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CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2009;7:456–462
ral Diosmectite Reduces Stool Output and Diarrhea Durationn Children With Acute Watery Diarrhea
HRISTOPHE DUPONT,* JIMMY LEE KOK FOO,‡ PHILIPPE GARNIER,§ NICHOLAS MOORE,�
ÈLÈNE MATHIEX–FORTUNET,§ and EDUARDO SALAZAR–LINDO,¶ for the PERU AND MALAYSIA DIOSMECTITETUDY GROUPS
Paris Descartes University, Cochin Saint-Vincent de Paul Hospital, Paris, France; ‡Kuala Terengganu Hospital, Kuala Terengganu, Malaysia; §Ipsen, Medical
epartment, Boulogne-Billancourt, Paris, France; �INSERM U657, Bordeaux University & Hospital, Bordeaux, France; and ¶DS Consult, Surco, Lima, PerurdefAbs
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ackground & Aims: Diosmectite is a clay used to treathildren with acute watery diarrhea. However, its effects ontool output reduction, the key outcome for pediatric an-idiarrheal drugs, have not been shown. Methods: Twoarallel, double-blind studies of diosmectite efficacy ontool reduction were conducted in children 1 to 36 monthsld in Peru (n � 300) and Malaysia (n � 302). Inclusionriteria included 3 or more watery stools per day for lesshan 72 hours and weight/height ratios of 0.8 or greater.xclusion criteria were the need for intravenous rehydra-
ion, gross blood in stools, fever higher than 39°C, orurrent treatment with antidiarrheal or antibiotic medica-ions. Rotavirus status was determined. Diosmectite dosageas 6 g/day (children 1–12 months old) or 12 g/day (chil-ren 13–36 months old), given for at least 3 days, followedy half doses until complete recovery. Patients were as-igned randomly to groups given diosmectite or placebo, inddition to oral rehydration solution (World Healthrganization). Results: Children in each study had com-arable average ages and weights. The frequencies of rota-irus infection were 22% in Peru and 12% in Malaysia.imilar amounts of oral rehydration solution were given tohildren in the diosmectite and placebo groups. Stool out-ut was decreased significantly by diosmectite in both stud-
es, especially among rotavirus-positive children. In pooledata, children had a mean stool output of 94.5 � 74.4 g/kgf body weight in the diosmectite group versus 104.1 � 94.2/kg in the placebo group (P � .002). Diarrhea durationas reduced by diosmectite, which was well tolerated.onclusions: These results show that diosmectite signif-
cantly decreased stool output in children with acute wateryiarrhea, especially those who were rotavirus-positive.
cute diarrheal diseases are the second most common life-threatening conditions worldwide among all infectious
iseases in children younger than 5 years old. Globally, 1.3illion episodes occur annually, with an average of 2 to 3pisodes per child.1–3
According to the World Health Organization,4 the manage-ent of acute watery diarrhea always includes immediate rehy-
ration by oral rehydration solution (ORS) or intravenous fluidsor more severe dehydration,2,5,6 maintenance of breastfeedingnd/or early refeeding, and use of antibiotics in selected cases suchs bloody diarrhea.
Diosmectite is a natural clay widely used for the treatment of
cute watery diarrhea in children, for which it has shownelevant pharmacological properties.7–9 Diosmectite shortensiarrhea duration10 –14 and normalizes transit.10 To date, how-ver, the effect of diosmectite on stool output, the key outcomeor pediatric antidiarrheal drugs,15 has not been shown.16
mong the treatments proposed for acute watery diarrhea, onlyismuth and racecadotril, an enkephalinase inhibitor, havehown decreased stool output.17,18
We conducted 2 parallel, double-blind, placebo-controlledtudies in Peru and Malaysia to determine the actual effect ofral diosmectite on stool output reduction in acute wateryiarrhea in infants and children as an adjunct to the currentlyecommended ORS formula.4
MethodsSubjectsThe Peru and Malaysia studies included children with
cute watery diarrhea, in primary care hospitals.According to previous studies it was expected that the de-
rease of total 72-hour stool output would be 30 g/kg ofodyweight with active drug compared with placebo, with aommon standard deviation (SD) of 80 g/kg. For rejection of a-sided null hypothesis with a type I error of 5% and a type IIrror of 20%, at least 112 patients had to be included per group.
e decided to include 300 patients in total in each study, 150n diosmectite and 150 on placebo.
