Original Studies

A Multicenter, Randomized, Double-blind, Placebo-controlled

Trial of Saccharomyces boulardii in Infants and Children
With Acute Diarrhea
Florian Mourey*, Varun Sureja, MPharm,† Dharmeshkumar Kheni, MPharm,† Parthiv Shah, MD,‡
Devang Parikh, MD,§ Unmesh Upadhyay, MD,¶ Milan Satia, PhD,║ Dhara Shah, MPharm,║
Charlotte Troise, PharmD,* and Amélie Decherf*

Aim: This study was designed to assess the efficacy and safety of Saccha-
romyces cerevisiae variant boulardii CNCM I-3799 (S. boulardii CNCM
D iarrhea is one of the most common infectious diseases and
remains a leading cause of death in children under 5 years
of age in low- and middle-income countries.1 Although important
I-3799) in the management of acute diarrhea in children.
Methods: A total of 100 infants and children 3–36 months of age with
reductions in the number of deaths have been reported since several
acute diarrhea received medical care according to the World Health
decades,1,2 millions children worldwide suffer from diarrhea every
Organization guidelines on the management of acute diarrhea in children
year and are at risk of dehydration and malnutrition. Dehydration is
and were randomly allocated to the probiotic group (S. boulardii CNCM
the principal cause of death from diarrhea. Fluids and electrolytes
I-3799 at a daily dose of 5 billion CFU twice daily) or to the placebo
replacement therapy by oral rehydration solution (ORS) is conse-
group. Infants and children were treated for 5 days and an extended fol-
quently central in the World Health Organization (WHO) guidelines
low-up was planned 1 and 2 months after the end of the treatment period.
on the management of acute diarrhea in children.3 Nevertheless, oral
Primary endpoint was the time of recovery from diarrhea defined as the
rehydration has no effect on the duration of diarrhea, prompting a
duration of diarrhea. Other parameters, such as frequency and consistency
growing interest in adjunctive solution to limit the burden of the dis-
of stools, associated with the severity of diarrhea episodes were defined
ease. Alongside rehydration therapy, the WHO also recommends the
as secondary endpoints.
use of zinc supplementation which has been shown to reduce the dura-
Results: The administration of S. boulardii CNCM I-3799 was associ-
tion and severity of diarrheal episodes.4 Other interventions have also
ated with beneficial effects on duration and severity of diarrhea. The time
been suggested and among them, there is considerable interest in the
of recovery from diarrhea was significantly shorter in the probiotic group
role of probiotics in promoting recovery from acute diarrhea. Indeed,
compared with the placebo group (65.8 ± 12 hours vs. 95.3 ± 17.6 hours,
several meta-analyses have shown that probiotic supplementation, as
P = 0.0001). Faster remission in the probiotic group was also demon-
an adjunct to rehydration therapy in the management of acute diar-
strated by a shorter time before the first episode of semisolid stool [−23.5
rhea in children, is effective in reducing diarrhea duration.4–7 These
hours, diff (95% CI): −7.99 (−31.49 to −15.51), P = 0.0001] and the
consistent pieces of evidence have led to universal recommendations
faster normalization of stool consistency. S. boulardii CNCM I-3799 was
in favor of the use of probiotics for the management of acute diarrhea
well tolerated.
