search
Back to results

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

Primary Purpose

Dehydration, Gastroenteritis, Vomiting

Status
Completed
Phase
Phase 4
Locations
Pakistan
Study Type
Interventional
Intervention
Ondansetron
Placebo
Sponsored by
Dr. Stephen Freedman
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Dehydration focused on measuring Low-middle income country, Dehydration, Intravenous Rehydration, Pakistan

Eligibility Criteria

6 Months - 59 Months (Child)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Aga Khan University Hospital
  • Aga Khan Hospital for Women and Children (AKHWC)

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Ondansetron

Placebo (sugar pill)

Arm Description

4 mg oral disintegrating tablet of ondansetron Participant weight 8-15 kg = half dose (2mg) Participant weight greater than 15 kg = full dose (4mg)

Outcomes

Primary Outcome Measures

Intravenous (IV) Rehydration
IV rehydration is defined as the IV administration of ≥20 ml/kg over 4 hours 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

The proportion of children who vomit during the 4 hour observation period
The frequency of vomiting during the 4 hour observation period
Hospitalization > 24 hours
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
Volume of Oral Rehydration Solution (ORS) consumed (ml/kg) during the 4 hour observation period
Development of "SOME" dehydration during the 72 hours following randomization amongst children who are discharged
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.
Number of diarrheal stools during the 72 hours following randomization
Diarrheal stools are defined, in keeping with the WHO definition as "loose or liquid stools"
Treatment failure
This aggregate outcome will include children who experience the following: IV rehydration as defined in primary outcome Nasogastric rehydration for > 24 hours - this implies a failure of outpatient Oral Rehydration Therapy (ORT) Death within 72 hours (from any cause; in or out of hospital)
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)

Full Information

First Posted
May 30, 2013
Last Updated
February 28, 2018
Sponsor
Dr. Stephen Freedman
Collaborators
Bill and Melinda Gates Foundation, Thrasher Research Fund, Aga Khan University
search

1. Study Identification

Unique Protocol Identification Number
NCT01870648
Brief Title
Ondansetron Administration to Children With Gastroenteritis, Vomiting and SOME Dehydration in EDs in Pakistan
Acronym
OSEP
Official Title
Ondansetron Administration to Children With Gastroenteritis, Vomiting and SOME Dehydration in Emergency Departments in Pakistan
Study Type
Interventional

2. Study Status

Record Verification Date
February 2018
Overall Recruitment Status
Completed
Study Start Date
May 2014 (Actual)
Primary Completion Date
December 2017 (Actual)
Study Completion Date
December 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Dr. Stephen Freedman
Collaborators
Bill and Melinda Gates Foundation, Thrasher Research Fund, Aga Khan University

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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: 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. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Dehydration, Gastroenteritis, Vomiting, Diarrhea
Keywords
Low-middle income country, Dehydration, Intravenous Rehydration, Pakistan

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
918 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Ondansetron
Arm Type
Experimental
Arm Description
4 mg oral disintegrating tablet of ondansetron Participant weight 8-15 kg = half dose (2mg) Participant weight greater than 15 kg = full dose (4mg)
Arm Title
Placebo (sugar pill)
Arm Type
Placebo Comparator
Intervention Type
Drug
Intervention Name(s)
Ondansetron
Other Intervention Name(s)
Zofran
Intervention Description
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
Intervention Name(s)
Placebo
Other Intervention Name(s)
Sugar Pill
Intervention Description
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.
Primary Outcome Measure Information:
Title
Intravenous (IV) Rehydration
Description
IV rehydration is defined as the IV administration of ≥20 ml/kg over 4 hours 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.
Time Frame
within 72 hours of randomization
Secondary Outcome Measure Information:
Title
The proportion of children who vomit during the 4 hour observation period
Time Frame
within 4 hour observation period after randomization
Title
The frequency of vomiting during the 4 hour observation period
Time Frame
within 4 hour observation period after randomization
Title
Hospitalization > 24 hours
Description
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
Time Frame
72 hours after randomization; 24 hour follow up as needed; chart review 21 days after enrollment
Title
Volume of Oral Rehydration Solution (ORS) consumed (ml/kg) during the 4 hour observation period
Time Frame
within 4 hour observation period after randomization
Title
Development of "SOME" dehydration during the 72 hours following randomization amongst children who are discharged
Description
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.
Time Frame
within 72 hours of randomization
Title
Number of diarrheal stools during the 72 hours following randomization
Description
Diarrheal stools are defined, in keeping with the WHO definition as "loose or liquid stools"
Time Frame
within 72 hours of randomization
Title
Treatment failure
Description
This aggregate outcome will include children who experience the following: IV rehydration as defined in primary outcome Nasogastric rehydration for > 24 hours - this implies a failure of outpatient Oral Rehydration Therapy (ORT) Death within 72 hours (from any cause; in or out of hospital)
Time Frame
72 hours after randomization; 24 hour follow up as needed; chart review 21 days after enrollment
Title
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 Pre-specified Outcome Measures:
Title
Major Side Effects
Description
Uncommon events such as: Arrythmia and Death. This data is critical to estimate a safety profile of ondansetron in low to middle income countries
Time Frame
72 hours after randomization; 24 hour follow up as needed; chart review 21 days after enrollment
Title
Semi- and Intensive Care Unit Admission
Description
This data is critical to estimate a safety profile of ondansetron in low to middle income countries
Time Frame
72 hours after randomization; 24 hour follow up as needed; chart review 21 days after enrollment

10. Eligibility

Sex
All
Minimum Age & Unit of Time
6 Months
Maximum Age & Unit of Time
59 Months
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age 6 - 59 months (0.5 - 5 years) Symptoms consistent with gastroenteritis (must have a & b) 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 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Stephen Freedman, MD
Organizational Affiliation
University of Calgary
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Zulfiqar Bhutta, MD
Organizational Affiliation
Aga Khan University - World Health Organization
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Sajid B Soofi, MD
Organizational Affiliation
Aga Khan University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Aga Khan University Hospital
City
Karachi
Country
Pakistan
Facility Name
Aga Khan Hospital for Women and Children (AKHWC)
City
Kharadar, Karachi
Country
Pakistan

12. IPD Sharing Statement

Citations:
PubMed Identifier
31694979
Citation
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.
Results Reference
derived

Learn more about this trial

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

We'll reach out to this number within 24 hrs