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Reprint
Heat-inactivated Bifi dobacterium bifi dum
MIMBb75 (SYN-HI-001) in the treatment
of irritable bowel syndrome:
a multicentre, randomised, double-blind,
placebo-controlled clinical trial
Viola Andresen, Jürgen Gschossmann, Peter Layer
Lancet Gastroenterol Hepatol 2020; 5: 658–666
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Articles
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658
Lancet Gastroenterol Hepatol
2020; 5: 658–666
Published Online
April 8, 2020
https://doi.org/10.1016/
S2468-1253(20)30056-X
See Comment page 627
Department of Internal
Medicine, Israelitic Hospital,
University of Hamburg
Teaching Hospital, Hamburg,
Germany (V Andresen MD,
P Layer MD); and Department
of Internal Medicine, Hospital
Forchheim, Forchheim,
Germany (J Gschossmann MD)
Correspondence to:
Dr Peter Layer, Department of
Internal Medicine, Israelitic
Hospital, D-22297 Hamburg,
Germany
p.layer@ik-h.de
Heat-inactivated Bifidobacterium bifidum MIMBb75
(SYN-HI-001) in the treatment of irritable bowel syndrome:
a multicentre, randomised, double-blind, placebo-controlled
clinical trial
Viola Andresen, Jürgen Gschossmann, Peter Layer
Summary
Background Bifidobacterium bifidum MIMBb75 is one of a few probiotic strains that have been shown to be eective in
the treatment of irritable bowel syndrome (IBS) and its symptoms. Non-viable strains might have advantages over viable
bacteria for product stability and standardisation, as well as for tolerability because safety concerns have been raised for
specific patient groups who are susceptible to infection. We aimed to assess the ecacy of non-viable, heat-inactivated
(HI) B bifidum MIMBb75 (SYN-HI-001) in the treatment of IBS and its symptoms.
Methods We did a double-blind, placebo-controlled trial in which patients with IBS were recruited from 20 study sites
in Germany and randomly assigned to receive either two placebo capsules or two capsules with a combined total of
1 × 10⁹ non-viable B bifidum HI-MIMBb75 cells to be taken orally once a day for 8 weeks. Eligible patients were
diagnosed with IBS according to Rome III criteria and had abdominal pain (≥4 on an 11-point numerical rating scale)
on at least 2 days during a 2-week run-in phase. Patients with chronic inflammatory bowel diseases, systemic diseases,
cancer, autoimmune diseases, with an intake of antipsychotic medications 3 months before study start, or with an
intake of systemic corticosteroids within 1 month before study start were excluded. Randomisation was in a 1:1 ratio
according to a computer-generated blocked list. Patients, investigators, clinical monitors, project managers, and
statisticians were masked to the randomisation. The primary composite endpoint was the combination of at least 30%
improvement of abdominal pain and adequate relief of overall IBS symptoms being fulfilled in at least 4 of 8 weeks
during treatment. Analysis of the primary endpoint included all randomly assigned patients receiving at least one
dose of study medication and who had no severe protocol violation. Safety analysis included all patients who had
taken at least one dose of the study medication and was based on frequency and severity of adverse events, laboratory
evaluation, and global assessment of tolerability. This trial is registered with the ISRCTN registry, ISRCTN14066467,
and is completed: the results shown here represent the final analysis.
Findings Patients were screened between April 15, 2016, and Feb 3, 2017, and 443 patients were allocated to the
placebo group (n=222) or the B bifidum HI-MIMBb75 group (n=221). The composite primary endpoint was reached
by 74 (34%) of 221 patients in the B bifidum HI-MIMBb75 group compared with 43 (19%) of 222 in the placebo group
(risk ratio 1·7, 95% CI 1·3–2·4; p=0·0007). No serious adverse events occurred in the B bifidum HI-MIMBb75 group;
seven adverse events suspected to be related to the study product were reported in the B bifidum HI-MIMBb75 group
as were eight in the placebo group. No deaths were reported in this study. The most common reported adverse event
with a suspected relationship to the study product was abdominal pain, which was reported in two (<1%) patients in
the B bifidum HI-MIMBb75 group and one (<1%) in the placebo group. Tolerability was rated as very good or good by
200 (91%) patients in the B bifidum HI-MIMBb75 group compared with 191 (86%) in the placebo group.
Interpretation This study shows that B bifidum HI-MIMBb75 substantially alleviates IBS and its symptoms in a real-
life setting. These results indicate that specific beneficial bacterial eects are mediated independently of cell viability.
Funding Synformulas.
Copyright © 2020 Elsevier Ltd. All rights reserved.
Introduction
Irritable bowel syndrome (IBS) is one of the most
common gastrointestinal disorders, with an estimated
prevalence of up to 15% in the European population.1,2
This disease is characterised by recurrent episodes of
gastrointestinal symptoms, such as abdominal pain,
flatulence, bloating, diarrhoea, and constipation, and by
the absence of relevant abnormal findings in routine
diagnostic tests. In the absence of distinct biomarkers,
IBS is typically diagnosed on the basis of symptom
criteria, such as the Rome IV or Rome III criteria.3,4
Patients with IBS have a distinct impairment of their
quality of life, which has been found to be even worse
than in patients with other chronic diseases.5
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The cause of IBS has not yet been fully elucidated.
However, several colonic biopsy studies show that the
intestinal barrier is altered in patients with IBS, with
statistically significantly higher permea bility than in
healthy individuals.6–8 It is thought that an impaired
intestinal barrier facilitates the translocation of intra-
luminal content, including facultative pathogenic bacteria,
causing alterations of mucosal enteric neural functions,
leading to IBS and its symptoms.6–9 Accordingly,
enhancing the gut barrier is a useful treatment approach
for patients with IBS.