from the European and International Societies for Pediatric Gastro-
Conclusion: S. boulardii CNCM I-3799 supplementation in children with
enterology, Hepatology and Nutrition.8,9 More specifically, experts
acute diarrhea was shown effective in reducing the duration and severity of
have recommended the use of probiotic strains with clinically proven
diarrhea in infants and children.
efficacy such as Lactobacillus rhamnosus GG or S. cerevisiae vari-
ant boulardii (S. boulardii). On the contrary, recent clinical studies
Key Words: acute diarrhea, pediatric, probiotic, efficacy, safety have found no benefit of probiotics on the duration of diarrhea.10,11 A
systematic review and network meta-analysis12 designed to compare
(Pediatr Infect Dis J 2020;39:e347–e351)
and determine the most effective pharmacologic or nutritional inter-
ventions in reducing diarrhea duration supports the recommendation
towards the use of S. boulardii in the management of acute diarrhea
in children. S. boulardii associated with zinc supplementation has
Accepted for publication July 15, 2020. been shown superior to both standard treatment, zinc supplementa-
From the *Research & Applications, Gnosis by Lesaffre, Lesaffre International,
Marcq-en-Barœul, France; †Sundyota Numandis Probioceuticals Pvt. Ltd.; tion alone or supplementation with any of the other probiotic strains
‡Hitarth Children Hospital; §Bakeri Medical Research Centre; ¶Iqra Hospi- tested. Although the efficacy of S. boulardii in various indications in
tal; and ║Ethicare Clinical Trial Services, Ahmedabad, India. children and adults is already well documented in the literature, it is
Sundyota Numandis Probioceuticals Pvt. Ltd. funded this study. the first time that the efficacy and safety of the S. boulardii CNCM
F.M., C.T., and A.D. are full-time employees of Gnosis by Lesaffre (Lesaffre
Group). V.S. and D.K. are full-time employees of Sundyota Numandis Pro- I-3799 is evaluated in children with acute diarrhea.
bioceuticals Pvt. Ltd. Dr. M.S. and D.S. are full-time employees of Ethicare
Clinical Trial Services. Ethicare Clinical Trial Services received fees from MATERIALS AND METHODS
Sundyota Numandis Probioceuticals Pvt. Ltd. to set up and conduct the clini-
cal trial. Dr. P.S., Dr. D.P. and Dr. U.U. were investigators of the study and Aim
received fees from Ethicare Clinical Trial Services.
Address for correspondence: Florian Mourey, Research & Applications, Gnosis This randomized, double-blind, placebo-controlled trial was
by Lesaffre, Lesaffre International, 59700 Marcq-en-Barœul, France. E-mail: designed to evaluate the efficacy and safety of Saccharomyces cer-
[email protected] evisiae var. boulardii CNCM I-3799 in the management of acute
Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. This
is an open-access article distributed under the terms of the Creative Com- diarrhea in children.
mons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-
ND), where it is permissible to download and share the work provided it is Ethics and Regulatory Approval
properly cited. The work cannot be changed in any way or used commercially The study received institutional ethics committee approval,
without permission from the journal.
ISSN: 0891-3668/20/3911-e347 was performed in compliance with the Declaration of Helsinki and
DOI: 10.1097/INF.0000000000002849 carried out according to the general principles of the International

