Lao Zinc Study: Effects of Two Forms of Daily Preventive Zinc Versus Therapeutic Zinc Supplementation

Not Applicable

Completed

• Conditions: Diarrhea
• Interventions: Dietary Supplement: therapeutic placebo supplement; Dietary Supplement: preventive zinc supplement; Dietary Supplement: MNP; Dietary Supplement: therapeutic zinc supplement; Dietary Supplement: placebo powder; Dietary Supplement: preventive placebo supplement

• Registration Number: NCT02428647
• Lead Sponsor: University of California, Davis

Brief Summary

The study will be conducted as a community-based, randomized, placebo-controlled, trial with four study groups. The overall objective of the study is to determine the optimal method for delivering zinc to young children, both for the prevention of zinc deficiency and treatment of diarrhea. In particular, the investigators plan to compare the impact on physical growth, morbidity, micronutrient status, immune function, environmental enteric dysfunction, parasite burden and hair cortisol concentration of: 1) daily preventive zinc supplementation as a micronutrient powder (MNP); 2) placebo powders; 3) daily preventive zinc supplementation as dispersible tablets; 4) therapeutic zinc supplementation as dispersible tablets given in relation to episodes of diarrhea.

In addition to the major outcomes mentioned above, the investigators will monitor adherence to the interventions, neuro-behavioral development, and the occurrence of any adverse events.

Detailed Description

Zinc is an essential nutrient that is required for children's normal growth and resistance to infections, including diarrhea and pneumonia, two major causes of child mortality. Current strategies for controlling the growth and infection-related complications of zinc deficiency include: 1) daily or weekly preventive zinc supplementation, and 2) therapeutic zinc supplementation for 10-14 days in relation to episodes of diarrhea. Information is needed on the relative impact of these intervention strategies on children's growth and risk of new episodes of diarrhea (and other infections).

Preventive zinc supplements can be delivered either as a single nutrient (zinc) supplement or as a multiple micronutrient (MMN) supplement, such as micronutrient powders (MNP) added to young children's complementary food. Available research indicates that zinc delivered in MNP at the currently recommended dose (4.1-5 mg/d) has not had a measurable impact on zinc-related functional outcomes, like growth and prevention of infection. Moreover, some studies of MMN supplements have detected a greater incidence of diarrhea in the MMN group than in the non-intervention or placebo control groups. Thus, despite the beneficial effects of MNP on prevention of anemia and enhancing iron status, questions have been raised about the desirability of providing zinc in MNP (containing iron and other nutrients) versus a single nutrient formulation offered between meals. For these reasons, the present study is designed to compare both the zinc delivery plan (i.e., preventive versus therapeutic supplementation) as well as the form of delivering zinc (i.e., as a dispersible tablet given between meals or as a MNP given with meals) and to permit assessment of any adverse effects of MNP on the incidence of diarrhea.

The study will be conducted as a community-based, randomized, placebo-controlled trial with four study groups in rural communities of Khammouane Province in Central Lao PDR.

The project team will enroll a total of \~3,400 children whose ages will range from 6-23 months. Children will be randomly assigned to one of four study group: 1) preventive zinc supplementation provided as LI-MNP plus ORS and placebo tablets for treatment of diarrhea; 2) placebo preventive supplementation provided as placebo powder plus ORS and placebo tablets for diarrhea ; 3) preventive zinc supplementation provided as dispersible zinc tablets (containing 7 mg zinc, to be given between meals) plus ORS and placebo tablets for diarrhea; and 4) therapeutic zinc supplementation provided as dispersible tablets (containing 20 mg zinc) for diarrhea plus ORS and placebo preventive tablets.

The major outcomes that will be monitored include adherence to the interventions; physical growth; incidence, duration and severity of episodes of diarrhea; changes in MN status; immune function; environmental enteric dysfunction; parasite burden; hair cortisol concentration; neuro-behavioral development; and the occurrence of any adverse events.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2015-02-09
• Study First Submitted QC: 2015-04-28
• Study First Posted: 2015-04-29
• Study Start: 2015-09
• Primary Completion: 2017-05
• Study Completion: 2017-07
• Status Verified: 2022-01
• Last Update Submitted: 2022-01-04
• Last Update Posted: 2022-01-20

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 3433

Inclusion Criteria

• Signed informed consent from at least one parent or primary caregiver
• Age 6-23 months initially
• Permanent resident of study area
• Planned availability during the period of the study
• Acceptance of home visitors