Some probiotic strains can adhere well to epithelial
cells and strengthen intestinal barrier function, providing
an explanation for the ecacy of at least some probiotics
in the treatment of IBS.10–12 Lactobacillus rhamnosus GG
has been shown to accelerate the maturation of the
intestinal barrier in an animal model, and Saccharomyces
bouldarii has been shown to decrease intestinal permea-
bility in patients with Crohn’s disease.10 Further more,
cytokine-induced epithelial barrier dysfun ction in human
epithelial cells can be prevented by Lactobacillus casei and
by a combination of Streptococcus thermophilus and
Lactobacillus acidophilus.11,12 The potential of Bifido-
bacterium bifidum MIMBb75 as a treatment for IBS has
been particularly intriguing because of its therapeutic
ecacy in improving symptoms of IBS and
simultaneously improving quality of life for patients.9
Furthermore, B bifidum MIMBb75 has been shown to
exert strong adhesion to human intestinal epithelial
Caco-2 cells, with an observed adhesion index markedly
exceeding that of other commercial probiotics.9,13 It has
been suggested that the clinical eects of B bifidum
MIMBb75 involve, and are likely to be mediated by, its
marked mucosal adhesive properties.9,13 Adhesion of
Bifidobacteria strains such as B bifidum MIMBb75 to
epithelial cells depends mainly on the cell surface
hydrophobicity and occurs by attractive physical forces
between the hydrophobic cell surface and the epithelial
cells—so-called hydrophobic interactions.14 Notably,
follow ing gentle heat inactivation, the B bifidum strain
heat-inactivated (HI)-MIMBb75 (SYN-HI-001) has been
rendered non-viable but still morphologically intact, and
has preserved (and even increased) its Caco-2 cell-
adhesive properties (unpub lished). The ecacy of various
bacterial strains for the treatment of IBS is highly strain-
specific and even closely related strains might dier
substantially in their ecacy and related properties such
as adhesion to Caco-2 cells.15–18 Strains such as B bifidum
MIMBb75 or Bacillus coagulans MTCC5856 have been
found to be ecacious in IBS.9,19 Viable B bifidum
MIMBb75 has been shown to eectively alleviate IBS and
its symptoms such as abdominal pain, discomfort,
distension, and bloating in a placebo-controlled trial.9 In
patients with diarrhoea-predominant IBS, supple men-
tation of B coagulans MTCC5856 together with standard
care for this condition significantly decreased clinical
symptoms (bloating, vomiting, diarrhoea, abdom inal
pain, and stool frequency) compared with placebo.19
However, several other multi strain and monostrain
preparations were found to be ineective in IBS.20,21
Research in context
Evidence before this study
We searched PubMed for the terms “bacteria”, “probiotics”,
“non-viable”, “inactivated”, and “irritable bowel syndrome”
for relevant published randomised placebo-controlled studies
and meta-analyses investigating the efficacy of viable and
non-viable bacterial strains in irritable bowel syndrome (IBS),
up to July 31, 2019. We did not use any language restrictions.
We found that the efficacy of viable probiotic strains is highly
strain-specific and only a few strains have been shown to
significantly alleviate IBS symptoms. Bifidobacterium bifidum
MIMBb75 has been particularly intriguing because of its
therapeutic efficacy. Although generally, the use of viable
probiotic strains is considered to be safe, severe infections or
even septic complications have been reported rarely,
particularly in severely ill or immunocompromised patients.
Therefore, non-viable bacterial strains could be a safe
alternative and have further advantages over viable bacteria
with regard to product stability and standardisation, which
could be particularly relevant for patients who are travelling
or who are living in warm and humid climate zones. However,
to our knowledge, there have been no placebo-controlled
studies investigating the efficacy of non-viable bacteria in IBS
compared with placebo.
Added value of this study
To our knowledge, this is the first time that the efficacy and
safety of a non-viable bacterial strain has been investigated in a
placebo-controlled study for the treatment of IBS. The findings
show that non-viable, heat-inactivated (HI) B bifidum MIMBb75
(SYN-HI-001) improves IBS and its symptoms significantly more
than does placebo, and thus are the first demonstration of
substantial and clinically relevant efficacy of non-viable bacteria
in the treatment of IBS. The treatment was not associated with
any safety risk and the tolerability was rated very good.
Implications of all the available evidence
These results show that some beneficial bacterial effects are
mediated independent of cell viability and can be preserved in
non-viable bacterial preparations. B bifidum HI-MIMBb75 has
been rendered non-viable but still morphologically intact, and
its strong adhesive properties have been preserved (and even
increased). In this study, B bifidum MIMBb75 in its non-viable
form appears to reach or even to surpass the effects observed in
response to the corresponding viable form. Because of these
promising results, we expect more research will be done to
understand the applications of non-viable bacterial strains in IBS
and potentially in other gastroenterological diseases.
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660
Non-viable bacteria might have advantages over some
living probiotics because the use of non-viable bacteria is
associated with better standardisation, greater stability,
and improved safety.22 However, inactivation of bacteria
has repeatedly been found to decrease their ecacy.23–25
For example, Tsuchiya and colleagues25 reported that the
viable but not the non-viable form of a specific strain
composition could alleviate IBS symptoms. So far,
clinical eects of non-viable bacteria on IBS symptoms
have not been shown in controlled trials.26 Therefore, we
aimed to assess the ecacy of non-viable B bifidum
HI-MIMBb75 in IBS compared with placebo.
Methods
Study design
This was a large-scale, multicentre, double-blind,
randomised, placebo-controlled, two-arm inter ventional
clinical study. Participants were recruited in 20 primary
care and referral centres in Germany (see appendix p 1
for full list of participating centres). The study protocol
was approved by the Hamburg State Ethics Committee
before the study started and the trial was done in
compliance with the Declaration of Helsinki and the
Guideline for Good Clinical Practice (CPMP/
ICH/135/95).
Participants
Participants were recruited by the principal investigators
and by using advertisements (eg, flyers in physician
oces, newspapers, and banners in public transportation).
Eligible patients (aged 18 years and older) were assessed
by a physician and were only included if they met all
inclusion and exclusion criteria, including criteria for IBS
according to Rome III. In addition to the Rome III criteria,
the main inclusion criterion was abdominal pain (≥4 on
an 11-point numerical rating scale) on at least 2 days
during the 2-week run-in phase. Individuals with
inflammatory organic gastrointestinal diseases, systemic
diseases, cancer, autoimmune diseases, diabetes, lactose
intolerance, immune deficiency, abdom inal surgery
(except appendectomy, hernia surgery, cholecystectomy,
or caesarean section), hyperthyroidism or non-medically
adjusted hypothyroidism, use of anti psychotic medications
within 3 months before the start of the study, use of
systemic corticosteroids within 1 month before the start of
the study, major psychiatric disorder, coeliac disease, or
pregnancy were excluded. Patients older than 55 years
with no negative diagnostic result of sigmoidoscopy or
colonoscopy within the past 5 years were also excluded.
