Acute diarrhoea is one of the leading causes of morbidity worldwide [
Various guidelines are available for the treatment of acute diarrhoea in adults [
Diosmectite, an activated natural aluminosilicate clay consisting of a double aluminium and magnesium silicate, is an adsorbent widely used for the treatment of acute infectious diarrhoea in children. In children, diosmectite efficacy in the treatment of acute watery diarrhoea has been assessed in a recent meta-analysis. Combined data from six randomized, controlled trials have shown that diosmectite significantly reduces diarrhoea duration by one day and increases the chance of recovery on intervention day three versus control group [
In adults, no prospective, randomized, placebo-controlled trial on the efficacy of diosmectite in the treatment of acute diarrhoea has yet been conducted. Diosmectite was compared to loperamide only, in four open, prospective trials that showed similar effects for both drugs in the treatment of acute infectious diarrhoea [
Like other adsorbents, diosmectite is not absorbed in the intestine. It can adsorb eight times its own weight of water, thereby diminishing free stool water. It also adsorbs toxins, bacteria, and rotavirus, preventing their adherence to intestinal membranes. Diosmectite strengthens the mucosal barrier, and, in the absence of mucus, prevents its disruption [
This demonstrated efficacy in children suggests that, compared to placebo, diosmectite could improve recovery from acute watery diarrhoea in adults, but this has never been studied. We therefore undertook a multicentre, randomized, double-blind, placebo-controlled trial to assess the efficacy of diosmectite for the treatment of acute watery diarrhoea in adults.
The study included outpatient males and nonpregnant women aged 18 to 65 years in 23 primary and secondary care centres in Tunisia.
Inclusion criteria were an acute diarrhoea episode defined as at least three watery stools per day over a period of 48 hours or less, and patients with usually normal bowel movements, that is, at least three normal stools per week and three or less normal stools per day.
Exclusion criteria related to the diarrhoea episode were fever >39°C, blood or pus in stools, previous history of acute watery diarrhoea over the past 30 days, dehydration requiring intravenous rehydration, traveller’s diarrhoea, history of chronic diarrhoea (three or more loose or watery stools per day for at least 12 weeks, consecutive or not, in the preceding 12 months), and motor diarrhoea defined as urgent, morning postprandial need for defaecation. Exclusion criteria related to drug use were patients having used antidiarrhoeal agents over the month prior to baseline, patients requiring the daily intake of a drug treatment with narrow therapeutic margin, and patients with diarrhoea possibly induced by antibiotics, laxative agents, thyroid hormones, or colchicine.
This was a multicentre, placebo-controlled, double-blind, randomized study with parallel groups conducted in 23 centres in Tunisia. Tunisia was chosen for its good medical practice and compliant organization and its prevalence of acute infectious diarrhoea comparable to that of industrialized countries [
Newly diagnosed ambulatory patients suffering from acute diarrhoea presumed to be of infectious origin were randomized to receive diosmectite or placebo. During their participation, patients recorded in diaries their stool frequency, presence of blood in stools, and abdominal pain/cramps. An acute diarrhoea episode was regarded to have resolved after the patient had one formed stool followed by a nonwatery stool.
The study was registered at
Patients were randomly treated with either diosmectite or placebo. Patients were randomized at visit 1, in sequential ascending order within each centre. The investigator only dispensed the study drug to the patients included in the study. For each study site, the sponsor-assigned biostatistician prepared a list of treatment allocation codes, which were confidentially supplied to the drug supplier. The master list and the copy given to the Clinical Trial Supplies Unit were kept confidential in a safe and secure location. The randomization list was not released until approval was received for the study to be unblinded for analysis. For both diosmectite and placebo, treatment was two sachets each containing 3 g of powder for oral suspension three times a day (morning, lunch and dinner). From day 1 to day 4, the treatment was mandatory (i.e., six sachets per day). From day 5, the dose was six sachets per day until recovery, that is, one formed stool followed by a nonwatery stool, with a maximum of seven days of treatment.
Diosmectite is a powder for oral suspension in a sachet, composed of 3.000 g diosmectite, 0.004 g vanillin, 0.007 g sodium saccharin, and 0.749 g glucose monohydrate. A placebo formula was specifically developed. It was a powder for oral suspension in a sachet, composed of 1.000 g titanium dioxide, 1.181 g maltodextrin (Roquette Glucidex IT 38), 0.004 g vanillin, 0.007 g sodium saccharin, 2.150 g glucose monohydrate, and 0.018 g caramel colouring E150B. Placebo was inert and identical to diosmectite in size, weight, colour, smell, taste, and appearance, either as a powder or a water solution. Its absence of pharmacological activity was demonstrated on an animal model of watery diarrhoea (data not shown). Treatment compliance was assessed at visit 2 or 3, based on sachet consumption recorded in the patient diary, overall count of used and unused sachets, and answers to questions on study drug compliance.
