 (6) 1 (2) 2 (4) 2 (4) 4 (4)
Azithromycin plus amoxicillin (i.v.) 1 (2) 0 (0) 1 (2) 0 (0) 1 (1)
Cefuroxime 0 (0) 1 (2) 0 (0) 1 (2) 1 (1)
Cefuroxime plus clarithromycin 1 (2) 0 (0) 1 (2) 0 (0) 1 (1)
Clarithromycin 8 (16) 9 (18) 13 (25) 4 (8) 17 (17)
Co-amoxiclav 5 (10) 5 (10) 2 (4) 8 (16) 10 (10)
Co-amoxiclav plus azithromycin 2 (4) 0 (0) 0 (0) 2 (4) 2 (2)
Co-amoxiclav (i.v.) 1 (2) 0 (0) 1 (2) 0 (0) 1 (1)
Erythromycin 3 (6) 4 (8) 3 (6) 4 (8) 7 (7)
Phenoxymethylpenicillin 2 (4) 4 (8) 4 (8) 2 (4) 6 (6)
Who prescribed the antibiotic, n(%)a
CAP-IT investigator 3 (6) 3 (7) 3 (6) 3 (7) 6 (6)
Other hospital doctor 18 (38) 16 (36) 17 (36) 17 (37) 34 (37)
GP 24 (50) 25 (56) 27 (57) 22 (48) 49 (53)
Other 3 (6) 1 (2) 0 (0) 4 (9) 4 (4)
Time new antibiotic started, n(%)
Days 0–14 29 (57) 25 (51) 28 (55) 26 (53) 54 (54)
Days 15–28 22 (43) 24 (49) 23 (45) 23 (47) 46 (46)
i.v., intravenous; URTI, upper respiratory tract infection.
a Information about the prescriber was missing in seven cases because this was not asked for at the beginning of
the trial.
RESULTS
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32
The most commonly prescribed antibacterial was oral amoxicillin, which was prescribed in 49 (49%)
participants who met the criteria for a primary end point. Oral clarithromycin and co-amoxiclav
accounted for 17% and 10% of prescriptions for participants who met the criteria for a primary end
point, respectively, and erythromycin, phenoxymethylpenicillin and azithromycin accounted for 7%, 6%
and 4%, respectively.
Analysis of primary end point
Overall
Overall, 100 participants in the analysis population (n=814) met the criteria for a primary end
point during the follow-up period (i.e. a cumulative proportion of 12.5%, 90% CI 10.7% to 14.6%,
as estimated with Kaplan–Meier methods).
Dose randomisation
The observed number of primary end points was similar in the lower-dose arm (n=51, 12.6%) and
in the higher-dose arm (n=49, 12.4%). The estimated risk difference at day 28 was 0.2% (90% CI
–3.7% to 4.0%), meeting the criterion for non-inferiority (Figure 7).
Duration randomisation
A total of 51 (12.5%) participants experienced a primary end point in the shorter-duration arm and
49 (12.5%) participants experienced a primary end point in the longer-duration arm. The estimated
risk difference at day 28 was 0.1% (90% CI –3.8% to 3.9%), again satisfying the non-inferiority
criterion (Figure 8).
Interaction effects
The outcomes for the analyses of interaction effects between the two randomisations (i.e. dose and
duration), between pre-exposure to antibiotics and dose randomisation and between pre-exposure to
antibiotics and duration randomisation are shown in Figures 9–11, respectively.
There was no evidence of an interaction between either of the two randomisation arms (p=0.625),
between the dose randomisation arm and pre-exposure to antibiotics (p=0.456) or between the
duration randomisation arm and pre-exposure to antibiotics (p=0.592). This justifies analysis of the
‘main effects’for the two randomisations (see Figures 7 and 8).
0
0 4 8 12 16
Day of trial
20 24 28
410
404
Number at risk
Lower dose
Higher dose
398
395
387
385
382
381
370
369
361
361
353
348
320
311
20
40
60
Percentage of children with primary end point
80
100
Lower dose: 51
(12.6%, 90% CI 10.1% to 15.6%)
Higher dose: 49
(12.4%, 90% CI 10.0% to 15.5%)
Difference:
0.2% (90% CI –3.7% to 4.0%)
n (%) with primary end point by day 28
FIGURE 7 Kaplan–Meier curve for primary end point: dose randomisation.
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Primary end-point sensitivity analyses
The results of the sensitivity and subgroup analyses are summarised in Figures 12 and 13. Non-
inferiority was demonstrated for all sensitivity analyses for both dose and duration comparisons.
All systemic antibacterial treatments
The first sensitivity analysis repeated the primary analysis and considered all systemic antibacterial
treatments other than trial medication, regardless of reason and indication. The total number of
participants experiencing an end point in this analysis was 139 of 814 participants (17.4%, 90% CI
15.3% to 19.7%).
0
0481216
Day of trial
20 24 28
413
401
Number at risk
Shorter duration
Longer duration
404
389
394
378
389
374
376
363
370
352
357
344
323
308
20
40
60
Percentage of children who met the
primary end point
80
100
Shorter: 51
(12.5%, 90% CI 10.1% to 15.5%)
Longer: 49
(12.5%, 90% CI 10.0% to 15.5%)
Difference:
0.1% (90% CI –3.8% to 3.9%)
n (%) with primary end point by day 28
FIGURE 8 Kaplan–Meier curve for primary end point: duration randomisation.
0
02 6 10 14 18 22 264 8 12 16
Day of trial
20 24 28
208
202
205
199
Number at risk
Lower dose plus shorter duration
Lower dose plus longer duration
Higher dose plus shorter duration
Hi
g
her dose plus lon
g
er duration
202
196
202
193
196
191
198
187
193
189
196
185
189
181
187
182
185
176
185
176
180
173
177
171
166
154
157
154
20
40
60
Percentage of children with primary end point
(Kaplan–Meier estimate)
80
100 Lower dose plus shorter duration: 25
(12.1%, 90% CI 8.9% to 16.4%)
Lower dose plus longer duration: 26
(13.1%, 90% CI 9.7% to 17.7%)
Higher dose plus shorter duration: 26
(13.1%, 90% CI 9.6% to 17.6%)
Higher dose plus longer duration: 23
(11.8%, 90% CI 8.5% to 16.2%)
p-value for additive interaction
p
=
0.625
FIGURE 9 Kaplan–Meier curve for analysis of interaction between the two randomisations.
RESULTS
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34
For the dose comparison, the estimated risk difference at day 28 was 1.9% (90% CI –2.5% to 6.3%).
For the duration comparison, the estimated risk difference at day 28 was 1.0% (90% CI –3.4%
to 5.4%). For both comparisons, the upper limit of the 90% CI was less than the non-inferiority margin
of 8%, supporting the observations of the primary end-point analysis.
0
02 6 10 14 18 22 264 8 12 16
Day of trial
20 24 28
119
291
123
281
Number at risk
Lower dose, pre-treatment antibiotics
Lower dose, no pre-treatment antibiotics
Higher dose, pre-treatment antibiotics
Higher dose, no pre-treatment antibiotics
117
281
119
276
113
274
113
272
109
273
111
270
105
265
108
261
101
260
106
255
98
255
104
244
90
230
91
220
20
40
60
Percentage of children with a primary end point
(Kaplan–Meier estimate)
80
100 Lower dose, pre-treatment antibiotics: 17
(14.6%, 90% CI 10.0% to 20.9%)
Lower dose, no pre-treatment antibiotics: 34
(11.8%, 90% CI 9.0% to 15.4%)
Higher dose, pre-treatment antibiotics: 14
(11.7%, 90% CI 7.7% to 17.5%)
Higher dose, no pre-treatment antibiotics: 35
(12.8%, 90% CI 9.8% to 16.5%)
p-value for additive interaction p
=
0.456
FIGURE 10 Kaplan–Meier curve for analysis of interaction between pre-exposure with antibiotics and dose randomisation.
0
02 6 10 14 18 22 264 8 12 16
Day of trial
20 24 28
123
290
119
282
Number at risk
Shorter dose, pre-treatment antibiotics
Shorter dose, no pre-treatment antibiotics
Longer dose, pre-treatment antibiotics
Longer dose, no pre-treatment antibiotics
121
283
115
274
115
279
111
267
112
277
108
266
109
267
104
259
106
264
101
251
103
254
99
245
92
231
89
219
20
40
60
Percentage of children with primary end point
(Kaplan–Meier estimate)
80
100
Shorter dose, pre-treatment antibiotics: 17
(14.1%, 90% CI 9.7% to 20.2%)
Shorter dose, no pre-treatment antibiotics: 34
(11.9%, 90% CI 9.1% to 15.5%)
Longer dose, pre-treatment antibiotics: 14
(12.0%, 90% CI 7.9% to 18.1%)
Longer dose, no pre-treatment antibiotics: 35
(12.6%, 90% CI 9.7% to 16.4%)
p-value for additive interaction p
=
0.592
FIGURE 11 Kaplan–Meier curve for analysis of interaction between pre-exposure with antibiotics and duration
randomisation.
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35
Treatment events for community-acquired pneumonia/chest infection
In a second sensitivity analysis, only those treatment events for which the clinical indication was
adjudicated by the ERC to be CAP/chest infection were included. The total number of participants
experiencing an end point in this analysis was 76 out of 814 (9.4%, 90% CI 7.9% to 11.3%).
For the dose comparison, the estimated risk difference at day 28 was –0.7% (90% CI –4.7% to 3.4%).
For the duration comparison, the estimated risk difference at day 28 was 0.2% (90% CI –3.9% to 4.2%).