The Pediatric Infectious Disease Journal  •  Volume 39, Number 11, November 2020 www.pidj.com | e347
Mourey et al The Pediatric Infectious Disease Journal  •  Volume 39, Number 11, November 2020

Conference on Harmonization guidelines for Good Clinical Prac- subjects. Secondary endpoints were the frequency and consistency
tice. Parents received information on all aspects of the study and of stools, the time of the first semisolid stool, the daily ORS con-
were provided with a written informed consent to be signed before sumption, the time of first rehydration, the number and the dura-
participation of their child in the study. tion of relapses episodes. Stool consistency was evaluated using a
The study was registered prospectively in the Clini- previously described score system13 where feces were classified as
cal Trials Registry of India (CTRI) under the CTRI number 1 (normal), 2 (loose), 3 (semiliquid) or 4 (liquid). The time of first
CTRI/2017/07/009101. rehydration evaluation relies on clinical examination and interview
with the parent of the subjects. The occurrence and the duration of
Clinical Study Settings any new episode of diarrhea during the 2-month follow-up period,
This multicenter study was performed by Ethicare Clini- defined as relapses episodes, were collected during the extended
cal Trial Services and took place in 4 different study sites located follow-up visits 1 and 2 months after the end of the 5-day treatment
across Ahmedabad, India. period. The presence of rotavirus antigen at baseline and the end of
the treatment period is reported as an exploratory endpoint.
Participants
A total of 100 infants and children 3–36 months of age with Safety Assessments
acute diarrhea, defined as 3 or more loose stools in the last 24 hours, Safety was assessed considering the occurrence and evalu-
were included between January and December 2018. Volunteers ation of adverse events as well as any changes in vital signs (pulse
were excluded if they presented clinical signs of severe malnutrition rate, respiratory rate and temperature) from baseline. Adverse
or clinical signs of severe dehydration if the investigator reported events were recorded throughout the study and investigators,
clinical evidence of coexisting acute systemic illnesses (eg, sepsis blinded to treatment assignment, had to estimate their severity and
and pneumonia) or clinical evidence of chronic disease (eg, chronic to evaluate whether they could be related to the study or the tested
liver disease). Volunteers were also excluded in case of antibiotic product. Any deterioration of the health status of the children which
medication or probiotic consumption in the week before inclusion. requires either rescue medicine or hospitalization for intravenous
fluid replacement therapy was considered as an adverse event and
Interventions the children were classified as being in treatment failure.
All children were given standard treatment which consisted
of an ORS (Electral, FDC Limited) as per WHO recommendations3 Statistical Analysis
and a daily dose of zinc (Zinconia, Zuventus Healthcare Ltd) at Based on the results from a meta-analysis assessing the effi-
10 mg for children less than 1-year-old and at 20 mg for children cacy of S. boulardii in the management of diarrhea in children,6 a
above 1-year-old. Children were randomly allocated to the inter- mean difference in the duration of diarrhea of 20 hours was assumed
vention group or the control group. Participants in the intervention with a standard deviation of 30 hours. To detect this difference with
group received 2 sachets per day of the test product (LesunBerry a power of 80% and a significance level of 0.05, a minimum of 37
Sundyota Numandis), each containing 5 billion CFU of the probi- subjects per arm is needed. To make allowance for potential pro-
otic yeast S. cerevisiae var. boulardii CNCM I-3799, a proprietary tocol deviations, treatment failures or premature withdrawals, a
strain of Lesaffre Group (Marcq-en-Barœul, France). S. boulardii total of 50 subjects per group was considered appropriate. Clinical
CNCM I-3799 is stabilized by fluid-bed gentle drying technology study endpoints depending on continuous variables were analyzed
which confers adequate viability to the probiotic together with an using unpaired t test, while χ2 test was used for analyzing categori-
improved flowability. Participants in the control group were given cal variables. Statistical significance was set at P < 0.05. Primary
sachet of identical appearance containing only maltodextrin and analysis was performed on the efficacy analysis population, which
received the same instructions. Active and placebo products were comprised subjects who completed the study in compliance with the
similar in color and flavor. protocol as well as subjects considered as being in treatment failure.

Study Design and Procedures RESULTS

This clinical study consisted of a treatment period of 5 days
and an extended follow-up 1 and 2 months after the end of the treat- Patients
ment period. The intervention period included 4 visits to the inves- A total of 112 subjects were included in this study, received
tigation center. The first visit was a screening visit during which the ORS and zinc supplementation and were randomly allocated to the
eligibility of the subject was verified. Subjects fulfilling the eligibil- group receiving S. boulardii CNCM I-3799 (n = 57) or the group
ity criteria were then randomly allocated to the intervention group receiving the placebo (n = 55). Twenty-three subjects did not com-
or to the control group. From randomization to the end of the 5-day plete the study [treatment failure (n = 11), protocol deviation (n = 3),
treatment period, parents or legal guardian were asked to record the consent withdrawal (n = 4) and lost to follow-up (n = 5)]. Efficacy
following parameters in a subject diary: the total number of stools analysis population (n = 100: probiotic group n = 49 and placebo
daily as well as stool’s consistency, the date and time of the first semi- group n = 51) includes subjects who completed the study in com-
solid stool and the total volume of ORS taken during the day. In addi- pliance with the protocol as well as subjects considered as being
tion, stool collection for detection of rotavirus antigen at baseline and in treatment failure. The flow of the study is presented in Figure 1.
the end of the 5-day treatment period was conducted in a subset of 20 Baseline characteristics of the study population are pre-
subjects per group. Extended follow-up visits were planned to check sented in Table 1. Both groups were similar with regard to demo-
the occurrence and duration of any new episode of diarrhea. graphic characteristics and duration of diarrhea before enrollment
in the study protocol.
Efficacy Assessments
The primary endpoint was the time of recovery from diar- Primary Endpoint
rhea defined as the duration of diarrhea assessed according to the At baseline, the mean duration of diarrhea before inter-
consistency of stool: 3 consecutive semisolid stool or no stool in vention was similar in both study groups (40.4 ± 24.3 hours in
the last 12 hours was considered as recovery from diarrhea. Time S. boulardii group vs. 43.6 ± 31.4 hours in the placebo group,
and date of semisolid stools were collected by the parents of the P = 0.57). After randomization, a statistically significant difference

e348 | www.pidj.com © 2020 The Author(s). Published by Wolters Kluwer Health, Inc.

