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

NCT03078842 | Completed DMC

• 1 other identifier: ERC.0002738
• Study Type: interventional
• Target: 4,500
• Locations: 2 countries
• Sites: 2

Brief Summary

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.

Conditions

Diarrhea

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (6)

• Proportion of children experiencing serious adverse events (SAEs)

  Measured until 60 days

• Proportion with intermediate duration of diarrhoea

  Measured daily for 15 days

• Proportion of guardians with positive attitude towards treatment

  Day 15

• Treatment adherence

  Measured daily for 15 days

• Mean serum plasma zinc concentration at Days 1, 3, 7, 15, 21 and 30

  Days 1, 3, 7, 15, 21 and 30

Study Arms (3)

Zinc-20

ACTIVE COMPARATOR

Zinc tablets, 20 mg per day

Dietary Supplement: Zinc tablets, 20 mg per day

Zinc-10

EXPERIMENTAL

Zinc tablets, 10 mg per day

Dietary Supplement: Zinc tablets, 10 mg per day

Zinc-05

EXPERIMENTAL

Zinc tablets, 5 mg per day

Dietary Supplement: Zinc tablets, 5 mg per day

Interventions

Zinc tablets, 20 mg per day DIETARY_SUPPLEMENT

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

Zinc-20

Zinc tablets, 10 mg per day DIETARY_SUPPLEMENT

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

Zinc-10

Zinc tablets, 5 mg per day DIETARY_SUPPLEMENT

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

Zinc-05

Eligibility Criteria

• Age: 6 Months - 59 Months
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Ayesha De Costa: lead
• Center for Public Health Kinetics: collaborator
• Muhimbili University of Health and Allied Sciences: collaborator
• Boston Children's Hospital: collaborator

Study Sites (2)

Centre for Public Health Kinetics

New Delhi, India

Location

Muhimbili University of Health and Allied Sciences

Dar es Salaam, Tanzania

Location

Related Publications (3)

• Kisenge R, Dhingra U, Rees CA, Liu E, Dutta A, Saikat D, Dhingra P, Somji S, Sudfeld C, Simon J, Ashorn P, Sazawal S, Duggan CP, Manji K. Risk factors for moderate acute malnutrition among children with acute diarrhoea in India and Tanzania: a secondary analysis of data from a randomized trial. BMC Pediatr. 2024 Jan 19;24(1):56. doi: 10.1186/s12887-024-04551-2.

  PMID: 38238656 DERIVED

• 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.

  PMID: 32966722 DERIVED

• 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.

  PMID: 31206083 DERIVED

MeSH Terms

Conditions

Diarrhea

Interventions

Zinc

Condition Hierarchy (Ancestors)

Signs and Symptoms, Digestive; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Metals, Heavy; Elements; Inorganic Chemicals; Transition Elements; Metals

Study Officials

• Rajiv Bahl, MBBS

  World Health Organization

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: All participants will get dispersible zinc tablets that, contain either 20 mg, 10 mg, or 5 mg of zinc. All tablets look and taste the same. Randomization and tablet package labelling was done in Geneva, and no-one at the trial sites knows the actual zinc content of tablets packaged for each participant number.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Scientist

Study Record Dates

• First Submitted: March 7, 2017
• First Posted: March 13, 2017
• Study Start: January 23, 2017
• Primary Completion: February 8, 2019
• Study Completion: February 1, 2020
• Last Updated: October 8, 2020

Record last verified: 2020-10

Data Sharing

• IPD Sharing: Will share

Locations

IN (1); TA (1)