Indian Pediatr 2016;53:595-600
Racecadotril in the
Management of Rotavirus and Non-rotavirus Diarrhea in Under-five
Children: Two Randomized, Double-blind, Placebo-controlled
Gagandeep Kang, Sowmyanarayanan V Thuppal, Rajan
Srinivasan, Rajiv Sarkar, Beula Subashini, Srinivasan Venugopal,
Kulandaipalayam Sindhu, Dhivya Anbu, *Nathalie
Svensson and $Anuradha
From the Departments of Gastrointestinal Sciences,
Christian Medical College, Vellore, India; *Service des Urgences
Pédiatriques, Hôpital d’enfants Armand Trousseau, Assistance
Publique-Hôpitaux de Paris, Paris, France; #Division of
Molecular Virology, Department of Clinical and Experimental Medicine,
Medical Faculty, Linko ping University, Linko ping, Sweden; and $Community
Health, Christian Medical College, Vellore, India.
Correspondence to: Dr. Gagandeep Kang, Professor and
Head, Division of Gastrointestinal Sciences, Christian Medical College,
Received: July 06, 2015;
Initial review: September 26, 2015;
Accepted: May 07, 2016.
Objective: To study the effect of racecadotril on
reduction in the duration of acute rotavirus and non-rotavirus diarrhea.
Design: Two randomized double-blind
Setting: Community-based trial in an urban area
in Vellore, hospital-based trial at a secondary hospital in Vellore
Participants: 199 and 130 3-59 month old children
in the community- and hospital-based trials, respectively.
Methods: Racecadotril (1.5 mg/kg/dose, thrice a
day for three days) or placebo were given to manage acute diarrhea in
Main outcome measure: Median duration of
Results: Among 124 children completing the
hospital trial, the median duration of diarrhea was 25 h in both arms (P=0.5);
median total stool weight was 74 g/kg and 53.5 g/kg in racecadotril
group and placebo group, respectively (P=0.4); and average fluid
intake per day was 3.6 mL/kg/h and 3mL/kg/h in racecadotril and placebo
arms, respectively (P=0.3). Among rotavirus-positive children,
median duration of diarrhea was 26.9 h and 30.2 h in racecadotril and
placebo arms, respectively (P=0.7). In the community, 196
completed the trial, the median duration of diarrhea was 2 days for both
arms (P=0.8) and rotavirus positive children had similar outcomes
with median diarrheal duration of 3 d in both arms (P=0.4).
Conclusion: Treatment with racecadotril did not
reduce diarrheal duration, stool volume or the requirement for fluid
replacement in children with acute gastroenteritis, both with and
without rotavirus infection.
Keywords: Antidiarrheal, Anti-secretory, Outcome, Treatment.
which has been shown to be safe and effective in
decreasing the duration of diarrhea in children .
Infectious diarrhea is a leading cause of death
among children under 5 years of age, particularly in developing
countries . Oral rehydration therapy (ORT) has been shown to reduce
mortality due to dehydration , but does not reduce the duration of
illness or stool frequency. Racecadotril, (acetorphan: N-((R,
S)-3-acetylmercapto-2benzylpropanoyl)-glycine, benzyl ester) is an
enkaphalinase inhibitor augmenting the anti-secretary action of
enkaphalin in the submucous myentric neurons [3,4],
Clinical trials comparing the efficacy of
racecadotril with acute gastroenteritis have shown varying results.
While some trials have reported a significant reduction in stool output,
frequency of bowel movement and diarrheal duration [5-8], others did not
find any such association [9-10]. We evaluated the efficacy of
racecadotril in children less than 5 years of age with acute diarrhea in
two randomized control trials in hospital and community settings in
Study design and participants: Two randomized,
double-blind, placebo-controlled trials were conducted one at the
Community Health and Development (CHAD) hospital and the other at an
urban area of approximately 150000 population served by a study clinic
run by the Christian Medical College (CMC), Vellore, India between April
2008 and September 2010.
