![Effect of treatment on the change from baseline in FEV 1 (A [low dose] and B [high dose]) and FEV 1 % predicted (C [low dose] and D [high dose]) over the course of study, after treatment with FP-Sal Forspiro mDPI (test) or Seretide Accuhaler (reference).](https://www.researchgate.net/profile/Piotr-Kuna/publication/280588777/figure/fig2/AS:398242220134400@1471959752520/Effect-of-treatment-on-the-change-from-baseline-in-FEV-1-A-low-dose-and-B-high-dose_Q320.jpg)
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Randomized equivalence trial: A novel multidose dry powder
inhaler and originator device in adult and adolescent asthma
Piotr Kuna, Ph.D.,
1
Ursula Thyroff-Friesinger, Ph.D.,
2
Ingolf Gath, Ph.D.,
2
and Spencer Jones, Ph.D.
3
ABSTRACT
Background: Guideline-defined asthma control can be achieved and maintained in patients by treatment with fluticasone
propionate–salmeterol (FP-Sal).
Objective: To compare the efficacy and safety of FP-Sal delivered via a novel multidose dry powder inhaler (mDPI)
versus an originator device in adolescent and adult patients with moderate-to-severe persistent asthma.
Methods: Patients ages 12–65 years (N⫽555) were randomized to treatment with FP-Sal novel mDPI 100
g–50
gor
500
g–50
g, or originator device 100
g–50
gor500
g–50
g in a double-blind, double-dummy, parallel-group,
multicenter study. Primary efficacy measures were absolute change in forced expiratory volume in 1 second (FEV
1
) from
baseline and the area under the 12-hour serial FEV
1
curve at the end of 12 weeks of treatment. Secondary end points included
mean changes in FEV
1
; FEV
1
% predicted; morning predose peak expiratory flow; daytime, nighttime, total asthma symptom
scores; rescue medication use; percentage of patients with guideline-defined controlled asthma; global efficacy evaluation;
patients’ device preference; and safety.
Results: FP-Sal mDPI and originator device–mediated increases in FEV
1
from baseline to the end of treatment were not
significantly different, difference in least squares mean, ⫺0.065 L (95% confidence interval, ⫺0.154 to 0.024 L) at 100
g–50
g, and ⫺0.032 L (95% confidence interval, ⫺0.121 to 0.057 L) at 500
g–50
g). Both doses of FP-Sal mDPI improved FEV
1
area under the 12-hour serial FEV
1
curve from baseline and all secondary efficacy measures with no significant differences from
the originator device at equivalent doses, with similar safety profiles.
Conclusions: FP-Sal mDPI demonstrated equivalent efficacy and safety profile to the originator device and is an alternative
in this patient group.
(Allergy Asthma Proc 36:352–364, 2015; doi: 10.2500/aap.2015.36.3886)
The Global Initiative for Asthma (GINA) guidelines
1
recommend that, for adults and children ages ⱖ5
years with uncontrolled asthma on low-dose inhaled
corticosteroid (ICS) alone, a long-acting

2-agonist
(LABA) should be added to the treatment regimen.
Several studies indicate that guideline-defined totally
controlled or well-controlled asthma can be achieved
and maintained in most patients with asthma by treat-
ment with ICS-LABA combinations, e.g., fluticasone
propionate–salmeterol (FP-Sal).
2–4
AirFluSal (Sandoz, International GmbH, Germany),
a FP-Sal combination delivered by the novel Forspiro
multidose dry powder inhaler (FP-Sal Forspiro mDPI)
(Sandoz) is a new dry powder preparation. It is similar
to the currently available Seretide Accuhaler (origina-
tor device) preparation (GlaxoWellcome, London,
U.K.), both in terms of the active drugs used and the
doses delivered per actuation (fluticasone-17-propi-
onate 100 or 500
g and salmeterol 50
g). FP-Sal
Forspiro mDPI, however, differs from the Seretide Ac-
cuhaler with respect to the inhalation device used for
drug delivery, which was developed and tested for
intuitive usability in collaboration with patients in this
study.
5
In line with European Union regulatory requirements
for clinical documentation for orally inhaled products,
6
the primary aim of this study was to evaluate the long-
term efficacy, safety, and equivalence (noninferiority) of
FP-Sal Forspiro mDPI (test) compared with Seretide Ac-
cuhaler (reference) in adolescent and adult patients with
moderate-to-severe persistent asthma.
METHODS
For further details of the study methodology, see
Supplemental Appendix 1. Clinical trial registration:
EudraCT no. 2007–005620-32.
P. Kuna was the principal investigator for the study.
All the authors were involved in the study design,
From the
1
Division of Internal Medicine, Barlicki University Hospital, Medical
University of Lo´dz, Lo´ dz, Poland,
2
Clinical Research Department, Hexal AG, Holz-
kirchen, Germany, and
3
Global Medical Affairs Respiratory, Sandoz International
GmbH, Holzkirchen, Germany
The study was funded by Hexal AG, Holzkirchen, Germany, an affiliate of Sandoz
International GmbH. Medical writing assistance was also funded by Sandoz Interna-
tional GmbH
I. Gath and U. Thyroff-Friesinger are employees of Hexal AG. S. Jones is an employee
of Sandoz International GmbH. P. Kuna has received speaking fees from AstraZeneca,
MSD, Boehringer Ingelheim, Pfizer, GlaxoSmithKline, Novartis, Teva, Sandoz,
Chiesi, Meda, Polpharma, Krka, Adamed, FAES, Allergopharma, and Stallergen, and
served as a consultant on advisory boards of AstraZeneca, Novartis, MSD, Boehringer
Ingelheim, Chiesi, Almirall, FAES, Allergopharma, and ALK
Address correspondence to Spencer Jones, Sandoz International GmbH, Industri-
estrasse 25, 83607 Holzkirchen, Germany
Copyright ©2015, OceanSide Publications, Inc., U.S.A.
