Ondansetron Administration to WELL Children With Gastroenteritis Associated Vomiting in EDs in Pakistan (OWEP)

Study Description

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Brief Summary:

The primary objective is to determine if the administration of a single dose of oral ondansetron (an anti-vomiting medication), compared to placebo, results in a reduction in intravenous (IV) rehydration therapy in children presenting for emergency department care with vomiting and diarrhea in Pakistan.

Condition or disease	Intervention/treatment	Phase
Dehydration; Gastroenteritis; Vomiting; Diarrhea	Drug: Ondansetron; Drug: Placebo	Phase 4

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Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	625 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
Official Title:	Ondansetron Administration to WELL Children With Gastroenteritis Associated Vomiting in Emergency Departments in Pakistan
Actual Study Start Date :	May 2014
Actual Primary Completion Date :	January 20, 2017
Actual Study Completion Date :	February 3, 2017

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Ondansetron; 4 mg oral disintegrating tablet of ondansetron Participant weight 8-15 kg = half dose (2mg) Participant weight greater than 15 kg = full dose (4mg)	Drug: Ondansetron; Eligible children will receive one weight based (0.13 - 0.26 mg/kg) dose of an oral ondansetron disintegrating tablet. Subsequent therapy will be in accordance with World Health Organization guidelines as dictated by the child's hydration status.; Other Name: Zofran
Placebo Comparator: Placebo (sugar pill)	Drug: Placebo; Eligible children will receive one dose of an oral disintegrating Placebo (sugar pill) tablet. Subsequent therapy will be in accordance with World Health Organization guidelines as dictated by the child's hydration status.; Other Name: Sugar Pill

Outcome Measures

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Primary Outcome Measures :

1. Intravenous (IV) Rehydration [ Time Frame: within 72 hours of randomization ]
   IV rehydration is defined as the IV administration of ≥20 ml/kg over 4 hours of an isotonic fluid for the purpose of rehydration within 72 hours of randomization. This definition allows for the occurrence of the primary outcome in children who receive maintenance plus replacement of losses and not simply those who receive a fluid bolus. This will not include those who simply receive maintenance fluids (e.g. 4 ml/kg/hr for those weighing < 10 kg). This will also enable us to exclude children who undergo IV insertion for the purpose of medication administration. IV rehydration is a powerful marker of treatment failure, a decrease in which is likely to impact practice and influence decision makers since it is drastically more expensive that ORT, it is painful and is associated with a greater risk of adverse events.

Secondary Outcome Measures :

1. The proportion of children who vomit during the 4 hour observation period [ Time Frame: within 4 hour observation period after randomization ]
2. The frequency of vomiting during the 4 hour observation period [ Time Frame: within 4 hour observation period after randomization ]
3. Hospitalization > 24 hours [ Time Frame: 72 hours after randomization; 24 hour follow up as needed; chart review 21 days after enrollment ]
   Total length of stay from Emergency Department (ED) arrival until discharge of > 24 hours, regardless of whether time is spent in the ED or inpatient unit
4. Volume of Oral Rehydration Solution (ORS) consumed (ml/kg) during the 4 hour observation period [ Time Frame: within 4 hour observation period after randomization ]
5. Development of "SOME" dehydration during the 72 hours following randomization amongst children who are discharged [ Time Frame: within 72 hours of randomization ]

   All children will be presumed to not be dehydrated at the time of discharge regardless of severity of dehydration at the time of ED presentation.

   SOME Dehydration = 2 or more of the following signs:

   • Restlessness, irritability
   • Sunken Eyes
   • Drinks eagerly, thirsty
   • Skin pinch goes back slowly
6. Number of diarrheal stools during the 72 hours following randomization [ Time Frame: within 72 hours of randomization ]
   Diarrheal stools are defined, in keeping with the WHO definition as "loose or liquid stools"
7. Treatment failure [ Time Frame: 72 hours after randomization; 24 hour follow up as needed; chart review 21 days after enrollment ]

   This aggregate outcome will include children who experience the following:

   1. IV rehydration as defined in primary outcome
   2. Nasogastric rehydration for > 24 hours - this implies a failure of outpatient Oral Rehydration Therapy (ORT)
   3. Death within 72 hours (from any cause; in or out of hospital)
8. Response based on infectious etiology (i.e. bacterial vs. viral), duration of illness (i.e. < 48 vs. ≥ 48 hours), and age (< 18 months vs. ≥ 18 months) [ Time Frame: 72 hours after randomization; 24 hour follow up as needed; chart review 21 days after enrollment ]