Inclusion CriteriaPatients had to be aged 1 to 36 months, with a weight
in kg) to height (decimeters) ratio of at least 0.8 to rule outalnutrition, with at least 3 watery stools per day (moderate
cute watery diarrhea) for less than 72 hours with at least 1atery stool during the 12 hours before inclusion, and dehy-ration signs requiring the use of ORS according to Worldealth Organization guidelines. Only male children were in-
luded to separate stools from urine by using modified diapersith urine bags attached.
Exclusion criteria were severe dehydration requiring intrave-ous rehydration, gross blood in stools, fever of 39°C or higher,ecent history of diarrhea, previous history of persistent diar-
Abbreviations used in this paper: AE, adverse event; CI, confidencenterval; ORS, oral rehydration solution; SD, standard deviation.
© 2009 by the AGA Institute1542-3565/09/$36.00
doi:10.1016/j.cgh.2008.12.007
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April 2009 DIOSMECTITE IN CHILDREN WITH ACUTE DIARRHEA 457
hea, previously diagnosed malabsorption disease, current treat-ent with an antidiarrheal medication, drug-induced diarrhea,
r any other treatment possibly interfering with the study drug.xclusively breastfed children or children unable to drink alsoere excluded.
Study DesignThe 2 studies were randomized, placebo-controlled,
ouble-blind, multicenter trials conducted in compliance withood Clinical Practices (US Food and Drug Administration1CFR-1A part 50 subpart D concerning children in clinical
nvestigations; European Clinical Trials Directives 2001/20/ECnd 2005/28/EC, corresponding to ICH E6), the Declaration ofelsinki (Release of Edinburgh, Scotland, October 2000), anderuvian and Malaysian regulatory texts related to protection ofersons participating in biomedical research. At least one par-nt or the legal representative of the patient gave written in-ormed consent. Studies were registered at www.ClinicalTrials.ov under the identifiers following: NCT00352989 for the Malay-ia study, and NCT00352716 for the Peru study.
InterventionsChildren were randomized at visit 1 in sequential as-
ending order within each center to be treated with eitheriosmectite (Smecta; Ipsen, Paris, France) or placebo, in addi-ion to ORS. The study drug was dispensed by the investigatornly. For each study, the sponsor-assigned biostatistician pre-ared a list of treatment allocation codes to be kept confidentialntil approval was received for the study to be unblinded fornalysis.
Diosmectite is a powder for oral suspension in sachet, com-osed of 3.000 g diosmectite, 0.004 g vanillin, 0.007 g sodiumaccharin, and 0.749 g glucose monohydrate (147 mOsm/L).lacebo, specifically developed for these studies, was an identicalowder, composed of 1.000 g titanium dioxide, 1.181 g maltodex-rin (Roquette Glucidex IT 38, Lestrem, France), 0.004 g vanillin,.007 g saccharin sodium, 2.150 g glucose monohydrate, and.018 g caramel coloring E150B (46 mOsm/L). Placebo was
dentical to diosmectite in size, weight, color, smell, taste, andppearance, and was inert, as shown on an animal model ofatery diarrhea (data not shown). The dosing regimen was thatsed commonly by pediatricians: for children younger than 12onths, 2 sachets per day for 3 days and then 1 sachet per day;
osage was doubled for older children. After 3 days, childrenere discharged from the hospital and half the dosage of drugas continued until complete recovery. Complete recovery wasefined as the first formed stool onset followed by either aonwatery stool or a 24-hour period without stool. This wasssessed using the data reported by the parents in a diary.
The 245 mOsm/L ORS formulation was used according totandard practice and current World Health Organizationuidelines: the volume of ORS used was equivalent to theolume of stool until the end of the risk of dehydration.4 Theame ORS, a powder in sachets to be diluted in 1 L of waterHidrax; Medifarma S.A., Lima, Peru), was used in both studies.arly refeeding was promoted. For children partially breastfed,
he mother stayed in the hospital.