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analysis of data, interpretation of the work, and writ-
ing the manuscript. P. Kuna, I. Gath, and U. Thyroff-
Friesinger were involved in the collection of the data.
All the authors equally made the final decision to
submit the work.
Patients
Male and female patients ages 12–65 years were
enrolled in the study if they had a documented GINA
guideline-defined
7
medical history of moderate-to-se-
vere persistent asthma for at least 6 months and had
regularly used ICS or ICS plus LABA over the 6
months preceding the screening visit. All the patients
were also required to be receiving regular treatment
with high-dose ICS alone or low-to-high–dose ICS plus
LABA for the 4 weeks preceding the screening and to
have a forced expiratory volume in 1 second (FEV
1
)of
at least 50% of the predicted value at least 6 hours and
12 hours after treatment with rapid-acting

2-agonists
(including salbutamol, terbutaline, fenoterol, and re-
proterol) and LABA, respectively. At the screening, all
the patients also had to demonstrate a reversibility in
airflow limitation of at least 12% and a 0.2-L increase in
FEV
1
from the prebronchodilator value.
Study Design
This was a randomized, double-blind, double-
dummy, parallel-group, multicenter, phase III, thera-
peutic equivalence study to investigate whether effi-
cacy and safety between the two groups was
sufficiently comparable to exclude a clinically relevant
difference. The investigation was conducted in 32 cen-
ters across five European countries between July 2009
and February 2010. The study involved a 2-week run-
in, wash-out period, followed by a 12-week double-
blind treatment period. Before and during the run-in,
wash-out period, the patients were assessed for inclu-
sion. During the run-in, wash-out period, all asthma
treatments except reliever medication (salbutamol 0.1
mg; SalbuHEXAL Easyhaler 0.1 mg/dose [Hexal AG,
Holzkirchen, Germany]) were stopped and the patients
were given training on the correct use and handling of
the inhaler device and an asthma monitor used for
peak expiratory flow (PEF) assessment.
At the baseline clinic visit (visit 0), all eligible pa-
tients were randomized in a 1:1:1:1 ratio to one of four
treatment groups (group A, FP-Sal Forspiro mDPI [100
g–50
g]) plus placebo Accuhaler; group B, Seretide
100 Accuhaler [100
g–50
g] plus placebo Forspiro
mDPI; group C, FP-Sal Forspiro mDPI [500
g–50
g]
plus placebo Accuhaler; group D, Seretide 500 Accu-
haler [500
g–50
g] plus placebo Forspiro mDPI) for
12 weeks. The study medications were supplied and
administered in a double-blind manner by way of a
double-dummy design. The patients returned to the
clinic at 2-week intervals (visits 1–6).
Assessment of Efficacy
Primary and Secondary Efficacy Measures. The first pri-
mary efficacy measure was the absolute change in
FEV
1
from baseline (visit 0) to the end of the 12-week
treatment period (visit 6) for demonstration of nonin-
feriority of FP-Sal Forspiro mDPI to Seretide Accuhaler
at both the low and high doses (100
g–50
g and 500
g–50
g) as well as superiority of both doses of FP-Sal
Forspiro mDPI over a literature-based “putative” placebo
value of 0.130 L.
8
The area under the 12-hour serial FEV
1
curve (AUC
0–12
) at the end of the 12-week treatment
period (visit 6) relative to the preinhalation FEV
1
was
evaluated as a second primary efficacy measure.
Assessment of FEV
1
by Investigator. FEV
1
and forced
vital capacity were measured by spirometry at each
study visit according to American Thoracic Society/
European Respiratory Society criteria.
9
Only the high-
est FEV
1
values from each spirometry session were
used for calculations and analyses. The predicted FEV
1
values were calculated according to the European
Community for Coal and Steel.
10,11
Assessment of PEF by Patients at Home. Each patient
was provided with a numbered identifiable asthma mon-
itor (Vitalograph asma-1) (Vitalograph Inc., Lenexa, KS)
at the screening visit, and the participant or guardian was
instructed on the correct use of the monitor. Triplicate
readings of PEF were taken twice daily, before the study
medication was taken, in the morning on waking and in
the evening before going to bed. All readings were re-
corded on diary cards.
Evaluation of Asthma Symptom Scores. Patients evalu-
ated daytime symptom scores (for wheezing, shortness
of breath, chest tightness, or cough) on a 6-point scale,
in which 0 ⫽no asthma symptoms during the day, 1 ⫽
asthma symptoms for one short period during the day,
2⫽asthma symptoms for two or more short periods
during the day, 3 ⫽asthma symptoms for most of the
day that did not affect normal daily activity, 4 ⫽
asthma symptoms for most of the day that did affect
normal daily activity, and 5 ⫽asthma symptoms so
severe that they affected work and/or school, and
normal daily activity. Similarly, nighttime symptom
scores were recorded.