Other Outcome Measures:

1. Major Side Effects [ Time Frame: 72 hours after randomization; 24 hour follow up as needed; chart review 21 days after enrollment ]
   Uncommon events such as: Arrythmia and Death. This data is critical to estimate a safety profile of ondansetron in low to middle income countries
2. Semi- and Intensive Care Unit Admission [ Time Frame: 72 hours after randomization; 24 hour follow up as needed; chart review 21 days after enrollment ]
   This data is critical to estimate a safety profile of ondansetron in low to middle income countries

Eligibility Criteria

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Ages Eligible for Study:	6 Months to 59 Months (Child)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Age 6 - 59 months (0.5 - 5 years)

• Symptoms consistent with gastroenteritis (must have a & b)

  1. 1 episode of nonbilious, nonbloody vomiting within the 4 hours preceding triage The requirement for only 1 vomiting episode is based on prior work which similarly required 1 vomiting episode within 4 hours of triage. The later study reported a 17% absolute reduction in the use of IV rehydration. The vast majority of children seeking care and enrolled in the aforementioned study had a significantly greater number of vomiting episodes in the preceding 24 hour (mean >9 episodes).
  2. Presence of ≥ 1 episode of diarrhea during the illness We require the presence of only 1 diarrheal stool to enhance our probability of enrolling children with enteritis (as opposed to other diagnoses). In fact, of the 8 RCTs performed using antiemetics in children with gastroenteritis in developed countries, only 1 even required the presence of any diarrhea as part of the eligibility criteria (and that study required a single diarrheal stool).
• Presence of NO dehydration (NO=not enough signs to classify as some or severe dehydration)

Exclusion Criteria:

• Weight <8 kg
• Vomiting or diarrhea for > 7 days
• Malnutrition: The World Health Organization (WHO) definition will be employed - weight for height below -3z scores of the median WHO growth standards
• Severe dehydration (WHO criteria) or hypotension defined as a systolic blood pressure <70 mm Hg in infants 1 month to 12 months, < 70 mm Hg + (2 x age in years) in children 1-10 years, < 90 mm Hg in children ≥ 10 years
• Prior abdominal surgery (excluding hernia)
• Bilious or bloody vomitus
• Known hypersensitivity to ondansetron or any serotonin receptor antagonist
• History or family history of prolonged QT syndrome
• Taking apomorphine or any medication that is generally accepted as having a risk of causing torsades de pointes
• Patients previously enrolled in the study
• Follow-up will not be possible

Contacts and Locations

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Locations

Pakistan
Aga Khan University Hospital
Karachi, Pakistan
Aga Khan Hospital for Women and Children (AKHWC)
Kharadar, Karachi, Pakistan

Sponsors and Collaborators

Dr. Stephen Freedman

Thrasher Research Fund

Bill and Melinda Gates Foundation

Aga Khan University

Investigators

Principal Investigator:	Stephen Freedman, MD	University of Calgary
Principal Investigator:	Zulfiqar Bhutta, MD	Aga Khan University - World Health Organization
Principal Investigator:	Sajid B Soofi, MD	Aga Khan University

More Information

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Responsible Party:	Dr. Stephen Freedman, Associate Professor of Pediatrics; Alberta Children's Hospital Foundation Professor in Child Health and Wellness Alberta Children's Hospital Theme Lead, University of Calgary
ClinicalTrials.gov Identifier:	NCT01870635 History of Changes
Other Study ID Numbers:	RSO1026252
First Posted:	June 6, 2013
Last Update Posted:	March 2, 2018
Last Verified:	February 2018

Keywords provided by Dr. Stephen Freedman, University of Calgary:

Low-middle income country; Dehydration; Intravenous Rehydration; Pakistan

Additional relevant MeSH terms:

Vomiting; Diarrhea; Gastroenteritis; Dehydration; Signs and Symptoms, Digestive; Signs and Symptoms; Gastrointestinal Diseases; Digestive System Diseases; Water-Electrolyte Imbalance; Metabolic Diseases; Pathologic Processes; Ondansetron; Antiemetics; Autonomic Agents	Peripheral Nervous System Agents; Physiological Effects of Drugs; Gastrointestinal Agents; Antipruritics; Dermatologic Agents; Serotonin Antagonists; Serotonin Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antipsychotic Agents; Tranquilizing Agents; Central Nervous System Depressants; Psychotropic Drugs; Anti-Anxiety Agents