ObjectivesThe primary objective was to compare the efficacy of
iosmectite with that of placebo on stool output reduction in b
hildren with acute watery diarrhea. The secondary objectivesere to compare diosmectite and placebo for diarrhea durationnd safety.
EfficacyPrimary outcome measure. The 72-hour cumula-
ive stool output, in g/kg baseline body weight, was measuredver the 72 hours after the first sachet intake, regardless ofhether the watery diarrhea had stopped or not. Study nurseseasured stool output by deducting the weight of a dry diaper
rom that of the soiled diaper, using daily calibrated electroniccales with a precision of 1 g. Special diapers were prepared byutting a circle in the area corresponding to the child’s penis.n anti-allergic tape then was placed at the edge of the circlend stuck on a urine collection bag, thereby adapting thepen end to the circle. The procedure for stool collection wastandardized in each center by means of specific training
eetings.Secondary criterion. Blind review of data found that
he stool consistency reported differed between Peru and Ma-aysia. Although all of the children had a formed stool by thend of the study in Peru, only 60% of the children had a formedtool by the end of the study in Malaysia. Therefore, it wasecided under blind conditions, in accordance with the 3 studyoordinators, that diarrhea duration would be defined accord-ng to country specificities: time from the first sachet intake tohe first formed stool for Peru, to the first soft or formed stoolor Malaysia, followed by a nonwatery stool or 24 hours with-ut stools.
Rotavirus StatusThe rotavirus status of a stool sample collected at
nclusion was assessed after confirmed inclusion, using an en-yme-linked immunosorbent assay (Ridascreeen; R-Biopharm,armstadt, Germany) in Peru and a rotavirus latex agglutina-
ion test (Rotalex; Orion Diagnostica, Espoo, Finland) in Ma-aysia. This did not influence inclusion status.
TolerabilityTreatment-emergent adverse events (AEs) were defined
s any AE occurring or increasing after the first treatmentdministration and before the last treatment was given. AEsere coded according to the Medical Dictionary for Regulatoryctivities (MedDRA) version 9.1. Patients were counted onlynce within the same body system.
Statistical AnalysesAll analyses were prespecified and performed on intent-
o-treat populations. Variables were described by mean and SD,edian and range, and number and percentage. Tests were
-sided and the level of significance (�) was set at .05. Theilcoxon test was used for quantitative variables without nor-al distribution. The chi-squared and the Fisher exact testsere used for qualitative variables.
The main analysis was the comparison of diosmectite andlacebo with regard to the primary outcome (72-hour cumula-ive stool output) adjusted to rotavirus status. It was analyzedsing analysis of variance with 2 factors (treatment group andotavirus status) for data of individual studies.19 Interaction
etween 2 factors was kept in the model if the P value was .15
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458 DUPONT ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 7, No. 4
r less.20 Diarrhea duration was described using the Kaplan–eier survival curve and compared using the log-rank test.We also analyzed the pooled individual data of these 2
tudies, conducted simultaneously in Peru and Malaysia ac-ording to the same design, inclusion/exclusion criteria, meth-dology, and training of investigators and nurses, using analy-is of variance with 3 factors (treatment, rotavirus status, andtudy).19
Statistical analyses were performed by CRC (Kuala Lumpur,alaysia) for the Malaysia study, and by Fovea (Rueil-Malmai-
on, France) for the Peru study, under the supervision of Pro-essor Nicholas Moore (INSERM U657 Bordeaux, France) andlisabeth Leger-Picherit (Head of Biometry, Ipsen, Boulogne-illancourt, France).
ResultsPeru StudyStudy populations. Three hundred patients were in-
luded in the intent-to-treat population (153 in the placeboroup and 147 in the diosmectite group) between June 23,006, and February 1, 2007, in 11 primary care hospitals located
n Lima (n � 9), Huacho (n � 1), and Ica (n � 1). Seventy-eightajor deviations to the protocol were observed in 40 patients:inclusion criteria were not respected, 39 patients were hospi-
alized for fewer than 70 hours, and 34 had treatment exposureor less than 48 hours. The per-protocol population was there-ore 260 patients, 128 in the diosmectite group and 132 in thelacebo group.