Guideline-Defined Asthma Control. Asthma control was
defined according to GINA (daytime symptoms ⱕ2/wk,
no limitation of activities, no nocturnal symptoms or
awakenings, reliever or rescue medication need ⱕ2/wk,
no asthma exacerbations, and FEV
1
ⱖ80% predicted).
1
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The number of participants with “controlled asthma”
was assessed at the end of treatment.
Incidence and Severity of Asthma Exacerbations. All
asthma exacerbations experienced during the run-in
and treatment periods (visit ⫺1 to visit 6) were docu-
mented and classified by the investigator as moderate
or severe. Exacerbations were classified as moderate
when the patient had to be treated with oral or
parenteral corticosteroids and demonstrated a PEF
of 60–80% predicted after initial treatment with in-
haled rapid-acting

2-agonists. Exacerbations were
classified as severe when they led to the patient’s
withdrawal from the study after emergency hospital
treatment and/or hospitalization and treatment with
oral or parenteral corticosteroids, and PEF was
⬍60% predicted after initial treatment with inhaled
rapid-acting

2-agonists.
Global Evaluation of Efficacy by Patient and Investigator.
An overall assessment of efficacy was made at visit 6
by the patient or guardian and the investigator by
using a 5-point Likert rating scale: 1, very good; 2,
good; 3, satisfactory; 4, bad; and 5, very bad.
Patient Preference for a Device. The patient’s prefer-
ence for a device was assessed at the end of the study
(visit 6 or early termination visit) by a 100-mm visual
analog scale (VAS), which ranged from extremely poor
to extremely good, and by a modified questionnaire
12
by using emoticons on a 5-point scale (two sad, 0; one
sad, 1; one normal, 2; one happy, 3; and two happy, 4).
Assessment of Safety. Safety was assessed by docu-
mentation of adverse events (AE), routine laboratory
assessments (including hematology, clinical and/or
biochemistry, and oropharyngeal swabs for Candida
albicans infection), physical examinations, vital signs
(including systolic and diastolic arterial blood pressure
and pulse rate measured after 5 minutes of supine rest),
and 12-lead electrocardiograms (ECG). The incidence, se-
verity, and type of AEs reported by the patients over the
course of treatment were classified according to ICH
guidance Topic E2A,
13
and coded by using the Medical
Dictionary for Regulatory Activities (MedDRA version
12.1).Treatment-emergent AEs (TEAE) were further sum-
marized by severity and association to treatment.
Statistical Analyses
Data Management and Statistical Analyses. All data
were managed and analyzed by an independent con-
tract research organization (SCOPE International AG,
Vilnius, Lithuania). The description of statistical anal-
yses can be found in Supplemental Appendix I.
RESULTS
A total of 592 patients were screened, of whom 555
(93.8%) were randomized to treatment and 533 com-
pleted the study (Fig. 1). Twenty-two patients dis-
Figure 1. Patient disposition.
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continued the study prematurely (seven withdrew
consent, six were lost to follow-up, four withdrew
because of an AE, three were excluded due to non-
eligibility, and two because of inadvertent unblind-
ing of treatment). Overall, the 555 randomized pa-
tients comprised the safety set, and 550 and 524
patients comprised the full analysis set and per pro-
tocol set, respectively (138/134 patients in group A,
FP-Sal Forspiro mDPI 100
g–50
g; 136/129 in
group B, Seretide 100 Accuhaler 100
g–50
g; 135/
127 in group C, FP-Sal Forspiro mDPI 500
g–50
g;
and 141/134 in group D, Seretide 500 Accuhaler 500
g–50
g). The demographic and baseline clinical
characteristics of each study group in the full anal-
ysis set are shown in Table 1. All treatment groups
were comparable in terms of patient demographics
and asthma history.
Efficacy Outcomes
The total mean compliance, based on patient diaries
and the inhalation device counter data, was ⬃99% in
all treatment groups.
Primary Efficacy Measures. The mean (standard devi-
ation) preinhalation baseline FEV
1
at visit 0 was noted
to be ⬃0.1 L lower in patients treated with both doses
of FP-Sal Forspiro mDPI than in patients treated with
Seretide Accuhaler (1.986 ⫾0.514 L versus 2.097 ⫾
0.537 L at low dose; and 2.063 ⫾0.509 L versus 2.177 ⫾
0.538 L at high dose). Assessment of the effect of treat-
ment on the absolute change in FEV
1
from baseline
(visit 0) to the end of the 12-week treatment period
(visit 6) for per protocol set, the first primary efficacy
measure, demonstrated that FP-Sal Forspiro mDPI was
comparable and noninferior to Seretide Accuhaler at
both doses investigated, as indicated by the lower limit
of the 95% confidence interval (CI) for the difference in
absolute change in FEV
1
from baseline not exceeding
the predefined noninferiority margin of ⫺0.2 L at ei-
ther dose (Table 2).
Assessment of the AUC
0–12
at the end of treatment
(visit 6) relative to the preinhalation FEV
1
, the second
primary efficacy measure, also demonstrated FP-Sal
Forspiro mDPI to be comparable and noninferior to
Seretide Accuhaler at both doses investigated, as indi-
cated by no significant difference between treatment
ratios and the predefined noninferiority margin of 0.8
(80%) being less than the lower limit of the 95% CI for
the difference in treatment ratios at both the low and
high doses investigated (Table 2). The assessments of
both these primary efficacy measures were found to be
similar for the full analysis set (Table 2).
