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

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

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.

Study Overview

• Status: Completed
• Conditions: Diarrhea
• Intervention / Treatment: Dietary supplement: Zinc tablets, 20 mg per day; Dietary supplement: Zinc tablets, 10 mg per day; Dietary supplement: Zinc tablets, 5 mg per day

• Study Type: Interventional
• Enrollment (Actual): 4500
• Phase: Not Applicable

Contacts and Locations

Study Locations

• India
  • New Delhi, India
    • Centre for Public Health Kinetics
• Tanzania
  • Dar es Salaam, Tanzania
    • Muhimbili University of Health and Allied Sciences

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 1 year (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Zinc-20; Zinc tablets, 20 mg per day	Dietary supplement: Zinc tablets, 20 mg per day; 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
Experimental: Zinc-10; Zinc tablets, 10 mg per day	Dietary supplement: Zinc tablets, 10 mg per day; 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
Experimental: Zinc-05; Zinc tablets, 5 mg per day	Dietary supplement: Zinc tablets, 5 mg per day; 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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Ayesha De Costa
• Collaborators: Boston Children's Hospital; Muhimbili University of Health and Allied Sciences; Center for Public Health Kinetics
• Investigators: Study Director: Rajiv Bahl, MBBS, World Health Organization

Publications and helpful links

General Publications

• Dhingra U, Kisenge R, Sudfeld CR, Dhingra P, Somji S, Dutta A, Bakari M, Deb S, Devi P, Liu E, Chauhan A, Kumar J, Semwal OP, Aboud S, Bahl R, Ashorn P, Simon J, Duggan CP, Sazawal S, Manji K. Lower-Dose Zinc for Childhood Diarrhea - A Randomized, Multicenter Trial. N Engl J Med. 2020 Sep 24;383(13):1231-1241. doi: 10.1056/NEJMoa1915905.
• Somji SS, Dhingra P, Dhingra U, Dutta A, Devi P, Kumar J, Deb S, Semwal OP, Sazawal S, Manji K, Kisenge R, Bakari M, Aboud S, Liu E, Sudfeld C, Duggan CP, Ashorn P, Bahl R, Simon JL. Effect of dose reduction of supplemental zinc for childhood diarrhoea: study protocol for a double-masked, randomised controlled trial in India and Tanzania. BMJ Paediatr Open. 2019 Apr 24;3(1):e000460. doi: 10.1136/bmjpo-2019-000460. eCollection 2019. Erratum In: BMJ Paediatr Open. 2020 Oct 12;4(1):e000460corr1.

Study record dates

Study Major Dates

• Study Start (Actual): January 23, 2017
• Primary Completion (Actual): February 8, 2019
• Study Completion (Actual): February 1, 2020

Study Registration Dates

• First Submitted: March 7, 2017
• First Submitted That Met QC Criteria: March 7, 2017
• First Posted (Actual): March 13, 2017

Study Record Updates

• Last Update Posted (Actual): October 8, 2020
• Last Update Submitted That Met QC Criteria: October 5, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Signs and Symptoms, Digestive; Diarrhea; Physiological Effects of Drugs; Trace Elements; Micronutrients; Zinc
• Other Study ID Numbers: ERC.0002738

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: The exact mechanism of data sharing has not yet been decided among the researchers. But the study is funded by an Organization (Bill & Melinda Gates Foundation) that requires data sharing.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No