Children had a mean (�SD) age of 12.5 � 6.1 months, aean weight of 9.35 � 1.67 kg, and a mean height of 75.3 � 7.3
m, with no difference between study groups. Mean (�SD) totalmount of ORS intake during the hospitalization period was426 � 983 mL. There was no significant difference betweenhe diosmectite and placebo groups for rotavirus status or ORSse.
Efficacy. Mean (�SD) 72-hour cumulative stool out-ut was lower in the diosmectite group (102.0 � 65.5 g/kg)han in the placebo group (118.8 � 92.5 g/kg) (P � .032) (Table). Diarrhea lasted significantly shorter with diosmectite (me-ian, 68.17 h; 95% confidence interval [CI], 60.25– 85.02 h) thanith placebo (median, 118.92 h; 95% CI, 94.92–140.50 h) (P �
001). This result was found in both the rotavirus-negative andhe rotavirus-positive children. In rotavirus-negative children,
able 1. Seventy-Two–Hour Stool Output in the Diosmectite a
Diosmectite
N 72-h stool output, g/kg
eru study 126 102.0 � 65.5Rotavirus � 26 146.9 � 90.1Rotavirus � 100 90.3 � 52.0alaysia study 142 87.9 � 81.2Rotavirus � 18 91.8 � 103.0Rotavirus � 124 87.4 � 78.0
ooled data 268 94.5 � 74.4Rotavirus � 44 124.3 � 98.3Rotavirus � 224 88.7 � 67.5
OTE. Pooled data are presented as mean � SD and according to rotavir
edian diarrhea duration was 71.1 hours (95% CI, 60.3–108.8) with diosmectite versus 119.8 hours (95% CI, 102.4 –148.8 h)ith placebo (P � .001) (Figure 1). In rotavirus-positive chil-ren the median diarrhea duration was 66.8 hours (95% CI,3.8 – 69.8 h) with diosmectite and 107.3 hours (95% CI, 69.5–46.3 h) with placebo (P � .001).
Secondary analyses of primary outcome showed that rotavi-us-positive patients had a significantly higher cumulative stoolutput (169.2 � 109.7 g/kg) than rotavirus-negative patients93.9 � 61.2 g/kg) (P � .001). Interaction between treatmentfficacy and rotavirus status was at a P level of .132. In rotavi-us-positive patients, the mean 72-hour stool output wasower with diosmectite (146.9 � 90.1 g/kg) than with pla-ebo (187.9 � 122.1 g/kg) (P � .039). No significant differenceas found in rotavirus-negative patients (P � .488).
lacebo Groups (g/kg)
Placebo
N 72-h stool output, g/kg P
132 118.8 � 92.5 .03231 187.9 � 122.1 .039
101 97.6 � 69.3 .488144 90.7 � 94.0 .00716 184.5 � 192.4 .002
128 79.0 � 65.9 .434276 104.1 � 94.2 .002
47 186.8 � 147.2 �.001229 87.2 � 67.9 .878
igure 1. Diarrhea duration in the diosmectite and placebo patients inhe Peru study according to rotavirus status, Kaplan–Meier survivalurves are shown.
nd P
us status from the results of the Peru and Malaysia studies.
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April 2009 DIOSMECTITE IN CHILDREN WITH ACUTE DIARRHEA 459
Malaysia StudyStudy populations. A total of 302 patients were in-
luded in the intent-to-treat population (150 in the placeboroup and 152 in the diosmectite group) between July 11, 2006,nd March 24, 2007, in 17 primary care hospitals locatedhroughout Malaysia. Twenty-nine major deviations to the pro-ocol were observed in 17 patients: 3 inclusion/exclusion crite-ia not respected, 13 patients hospitalized fewer than 70 hours,1 had treatment exposure for less than 72 hours, 1 prohibitedoncomitant medication was used and 1 patient had grosslood in stools during the first 72 hours. The per-protocolopulation was therefore 285 patients, 140 in the diosmectiteroup and 145 in the placebo group.
