Zinc-MNP Trial for Prevention of Diarrhea and Promotion of Linear Growth

Study Overview
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Brief Summary
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This is a randomized, double-blind, community-based efficacy trial of different doses, forms, and frequencies of zinc supplementation for the prevention of diarrhea and promotion of linear growth among children 9-11 months of age in Dhaka, Bangladesh.

Detailed Description
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Zinc is essential to support growth in young children especially for tissues undergoing rapid cellular differentiation and turnover, such as those in the immune system and gastrointestinal tract. Therapeutic zinc supplementation has been initiated in low-income countries as part of diarrhea treatment programs to support these needs for young children but, the effects of preventive supplemental zinc as a tablet or as a multiple micronutrient powder (MNP) on child growth and diarrheal disease are mixed and pose programmatic uncertainties. Thus, a randomized, double-blind community-based efficacy trial of five different doses, forms, and frequencies of preventive zinc supplementation vs. a placebo was designed for a study in children aged 9-11 months in an urban community in Dhaka, Bangladesh. The primary outcomes of this 24-week study are incidence of diarrheal disease and linear growth. Study workers will conduct in-home morbidity checks twice weekly; anthropometry will be measured at baseline, 12 weeks and 24 weeks. Serum zinc and other related biomarkers will be measured in a subsample along with an estimate of the exchangeable zinc pool size using stable isotope techniques in a subgroup. Therapeutic zinc will be provided as part of diarrhea treatment, in accordance with Bangladesh's national policy. Therefore, the proposed study will determine the additional benefit of a preventive zinc supplementation intervention.

Official Title
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Randomized, Double-blind, Community-based Efficacy Trial of Various Doses of Zinc in Micronutrient Powders or Tablets in Young, Bangladeshi Children

Conditions
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Diarrhea, Stunting

Intervention / Treatment
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* Dietary Supplement: Standard MNP
* Dietary Supplement: High zinc, low iron MNP
* Dietary Supplement: High zinc, low/no iron on alternating days
* Dietary Supplement: Dispersible zinc supplement
* Dietary Supplement: Intermittent zinc supplement
* Dietary Supplement: Placebo powder


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 9-11 months of age Weight-for-length Z score >= -3 according to the 2006 World Health Organization Growth Standards Hemoglobin concentration > = 7.0 g/dL Exclusion Criteria: Presence of severe acute malnutrition, defined as a WLZ <-3 and/or the presence of bipedal edema and/or mid-upper arm circumference <115 mm; Presence of severe anemia, defined as a hemoglobin concentration < 7.0 g/dL Congenital anomalies (e.g. cardiac defects, cleft lip or palate) or any other conditions that interfere with feeding; Chromosomal anomalies and other organic problems (e.g. jaundice, tuberculosis) Currently consuming MNPs with no intention of stopping

