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

Overview

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.

Full Title of Study: “Randomized, Double-blind, Community-based Efficacy Trial of Various Doses of Zinc in Micronutrient Powders or Tablets in Young, Bangladeshi Children”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Prevention
    • Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: January 12, 2020

Detailed Description

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.

Interventions

  • Dietary Supplement: Standard MNP
    • 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.
  • Dietary Supplement: High zinc, low iron MNP
    • 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.
  • Dietary Supplement: High zinc, low/no iron on alternating days
    • 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.
  • Dietary Supplement: Dispersible zinc supplement
    • 10 mg zinc in a dispersible tablet. Daily supplementation for 24 weeks.
  • Dietary Supplement: Intermittent zinc supplement
    • 10 mg zinc in a dispersible tablet. Daily supplementation for 14 days at baseline and 3 months, placebo tablet on all other days.
  • Dietary Supplement: Placebo powder
    • Daily provision of a placebo powder for 24 weeks.

Arms, Groups and Cohorts

  • Experimental: 1. Standard MNP
  • Experimental: 2. High zinc, low iron MNP
  • Experimental: 3. High zinc, low/no iron
  • Active Comparator: 4. Dispersible zinc supplement
  • Experimental: 5. Intermittent zinc supplement
  • Placebo Comparator: 6. Placebo powder

Clinical Trial Outcome Measures

Primary Measures

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

Secondary Measures

  • Change in stunting prevalence
    • Time Frame: Measured at enrollment and the end of the 24-week follow-up period
    • Change in the prevalence of stunting (LAZ <-2) in the study population over the 24-week follow-up period
  • Change in wasting prevalence
    • Time Frame: Measured at enrollment and at the end of the 24-week follow-up period
    • Change in the prevalence of wasting (WLZ <-2) in the study population over the 24-week follow-up period
  • Incidence of dysentery
    • Time Frame: Measured twice weekly for 24 weeks
    • Dysentery is defined as any diarrheal episode in which the loose or watery stools contain visible red blood
  • Incidence of diarrhea with dehydration
    • Time Frame: Measured twice weekly for 24 weeks
    • Incidence of diarrhea with dehydration over the 24-week follow-up period
  • Incidence of hospitalizations
    • Time Frame: Assessed twice weekly for 24 weeks
    • Hospitalization is defined as an overnight stay in the hospital due to illness
  • Change in mean serum zinc concentration
    • Time Frame: 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 mean serum zinc concentration among children in the biochemistry sub-group over the 24-week follow-up period
  • Change in the prevalence of zinc deficiency
    • Time Frame: 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 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
  • Change in the exchangeable zinc pool size
    • Time Frame: 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 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
  • Change in ferritin concentrations
    • Time Frame: 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 mean concentrations of ferritin from enrollment to the end of the 24-week follow-up period among participants in the biochemistry subgroup.
  • Change in concentrations of soluble transferrin receptor
    • Time Frame: 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 mean concentrations of soluble transferrin receptor from enrollment to the end of the 24-week follow-up period among participants in the biochemistry subgroup.
  • Change in gut microbiota
    • Time Frame: 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 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.
  • Change in amino acid metabolites associated with gut permeability
    • Time Frame: 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.
    • 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.
  • Change in lipid metabolites associated with gut permeability
    • Time Frame: 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.
    • 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.
  • Change in genome wide gene expression by RNA-sequencing
    • Time Frame: 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.
    • 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.
  • Change in specific gene expression by quantitative Polymerase Chain Reaction
    • Time Frame: 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.
    • 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.
  • Change in cellular immune function by leukocyte profiles
    • Time Frame: 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.
    • 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.
  • Change in serum cytokines
    • Time Frame: 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.
    • 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.

Participating in This Clinical Trial

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

Gender Eligibility: All

Minimum Age: 9 Months

Maximum Age: 11 Months

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • UCSF Benioff Children’s Hospital Oakland
  • Collaborator
    • International Centre for Diarrhoeal Disease Research, Bangladesh
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Robert Black, MD, MPH, Principal Investigator, Johns Hopkins Bloomberg School of Public Health

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