Patients attended the study centres three times: at screening (patients included in the study began treatment at once), at midstudy (day 4 or 5 after inclusion), and for a concluding examination (day 8 or 9 after inclusion).
At baseline visit (visit 1), written informed consent was collected, patients were given a diary, and the following data were collected: demographics, vital signs, weight, physical examination results, use of concomitant medication, previous medical history, and case history of the acute diarrhoea episode including date of first watery stool, number of stools over the past 24 hours, and presence of other associated symptoms over the past 24 hours (nausea, abdominal pain, anal irritation). Patients were asked to record the following data every day in the diary: date, hour of stool onset, stool consistency (watery, loose, formed, or hard), presence of symptoms such as nausea, abdominal pain, and anal irritation, and study drug consumption (number of sachets taken each day). To standardize the rating of stool consistency, patients were shown a scheme explaining the different stool consistencies and corresponding ratings [
During the second and the third visits (visit 2 and visit 3), investigators collected vital signs, physical examination, weight, adverse events, clinical data, study drug use in the diary, stool consistency, and stool time. In addition, the number of treatment sachets used and unused that were kept by the investigator was recorded at visit 3.
The primary objective was to compare the efficacy of diosmectite to that of placebo in adults with acute watery diarrhoea, taking time to recovery as a primary endpoint. The secondary objectives were to compare diosmectite and placebo with regards to the other efficacy parameters and safety in adults with acute watery diarrhoea.
Time to recovery was defined as the time (hours) from first study drug intake (H0) to diarrhoea recovery. Recovery was defined as the first formed or hard stool followed by a nonwatery stool. Time to recovery was determined from the data collected in diaries. However, if the diary was lost or unusable, analyses were performed from data collected in the case report form, after blind review decision.
Secondary efficacy endpoints were time (hours) from the first sachet intake to the last watery stool and, per 12-hour period, number of stools, number of watery stools, percentage of patients having recovered (defined as having achieved the primary efficacy endpoint), and percentage of patients with associated symptoms such as nausea, abdominal pain, and anal irritation.
The safety evaluation was carried out during the follow-up visits and was based on monitoring of any adverse event (AE) occurring from the moment patients had given informed consent to 7 days after the end of the study. AEs were coded according to the Medical Dictionary for Regulatory Activities (MedDRA) version 9.1. Safety variables were the frequency of adverse events, with a special attention to incidence of nausea, abdominal pain, and anal irritation.
Primary and secondary endpoints were compared in both groups using appropriate statistical tests: Wilcoxon’s test for quantitative parameters without normal distribution described by median and range; Student’s
With regards to the primary endpoint, statistical analysis was based on Wilcoxon’s test in the intention-to-treat (ITT) population. The ITT population included randomized patients having taken the study drug at least once together with a primary endpoint that was assessable. Per-protocol (PP) population included ITT patients without major protocol deviations as defined after a blind review. PP analyses were supportive only. To assess robustness of the results, it was decided to perform post hoc analyses of primary efficacy data in ITT and PP populations using the “time to event” Gehan-Wilcoxon test, which takes into account censored data and their specific distributions with early events and late censures. Secondary efficacy analyses were conducted in the ITT population.
Sample size determination was based on the hypothesis that time to recovery was significantly shorter under diosmectite than under placebo (one-sided hypothesis). From previous studies, the expected difference of the primary efficacy criterion between diosmectite and placebo was 24 hours, with an estimated standard deviation (SD) of 61.7 hours. With an alpha risk of 5% and a beta risk of 20%, the number of patients to be included per group was 140 to obtain 104 “assessable” patients per group, that is, for which the primary outcome could be assessed.
Statistical analyses were performed using SAS (SAS Institute, version 8.1, North Carolina, USA).
Between January 2005 and July 2006, 23 physicians assessed 346 patients for eligibility (from 1 to 52 patients per physician, mean = 15 patients per physician). A flow chart of all the screened patients (
Flow chart of study populations. Diosmectite (6 g three times a day) or placebo in the treatment of acute diarrhoea in adults.