As for the first sensitivity analysis, for both comparisons the upper limit of the 90% CI was less than
the non-inferiority margin, supporting the observations of the primary end-point analysis.
All treatment events for community-acquired pneumonia/chest infection
A third sensitivity analysis considered treatment events for which the clinical indication was adjudicated
by the ERC to be CAP/chest infection, including those adjudicated ‘unlikely’to be clinically indicated.
The number of participants experiencing an end point in this analysis was 78 of 814 participants
(9.7%, 90% CI 8.1% to 11.6%).
0246810–2–4–6
Favours higherFavours lower
Difference in proportions of retreatment by day 28 (%, 90% CI)
End point Difference (90% CI) Lower Higher
Primary end point,
primary analysis
0.2 (–3.7 to 4.0) 12.6 12.4
All systemic
antibacterial retreatments
1.9 (–2.5 to 6.3) 18.3 16.4
Retreatment due to
CAP/chest infection
–0.7 (–4.7 to 3.4) 9.1 9.8
Primary end point,
subgroup severe CAP
3.8 (–2.4 to 10.0) 17.3 13.5
FIGURE 12 Forest plot summarising sensitivity and subgroup analyses outcomes in terms of difference in proportions of
retreatment by day 28 for the dose randomisation.
0246810–2–4–6
Favours longerFavours shorter
Difference in proportions of retreatment by day 28 (%, 90% CI)
End point Difference (90% CI) Lower Higher
Primary end point,
primary analysis
0.1 (–3.8 to 3.9) 12.5 12.5
All systemic
antibacterial retreatments
1.0 (–3.4 to 5.4) 17.9 16.8
Retreatment due to
CAP/chest infection
0.2 (–3.9 to 4.2) 9.5 9.4
Retreatment
after day 3
0.6 (–3.7 to 5.0) 11.3 10.7
Primary end point,
subgroup severe CAP
1.2 (–5.0 to 7.4) 16 14.8
FIGURE 13 Forest plot summarising sensitivity and subgroup analyses outcomes in terms of difference in proportions of
retreatment by day 28 for the duration randomisation.
RESULTS
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36
For the dose comparison, the estimated risk difference at day 28 was –0.7% (90% CI –4.8% to 3.4%).
For the duration comparison, the estimated risk difference at day 28 was 0.2% (90% CI –3.9%
to 4.3%). For both comparisons, the upper limit of the 90% CI was less than the non-inferiority margin,
supporting the observations of the primary end-point analysis.
Only treatment events started after the first 3 days (duration randomisation)
A final sensitivity analysis considered only ERC-adjudicated primary end points when non-trial antibacterial
treatment was started after the first 3 days. This assessment was relevant for the duration randomisation
only, and the estimated risk difference at day 28 was 0.6% (90% CI –3.7% to 5.0%). Non-inferiority
was demonstrated, with the upper CI (5.0%) less than the non-inferiority margin of 8%, supporting the
observations of the primary end-point analysis.
On-treatment analyses
The on-treatment analyses gave very similar results to the primary analysis. For both the dose and the
duration comparison, the upper 90% CI limit of the estimated difference at day 28 was lower than the
non-inferiority margin of 8% for both definitions of non-adherence (see Appendix 3,Figures 21–24).
Subgroup analyses
Participants with severe community-acquired pneumonia
This a priori subgroup analysis repeated the primary analysis, limited to participants defined as having
severe CAP. Table 18 shows the total number (%) of participants with each abnormality by randomisation
group. Only 155 (19%) participants had none of these abnormalities at presentation; 291 (35.7%)
participants had one, 341 (41.9%) had two and 27 (3.3%) had three. A total of 368 (45.2%) participants
were included in the subgroup analysis.
TABLE 18 Abnormalities at presentation considered for subgroup analysis for severe CAP
Abnormality
Treatment arm, n(%)
p-value
Treatment arm, n(%)
p-value
Total (N=814),
n(%)
Lower dose
(N=410)
Higher dose
(N=404)
Shorter duration
(N=413)
Longer duration
(N=401)
Chest
retractions
239 (58.4) 244 (60.4) 0.57 239 (58.0) 244 (60.8) 0.41 483 (59.4)
Oxygen
saturation
<92%
18 (4.4) 25 (6.2) 0.25 18 (4.4) 25 (6.3) 0.23 43 (5.3)
High
respiratory
rate
270 (65.9) 258 (64.3) 0.65 262 (63.7) 266 (66.5) 0.41 528 (65.1)
Number of
abnormalities
0.62 0.47
0 75 (18.3) 80 (19.8) 82 (19.9) 73 (18.2) 155 (19.0)
1 155 (37.8) 136 (33.7) 154 (37.3) 137 (34.2) 291 (35.7)
2 168 (41.0) 173 (42.8) 166 (40.2) 175 (43.6) 341 (41.9)
3 12 (2.9) 15 (3.7) 11 (2.7) 16 (4.0) 27 (3.3)
>1 180 (43.9) 188 (46.5) 0.45 177 (42.9) 191 (47.6) 0.17 368 (45.2)
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37
In total, 56 (15.4%) participants experienced a primary end point. There was no significant difference
between the arms for either the dose comparison (p=0.283) or the duration comparison (p=0.821).
For duration randomisation, the estimated risk difference at day 28 was 1.2% (90% CI –5.0% to 7.4%)
(Figure 14). For dose randomisation, the estimated difference at day 28 was 3.8% (90% CI –2.4% to 10.0%).
This is consistent with no effect, although the 90% CI crossed the non-inferiority margin (Figure 15).
Seasonal effect
A further a priori planned subgroup analysis repeated the primary analysis, but including only events
occurring during the two winter periods spanned by CAP-IT (i.e. 2017/18 and 2018/19), based on
Public Health England reports of circulating viruses/bacteria.
The overall event rate in 2017/18 was 14.1% and 12.2% in 2018/19 (p=0.515). There was no evidence of
an interaction with either the duration or dose randomisations (p=0.848 and p=0.677, respectively).
0
0 4 8 12 16
Day of trial
20 24 28
177
191
Number at risk
Shorter duration
Longer duration
174
182
168
179
165
175
159
169
156
163
147
161
133
145
20
40
60
Percentage of children with a primary end point
80
100
Shorter duration: 28
(16.0%, 90% CI 12.0% to 21.2%)
Longer duration: 28
(14.8%, 90% CI 11.1% to 19.6%)
Difference:
1.2% (90% CI –5.0% to 7.4%)
n (%) with a primary end point by day 28
Log-rank p
=
0.821
FIGURE 14 Kaplan–Meier curve for severe CAP subgroup primary analysis for duration randomisation.
0
0481216
Day of trial
20 24 28
180
188
Number at risk
Lower dose
Higher dose
173
183
168
179
164
176
157
171
152
167
146
162
135
143
20
40
60
Percentage of children with a primary end point
80
100
Log-rank p
=
0.283
Lower dose: 31
(17.3%, 90% CI 13.2% to 22.6%)
Higher dose: 25
(13.5%, 90% CI 9.9% to 18.3%)
Difference:
3.8% (90% CI –2.4% to 10.0%)
n (%) with a primary end point by day 28
FIGURE 15 Kaplan–Meier curve for severe CAP subgroup primary analysis for dose randomisation.
RESULTS
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38
Streptococcus pneumoniae carriage and resistance
Carriage and resistance to penicillin of S. pneumoniae isolates were assessed by analysis of
nasopharyngeal samples collected from participants at baseline, at the final visit and at any
unscheduled visits during follow-up.
Availability of nasopharyngeal culture results
Of the 814 participants in the analysis population, 647 (79%) had a nasopharyngeal sample taken at
baseline and 437 (54%) had a sample taken at the final visit. There were 376 (46%) participants who
had both a baseline and final visit sample taken, 271 (33%) who had just a baseline sample taken
and 61 (7%) who had just a final visit sample taken. The remaining 106 (13%) participants did not
have a sample taken. In addition, 28 (4%) participants had a sample taken at an unscheduled visit and
four participants had samples taken at two unscheduled visits (1%) (Table 19).
Streptococcus pneumoniae carriage
Overall, 272 of 647 (42%) baseline samples and 129 of 437 (30%) final visit samples were culture
positive for S. pneumoniae. Of the participants with a culture result at both baseline and final visit,
70 of 376 (19%) were positive for S. pneumoniae at both visits, 100 of 376 (27%) were positive at
baseline only and 41 of 376 (11%) were positive at the final visit only. The remaining 165 (44%)
sample cultures were negative at both visits (Table 20).
Streptococcus pneumoniae penicillin non-susceptibility
No penicillin-resistant pneumococcal isolates were identified in CAP-IT. Penicillin non-susceptibility
was detected in 45 of 647 (7%) baseline samples providing a culture result (either positive or negative)
(17% of S. pneumoniae-positive samples) and in 21 (5%) samples taken at the final visit and providing a
culture result (either positive or negative) (16% of S. pneumoniae-positive samples). Of participants with
positive or negative culture results at both baseline and final visit, 23 (6%) had pneumococcal penicillin
non-susceptibility identified in the baseline sample only, 11 (3%) participants had pneumococcal penicillin
non-susceptibility identified in in the final visit sample only and seven (2%) participants had pneumococcal
penicillin non-susceptibility identified in both baseline and final visit samples. In the remaining 335 (89%)
participants, penicillin resistance was not identified in either sample culture.