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Exclusion Criteria

• Weight-for-height z-score (WHZ) <-3Z with respect to WHO 2006 standards
• Presence of bipedal edema
• Severe illness warranting hospital referral
• Congenital abnormalities potentially interfering with growth
• Chronic medical condition (e.g. malignancy) requiring frequent medical attention
• Known HIV infection of index child or child's mother
• Hemoglobin <70 g/L
• Currently consuming zinc supplements
• Current participation in any other clinical trial

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
placebo powder	therapeutic placebo supplement	placebo powder plus ORS and therapeutic placebo supplements for diarrhea
preventive zinc supplements	preventive zinc supplement	preventive zinc supplements provided as dispersible zinc tablets (containing 7 mg zinc, to be given between meals) plus ORS and therapeutic placebo supplements for diarrhea
placebo powder	placebo powder	placebo powder plus ORS and therapeutic placebo supplements for diarrhea
micronutrient powder (MNP)	MNP	preventive zinc supplements provided as MNP (containing 10 mg zinc and 14 other nutrients, including 6 mg iron, 0.56 mg copper, 17 μg selenium, 90 μg iodine, 400 μg RE vitamin A, 5 μg vitamin D, 5 mg vitamin E, 30 mg ascorbic acid, 0.5 mg vitamin B1, 0.5 mg vitamin B2, 6 mg niacin, 0.5 mg vitamin B6, 0.9 μg vitamin B12, and 150 μg folate,) plus ORS and therapeutic placebo supplements for diarrhea
micronutrient powder (MNP)	therapeutic placebo supplement	preventive zinc supplements provided as MNP (containing 10 mg zinc and 14 other nutrients, including 6 mg iron, 0.56 mg copper, 17 μg selenium, 90 μg iodine, 400 μg RE vitamin A, 5 μg vitamin D, 5 mg vitamin E, 30 mg ascorbic acid, 0.5 mg vitamin B1, 0.5 mg vitamin B2, 6 mg niacin, 0.5 mg vitamin B6, 0.9 μg vitamin B12, and 150 μg folate,) plus ORS and therapeutic placebo supplements for diarrhea
therapeutic zinc supplements	therapeutic zinc supplement	preventive placebo supplements provided as dispersible tablets plus ORS and dispersible therapeutic zinc tablets (containing 20 mg zinc) for diarrhea
therapeutic zinc supplements	preventive placebo supplement	preventive placebo supplements provided as dispersible tablets plus ORS and dispersible therapeutic zinc tablets (containing 20 mg zinc) for diarrhea
preventive zinc supplements	therapeutic placebo supplement	preventive zinc supplements provided as dispersible zinc tablets (containing 7 mg zinc, to be given between meals) plus ORS and therapeutic placebo supplements for diarrhea

Primary Outcome Measures

Name	Time	Method
Change in length and length-for-age Z-score	36 weeks
Innate and adaptive immune defense	32 weeks	production of cytokines by cultures of peripheral blood white blood cells; and change in concentrations of naïve and memory CD4 and CD8 T-cells and regulatory (Treg) T-cells in a sub-set of 500 children
Change in weight and weight-for-age Z-score	36 weeks
Change in hemoglobin concentration	32 weeks
Incidence of diarrhea	36 weeks
Change in micronutrient status	32 weeks	plasma zinc, ferritin, transferrin receptor; and retinol binding protein (RBP) concentrations, measured in a subsample of 560 participants, and controlling for the presence of elevated acute phase protein

Secondary Outcome Measures

Name	Time	Method
Change in stool calprotectin concentration	36 weeks
Helminths parasite infection	36 weeks	Helminth parasite infections will be assessed using duplicate Kato-Katz thick smears
Change in mid-upper circumference	36 weeks
Intestinal protozoa parasite infection	36 weeks	Intestinal protozoan infections will be assessed by a modified formalin-ethyl acetate concentration technique
Achievement of gross motor developmental milestones	after 4, 8, 12, 16, 20, 24, 32 and 36 weeks	Gross motor developmental milestones as recommended by the World Health Organization include: sitting without support, crawling, standing with assistance, walking with assistance, standing alone, walking alone
Change in hair cortisol concentration	36 weeks
B-vitamin status	36 weeks	erythrocyte thiamine diphosphate, plasma folate and B12 concentrations and erythrocyte glutathione reductase activation coefficient (EGRac) measured in a randomly selected sub-sample of 260 children (MNP and control group only)
Change in stool neopterin concentration	36 weeks
Acute and chronic sleep pattern	after 4, 8, 12, 16, 20, 24, 32 and 36 weeks	Assessed by Brief Infant Child Sleep Questionnaire

Trial Locations

Locations (1)

Lao Tropical and Public Health Institute; 🇱🇦 Vientiane, Lao People's Democratic Republic