Ages Eligible for Study
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Minimum Age: 9 Months
Maximum Age: 11 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1. Standard MNP<br> | Dietary Supplement: Standard MNP<br>* Standard MNP, 15 micronutrients (Vitamin A 400 µg, vitamin D 5 µg, vitamin E 5 mg, vitamin C 30 mg, thiamine 0.5 mg, riboflavin 0.5 mg, niacin 6 mg, pyridoxine 0.5 mg, vitamin B12 0.9 mg, folate 150 µg, iron 10 mg, zinc 4.1 mg, copper 0.56 mg, selenium 17.0 µg and iodine 90 µg). Daily supplementation for 24 weeks.<br>|
| Experimental: 2. High zinc, low iron MNP<br> | Dietary Supplement: High zinc, low iron MNP<br>* Same as group 1, except with 10 mg zinc instead of 4.1 mg and 6 mg iron instead of 10 mg. Daily supplementation for 24 weeks.<br>|
| Experimental: 3. High zinc, low/no iron<br> | Dietary Supplement: High zinc, low/no iron on alternating days<br>* Same as study group 1, except with 10 mg zinc instead of 4.1 mg, and 6 mg iron and no iron on alternating days instead of 10 mg. Daily supplementation for 24 weeks.<br>|
| Active Comparator: 4. Dispersible zinc supplement<br> | Dietary Supplement: Dispersible zinc supplement<br>* 10 mg zinc in a dispersible tablet. Daily supplementation for 24 weeks.<br>|
| Experimental: 5. Intermittent zinc supplement<br> | Dietary Supplement: Intermittent zinc supplement<br>* 10 mg zinc in a dispersible tablet. Daily supplementation for 14 days at baseline and 3 months, placebo tablet on all other days.<br>|
| Placebo Comparator: 6. Placebo powder<br> | Dietary Supplement: Placebo powder<br>* Daily provision of a placebo powder for 24 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of diarrhea | Incidence of diarrhea is defined as the number of diarrheal episodes per person-weeks of follow-up | Incidence over the 24-week follow-up period | 
| Change in length-for-age Z score | Change in length-for-age Z score from enrollment to the end of the 24-week follow-up period | Measured at enrollment and the end of the 24-week follow-up period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in stunting prevalence | Change in the prevalence of stunting (LAZ <-2) in the study population over the 24-week follow-up period | Measured at enrollment and the end of the 24-week follow-up period | 
| Change in wasting prevalence | Change in the prevalence of wasting (WLZ <-2) in the study population over the 24-week follow-up period | Measured at enrollment and at the end of the 24-week follow-up period | 
| Incidence of dysentery | Dysentery is defined as any diarrheal episode in which the loose or watery stools contain visible red blood | Measured twice weekly for 24 weeks | 
| Incidence of diarrhea with dehydration | Incidence of diarrhea with dehydration over the 24-week follow-up period | Measured twice weekly for 24 weeks | 
| Incidence of hospitalizations | Hospitalization is defined as an overnight stay in the hospital due to illness | Assessed twice weekly for 24 weeks | 
| Change in mean serum zinc concentration | Change in mean serum zinc concentration among children in the biochemistry sub-group over the 24-week follow-up period | Measured at enrollment and at the end of the 24-week follow-up period in a subgroup of participants in all 6 intervention groups | 
| Change in the prevalence of zinc deficiency | Change in the prevalence of zinc deficiency (serum zinc concentration <9.9 umol/L) in the biochemistry subgroup from baseline to the end of the 24-week follow-up period | Measured at enrollment and at the end of the 24-week follow-up period in subgroup of participants in all 6 intervention groups | 
| Change in the exchangeable zinc pool size | Change in the exchangeable zinc pool size from enrollment to the end of the 24-week follow-up period in a subgroup of participants randomized to the high zinc, low-iron MNP group, dispersible zinc supplement group, and placebo group | Measured at enrollment and at the end of the 24-week follow-up period in a subgroup of participants randomized to the high zinc, low-iron MNP, dispersible zinc supplement, and placebo groups. | 
| Change in ferritin concentrations | Change in mean concentrations of ferritin from enrollment to the end of the 24-week follow-up period among participants in the biochemistry subgroup. | Measured at enrollment and at the end of the 24-week follow-up period in a subgroup of participants in all 6 intervention groups | 
| Change in concentrations of soluble transferrin receptor | Change in mean concentrations of soluble transferrin receptor from enrollment to the end of the 24-week follow-up period among participants in the biochemistry subgroup. | Measured at enrollment and at the end of the 24-week follow-up period in a subgroup of participants in all 6 intervention groups | 
| Change in gut microbiota | Change in the composition of gut microbiota from enrollment to the end of the 24-week follow-up period among a subgroup of participants randomized to the high zinc, low-iron; dispersible zinc supplement; and placebo powder groups. | Measured at enrollment and at the end of the 24-week follow-up period in a subgroup of participants randomized to the high zinc, low-iron MNP, dispersible zinc supplement, and placebo groups. | 
| Change in amino acid metabolites associated with gut permeability | To compare the change in amino acid metabolites associated with gut permeability from enrollment to the end of the 24-week follow-up period among a subgroup of participants randomized to the high zinc, low-iron MNP; dispersible zinc supplement; and placebo groups. | Measured at enrollment and at the end of the 24-week follow-up period in a subgroup of participants randomized to the high zinc, low-iron MNP, dispersible zinc supplement, and placebo groups. | 
| Change in lipid metabolites associated with gut permeability | To compare the change in lipid metabolites associated with gut permeability from enrollment to the end of the 24-week follow-up period among a subgroup of participants randomized to the high zinc, low-iron MNP; dispersible zinc supplement; and placebo groups. | Measured at enrollment and at the end of the 24-week follow-up period in a subgroup of participants randomized to the high zinc, low-iron MNP, dispersible zinc supplement, and placebo groups. | 
| Change in genome wide gene expression by RNA-sequencing | To compare the change in genome wide gene expression, measured with RNA-sequencing, from enrollment to the end of the 24-week follow-up period among a subgroup of participants randomized to the high zinc, low-iron MNP; dispersible zinc supplement; and placebo groups. | Measured at enrollment and at the end of the 24-week follow-up period in a subgroup of participants randomized to the high zinc, low-iron MNP, dispersible zinc supplement, and placebo groups. | 
| Change in specific gene expression by quantitative Polymerase Chain Reaction | To compare the change in specific gene expression, measured by quantitative Polymerase Chain Reaction, from enrollment to the end of the 24-week follow-up period among a subgroup of participants randomized to the high zinc, low-iron MNP; dispersible zinc supplement; and placebo groups. | Measured at enrollment and at the end of the 24-week follow-up period in a subgroup of participants randomized to the high zinc, low-iron MNP, dispersible zinc supplement, and placebo groups. | 
| Change in cellular immune function by leukocyte profiles | To compare the change in cellular immune function by leukocyte profiles, from enrollment to the end of the 24-week follow-up period among a subgroup of participants randomized to the high zinc, low-iron MNP; dispersible zinc supplement; and placebo groups. | Measured at enrollment and at the end of the 24-week follow-up period in a subgroup of participants randomized to the high zinc, low-iron MNP, dispersible zinc supplement, and placebo groups. | 
| Change in serum cytokines | To compare the change in serum cytokines, measured by Luminex analysis, from enrollment to the end of the 24-week follow-up period among a subgroup of participants randomized to the high zinc, low-iron MNP; dispersible zinc supplement; and placebo groups. | Measured at enrollment and at the end of the 24-week follow-up period in a subgroup of participants randomized to the high zinc, low-iron MNP, dispersible zinc supplement, and placebo groups. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Zinc, Multiple micronutrient powders, Diarrhea, Stunting