Ondansetron Administration to Children With Gastroenteritis, Vomiting and SOME Dehydration in EDs in Pakistan

NCT ID: NCT01870648

Last Updated: 2018-03-02

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 918 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-05-31
• Study Completion Date: 2017-12-31

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 some dehydration, vomiting and diarrhea in Pakistan.

SOME Dehydration is defined as 2 or more of the following signs and symptoms:

• Restlessness, irritability
• Sunken Eyes
• Drinks eagerly, thirsty
• Skin pinch goes back slowly

Detailed Description

Gastroenteritis remains one of the most common causes of morbidity and mortality in children <5 years of age worldwide. A critical factor in the reduction in mortality over the past 30 years has been the introduction of oral rehydration therapy (ORT) for the treatment of dehydration.

However, its use has stagnated in many low- and middle-income countries (LMIC) where many children lack access to alternatives such as intravenous (IV) rehydration. When such children have fluid losses that cannot be replaced orally due to intractable vomiting, death is common. Finding a safe, non-invasive, and effective strategy to reduce vomiting in children would substantially decrease the need for IV rehydration and hence morbidity and mortality in LMICs. Although antiemetic agents are included in the WHO list of Essential Medicines, their use in children with gastroenteritis is not endorsed by the World Health Organization (WHO). Concerns include a lack of evidence that antiemetic agents can improve outcomes and that they are associated with dangerous side effects. However, in high-income settings, studies on ondansetron, an antiemetic agent, have demonstrated that it can reduce vomiting, IV rehydration, and hospitalization. Recent reviews by prominent organizations (e.g. International child Health Review Collaboration; the Committee on the Selection and Use of Essential Medicines) have indicated an interest in ondansetron use in children with gastroenteritis, and they have concluded that further evidence is required. This trial aims to determine if the administration of a single dose of oral ondansetron results in improved outcomes in children brought for emergency department care with vomiting and diarrhea in Pakistan.

Two trials will be conducted under the umbrella of one study. The proposed trials will be identical with the exception of the severity of dehydration at enrollment (either "some" or none "well"). The trials will have the following specific aims:

1. To determine, in children 6 - 59 months of age with AGE with vomiting and diarrhea who have "NO" dehydration, if there is a reduction in the proportion of children administered IV rehydration in those who receive oral ondansetron in addition to all WHO standards of care, compared to those receiving an oral placebo in addition to all WHO standards of care.

2. To determine, in children 6 - 59 months of age with AGE with vomiting and diarrhea who have "SOME" dehydration, if there is a reduction in the proportion of children administered IV rehydration in those who receive oral ondansetron in addition to all WHO standards of care, compared to those receiving an oral placebo in addition to all WHO standards of care.

IV rehydration is a powerful marker of treatment failure and reducing the need for IV rehydration therapy in either of these 2 groups of children will be viewed as a significant advance by healthcare providers and decision makers. Previous studies of ondansetron have not been conducted in low and middle income countries (LMIC), have been of relatively small sample sizes, have not employed WHO dehydration scales, and have not focused on young children (i.e. <5 years). These will be the first pediatric randomized, double-blind trials, in a LMIC, defining the impact of oral ondansetron administration in children with AGE on the need for IV rehydration. As such therapy is unavailable to a large number of children in LMIC countries, the ability to demonstrate that ondansetron can reduce the use of IV rehydration will provide compelling evidence that this drug has the potential to save lives around the world. We postulate that oral ondansetron administration to children in LMIC, if beneficial in our study population, could serve as a feasible and reliable intervention that is available for provision by non-hospital based, outreach, and healthcare providers in remote regions of the world.

This study may have immediate impact on patient management. Based on the results, it will be discovered if oral ondansetron plays a role in reducing the need for intravenous rehydration in children with gastroenteritis in Pakistan. As ondansetron is now available in generic formulations, and is relatively inexpensive, it is anticipated that if this study is positive, ondansetron will be considered for inclusion in the WHO - gastroenteritis care package. This could ultimately lead to a decrease in the need for intravenous rehydration in children in countries such as Pakistan.

Conditions

Dehydration; Gastroenteritis; Vomiting; Diarrhea

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

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)

Group Type: EXPERIMENTAL

Ondansetron

Intervention Type: DRUG

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.

Placebo (sugar pill)

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

Zofran; Sugar Pill

Eligibility 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).29

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 "SOME" dehydration - 2 or more of the following signs: i. Restlessness, irritability; ii. Sunken Eyes; iii.Drinks eagerly, thirsty; iv.Skin pinch goes back slowly

Exclusion Criteria

• Weight <8 kg
• Vomiting or diarrhea for > 7 days
• Malnutrition: The 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

• Minimum Eligible Age: 6 Months
• Maximum Eligible Age: 59 Months
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Bill and Melinda Gates Foundation

OTHER

Sponsor Role: collaborator

Thrasher Research Fund

OTHER

Sponsor Role: collaborator

Aga Khan University

OTHER

Sponsor Role: collaborator

Dr. Stephen Freedman

OTHER

Sponsor Role: lead

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

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Stephen Freedman, MD

Role: PRINCIPAL_INVESTIGATOR

University of Calgary

Zulfiqar Bhutta, MD

Role: PRINCIPAL_INVESTIGATOR

Aga Khan University - World Health Organization

Sajid B Soofi, MD

Role: PRINCIPAL_INVESTIGATOR

Aga Khan University

Locations

Aga Khan University Hospital

Karachi, , Pakistan

Aga Khan Hospital for Women and Children (AKHWC)

Kharadar, Karachi, , Pakistan

Countries

Pakistan

References

Freedman SB, Soofi SB, Willan AR, Williamson-Urquhart S, Siddiqui E, Xie J, Dawoud F, Bhutta ZA. Oral Ondansetron Administration to Dehydrated Children in Pakistan: A Randomized Clinical Trial. Pediatrics. 2019 Dec;144(6):e20192161. doi: 10.1542/peds.2019-2161. Epub 2019 Nov 6.

Reference Type: DERIVED

PMID: 31694979 (View on PubMed)

Other Identifiers

RSO1026396

Identifier Type: -

Identifier Source: org_study_id