On the basis of blood sample analysis (haematology,
chemistry, and hormones), investigators excluded patients
with abnormal laboratory results. Criteria were defined
according to the current European Medicines Agency
guideline recommendations (see appendix pp 2–3 for
complete inclusion and exclusion criteria and parameters
measured in blood).3 All participants gave their written
informed consent.
Randomisation and masking
Participants were randomly assigned in a 1:1 ratio to
treatment with B bifidum HI-MIMBb75 or placebo
according to a computer-generated blocked randomisation
list with a block size of four. The randomisation list
assigning a unique randomisation number to a treatment
was generated and kept sealed by an unmasked
randomisation administrator (independent of study
conduct and data analysis). The patients, investigators,
clinical monitors, project managers, and statisticians
were all masked to the randomisation. The packaging of
the placebo and of the B bifidum HI-MIMBb75 were
identical in appearance, were labelled in advance with the
randomisation number, and distributed to the study sites
as multiples of the block size. Investigators allocated the
study products with the randomisation numbers in
ascending sequence to the patients without skipping any
number. This procedure was subject to monitoring. For
use in emergencies, investigators received a sealed
envelope for each randomisation number. If any envelope
was opened, the time, date, and reason for opening had to
be written on the envelope, signed by the investigator. At
the end of the study, all envelopes were returned to the
sponsor unopened, confirming that masking was
maintained throughout the study.
Procedures
Over a total of 12 weeks per patient, five physician visits
were carried out: one at screening, one after a 2-week
run-in phase (randomisation), one after 4 weeks of
treatment (control visit), one after 8 weeks of treatment
(end of treatment), and one after a further 2-week wash-
out phase (end of study; appendix p 3). Patients recorded
daily their global and individual IBS symptoms in a
patient diary throughout the 12-week study. The patients
visited the physicians, who recorded the severity of IBS
symptoms (all visits) and health-related quality of life
(visits 2–4), as well as other parameters, possible adverse
events, and use of medication (all visits).
At visit 1, a complete physical examination and medical
history documentation, including a global IBS question-
naire, were done and patients were screened for inclusion
and exclusion criteria. A blood sample was collected for
safety analyses and pregnancy testing in female patients.
Participants were instructed to maintain their eating and
lifestyle habits throughout the study and received a patient
diary. Bisacodyl and loperamide could be used as rescue
medication but ingestion of probiotics or other products
that could influence the ecacy of the study product were
not allowed (eg, antibiotic drugs 3 months before the start
of the study and during the study; systemic corticosteroids
1 month before the start of the study and during the study;
analgesics, laxatives, chemotherapeutics, spasmolytics,
antidiarrhoeal drugs, or probiotics during the study). At
visit 2, diaries of the 2-week run-in phase were reviewed by
the physicians (or their sta). Patients who had recorded a
pain score of at least 4 on 2 days during the run-in phase
See Online for appendix
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and who met study inclusion and exclusion criteria were
randomly assigned to receive for 8 weeks either two
capsules with a combined total of 1 × 10 B bifidum
HI-MIMBb75 cells, or two placebo capsules. The two
capsules were to be taken orally once a day. All randomly
assigned patients received 112 capsules, which were
sucient for 8 weeks of treatment, and had to return all
unused study product after the end of treatment.
Compliance was checked by the investigator, who counted
the number of returned capsules. Patients could pre-
maturely stop study participation by their own decision or
by decision of the investigator (eg, in case of severe side-
eects attributable to the study treatment). At visit 5 (the
final visit), a second blood sample was collected for safety
analysis.
The treatment was obtained by heat-inactivation of viable
bacterial strain B bifidum MIMBb75, which resulted in
morphologically intact, non-viable cells of B bifidum
HI-MIMBb75. The preparation was filled into uncoated
capsules of 0·5 × 10⁹ non-viable cells per capsule by a
contract manufacturer of the sponsor (C Hedenkamp,
Hövelhof, Germany). Placebo capsules with an identical
appearance to the B bifidum HI-MIMBb75 capsules were
filled with maltodextrin by the same contract manufacturer.
The study product was prepared under good manufacturing
process conditions and was supplied to the sponsor.
Clinical monitors distributed the study products to the
study sites.
Outcomes
The prospectively chosen primary outcome was the
composite response, defined as a combination of pain
response and global relief response (adequate relief of IBS
symptoms), with both response criteria being fulfilled in at
least 4 out of 8 weeks during treatment. Pain was assessed
daily by patients by grading abdominal pain during the last
24 h using an 11-point numerical rating scale ranging from
0 to 10. These daily results were used to compute mean
values for each week. Pain response was defined as at least
a 30% improvement in these weekly averages compared
with baseline (defined as mean pain value for the last week
of the run-in phase). To assess global symptom relief, a
7-point Likert scale was used. Patients were asked weekly
during the 8-week treatment phase to answer the
question “Compared to the way you usually felt before
taking the study product how would you rate your relief
of symptoms (abdominal pain/discomfort, bowel habits,
and other IBS symptoms) during the last 7 days?”
Possible answers ranged from 1 (very much relieved),
2 (considerably relieved), 3 (somewhat relieved),
4 (unchanged), 5 (somewhat worse), 6 (considerably
worse), to 7 (very much worse). Adequate relief of IBS
symptoms was defined as a score of 3 or less.
Secondary endpoints included change in the subject’s
global assessment (SGA) of IBS symptoms, as well as
change in individual IBS symptoms, such as abdominal
pain (assessed on the 11-point numerical rating scale),
distension or bloating, and urgency (both recorded on the
7-point Likert scale). Additionally, individual symptom
scores were combined into a composite symptom score
consisting of the arithmetic mean of SGA and the three
individual symptom scores. Furthermore, number of
bowel movements, stool form (via the Bristol Stool Form
Scale [BSFS]), sensation of incomplete bowel evacuation,
and intake of medication were recorded daily in the
patient diary.
