Efficacy of Racecadotril in acute diarrhea in children: systematic review of the literature and meta-analysis of randomized clinical trials

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Standard treatment is oral rehydration, but antidiarrheal drugs are still widely used. However, their efficacy is debated: several trials and meta-analyses show results that are sometimes contradictory, but often reach the same conclusions : generally, the results are significant, but with a low level of evidence. Objective : The aim of this study was to evaluate the efficacy of Racecadotril in acute diarrhea in children, through a systematic literature review and meta-analysis of randomized trials, using the REB method. Method : A bibliographic search was conducted for articles published until 10/02/2023. The risk of bias was assessed using the RoB2 tool. The endpoints were duration of diarrhea, stool production and length of hospitalization. The REB method was used to assess the overall level of evidence of efficacy. Results : 5 trials were selected and included 904 patients. The conclusion was the absence of evidence of effect on the three endpoints. Conclusion: This study shows that there is no solid evidence that the three drugs are effective in treating acute diarrhea in children, but new randomized trials of good methodological quality could provide more significant results. Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Acute diarrhea in children is a public health problem since the WHO estimates the worldwide number of cases at 1.7 billion per year, leading to approximately 525,000 deaths among children under 5 years of age, thus constituting the second cause of death in this age group[1]. The main complication of acute diarrhea is dehydration. The resulting deaths are mostly avoidable, if the losses are quickly compensated[2]. The prevention relies on oral rehydration solutions (ORS)[3], which has been recommended as the standard treatment for acute diarrhea in children[2]. Racecadotril is one of the symptomatic treatments available. However, its efficacy is questionable. 9 meta-analyses dating from 2009 to 2021[4–12] generally have the same conclusions : overall, the results are significant but with a low level of evidence. The REB (Rebuild the Evidence Base) [13,14] method proposes to define a preliminary method for interpreting and reading the results of randomized controlled trials (RCTs) and their meta-analysis. Only RCTs with low risk of bias whose results are confirmatory, which means presented in accordance with a pre-specified protocol, are kept for analysis. The aim of this study is to evaluate the level of evidence of Racecadotril in acute diarrhea in children on the duration of diarrhea, stool production, and duration of hospitalization, using the REB method criteria. Method The writing followed the PRISMA guidelines[15]. A protocol was registered on 01/16/2023 on PROSPERO under the number CRD42023389523. Eligibility Criteria Clinical trials had to be randomized and double-blind with a comparison of Racecadotril against placebo, in children aged under 18 years suffering from acute diarrhea. No language restrictions were used. Research method : A bibliographic search was conducted until the 2 nd of October 2023 in the Cochrane Library (CENTRAL), Medline via Pubmed and ClinicalTrials.gov databases. Trials not included in these databases, but cited in pre-existing meta-analyses [4–12,16–19] and meeting the eligibility criteria were included. The research was carried out by 2 researchers (IB and LG). In the Cochrane Library database, the following equation was used, searching the full text, and selecting only the results from the “Trials” tab : (racecadotril* OR acetorphan*) In the Medline database (PubMed), the following equation was used, with a full text search, without using a filter : (racecadotril OR acetorphan) AND [(randomized OR randomized) OR controlled] In the ClinicalTrials.gov database, the following equation was used, in the “Other terms” tab, selecting “All ” in the “Study type” section, without using a filter: (racecadotril OR acetorphan) The same researchers selected the trials and independently reviewed the titles and abstracts to identify those potentially eligible, before pooling and discussing. In case of discrepancy, a third researcher was contacted (RB). When the title and abstract didn’t allow a study to be included or excluded, the full text was analysed. Risk of bias The methodological quality of the included studies was assessed using the “Revised Cochrane risk-of-bias tool for randomized trials” (RoB2)[20]. The evaluation was carried out by 2 researchers (IB and LG). In case of discrepancy, a third researcher was contacted (RB). For studies presenting multiple primary endpoints, methods for controlling the multiplicity of statistical tests allowing control of inflation of the overall alpha risk were sought. If there was no adjustment method, the result of the study was considered exploratory (even if a statistical difference was found) due to a high risk of false positives linked to the multiplicity of statistical tests[21]. Quantification and synthesis of results : A quantitative synthesis was planned whenever possible, using Review Manager software (Revman®) version 5.4. However there were not enough eligible trials to conduct a meta analysis. Overall risk of bias and assessment of the level of evidence The overall level of evidence of effectiveness for each endpoint was assessed using the REB method[13,14]. Results Selection of studies The selection of trials is summarized in the flow chart in Figure 1 according to the PRISMA recommendations[22]. The research identified 177 articles. After removing duplicates, 142 articles remained, of which 126 were excluded after reading the titles and abstracts because they didn’t meet the inclusion criteria. Of the remaining 16 articles, 11 were excluded, either because the full article wasn’t found or for other reasons presented in Appendix 1. 5 trials were included in the qualitative analysis : Cézard et al [23] , Gharial et al [24] , Kang et al [25] , Salazar-Lindo et al [26] , Sarangi et al [27] . All of them could be used for the quantitative analysis, but not always for all the endpoints (some were excluded either due to lack of data or because the data was difficult to compare quantitatively). Characteristics of selected studies The main characteristics of the included studies are presented in Table 1 (the details are available in Appendix 2). The 5 selected studies [23–27] included a total of 904 patients. 4 of these studies evaluated the duration of diarrhea[23,23–26], but it was the primary endpoint only for Kang et al [25]. All 5 studies assessed stool production[23–27], and this was the primary endpoint for Cézard et al [23] , Gharial et al [24], Salazar et al [26]and Sarangi et al [27]. The measurement used was the one at 48 hours except for Kang et al [25]which measured this outcome when the patient left the hospital. 3 studies evaluated the length of hospitalization[24,25,27]. 