TABLE 19 Availability of nasopharyngeal culture results
Culture result
Group, n(%)
p-value
Total (N=814),
n(%)PED (N=591) Ward (N=223)
Baseline culture available 474 (80) 173 (78) 0.41 647 (79)
Final visit culture available 316 (53) 121 (54) 0.84 437 (54)
If final visit happened hospital, at home 316 (89) 121 (92) 0.25 437 (90)
Summary availability
None 75 (13) 31 (14) 0.84 106 (13)
Both baseline and final visit 274 (46) 102 (46) 376 (46)
Baseline only 200 (34) 71 (32) 271 (33)
Final visit only 42 (7) 19 (9) 61 (7)
Unscheduled visit: number of culture samples available
0 490 (95) 186 (97) 0.37 676 (95)
1 22 (4) 6 (3) 28 (4)
2 4 (1) 0 (1) 4 (1)
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39
There was no evidence of a difference between the lower- and higher-dose randomisation groups in the
penicillin non-susceptibility of isolates cultured from either baseline or final visit samples, or between
the shorter- and longer-duration randomisation groups in the penicillin non-susceptibility of isolates
cultured from baseline samples (see Table 21). The proportion of pneumococcal isolates cultured from
final visit samples that were penicillin non-susceptible was slightly higher in the shorter-duration group
(n=14, 7% of all samples, 22% of S. pneumoniae-positive samples) than in the longer-duration group
[n=7, 3% of all samples (p=0.063), 11% of S. pneumoniae-positive samples (p=0.10)]. This pattern was
also found when the analysis was limited to participants with a positive culture result for S. pneumoniae
(excluding all samples with a negative culture result), with penicillin non-susceptibility detected in 22%
(n=14) of samples taken from participants in the shorter-duration arm and in 11% (n=7) of samples
from participants in the longer-duration arm (p=0.10).
Streptococcus pneumoniae amoxicillin resistance/non-susceptibility
Amoxicillin non-susceptibility or resistance was detected in S. pneumoniae isolates cultured from seven
(2%) baseline samples with a culture result (either positive or negative) and in four final visit (1%)
samples with a culture result (either positive or negative). Among participants for whom culture results
(positive or negative) were available for both baseline and final visit samples, amoxicillin resistance
was detected in isolates cultured from the baseline sample only in the case of one (<1%) participant,
in isolates cultured from the final visit sample only in the case of two (1%) participants and in isolates
from both samples in the case of one (<1%) participant. In the remaining 361 (99%) participants, neither
amoxicillin non-susceptibility nor resistance was identified in any samples.
There was no evidence of a difference between the lower- and higher-dose groups in the amoxicillin
non-susceptibility of isolates cultured from either baseline or final visit sample cultures, or between
the shorter- and longer-duration groups groups in the amoxicillin non-susceptibility of isolates cultured
from either baseline or final visit samples (Table 21). This was also found when the analysis of amoxicillin
non-susceptibility was limited to participants whose samples provided a positive culture result for
S. pneumoniae (excluding all samples with a negative culture result).
Community-acquired pneumonia symptoms
Parent/guardian-reported symptom data were elicited at follow-up telephone calls and through parental/
guardian completion of a daily diary up to day 14.The proportion of participants for whom parent/
guardian-reported symptom data from any source were available reduced from days 3 (93%), 7 (88%),
14 (83%) and 21 (76%) to day 28 (75%) (Figure 16).
TABLE 20 Streptococcus pneumoniae carriage
S. pneumoniae carriage
Treatment arm, n(%)
p-value
Treatment arm, n(%)
p-value Total, n(%)Lower dose Higher dose
Shorter
duration
Longer
duration
Baseline: positive 133 (41) 139 (43) 132 (42) 140 (42) 272 (42)
Final visit: positive 66 (29) 63 (30) 0.98 65 (32) 64 (28) 0.35 129 (30)
Summary: pneumococcal carriagea
Never 93 (48) 72 (40) 76 (44) 89 (43) 165 (44)
Baseline only 46 (24) 54 (30) 39 (23) 61 (30) 100 (27)
Final visit only 21 (11) 20 (11) 20 (12) 21 (10) 41 (11)
Both 34 (18) 36 (20) 36 (21) 34 (17) 70 (19)
a Patients with culture results at both time points.
RESULTS
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40
TABLE 21 Penicillin and amoxicillin resistance/non-susceptibility in all participants with a culture result, either negative
or positive for S. pneumoniae
Penicillin and amoxicillin
resistance/non-susceptibility
Treatment arm, n(%)
p-value
Treatment arm, n(%)
p-valueLower dose Higher dose Shorter duration Longer duration
Penicillin non-susceptibility at baseline
No 302 (92) 299 (93) 0.59 293 (92) 308 (93) 0.65
Yes 25 (8) 21 (7) 24 (8) 22 (7)
Penicillin non-susceptibility at the final visit
No 212 (95) 204 (96) 0.58 191 (93) 225 (97) 0.063
Yes 12 (5) 9 (4) 14 (7) 7 (3)
Penicillin non-susceptibility: summarya
Never 175 (90) 166 (91) 0.79 151 (88) 190 (93) 0.29
Baseline only 10 (5) 9 (5) 9 (5) 10 (5)
Final visit only 6 (3) 3 (2) 6 (4) 3 (1)
Both baseline and final visit 3 (2) 4 (2) 5 (3) 2 (1)
Amoxicillin resistance/non-susceptibility at baseline
No 318 (98) 311 (99) 0.27 309 (99) 320 (98) 0.28
Yes 5 (2) 2 (1) 2 (1) 5 (2)
Amoxicillin resistance/non-susceptibility at the final visit
No 218 (99) 210 (99) 0.97 199 (99) 229 (99) 0.89
Yes 2 (1) 2 (1) 2 (1) 2 (1)
Amoxicillin resistance/non-susceptibility: summarya
Never 185 (99) 176 (99) 0.26 162 (99) 199 (99) 0.56
Baseline only 1 (1) 0 (0) 0 (0) 1 (<1)
Final visit only 0 (0) 2 (1) 1 (1) 1 (<1)
Both baseline and final visit 1 (1) 0 (0) 1 (1) 0 (0)
a In patients with culture results at both time points.
0
20
40
Percentage of participants
60
80
100
Telephone call/visit only
Diary only
Both
Neithera
37
Day of trial
14 21 28
22 22 27
76 75
0
24
0
25
7
49
17
55
61
12
66
7
Data source
FIGURE 16 Availability of symptom data over time, by data source. a, No data available because telephone call/visit did
not happen or no data were reported.
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41
Time to resolution of community-acquired pneumonia symptoms: overall
Severity was elicited for nine CAP symptoms, each of which was analysed separately in terms of time
to resolution. As multiple comparisons were performed, the p-value from each individual analysis needs
to be interpreted cautiously. Participants were included in the analysis only if a symptom was present
at trial entry. Cough had the longest median time to resolution (11 days), followed by the related
symptom wet cough (phlegm) (6 days). An estimated 20% of participants still had cough symptoms at
day 28 (Figure 17). Vomiting and fever both resolved rapidly, in a median of 1 day and 2 days, respectively.
The remaining symptoms had a median time to resolution of between 3 and 5 days.
Time to resolution of community-acquired pneumonia symptoms: dose randomisation
There was no significant difference between participants receiving lower and higher doses in time to
resolution of any of the nine symptoms (log-rank p>0.05).
Time to resolution of community-acquired pneumonia symptoms: duration randomisation
For duration randomisation, there was no significant difference between groups for seven symptoms
(log-rank p>0.05). However, there was a difference in time to resolution of cough (p=0.040) and sleep
disturbed by cough (p=0.026), with a significantly faster time to resolution in the longer-duration arm
in both cases (Figures 18 and 19).
0
02 6 10 14 18 22 264 8 12 16
Day of trial
Symptom
20 24 28 30
20
40
60
Percentage of participants
with symptom present at baseline
80
100
Cough
Fever
Phlegm
Wheeze
Sleep disturbance
Vomiting
Eating less
Interference with
normal activities
Breathing faster
FIGURE 17 Kaplan–Meier curves for time to symptom resolution across all randomisation arms. Participants excluded if
symptom not present at enrolment.
0
0 2 4 6 8 10 12 14 16
Day of trial
Treatment arm
18 20 22 24 26 28
p
=
0.040
20
40
60
Percentage of children (Kaplan–Meier estimate)
80
100
Shorter duration
Longer duration
FIGURE 18 Kaplan–Meier curve for time to resolution of cough in the duration treatment arms. Participants excluded if
symptom not present at enrolment.
RESULTS
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42
Sensitivity analysis for duration randomisation
As symptom resolution within the first 3 days from randomisation cannot, by definition, be related to
the treatment duration randomisation, a prespecified sensitivity analysis was performed, changing the
time origin to day 4 for the comparison of shorter and longer treatment.
Log-rank tests were repeated and the same pattern was observed as in the main analyses. Participants
in the shorter-duration arm had a significantly longer time to resolution of cough (p=0.039) and sleep
disturbed by cough (p=0.031) than participants in the longer-duration arm. There was no evidence
of a significant difference between the two duration arms in time to resolution of the remaining
seven symptoms.
Adverse events
Serious adverse events
In total, 43 (5.3%) participants experienced a SAE, one participant (0.1%) experienced a serious adverse
reaction (SAR) and no participants experienced a suspected unexpected SAR. There was no evidence
of differences between proportions of participants experiencing a SAE in any of the dose or duration
treatment arms (Table 22).
0
0 2 4 6 8 10 12 14 16
Day of trial
18 20 22 24 26 28
p
=
0.026
20
40
60
Percentage of children (Kaplan–Meier estimate)
80
100
Shorter duration
Longer duration
Treatment arm
FIGURE 19 Kaplan–Meier curve for time to resolution of sleep disturbed by cough in the duration treatment arms.