Children had a mean (�SD) age of 15.9 � 8.5 months, aean weight of 9.02 � 2.05 kg, and a mean height of 77.3 � 8.7
m, with no difference between study groups. Mean (�SD) totalmount of ORS intake during the hospitalization period was022 � 674 mL. There was no significant difference betweenhe diosmectite and placebo groups for rotavirus status or ORSse.
Efficacy. The mean (�SD) 72-hour stool output wasower with diosmectite (87.9 � 81.2 g/kg) than with placebo90.7 � 94.0 g/kg) (P � .007) (Table 1). Diarrhea lasted signif-cantly shorter with diosmectite (median, 25.1 h; 95% CI, 20.50 –9.00 h) than with placebo (median, 32.6; 95% CI, 27.5–39.3 h)
P � .001). In rotavirus-negative children, diarrhea lasted sig-ificantly shorter with diosmectite (median, 24.2 h; minimum–aximum, 0 –129 h) than with placebo (median, 32.4 h; mini-um–maximum, 0 –152 h) (P � .002) (Figure 2). In rotavirus-
ositive children, the difference in diarrhea duration was nottatistically significant between placebo (median, 31.6 h; mini-
um–maximum, 0 –114 h) and diosmectite (median, 16.4 h;inimum–maximum, 0 –76 h) (P � .244).
igure 2. Diarrhea duration in the diosmectite and placebo patients inhe Malaysia study according to rotavirus status, Kaplan–Meier survival
surves are shown.
As for the Peru study, secondary analyses of primary out-ome showed that cumulative stool output was significantlyigher in rotavirus-positive patients (135.4 � 156.5 g/kg) than
n rotavirus-negative patients (83.1 � 72.1 g/kg) (P � .001). Aignificant interaction between treatment efficacy and rotavirustatus was found (P � .001). In rotavirus-positive patients, the
ean 72-hour cumulative stool output was twice as low in theiosmectite group (91.8 � 103.0 g/kg) than in the placeboroup (184.5 � 192.4 g/kg) (P � .002). No significant differenceas found in rotavirus-negative patients (P � .434).
Pooled Efficacy DataThe mean (�SD) 72-hour stool output was lower with
iosmectite (94.5 � 74.4 g/kg) than with placebo (104.1 � 94.2/kg) (P � .002). Adjusted means on unbalanced rotavirusactor (least-squares means � standard error of the mean) were05.5 � 6.7 g/kg with diosmectite versus 134.8 � 6.6 g/kg withlacebo, a 30% reduction in 72-hour stool weight.
In secondary analyses, a significant rotavirus effect (P �001) and a significant interaction between treatment and rota-irus status (P � .001) were found. A study effect was foundP � .035) but there was no interaction between treatment andtudy (P � .724). A significant treatment effect was found inotavirus-positive patients (P � .001) but not in rotavirus-egative patients (P � .878). Rotavirus-positive diosmectite-reated patients had a lower mean (�SD) stool output (124.3 �8.3 g/kg) than rotavirus-positive placebo-treated patients186.8 � 147.2 g/kg).
TolerabilityIn Peru, 185 AEs were reported, of which 145 were
reatment-emergent AEs, 18 were serious (Table 2). In Malaysia,35 AEs were reported, of which 110 were treatment-emergentEs, and 20 were serious. Most frequent treatment-emergentEs were fever and vomiting. No difference in frequency of AEsas observed between diosmectite and placebo.
DiscussionThe present studies show that diosmectite, used as an
djunct therapy to the ORS currently recommended by theorld Health Organization,4 decreased 72-hour stool output in
hildren, particularly if rotavirus-positive, and shortened theuration of acute watery diarrhea.
This study shows a significant effect of diosmectite on stoolutput, studied as a primary outcome, and diarrhea dura-ion.7,10 –14,21 In a previous study, Madkour et al13 showed thatiosmectite shortens diarrhea duration in children and de-reases the number of stools. Similar reductions in stool outputn acute watery diarrhea were shown only for bismuth17 andacecadotril.18 Furthermore, the efficacy of diosmectite wehowed on stool weight is supported by the fact that thelacebo we have used has a lower osmolarity than diosmectite
46 vs 147 mOsm/L, respectively). The significant result foundith diosmectite is therefore probably an underestimation of its
eal efficacy. It also is noteworthy that this effect of diosmectiteas found despite decreased total stool output over the pastecade, as illustrated by the lower stool output found in theresent study compared with previous studies conducted underimilar conditions, which strengthens our findings.13,17,18 As
hown by a Cochrane review by Hahn et al,22 this may be the
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460 DUPONT ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 7, No. 4
esult of the use, since 2004, of an ORS of decreased osmolarity245 vs 311 mOsm/L previously).