All study treatments were shown to be superior to
the putative placebo, as indicated by the lower limit of
the 95% CI for the difference in absolute change from
baseline in FEV
1
at the end point and at each treatment
visit being higher than the putative placebo value of
0.130 L, which represents the highest placebo effect
Table 1 Demographic and baseline clinical characteristics of patients in full analysis set
Parameter FP-Sal Forspiro
mDPI
100
g–50
g
(Nⴝ138)
Seretide 100
Accuhaler
100
g–50
g
(Nⴝ136)
FP-Sal Forspiro
mDPI
500
g–50
g
(Nⴝ135)
Seretide 500
Accuhaler
500
g–50
g
(Nⴝ141)
Age, y
Mean (SD) 46.1 ⫾14.9 45.5 ⫾14.4 43.8 ⫾14.9 45.5 ⫾14.2
Min-max 12–64 12–64 12–64 12–65
Sex, no. (%)
Men 47 (34.1) 59 (43.4) 53 (39.3) 66 (46.8)
Women 91 (65.9) 77 (56.6) 82 (60.7) 75 (53.2)
Asthma duration, mo
Mean (SD) 131.9 ⫾103.2 123.8 ⫾105.8 128.2 ⫾105.8 130.3 ⫾132.4
Min-max 6–573 6–524 6–573 6–645
Severity of asthma type, no. (%)
Persistent moderate 124 (89.9) 118 (86.8) 119 (88.1) 123 (87.2)
Persistent severe 14 (10.1) 18 (13.2) 16 (11.9) 18 (12.8)
Baseline FEV
1
, mean (SD), L* 2.00 ⫾0.52 2.08 ⫾0.53 2.08 ⫾0.52 2.15 ⫾0.54
Increase in FEV
1
after inhalation
of salbutamol, mean (SD), % reversibility
24.76 ⫾11.76 25.26 ⫾12.80 23.82 ⫾8.34 23.88 ⫾9.88
N⫽Number of patients in specified treatment group; min ⫽minimum; max ⫽maximum; no. ⫽number of patients with data
available; % ⫽percentage based on N;SD ⫽standard deviation.
*Baseline is defined as mean value of preinhalation 1 and 2 at visit 0.
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found in a survey of historical studies with similar
design characteristics (Table 3).
Mean Change in FEV
1
and FEV
1
% Predicted Over the
Course of the Study. FEV
1
was increased maximally
between visit 0 and visit 1 in both FP-Sal Forspiro
mDPI and Seretide Accuhaler treatment groups at both
doses (0.279 L versus 0.332 L at low dose; and 0.365 L
versus 0.367 L at high dose) and then changed mini-
mally to the end of the treatment period (range, 12–45
Table 2 Effect of treatment on primary efficacy end points
Primary Efficacy Measure Difference Between FP-Sal Forspiro mDPI and Seretide Accuhaler Treated
Groups
FP-Sal 100
g–50
g
(groups A and B), LS
mean difference (95% CI)
pValue FP-Sal 500
g–50
g
(groups C and D), LS
mean difference (95% CI)
pValue
Absolute change from baseline
in FEV
1
at visit 6 or ET, L*
PPS ⫺0.065 (⫺0.154 to 0.024) 0.149 ⫺0.032 (⫺0.121 to 0.057) 0.482
FAS ⫺0.068 (⫺0.154 to 0.019) 0.125 ⫺0.037 (⫺0.124 to 0.049) 0.399
Ratio for FEV
1
AUC
0–12
and
preinhalation FEV
1
at visit
6orET
PPS 1.001 (0.984–1.018) 0.902 1.008 (0.992–1.025) 0.333
FAS 1.001 (0.985–1.018) 0.868 1.008 (0.992–1.025) 0.337
Group A ⫽FP-Sal Forspiro mDPI (100
g–50
g); group B ⫽Seretide 100 Accuhaler (100
g–50
g); group C ⫽FP-Sal
Forspiro mDPI (500
g–50
g); group D ⫽Seretide 500 Accuhaler (500
g–50
g); ET ⫽early termination; FAS ⫽full
analysis set; PPS ⫽per protocol set.
*Baseline is defined as mean value of preinhalation 1 and 2 at visit 0.
Table 3 Treatment superiority over putative placebo (130 mL), based on absolute change in FEV
1
(mL) from
baseline to each study visit in FAS*
Efficacy
Assessment
FP-Sal Forspiro
mDPI (100
g–
50
g) (Nⴝ138)
Seretide 100
Accuhaler (100
g–
50
g) (Nⴝ136)
FP-Sal Forspiro
mDPI (500
g–50
g)
(Nⴝ135)
Seretide 500
Accuhaler (500
g–
50
g) (Nⴝ141)
Visit 1
LS mean
(95% CI)
275.07 (212.93–337.21) 299.26 (236.63–361.88) 362.81 (299.04–426.58) 356.74 (294.15–419.33)
Visit 2
LS mean
(95% CI)
289.85 (223.22–356.48) 310.88 (243.21–378.55) 328.47 (263.10–393.83) 384.40 (320.36–448.43)
Visit 3
LS mean
(95% CI)
303.64 (237.62–369.66) 327.42 (260.06–394.79) 357.25 (292.89–421.61) 374.04 (310.99–437.08)
Visit 4
LS mean
(95% CI)
277.24 (209.47–345.01) 345.72 (277.18–414.27) 402.06 (340.64–463.48) 385.70 (325.53–445.87)
Visit 5
LS mean
(95% CI)
302.74 (236.24–369.25) 380.57 (313.19–447.95) 383.48 (317.32–449.64) 407.19 (342.60–471.77)
End point
LS mean
(95% CI)
262.34 (199.94–324.74) 329.93 (267.04–392.81) 328.81 (266.10–391.53) 365.99 (303.92–428.07)
FAS ⫽full analysis set.
