Zinc Dosing Trial - Does Dose Reduction Reduce Side Effects But Retain Efficacy in Diarrhoea Management

Study Overview
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Brief Summary
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Diarrhoea continues to be a major cause of child deaths. Current treatment of acute watery diarrhoea includes oral rehydration solution (ORS), zinc and continued feeding. The use of zinc is based on a number of studies that showed that zinc reduces the duration and severity of diarrhoea. The recommended dose of zinc in 6-59 month old children is 20mg/day for 10-14 days. This dose is associated with an increased risk of vomiting. No dosing studies are available to determine the optimal dose of zinc, which while maintaining the benefits also has a low risk of vomiting. The investigators will conduct a double-blind randomized controlled trial of three doses of zinc (20mg/day, 10mg/day and 5mg/day) in two settings - one in Sub-Saharan Africa and the other in South Asia. The study population will be 4500 children with diarrhoea of less than 72 hours duration who are aged 6-59 months. They will be recruited from outpatient health facilities. All enrolled children will receive ORS and continued feeding as recommended by the World Health Organization. Those allocated to the standard zinc dose will receive an oral dispersible tablet with 20mg zinc daily for 14 days. Those allocated to lower dose zinc will receive identical tablets with either 10mg or 5mg zinc daily for 14 days. Enrolled children will be followed by until recovery from diarrhoea or 15 days after enrolment, whichever is later. In addition, study children will be assessed again at thirty (30), forty-five (45), and sixty (60) days to estimate impact on post illness outcomes. Primary outcomes will be mean duration of diarrhoea, proportion of episodes that last longer than 5 days, mean number of stools and proportion of children with vomiting.

Official Title
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Establishing the Optimal Dose of Therapeutic Zinc Supplementation for the Treatment of Acute Diarrhea in Under Five Children - a Dose Response Trial in a South Asian and a Sub-Saharan African Setting

Conditions
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Diarrhea

Intervention / Treatment
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* Dietary Supplement: Zinc tablets, 20 mg per day
* Dietary Supplement: Zinc tablets, 10 mg per day
* Dietary Supplement: Zinc tablets, 5 mg per day


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 6 to 59 completed months of age Acute diarrhoea of less than 3 days at the time of screening or dysentery, defined as visible blood in the stool, of less than 3 days at the time of screening Likely to stay within the study area for the next 2 months Written informed consent from caretaker Exclusion Criteria: Presence of severe acute malnutrition (WHZ<-3 or oedema) Presence of severe dehydration that cannot be corrected in 4 to 6 hours Signs of severe pneumonia (WHO definition of pneumonia with danger signs), sepsis, rapid diagnostic test (RDT) -confirmed malaria or other severe illness Previously or currently enrolled in the study Currently enrolled in another study Other child currently enrolled in the study in the same household Not intending to remain in study area for the duration of the study Parents refuse participation in the study

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 59 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Zinc-20<br>Zinc tablets, 20 mg per day | Dietary Supplement: Zinc tablets, 20 mg per day<br>* Participants will receive rehydration, dietary counseling, and 1 tablet per day for 14 days of zinc-tablets, each of which contains 20 mg of zinc<br>|
| Experimental: Zinc-10<br>Zinc tablets, 10 mg per day | Dietary Supplement: Zinc tablets, 10 mg per day<br>* Participants will receive rehydration, dietary counseling, and 1 tablet per day for 14 days of zinc-tablets, each of which contains 10 mg of zinc<br>|
| Experimental: Zinc-05<br>Zinc tablets, 5 mg per day | Dietary Supplement: Zinc tablets, 5 mg per day<br>* Participants will receive rehydration, dietary counseling, and 1 tablet per day for 14 days of zinc-tablets, each of which contains 5 mg of zinc<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion with long duration of diarrhoea | Diarrhoea continuing beyond five days | Measured daily for 15 days | 
| Continuation of diarrhoea symptoms | Total number of loose or watery stools after enrolment | Measured daily for 15 days | 
| Proportion of children vomiting after zinc treatment | Vomiting within 30 minutes of administration of zinc tablet | Measured daily for 15 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of children experiencing serious adverse events (SAEs) | Serious adverse events (life-threatening or requiring hospitalization) | Measured until 60 days | 
| Proportion with intermediate duration of diarrhoea | Diarrhoea continuing beyond three days | Measured daily for 15 days | 
| Proportion of guardians with positive attitude towards treatment | The guardians will be asked if was easy to administer the treatment, if they think the child liked the treatment, if they saw any changes in the children after the treatment and if they would recommend this treatment to their friends' children. | Day 15 | 
| Treatment adherence | Mean number of tablets consumed by the study child during the 14 day treatment period. | Measured daily for 15 days | 
| Mean serum plasma zinc concentration at Days 1, 3, 7, 15, 21 and 30 | Mean serum plasma zinc concentration at Days 1, 3, 7, 15, 21 and 30 | Days 1, 3, 7, 15, 21 and 30 | 
| Illness symptoms between day 15 and 60 after the treatment | 2-week period prevalence and number of days with diarrhoea, fever, or respiratory symptoms | Days 30, 45, 60 |