Diosmectite has been used for years in the treatment of acuteatery diarrhea with an excellent safety record, further docu-ented here. This positive safety profile could be owing to a
herapeutic effect restricted to the luminal side of the intestine,hus avoiding any side effect related to interaction with gut
otility, such as constipation, bacterial proliferation, and toxicegacolon.23–25 Moreover, we found that diosmectite reduces
iarrhea duration. This, in addition to the reduction of stoolutput volume, supports its use as an adjunct treatment toRS.21 Our data therefore suggest that diosmectite could be
ost effective in the management of acute watery diarrhea. Inhildren whose disease necessitates hospitalization, shortenediarrhea duration is beneficial for the social, professional, andnancial situation of the parents,23,24 especially in low-incomeountries where the high prevalence of acute diarrhea is notatched by adequate health insurance.Many studies have focused only on the water-binding effect
f clays and subsequent modification of stool form. However, ifiosmectite were only binding water, it would have delayedecovery without altering stool volume. Therefore, the de-reased stool weight and time to recovery we have found withiosmectite strongly supports the already demonstrated effect
able 2. AEs Reported in the Peru and Malaysia Studies
Diosmectite,n (no. ofpatients)
Placebo,n (no. ofpatients)
Either,n (no. ofpatients)
eru studyAEs 91 (70) 94 (67) 185 (137)
Treatment-emergent AEs 68 (55) 77 (56) 145 (111)Fever 10 (10) 13 (13) 23 (23)Vomiting 7 (7) 13 (13) 20 (20)Pharyngitis/
nasopharyngitis14 (14) 5 (5) 19 (19)
Diarrhea 2 (2) 7 (7) 9 (9)Rhinitis 6 (6) 2 (2) 8 (8)Othersa 29 37 66
Serious treatment-emergent AEsb
6 (6) 12 (11) 18 (17)
alaysia studyAEs 61 (48) 74 (55) 135 (103)
Treatment-emergent AEs 51 (41) 59 (43) 110 (84)Fever 11 (11) 12 (12) 23 (23)Vomiting 4 (4) 6 (6) 10 (10)Dermatitis contact 4 (4) 4 (4) 8 (8)Rhinorrhea 1 (1) 4 (4) 5 (5)Othersa 31 33 64
Serious treatment-emergent AEsb
8 (8) 12 (11) 20 (19)
OTE. Results are expressed as the number of events and theumber of patients concerned. In case of multiple treatment-emer-ent AEs being reported for the same patient with the same wording,he strongest relationship to the compound, and the maximum sever-ty were retained in statistical analyses.Each represented less than 2% of the patients. Anal discomfort,onstipation, dehydration, rash, respiratory tract infections, and skinrritation were included.Serious treatment-emergent AEs were not considered treatment-elated by investigators.
f diosmectite on other factors than water-binding and stool m
orm. Diosmectite adsorbs bacteria, viruses, and bacterial tox-ns,8,26 –31 has a covering effect and interacts with intestine,7 has
protective effect against intestinal inflammation induced byumor necrosis factor-�,9 and, as we have shown previously,iosmectite increases the absorptive capacity of the intestinalucosa.7
In 1985, Edelman32 stated the characteristics of the idealntisecretory compound for the treatment of infectious diar-hea: inhibits fluid secretion or stimulates fluid absorption byntestinal mucosa, onset of action within minutes, limited con-tipating effects, high therapeutic index, noninterference withecovery of local bowel function, minimal central nervous sys-em effects, low abuse potential, and low cost. These appearlobally met by diosmectite, in terms of both efficacy and safety.