*Baseline is defined as the mean value of preinhalation 1 and 2 at visit 0.
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mL in all treatment groups) (Fig. 2Aand B). The
change in FEV
1
% predicted followed a similar pattern
to that for FEV
1
, increasing from a mean of ⬃68% at
baseline to ⬃77–80% at visit 6 in all the treatment
groups (Fig. 2 Cand D).
Change in Morning PEF. The FP-Sal Forspiro mDPI–
induced increase from the baseline period in morning
PEF was comparable with that for Seretide Accuhaler at
both doses investigated (Table 4). FP-Sal Forspiro mDPI
was noninferior to Seretide Accuhaler as indicated by no
significant difference between LS means (⫺7.29 L/min
[95% CI, ⫺21.06 to 6.47 L/min] and 8.96 L/min [95% CI,
⫺6.14 to 24.06 L/min], respectively, at the low and high
doses investigated) and the lower limit of the 95% CI for
the difference in change being higher than the noninferi-
ority margin set to ⌬⫽⫺25 L/min in accordance with
published acceptance limits.
14,15
Figure 2. Effect of treatment on the change from baseline in FEV
1
(A [low dose] and B [high dose]) and FEV
1
% predicted (C [low dose]
and D [high dose]) over the course of study, after treatment with FP-Sal Forspiro mDPI (test) or Seretide Accuhaler (reference).
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Change in Asthma Symptom Scores. At baseline, the
mean asthma symptom scores did not differ signifi-
cantly among any treatment groups. The mean scores
decreased from baseline to similar levels in FP-Sal For-
spiro mDPI and Seretide Accuhaler treated groups at
both doses by the end of treatment (Table 4).
Rescue Medication Use. The mean number of daily
reliever actuations decreased by ⬎75% from baseline to
the evaluation period, to ⬃0.5 actuations in all the
treatment groups (Table 4). Similarly, rescue-free days
increased from 12–15% at baseline to ⬃70% in all the
treatment groups. Moreover, 53–56% of the patients in
all the treatment groups did not report using rescue
medication for ⬎75% of the entire treatment period.
Incidence and Severity of Exacerbations. There were
no moderate or severe asthma exacerbations during
the baseline period, and only nine patients developed
an exacerbation of moderate severity while on the
study treatment (Table 4). The mean duration of these
asthma exacerbations was 7.3 and 6.0 days in the low-
dose FP-Sal Forspiro mDPI and Seretide Accuhaler
groups, respectively, and 8.3 and 6.5 days in the high-
dose FP-Sal Forspiro mDPI and Seretide Accuhaler
groups, respectively.
Patients With Controlled Asthma. The proportion of
patients with GINA-defined controlled asthma
1
at the
end of treatment was comparable among all the treat-
ment groups and ranged from 26.1% to 32.8% (Table 4).
Global Assessment of Efficacy. Between 86% and 94%
of the investigators and between 89% and 96% of the
patients rated all treatments to be “good” or “very
good” compared with 0.9% (five each of investigators
Table 4 Effect of treatment on different secondary efficacy end points
Efficacy Assessment FP-Sal
Forspiro mDPI
(100
g–50
g)
Seretide 100
Accuhaler
(100
g–50
g)
FP-Sal Forspiro
mDPI
(500
g –50
g)
Seretide 500
Accuhaler
(500
g–50
g)
Morning predose PEF in PPS N⫽134 N⫽129 N⫽127 N⫽134
Change from baseline to evaluation
period, mean (SD), L/min*#
17.2 ⫾55.0 23.2 ⫾59.8 34.8 ⫾58.3 25.2 ⫾60.6
Asthma symptom score in FAS N⫽138 N⫽136 N⫽135 N⫽141
Change from baseline to evaluation
period, mean (SD)§¶
Daytime ⫺0.96 ⫾0.73 ⫺1.01 ⫾0.69 ⫺0.88 ⫾0.65 ⫺1.04 ⫾0.76
Nighttime ⫺0.58 ⫾0.65 ⫺0.56 ⫾0.54 ⫺0.52 ⫾0.53 ⫺0.62 ⫾0.67
Total㛳⫺1.52 ⫾1.24 ⫺1.56 ⫾1.07 ⫺1.38 ⫾0.98 ⫺1.65 ⫾1.29
Rescue medication use
(actuations/patient/day) in FAS
N⫽138 N⫽136 N⫽135 N⫽141
Absolute change from baseline to
evaluation, mean (SD)§¶
⫺2.1 ⫾1.4 ⫺1.9 ⫾1.4 ⫺2.0 ⫾1.4 ⫺2.2 ⫾1.7
% Relative change from baseline to
evaluation, mean (SD)§¶
⫺78.2 ⫾34.9 ⫺76.8 ⫾34.1 ⫺75.4 ⫾37.4 ⫺78.3 ⫾34.1
Incidence and severity of asthma
exacerbations in FAS
N⫽138 N⫽136 N⫽135 N⫽141
With incidence (1 exacerbation of
moderate severity only), no. (%)**
3 (2.2) 1 (0.7) 3 (2.2) 2 (1.4)
Patients with controlled asthma in PPS## N⫽134 N⫽129 N⫽127 N⫽134
No. (%) 35 (26.1) 39 (30.2) 37 (29.1) 44 (32.8)
FAS ⫽full analysis set; PPS ⫽per protocol set.