4 studies evaluated tolerance to treatments[23,24,26,27], but in a manner that was difficult to compare quantitatively with the others. None showed a significant difference between the 2 groups. Some studies also evaluated other criteria, but which were not evaluated by the other studies, or in a way that was hardly comparable quantitatively. Assessment with the REB method The risk of bias of each study, assessed by the RoB2, is represented in figures 2, 3 and 4, for each studied endpoint. The detailed evaluations are presented in Appendix 4. The duration of diarrhea was assessed by 4 of the 5 trials[23–26]. Only the study of Gharial et al [24]was judged to have low risk of bias. Therefore no meta-analysis could be done. This study concluded that there was no significant result, with a mean duration of 2.7 days (SD = 0.23) vs. 2.8 days (SD = 0.25) in the Placebo group, p = 0.27. According to the REB method, Racecadotril therefore presents a “lack of evidence” on the duration of diarrhea. Stool production at 48 hours was assessed by the 5 trials[23–27]. The risk of bias was judged “low” only for Gharial et al [24]. Therefore no meta-analysis could be done. This study concluded that there was no significant result, with a mean number of stools at 48 hours of 6.7 (SD = 0.7) vs 6.6 (SD = 0.48) in the Placebo group, p = 0.19. According to the REB method, Racecadotril therefore presents a “lack of evidence” on stool production at 48 hours. Length of hospitalization was assessed in 3 of the 5 trials[24,25,27]. The risk of bias was judged “low” only for Gharial et al [24]. Therefore no meta-analysis could be done. This study concluded that there was no significant result, with an average length of 5.5 days (SD = 0.46) vs. 5.8 days (SD = 0.62) in the Placebo group, p = 0.48. According to the REB method, Racecadotril therefore presents a “lack of evidence” on the length of hospitalization. Discussion For Racecadotril, according to the REB method, this study showed a “lack of evidence” of effect on the duration of diarrhea, on stool production at 48 hours and on the length of hospitalization. Therefore, according to this method, Racecadotril does not present solid evidence of a significant benefit on acute diarrhea in children, whatever the endpoint studied. However, carrying out new clinical trials with a good methodological quality could provide more encouraging results. Limits The first limit is the age of the studied trials, with many risks of bias in the conduct of the studies and their analyzes by their authors : the protocols are not often pre-recorded, the methodology is often insufficiently described , not always corresponding to current transparency requirements. Many trials also have a small number of participants. The number of included trials was relatively low, with only 5 trials or even fewer for the quantitative analysis. However, the aim of this study was to determine the current level of evidence, rather than to quantify the effect itself. This objective is achieved in this study. The definition of cure of diarrhea was often differentamong the studies , as were the endpoints and the follow-up times. However, the time for measuring the quantity of stools was the same (48 hours), except for one study not specifying the measurement time ( Kang et al [25]). The assessment of the risk of bias also presents a limit : despite the ROB2 tool which helps to have a rigorous method, there still remains interpretations in the analysis. The tolerance of diarrhea complications and medications is different depending on the age of the child. However the majority of the population was between 3 months and 3 years old. Finally, some articles presented data that were sometimes complicated to analyze due to inaccuracies in the presentation of the results, which could then be considered in several ways in the analyses. We tried to control this limit by carrying out sensitivity analyzes whenever necessary. Confrontation with literature The overall result of this study differs from that of previous meta-analyses. Most of them found a significant effect without an increase in the risk of adverse effects, however often with a low level of evidence[4,5,7,9–11] one of them ( Liang et al [11]) speaking of insufficient data to recommend the routine use of Racecadotril. Our study tends to note the absence of evidence to date. Further high-quality randomized trials would therefore be necessary to be able to confirm a significant effect with a good level of evidence. Implication for practice The result of this review does not provide a clear argument in favor of the use of Racecadotril in acute diarrhea in children. Racecadotril has no particular age-related contraindication, and its actual benefit is considered moderate by the HAS, which maintains its authorization in infants below 12 months in the absence of other recommended alternative for this age[28]. The results of our study rather suggest not using it, including in infants below 12 months, in the absence of proof of efficacy, the treatment being based on ORS. Implication for research It would be interesting for Racecadotril to have well-conducted randomized trials to have results of a confirmatory nature and with a low risk of bias in pediatric populations. Indeed, it seems to have a good tolerance profile. Furthermore, besides the REB method, we also did an analysis with the GRADE method[29] which included trials that were not always at low risk of bias. We still couldn’t conclude to a significant effet because of a lack of data in some trials, but sensitivity analyzes carried out with simulated dispersion values for studies where these were missing modified the result in favor of Racecadotril for the duration of diarrhea. A meta-analysis including more trials might show a more significant result. In the meantime, its effectiveness remains uncertain. Declarations Author contributions IB and LG conducted the literature review, performed the trial analyses, and drafted the first version of the manuscript. CB contributed her expertise and provided critical revision of the final version. RB supervised the overall work, assisted with data analysis and interpretation, and wrote the final version of the manuscript. Funding Declaration No Funding References Maladies diarréhiques [Internet]. [cité 29 oct 2023]. Disponible sur: https://www.who.int/fr/news-room/fact-sheets/detail/diarrhoeal-disease Overview | Diarrhoea and vomiting caused by gastroenteritis in under 5s: diagnosis and management | Guidance | NICE [Internet]. NICE; 2009 [cité 29 oct 2023]. Disponible sur: https://www.nice.org.uk/guidance/cg84 Diarrhée aiguë du nourrisson et de l’enfant [Internet]. G.F.H.G.N.P. [cité 28 oct 2023]. Disponible sur: https://www.gfhgnp.org/recommandations-et-documents/diarrhee-aigue-nourrisson-de-lenfant/ Salazar Lindo E, Lehert P, Baumer P. The first mixed treatment comparison in acute diarrhoea in children (individual patient data meta-analysis). J Pediatr Gastroenterol Nutr. 2009;48:E30‑1. Lehert P, Chéron G, Calatayud GA, Cézard J-P, Castrellón PG, Garcia J-MM, et al. Racecadotril for childhood gastroenteritis: an individual patient data meta-analysis. Dig Liver Dis. 2011;43:707‑13. Florez ID, Veroniki A-A, Reem A-K, Yepes-Nunez J, Perez-Gaxiola G, Sierra JM, et al. Systematic review and network meta-analysis of treatments for acute diarrhoea and gastroenteritis in children. J Pediatr Gastroenterol Nutr. 2016;63:S38‑9. Gutiérrez-Castrellón P, Ortíz-Hernández AA, Llamosas-Gallardo B, Acosta-Bastidas MA, Jiménez-Gutiérrez C, Diaz-García L, et al. [Efficacy of racecadotril vs. smectite, probiotics or zinc as an integral part of treatment of acute diarrhea in children under five years: A meta-analysis of multiple treatments]. Gac Med Mex. 2015;151:329‑37. Gordon M, Akobeng A. Racecadotril for acute diarrhoea in children: systematic review and meta-analyses. Arch Dis Child. 2016;101:234‑40. Florez ID, Veroniki A-A, Al Khalifah R, Yepes-Nuñez JJ, Sierra JM, Vernooij RWM, et al. Comparative effectiveness and safety of interventions for acute diarrhea and gastroenteritis in children: A systematic review and network meta-analysis. PLoS One. 2018;13:e0207701. Eberlin M, Chen M, Mueck T, Däbritz J. Racecadotril in the treatment of acute diarrhea in children: a systematic, comprehensive review and meta-analysis of randomized controlled trials. BMC Pediatr. 2018;18:124. Liang Y, Zhang L, Zeng L, Gordon M, Wen J. Racecadotril for acute diarrhoea in children. Cochrane Database Syst Rev. 2019;12:CD009359. Farahdina F, Rizaliansyah F, Aulya JU, Fajar JK. Racecadotril for treating acute diarrhea in children a systematic review and meta-analysis. Arch Hell Med. 2021;38:618‑23. Boussageon R, Blanchard C, Charuel E, Menini T, Pereira B, Naudet F, et al. Project rebuild the evidence base (REB): A method to interpret randomised clinical trials and their meta-analysis to present solid benefit-risk assessments to patients. Therapie. 