Clinical trial NCT03078842: Zinc Dosing Trial - Does Dose Reduction Reduce Side Effects But Retain Efficacy in Diarrhoea Management
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Diarrhea
Lead sponsor: World Health Organization
Sponsor class: OTHER
Collaborators: name: Center for Public Health Kinetics
name: Muhimbili University of Health and Allied Sciences
name: Boston Children's Hospital
First posted: 2017-03-13
Enrollment: 4500
Sex: ALL
Minimum age (years): 6
Maximum age (years): 59
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Proportion with long duration of diarrhoea
timeFrame: Measured daily for 15 days
measure: Continuation of diarrhoea symptoms
timeFrame: Measured daily for 15 days
measure: Proportion of children vomiting after zinc treatment
timeFrame: Measured daily for 15 days
Secondary outcomes:
measure: Proportion of children experiencing serious adverse events (SAEs)
timeFrame: Measured until 60 days
measure: Proportion with intermediate duration of diarrhoea
timeFrame: Measured daily for 15 days
measure: Proportion of guardians with positive attitude towards treatment
timeFrame: Day 15
measure: Treatment adherence
timeFrame: Measured daily for 15 days
measure: Mean serum plasma zinc concentration at Days 1, 3, 7, 15, 21 and 30
timeFrame: Days 1, 3, 7, 15, 21 and 30
measure: Illness symptoms between day 15 and 60 after the treatment
timeFrame: Days 30, 45, 60
Other outcomes:
Locations:
city: New Delhi
country: India
facility: Centre for Public Health Kinetics
city: Dar es Salaam
country: Tanzania
facility: Muhimbili University of Health and Allied Sciences
Study officials:
affiliation: World Health Organization
name: Rajiv Bahl, MBBS
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.