The Pediatric Infectious Disease Journal  •  Volume 39, Number 11, November 2020 S. boulardii in Acute Diarrhea Management

FIGURE 1.  Flowchart of

participants through the study
of Saccharomyces boulardii in
acute diarrhea management.

in the overall duration of diarrhea was found between the groups. CNCM I-3799 [−9.1 hours, diff (95% CI): −2.36 (−11.46 to −6.74),
S. boulardii CNCM I-3799 shortened recovery time from diarrhea P = 0.0001) although no difference in daily total ORS consumption
in comparison with placebo [−29.5 hours, diff (95% CI): − 6.22 was reported between the groups. Daily stool frequencies were similar
[−35.74 to −23.26], P = 0.0001] (Fig. 2). This 1-day faster remission between the groups, the maximum intergroup difference was reported
with S. boulardii supplementation was also complemented by the on day 2 with a statistically significant reduction in the mean number
higher number of infants and children in the S. boulardii group con- of bowel movements occurring in the S. boulardii group [−0.5, diff
sidered as recovered from diarrhea over the supplementation period. (95% CI): − 0.46 (−0.93 to −0.01), P = 0.044] but no statistically sig-
Recovery from diarrhea started on day 2 in S. boulardii group with nificant differences were observed on the days 3, 4 and 5 of treatment
10.9% of subjects considered as recovered from diarrhea. Within period. Duration of diarrhea and changes in stool consistency and fre-
3 days from randomization, 82.6 % of subjects in the S. boulardii quency in placebo and S. boulardii groups are presented in Table 2.
group were considered as recovered, whereas only 16.3% of sub- No difference in number or duration of the new episode of diarrhea
jects in the placebo group were considered as recovered (descriptive was seen during the monthly observational follow-up conducted over
statistics only). Percentage of subjects who recovered from diarrhea 2 months after the end of the treatment period.
over the treatment period is presented in Figure 3.
Exploratory Endpoint
Secondary Endpoints In both study groups, 11 subjects were tested positive for
Several clinical features associated with diarrhea were sig- rotavirus antigen at baseline. At the end of the 5-day treatment
nificantly different between the groups over the course of the treat-
ment period. The first semisolid stool appeared significantly faster in
the group receiving S. boulardii [−23.5 hours, diff (95% CI): −7.99
(−31.49 to −15.51), P = 0.0001]. Similarly, faster improvements in
stool consistency were reported in the probiotic group and statisti-
cally significant between-group differences in stool consistency were
reported from day 3 up to the end of the intervention period. Rehydra-
tion occurred significantly faster in the group receiving S. boulardii

TABLE 1.  Baseline Characteristics of Participants:

Comparison Between Saccharomyces boulardii and
Placebo Groups

S. boulardii
CNCM I-3799 Placebo P

Age (months ± SD) 13.2 ± 8.1 13.3 ± 8. 2 0.77

Gender (female/male) 23/26 23/28 0.71
Weight (kg ± SD) 8.8 ± 2.8 9.5 ± 4.8 0.96
Height (cm ± SD) 75.7 ± 9.7 71.2 ± 11.9 0.13
Diarrhea duration before 40.4 ± 24.3 43.6 ± 31.4 0.57
intervention (hours ± SD) FIGURE 2.  Time of recovery from diarrhea in placebo and
SD, standard deviation. Saccharomyces boulardii groups.

© 2020 The Author(s). Published by Wolters Kluwer Health, Inc. www.pidj.com | e349

Mourey et al The Pediatric Infectious Disease Journal  •  Volume 39, Number 11, November 2020

TABLE 3.  Summary of Adverse Events in

Saccharomyces boulardii and Placebo Groups

S.boulardii
CNCM I-3799 Placebo

Total number of adverse events (percentage 7 (14.3%) 9 (17.6%)

of subject with at least 1 adverse event)
Total number of adverse events of mild 2 2
intensity
Total number of adverse events of moderate 5 7
intensity
Total number of adverse events of severe 0 0
intensity
Treatment failure 3 8