2023;78:353‑65. Projet REB - Reconstruire l’Evidence Base [Internet]. Faculté de médecine Lyon Est. [cité 29 oct 2023]. Disponible sur: https://lyon-est.univ-lyon1.fr/formation/medecine/3eme-cycle/des-medecine-generale/college-universitaire-de-medecine-generale-cumg/projet-reb-reconstruire-levidence-base Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;n71. Szajewska H, Dziechciarz P, Mrukowicz J. Meta-analysis: Smectite in the treatment of acute infectious diarrhoea in children. Aliment Pharmacol Ther. 2006;23:217‑27. Das RR, Sankar J, Naik SS. Efficacy and safety of diosmectite in acute childhood diarrhoea: a meta-analysis. Arch Dis Child. 2015;100:704‑12. Li S-TT, Grossman DC, Cummings P. Loperamide therapy for acute diarrhea in children: systematic review and meta-analysis. PLoS Med. 2007;4:e98. Pérez-Gaxiola G, Cuello-García CA, Florez ID, Pérez-Pico VM. Smectite for acute infectious diarrhoea in children. Cochrane Database Syst Rev. 2018;4:CD011526. Risk of bias tools - Current version of RoB 2 [Internet]. [cité 29 oct 2023]. Disponible sur: https://www.riskofbias.info/welcome/rob-2-0-tool/current-version-of-rob-2 Dmitrienko A, D’Agostino RB. Multiplicity Considerations in Clinical Trials. N Engl J Med. 2018;378:2115‑22. PRISMA [Internet]. [cité 29 oct 2023]. Disponible sur: http://www.prisma-statement.org/PRISMAStatement/FlowDiagram Cézard J, Duhamel J, Meyer M, Pharaon I, Bellaiche M, Maurage C, et al. Efficacy and tolerability of racecadotril in acute diarrhea in children. Gastroenterology. 2001;120:799‐805. Gharial J, Laving A, Were F. Racecadotril for the treatment of severe acute watery diarrhoea in children admitted to a tertiary hospital in Kenya. BMJ open gastroenterology [Internet]. 2017;4. Disponible sur: https://www.cochranelibrary.com/central/doi/10.1002/central/CN-01441515/full Kang G, Thuppal S, Srinivasan R, Sarkar R, Subashini B, Venugopal S, et al. Racecadotril in the Management of Rotavirus and Non-rotavirus Diarrhea in Under-five Children: two Randomized, Double-blind, Placebo-controlled Trials. Indian pediatrics. 2016;53:595‐600. Salazar-Lindo E, Santisteban-Ponce J, Chea-Woo E, Gutierrez M. Racecadotril in the treatment of acute watery diarrhea in children. New England journal of medicine. 2000;343:463‐467. Sarangi R, Biswal B, Dash B, Dhanawat A. Tolerability and efficacy of racecadotril in acute diarrhoea, a prospective, randomised, parallel study in an indian tertiary care teaching hospital. Hong kong journal of paediatrics. 2021;26:149‐154. Haute Autorité de Santé. Commission de la transparence - Racécadotril [Internet]. 2016. Disponible sur: https://www.has-sante.fr/upload/docs/evamed/CT-14259_TIORFAN-TIORFANOR_PIS_RI_Avis1_CT14259.pdf Cochrane Consumers and Communication La Trobe University, Ryan R, Hill S. How to GRADE. 2018 [cité 29 oct 2023]; Disponible sur: https://opal.latrobe.edu.au/articles/journal_contribution/How_to_GRADE/6818894/1 Table Table 1: Simplified data table (detailed characteristics of each study available in appendix 2) Study NOT ITT Intervention Comparator Definition of healing Results: Intervention vs. placebo Judgment criteria Results (drug vs. placebo) Cézard et al 2001 [23] 172 No Racecadotril: (1.5 mg/kg, orally 3 times/day) + ORS Placebo + ORS 2 stools formed in a row or No stools for 12 hours PE : Average stool flow at 48 hours (in g/h) - 40% for racecadotril (S) (no precise figure… just bar chart) SE : Average stool flow at 24 hours - 35% for racecadotril (S) SE : Median duration of diarrhea (in hours) 6.9 vs 36 (S) (only rotavirus + group) CJS: Tolerance 21 AEs: 9 patients in each group (Racecadotril: 10; Placebo: 11; most mild to moderate, 1 in each presumed treatment-related group) Gharial et al 2017 [24] 120 Yes Racecadotril: 3 times a day for 3 days max (10mg if 12 months) + ORS + Zinc Placebo + ORS + Zinc Appearance of less than 3 stools formed in 24 hours PE : Average number of stools at 48 hours 6.7 vs. 6.6 (NS) SE : Average duration of diarrhea (in days) 2.7 vs. 2.8 (NS) SE : Average length of hospitalization (in days) 5.5 vs. 5.8 (NS) SE : Number of adverse events 14 vs 14 (23% on both sides, 2 deaths on each side, 3 cases of seizures on the placebo side) Kang et al 2016 [25] 329 No Racecadotril: 1.5 mg/kg, 3 times/day for a minimum of 3 days (up to 5 days if diarrhea persists) + ORS Placebo + ORS Last abnormal bowel movement, or start of a 12-hour period without a bowel movement PE : Median duration of diarrhea G1 (inpatients): 25.5h vs 25h (NS) G2 (outpatients): 2d vs 2d SE : Median stool weight at hospital discharge, after at least 12 hours without stools (in g/kg/h) G1 (inpatients): 2.9 vs 2.2 (NS) G2 (outpatients): not given SE : Average fluid intake (ml/kg/h) G1 (inpatients): 3.6 vs 3 (NS) SE : Median length of hospitalization G1 (inpatients): 3d vs 3d (NS) SE : Presence of vomiting G1 (inpatients): 44.3% vs 39.7% (NS) Salazar-Lindo et al 2000 [26] 135 Yes Racecadotril: 3 times/day: 10 mg if 10kg Maximum 5 days, or when diarrhea stops if it occurred before + ORS Placebo + ORS 2 stools formed in a row or No stools for 12 hours PE : Stool weight at 48 hours (in g/kg) Total : 92g/kg vs 170g/kg (S) Rotavirus + patients: 105 vs 195 (S) SE : Stool flow at 48 hours (in g/kg/h) 1.8 vs. 3.1 (S) SE : Total stool weight Total : 157g vs 331g (S) Rotavirus + patients: 174g vs 397g (S) SE : Median duration of diarrhea Total: not given Rotavirus -: 28h vs 52h (S)Rotavirus +: 28h vs 72h (S) SE : Healing at 5 days 84% vs. 66% SE : Adverse effects (number of patients) Vomiting: 35 (51%) vs 35 (52%) Others: 7 (10%) vs 5 (7%) (none were serious) Sarangi et al 2021 [27] 148 No Racecadotril: 1.5 mg/kg, every 8 hours Until diarrhea stops or up to 5 days maximum if diarrhea persists + ORS Placebo every 8 hours + ORS 2 stools formed in a row or No stools for 12 hours PE : Stool volume at 48 hours (in g/kg) Total: 79.52 vs 191.04 (S) Rotavirus +: 89.47 vs 208.0 (S) SE : Stool flow at 48 hours (in g/h) Total: 28.5 vs 35.9 (S) Rotavirus +: 34.84 vs 38.55 (NS) SE : Length of hospitalization Total: 62.4h vs 95.6h (S) Rotavirus +: 60.32h vs 104.4h (S) SE : Average ORS consumption 342.15ml vs 318.65ml (NS) SE : Tolerability No significant difference, and no serious adverse events in the 2 groups PE : primary endpoint ; SE : secondary endpoint ; AE : adverse effects ; IV : Intravenous ; LGG : Lactobacillus GG ; NS : described as not significant by the authors ; S : described as significant by the authors ; ORS : Oral rehydration solution Additional Declarations No competing interests reported. Supplementary Files SupplementalmaterialVersionEJCP.docx Cite Share Download PDF Status: Published Journal Publication published 08 Jan, 2026 Read the published version in European Journal of Clinical Pharmacology → Version 1 posted Editorial decision: Revision requested 23 Aug, 2025 Reviews received at journal 13 Aug, 2025 Reviews received at journal 30 Jul, 2025 Reviewers agreed at journal 22 Jul, 2025 Reviewers agreed at journal 21 Jul, 2025 Reviewers agreed at journal 20 Jul, 2025 Reviewers invited by journal 20 Jul, 2025 Editor assigned by journal 15 Jul, 2025 Submission checks completed at journal 15 Jul, 2025 First submitted to journal 07 Jul, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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2","display":"","copyAsset":false,"role":"figure","size":55773,"visible":true,"origin":"","legend":"\u003cp\u003eRisk of bias of Racecadotril for duration of diarrhea\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7066734/v1/ff9129c179b144a9e9d9e674.png"},{"id":87551032,"identity":"31d88b69-27ec-4c61-bdf3-6823cb7dd9bb","added_by":"auto","created_at":"2025-07-25 06:19:26","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":63128,"visible":true,"origin":"","legend":"\u003cp\u003eRisk of bias of Racecadotril for stool production at 48 hours\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7066734/v1/0ca32ee160c3307e20d672bd.png"},{"id":87552410,"identity":"ae340a3f-1da5-4fcc-9015-eeae4ec91e1c","added_by":"auto","created_at":"2025-07-25 06:27:26","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":53892,"visible":true,"origin":"","legend":"\u003cp\u003eRisk of bias of Racecadotril for length of hospitalization\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-7066734/v1/abee23463cdec5e7d672cd65.png"},{"id":100070112,"identity":"6d245f0c-21e3-4643-be93-8c9ae8bff7d4","added_by":"auto","created_at":"2026-01-12 16:16:27","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1030373,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7066734/v1/2127e17b-094b-45a8-800b-145916bacaa9.pdf"},{"id":87551034,"identity":"077c58fc-54b4-4444-a1a6-c65a27b0a7e5","added_by":"auto","created_at":"2025-07-25 06:19:26","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":128263,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementalmaterialVersionEJCP.docx","url":"https://assets-eu.researchsquare.com/files/rs-7066734/v1/5d83e65a5245a5e723317e42.