Throughout the study period (ie, visits 2–5), the IBS-
severity scoring system (IBS-SSS) was used for grading
IBS symptom severity, which is based on five visual
analogue scales (VAS; 0–100) and comprises abdominal
pain severity, abdominal pain frequency (number of
days with pain during the past 10 days), abdominal
bloating severity, bowel movement satisfaction (0 being
very satisfied, and 100 being very unsatisfied), and
interference of IBS with daily activities for the past
10 days. Moreover, health-related quality of life was
assessed by the use of the short form 12 (SF-12)
questionnaire before, during, and at the end of treatment
(ie, at visits 2, 3, and 4).
Secondary ecacy variables also included response
based on a 50% rule of symptom relief during treatment
(at least improvement in 4 of 8 weeks within the treatment
period and improvement defined as a reduction of at least
one point from baseline). A full list of secondary endpoints
is included in the appendix (p 8). Safety analysis was
based on frequency and severity of adverse events,
laboratory evaluation, and global assessment of
tolerability. Adverse events were recorded throughout
the study, and global tolerability was assessed by using a
5-point numerical rating scale. Adverse events were
graded by severity (mild, moderate, severe) and the
causal relationship to the study product was assessed by
the investigator. Adverse events were coded using
Medical Dictionary for Regulatory Activities (MedDRA)
version 19.0. Coding was done using the German version
of MedDRA, and the corresponding English version was
used for the final analysis. Adverse events were tabulated
on the basis of preferred terms of MedDRA.
Statistical analysis
We tested the null hypothesis that no dierence exists
between the composite response rates of the two groups.
The sample size calculation was based on the estimated
responses of the placebo and treatment group for the
primary endpoint and the estimated dierences between
the IBS subgroups for main symptom scores. On the
basis of the available literature, a placebo response rate of
20% and a dierence of 17% between the treatment
groups were estimated for the primary endpoint. A sample
size of 350 evaluable patients was calculated to be needed
for 80% power. With an estimated drop-out rate of 15–20%
after randomisation, 412 randomly allocated patients were
planned and 507 were recruited to account for possible
withdrawals before the start of the study.
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The primary objective of this study was to assess
whether the combined response rate of pain and
adequate IBS symptom relief response is significantly
larger in the B bifidum HI-MIMBb75 group than in the
placebo group. The data from the patient diaries were
entered into the study database by the data manager and
evaluated centrally. The Cochrane-Mantel-Haenszel test
stratified by study centre was used for the comparison
of treatment groups, and p<0·05 was considered to be
statistically significant. The primary analysis included
all successfully randomly assigned patients receiving at
least one dose of study medication and who had no
severe protocol violation. Missing ecacy data were
replaced using the last value carried forward approach
and patients for whom only baseline data obtained from
the 2-week run-in period were available for the primary
endpoint were automatically counted as non-responders
in the evaluation of the primary ecacy criterion. For
sensitivity analysis, an additional per-protocol analysis
was done. The per-protocol population was defined as
the primary analysis population excluding patients with
missing or inade quate measurement of the primary
endpoint, less than 80% intake of the anticipated study
product, or major protocol violations.
Secondary endpoints were analysed on the basis of
available data using descriptive statistics, confidence
intervals, and test statistics. Tests applied were the
Wilcoxon rank sum test for continuous variables and the
Fisher’s exact test for binary variables. p values reported in
secondary endpoint analyses are for descriptive purposes
only and are two-sided. All analyses, including subgroup
analysis of specific endpoints according to IBS type, were
prespecified in the protocol.
Adverse events were analysed in the safety population
(patients who had taken at least one dose of the study
medication). All statistical analyses were done using
SAS version 9.4. The trial is registered at the ISRCTN
clinical trial registry, ISRCTN14066467.
Role of the funding source
The funder of the study had no role in study design, data
collection, data analysis, data interpretation, or writing of
the report. The corresponding author had full access to
all of the data in the study and had the final responsibility
for the decision to submit for publication.
Results
507 patients were assessed for eligibility from
April 15, 2016, to Feb 3, 2017, and 443 patients were
enrolled and randomly assigned to receive either placebo
(n=222) or B bifidum HI-MIMBb75 (n=221). All
443 patients were included in the primary and safety
analyses (intention-to-treat [ITT] population). The
median follow-up for the ITT population was 71 days
(IQR 70–74). 66 patients (35 in the placebo group and
31 in the B bifidum HI-MIMBb75 group) dropped out
(13 from the placebo group and 14 from the B bifidum
HI-MIMBb75 group) or had major protocol violations
(22 in the placebo group and 17 in the B bifidum
HI-MIMBb75 group). 377 patients (187 in the placebo
group and 190 in the B bifidum HI-MIMBb75 group)
were included in the per-protocol analysis (figure 1).
Baseline characteristics were well balanced between
treatment groups. Patients were classified according to
the recommendations of the European Medicines
Agency3 by their predominant stool pattern in the run-in
phase using the BSFS, with 107 (24%) of 443 participants
being classified as having constipation-predominant IBS,
177 (40%) classified as having diarrhoea-predominant
IBS, 34 (8%) classified as having mixed IBS, and 125 (28%)
Figure 1: Trial profile
HI=heat inactivated
222 assigned to placebo group
187 included in per-protocol analysis
22 had major protocol violations
13 discontinued
5 adverse events
4 non-compliance or no follow-up
4 other reasons
221 assigned to Bifidobacterium bifidum HI-MIMBb75
group
190 included in per-protocol analysis
17 had major protocol violations
14 discontinued
6 adverse events
4 non-compliance or no follow-up
4 other reasons
443 randomly assigned
507 patients screened for eligibility
42 ineligible
22 excluded for other reasons
Bifidobacterium
bifidum
HI-MIMBb75
(n=221)
Placebo (n=222)
Age, years 40·1 (12·8) 42·6 (13·8)
Female sex 155 (70%) 152 (69%)
Height, cm 172·4 (8·9) 171·3 (9·1)
Weight, kg 73·2 (17·7) 72·8 (16·6)
Body-mass index, kg/m² 24·5 (5·3) 24·7 (5·0)
Abdominal pain run-in week 1* 4·02 (1·71) 4·18 (1·75)
Abdominal pain run-in week 2* 4·08 (1·94) 4·04 (1·88)
Irritable bowel syndrome type
Constipation predominant 54 (24%) 53 (24%)
Diarrhoea predominant 95 (43%) 82 (37%)
Mixed 14 (6%) 20 (9%)
Unsubtyped 58 (26%) 67 (30%)
Data are n (%) or mean (SD). HI=heat inactivated. *Mean of values assessed daily
by participants on 11-point numerical rating scale.