All children between 3 and 59 months of age with
acute diarrhea (defined as ³3
episodes of loose, watery stools in last 24 hours  for less than 3
days of duration were enrolled. In the hospital study, children were
enrolled only if the study physician recommended hospitalization for
management of diarrhea. In the community study, children were enrolled
only if the study physician recommended management of the diarrheal
episode at home. Children with weight less than 5 kg, with severe
co-existing disease, including pneumonia, meningitis, or severe
malnutrition (defined as Grade III or Grade IV malnutrition IAP Grading
based on weight for age), chronic diarrhea (duration>14 d), or with
blood and mucus in stool were excluded from both trials. Those with
history of having received antibiotics, probiotics, steroids, herbal
medicines, antiemetics or antimotilty drugs or other treatment of
unknown nature were also excluded. Children who fulfilled the
eligibility criteria and whose parents or legal guardians provided
written informed consent were randomized to receive either racecadotril
or an identical placebo. The studies were approved by the Institutional
Review Board, Ethics committee and registered with the Clinical Trials
Registry of India (CTRI/2010/091/003067 and CTRI/2007/091/000001).
Sample size: The sample size for these studies
were calculated based on the primary outcome of a reduction in diarrheal
duration of 24 hours. With an alpha error of 5% and a power of 80%, in
order to show at least a one-day reduction in duration of diarrhea
following intervention, 65 children needed to be enrolled in each arm of
each trial. In the community trial, to account for disease progression
and increased loss to follow up, the sample size was increased to 100 in
Randomization and blinding: For both settings,
individual randomization codes were generated by a statistician not
associated with the study. The randomization was performed in multiple
permuted blocks with 1:1 allocation ratio. Sealed envelopes with the
randomization codes were given directly to the hospital pharmacy which
provided identically packed study drug or placebo. The placebo contained
a mixture of lactose, calcium stearate and sterile starch powder.
Intervention: Racecadotril (Zedott, Torrent
Pharmaceuticals Ltd, Gujarat, India) or placebo were administered at a
dose of 1.5 mg/kg, three times a day for three days if the child’s
diarrheal episode ended by the third day or up to five days if the
diarrheal episode had not ended by the third day. Apart from
interventional products, all children received treatment as per the
World Health Organisation (WHO) recommendations as the standard of care
. In the hospital, the study intervention was administered by a study
nurse. In the community-based study, racecadotril and placebo were
packed as powder with 9 packets for every child, given to mothers with
instructions for storage at room temperature and daily administration of
three doses. All children were followed-up at home by a field worker
daily and if the child required hospitalization, the child was referred
to CHAD hospital.
Data Collection: Both studies collected baseline
demographic details of age (months), gender and weight (kg). The
community trial also assessed the socio-economic status using the
modified Kuppuswamy scale . At the time of enrolment, a detailed
clinical history was elicited by the study physician containing
information on the duration of diarrhea, maximum number of stool passed
in a 24-hour time-frame, presence of vomiting and/or fever, history of
previous illnesses, and a detailed drug and vaccination history
(including history of rotavirus vaccination). Severity of diarrhea was
assessed at admission for all hospitalized children using the 20-point
Vesikari scoring system . An episode was considered mild for scores
0-5, moderate for 6-10 and severe for score
³11. Level of
dehydration was assessed using the WHO Integrated Management of Neonatal
and Childhood Illness classification .
Study outcomes: The primary outcome was median
duration of diarrhea in hours, defined as the time from onset of
diarrhea to the time of resolution, identified as the time of the last
abnormal stool or the start of a 12-hour period with no stool. This was
recorded by a study nurse in the hospital and by mother’s recall during
the field worker’s visit in the community-based study. Secondary
outcomes for the hospital study included diarrheal stool volume (total
and average), rehydration requirement (oral and intravenous) and
presence of vomiting after administering the drug or placebo. In the
hospital study, for male children urine collection bags (Minicom,
Techplast, Mumbai, India) were used to collect urine and stool
separately for measuring stool weight using pre-weighed diapers, while
this was not done for the female children or in the community-based
study. In the hospital study, for female children, while attempts were
made to avoid urine, where unavoidable both urine and stool were
collected together. Stool volume was calculated and compared separately
for male and female children. In hospital, the requirement of
rehydration fluid was calculated based on the intravenous fluid and oral
rehydration solution requirement per kg of baseline body weight per day.