*Baseline is defined as 14-day run-in period from visit ⫺1 to visit 0 with at least 10 evaluable recordings.
#Evaluation period is defined as 14 days on treatment with at least 10 evaluable recordings.
§Baseline period is defined as 14-day run-in period from visit ⫺1 to visit 0.
¶Evaluation period is defined as last 14 days on treatment.
㛳Total asthma symptoms score is calculated as the sum of daytime and nighttime symptom scores.
**No patient had ⬎1 asthma exacerbation or of high severity in any treatment group.
##Controlled asthma defined as “patients with FEV
1
ⱖ80, daytime symptoms ⱕ2/wk and no nighttime symptoms, no asthma
exacerbation, rescue medication use ⱕ2/wk, and no limitations of activities (symptom score ⬍4)” according to GINA
1
.
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and patients) who rated their treatment as “bad” or
“very bad” (Table 5).
Patient Preference for a Device. Overall, patients
rated both devices similarly (mean [standard devia-
tion] FP-Sal Forspiro mDPI 81.97 ⫾13.89 mm VAS and
Seretide Accuhaler 79.67 ⫾16.48 mm VAS) (Fig. 3),
with 94% of all the patients indicating ease of handling
to be the most important feature for both inhaler de-
vices. Assessment of the devices’ attributes by means
of a questionnaire also indicated similar overall pref-
erence for both inhalers, although the FP-Sal Forspiro
mDPI was rated numerically higher than the Seretide
Accuhaler inhaler with respect to ease in closing the
Table 5 Global evaluation of treatment in full analysis set
Efficacy Assessment FP-Sal Forspiro mDPI
(100
g–50
g)
(Nⴝ138)
Seretide 100
Accuhaler
(100
g–50
g)
(Nⴝ136)
FP-Sal Forspiro mDPI
(500
g–50
g)
(Nⴝ135)
Seretide 500
Accuhaler
(500
g–50
g)
(Nⴝ141)
By investigator, no. (%)*
Very good 71 (52.5) 74 (56.1) 69 (53.1) 67 (48.2)
Good 46 (33.8) 48 (36.4) 47 (36.2) 63 (45.3)
Satisfactory 16 (11.8) 10 (7.6) 12 (9.2) 9 (6.5)
Bad 1 (0.7) 0 2 (1.5) 0
Very bad 2 (1.5) 0 0 0
Missing 2 4 5 2
By patient, no, (%)*
Very good 73 (53.7) 76 (57.6) 69 (53.1) 73 (52.9)
Good 50 (36.8) 51 (38.6) 47 (36.2) 55 (39.9)
Satisfactory 11 (8.1) 5 (3.8) 12 (9.2) 9 (6.5)
Bad 1 (0.7) 0 2 (1.5) 0
Very bad 1 (0.7) 0 0 1 (0.7)
Missing 2 4 5 3
*Based on nonmissing values for each treatment group.
Figure 3. Patients’ preferences for a device.
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device and completeness of the instructions for use of
the device (median score, 4.0 versus 3.0 for both attri-
butes).
Safety Assessment
The overall safety profiles were similar in all the
study groups. Approximately 23–27% of the patients in
any treatment group experienced at least one mild-to-
moderate severity TEAE, of which the most common
were nasopharyngitis, respiratory tract viral infections,
influenza, upper tract respiratory infection, dysphonia,
throat irritation, asthma exacerbation, and headache
(Table 6). A total of five moderate severity TEAEs
resulted in one patient from each treatment group
discontinuing the study (Table 6), and although one
serious TEAE (patient hospitalized due to loss of con-
sciousness) was reported in the FP-Sal Forspiro mDPI
500
g–50
g treated group, this was assessed to be
mild and not related to the study medication. No death
or paradoxical bronchoconstriction after the first ad-
ministration of the study medications was reported.
There were no clinically relevant changes from
baseline mean and median values in any hemato-
logic or clinical chemistry variables over time or
between the treatment groups. However, assessment
of relevant changes in individual patients, catego-
rized as low, normal, or high with respect to the
reference range, were noted for hemoglobin levels,
red and white blood cell counts, potassium level, and
alanine aminotransferase level during the study (Ta-
ble 7). Serum cortisol levels for most patients were
noted to be in the normal range, of 0.171–0.535
mol/L and were not altered by any study medica-
tion in most patients over the course of 12 weeks of
treatment (Table 7). At visit 6 or at early termination,
the mean cortisol AUC
0–12
expressed as the average
of the 12-hour assessment (AUC
0–12/12
) for Forspiro
mDPI 100
g–50
g and Seretide 100 Accuhaler 100
g–50
g treated groups was 0.248
mol/L and
0.244
mol/L, respectively (LS mean [95% CI] for
Forspiro mDPI versus 100 Accuhaler 1.033 [95% CI,
0.9184–1.1622]), and 0.231
mol/L and 0.223
mol/L for Forspiro mDPI 500
g–50
g and
Seretide 500 Accuhaler 500
g–50
g treated groups,
respectively (LS mean [95% CI] for Forspiro mDPI
versus 500 Accuhaler 1.049 [95% CI, 0.9095- 1.2103]).