Participants excluded if symptom not present at enrolment.
TABLE 22 Summary of SAEs
SAE summary
Treatment arm, n(%)
p-value
Treatment arm, n(%)
p-value
Total (N=814),
n(%)
Lower dose
(N=410)
Higher dose
(N=404)
Shorter duration
(N=413)
Longer duration
(N=401)
Number of SAEs per participant
0 387 (94.4) 384 (95.0) 0.67 388 (93.9) 383 (95.5) 0.32 771 (94.7)
1 23 (5.6) 20 (5.0) 25 (6.1) 18 (4.5) 43 (5.3)
SAR confirmed 0 (0.0) 1 (0.2) 0.50 1 (0.2) 0 (0.0) 1.00 1 (0.1)
SUSAR
confirmed
00 0 0 0
SUSAR, suspected unexpected serious adverse reaction.
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43
Of the 43 SAEs, 42 (98%) were hospitalisations and one (2%) (exacerbation of asthma, unrelated to the
trial medication) was classified as life-threatening (Table 23), necessitating intubation and transfer of
the patient to a paediatric intensive care unit. Respiratory events were the most common diagnoses,
accounting for 35 of 43 SAEs (81%), of which 16 (37%) were classified as respiratory distress, eight
(19%) were lower respiratory tract infection and five (12%) were pneumonia; the remaining six were
asthma (n=3, 7%), bronchiolitis (n=2, 5%) and influenza (n=1, 2%). Most SAEs occurred between
days 1 and 4 (n=29, 67%).
TABLE 23 Serious adverse event details
SAE details
Treatment arm, n(%)
Total (N=43),
n(%)
Shorter duration
(N=25)
Longer duration
(N=18)
Lower dose
(N=23)
Higher dose
(N=20)
Type of SAE
Life-threatening 0 1 (6) 0 1 (5) 1 (2)
Hospitalisation 25 (100) 17 (94) 23 (100) 19 (95) 42 (98)
Body system
Dermatological 1 (4) 1 (6) 1 (4) 1 (5) 2 (5)
Cyanosis peripheral 0 1 (6) 1 (4) 0 1 (2)
Herpes simplex oral 1 (4) 0 0 1 (5) 1 (2)
Gastrointestinal 4 (16) 0 2 (9) 2 (10) 4 (9)
Coffee ground vomiting 1 (4) 0 0 1 (5) 1 (2)
Epiploic appendagitis 1 (4) 0 1 (4) 0 1 (2)
Salmonella gastroenteritis 1 (4) 0 1 (4) 0 1 (2)
Vomiting 1 (4) 0 0 1 (5) 1 (2)
Neurological 1 (4) 1 (6) 2 (9) 0 2 (5)
Cerebellar tumour 0 1 (6) 1 (4) 0 1 (2)
Febrile seizure 1 (4) 0 1 (4) 0 1 (2)
Respiratory 19 (76) 16 (89) 18 (78) 17 (85) 35 (81)
Asthma 1 (4) 2 (11) 0 3 (15) 3 (7)
Bronchiolitis 2 (8) 0 2 (9) 0 2 (5)
Influenza 1 (4) 0 1 (4) 0 1 (2)
Lower respiratory tract
infection viral
1 (4) 7 (39) 3 (13) 5 (25) 8 (19)
Pneumonia 2 (8) 3 (17) 5 (22) 0 5 (12)
Respiratory distress 12 (48) 4 (22) 7 (30) 9 (45) 16 (37)
Trial study day of hospitalisationa
Days 0–3 20 (80) 9 (50) 16 (70) 13 (65) 29 (67)
Days 4–7 0 2 (11) 1 (4) 1 (5) 2 (5)
Days 8–14 2 (8) 1 (6) 1 (4) 2 (10) 3 (7)
Days 15–21 0 2 (11) 0 2 (10) 2 (5)
Days 22–28 3 (12) 4 (22) 5 (22) 2 (10) 7 (16)
RESULTS
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44
The SAR was a diagnosis of vomiting, originally classified by the site investigator as unlikely to be
related to the IMP. However, on clinical review by the Trial Management Team, it was felt that the SAE
could be related to the IMP and the event was, therefore, reclassified as a SAR.
Specified clinical adverse events (diarrhoea, thrush and skin rash)
Presence and severity of diarrhoea, thrush and skin rash were elicited from parents at trial entry and
throughout follow-up. Diarrhoea was the most common clinical AE and was present in 345 (43.6%)
participants after baseline. Skin rash was present in 193 (24.4%) participants and oral thrush in 57
(7.2%) participants after baseline. For both dose and duration randomisations, there was no evidence
of a difference between the randomised arms in terms of overall prevalence of diarrhoea and oral
thrush after baseline (Table 24). For skin rash, there was some evidence of a difference between shorter-
and longer-duration arms in terms of prevalence after baseline, with the number of participants ever
having skin rash after baseline being 106 (27.4%) in the longer-duration arm and 87 (21.5%) in the
shorter-duration arm (p=0.055).
TABLE 23 Serious adverse event details (continued )
SAE details
Treatment arm, n(%)
Total (N=43),
n(%)
Shorter duration
(N=25)
Longer duration
(N=18)
Lower dose
(N=23)
Higher dose
(N=20)
Event grade
1 11 (44) 4 (22) 9 (39) 6 (30) 15 (35)
2 6 (24) 9 (50) 7 (30) 8 (40) 15 (35)
3 8 (32) 3 (17) 6 (26) 5 (25) 11 (26)
4 0 2 (11) 1 (4) 1 (5) 2 (5)
Relationship to trial medication
Not related 20 (80) 16 (89) 19 (83) 17 (85) 36 (84)
Unlikely 5 (20) 2 (11) 4 (17) 3 (15) 7 (16)
Possibly 0 0 0 0 0
Probably 0 0 0 0 0
Definitely 0 0 0 0 0
Expected of trial medication
Expected 7 (29) 0 5 (22) 2 (11) 7 (17)
Unexpected 17 (71) 18 (100) 18 (78) 17 (89) 35 (83)
Action on trial medication
None 16 (64) 8 (44) 10 (43) 14 (70) 24 (56)
Treatment delayed 1 (4) 0 1 (4) 0 1 (2)
Treatment stopped 8 (32) 10 (56) 12 (52) 6 (30) 18 (42)
Started new antibiotic during
SAE?
12 (48) 15 (83) 16 (70) 11 (55) 27 (63)
Event status at the end of follow-up
Resolved 24 (96) 17 (94) 21 (91) 20 (100) 41 (95)
Ongoing at study exit 1 (4) 1 (6) 2 (9) 0 2 (5)
a This includes the life-threatening SAE.
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TABLE 24 Prevalence of diarrhoea, oral thrush and skin rash after baseline
Prevalence of diarrhoea,
oral thrush and skin rash
Treatment arm, n(%) Total
(N=814),
n(%)
Lower dose
(N=410)
Higher dose
(N=404)
Shorter duration
(N=413)
Longer duration
(N=401)
First diarrhoea after baselinea
No 276 (78.0) 252 (76.4) 259 (75.1) 269 (79.4) 528 (77.2)
Yes 78 (22.0) 78 (23.6) 86 (24.9) 70 (20.6) 156 (22.8)
p-value p=0.62 p=0.18
New diarrhoea after baseline or worse than at baseline
No 303 (75.6) 288 (73.8) 296 (73.3) 295 (76.2) 591 (74.7)
Yes 98 (24.4) 102 (26.2) 108 (26.7) 92 (23.8) 200 (25.3)
p-value p=0.58 p=0.34
Ever diarrhoea after baseline
No 234 (58.2) 213 (54.6) 217 (53.7) 230 (59.3) 447 (56.4)
Yes 168 (41.8) 177 (45.4) 187 (46.3) 158 (40.7) 345 (43.6)
p-value p=0.31 p=0.11
First thrush after baselineb
No 386 (96.3) 381 (96.0) 390 (96.8) 377 (95.4) 767 (96.1)
Yes 15 (3.7) 16 (4.0) 13 (3.2) 18 (4.6) 31 (3.9)
p-value p=0.83 p=0.33
New thrush after baseline or worse than at baseline
No 385 (96.0) 374 (95.9) 390 (96.5) 369 (95.3) 759 (96.0)
Yes 16 (4.0) 16 (4.1) 14 (3.5) 18 (4.7) 32 (4.0)
p-value p=0.94 p=0.40
Ever thrush after baseline
No 374 (93.3) 360 (92.3) 379 (93.8) 355 (91.7) 734 (92.8)
Yes 27 (6.7) 30 (7.7) 25 (6.2) 32 (8.3) 57 (7.2)
p-value p=0.60 p=0.26
First rash after baselinec
No 310 (86.6) 317 (86.8) 329 (88.4) 298 (84.9) 627 (86.7)
Yes 48 (13.4) 48 (13.2) 43 (11.6) 53 (15.1) 96 (13.3)
p-value p=0.92 p=0.16
New rash after baseline or worse than at baseline
No 348 (86.8) 331 (84.9) 354 (87.6) 325 (84.0) 679 (85.8)
Yes 53 (13.2) 59 (15.1) 50 (12.4) 62 (16.0) 112 (14.2)
p-value p=0.44 p=0.14
Ever rash after baseline
No 307 (76.6) 291 (74.6) 317 (78.5) 281 (72.6) 598 (75.6)
Yes 94 (23.4) 99 (25.4) 87 (21.5) 106 (27.4) 193 (24.4)
p-value p=0.52 p=0.055
a Excludes all participants with diarrhoea at trial entry.
b Excludes all participants with thrush at trial entry.
c Excludes all participants with rash at trial entry.