A secondary outcome for the community study was presence of vomiting,
fever and history of day care and/or hospital visit during the period of
Screening for rotavirus was performed from the first
stool sample collected immediately post-enrolment. A 10% fecal
suspension was screened for rotavirus using a commercial enzyme
immunoassay (EIA) for detection of VP6 antigen (Rota IDEIA, Dako Ltd,
Ely, United Kingdom) according to the manufacturer’s instructions.
Statistical analysis: Data were collected using
case records for each child and entered into an EpiInfo database. All
variables were examined using descriptive statistics, dispersion for
continuous variables, frequency counts and marginal percentages with 95%
confidence intervals (CI) for categorical variables. Comparisons between
the two groups were done using t-tests for normally distributed
variables (or non-parametric tests for non-normally distributed
variables) and chi-square tests for categorical variables. All
differences were considered statistically significant if the two-tailed
P-value was <0.05. Data analysis was performed using STATA 10 for
Windows (Stata Corp, College Station, TX USA). Subgroup analysis was
done for children who had rotavirus diarrhea compared those who had
other cause diarrhea.
Hospital-based study: Of the 130 children
enrolled, per-protocol analysis could be conducted for 124 children,
(61/65 in the children assigned to the racecadotril group, 63/65
children in the placebo group), with 6 children not available for
follow-up (Fig. 1). At baseline, the median (IQR) duration
of diarrhea prior to enrollment was 2 (1,3) days in both groups; 31
(47.7%) children in the racecadotril group and 28 (43.1%) in the placebo
group tested positive for rotavirus (P=0.60). Severe dehydration
(>10%) was seen in 4 (6.2%) children in the racecadotril group and 6
(9.2%) in the placebo group (Table I). A total of 14
(10.8%) children required >3 days of treatment. The proportion of
children receiving >3 days of treatment was comparable between
racecadotril and placebo groups (6/61, 9.8% vs. 8/63, 12.7%; P=0.62).
The duration of hospitalization was also similar in children receiving
racecadotril and placebo (median [IQR] = 3 [2,4] in both groups, P=0.96).
Fig. 1 Trial profile.
TABLE I Baseline Characteristics of Children with Acute Diarrhea in the Hospital and the Community Trials
Hospital trial (n=130)
Community trial (n=199)
Age (mo); mean (SD)
Male gender; No. (%)
Duration of diarrhea (d); median (IQR)
No. of diarrheal episodes 24 h prior to admission; madian
Vomiting; No (%)
Weight (Kg); mean (SD)
Rotavirus positive; No. (%)
Dehydration; No. (%)
Severe Vesikari Category (n=101)
The primary outcome of diarrheal duration in hours
did not change with racecadotril treatment with the median (IQR) being
25.5 (14.8, 44.3) and 25.0 (17,44.5) hours in rececadotril and placebo
groups, respectively. The total and average stool weight among the two
groups were also similar. The findings were similar when the total and
the average stool weights were compared separately for males and females
(data not presented). Other outcomes were also similar (Table
TABLE II Effect of Racecadotril on Diarrheal Outcomesin the Hospital Trial
Duration of diarrhea (h); median (IQR)
Volume of stool (g/kg body Wt); median (IQR)
Vol. of stool (g/Kg/h); Median (IQR)
Fluid intake (mL/Kg/h); Median (IQR)
Presence of vomiting (overall); No. (%)
Presence of vomiting beyond 12 h; No. (%)
A total of 58 (46.7%) children tested positive for
rotavirus of whom 31 (53.4%) were assigned to the racecadotril group and
the remaining to the placebo group. The median (IQR) diarrheal duration
was 26.9 (17.1,54.9) hours in the rotavirus positive racecadotril group
and 30.2 (19, 47.1) hours in the placebo group (P=0.79). The
total stool volume passed had a median (IQR) of 75.8 (24.6,200.8) g/kg
with racecadotril and 91.6 (9.5,194.7) g/kg in the placebo group (P=0.67).
Other clinical outcomes including stool volumes (total, and average)
were also similar among those positive for rotavirus (Web
Community-based trial: Of the 199 (102 in
racecadotril, 97 in placebo) children randomized, 196 (98%) were
available for per-protocol analysis. Both arms were comparable, in terms
of socioeconomic status, education of head of household, family size,
number of siblings and breast feeding practices (data not presented).