Table 1: Baseline characteristics of the intention-to-treat population
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classified as having unsubtyped IBS, with no significant
dierences between the B bifidum HI-MIMBb75 and
placebo groups in terms of IBS subtype. Mean patient age
was 41·3 years (SD 13·3), and 307 (69%) participants were
women (table 1).
The primary endpoint of composite response was met
in 74 (34%) of 221 patients in the B bifidum HI-MIMBb75
group and in 43 (19%) of 222 patients in the placebo
group (table 2; appendix p 3). The risk ratio (RR) was
1·7 (95% CI 1·3–2·4) in favour of treatment with
B bifidum HI-MIMBb75 (p=0·0007; table 2), and the
number needed to treat (NNT) was 7·1 (3·0–11·2).
Similar results were found in the per-protocol analysis:
70 (37%) of 190 patients in the B bifidum HI-MIMBb75
group, and 37 (20%) of 187 in the placebo group met the
primary endpoint of composite response. The RR was
1·8 (1·3–2·5; p=0·0004) and NNT was 5·9 (2·8–8·9).
Over the duration of the study, the proportion of
patients with a composite response increased between
week 1–4 and week 5–8 in the treatment group as well as
in the placebo group, but the dierence between the
groups was maintained (B bifidum HI-MIMBb75 group:
70 [32%] patients in week 1–4 and 87 [39%] patients in
week 5–8 had a composite response; placebo group:
44 [20%] patients in week 1–4 and 66 [30%] patients in
week 5–8 had a composite response) and remained
significant (week 1–4: RR 1·6 [95% CI 1·1–2·2], p=0·0047;
week 5–8: 1·3 [1·0–1·7], p=0·036; table 2).
A significantly greater proportion of patients in the
B bifidum HI-MIMBb75 group (133 [60%] of 221) reported
adequate symptom relief, defined as a Likert score of 3 or
less, than in the placebo group (98 [44%] of 222). RR was
1·4 (95% CI 1·1–1·6; p=0·0009; table 2; appendix p 4),
with NNT 6·2 (2·7–9·8). Patients in the B bifidum
HI-MIMBb75 group reported consistently greater
symptom relief throughout the study compared with
patients in the placebo group. At the end of week 1 of
treatment, the mean symptom relief score in the B bifidum
HI-MIMBb75 group was 3·62 and in the placebo group
was 3·78 (p=0·051); at the end of treatment, the mean
symptom relief score in the B bifidum HI-MIMBb75
group was decreased to 3·08 (3·44 in the placebo group;
p=0·0006; figure 2).
IBS-SSS was assessed at physician visits 2–5. At the end
of treatment, the proportion of patients with an
improvement in IBS-SSS of at least 50% was signifi cantly
greater in the B bifidum HI-MIMBb75 group (91 [41%]
of 221) than in the placebo group (64 [29%] of 222). Risk
dierence was 12·35 (95% CI 2·89–21·33; p=0·0072;
table 2). Similar results were obtained in the per-protocol
analysis (data not shown). Correspondingly, decreases in
IBS-SSS sum scores between baseline and the end of
treatment diered significantly between the two groups
in the ITT analysis: in the B bifidum HI-MIMBb75 group,
the sum score decreased by 101 points; in the placebo
group, the sum score decreased by 71 points (p=0·0013;
table 3, appendix p 4).
As measured on VAS from 1 to 100, bowel movement
satisfaction was reduced (and therefore improved) by
23·7 points in the B bifidum HI-MIMBb75 group,
compared with a reduction of 16·6 points in the placebo
group (p=0·021). Days with pain was reduced by
22·7 points in the B bifidum HI-MIMBb75 group,
compared with a reduction of 14·3 points in the placebo
group (p=0·0080). Impact on daily life was reduced by
20·1 points in the B bifidum HI-MIMBb75 group,
compared with a reduction of 14·2 points in the placebo
group (p=0·012; table 3).
The secondary endpoints of change in SGA of IBS
symptoms and change in abdominal pain, distension or
bloating, and urgency as individual symptoms were
assessed on a daily basis in the patient diary. Patients in
the B bifidum HI-MIMBb75 group showed a significant
reduction in SGA by 0·76 points from baseline to the end
of treatment versus 0·54 points in the placebo group
(p=0·013). Patients in the B bifidum HI-MIMBb75 group
Bifidobacterium
bifidum
HI-MIMBb75
Placebo RR or RD (95% CI) p value
Composite response 74/221 (34%) 43/222 (19%) RR 1·7 (1·3–2·4) 0·0007*
Composite response
(PP population)
70/190 (37%) 37/187 (20%) RR 1·8 (1·3–2·5) 0·0004*
Composite response
(over treatment weeks 1–4)
70/221 (32%) 44/222 (20%) RR 1·6 (1·1–2·2) 0·0047†
Composite response
(over treatment weeks 5–8)
87/221 (39%) 66/222 (30%) RR 1·3 (1·0–1·7) 0·036†
Adequate relief 133/221 (60%) 98/222 (44%) RR 1·4 (1·1–1·6) 0·0009†
IBS-SSS (improvement by ≥50%) 91/221 (41%) 64/222 (29%) RD 12·35 (2·89–21·33) 0·0072†
Data are n/N (%), unless otherwise indicated. Results are analysed in the ITT population, unless otherwise indicated.
HI=heat inactivated. IBS-SSS=irritable bowel syndrome-severity scoring system. ITT=intention to treat. PP=per
protocol. RD=risk difference. RR=risk ratio. *Cochran-Mantel-Haenzel. †Fisher’s exact test.
Table 2: Summary of efficacy parameters analysed as responder
Figure 2: Effects of Bifidobacterium bifidum HI-MIMBb75 and placebo on
symptom relief
Symptom relief was recorded on a 1–7 scale on a weekly basis. Bars represent the
95% CIs. HI=heat inactivated.