RESULTS
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46
In addition, when considering skin rash severity during the treatment period only, there was evidence
of a difference between the shorter- and longer-duration arms. Participants in the longer-duration arm
experienced greater skin rash severity than participants in the shorter-duration arm at days 3 (p=0.019)
and 7 (p=0.005) (Figure 20). There was no evidence of a difference between dose randomisation arms
in terms of skin rash severity during the treatment period, and there was no evidence of a difference
between the dose and duration randomisation arms in severity of diarrhoea or oral thrush during the
treatment period (see Table 24).
Health-care services
Utilisation of health-care services was unrelated to randomisation arm. Hospital admissions and visits to
the ED without admission were reported in 46 (5.7%) and 43 (5.3%) participants, respectively, whereas a
larger proportion of participants reported using any health-care service (n=304, 37.3%) (Table 25).
0
Percentage of participants
15
10
5
Severe/very bad
Bad
Moderate
Slight/little
Shorter
duration
Longer
duration
Shorter
duration
Longer
duration
Shorter
duration
Longer
duration
Trial entry Day 3
Treatment period
Day 7
Skin rash severity
6
3
1
01
3
9
01
1
2
03
0
1
7
1
3
00
1
1
7
FIGURE 20 Skin rash severity during treatment period: duration randomisation.
TABLE 25 Health-care service utilisation
Health-care
service
utilisation
Treatment arm, n(%)
p-value
Treatment arm, n(%)
p-value
Total (N=814),
n(%)
Lower dose
(N=410)
Higher dose
(N=404)
Shorter duration
(N=413)
Longer duration
(N=401)
Ever admitted to hospital?
Yes 24 (5.9) 22 (5.4) 0.80 27 (6.5) 19 (4.7) 0.27 46 (5.7)
No 386 (94.1) 382 (94.6) 386 (93.5) 382 (95.3) 768 (94.3)
Visited ED (without admission)?
Yes 21 (5.1) 22 (5.4) 0.84 18 (4.4) 25 (6.2) 0.23 43 (5.3)
No 389 (94.9) 382 (94.6) 395 (95.6) 376 (93.8) 771 (94.7)
Ever used any other health-care service?
Yes 149 (36.3) 155 (38.4) 0.55 152 (36.8) 152 (37.9) 0.75 304 (37.3)
No 261 (63.7) 249 (61.6) 261 (63.2) 249 (62.1) 510 (62.7)
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Daily activities and child care
Data on daily activities and child care were available from parent/guardian-completed diaries for
441 participants (Table 26). No differences in reported disruption to daily activities and child care were
found between randomisation arms. In total, 73.9% of participants reported that the child had missed
school, day care or nursery, and the median number of days missed was 4 (IQR 0–6) days. In addition,
63.8% of parents reported missing work, with a median of 3 (IQR 0–5) days missed, and 34.9% of
parents reported requiring additional care for the child.
TABLE 26 Daily activities and child care
Daily activity/child care
Treatment arm
p-value
Treatment arm
p-value
Total
(N=441)
Lower dose
(N=298)
Higher dose
(N=289)
Shorter
duration
(N=291)
Longer
duration
(N=296)
Child missed school, day care or nursery: ever, n(%)
Yes 152 (71.0) 174 (76.7) 0.18 159 (72.3) 167 (75.6) 0.43 326 (73.9)
No 62 (29.0) 53 (23.3) 61 (27.7) 54 (24.4) 115 (26.1)
Days child missed school, day
care or nursery, median (IQR)
4(0–5) 4 (2–6) 0.14 4 (0–6) 4 (2–6) 0.62 4 (0–6)
Parent missed work: ever, n(%)
Yes 128 (64.0) 136 (63.6) 0.92 127 (62.9) 137 (64.6) 0.71 264 (63.8)
No 72 (36.0) 78 (36.4) 75 (37.1) 75 (35.4) 150 (36.2)
Days parent missed work,
median (IQR)
3(0–4) 3 (0–5) 0.43 3 (0–4) 3 (0–5) 0.20 3 (0–5)
Parent missed other activities: ever, n(%)
Yes 50 (33.6) 56 (33.7) 0.97 53 (34.2) 53 (33.1) 0.84 106 (33.7)
No 99 (66.4) 110 (66.3) 102 (65.8) 107 (66.9) 209 (66.3)
Days parent missed other
activities: cumulative, median
(IQR)
0(0–4) 0 (0–4) 0.88 0 (0–5) 0 (0–4) 0.50 0 (0–4)
Additional care needed for child: ever, n(%)
Yes 73 (36.3) 72 (33.5) 0.54 73 (34.9) 72 (34.8) 0.98 145 (34.9)
No 128 (63.7) 143 (66.5) 136 (65.1) 135 (65.2) 271 (65.1)
Days additional care needed
for child: cumulative, median
(IQR)
0(0–3) 0 (0–3) 0.54 0 (0–3) 0 (0–3) 0.83 0 (0–3)
Note
Data are as reported in the symptom diary.
RESULTS
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Chapter 4 Discussion
We investigated the impact of dose and duration of amoxicillin treatment for uncomplicated CAP
in children discharged from hospital after assessment in a PED, or after a short stay on an
assessment unit or inpatient ward. Regarding duration, we focused on oral amoxicillin treatment after
discharge rather than total treatment duration, given that discharge home is a key time point for
clinical decision-making, as close monitoring of the child will no longer be possible. In this population,
we found a 3-day treatment course of amoxicillin to be non-inferior to a 7-day course, and a lower
total daily dose to be non-inferior to a higher dose, in terms of antibiotic retreatment for respiratory
tract infection within 28 days.
Limitations
In contrast to the majority of trials addressing optimal antibiotic treatment duration and dose of a
single drug for childhood pneumonia, CAP-IT was conducted in a high-income setting where the
expected mortality, even from moderate to severe CAP, is low. We selected antibiotic retreatment
for respiratory tract infection during a follow-up period of 28 days as a clinically relevant and
ascertainable event with limited risk of bias in a placebo-controlled trial.84
To further guard against bias, an independent ERC, comprising experienced clinicians, adjudicated all
antibiotic retreatments during the trial period, regarding the reason (i.e. respiratory tract infection or
other) and clinical indication. Of note, the primary end point could be ascertained in 97% of CAP-IT
participants either at final follow-up or through contact with the GP. Therefore, we consider the impact
of loss to follow-up negligible.
We aimed to exclude children in whom antibiotics would not be expected to have any beneficial effect,
primarily those likely to have obstructive airway disease only. However, a mixed picture was common
for hospitalised children, with 16% of children receiving either salbutamol or steroids during their hospital
stay. Mostly, this affected children with pre-existing hyper-reactive airway disease, and treatment was
discontinued in a majority of cases by the time children were discharged home. Compared with the 48%
bronchodilator use observed in the most recent UK paediatric pneumonia audit85 the use of salbutamol or
steroids was low in CAP-IT, indicating that there was a strong clinical suspicion of CAP likely to benefit
from antibiotics in enrolled children.
We observed no relevant impact of either amoxicillin duration or dose on pneumococcal penicillin
non-susceptibility at 28 days, but did not assess pneumococcal resistance at other time points. We did
not obtain end-of-treatment samples on all children for resistance analysis for several reasons. First, an
additional face-to-face visit would have been a major barrier to participation for many families. Second,
penicillin colonisation rates at, or shortly after, the end of antibiotic treatment are expected to be very
low, whereas significant recolonisation or regrowth was expected (and observed) by 28 days. Finally,
we considered penicillin-resistant pneumococcal colonisation at final follow-up to be the most relevant
population- and individual-level resistance marker, as children colonised at this time point could
transmit resistant pneumococci to others and would be at higher risk of potentially more difficult to
treat respiratory tract infections in the future.86
Generalisability
Children were enrolled in the trial based on clinically diagnosed pneumonia requiring antibiotic
treatment with amoxicillin, and are typical of children treated for pneumonia with amoxicillin in PEDs.
We included children discharged from hospital within 48 hours of admission for observation or initial
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clinical management, as hospital stays for acute respiratory tract infections, including pneumonia,
are mostly of very short duration.87,88 Data from the pilot phase confirmed that these children could
be considered part of the same spectrum of disease as those discharged directly home from the ED.
Only 13% of screened children were not approached because of physician preference for an antibiotic
other than amoxicillin at discharge. This is in keeping with guidance suggesting that amoxicillin is used
as the first-line antibiotic for oral treatment of uncomplicated childhood pneumonia in the community.
We excluded children with complicated pneumonia requiring prolonged hospitalisation, and those receiving
non-beta-lactam treatment. Our findings, therefore, cannot be directly generalised to more severely
ill children or those treated for atypical pneumonia. However, it is highly likely that our observations
are relevant to children with mild to moderate pneumonia seen in primary care, who would be treated
with oral amoxicillin at home. In primary care, the acuity of disease is generally lower and a lower rate
of pneumonia likely to benefit from antibiotic treatment is expected.
No nasopharyngeal penicillin-resistant pneumococcal isolates were observed in the trial, either at baseline
or at final follow-up, which is consistent with reported low penicillin resistance levels in northern
Europe.89 Therefore, our findings for the effectiveness of lower compared with higher amoxicillin dose,
and impact on resistance, may be of limited generalisability to children with pneumonia in other high-
income settings with higher pneumococcal penicillin resistance prevalence.