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Efficacy of Racecadotril in acute diarrhea in children: systematic review of the literature and meta-analysis of randomized clinical trials","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAcute diarrhea in children is a public health problem since the WHO estimates the worldwide number of cases at 1.7 billion per year, leading to approximately 525,000 deaths among children under 5 years of age, thus constituting the second cause of death in this age group[1]. The main complication of acute diarrhea is dehydration. The resulting deaths are mostly avoidable, if the losses are quickly compensated[2]. The prevention relies on oral rehydration solutions (ORS)[3], which has been recommended as the standard treatment for acute diarrhea in children[2].\u003c/p\u003e\n\u003cp\u003eRacecadotril is one of the symptomatic treatments available. However, its efficacy is questionable. 9 meta-analyses dating from 2009 to 2021[4\u0026ndash;12] generally have the same conclusions : overall, the results are significant but with a low level of evidence.\u003c/p\u003e\n\u003cp\u003eThe REB (Rebuild the Evidence Base)\u003csup\u003e\u0026nbsp;\u003c/sup\u003e[13,14]\u0026nbsp;method proposes to define a preliminary method for interpreting and reading the results of randomized controlled trials (RCTs) and their meta-analysis. Only RCTs with low risk of bias whose results are confirmatory, which means presented in accordance with a pre-specified protocol, are kept for analysis.\u003c/p\u003e\n\u003cp\u003eThe aim of this study is to evaluate the level of evidence of Racecadotril in acute diarrhea in children on the duration of diarrhea, stool production, and duration of hospitalization, using the REB method criteria.\u003c/p\u003e"},{"header":"Method","content":"\u003cp\u003eThe writing followed the PRISMA guidelines[15].\u003c/p\u003e\n\u003cp\u003eA protocol was registered on 01/16/2023 on PROSPERO under the number CRD42023389523.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEligibility Criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eClinical trials had to be randomized and double-blind with a comparison of Racecadotril against placebo, in children aged under 18 years suffering from acute diarrhea. No language restrictions were used.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResearch method :\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA bibliographic search was conducted until the 2\u003csup\u003end\u003c/sup\u003e of October 2023 in the Cochrane Library (CENTRAL), Medline via Pubmed and ClinicalTrials.gov databases. Trials not included in these databases, but cited in pre-existing meta-analyses\u0026nbsp;[4–12,16–19]\u0026nbsp;and meeting the eligibility criteria were included.\u003c/p\u003e\n\u003cp\u003eThe research was carried out by 2 researchers (IB and LG).\u003c/p\u003e\n\u003cp\u003eIn the Cochrane Library database, the following equation was used, searching the full text, and selecting only the results from the “Trials” tab :\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e(racecadotril* OR acetorphan*)\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eIn the Medline database (PubMed), the following equation was used, with a full text search, without using a filter :\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e(racecadotril OR acetorphan) AND [(randomized OR randomized) OR controlled]\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eIn the ClinicalTrials.gov database, the following equation was used, in the “Other terms” tab, selecting “All ” in the “Study type” section, without using a filter:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e(racecadotril OR acetorphan)\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eThe same researchers selected the trials and independently reviewed the titles and abstracts to identify those potentially eligible, before pooling and discussing. In case of discrepancy, a third researcher was contacted (RB). When the title and abstract didn’t allow a study to be included or excluded, the full text was analysed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRisk of bias\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe methodological quality of the included studies was assessed using the “Revised Cochrane risk-of-bias tool for randomized trials” (RoB2)[20]. The evaluation was carried out by 2 researchers (IB and LG). In case of discrepancy, a third researcher was contacted (RB).\u003c/p\u003e\n\u003cp\u003eFor studies presenting multiple primary endpoints, methods for controlling the multiplicity of statistical tests allowing control of inflation of the overall alpha risk were sought. If there was no adjustment method, the result of the study was considered exploratory (even if a statistical difference was found) due to a high risk of false positives linked to the multiplicity of statistical tests[21].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eQuantification and synthesis of results :\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA quantitative synthesis was planned whenever possible, using Review Manager software (Revman®) version 5.4. However there were not enough eligible trials to conduct a meta analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOverall risk of bias and assessment of the level of evidence\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe overall level of evidence of effectiveness for each endpoint was assessed using the REB method[13,14].\u0026nbsp;\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eSelection of studies\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe selection of trials is summarized in the flow chart in Figure 1 according to the PRISMA recommendations[22].\u003c/p\u003e\n\u003cp\u003eThe research identified 177 articles. After removing duplicates, 142 articles remained, of which 126 were excluded after reading the titles and abstracts because they didn’t meet the inclusion criteria. Of the remaining 16 articles, 11 were excluded, either because the full article wasn’t found or for other reasons presented in Appendix 1.\u003c/p\u003e\n\u003cp\u003e5 trials were included in the qualitative analysis : \u003cem\u003eCézard et al\u003c/em\u003e[23]\u003cem\u003e, Gharial et al\u003c/em\u003e[24]\u003cem\u003e, Kang et al\u003c/em\u003e[25]\u003cem\u003e, Salazar-Lindo et al\u003c/em\u003e[26]\u003cem\u003e, Sarangi et al\u003c/em\u003e[27]\u003cem\u003e.\u0026nbsp;\u003c/em\u003eAll of them could be used for the quantitative analysis, but not always for all the endpoints (some were excluded either due to lack of data or because the data was difficult to compare quantitatively).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCharacteristics of selected studies\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe main characteristics of the included studies are presented in Table 1 (the details are available in Appendix 2).\u003c/p\u003e\n\u003cp\u003eThe 5 selected studies [23–27] included a total of 904 patients.\u003c/p\u003e\n\u003cp\u003e4 of these studies evaluated the duration of diarrhea[23,23–26], but it was the primary endpoint only for \u003cem\u003eKang et al\u003c/em\u003e[25].\u003c/p\u003e\n\u003cp\u003eAll 5 studies assessed stool production[23–27], and this was the primary endpoint for \u003cem\u003eCézard et al\u003c/em\u003e[23]\u003cem\u003e, Gharial et al\u003c/em\u003e[24], \u003cem\u003eSalazar et al\u003c/em\u003e[26]and \u003cem\u003eSarangi et al\u003c/em\u003e[27]. The measurement used was the one at 48 hours except for \u003cem\u003eKang et al\u0026nbsp;\u003c/em\u003e[25]which measured this outcome when the patient left the hospital.