Multi-DOSE Oral Ondansetron for Pediatric Acute GastroEnteritis (DOSE-AGE)

Multi-dose Oral Ondansetron For Pediatric Gastroenteritis: A Pragmatic Randomized Controlled Trial

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.

Study Overview

• Status: Recruiting
• Conditions: Vomiting; Diarrhea; Acute Gastroenteritis; Viral Illness
• Intervention / Treatment: Drug: Ondansetron Oral Solution; Drug: Oral Placebo

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.

• Study Type: Interventional
• Enrollment (Estimated): 1030
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Sarah Williamson-Urquhart; Phone Number: 403-955-2482; Email: sarah.urquhart@ahs.ca
• Study Contact Backup: Name: Stephen Freedman, MD; Phone Number: 403-955-7740; Email: stephen.freedman@ahs.ca

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T3B 6A8
      • Recruiting
      • Alberta Children's Hospital
      • Contact: Sarah Williamson-Urquhart; Phone Number: 403-955-2482; Email: sarah.urquhart@ahs.ca
      • Principal Investigator: Stephen Freedman, MD
      • Sub-Investigator: Graham Thompson, MD
      • Sub-Investigator: Antonia Stang, MD
    • Edmonton, Alberta, Canada, T6G 2C8
      • Recruiting
      • Stollery Children's Hospital
      • Principal Investigator: Andrew Dixon, MD
      • Contact: Patricia Candelaria; Phone Number: 780-248-5440; Email: stacruz@ualberta.ca
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3A 1S1
      • Recruiting
      • Children's Hospital of Winnipeg
      • Contact: Jeannine Schellenberg; Phone Number: 204-789-3206; Email: JSchellenberg@chrim.ca
      • Principal Investigator: Darcy Beer, MD
      • Sub-Investigator: Scott Sawyer, MD
  • Ontario
    • London, Ontario, Canada, N6A 5W9
      • Recruiting
      • Children's Hospital London Health Sciences Centre
      • Principal Investigator: Gary Joubert, MD
      • Contact: Patrick Siedlecki, PhD; Phone Number: 56174 519-685-8500; Email: Leslie.Boisvert@lhsc.on.ca
    • Ottawa, Ontario, Canada, K1H 8L1
      • Active, not recruiting
      • Children's Hospital of Eastern Ontario (CHEO)
  • Quebec
    • Montreal, Quebec, Canada, HT3 1C5
      • Active, not recruiting
      • Centre Hospitalier Universitaire Sainte Justine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 months to 15 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosis of acute intestinal infectious process (as defined by the protocol) confirmed. by the treating MD.
• 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.
• History or family history of G6PD deficiency
• Unable to complete follow-up.
• Previously enrolled in this study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ondansetron Oral Solution; Ondansetron Oral Solution (4mg/5mL solution) - Dose = 0.15mg/kg. One dose every 8 hours (q8h). Six doses over 48 hours.	Drug: Ondansetron Oral Solution; Six doses of oral ondansetron (0.15mg/kg) to be administered q8h (every 8 hours) to a maximum of 3 times in a 24 hour period, are provided to the participant/caregiver for use after emergency department disposition (i.e. home use).; Other Names: Zofran
Placebo Comparator: Placebo Oral Solution; Compounded Placebo Oral Solution to match experimental arm	Drug: Oral Placebo; Six doses of oral placebo (0.15mg/kg) to be administered q8h (every 8 hours) to a maximum of 3 times in a 24 hour period, are provided to the participant/caregiver for use after emergency department disposition (i.e. home use).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	The Modified Vesikari Scale Score (MVS) is a composite measure which includes several variables representing the severity of disease - points are summed to provide an overall score: Duration of diarrhea (hours): 0 (0 points), 1-96 (1 point), 97-120 (2 points), ≥121 (3 points); Maximum number of watery stools per 24 hour period: 0 (0 points), 1-3 (1 point), 4-5 (2 points), ≥6 (3 points); Duration of vomiting (hours): 0 (0 points), 1-24 (1 point), 25-48 (2 points), ≥49 (3 points); Maximum number of vomiting episodes per 24 hour period: none (0 points), 1 (1 point), 2-3 (2 points), ≥5 (3 points).; Maximum recorded rectal temperature (degrees Celsius): <37.0 (0 points), 37.1-38.4 (1 point), 38.5-38.9 (2 points), ≥39.0 (3 points); Unscheduled health care visit: None (0 points), Primary Care (2 points), emergency department (3 points); Treatment: None (0 points), Rehydration with IV fluids (1 point), Hospitalization (2 points)	Measured 24, 48, and 168 hours after baseline visit

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Vomiting Duration	Number of hours of vomiting following ED disposition.	Measured 24, 48, and 168 hours after baseline visit
Vomiting Frequency	Number of episodes of vomiting following ED disposition.	Measured 24, 48, and 168 hours after baseline visit
Vomiting Proportion	The proportion who experience vomiting following ED disposition.	Measured 24, 48, and 168 hours after baseline visit
Proportion of participants who require an unscheduled health care visit	Unscheduled health care provider visits following Emergency Department disposition. Is there a difference in the proportion who require an unscheduled health care provider visit following ED disposition.	Measured 24, 48, and 168 hours after baseline visit
Proportion of participants who require Intravenous (IV) Rehydration	Is there a difference in the proportion who require intravenous rehydration following ED disposition.	Measured 24, 48, and 168 hours after baseline visit
Satisfaction with care: 5 point Likert Scale	Caregivers will be asked about their level of satisfaction with the therapy provided measured on the following 5 point Likert scale (choose one option): 1 - Very dissatisfied; 2 - Dissatisfied; 3 - Neither satisfied, nor dissatisfied; 4 - Satisfied; 5 - Very Satisfied	168 hours after baseline

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety Profile of Multiple Doses of Oral Ondansetron	To determine if the discharge of children with AGE associated vomiting who are administered ondansetron in the ED with additional doses to be taken at home is associated with adverse events (e.g. diarrhea, revisits) as compared with placebo.	Measured 24, 48, and 168 hours after baseline visit

Collaborators and Investigators

• Sponsor: University of Calgary
• Collaborators: University of Manitoba; The Hospital for Sick Children; Canadian Institutes of Health Research (CIHR); University of Alberta; Alberta Children's Hospital Research Institute; University of Ottawa; Western University, Canada; Université de Montréal; Women and Children's Health Research Institute (WCHRI); Children's Hospital Research Institute of Manitoba
• Investigators: Principal Investigator: Stephen Freedman, MD, University of Calgary

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): September 4, 2019
• Primary Completion (Estimated): June 1, 2024
• Study Completion (Estimated): June 1, 2024

Study Registration Dates

• First Submitted: February 19, 2019
• First Submitted That Met QC Criteria: February 21, 2019
• First Posted (Actual): February 22, 2019

Study Record Updates

• Last Update Posted (Actual): October 4, 2023
• Last Update Submitted That Met QC Criteria: October 2, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Vomiting; Gastroenteritis; Pediatrics; Ondansetron; Zofran; DOSE-AGE
• Additional Relevant MeSH Terms: Digestive System Diseases; Signs and Symptoms, Digestive; Gastrointestinal Diseases; Vomiting; Diarrhea; Gastroenteritis; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Antiemetics; Gastrointestinal Agents; Dermatologic Agents; Serotonin Agents; Serotonin Antagonists; Serotonin 5-HT3 Receptor Antagonists; Antipruritics; Ondansetron
• Other Study ID Numbers: OND18-2045

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No