Thus, these results showed equivalence between the
treatments when applying the 80–125% bioequiva-
lence limits. Any changes noted in ECGs, heart rate,
or systolic and diastolic blood pressures were also
not clinically relevant in any treatment group.
DISCUSSION
This multicenter, randomized, double-blind, dou-
ble-dummy, parallel group study assessed the non-
inferiority of a generic preparation of FP-Sal For-
Table 6 Incidence of TEAEs reported over 12 weeks
TEAE Assessment FP-Sal Forspiro
mDPI
(100
g–50
g)
(Nⴝ139)
Seretide 100
Accuhaler
(100
g–50
g)
(Nⴝ137)
FP-Sal Forspiro
mDPI
(500
g–50
g)
(Nⴝ136)
Seretide 500
Accuhaler
(500
g–50
g)
(Nⴝ143)
Patients reporting ⱖ1 TEAE,
no. (%)
38 (27.3) 31 (22.6) 33 (24.3) 35 (24.5)
Incidence ⱖ2% in any
group, no. (%)
Nasopharyngitis 6 (4.3) 6 (4.4) 5 (3.7) 4 (2.8)
RTI-viral 4 (2.9) 3 (2.2) 1 (0.7) 4 (2.8)
Influenza 0 (0) 4 (2.9) 2 (1.5) 4 (2.8)
URTI 1 (0.7) 1 (0.7) 3 (2.2) 6 (4.2)
Dysphonia 3 (2.2) 4 (2.9) 6 (4.4) 2 (1.4)
Throat irritation 2 (1.4) 3 (2.2) 1 (0.7) 1 (0.7)
Asthma exacerbation 3 (2.2) 1 (0.7) 3 (2.2) 2 (1.4)
Headache 5 (3.6) 1 (0.7) 0 (0) 4 (2.8)
Patients discontinuing due to
TEAE, no. (%)
1 (0.7) 1 (0.7) 1 (0.7) 1 (0.7)
TEAE type Asthma
exacerbation
Vulvovaginal
mycotic
infection
Dysphonia* Headache,
hypertension
RTI-viral ⫽Respiratory tract viral infection; URTI ⫽upper tract respiratory infection.
*Suspected relationship to treatment.
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spiro mDPI 100
g–50
g and 500
g–50
gto
Seretide Accuhaler 100
g–50
g and 500
g–50
g,
over a 12-week period in terms of efficacy and safety
in adolescent and adult patients with moderate-to-
severe persistent asthma. Overall, the study demon-
strated that, by the end of treatment and at specified
time points over the course of the study, FP-Sal
Forspiro mDPI led to absolute improvements from
baseline in FEV
1
that were comparable with, and not
significantly different from, those seen with Seretide
Accuhaler at either dose, which indicated noninferi-
ority of the generic preparation. Changes from base-
line in FEV
1
, AUC
0–12
, FEV
1
% predicted, and morn-
ing PEF were also improved by both doses of FP-Sal
Forspiro mDPI to comparable, and not significantly
different, levels with equivalent doses of Seretide
Accuhaler over the course of the study. Furthermore,
the two products produced similar improvements in
other outcome measures, including change in day-
time, nighttime, total asthma symptom scores; rescue
and/or reliever medication use and days without
rescue medication; control of exacerbations; and the
number of patients with guideline-defined con-
trolled asthma as well as the efficacy being rated by
86–96% of all the investigators and patients as
“good” or “very good.” Assessment of the safety
profiles showed that FP-Sal Forspiro mDPI was as
well tolerated as Seretide Accuhaler with respect to
the type, intensity, and incidence of total and drug-
related AEs, laboratory test results (hematologic and
clinical chemistry), ECGs, and vital signs, in line
with the known AEs for this drug combination.
As might be expected, the findings from the present
study are in accordance with those of several studies
Table 7 Laboratory variables with most frequent individual patient changes from visit ⴚ1 to visit 6 or early
termination
Variable,
Categorized
Shift
FP-Sal Forspiro
mDPI
(100
g–50
g),
no. (%) (Nⴝ139)
Seretide 100
Accuhaler
(100
g–50
g),
no. (%) (Nⴝ137)
FP-Sal Forspiro
mDPI
(500
g–50
g),
no. (%) (Nⴝ136)
Seretide 500
Accuhaler
(500
g–50
g),
no. (%) (Nⴝ143)
Hemoglobin
Normal to low 10 (7.2) 15 (10.9) 16 (11.8) 12 (8.4)
Red blood cells
Normal to low 21 (15.1) 18 (13.1) 17 (12.5) 18 (12.6)
White blood cells
Normal to low 23 (16.5) 22 (16.1) 20 (14.7) 19 (13.3)
Low to normal 5 (3.6) 2 (1.5) 8 (5.9) 7 (4.9)
Potassium
Normal to
high
11 (7.9) 9 (6.6) 3 (2.2) 12 (8.4)
High to
normal
8 (5.8) 7 (5.1) 10 (7.4) 8 (5.6)
ALT
Normal to
high
7 (5.0) 5 (3.6) 6 (4.4) 7 (4.9)
High to
normal
14 (10.1) 9 (6.6) 13 (9.6) 13 (9.1)
Serum cortisol*
Low to normal 12 (8.6) 7 (5.1) 7 (5.1) 8 (5.6)
Low to high 0 0 0 1 (0.7)
Normal to low 8 (5.8) 8 (5.8) 6 (4.4) 10 (7.0)
Normal to
high
11 (7.9) 8 (5.8) 3 (2.2) 11 (7.7)
High to low 0 1 (0.7) 1 (0.7) 0
High to
normal
4 (2.9) 8 (5.8) 12 (8.8) 10 (7.0)
N⫽Number of patients in specified treatment group; no. ⫽number of patients with data available; % ⫽percentage based
on N;ALT ⫽alanine transaminase.
