Clinical trial NCT03851835: Multi-DOSE Oral Ondansetron for Pediatric Acute GastroEnteritis
Official title: Multi-dose Oral Ondansetron For Pediatric Gastroenteritis: A Pragmatic Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Acute Gastroenteritis
Viral Illness
Vomiting
Diarrhea
Keywords: Vomiting
Zofran
Ondansetron
Gastroenteritis
Pediatrics
DOSE-AGE
Lead sponsor: University of Calgary
Sponsor class: OTHER
Collaborators: name: Canadian Institutes of Health Research (CIHR)
name: Women and Children's Health Research Institute (WCHRI)
name: The Hospital for Sick Children
name: Children's Hospital Research Institute of Manitoba
name: University of Manitoba
name: Université de Montréal
name: University of Ottawa
name: University of Alberta
name: Alberta Children's Hospital Research Institute
name: Western University, Canada
First posted: 2019-02-22
Enrollment: 1030
Sex: ALL
Minimum age (years): 6
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: A phase III, double-blind, parallel-design, randomized, placebo-controlled trial to compare multi-dose oral Ondansetron with placebo as treatment for vomiting secondary to acute gastroenteritis (AGE), after Emergency Department discharge.

Detailed description: The annual burden of acute gastroenteritis in the United States includes 17 million related episodes and 473,832 hospitalizations. Although oral-rehydration therapy is recommended for children with mild-to-moderate dehydration, it has historically been underused with emergency department (ED) clinicians being more likely to choose intravenous over oral rehydration especially when vomiting is a major symptom. In fact, nearly 95% of children undergoing oral rehydration in Canadian EDs present with recent vomiting. To address this issue, the investigators conducted both a landmark clinical trial and a recent meta-analysis that have demonstrated that the ED use of ondansetron, an anti-emetic, leads to reductions in intravenous rehydration and hospitalization and is cost-effective. However, the available data revealed some associations with increased diarrhea and no evidence of benefits associated with ongoing ondansetron use following ED discharge. Despite the lack of available data, the provision of multiple doses of ondansetron for home use has become routine in many EDs across North America. The literature has differing opinions on the topic of ongoing ondansetron use after ED discharge and given the limited evidence supporting its use, the potential side effects and additional cost, there is an urgent need to definitively evaluate the effect of multiple doses of ondansetron in children, focusing on family-centred, post-index visit outcomes.

A phase III, double-blind, parallel-design, randomized, placebo controlled trial to compare multi-dose oral Ondansetron with placebo as treatment for vomiting secondary to acute gastroenteritis (AGE), after Emergency Department discharge will be conducted. Children and youth, age 6 months to 17.99 years will be enrolled at six (6) Canadian Emergency Departments. The total number of participants recruited will be 1030. Participants will be enrolled at six (6) pediatric emergency departments across Canada.

Children who are provided a minimum of one dose of ondansetron as part of their routine clinical care AND meet other eligibility criteria will be randomized to receive an at-home kit with six (6) doses of Ondansetron Hydrochloride Dihydrate Oral Solution (4mg/5mL solution; dosed at 0.15mg/kg to a maximum single dose of 8mg) or equivalent volume in a Placebo Oral Solution to be administered no sooner than 8 hours after the initial clinical dose was provided by the ED physician. Over the subsequent 48 hours, the study intervention will be administered at a rate of 1 dose every 8 hours (q8h) to a maximum of 3 doses a day (in a 24-hour period (TID)) at the caregiver's discretion. Two (2) additional doses will be provided to the caregiver in case the child vomits a dose.

Eligibility criteria: Inclusion Criteria:

* Willingness to comply with all study procedures and availability for the duration of the study.
* Diagnosis of acute intestinal infectious process (as defined by the protocol) confirmed. by the treating physician.
* Age 6 months to 17.99 years.
* Presence of ≥ 3 episodes of vomiting in the preceding 24-hour period.
* Duration of vomiting and/or diarrheal symptoms \< 72 hours.
* A minimum of 1 episode of vomiting within 6 hours of the screening process performed by the research team.
* A minimum of 1 dose of ondansetron (oral or intravenous) provided during the current emergency department visit.