recorded during this study, none were judged as possibly linked to

the research or the investigational product.
FIGURE 3.  Percentage of subjects in Saccharomyces
boulardii and placebo groups who recovered from diarrhea DISCUSSION
over the treatment period. This multicenter, randomized, double-blind and placebo-
controlled study demonstrates that the strain S. boulardii CNCM
I-3799 is effective in the management of acute diarrhea in chil-
period, all the subjects in the probiotic group were tested negative
dren. S. boulardii, administered as an adjunctive standard treatment
for rotavirus antigen whereas rotavirus antigen was still detected in
of ORS and zinc supplementation, was associated with beneficial
2 subjects in the placebo group.
effects on several clinical features of diarrhea. Faster remission in
the group receiving the probiotic is consistent with previous find-
Safety Evaluation
ings of several authors reporting an approximately 1 day faster
No serious adverse event linked to the research or to the recovery from diarrhea with S. boulardii.14–18 After 3 days of treat-
study product was recorded during the study in either study group. ment, more children in the probiotic group had recovered from
The frequency of subjects with at least 1 adverse event was similar diarrhea than those in the placebo group. Consistently, Correa et al.
in the group receiving S. boulardii and in the placebo group (14.3% reported a lower frequency of patients with diarrhea within 3 days
vs. 17.6%, respectively). A summary of adverse events is given in from randomization in the group supplemented with S. boulardii
Table 3. A total of 16 adverse events were recorded as follows: 3 (RR 0.54, 95% CI: 0.38–0.77, P < 0.001). In the present study, the
subjects reported fever (2 in the probiotic group and 1 in the pla- faster recovery in the probiotic group appears to be associated with
cebo group), 1 subject reported severe weakness (placebo group), 1 a faster improvement in stool consistency rather than an effect of
subject reported vomiting (placebo group) and 11 subjects reported treatment in stool frequency. Similar results have been previously
an increase in diarrhea symptoms which required administration reported by Riaz et al. who reported a faster normalization of stool
of intravenous fluid therapy or rescue medicine (3 in the probiotic consistency in the group receiving S. boulardii [−14.6 hours, diff
group and 8 in the placebo group). A total of 11 subjects were (95% CI): −10.85 (−25.5 to −3.79), P = 0.009] in the absence of
then considered as treatment failure. Among the 16 adverse events statistically significant differences in stool frequency.17

TABLE 2.  Duration of Diarrhea and Changes in Stool Consistency and Frequency in
Placebo and Saccharomyces boulardii Groups

S. boulardii Treatment effect

CNCM I-3799 Placebo Δ Change and CI 95% P

Duration of diarrhea
 Time of recovery from diarrhea (hours) 65.8 ± 12 95.3 ± 17.6 − 29.5 (−35.74 to −23.26) 0.0001
Changes in stool consistency
 Time of first semisolid stool (hours) 45.5 ± 11.6 69 ± 24.8 − 23.5 (−31.49 to −15.51) 0.0001
 Mean daily stool consistency:
   Day 1 3.7 ± 0.4 3.7 ± 0.4 0 (−0.17 to 0.17) 1
   Day 2 3.2 ± 0.6 3.3 ± 0.7 − 0.1 (−0.39 to 0.11) 0.28
   Day 3 2.4 ± 0.8 2.9 ± 0.7 − 0.5 (−0.79 to −0.19) 0.0015
   Day 4 1.7 ± 0.6 2.4 ± 0.7 − 0.7 (−0.95 to −0.42) 0.0001
   Day 5 1.3 ± 0.5 1.7 ± 0.7 − 0.4 (−0.72 to −0.22) 0.0003
Changes in stool frequency
 Mean daily stool frequency:
   Day 1 4.2 ± 1.4 4.5 ± 1.4 − 0.3 (−0.77 to 0.35) 0.46
   Day 2 3.1 ± 0.9 3.6 ± 1.3 − 0.5 (−0.93 to −0.01) 0.044
   Day 3 2.5 ± 1.1 2.7 ± 1.3 − 0.2 (−0.65 to 0.29) 0.453
   Day 4 1.9 ± 0.9 2.3 ± 1.2 − 0.4 (−0.83 to 0.44) 0.078
   Day 5 2.0 ± 1.4 1.9 ± 1.1 − 0.1 (−0.35 to 0.63) 0.57

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The Pediatric Infectious Disease Journal  •  Volume 39, Number 11, November 2020 S. boulardii in Acute Diarrhea Management

The beneficial effect of S. boulardii CNCM I-3799 sup- 5. Szajewska H, Skórka A. Saccharomyces boulardii for treating acute gastro-
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