\u003c/p\u003e\n\u003cp\u003e3 studies evaluated the length of hospitalization[24,25,27].\u003c/p\u003e\n\u003cp\u003e4 studies evaluated tolerance to treatments[23,24,26,27], but in a manner that was difficult to compare quantitatively with the others. None showed a significant difference between the 2 groups.\u003c/p\u003e\n\u003cp\u003eSome studies also evaluated other criteria, but which were not evaluated by the other studies, or in a way that was hardly comparable quantitatively.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAssessment with the REB method\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe risk of bias of each study, assessed by the RoB2, is represented in figures 2, 3 and 4, for each studied endpoint. The detailed evaluations are presented in Appendix 4.\u003c/p\u003e\n\u003cp\u003eThe duration of diarrhea was assessed by 4 of the 5 trials[23–26]. Only the study of \u003cem\u003eGharial\u003c/em\u003e \u003cem\u003eet al\u003c/em\u003e[24]was judged to have low risk of bias. Therefore no meta-analysis could be done. This study concluded that there was no significant result, with a mean duration of 2.7 days (SD = 0.23) \u003cem\u003evs.\u0026nbsp;\u003c/em\u003e2.8 days (SD = 0.25) in the Placebo group, \u003cem\u003ep\u0026nbsp;\u003c/em\u003e= 0.27. According to the REB method, Racecadotril therefore presents a “lack of evidence” on the duration of diarrhea.\u003c/p\u003e\n\u003cp\u003eStool production at 48 hours was assessed by the 5 trials[23–27]. The risk of bias was judged “low” only for \u003cem\u003eGharial et al\u003c/em\u003e[24]. Therefore no meta-analysis could be done. This study concluded that there was no significant result, with a mean number of stools at 48 hours of 6.7 (SD = 0.7) \u003cem\u003evs\u0026nbsp;\u003c/em\u003e6.6 (SD = 0.48) in the Placebo group, \u003cem\u003ep\u0026nbsp;\u003c/em\u003e= 0.19. According to the REB method, Racecadotril therefore presents a “lack of evidence” on stool production at 48 hours.\u003c/p\u003e\n\u003cp\u003eLength of hospitalization was assessed in 3 of the 5 trials[24,25,27]. The risk of bias was judged “low” only for \u003cem\u003eGharial et al\u003c/em\u003e[24]. Therefore no meta-analysis could be done. This study concluded that there was no significant result, with an average length of 5.5 days (SD = 0.46) \u003cem\u003evs.\u0026nbsp;\u003c/em\u003e5.8 days (SD = 0.62) in the Placebo group, \u003cem\u003ep\u0026nbsp;\u003c/em\u003e= 0.48. According to the REB method, Racecadotril therefore presents a “lack of evidence” on the length of hospitalization.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eFor Racecadotril, according to the REB method, this study showed a “lack of evidence” of effect on the duration of diarrhea, on stool production at 48 hours and on the length of hospitalization.\u003c/p\u003e\n\u003cp\u003eTherefore, according to this method, Racecadotril does not present solid evidence of a significant benefit on acute diarrhea in children, whatever the endpoint studied. However, carrying out new clinical trials with a good methodological quality could provide more encouraging results.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLimits\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe first limit is the age of the studied trials, with many risks of bias in the conduct of the studies and their analyzes by their authors : the protocols are not often pre-recorded, the methodology is often insufficiently described , not always corresponding to current transparency requirements. Many trials also have a small number of participants.\u003c/p\u003e\n\u003cp\u003eThe number of included trials was relatively low, with only 5 trials or even fewer for the quantitative analysis.\u003c/p\u003e\n\u003cp\u003eHowever, the aim of this study was to determine the current level of evidence, rather than to quantify the effect itself. This objective is achieved in this study.\u003c/p\u003e\n\u003cp\u003eThe definition of cure of diarrhea was often differentamong the studies , as were the endpoints and the follow-up times. However, the time for measuring the quantity of stools was the same (48 hours), except for one study not specifying the measurement time (\u003cem\u003eKang et al\u003c/em\u003e[25]).\u003c/p\u003e\n\u003cp\u003eThe assessment of the risk of bias also presents a limit : despite the ROB2 tool which helps to have a rigorous method, there still remains interpretations in the analysis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe tolerance of diarrhea complications and medications is different depending on the age of the child. \u0026nbsp;However the majority of the population was between 3 months and 3 years old.\u003c/p\u003e\n\u003cp\u003eFinally, some articles presented data that were sometimes complicated to analyze due to inaccuracies in the presentation of the results, which could then be considered in several ways in the analyses. We tried to control this limit by carrying out sensitivity analyzes whenever necessary.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConfrontation with literature\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe overall result of this study differs from that of previous meta-analyses. Most of them found a significant effect without an increase in the risk of adverse effects, however often with a low level of evidence[4,5,7,9–11] one of them (\u003cem\u003eLiang et al\u003c/em\u003e[11]) speaking of insufficient data to recommend the routine use of Racecadotril. Our study tends to note the absence of evidence to date. Further high-quality randomized trials would therefore be necessary to be able to confirm a significant effect with a good level of evidence.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eImplication for practice\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe result of this review does not provide a clear argument in favor of the use of Racecadotril in acute diarrhea in children.\u003c/p\u003e\n\u003cp\u003eRacecadotril has no particular age-related contraindication, and its actual benefit is considered moderate by the HAS, which maintains its authorization in infants below 12 months in the absence of other recommended alternative for this age[28]. The results of our study rather suggest not using it, including in infants below 12 months, in the absence of proof of efficacy, the treatment being based on ORS.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eImplication for research\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIt would be interesting for Racecadotril to have well-conducted randomized trials to have results of a confirmatory nature and with a low risk of bias in pediatric populations. Indeed, it seems to have a good tolerance profile. Furthermore, besides the REB method, we also did an analysis with the GRADE method[29] which included trials that were not always at low risk of bias. We still couldn’t conclude to a significant effet because of a lack of data in some trials, but sensitivity analyzes carried out with simulated dispersion values for studies where these were missing modified the result in favor of Racecadotril for the duration of diarrhea. A meta-analysis including more trials might show a more significant result. In the meantime, its effectiveness remains uncertain.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;IB and LG conducted the literature review, performed the trial analyses, and drafted the first version of the manuscript. CB contributed her expertise and provided critical revision of the final version. RB supervised the overall work, assisted with data analysis and interpretation, and wrote the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding Declaration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo Funding\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eMaladies diarr\u0026eacute;hiques [Internet]. [cit\u0026eacute; 29 oct 2023]. Disponible sur: https://www.who.int/fr/news-room/fact-sheets/detail/diarrhoeal-disease\u003c/li\u003e\n \u003cli\u003eOverview | Diarrhoea and vomiting caused by gastroenteritis in under 5s: diagnosis and management | Guidance | NICE [Internet]. NICE; 2009 [cit\u0026eacute; 29 oct 2023]. Disponible sur: https://www.nice.org.uk/guidance/cg84\u003c/li\u003e\n \u003cli\u003eDiarrh\u0026eacute;e aigu\u0026euml; du nourrisson et de l\u0026rsquo;enfant [Internet]. G.F.H.G.N.P. [cit\u0026eacute; 28 oct 2023]. Disponible sur: https://www.gfhgnp.org/recommandations-et-documents/diarrhee-aigue-nourrisson-de-lenfant/\u003c/li\u003e\n \u003cli\u003eSalazar Lindo E, Lehert P, Baumer P. The first mixed treatment comparison in acute diarrhoea in children (individual patient data meta-analysis). J Pediatr Gastroenterol Nutr. 2009;48:E30‑1.