Twice-daily dosing of amoxicillin in line with WHO and other international recommendations was used
in CAP-IT, rather than administration in three daily doses, as recommended by the BNFc. This was
selected as it is known to maximise adherence, which would be particularly important in children
allocated to the lower-dose and shorter-duration arms. In addition, patient representatives involved
in the design phase indicated this approach to be particularly family friendly, as an additional mid-day
dose is difficult to give to children who attend day care. Consequently, our findings, especially
for antimicrobial resistance outcomes, may not be generalisable to children being treated with a
thrice-daily amoxicillin regimen. However, participants in CAP-IT had rates of antibiotic retreatment
and secondary or rehospitalisation similar to those described in observational studies conducted in
settings with standard administration of amoxicillin in three doses.41,87,90,91
Interpretation
To the best of our knowledge, few head-to-head comparisons of the same antibiotic in different
dosing or duration regimens have been conducted in children being treated for pneumonia. Most of
the existing literature reports on trials conducted in low- and middle-income settings prior to the
widespread availability of PCVs and in an era with lower pneumococcal penicillin resistance.92,93 Two
recent relevant trials94,95conducted in Malawi investigated 3-day compared with 5-day amoxicillin
treatment and 3-day amoxicillin treatment compared with placebo in young children with non-severe
pneumonia and not infected with human immunodeficiency virus. In summary, 3-day treatment at a
dose corresponding to the higher total daily dose in CAP-IT was found to be non-inferior to 5-day
treatment for early treatment failure, but this was not the case for placebo compared with 3-day
treatment. The same trial identified the number needed to treat for children with non-severe fast-
breathing pneumonia to be 33. These trials used high-sensitivity, but low-specificity eligibility criteria
appropriate for a high-mortality setting. Evidence specific to high-income settings is lacking and has
led some guideline-setting bodies to question the generalisability of findings from large trials in low-
or middle-income countries to high-income settings. The persisting evidence gap for children identified
as having pneumonia applying higher specificity clinical criteria in high-income settings has now been
addressed by CAP-IT.
A relatively high retreatment rate of 12.5% was observed in the CAP-IT cohort. This is consistent with
similarly high retreatment rates in primary care reported in large observational studies, but has not
DISCUSSION
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50
previously been described for children with CAP seen in EDs or discharged from hospital after a short
stay. Similarly, the secondary or rehospitalisation rate of around 5% was similar to that described for
children with pneumonia in observational studies.
We observed remarkably similar retreatment rates for respiratory tract infections between the 3- and
7-day treatment durations, despite 2-day slower resolution of mild cough, on average, in the shorter-
duration arm. We did not identify any differences between the lower- and higher-dose treatment arms.
Antibiotic retreatment for respiratory tract infection during the follow-up period could be related to
true failure of the initial treatment or could be linked to persistent symptoms unlikely to be responsive
to amoxicillin because they were mainly triggered by a viral (co-)infection or new respiratory tract
infection episodes.
Children and parents in the 3-day randomisation arm were not reported to have spent a longer time
away from day care or school and work, making it unlikely that cough had a major impact on children’s
usual routines. Slightly longer time to symptom resolution in placebo arms or placebo-controlled
shorter-duration arms has been reported for acute otitis media.96 However, it is unclear how children
being mildly symptomatic for longer is weighed against the benefits of shorter treatment by children
and their families. When symptoms are minor, shorter treatment is likely to be a key factor in allowing
children to return to usual activities and will maximise adherence.97,98
Antimicrobial resistance was a key secondary outcome in CAP-IT. Colonisation by penicillin-non-
susceptible pneumococci at 28 days was similar for both randomisation arms. In general, the observed
prevalence of pneumococcal penicillin non-susceptibility and the complete absence of penicillin-
resistant pneumococci was in line with the UK being a low-resistance setting. Pneumococcal penicillin
resistance alone is unlikely to reflect the full impact of amoxicillin dose and duration on the child
nasopharyngeal microflora, including the presence of resistance genotypes. Next-generation
sequencing approaches could provide in-depth information about differential changes in the
microbiome and resistome with higher or lower amoxicillin dose and shorter or longer treatment
duration. However, the interpretation of such analyses is likely to be complex, and will need to take
account of the interactions between different pneumococcal subpopulations, as well as between
pneumococci and other bacteria in a densely populated niche. An analysis of nasopharyngeal samples
obtained in CAP-IT using next-generation sequencing approaches is ongoing.
Several other trials have generated results that complement CAP-IT findings, or are expected to in the
near future. In the UK, this includes the primary care-based ARTIC PC (Antibiotics for lower Respiratory
Tract Infection in Children presenting in Primary Care) study,99 a randomised placebo-controlled trial
investigating the benefit of a 7-day course of oral amoxicillin in children with possible lower respiratory
tract infection (but not considered to have pneumonia clinically). The SAFER (Short-Course Antimicrobial
Therapy for Pediatric Community-Acquired Pneumonia) trial100 in Canada and SCOUT-CAP (Short
Course Outpatient Therapy of Community Acquired Pneumonia) study in the USA both target children
presenting to EDs but not admitted to hospital, the former comparing 5- and 10-day treatment courses
with amoxicillin and the latter a selection of beta-lactams. The SCOUT-CAP study is expected to report
on results at the end of 2021. Finally, a Canadian open-label RCT (NCT03031210) is investigating twice-
compared with thrice-daily amoxicillin dosing in children treated for pneumonia. The total daily dose in
this trial corresponds to the higher total daily dose investigated in CAP-IT.
Implications
For clinical practice, CAP-IT supports routine use of shorter, 3-day, oral amoxicillin courses at current
doses for children presenting to hospital with uncomplicated clinically diagnosed CAP for community-
based treatment after discharge from acute care. A slightly longer time to resolution of mild cough can
be expected in children treated for 3 days, compared with children treated for 7 days.
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For research, existing systematic reviews and meta-analyses should be updated to include CAP-IT and
other high-income setting trials. A series of relevant trials includes studies already completed or about
to complete. Their inclusion, for example in existing Cochrane reviews, would ensure that key reference
systematic reviews are relevant globally.
The question of the comparison between two and three times daily dosing of amoxicillin needs to be
addressed. However, this may best be tackled by modelling and simulation based on high-quality
pharmacokinetic data analysed using modern pharmacometric approaches. Such data are needed from
a variety of settings, including low/high prevalence of pneumococcal penicillin resistance, varying
pneumococcal vaccine coverage and low-, middle- and high-income settings characterised by varying
prevalence of important covariates, such as malnutrition and obesity. Data from adults suggest that gut
amoxicillin absorption may be saturable, limiting the expected utility of high-dose regimens.101
A proportion of children screened for CAP-IT were identified to be ineligible because the managing
clinician was planning treatment with an antibiotic other than amoxicillin. Trial data supporting the
use of macrolides (targeting atypical pathogens) or alternative beta-lactams, such as amoxicillin/
clavulanate (co-amoxiclav, targeting Gram-negative respiratory pathogens producing beta-lactamases),
are lacking.
DISCUSSION
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Chapter 5 Conclusions
lFor children presenting to acute care settings with uncomplicated, clinically diagnosed, moderate or
moderate to severe CAP who can be managed at home, there is no evidence to suggest that a longer
7-day treatment course of oral amoxicillin offers any advantage over a shorter 3-day course, in terms
of antibiotic retreatment for respiratory tract infection within 4 weeks. Therefore, the trial supports
routine use of 3-day oral amoxicillin courses after discharge from hospital in this population.
lSlightly longer time to resolution of mild cough was observed in children treated for 3 days than in
those treated for 7 days. Given the advantages of a shorter duration of treatment for adherence
and the observed declining adherence during treatment days 4–7 in the trial, a 3-day course of oral
amoxicillin nonetheless appears preferable. This would have the added benefit of greater harmonisation
of antibiotic treatment duration guidance between low-/middle-income and high-income settings.
lSimilarly, we found that lower total daily doses of oral amoxicillin were non-inferior to higher daily
doses, in terms of antibiotic retreatment for respiratory tract infection within 4 weeks. Dosing
regimens were also similar in terms of impact on pneumococcal antimicrobial resistance and safety.
lOf note, a weight-banded approach was used for dose selection, resulting in less variability in total
daily dose compared with an age-banded approach (as is used in the UK in clinical practice). Based
on the age-banded approach, both doses studied in CAP-IT are expected to be prescribed in the UK
because of variations in weight within broad age bands.
lEither (lower and higher) total daily dose is feasible to deliver in high-income settings where
amoxicillin suspensions of different concentrations are available and are prescribed in preference
to solid child-appropriate formulations (i.e. solid forms that are liquid on ingestion or become liquid
on administration). As a result, moving between lower and higher total daily doses does not result in
greater volumes per dose for treated children.
lHowever, the situation is different in low- and middle-income settings, where the preferred
formulation is dispersible tablets. The lowest-concentration child-appropriate solid formulation
supported by the United Nations International Children's Emergency Fund (UNICEF) and WHO
contains 250 mg of amoxicillin in a non-divisible dispersible tablet. Administration of this tablet twice
a day to young infants (weighing 4–10 kg) gives a wide dose range of 50 (10 kg) to 125 (4 kg) mg/kg
per day, with many children expected to receive doses in the higher dose range of CAP-IT. CAP-IT
results did not identify any clinically relevant disadvantages to using higher doses; therefore,
supporting the continued use of existing dispersible tablets.
lWe did not formally compare twice- with thrice-daily dosing. However, we note that children in
CAP-IT had good clinical outcomes, with antibiotic retreatment rates and secondary or re-admission
rates similar to those described for children with acute lower respiratory tract infections in observational
studies in the UK where amoxicillin treatment would generally be given three times daily.