In the present study, diarrhea duration was shorter and stoolutput was lower in Malaysia than in Peru. Shorter diarrheauration in Malaysia mostly is owing to different definitionsetween countries: time from the first sachet intake to the firstormed stool for Peru, and time from the first sachet intake tohe first soft or formed stool for Malaysia. Indeed, it was founduring blind review that a very high proportion (40%) of thealaysian children had no formed stool by the end of the study,hich was not found in Peruvian children (0% without formed
tool). To be in accordance with the specificities of this country,nd before treatment allocation code was unblinded, the defi-ition of diarrhea duration was modified in the Malaysia study,hich gave a shorter mean diarrhea duration. Nevertheless, the
act that Malaysian children had fewer formed stools and lowertool output is interesting and several hypotheses may be raisedo explain these findings. Because rotavirus infection increasestool output,18,33,34 increased stool output may be related to thewice-higher incidence of rotavirus infection in Peruvian chil-ren (22%), as compared with Malaysian children (12%). Aecond explanation may be that stool consistency and stooleight may have been altered by a higher incidence of malnu-
rition in Malaysian children.35 This is supported by their lowerean body weight as compared with Peruvian children (9.0 vs
.4 kg), despite a higher mean age (15.9 vs 12.5 mo). Finally, thislso may be related to social differences between these 2 coun-ries (eg, alimentary habits, period of weaning), which may leado differences in usual stool consistency in these childrenounger than 36 months of age, or to different estimations ofhat is a formed stool. However, additional epidemiologic datare required to explain this unexpectedly high proportion ofhildren without formed stool in the Malaysia study.
Although they were not designed with this aim, the presenttudies showed that diosmectite was particularly efficient inotavirus-positive children. This may be related to both theigher stool output in rotavirus-positive patients and pharma-ological properties of diosmectite. Rotavirus increases the se-erity of diarrhea, especially with regard to stool output.18,33,34
he increased efficacy of diosmectite in rotavirus patients coulde related to the fact that a pharmacological effect is more likelyhown when symptoms are more pronounced. On the otherand, rotavirus induces a secretory process at the enterocyte
evel that could be counteracted by diosmectite. A previousouble-blind study of intestinal permeability in children withcute diarrhea showed that, in addition to the effects citedreviously, diosmectite increases mannitol absorption, thusuggesting an increased absorptive capacity of the intestinal
ucosa with diosmectite.7 Nonetheless, the design of the
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April 2009 DIOSMECTITE IN CHILDREN WITH ACUTE DIARRHEA 461
resent studies does not allow us to do more than raise hypoth-ses about this particular efficacy of diosmectite in rotavirus-ositive children. Specific pharmacological studies thereforehould be conducted to deepen this very interesting and unex-ected finding.
Nevertheless, although diosmectite appears more efficaciousn rotavirus-positive children, many countries cannot affordystematic rotavirus testing. Because rotavirus-negative patientsre no worse off when using diosmectite, and generally have lessevere diarrhea than rotavirus-positive patients, there is in facto disadvantage in using diosmectite in rotavirus-negative pa-ients. On the contrary, our results show a clear disadvantage inot using diosmectite in rotavirus-positive children, which haveore severe diarrhea and are at higher risk of complications.he public health point of view is therefore in favor of the usef diosmectite in the treatment of acute watery diarrhea inhildren.
In conclusion, because it decreases stool output and theuration of diarrhea, especially in cases associated with rotavi-us, the virus that causes severe diarrhea, diosmectite could beecommended as an adjunct therapy to the currently recom-
ended ORS4 for the management of acute watery diarrhea inhildren.
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eprint requestsAddress requests for reprints to: Eduardo Salazar-Lindo, MD, DS
onsult, Avenue El Polo 740, Office C-410, Surco, Lima 033, Peru.-mail: [email protected]; fax: (51) 1-435-6533.