1 2 3 4 5 6 7 8
4·0
3·8
3·6
3·4
3·2
3·0
0
Mean symptom score
Week
Bifidobacterium bifidum HI-MIMBb75
Placebo
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664
also showed a reduction in abdominal pain by 1·29 points
versus 0·93 points in the placebo group (p=0·011), and a
reduction in distension or bloating by 0·69 points versus
0·50 points in the placebo group (p=0·046). Patients in
the B bifidum HI-MIMBb75 group showed a reduction in
urgency of 0·69 versus a reduction of 0·52 in the placebo
group (p=0·087). A composite score 1–4 was calculated for
the IBS symptoms (SGA, abdominal pain, distension or
bloating, and urgency). The patients in the B bifidum
HI-MIMBb75 group showed a significantly greater
improvement in the composite score compared with the
placebo group (change from baseline to end of treatment
in the B bifidum HI-MIMBb75 group: –1·21 points; in the
placebo group: –0·89 points; p=0·026). Furthermore,
discomfort and pain associated with bowel movement
were assessed on a weekly basis in the patient diary.
Discomfort was reduced by 1·35 points versus 0·92 points
in the placebo group (p=0·0015), and pain associated with
bowel movement was reduced by 0·88 points versus
0·46 points in the placebo group (p=0·023; table 3).
The improvement in the SF-12 sum score was
significantly greater in the B bifidum HI-MIMBb75 group
compared with in the placebo group. SF-12 sum score
increased from baseline to the end of treatment by 5·82
in the B bifidum HI-MIMBb75 group and by 4·06 in the
placebo group (p=0·038). SF-12 mental health sum score
improved from baseline to the end of treatment by
3·31 in the B bifidum HI-MIMBb75 group and by 1·66 in
the placebo group (p=0·031). SF-12 physical health sum
score showed a numerically larger improvement in the
B bifidum HI-MIMBb75 group (2·51) compared with
placebo (2·40), but the dierence was not statistically
significant (p=0·90; table 3; appendix p 4).
Subgroup analyses showed improvement of IBS type-
specific symptoms between baseline and end of treatment.
In patients with constipation-predominant IBS who
received B bifidum HI-MIMBb75, the number of bowel
movements per week increased by 1·7. By contrast, in the
placebo group, bowel movements per week decreased by
1·0 (p=0·022; table 3). In the subgroup of patients with
diarrhoea-predominant IBS, stool consistency improved
significantly more in the B bifidum HI-MIMBb75 group
(BSFS decreased by 0·68) than in the placebo group
(BSFS decreased by 0·48; p=0·039; table 3). In both the
mixed-IBS and the unsubtyped-IBS subgroups, bowel
movement satisfaction was significantly improved in
patients taking B bifidum HI-MIMBb75. At the end of
treatment, the dierence in mean change from baseline
(B bifidum HI-MIMBb75 – placebo) was –27·41 (95 % CI
–49·26 to –5·55) in the mixed subgroup, and –13·71
(–24·66 to –2·76) in the unsubtyped subgroup (table 3).
15 adverse events were reported with a suspected
relationship to the study product, seven in the B bifidum
HI-MIMBb75 group and eight in the placebo group
(table 4). Three patients had a treatment interruption (one
in the B bifidum HI-MIMBb75 group and two in the
placebo group) and nine patients permanently stopped
Bifidobacterium
bifidum
HI-MIMBb75
Placebo p value* Treatment
difference, B bifidum
HI-MIMBb75 –
placebo (95% CI)
IBS-SSS –101 –71 0·0013 ··
IBS-SSS (PP) –102 – 74 0·0048 ··
Bowel movement satisfaction† –23·7 –16·6 0·021 ··
Days with pain† –22·7 –14·3 0·0080 ··
Impact on daily life† –20·1 –14·2 0·012 ··
SGA of IBS symptoms –0·76 –0·54 0·013 ··
Abdominal pain‡ –1·29 –0·93 0·011 ··
Distension or bloating§ –0·69 –0·50 0·046 ··
Composite score 1–4 –1·21 –0·89 0·026 ··
Discomfort§ –1·35 –0·92 0·0015 ··
Pain associated with bowel
movement§
–0·88 –0·46 0·023 ··
SF-12 sum score 5·82 4·06 0·038 ··
SF-12 mental health sum score 3·31 1·66 0·031 ··
SF-12 physical health sum score 2·51 2·40 0·90 ··
Number of bowel movements per
week (in constipation-predominant
subgroup)
1·7 –1·0 0·022 ··
Stool consistency¶ (in diarrhoea-
predominant subgroup)
–0·68 –0·48 0·039 ··
Bowel movement satisfaction†
(in mixed subgroup)
·· ·· ·· –27·41
(–49·26 to –5·55)
Bowel movement satisfaction†
(in unsubtyped subgroup)
·· ·· ·· –13·71
(–24·66 to –2·76)
Results are analysed for patients in the ITT population and all IBS patients, unless otherwise indicated. BSFS=Bristol
Stool Form Scale. HI=heat inactivated. IBS-SSS=irritable bowel syndrome-severity scoring system. ITT=intention to
treat. PP=per protocol. SF-12=health-related quality of life short form-12. SGA=subject's global assessment.
VAS=visual analogue scale. *p (categorial): Fisher’s exact test (2 × 2 tables) or χ² test in higher dimensions. †Assessed
using VAS 0–100 as part of the IBS-SSS. ‡Assessed using an 11-point numerical rating scale. §Assessed using a 7-point
Likert scale. ¶Assessed using the BSFS.
Table 3: Summary of efficacy parameters analysed as change from baseline
Bifidobacterium
bifidum
HI-MIMBb75
(n=221)
Placebo
(n=222)
p value
Abdominal distension 1 (<1%) 1 (<1%) 1·0
Abdominal pain 2 (<1%) 1 (<1%) 0·62
Upper abdominal pain 0 1 (<1%) 1·0
Constipation 0 1 (<1%) 1·0
Diarrhoea 0 2 (<1%) 0·50
Gastroenteritis 1 (<1%) 0 0·50
Aggravated irritable
bowel syndrome
1 (<1%) 0 0·50
Liver function test 0 2 (<1%) 0·50
Nausea 1 (<1%) 0 0·50
Urinary incontinence 1 (<1%) 0 0·50
Data are n (%). HI=heat inactivated. MedDRA=Medical Dictionary for Regulatory
Activities.
Table 4: Incidence of adverse events with suspected relationship to the
study drug by preferred term (according to MedDRA)
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taking the study product (four in the B bifidum
HI-MIMBb75 group and five in the placebo group) because
of an adverse event. No significant dierences in the side-
eects profile of B bifidum HI-MIMBb75 versus placebo
were noted. Two patients reported serious adverse events:
acute coronary syndrome and femoral neck fracture,
which were both rated as not treatment related and which
both occurred in the placebo group. No deaths were
reported in this study.