\u003c/li\u003e\n \u003cli\u003eLehert P, Ch\u0026eacute;ron G, Calatayud GA, C\u0026eacute;zard J-P, Castrell\u0026oacute;n PG, Garcia J-MM, et al. Racecadotril for childhood gastroenteritis: an individual patient data meta-analysis. Dig Liver Dis. 2011;43:707‑13.\u003c/li\u003e\n \u003cli\u003eFlorez ID, Veroniki A-A, Reem A-K, Yepes-Nunez J, Perez-Gaxiola G, Sierra JM, et al. Systematic review and network meta-analysis of treatments for acute diarrhoea and gastroenteritis in children. J Pediatr Gastroenterol Nutr. 2016;63:S38‑9.\u003c/li\u003e\n \u003cli\u003eGuti\u0026eacute;rrez-Castrell\u0026oacute;n P, Ort\u0026iacute;z-Hern\u0026aacute;ndez AA, Llamosas-Gallardo B, Acosta-Bastidas MA, Jim\u0026eacute;nez-Guti\u0026eacute;rrez C, Diaz-Garc\u0026iacute;a L, et al. [Efficacy of racecadotril vs. smectite, probiotics or zinc as an integral part of treatment of acute diarrhea in children under five years: A meta-analysis of multiple treatments]. Gac Med Mex. 2015;151:329‑37.\u003c/li\u003e\n \u003cli\u003eGordon M, Akobeng A. Racecadotril for acute diarrhoea in children: systematic review and meta-analyses. Arch Dis Child. 2016;101:234‑40.\u003c/li\u003e\n \u003cli\u003eFlorez ID, Veroniki A-A, Al Khalifah R, Yepes-Nu\u0026ntilde;ez JJ, Sierra JM, Vernooij RWM, et al. Comparative effectiveness and safety of interventions for acute diarrhea and gastroenteritis in children: A systematic review and network meta-analysis. PLoS One. 2018;13:e0207701.\u003c/li\u003e\n \u003cli\u003eEberlin M, Chen M, Mueck T, D\u0026auml;britz J. Racecadotril in the treatment of acute diarrhea in children: a systematic, comprehensive review and meta-analysis of randomized controlled trials. BMC Pediatr. 2018;18:124.\u003c/li\u003e\n \u003cli\u003eLiang Y, Zhang L, Zeng L, Gordon M, Wen J. Racecadotril for acute diarrhoea in children. Cochrane Database Syst Rev. 2019;12:CD009359.\u003c/li\u003e\n \u003cli\u003eFarahdina F, Rizaliansyah F, Aulya JU, Fajar JK. Racecadotril for treating acute diarrhea in children a systematic review and meta-analysis. Arch Hell Med. 2021;38:618‑23.\u003c/li\u003e\n \u003cli\u003eBoussageon R, Blanchard C, Charuel E, Menini T, Pereira B, Naudet F, et al. Project rebuild the evidence base (REB): A method to interpret randomised clinical trials and their meta-analysis to present solid benefit-risk assessments to patients. Therapie. 2023;78:353‑65.\u003c/li\u003e\n \u003cli\u003eProjet REB - Reconstruire l\u0026rsquo;Evidence Base [Internet]. Facult\u0026eacute; de m\u0026eacute;decine Lyon Est. [cit\u0026eacute; 29 oct 2023]. Disponible sur: https://lyon-est.univ-lyon1.fr/formation/medecine/3eme-cycle/des-medecine-generale/college-universitaire-de-medecine-generale-cumg/projet-reb-reconstruire-levidence-base\u003c/li\u003e\n \u003cli\u003ePage MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;n71.\u003c/li\u003e\n \u003cli\u003eSzajewska H, Dziechciarz P, Mrukowicz J. Meta-analysis: Smectite in the treatment of acute infectious diarrhoea in children. Aliment Pharmacol Ther. 2006;23:217‑27.\u003c/li\u003e\n \u003cli\u003eDas RR, Sankar J, Naik SS. Efficacy and safety of diosmectite in acute childhood diarrhoea: a meta-analysis. Arch Dis Child. 2015;100:704‑12.\u003c/li\u003e\n \u003cli\u003eLi S-TT, Grossman DC, Cummings P. Loperamide therapy for acute diarrhea in children: systematic review and meta-analysis. PLoS Med. 2007;4:e98.\u003c/li\u003e\n \u003cli\u003eP\u0026eacute;rez-Gaxiola G, Cuello-Garc\u0026iacute;a CA, Florez ID, P\u0026eacute;rez-Pico VM. Smectite for acute infectious diarrhoea in children. Cochrane Database Syst Rev. 2018;4:CD011526.\u003c/li\u003e\n \u003cli\u003eRisk of bias tools - Current version of RoB 2 [Internet]. [cit\u0026eacute; 29 oct 2023]. Disponible sur: https://www.riskofbias.info/welcome/rob-2-0-tool/current-version-of-rob-2\u003c/li\u003e\n \u003cli\u003eDmitrienko A, D\u0026rsquo;Agostino RB. Multiplicity Considerations in Clinical Trials. N Engl J Med. 2018;378:2115‑22.\u003c/li\u003e\n \u003cli\u003ePRISMA [Internet]. [cit\u0026eacute; 29 oct 2023]. Disponible sur: http://www.prisma-statement.org/PRISMAStatement/FlowDiagram\u003c/li\u003e\n \u003cli\u003eC\u0026eacute;zard J, Duhamel J, Meyer M, Pharaon I, Bellaiche M, Maurage C, et al. Efficacy and tolerability of racecadotril in acute diarrhea in children. Gastroenterology. 2001;120:799‐805.\u003c/li\u003e\n \u003cli\u003eGharial J, Laving A, Were F. Racecadotril for the treatment of severe acute watery diarrhoea in children admitted to a tertiary hospital in Kenya. BMJ open gastroenterology [Internet]. 2017;4. Disponible sur: https://www.cochranelibrary.com/central/doi/10.1002/central/CN-01441515/full\u003c/li\u003e\n \u003cli\u003eKang G, Thuppal S, Srinivasan R, Sarkar R, Subashini B, Venugopal S, et al. Racecadotril in the Management of Rotavirus and Non-rotavirus Diarrhea in Under-five Children: two Randomized, Double-blind, Placebo-controlled Trials. Indian pediatrics. 2016;53:595‐600.\u003c/li\u003e\n \u003cli\u003eSalazar-Lindo E, Santisteban-Ponce J, Chea-Woo E, Gutierrez M. Racecadotril in the treatment of acute watery diarrhea in children. New England journal of medicine. 2000;343:463‐467.\u003c/li\u003e\n \u003cli\u003eSarangi R, Biswal B, Dash B, Dhanawat A. Tolerability and efficacy of racecadotril in acute diarrhoea, a prospective, randomised, parallel study in an indian tertiary care teaching hospital. Hong kong journal of paediatrics. 2021;26:149‐154.\u003c/li\u003e\n \u003cli\u003eHaute Autorit\u0026eacute; de Sant\u0026eacute;. Commission de la transparence - Rac\u0026eacute;cadotril [Internet]. 2016. Disponible sur: https://www.has-sante.fr/upload/docs/evamed/CT-14259_TIORFAN-TIORFANOR_PIS_RI_Avis1_CT14259.pdf\u003c/li\u003e\n \u003cli\u003eCochrane Consumers and Communication La Trobe University, Ryan R, Hill S. How to GRADE. 2018 [cit\u0026eacute; 29 oct 2023]; Disponible sur: https://opal.latrobe.edu.au/articles/journal_contribution/How_to_GRADE/6818894/1\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table","content":"\u003cp\u003eTable 1: Simplified data table (detailed characteristics of each study available in appendix 2)\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"972\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStudy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNOT\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eITT\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIntervention\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eComparator\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDefinition of healing\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 519px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eResults: Intervention vs. placebo\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 69px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 81px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 276px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eJudgment criteria\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 243px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eResults (drug vs. placebo)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"4\" style=\"width: 69px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eC\u0026eacute;zard et al\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e2001\u003csup\u003e\u0026nbsp;\u003c/sup\u003e\u003c/strong\u003e[23]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" style=\"width: 67px;\"\u003e\n \u003cp\u003e172\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" style=\"width: 26px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u003cu\u003eRacecadotril:\u0026nbsp;\u003c/u\u003e\u003cbr\u003e\u0026nbsp;(1.5 mg/kg, orally 3 times/day) + ORS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" style=\"width: 81px;\"\u003e\n \u003cp\u003ePlacebo + ORS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" style=\"width: 97px;\"\u003e\n \u003cp\u003e2 stools formed in a row or\u0026nbsp;\u003cbr\u003e\u0026nbsp;No stools for 12 hours\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 276px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePE : Average stool flow at 48 hours (in g/h)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 243px;\"\u003e\n \u003cp\u003e- 40% for racecadotril (S)\u0026nbsp;\u003cbr\u003e\u0026nbsp;(no precise figure\u0026hellip; just bar chart)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 276px;\"\u003e\n \u003cp\u003eSE : Average stool flow at 24 hours\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 243px;\"\u003e\n \u003cp\u003e- 35% for racecadotril (S)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 276px;\"\u003e\n \u003cp\u003eSE : \u003cstrong\u003eMedian duration\u0026nbsp;\u003c/strong\u003eof diarrhea (in hours)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 243px;\"\u003e\n \u003cp\u003e6.9 vs 36 (S) (only rotavirus + group)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 276px;\"\u003e\n \u003cp\u003eCJS: Tolerance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 243px;\"\u003e\n \u003cp\u003e21 AEs: 9 patients in each group (Racecadotril: 10; Placebo: 11; most mild to moderate, 1 in each presumed treatment-related group)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"4\" style=\"width: 69px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eGharial et al\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e2017\u0026nbsp;\u003c/strong\u003e[24]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" style=\"width: 67px;\"\u003e\n \u003cp\u003e120\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" style=\"width: 26px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u003cu\u003eRacecadotril:\u003c/u\u003e\u0026nbsp;\u003cbr\u003e\u0026nbsp;3 times a day for 3 days max (10mg if \u0026lt; 12 months, 30mg if \u0026gt; 12 months) + ORS + Zinc\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" style=\"width: 81px;\"\u003e\n \u003cp\u003ePlacebo + ORS + Zinc\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" style=\"width: 97px;\"\u003e\n \u003cp\u003eAppearance of less than 3 stools formed in 24 hours\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 276px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePE : Average number of stools at 48 hours\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 243px;\"\u003e\n \u003cp\u003e6.7 vs. 6.6 (NS)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 276px;\"\u003e\n \u003cp\u003eSE : Average duration of diarrhea (in days)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 243px;\"\u003e\n \u003cp\u003e2.7 vs. 2.8 (NS)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 276px;\"\u003e\n \u003cp\u003eSE : Average length of hospitalization (in days)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 243px;\"\u003e\n \u003cp\u003e5.5 vs. 5.8 (NS)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 276px;\"\u003e\n \u003cp\u003eSE : Number of adverse events\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 243px;\"\u003e\n \u003cp\u003e14 vs 14 (23% on both sides, 2 deaths on each side,\u0026nbsp;\u003cbr\u003e\u0026nbsp;3 cases of seizures on the placebo side)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"5\" style=\"width: 69px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eKang et al\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e2016\u0026nbsp;\u003c/strong\u003e[25]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\" style=\"width: 67px;\"\u003e\n \u003cp\u003e329\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\" style=\"width: 26px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u003cu\u003eRacecadotril:\u0026nbsp;\u003c/u\u003e\u003cbr\u003e\u0026nbsp;1.5 mg/kg, 3 times/day for a minimum of 3 days (up to 5 days if diarrhea persists)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e+ ORS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\" style=\"width: 81px;\"\u003e\n \u003cp\u003ePlacebo + ORS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\" style=\"width: 97px;\"\u003e\n \u003cp\u003eLast abnormal bowel movement, or start of a 12-hour period without a bowel movement\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 276px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePE : Median duration of diarrhea\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 243px;\"\u003e\n \u003cp\u003eG1 (inpatients): 25.5h vs 25h (NS)\u003c/p\u003e\n \u003cp\u003eG2 (outpatients): 2d vs 2d\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 276px;\"\u003e\n \u003cp\u003eSE :\u003cstrong\u003e\u0026nbsp;Median stool\u0026nbsp;\u003c/strong\u003eweight at hospital discharge, after at least 12 hours without stools (in g/kg/h)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 243px;\"\u003e\n \u003cp\u003eG1 (inpatients): 2.9 vs 2.2 (NS)\u0026nbsp;\u003cbr\u003e\u0026nbsp;G2 (outpatients): not given\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 276px;\"\u003e\n \u003cp\u003eSE : Average fluid intake (ml/kg/h)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 243px;\"\u003e\n \u003cp\u003eG1 (inpatients): 3.6 vs 3 (NS)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 276px;\"\u003e\n \u003cp\u003eSE : \u003cstrong\u003eMedian length\u0026nbsp;\u003c/strong\u003eof hospitalization\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 243px;\"\u003e\n \u003cp\u003eG1 (inpatients): 3d vs 3d (NS)\u003cu\u003e\u0026nbsp;\u003c/u\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 276px;\"\u003e\n \u003cp\u003eSE : Presence of vomiting\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 243px;\"\u003e\n \u003cp\u003eG1 (inpatients): 44.3% vs 39.7% (NS)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"6\" style=\"width: 69px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eSalazar-Lindo et al\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e2000\u0026nbsp;\u003c/strong\u003e[26]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"6\" style=\"width: 67px;\"\u003e\n \u003cp\u003e135\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"6\" style=\"width: 26px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"6\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u003cu\u003eRacecadotril:\u003c/u\u003e\u0026nbsp;\u003cbr\u003e\u0026nbsp;3 times/day: 10 mg if \u0026lt; 10kg 20mg if \u0026gt; 10kg Maximum 5 days, or when diarrhea stops if it occurred before\u0026nbsp;\u003cbr\u003e\u0026nbsp;\u003cbr\u003e\u0026nbsp;+ ORS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"6\" style=\"width: 81px;\"\u003e\n \u003cp\u003ePlacebo + ORS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"6\" style=\"width: 97px;\"\u003e\n \u003cp\u003e2 stools formed in a row or\u0026nbsp;\u003cbr\u003e\u0026nbsp;No stools for 12 hours\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 276px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePE : Stool weight at 48 hours (in g/kg)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 243px;\"\u003e\n \u003cp\u003eTotal : 92g/kg vs 170g/kg (S)\u0026nbsp;\u003cbr\u003e\u0026nbsp;Rotavirus + patients: 105 vs 195 (S)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 276px;\"\u003e\n \u003cp\u003eSE : Stool flow at 48 hours (in g/kg/h)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 243px;\"\u003e\n \u003cp\u003e1.8 vs. 3.1 (S)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 276px;\"\u003e\n \u003cp\u003eSE : Total stool weight\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 243px;\"\u003e\n \u003cp\u003eTotal :\u003cu\u003e\u0026nbsp;\u003c/u\u003e157g vs 331g (S)\u0026nbsp;\u003cbr\u003e\u0026nbsp;Rotavirus + patients: 174g vs 397g (S)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 276px;\"\u003e\n \u003cp\u003eSE : \u003cstrong\u003eMedian duration\u0026nbsp;\u003c/strong\u003eof diarrhea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 243px;\"\u003e\n \u003cp\u003eTotal: not given\u0026nbsp;\u003cbr\u003e\u0026nbsp;Rotavirus -: 28h vs 52h (S)Rotavirus +: 28h vs 72h (S)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 276px;\"\u003e\n \u003cp\u003eSE : Healing at 5 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 243px;\"\u003e\n \u003cp\u003e84% vs. 66%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 276px;\"\u003e\n \u003cp\u003eSE : Adverse effects (number of patients)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 243px;\"\u003e\n \u003cp\u003eVomiting: 35 (51%) vs 35 (52%)\u0026nbsp;\u003cbr\u003e\u0026nbsp;Others: 7 (10%) vs 5 (7%) (none were serious)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"5\" style=\"width: 69px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eSarangi et al\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e2021\u0026nbsp;\u003c/strong\u003e[27]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\" style=\"width: 67px;\"\u003e\n \u003cp\u003e148\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\" style=\"width: 26px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u003cu\u003eRacecadotril:\u003c/u\u003e\u0026nbsp;\u003cbr\u003e\u0026nbsp;1.5 mg/kg, every 8 hours Until diarrhea stops or up to 5 days maximum if diarrhea persists\u0026nbsp;\u003cbr\u003e\u0026nbsp;\u003cbr\u003e\u0026nbsp;+ ORS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\" style=\"width: 81px;\"\u003e\n \u003cp\u003ePlacebo every 8 hours\u0026nbsp;\u003cbr\u003e\u0026nbsp;+ ORS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\" style=\"width: 97px;\"\u003e\n \u003cp\u003e2 stools formed in a row\u0026nbsp;\u003cbr\u003e\u0026nbsp;or No stools for 12 hours\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 276px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePE : Stool volume at 48 hours (in g/kg)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 243px;\"\u003e\n \u003cp\u003eTotal: 79.52 vs 191.04 (S)\u0026nbsp;\u003cbr\u003e\u0026nbsp;Rotavirus +: 89.47 vs 208.0 (S)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 276px;\"\u003e\n \u003cp\u003eSE : Stool flow at 48 hours (in g/h)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 243px;\"\u003e\n \u003cp\u003eTotal: 28.5 vs 35.9 (S)\u003c/p\u003e\n \u003cp\u003eRotavirus +: 34.84 vs 38.55 (NS)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 276px;\"\u003e\n \u003cp\u003eSE : Length of hospitalization\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 243px;\"\u003e\n \u003cp\u003eTotal: 62.4h vs 95.6h (S)\u0026nbsp;\u003cbr\u003e\u0026nbsp;Rotavirus +: 60.32h vs 104.4h (S)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 276px;\"\u003e\n \u003cp\u003eSE : Average ORS consumption\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 243px;\"\u003e\n \u003cp\u003e342.15ml vs 318.65ml (NS)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 276px;\"\u003e\n \u003cp\u003eSE : Tolerability\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 243px;\"\u003e\n \u003cp\u003eNo significant difference, and no serious adverse events in the 2 groups\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\" valign=\"top\" style=\"width: 972px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePE : primary endpoint ; SE : secondary endpoint ; AE : adverse effects ; IV : Intravenous ; LGG : Lactobacillus GG ; NS : described as not significant by the authors ; S : described as significant by the authors ; ORS : Oral rehydration solution\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-clinical-pharmacology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejcl","sideBox":"Learn more about [European Journal of Clinical Pharmacology](http://link.springer.com/journal/228)","snPcode":"228","submissionUrl":"https://submission.nature.com/new-submission/228/3","title":"European Journal of Clinical Pharmacology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7066734/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7066734/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eIntroduction: \u003c/strong\u003eAcute diarrhea in children is a common disease. Standard treatment is oral rehydration, but antidiarrheal drugs are still widely used. However, their efficacy is debated: several trials and meta-analyses show results that are sometimes contradictory, but often reach the same conclusions : generally, the results are significant, but with a low level of evidence.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjective\u003c/strong\u003e: The aim of this study was to evaluate the efficacy of Racecadotril in acute diarrhea in children, through a systematic literature review and meta-analysis of randomized trials, using the REB method.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethod\u003c/strong\u003e: A bibliographic search was conducted for articles published until 10/02/2023. The risk of bias was assessed using the RoB2 tool. The endpoints were duration of diarrhea, stool production and length of hospitalization. The REB method was used to assess the overall level of evidence of efficacy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: 5 trials were selected and included 904 patients. The conclusion was the absence of evidence of effect on the three endpoints.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eThis study shows that there is no solid evidence that the three drugs are effective in treating acute diarrhea in children, but new randomized trials of good methodological quality could provide more significant results.\u003c/p\u003e","manuscriptTitle":"Efficacy of Racecadotril in acute diarrhea in children: systematic review of the literature and meta-analysis of randomized clinical trials","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-25 06:19:21","doi":"10.21203/rs.3.rs-7066734/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-08-23T08:17:40+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-13T19:28:39+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-30T05:43:54+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"82341094854963590353652240872426966670","date":"2025-07-22T19:05:00+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"62639842710611535795163098964202724862","date":"2025-07-21T09:04:55+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"137176217488511659935870372526842562214","date":"2025-07-20T19:07:35+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-07-20T19:04:09+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-07-15T04:42:27+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-07-15T04:42:22+00:00","index":"","fulltext":""},{"type":"submitted","content":"European Journal of Clinical Pharmacology","date":"2025-07-07T14:48:42+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-clinical-pharmacology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejcl","sideBox":"Learn more about [European Journal of Clinical Pharmacology](http://link.springer.com/journal/228)","snPcode":"228","submissionUrl":"https://submission.nature.com/new-submission/228/3","title":"European Journal of Clinical Pharmacology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"138d94d0-70ad-4242-928f-0a9e59292b35","owner":[],"postedDate":"July 25th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-01-12T16:10:09+00:00","versionOfRecord":{"articleIdentity":"rs-7066734","link":"https://doi.org/10.1007/s00228-025-03927-2","journal":{"identity":"european-journal-of-clinical-pharmacology","isVorOnly":false,"title":"European Journal of Clinical Pharmacology"},"publishedOn":"2026-01-08 15:59:09","publishedOnDateReadable":"January 8th, 2026"},"versionCreatedAt":"2025-07-25 06:19:21","video":"","vorDoi":"10.1007/s00228-025-03927-2","vorDoiUrl":"https://doi.org/10.1007/s00228-025-03927-2","workflowStages":[]},"version":"v1","identity":"rs-7066734","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7066734","identity":"rs-7066734","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}