Major protocol deviations were observed in 47 patients: 26 patients (15.7%) in the diosmectite group and 21 patients (12.9%) in the placebo group. These 47 patients were excluded from ITT population to constitute the PP population (
The two treatment groups were well balanced for basic demographic data and disease history. There was no difference between groups with regards to age, gender distribution, height, and weight, previous medical history (222/329 or 67.5% of the patients had no medical history) and concomitant treatments. The baseline clinical picture of acute diarrhoea episodes was not different between both groups (Table
Demographics, previous medical history, and characteristics of the acute diarrhoea episode.
Diosmectite | Placebo | ||
Demographics | |||
Male, | 89 (53.6) | 86 (52.8) | .88a |
Age (years), median [range] | 38.0 [19–63] | 38.0 [19–66] | .84b |
Height, females (cm), median [range] | 162.0 [150–180] | 162.0 [150–182] | .74b |
Height, males (cm), median [range] | 172.0 [158–202] | 173.0 [158–189] | .33b |
Weight, females (kg), median [range] | 64.0 [40–94] | 66.0 [44–102] | .29b |
Weight, males (kg), median [range] | 78.0 [49–107] | 76.0 [55–152] | .24b |
Characteristics of the diarrhoea episode | |||
Previous history of gastrointestinal disorders, | 9 (5.4) | 13 (8.0) | .35a |
Days from the 1st watery stool to inclusion, median [range] | 1.0 [0–3] | 1.0 [0–3] | .90b |
Nausea, abdominal pain, or anal irritation, | 156 (94) | 148 (90.8) | .28a |
Number of stools over the past 24 hours, median [range] | 5.0 [2–22] | 6.0 [3–20] | .17b |
Positive stool culture, | 40 (29.2) | 33 (22.9) | .23a |
Rotavirus | 16 (11.9) | 14 (10.0) | .61a |
Adenovirus | 7 (5.4) | 3 (2.2) | .21a |
| 13 (9.6) | 13 (9.3) | .92a |
| 4 (2.9) | 2 (1.4) | .44a |
Amoebiasis | 4 (2.9) | 1 (0.7) | .21a |
a2-tailed Chi-square test; bWilcoxon’s test.
In the ITT population (
In the PP analysis (
The percentage of therapeutic success, defined as patients having achieved the primary efficacy endpoint, per cumulative 12-hour period, was higher in the diosmectite group than in the placebo group in the following periods: 0–36 h (28.5% versus 19.2% [
Cumulative percentages of recovered patients per 12 h period. Recovery was the first formed stool followed by a nonwatery stool (primary endpoint). Diosmectite (6 g three times a day) or placebo in the treatment of acute diarrhoea in adults.
Median [range] time from first sachet intake to the last watery stool was 20.5 hours [0.0–160.8] in the diosmectite group and 23.0 hours [0.0–223.8] in the placebo group (
Nausea during the 24 hours before inclusion was present in 71.7% of the patients in the diosmectite group and 68.7% in the placebo group. Incidence decreased dramatically to <5% in both groups after 48 hours (N.S).
Abdominal pain before inclusion was present in 86.1% of the patients in the diosmectite group and 78.5% in the placebo group. Incidence decreased to <15% in both groups after 48 hours (N.S). Anal irritation before inclusion was present in 18.1% of the patients in the diosmectite group and 24.5% in the placebo group. Incidence decreased to <5% in both groups after 36 hours (N.S).
Both diosmectite and placebo were well tolerated. The median [range] duration of exposure was 4.2 days [0.3–7.5] in the diosmectite group and 4.2 days [0–10.1] in the placebo group. In total, 12 AEs occurred in 11 patients during the study: 6 AEs in 6 patients (3.5%) of the diosmectite group and 6 AEs in 5 patients (2.9%) of the placebo group. In both groups, the most frequently reported AEs were gastrointestinal disorders.
Particularly, incidence of new nausea episodes during the study was observed in 4.2% (7/166) of the patients in the diosmectite group and 3.7% (6/163) in the placebo group. Incidence of abdominal pain episodes was observed in 2.4% (4/166) of the patients in the diosmectite group and 8.6% (14/163) in the placebo group. Finally, incidence of anal irritation episodes was observed in 12.6% (21/166) of the patients in the diosmectite group and 29.4% (48/163) in the placebo group.