DOI: 10.3310/hta25600 Health Technology Assessment 2021 Vol. 25 No. 60
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Care. This is an Open Access publication distributed under the terms of the Creative Commons Attribution CC BY 4.0 licence, which permits unrestricted use, distribution,
reproduction and adaption in any medium and for any purpose provided that it is properly attributed. See: https://creativecommons.org/licenses/by/4.0/. For attribution the
title, original author(s), the publication source –NIHR Journals Library, and the DOI of the publication must be cited.
53
Acknowledgements
We would like to thank all of the patients, their families and the staff from the participating
centres for their vital contributions to CAP-IT.
Trial Steering Committee
Elizabeth Molyneux (chairperson), Chris Butler, Alan Smyth and Catherine Pritchard (PPI).
Independent Data Monitoring Committee
Tim Peto (chairperson), Simon Cousens and Stuart Logan.
Independent End-Point Review Committee
Alasdair Bamford (chairperson), Anna Turkova, Anna Goodman and Felicity Fitzgerald.
Trial Management Group
Mike Sharland (chairperson), Julia Bielicki, Mark Lyttle, Colin Powell, Paul Little, Saul Faust, Adam Finn,
Julie Robotham, Mandy Wan, David Dunn, Wolfgang Stöhr, Lynda Harper, Sam Barratt, Nigel Klein,
Louise Rogers, Elia Vitale and Diana Gibb.
Investigator sites
Alder Hey Children’s Hospital NHS Foundation Trust, Liverpool: Dan Hawcutt (principal investigator),
Matt Rotheram, Liz D Lee and Rachel Greenwood-Bibby.
Birmingham Children’s Hospital: Stuart Hartshorn (principal investigator), Deepthi Jyothish, Louise Rogers
and Juliet Hopkins.
Bristol Royal Hospital for Children: Mark Lyttle (principal investigator), Stefania Vergnano, Lucie Aplin,
Pauline Jackson, Gurnie Kaur, Beth Pittaway, Michelle Ross, Sarah Sheedy, Alice Smith and Yesenia Tanner.
Chelsea and Westminster Hospital NHS Foundation Trust, London: James Ross (principal investigator),
Poonam Patel, Nabila Burney, Hannah Fletcher, Jaime Carungcong and Kribashnie Nundlall.
City Hospitals Sunderland NHS Foundation Trust: Niall Mullen (principal investigator), Rhona McCrone
and Paul P Corrigan.
Countess of Chester Hospital: Susie Holt (principal investigator), John Gibbs, Caroline Burchett,
Caroline Lonsdale and Sarah De-Beger.
Darlington Memorial Hospital: Godfrey Nyamugunuduru (principal investigator), John Furness
(former principal investigator) and Dawn Eggington.
Derbyshire Children’s Hospital, Derby: Gisela Robinson (principal investigator), Lizzie Starkey and
Mel Hayman.
DOI: 10.3310/hta25600 Health Technology Assessment 2021 Vol. 25 No. 60
Copyright © 2021 Barratt et al. This work was produced by Barratt et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social
Care. This is an Open Access publication distributed under the terms of the Creative Commons Attribution CC BY 4.0 licence, which permits unrestricted use, distribution,
reproduction and adaption in any medium and for any purpose provided that it is properly attributed. See: https://creativecommons.org/licenses/by/4.0/. For attribution the
title, original author(s), the publication source –NIHR Journals Library, and the DOI of the publication must be cited.
55
Evelina London Children’s Hospital: Anastasia Alcock (principal investigator), Dani Hall
(former principal investigator), Ronny Cheung, Alyce B Sheedy and Mohammad Ahmad.
James Cook University Hospital, Middlesbrough: Arshid Murad (principal investigator), Katherine Jarman
and Joanna Green.
John Radcliffe Hospital, Oxford: Tanya Baron (principal investigator), Chris Bird (former principal
investigator I), Shelley Segal and Sally Beer.
King’s College Hospital, London: Fleur Cantle (principal investigator), Hannah Eastman,
Raine Astin-Chamberlain, Paul Riozzi and Hannah Cotton.
Leeds Children’s Hospital: Sean O’Riordan (principal investigator), Alice Downes, Marjorie Allen and
Louise Conner.
Leicester Royal Infirmary: Damian Roland (principal investigator), Srini Bandi and Rekha Patel.
Nottingham University Hospitals NHS Trust: Chris Gough (principal investigator), Megan McAulay and
Louise Conner.
Southport and Ormskirk Hospital NHS Trust: Sharryn Gardner (principal investigator), Zena Haslam
and Moira Morrison.
Our Lady’sChildren’s Hospital, Crumlin: Michael Barrett (principal investigator) and Madeleine Niermeyer.
Royal Alexandra Children’s Hospital, Brighton: Emily Walton (principal investigator), Akshat Kapur and
Vivien Richmond.
Royal Hospital for Children, Glasgow: Steven Foster (principal investigator), Ruth Bland, Ashleigh Neil,
Barry Milligan and Helen Bannister.
Royal London Hospital: Ben Bloom (principal investigator), Ami Parikh, Olivia Boulton and Imogen Skene.
Royal Manchester Children’s Hospital: Katherine Potier (principal investigator), Fiona Poole and
Jill L Wilson.
Sheffield Children’s NHS Foundation Trust: Judith Gilchrist (principal investigator), Noreen West,
Jayne Evans and Julie Morecombe.
St George’s Hospital, London: Paul Heath (principal investigator), Yasser Iqbal, Malte Kohns,
Elena Stefanova and Elia Vitale.
St Mary’s Hospital, London: Ian Maconochie (principal investigator), Suzanne Laing and Rikke Jorgensen.
University Hospital Lewisham: Maggie Nyirenda (principal investigator), Anastasia Alcock, Samia Pilgrim
and Emma Gardiner.
University Hospital of Wales, Cardiff: Jeff Morgan (principal investigator), Colin VE Powell
(former principal investigator), Jennifer Muller and Gail Marshall.
Southampton Children’s Hospital: Katrina Cathie (principal investigator), Jane Bayreuther, Ruth Ensom
and Emily Cornish.
ACKNOWLEDGEMENTS
NIHR Journals Library www.journalslibrary.nihr.ac.uk
56
Contributions of authors
Sam Barratt (https://orcid.org/0000-0003-3265-9486) (Clinical Trials Manager) contributed to
compiling data and drafting the report.
Julia A Bielicki (https://orcid.org/0000-0002-3902-5489) (Consultant in Paediatric Infectious
Diseases) drafted the report.
David Dunn (https://orcid.org/0000-0003-1836-4446) (Professor of Medical Statistics) performed
statistical analyses.
Saul N Faust (https://orcid.org/0000-0003-3410-7642) (Professor of Paediatric Immunology and
Infectious Diseases) contributed to drafting the report.
Adam Finn (https://orcid.org/0000-0003-1756-5668) (Professor of Paediatrics) performed
resistance analyses.
Lynda Harper (https://orcid.org/0000-0003-3430-0127) (Clinical Project Manager) contributed to
drafting the report.
Pauline Jackson (https://orcid.org/0000-0001-6461-953X) (Paediatric Nurse) contributed to drafting
the report.
Mark D Lyttle (https://orcid.org/0000-0002-8634-7210) (Consultant in Paediatric Emergency Medicine)
contributed to drafting the report.
Colin VE Powell (https://orcid.org/0000-0001-8181-875X) (Consultant in Paediatric Emergency
Medicine) contributed to drafting the report.
Louise Rogers (https://orcid.org/0000-0002-5037-847X) (Clinical Research Sister) contributed to
drafting the report.
Damian Roland (https://orcid.org/0000-0001-9334-5144) (Consultant in Paediatric Emergency
Medicine) contributed to drafting the report.
Wolfgang Stöhr (https://orcid.org/0000-0002-6533-2888) (Senior Medical Statistician) performed
statistical analyses.
Kate Sturgeon (https://orcid.org/0000-0003-2209-141X) (Senior Research Nurse) contributed to
drafting the report.
Elia Vitale (https://orcid.org/0000-0001-5750-8436) (Senior Paediatric Clinical Research Nurse)
contributed to drafting the report.
Mandy Wan (https://orcid.org/0000-0001-8802-0425) (Paediatric Clinical Trials Pharmacist)
contributed to drafting the report.
Diana M Gibb (https://orcid.org/0000-0002-9738-5490) (Professor, Epidemiology) drafted the report.
Mike Sharland (https://orcid.org/0000-0001-8626-8291) (Professor of Paediatric Infectious Diseases)
drafted the report.
DOI: 10.3310/hta25600 Health Technology Assessment 2021 Vol. 25 No. 60
Copyright © 2021 Barratt et al. This work was produced by Barratt et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social
Care. This is an Open Access publication distributed under the terms of the Creative Commons Attribution CC BY 4.0 licence, which permits unrestricted use, distribution,
reproduction and adaption in any medium and for any purpose provided that it is properly attributed. See: https://creativecommons.org/licenses/by/4.0/. For attribution the
title, original author(s), the publication source –NIHR Journals Library, and the DOI of the publication must be cited.
57
Data-sharing statement
All data requests should be submitted to the corresponding author for consideration. Access to
anonymised data may be granted following review.
Patient data
This work uses data provided by patients and collected by the NHS as part of their care and support.
