A pragmatic randomized controlled trial of multi-dose oral ondansetron for pediatric gastroenteritis (the DOSE-AGE study): statistical analysis plan

Anna Heath, Juan David Rios, Sarah Williamson-Urquhart, Petros Pechlivanoglou, Martin Offringa, Christopher McCabe, Gareth Hopkin, Amy C Plint, Andrew Dixon, Darcy Beer, Serge Gouin, Gary Joubert, Terry P Klassen, Stephen B Freedman, PERC-KIDSCAN DOSE-AGE Study Group, Stephen Freedman, Sarah Williamson-Urquhart, Terry Klassen, Tannis Erickson, Rick Watts, Pam Marples, Anna Heath, David Rios, Petros Pechlivanoglou, Chris McCabe, Gareth Hopkin, Amy Plint, Tremaine Rowe, Gary Joubert, Leslie Boisvert, Serge Gouin, Marie-Christine Auclair, Andrew Dixon, Manasi Rajagopal, Mithra Sivakumar, Darcy Beer, Jeannine Schellenberg, Anna Heath, Juan David Rios, Sarah Williamson-Urquhart, Petros Pechlivanoglou, Martin Offringa, Christopher McCabe, Gareth Hopkin, Amy C Plint, Andrew Dixon, Darcy Beer, Serge Gouin, Gary Joubert, Terry P Klassen, Stephen B Freedman, PERC-KIDSCAN DOSE-AGE Study Group, Stephen Freedman, Sarah Williamson-Urquhart, Terry Klassen, Tannis Erickson, Rick Watts, Pam Marples, Anna Heath, David Rios, Petros Pechlivanoglou, Chris McCabe, Gareth Hopkin, Amy Plint, Tremaine Rowe, Gary Joubert, Leslie Boisvert, Serge Gouin, Marie-Christine Auclair, Andrew Dixon, Manasi Rajagopal, Mithra Sivakumar, Darcy Beer, Jeannine Schellenberg

Abstract

Background: Acute gastroenteritis is a leading cause of emergency department visits and hospitalizations among children in North America. Oral-rehydration therapy is recommended for children with mild-to-moderate dehydration, but children who present with vomiting are frequently offered intravenous rehydration in the emergency department (ED). Recent studies have demonstrated that the anti-emetic ondansetron can reduce vomiting, intravenous rehydration, and hospitalization when administered in the ED to children with dehydration. However, there is little evidence of additional benefit from prescribing ondansetron beyond the initial ED dose. Moreover, repeat dosing may increase the frequency of diarrhea. Despite the lack of evidence and potential adverse side effects, many physicians across North America provide multiple doses of ondansetron to be taken following ED disposition. Thus, the Multi-Dose Oral Ondansetron for Pediatric Gastroenteritis (DOSE-AGE) trial will evaluate the effectiveness of prescribing multiple doses of ondansetron to treat acute gastroenteritis-associated vomiting. This article specifies the statistical analysis plan (SAP) for the DOSE-AGE trial and was submitted before the outcomes of the study were available for analysis.

Methods/design: The DOSE-AGE study is a phase III, 6-center, placebo-controlled, double-blind, parallel design randomized controlled trial designed to determine whether participants who are prescribed multiple doses of oral ondansetron to administer, as needed, following their ED visit have a lower incidence of experiencing moderate-to-severe gastroenteritis, as measured by the Modified Vesikari Scale score, compared with a placebo. To assess safety, the DOSE-AGE trial will investigate the frequency and maximum number of diarrheal episodes following ED disposition, and the occurrence of palpitations, pre-syncope/syncope, chest pain, arrhythmias, and serious adverse events. For the secondary outcomes, the DOSE-AGE trial will investigate the individual elements of the Modified Vesikari Scale score and caregiver satisfaction with the therapy.

Discussion: The DOSE-AGE trial will provide evidence on the effectiveness of multiple doses of oral ondansetron, taken as needed, following an initial ED dose in children with acute gastroenteritis-associated vomiting. The data from the DOSE-AGE trial will be analyzed using this SAP. This will reduce the risk of producing data-driven results and bias in our reported outcomes. The DOSE-AGE study was registered on ClinicalTrials.gov on February 22, 2019.

Trial registration: ClinicalTrials.gov NCT03851835 . Registered on 22 February 2019.

Keywords: Acute gastroenteritis; Emergency department; Ondansetron; Pediatrics; Statistical analysis plan.

Conflict of interest statement

Dr. Stephen Freedman has received in-kind grant support from Novartis and GlaxoSmithKline and is a consultant to RedHill BioPharma Ltd.

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