Two serious AEs were reported in two patients in the placebo group: one case of fracture of the lower limb and one case of appendicitis; both were assessed as unrelated to the study drug. AEs leading to permanent study medication discontinuation were reported in 3 patients in the diosmectite group (1.7%) and in 3 patients in the placebo group (1.7%). Gastrointestinal disorders (constipation, abdominal pain, appendicitis, and amoebiasis) were the main reason for discontinuation due to AEs in both groups.
During the study, no relevant abnormality was found with regards to body weight, blood pressure, and cardiac rhythm.
This is the first randomized, placebo-controlled trial prospectively comparing diosmectite to placebo for the treatment of acute diarrhoea in adults. This study showed that oral diosmectite sachet 6 g three times a day significantly shortened time to recovery in the treatment of acute diarrhoea in adults. This was further supported by the results found in the PP population. This study also confirmed the good safety profile of diosmectite, as illustrated by the limited number of AEs, of which only 3 were considered drug related (constipation).
The statistical analysis plan was based upon the assumption that the duration of the diarrhoea episode would be shorter than seven days for all patients, without any risk of data censure. It was therefore planned to compare mean diarrhoea durations using the Wilcoxon’s test, which is perfectly adapted to this type of data. The definition of diarrhoea duration required that patients are followed after the first formed stool to confirm the end of the diarrhoea episode. This definition of recovery was selected to guarantee the clinical relevance of the primary criterion. Of note is that it was much more constraining than previous trials, which defined recovery as the first nonliquid stool. However, according to the definition of recovery used in the study, 35 patients showed diarrhoea duration longer than seven days. Since the protocol planned a seven-day followup, these patients were censored in statistical analyses. Nevertheless, a post hoc time to event analysis taking data censure into account was carried out. The Gehan-Wilcoxon test was preferred to the Logrank test because of the particular distribution of the events considered and the onset of censures during study followup. Indeed, the Gehan-Wilcoxon test is more adapted than the Logrank test to early events and late censures. Moreover the latter is based upon the assumption of proportional hazards, which is most probably not verified in this trial since the active treatment is supposed to shorten time to recovery without modifying the risk of recovery. Acute watery diarrhoea is self-resolving, even in the absence of treatment. The results of the Gehan-Wilcoxon test confirmed the effectiveness of diosmectite. These results are consistent with the primary analysis and confirm that diosmectite shortens time to recovery.
Despite significantly shorter time to recovery in the diosmectite group, the proportions of patients achieving recovery were similar in both groups at the end of the study. This is explained by acute watery diarrhoea being self-resolving within seven days.
The trial was performed in a homogeneous Tunisian population with positive stool culture in 26% of the patients. These figures are consistent with those reported in the literature and previously in Tunisia [
The endpoints most frequently used in trials regarding antidiarrhoeal drugs in children and adults are stool volume and time from treatment onset to last liquid or first formed stool [
The only data to which the present results may be compared derive from trials comparing diosmectite to loperamide in the treatment of acute diarrhoea in adults [
This randomized, double-blind, placebo-controlled trial shows that diosmectite at a dose of 6 g three times a day reduced the time to recovery of an acute watery diarrhoea episode in adults. Diosmectite was also associated with a very good safety profile and did not decrease intestinal peristalsis. In summary, the results of the present study support the use of diosmectite in the management of acute watery diarrhoea in adults.
H. M.-Fortunet and P. Garnier are employees of Ipsen, the developer of diosmectite and owner of Smecta. F. Khediri, A. I. Mrad, M. Azzouz, H. Doughi, T. Najjar, and A. Cortot declare having received honoraria and/or compensation with regards to the study, as an investigator or coordinator, in relation with the time spent on the study. These authors declare no conflict of interest with regards to the present paper derived from the study, for which no compensation or stipend was received. There is no organic or regular relationship between these authors and Ipsen. These authors own no shares in Ipsen, and no member of their immediate family is employed by Ipsen.
F. Khediri, A. I. Mrad, M. Azzouz, H. Doughi, and T. Najjar substantially participated in data acquisition, revised the paper for important intellectual content, and approved the final version of the paper. H. M.-Fortunet and P. Garnier participated in conception, design, analysis of data, revised the paper for important intellectual content, and approved the final version of the paper. A. Cortot participated in conception, design, analysis and interpretation of data, drafted the paper, and revised it for important intellectual content, and approved the final version of the paper.
This study was sponsored by Ipsen. The authors would like to thank Dr. Guillaume Hébert from SC Partners who assisted in preparing the paper on behalf of Ipsen.