Using patient data is vital to improve health and care for everyone. There is huge potential to make
better use of information from people’s patient records, to understand more about disease, develop
new treatments, monitor safety, and plan NHS services. Patient data should be kept safe and secure, to
protect everyone’s privacy, and it’s important that there are safeguards to make sure that it is stored
and used responsibly. Everyone should be able to find out about how patient data are used. #datasaveslives
You can find out more about the background to this citation here: https://understandingpatientdata.org.uk/
data-citation.
ACKNOWLEDGEMENTS
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58
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Care. This is an Open Access publication distributed under the terms of the Creative Commons Attribution CC BY 4.0 licence, which permits unrestricted use, distribution,
reproduction and adaption in any medium and for any purpose provided that it is properly attributed. See: https://creativecommons.org/licenses/by/4.0/. For attribution the
title, original author(s), the publication source –NIHR Journals Library, and the DOI of the publication must be cited.
65
Appendix 1 Details of main protocol
amendment: joint analysis of paediatric
emergency department and ward groups
Initially, PED and ward groups were treated as separate strata because of (1) an expected higher
severity of CAP in the ward group, (2) the expected differences in prior receipt of antibiotic for
current episode having an impact on the duration of treatment analysis and (3) the need for different
trial procedures (i.e. consent process, enrolment and additional data capture during the inpatient
period for the ward group). However, based on the pilot phase, the following key aspects emerged and
formed the basis for the joint analysis of PED and ward groups. First, in a substantial proportion of
participating hospitals, children were first seen in a paediatric assessment unit before either being
formally admitted or discharged. This made the distinction between PED and ward less relevant,
especially as many paediatric assessment units admitted children for up to 48 hours. Second, although
clinical signs and symptoms at presentation to ED were (as expected) worse, on average, in ward
children than in PED children, considerable overlap in the two distributions was observed. Third, the
duration of prior antibiotic exposure in the ward group was much shorter than anticipated (<12 hours,
54%; <24 hours, 75%). Finally, there was no evidence of a difference between the primary end-point
rate between PED and ward groups.
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title, original author(s), the publication source –NIHR Journals Library, and the DOI of the publication must be cited.
67
Appendix 2 Community-acquired
pneumonia symptoms at trial entry by strata
TABLE 27 Community-acquired pneumonia symptoms at trial entry by stratum
Stratum
Strata, n(%)
p-value Total (N=814), n(%)PED (N=591) Ward (N=223)
Fever
Not present 54 (9.2) 111 (49.8) <0.001 165 (20.3)
Slight/little 71 (12.0) 31 (13.9) 102 (12.5)
Moderate 175 (29.7) 42 (18.8) 217 (26.7)
Bad 215 (36.4) 26 (11.7) 241 (29.6)
Severe/very bad 75 (12.7) 13 (5.8) 88 (10.8)
Cough
Not present 14 (2.4) 14 (6.3) <0.001 28 (3.4)
Slight/little 61 (10.3) 45 (20.2) 106 (13.0)
Moderate 246 (41.7) 96 (43.0) 342 (42.1)
Bad 208 (35.3) 59 (26.5) 267 (32.8)
Severe/very bad 61 (10.3) 9 (4.0) 70 (8.6)
Wet cough (phlegm)
Not present 174 (29.5) 72 (32.3) 0.58 246 (30.3)
Slight/little 125 (21.2) 44 (19.7) 169 (20.8)
Moderate 159 (26.9) 65 (29.1) 224 (27.6)
Bad 103 (17.5) 36 (16.1) 139 (17.1)
Severe/very bad 29 (4.9) 6 (2.7) 35 (4.3)
Breathing faster (shortness of breath)
Not present 77 (13.1) 57 (25.6) <0.001 134 (16.5)
Slight/little 151 (25.6) 70 (31.4) 221 (27.2)
Moderate 182 (30.8) 52 (23.3) 234 (28.8)
Bad 140 (23.7) 36 (16.1) 176 (21.6)
Severe/very bad 40 (6.8) 8 (3.6) 48 (5.9)
Wheeze
Not present 283 (48.0) 109 (48.9) 0.95 392 (48.2)
Slight/little 129 (21.9) 52 (23.3) 181 (22.3)
Moderate 112 (19.0) 37 (16.6) 149 (18.3)
Bad 56 (9.5) 21 (9.4) 77 (9.5)
Severe/very bad 10 (1.7) 4 (1.8) 14 (1.7)
continued
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69
TABLE 27 Community-acquired pneumonia symptoms at trial entry by stratum (continued )
Stratum
Strata, n(%)
p-value Total (N=814), n(%)PED (N=591) Ward (N=223)
Sleep disturbed by cough
Not present 67 (11.4) 56 (25.1) <0.001 123 (15.2)
Slight/little 95 (16.2) 55 (24.7) 150 (18.5)
Moderate 151 (25.7) 55 (24.7) 206 (25.4)
Bad 170 (28.9) 42 (18.8) 212 (26.1)
Severe/very bad 105 (17.9) 15 (6.7) 120 (14.8)
Vomiting (including after cough)
Not present 324 (54.9) 155 (69.5) 0.003 479 (58.9)
Slight/little 110 (18.6) 32 (14.3) 142 (17.5)
Moderate 83 (14.1) 18 (8.1) 101 (12.4)
Bad 49 (8.3) 15 (6.7) 64 (7.9)
Severe/very bad 24 (4.1) 3 (1.3) 27 (3.3)
Eating/drinking less
Not present 63 (10.7) 30 (13.5) 0.073 93 (11.4)
Slight/little 140 (23.7) 68 (30.5) 208 (25.6)
Moderate 184 (31.2) 67 (30.0) 251 (30.9)
Bad 157 (26.6) 41 (18.4) 198 (24.4)
Severe/very bad 46 (7.8) 17 (7.6) 63 (7.7)
Interference with normal activity
Not present 61 (10.3) 49 (22.0) <0.001 110 (13.5)
Slight/little 136 (23.1) 59 (26.5) 195 (24.0)
Moderate 198 (33.6) 63 (28.3) 261 (32.1)
Bad 140 (23.7) 40 (17.9) 180 (22.1)
Severe/very bad 55 (9.3) 12 (5.4) 67 (8.2)
APPENDIX 2
NIHR Journals Library www.journalslibrary.nihr.ac.uk
70
Appendix 3 On-treatment analysis of the
primary end point
The on-treatment analyses of the primary end point excluded participants who took <80% of
trial medication as scheduled (e.g. when patients missed two doses of medication, when a smaller
volume of medication was taken). When patients switched from medication to non-trial antibiotics
because of deterioration this was not regarded as non-adherence. For each randomised comparison,
non-adherence was analysed in two ways: (1) based on all trial medication including placebo and
(2) based on active drug only (Figures 21–24).
0
0 4 8 12 16
Day of trial
20 24 28
343
350
Number at risk
Lower dose
Higher dose
341
347
336
343
332
340
320
328
312
321
304
310
277
276
20
40
60
Percentage of children with a primary end point
80
100
Lower dose: 32
(9.5%, 90% CI 7.2% to 12.5%)
Higher dose: 35
(10.2%, 90% CI 7.8% to 13.3%)
Difference:
–0.7% (90% CI –4.5% to 3.1%)
n (%) with a primary end point by day 28
FIGURE 21 Dose randomisation: participants who took at least 80% of all trial medication, including placebo.
0
0 4 8 12 16
Day of trial
20 24 28
376
376
Number at risk
Lower dose
Higher dose
373
371
366
365
361
362
349
350
340
343
332
331
301
294
20
40
60
Percentage of children with a primary end point
80
100
Lower dose: 38
(10.3%, 90% CI 8.0% to 13.2%)
Higher dose: 40
(10.9%, 90% CI 8.5% to 13.9%)
Difference:
–0.6% (90% CI –4.4% to 3.1%)
n (%) with a primary end point by day 28
FIGURE 22 Dose randomisation: participants who took at least 80% of active trial drug.
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reproduction and adaption in any medium and for any purpose provided that it is properly attributed. See: https://creativecommons.org/licenses/by/4.0/. For attribution the
title, original author(s), the publication source –NIHR Journals Library, and the DOI of the publication must be cited.
71
0
0481216
Day of trial
20 24 28
337
356
Number at risk
Shorter duration
Longer duration
335
353
329
350
326
346
313
335
308
325
297
317
270
283
20
40
60
Percentage of children with a primary end point
80
100
Shorter duration: 35
(10.5%, 90% CI 8.1% to 13.7%)
Longer duration: 32
(9.2%, 90% CI 7.0% to 12.2%)
Difference:
1.3% (90% CI –2.5% to 5.1%)
n (%) with a primary end point by day 28
FIGURE 23 Duration randomisation: participants who took at least 80% of all trial medication, including placebo.
0
0481216
Day of trial
20 24 28
396
356
Number at risk
Shorter duration
Longer duration
391
353
381
350
377
346
364
335
358
325
346
317
312
283
20
40
60
Percentage of children with a primary end point
80
100
Shorter duration: 46
(11.8%, 90% CI 9.4% to 14.8%)
Longer duration: 32
(9.2%, 90% CI 7.0% to 12.2%)
Difference:
2.6% (90% CI –1.2% to 6.3%)
n (%) with a primary end point by day 28
FIGURE 24 Duration randomisation: participants who took at least 80% of active trial drug.
APPENDIX 3
NIHR Journals Library www.journalslibrary.nihr.ac.uk
72
EME
HS&DR
HTA
PGfAR
PHR
Part of the NIHR Journals Library
www.journalslibrary.nihr.ac.uk
This report presents independent research funded by the National Institute for Health Research (NIHR).
The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the
Department of Health and Social Care
Published by the NIHR Journals Library