*Shifts of preinhalation serum cortisol from visit 0 to visit 6 or early termination based on reference ranges.
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that investigated the effect of Seretide 50
g–250
gor
50
g–500
g FP-Sal in patients with moderate-to-
severe asthma.
14–21
An early study by Aubier et al.,
14
that investigated the effect of 12 weeks of treatment
with Seretide 50
g–500
g FP-Sal twice daily via a
single Seretide Accuhaler inhaler, demonstrated that
the adjusted mean morning PEF was improved by 35
L/min over the course of 1–12 weeks of treatment.
Similarly, FEV
1
was increased by ⬃0.220 L/min from
baseline by 12 weeks of treatment and the mean per-
centage of symptom-free days, symptom-free nights,
rescue-free days, and rescue-free nights increased over
weeks 1–12. By using a similar study design, Chap-
man et al.
15
demonstrated that Seretide 50
g–250
g
FP-Sal twice daily delivered via a single Seretide
Accuhaler inhaler led to a mean improvement in
morning PEF of 43 L/min by week 12 and an in-
crease from baseline in FEV
1
of 0.260 L/min by week
28 of treatment. Furthermore, the numbers of pa-
tients with daytime and nighttime symptom scores
of 0 were increased by 34% and 32%, respectively,
from baseline to week 12. In a more recent study,
Woodcock et al.
21
evaluated the effect of Seretide
250–500
g–50
g FP-Sal and demonstrated in-
creases in morning PEF, symptom-free and rescue
medication-free days, and a decrease in adjusted
mean asthma symptom scores. In another well-con-
trolled study, van Noord et al.
20
investigated the
clinical equivalence of a combination of FP-Sal 50
g–500
g administered daily for 12 weeks via a
novel hydrofluoroalkane metered-dose inhaler and a
dry powder Seretide Accuhaler inhaler, in 12–82-
year-old patients with moderate-to-severe asthma,
which showed that the FP-Sal metered-dose inhaler
was equivalent to the Seretide Accuhaler for the pri-
mary efficacy outcome of the mean change in morning
A) Device showing main components
B) Lid open showing mouthpiece and dose counter with warning of ≤10 doses remaining in
red
C) Used medicaon blisters for examinaon of residual medicaon
Tran spar ent
door
Lid
Lever
Body
(front)
Figure 4. Forspiro mDPI. (A) Device, showing main
components. (B) Lid open, showing mouthpiece and dose
counter with warning of ⱕ10 doses remaining in red. (C)
Used medication blisters for examination of residual
medication.
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PEF over the course of treatment (adjusted mean in-
creases of 50 and 48 L/min, respectively, with a treat-
ment difference of ⫺2 L/min [95% CI, ⫺11 to 7
L/min]).
20
Both treatments were equally well toler-
ated.
Although the findings of the present study were
unlike some of the aforementioned studies because
there was no specific placebo-treated group, the
findings were in accordance with several other stud-
ies that compared the effects of Seretide with other
antiasthma medications in the absence of a specific
placebo group in patients with moderate-to-severe
asthma.
14,15,18,19,22–24
Furthermore, in line with ICH
E4 guidance,
25
the ability of the studies to discrimi-
nate between the treatments (assay sensitivity) was
demonstrated by a positive correlation for differ-
ences between the high and low doses of both prep-
arations combined with statistical and clinical supe-
riority
22
of all treatments over the predetermined
placebo effect of 0.130 L, selected as the highest
value reported in relevant well-controlled stud-
ies.
8,16,17,26–28
Hence, the demonstration of assay sen-
sitivity according to ICH E4 further substantiated the
conclusion of therapeutic equivalence on both dose
levels.
Evidence-based guidelines for device selection and
outcomes of aerosol therapy have indicated that tailor-
ing the device to the patient’s needs and preference is
important, particularly because this may lead to better
adherence and clinical outcomes and reduced health
care expenditure.
22,23
The present study indicated that
Forspiro mDPI, the haptics and operation of which
were developed in close collaboration with the pa-
tients, has several attributes that patients rate highly.
5
In particular, the Forspiro mDPI is a simplified device
with an integrated dose counter
29
(Fig. 4Aand B),
which enables the user to ensure that the drug has been
delivered accurately by means of clear audible and
tactile feedback during piercing of the blister that con-
tained the drug as well as examination of the used
blisters for any remaining medication (Fig. 4 C). In
view of the results presented here, it can be concluded
that FP-Sal Forspiro mDPI (AirFluSal) and Seretide
Accuhaler are interchangeable at both doses investi-
gated from both efficacy and device handling points of
view.
ACKNOWLEDGMENTS
We thank all the centers involved in the study. Medical writing
assistance was provided by Synergy.
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