4. Discussion

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.

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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 [4, 6, 23, 25]. Of note is that most patients had a recent episode of acute diarrhoea, similar in both groups (median time from first watery stool to treatment onset = 1 [0-3] day from the 1st watery stool to inclusion (NS)), with at least one associated symptom such as nausea, abdominal pain, or anal irritation in >90% of the patients and a median number of six stools per day before treatment onset. Hence, it can be extrapolated that if the primary endpoint variable had been measured from the time of onset of diarrhoea, instead of from the first intake of study drug, the difference between the two groups would still have been the same, that is, 15.2 hours. Moreover, this pattern of diarrhoea is in accordance with the definition of acute diarrhoea in developed countries [4, 25, 26]. Therefore, it can be estimated that results of the present study can be extrapolated to western countries.

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 [12, 14, 26, 27]. Except in chronic diarrhoea, trials performed in adults rarely use stool volume as an endpoint. The clinical effect of diosmectite as an antidiarrhoeal agent in adults has been assessed mainly by the measurement of time to transit normalization [6, 26]. The definition of recovery chosen is again more stringent since it is based not only on the achievement of a normal stool but also by its following a nonwatery stool, thereby reflecting an actual cessation of the acute diarrhoea episode.

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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 [11-14]. However, heterogeneity in trial design, drug doses, and endpoint definition makes these results difficult to compare with those presented here. It can only be inferred from these studies that, depending on the modalities of treatment and recovery definition, diosmectite and loperamide can show similar improvements of the duration of acute diarrhoea in adults. This is further supported by the results from the prospective trials comparing loperamide to placebo in acute diarrhoea in adults [27-30]. In one study the endpoint was the mean number of stools per day [30] but in the other three studies, the definition of time to recovery was not very different to that chosen here: time between the first drug intake and the first 24-hour period without watery or loose stool that was not followed by the recurrence of diarrhoea during the following 24-48 hours. In these three trials, median times to recovery were respectively: 45 hours 15 minutes in the placebo group versus 23 hours and 30 minutes in the 1 mg loperamide group [27]; 34 hours 15 minutes in the placebo group versus 26 hours 30 minutes in the 1 mg loperamide group [29]; 40 hours 35 minutes in the placebo group versus 27 hours 55 minutes in the 1 mg loperamide group [28]. This corresponds to respective decreases of 21 hours, 12 hours 40 minutes, and 7 hours 45 minutes with loperamide, which can be considered to be a similar range to the results observed here with diosmectite. In addition, the trial data presented here employed a more stringent definition of recovery. In studies comparing loperamide to placebo, time to recovery was time to the last watery stool whereas in the present study it was time to the first formed or hard stool followed by a nonwatery stool.

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