None of the children reported receiving rotavirus vaccine.
Median duration of diarrhea at presentation and other
baseline characteristics were similar between both arms (Table
I). The proportion of children requiring treatment for >3 days was
comparable between children in the racecadotril and placebo groups
(8/99, 8.1% vs. 9/97, 9.3%; P=0.77). The primary outcome
of the median duration (IQR) of diarrhea at the end of trial was
unaffected at 2 (2,4) days for both groups (P=0.88). There were
no differences among other parameters (Table III).
TABLE III Effect of Racecadotril on Diarrheal Outcomes in the Community Trial
Diarrhea duration (d)
#Day care visit
*Median(IQR); All P>0.05; #for oral rehydration
A total of 29 (14.7%) children tested positive for
rotavirus in the community trial, of which 18 (62%) received
racecadotril and the remaining 11 (37.9%) received placebo. The outcomes
among those who were positive for rotavirus as compared to that of the
rotavirus negative group were similar in terms of diarrheal duration,
presence of vomiting and fever. There was a statistically significant
reduction of vomiting among rotavirus positive children receiving
racecadotril (5.6% vs. 63.6%; P=0.001). No such differences were
noted in the rotavirus negative children (Web Table II).
This paper reports findings from two clinical trials
in Southern India that recruited children from the hospital and the
community to study the effect of racecadotril on acute childhood
gastroenteritis, thereby capturing both mild and moderate-to-severe form
of the disease. The hospital trial had significantly more children with
rotavirus (45%) than the community trial (14.5%). We did not observe any
benefit of treatment with racecadotril in terms of duration of diarhea,
stool volume or rehydration fluid requirement.
Most studies evaluating the efficacy of racecadotril
on acute childhood gastroenteritis have been carried out in the hospital
setting [5-8]. Systematic reviews carried out using data from such
studies have reported a reduction in stool output and diarrheal duration
in children receiving racecadotril [16-18]. In contrast, the only study
conducted in an outpatient setting found no significant differences in
the number of bowel movements or the average duration of diarrhea
between children treated with racecadotril or standard oral rehydration
therapy . A possible reason for this lack of impact of racecadotril
on the treatment of diarrhea may be because children were brought to
hospital a median of two days after onset of diarrhea; earlier
intervention could have had a different outcome. It is also possible
that some of the children were infected or co-infected with pathogens
causing osmotic diarrhea such as Cryptosporidium, Salmonella
and Vibrio spp., all of which are important causes of childhood
diarrhea in developing countries . In such a scenario, racecadotril,
which acts only on secretory diarrhea, would not have had a significant
impact, irrespective of rotavirus etiology. In a study involving
Bangladeshi adults, the use of racecadotril did not provide any
additional benefit in the treatment of severe cholera .
Drugs from different manufacturers are not
necessarily equivalent and this may have been a limitation of this
study. There are few independent comparisons in most countries, of
efficacy of licensed drugs and it may be important for clinical
researchers to consider future studies in this area to ensure optimum
benefit to patient populations. Another limitation of this study was the
small sample size. This also restricted our ability to perform multiple
subgroup analyses (age-wise and severity-wise comparisons).
Trials conducted with rigorous methodologies in
multiple settings are required to inform evidence. This study indicates
the need for more evidence to advocate or refute use of racecadotril in
settings with high disease burden, where diarrheal episodes with
multiple etiologies cannot be ruled out.
Contributors: GK, SVT, RS, NP, LS, AB: conception
and design, acquisition of data, analysis and interpretation of data and
drafting manuscript; BS: recruitment, data collection, analysis,
drafting manuscript; SV: data analysis and drafting manuscript: KS:
recruitment, data collection, analysis, drafting manuscript; DA: data
collection, laboratory testing and data analysis;
Funding: Swedish International Development
Competing interest: None stated.
What is Already Known?
• Racecadotril has been shown to reduce
diarrheal duration especially in rotavirus diarrhea.
What This Study Adds?
• There is no significant effect of racecadotril on diarrheal
duration in community or hospital settings with both rotavirus
and non-rotavirus diarrhea.
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