cknowledgmentsThe authors are grateful to the nurses and study monitors who
reatly helped with the patients in the study, to the Clinical Researchenter (CRC), Kuala Lumpur Hospital, for monitoring in Malaysia, to Drlisabeth Leger-Picherit who performed the statistical analysis, and tor Guillaume Hébert from SC Partners who assisted in preparing theanuscript.The Peru Diosmectite Study Group: Dante Figueroa Quintanilla,
ablo Huamaní Echeccaya: Instituto Especializado de Salud del Niño,ima, Peru; Carlos Hurtado Rubio, Luis Chucas Asencio: Hospital Sanuan de Lurigancho, Lima, Peru; Luis Alvarado Martinez: Hospital deitarte, Lima, Peru; Victoria Reto Valiente, Carlos Hironaka Ichiy-nagui: Hospital Nacional Hipólito Unanue, Lima, Peru; Isabel Reyescosta, María Isabel Caciano Jares: Hospital Emergencias Pediátricas,ima, Peru; Jessika Leon Arias, Christian Carnero Sanchez: Hospitalunicipal Los Olivos, Lima, Peru; Hilda Vega Ponte, Soledad Garay
egashira: Hospital de Huacho, Huacho, Peru; Carlos Huamani Ruiz:ospital Nacional San Bartolomé, Lima, Peru; Juan Carlos Tirado:línica San Juan Bautista, Lima, Peru; Elsa Chea Woo, Aldo Maruyaito: Hospital Nacional Cayetano Heredia, Lima, Peru; and Patriciaastillo Raez: Hospital de Ica, Ica, Peru.The Malaysia Diosmectite Study Group: Jimmy Lee Kok Foo,
adhiah Binti Abu Bakar: Hospital Kuala Terengganu, Terengganu,alaysia; Teh Keng Hwang, Leong Ming Chern: Alor Setar Hospital,
edah, Malaysia; Yogeswary Sithamparanathan, N. Nachal: Tengku mmpuan Rahimah Hospital, Klang Selangor, Malaysia; Etherajan The-anirajan: Kluang Hospital, Johor, Malaysia; Soo Min Hong, Nor Ma-ani: Kajang Hospital, Selangor, Malaysia; Chan Lee Gaik, Hii Kinghing: Sarawak General Hospital, Kuching, Malaysia; Aisyah Mohdivai: Kulim Hospital, Kedah, Malaysia; Nazrul Neezam: Hospital Sul-
an Haji Ahmad Shah, Temerloh, Pahang, Malaysia; Revathy Nal-usamy, Jasvinder Kaur: Pulau Pinang Hospital, Pulau Pinang, Malay-ia; Tan Kah Kee, Wilson Pau Shu Cheng: Seremban Hospital, Negeriembilan, Malaysia; Neoh Siew Hong, Saiful Rijal bin Muhamad: Taip-
ng Hospital, Perak, Malaysia; Chin Choy Nyok, Selva Kumar: Hospitalengku Ampuan Afzan, Kuantan, Pahang, Malaysia; Norrashidah Hjbdul Wahab, Faizah Mohamed Jamli: Hospital Serdang, Selangor,alaysia; Kuan Geok Lan, Chin Fook Hin: Malacca Hospital, Malacca,alaysia; Ng Su Yuen: Teluk Intan Hospital, Perak, Malaysia; Choohoong Ming: Sungai Petani Hospital, Sungai Petani, Kedah, Malaysia;nd Nga Shih Hang: Seri Manjung Hospital, Perak, Malaysia.
onflicts of interestHélène Mathiex-Fortunet and Philippe Garnier are Ipsen employees.Christophe Dupont, Jimmy Lee Kok Foo, Nicholas Moore, and Edu-
rdo Salazar-Lindo have received honoraria and/or compensation inegards to the study, as an investigator, coordinator, or expert, inelation with the time spent on the study. The authors declare noonflict of interest in regards to the present article derived from thetudy, for which no compensation or stipend was received. There is norganic or regular relationship between the authors and Ipsen. Theuthors own no shares in Ipsen and no member of their immediateamily is employed by Ipsen. Guillaume Hébert, from SC Partners,ssisted in preparing the manuscript, according to a contract betweenpsen and SC Partners. The sponsor participated in study design,hoice and set-up of centers, training for standardized stool collection,roviding of materials (scales, diapers, World Health Organization oralehydration solution), data monitoring, data collection, and prepara-ion of the clinical study report.
undingThis study was supported by Ipsen, France, the developer of dios-
ectite and the owner of Smecta.