Medications taken for IBS symptoms were not
significantly dierent between the two treatment groups
(data not shown). Clinical and laboratory surveillance
data showed no risk signals (data not shown). Global
assessment of tolerability at the end of treatment was
rated very good or good by 200 (91%) of 221 patients in
the B bifidum HI-MIMBb75 group and 191 (86%) of
222 patients in the placebo group.
Discussion
In previous studies, the viable strain of B bifidum
MIMBb75 has been shown to significantly alleviate IBS
and its symptoms. However, it was unclear whether the
non-viable form of B bifidum MIMBb75 also has a
substantial eect on IBS. This randomised, placebo-
controlled study shows that B bifidum HI-MIMBb75
significantly reduces the entire symptom spectrum of IBS
of all subtypes, and thus, to the best of our knowledge, is
the first demonstration of substantial ecacy of a non-
viable bacterial strain preparation.
Compared with placebo, B bifidum HI-MIMBb75 was
associated with 1·7 times greater response rate for the
composite primary endpoint, defined as a combination
of at least a 30% improvement of abdominal pain
together with significant adequate relief of global IBS
symptoms in at least 50% of the treatment period.
Additionally, patients receiving B bifidum HI-MIMBb75
had greater relief of individual IBS symptoms, including
abdominal pain, distension and bloating, discomfort,
pain associated with bowel movement, and frequency of
bowel movement. Moreover, at the end of treatment,
several important parameters reflecting overall treatment
success were also significantly improved compared with
placebo, including health-related quality of life, IBS
symptom scores, and global symptom relief.
A potential limitation of this study is the considerable
placebo response, with a primary endpoint response rate
of 19%. On the other hand, in randomised controlled
clinical IBS trials, such placebo response rates are
common and the response seen in our trial is not
unusually high. Rather, global improvement response
rates to placebo in controlled IBS studies have been
reported to sometimes even exceed 40%.27–31
To our knowledge, no other non-viable bacterial strain
has been shown to significantly improve IBS and its
symptoms. Several studies have evaluated the
eectiveness of viable cells compared with non-viable
cells in acute diarrhoea; however, in these studies,
compared with the corresponding viable bacterial
preparations, non-viable preparations were either
inferior, or no eect could be shown.23–25,32 Conversely, in
this trial, the eect of the non-viable bacterial strain
appears to reach or even surpass the eects observed in
response to the corresponding viable form.9 These
results show for the first time that some beneficial
bacterial eects might be mediated independent of cell
viability, and could be preserved in non-viable bacterial
preparations. The strong adhesive properties of viable
B bifidum MIMBb75 to epithelial cells have been found
to be preserved (and increased) in the non-viable form
(unpublished).
The use of eective, non-viable bacterial strain
preparations have several substantial advantages over
some viable strains: although generally, the use of viable
probiotic micro-organisms is considered to be safe, severe
infectious or even septic complications have been reported
for specific viable strains or specific combinations of viable
strains in some patients, particularly in individuals who
are severely ill or immuno compromised.33,34 It might be
assumed that the use of non-viable bacteria for the
treatment of IBS could be a safe alternative, even in
patients who are potentially susceptible to infection.22 Our
study shows an excellent tolerability of B bifidum
HI-MIMBb75 and did not signal any safety risk for the use
in patients with IBS. A further advantage of non-viable
B bifidum HI-MIMBb75 is its far greater, temperature-
independent product stability compared with viable
bacteria, ensuring better standardisation even in regions
with warm or changing climates.
Contributors
PL was the lead author. All authors critically revised the manuscript and
undertook the quality control review.
Declaration of interests
PL has received reimbursement of travel expenses from Falk, outside of
the submitted work. VA has received speaker and consulting fees from
Allergan, Bayer, Falk, Ferring, Hexal, Kyowa Kirin, 4M-Medical, Sanofi,
Schwabe, and Shionogi, outside of the submitted work. JG has received
consultant fees from Synformulas, outside of the submitted work.
Data sharing
Besides the data presented in the Results and appendix, the authors have
not made arrangements to share further supporting data.
Acknowledgments
We thank Synformulas for funding the study. We also thank the patients
and personnel at each study site as well as the data manager for their
contribution to this study. Statistical analysis was done by Algora
Gesellschaft für Medizinstatistik und Vertriebssysteme. The Israelitic
Hospital received reimbursement for participating as study centre.
References
1 Lovell RM, Ford AC. Prevalence of gastro-esophageal reflux-type
symptoms in individuals with irritable bowel syndrome in the
community: a meta-analysis. Am J Gastroenterol 2012;
107: 1793–801.
2 Müller-Lissner SA, Bollani S, Brummer RJ, et al. Epidemiological
aspects of irritable bowel syndrome in Europe and North America.
Digestion 2001; 64: 200–04.
3 European Medicines Agency. Guideline on the evaluation of
medicinal products for the treatment of irritable bowel syndrome.
https://www.ema.europa.eu/en/documents/scientific-guideline/
guideline-evaluation-medicinal-products-treatment-irritable-bowel-
syndrome-revision-1_en.pdf (accessed March 2, 2020).
Articles
www.thelancet.com/gastrohep Vol 5 July 2020
666
4 Rome Foundation. Guidelines—Rome III diagnostic criteria for
functional gastrointestinal disorders. J Gastrointestin Liver Dis 2006;
15: 307–12.
5 Chang L. Review article: epidemiology and quality of life in
functional gastrointestinal disorders. Aliment Pharmacol Ther 2004;
20 (suppl 7): 31–39.
6 Piche T, Barbara G, Aubert P, et al. Impaired intestinal barrier
integrity in the colon of patients with irritable bowel syndrome:
involvement of soluble mediators. Gut 2009; 58: 196–201.
7 Vivinus-Nébot M, Dainese R, Anty R, et al. Combination of allergic
factors can worsen diarrheic irritable bowel syndrome: role of
barrier defects and mast cells. Am J Gastroenterol 2012; 107: 75–81.
8 Marshall JK, Thabane M, Garg AX, Clark W, Meddings J,
Collins SM. Intestinal permeability in patients with irritable bowel
syndrome after a waterborne outbreak of acute gastroenteritis in
Walkerton, Ontario. Aliment Pharmacol Ther 2004; 20: 1317–22.