Exclusion Criteria:

* Bilious or bloody vomit during current illness.
* Known hypersensitivity to ondansetron or any serotonin receptor antagonist (e.g. palonosetron, dolasetron, granisetron).
* Known allergic reaction to components of ondansetron (citric acid, sodium benzoate, sodium citrate dihydrate, and strawberry flavor, sorbitol) or the placebo medication (methylparaben, glycerin, citric acid, potassium sorbate, sorbitol, strawberry flavor).
* History or family history (first degree relative) of prolonged QT syndrome.
* Presence of complex congenital heart disease.
* History or family history (first degree relative) of cardiac arrhythmia.
* Concomitant use (within the past 48 hours) of any of the following: QTc prolonging medications, medications known to cause torsades de pointes, medications that cause electrolyte abnormalities, serotonergic or neuroleptic medications, or any 5-HT3 receptor antagonist excluding ondansetron.
* Unable to complete follow-up.
* Previously enrolled in this study.
* History or family history of G6PD deficiency.

Primary outcomes:
measure: Development of moderate to severe disease as defined by the Modified Vesikari Scale (MVS) Score of ≥ 9 following ED evaluation - change in the MVS score between Hour 0 and Hour 168 of the study.
timeFrame: Measured 24, 48, and 168 hours after baseline visit
Secondary outcomes:
measure: Vomiting Duration
timeFrame: Measured 24, 48, and 168 hours after baseline visit
measure: Vomiting Frequency
timeFrame: Measured 24, 48, and 168 hours after baseline visit
measure: Vomiting Proportion
timeFrame: Measured 24, 48, and 168 hours after baseline visit
measure: Proportion of participants who require an unscheduled health care visit
timeFrame: Measured 24, 48, and 168 hours after baseline visit
measure: Proportion of participants who require Intravenous (IV) Rehydration
timeFrame: Measured 24, 48, and 168 hours after baseline visit
measure: Satisfaction with care: 5 point Likert Scale
timeFrame: 168 hours after baseline
Other outcomes:
measure: Safety Profile of Multiple Doses of Oral Ondansetron
timeFrame: Measured 24, 48, and 168 hours after baseline visit
Locations:
city: Calgary
country: Canada
facility: Alberta Children's Hospital
state: Alberta
city: Edmonton
country: Canada
facility: Stollery Children's Hospital
state: Alberta
city: Winnipeg
country: Canada
facility: Children's Hospital of Winnipeg
state: Manitoba
city: London
country: Canada
facility: Children's Hospital London Health Sciences Centre
state: Ontario
city: Ottawa
country: Canada
facility: Children's Hospital of Eastern Ontario (CHEO)
state: Ontario
city: Montreal
country: Canada
facility: Centre Hospitalier Universitaire Sainte Justine
state: Quebec
Study officials:
affiliation: University of Calgary
name: Stephen Freedman, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Heath A, Rios JD, Williamson-Urquhart S, Pechlivanoglou P, Offringa M, McCabe C, Hopkin G, Plint AC, Dixon A, Beer D, Gouin S, Joubert G, Klassen TP, Freedman SB; PERC-KIDSCAN DOSE-AGE Study Group. A pragmatic randomized controlled trial of multi-dose oral ondansetron for pediatric gastroenteritis (the DOSE-AGE study): statistical analysis plan. Trials. 2020 Aug 24;21(1):735. doi: 10.1186/s13063-020-04651-1.
citation: Freedman SB, Williamson-Urquhart S, Heath A, Pechlivanoglou P, Hopkin G, Gouin S, Plint AC, Dixon A, Beer D, Joubert G, McCabe C, Finkelstein Y, Klassen TP; KidsCAN-Pediatric Emergency Research Canada (PERC) Innovative Pediatric Clinical Trials DOSE-AGE Study Group. Multi-dose Oral Ondansetron for Pediatric Gastroenteritis: study Protocol for the multi-DOSE oral ondansetron for pediatric Acute GastroEnteritis (DOSE-AGE) pragmatic randomized controlled trial. Trials. 2020 May 27;21(1):435. doi: 10.1186/s13063-020-04347-6.