9 Guglielmetti S, Mora D, Gschwender M, Popp K. Randomised
clinical trial: Bifidobacterium bifidum MIMBb75 significantly
alleviates irritable bowel syndrome and improves quality of life—
a double-blind, placebo-controlled study. Aliment Pharmacol Ther
2011; 33: 1123–32.
10 Lopetuso LR, Scaldaferri F, Bruno G, Petito V, Franceschi F,
Gasbarrini A. The therapeutic management of gut barrier leaking:
the emerging role for mucosal barrier protectors.
Eur Rev Med Pharmacol Sci 2015; 19: 1068–76.
11 Resta-Lenert S, Barrett KE. Probiotics and commensals reverse
TNF-α- and IFN-γ-induced dysfunction in human intestinal
epithelial cells. Gastroenterology 2006; 130: 731–46.
12 Eun CS, Kim YS, Han DS, Choi JH, Lee AR, Park YK. Lactobacillus
casei prevents impaired barrier function in intestinal epithelial cells.
APMIS 2011; 119: 49–56.
13 Guglielmetti S, Tamagnini I, Mora D, et al. Implication of an outer
surface lipoprotein in adhesion of Bifidobacterium bifidum to Caco-2
cells. Appl Environ Microbiol 2008; 74: 4695–702.
14 Pan WH, Li PL, Liu Z. The correlation between surface
hydrophobicity and adherence of Bifidobacterium strains from
centenarians’ faeces. Anaerobe 2006; 12: 148–52.
15 Brenner DM, Chey WD. Bifidobacterium infantis 35624: a novel
probiotic for the treatment of irritable bowel syndrome.
Rev Gastroenterol Disord 2009; 9: 7–15.
16 Ducrotté P, Sawant P, Jayanthi V. Clinical trial: Lactobacillus
plantarum 299v (DSM 9843) improves symptoms of irritable bowel
syndrome. World J Gastroenterol 2012; 18: 4012–18.
17 Farup PG, Jacobsen M, Ligaarden SC, Rudi K. Probiotics,
symptoms, and gut microbiota: what are the relations?
A randomized controlled trial in subjects with irritable bowel
syndrome. Gastroenterol Res Pract 2012; 2012: 214102.
18 Layer P, Andresen V, Pehl C, et al. S3-Leitlinie Reizdarmsyndrom:
Definition, Pathophysiologie, Diagnostik und Therapie.
Gemeinsame Leitlinie der Deutschen Gesellschaft für Verdauungs-
und Stowechselkrankheiten (DGVS) und der Deutschen
Gesellschaft für Neurogastroenterologie und Motilität (DGNM)1.
Z Gastroenterol 2011; 49: 237–93.
19 Majeed M, Nagabhushanam K, Natarajan S, et al. Bacillus coagulans
MTCC 5856 supplementation in the management of diarrhea
predominant irritable bowel syndrome: a double blind randomized
placebo controlled pilot clinical study. Nutr J 2016; 15: 21.
20 Ludidi S, Jonkers DM, Koning CJ, et al. Randomized clinical trial on
the eect of a multispecies probiotic on visceroperception in
hypersensitive IBS patients. Neurogastroenterol Motil 2014; 26: 705–14.
21 Hod K, Sperber AD, Ron Y, et al. A double-blind, placebo-controlled
study to assess the eect of a probiotic mixture on symptoms and
inflammatory markers in women with diarrhea-predominant IBS.
Neurogastroenterol Motil 2017; 29: e13037.
22 Adams CA. The probiotic paradox: live and dead cells are biological
response modifiers. Nutr Res Rev 2010; 23: 37–46.
23 Isolauri E, Juntunen M, Rautanen T, Sillanaukee P, Koivula T.
A human Lactobacillus strain (Lactobacillus casei sp strain GG)
promotes recovery from acute diarrhea in children. Pediatrics 1991;
88: 90–97.
24 Mitra AK, Rabbani GH. A double-blind, controlled trial of bioflorin
(Streptococcus faecium SF68) in adults with acute diarrhea due to
Vibrio cholerae and enterotoxigenic Escherichia coli. Gastroenterology
1990; 99: 1149–52.
25 Tsuchiya J, Barreto R, Okura R, Kawakita S, Fesce E, Marotta F.
Single-blind follow-up study on the eectiveness of a symbiotic
preparation in irritable bowel syndrome. Chin J Dig Dis 2004;
5: 169–74.
26 Lahtinen SJ. Probiotic viability—does it matter?
Microb Ecol Health Dis 2012; 23: 18567.
27 Hall KT, Lembo AJ, Kirsch I, et al. Catechol-O-methyltransferase
val158met polymorphism predicts placebo eect in irritable bowel
syndrome. PLoS One 2012; 7: e48135.
28 Patel SM, Stason WB, Legedza A, et al. The placebo eect in
irritable bowel syndrome trials: a meta-analysis.
Neurogastroenterol Motil 2005; 17: 332–40.
29 Ford AC, Harris LA, Lacy BE, Quigley EMM, Moayyedi P.
Systematic review with meta-analysis: the ecacy of prebiotics,
probiotics, synbiotics and antibiotics in irritable bowel syndrome.
Aliment Pharmacol Ther 2018; 48: 1044–60.
30 Liang D, Longgui N, Guoqiang X. Ecacy of dierent probiotic
protocols in irritable bowel syndrome: a network meta-analysis.
Medicine 2019; 98: e16068.
31 Meier R, Lied GA, Rasmussen SH, Asiller ÖÖ. Probiotics in
irritable bowel syndrome. Ann Nutr Metab 2010; 57 (suppl): 12–13.
32 Ouwehand AC, Salminen SJ. The health eects of cultured milk
products with viable and non-viable bacteria. Int Dairy J 1998;
8: 749–58.
33 Besselink MGH, van Santvoort HC, Buskens E, et al. Probiotic
prophylaxis in predicted severe acute pancreatitis: a randomised,
double-blind, placebo-controlled trial. Lancet 2008; 371: 651–59.
34 Enache-Angoulvant A, Hennequin C. Invasive Saccharomyces
infection: a comprehensive review. Clin Infect Dis 2005; 41: 1559–68.
