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

Study Overview
=================
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.

Official Title
-----------------
Lao Zinc Study: The Effects of Two Forms of Daily Preventive Zinc Supplementation Versus Therapeutic Zinc Supplementation for Diarrhea on Young Children's Physical Growth and Risk of New Episodes of Diarrhea

Conditions
-----------------
Diarrhea

Intervention / Treatment
-----------------
* Dietary Supplement: MNP
* Dietary Supplement: preventive zinc supplement
* Dietary Supplement: therapeutic zinc supplement
* Dietary Supplement: preventive placebo supplement
* Dietary Supplement: therapeutic placebo supplement
* Dietary Supplement: placebo powder


Participation Criteria
=================
Eligibility Criteria
-----------------
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 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

Ages Eligible for Study
-----------------
Minimum Age: 6 Months
Maximum Age: 23 Months

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: micronutrient powder (MNP)<br>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 | Dietary Supplement: MNP<br>* MNP containing 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<br>Dietary Supplement: therapeutic placebo supplement<br>* dispersible placebo tablet for 10 days during diarrhea episodes<br>|
| Placebo Comparator: placebo powder<br>placebo powder plus ORS and therapeutic placebo supplements for diarrhea | Dietary Supplement: therapeutic placebo supplement<br>* dispersible placebo tablet for 10 days during diarrhea episodes<br>Dietary Supplement: placebo powder<br>* placebo powder<br>|
| Active Comparator: preventive zinc supplements<br>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 | Dietary Supplement: preventive zinc supplement<br>* 7 mg zinc daily as dispersible tablet<br>Dietary Supplement: therapeutic placebo supplement<br>* dispersible placebo tablet for 10 days during diarrhea episodes<br>|
| Active Comparator: therapeutic zinc supplements<br>preventive placebo supplements provided as dispersible tablets plus ORS and dispersible therapeutic zinc tablets (containing 20 mg zinc) for diarrhea | Dietary Supplement: therapeutic zinc supplement<br>* 20 mg zinc per day for 10 days during diarrhea episodes, as dispersible tablet<br>Dietary Supplement: preventive placebo supplement<br>* dispersible daily placebo tablet<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in length and length-for-age Z-score |  | 36 weeks | 
| Change in weight and weight-for-age Z-score |  | 36 weeks | 
| Incidence of diarrhea |  | 36 weeks | 
| Change in hemoglobin concentration |  | 32 weeks | 
| Change in micronutrient status | 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 | 32 weeks | 
| Innate and adaptive immune defense | 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 | 32 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in mid-upper circumference |  | 36 weeks | 
| Achievement of gross motor developmental milestones | 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 | after 4, 8, 12, 16, 20, 24, 32 and 36 weeks | 
| Change in stool calprotectin concentration |  | 36 weeks | 
| Change in stool neopterin concentration |  | 36 weeks | 
| Change in hair cortisol concentration |  | 36 weeks | 
| Intestinal protozoa parasite infection | Intestinal protozoan infections will be assessed by a modified formalin-ethyl acetate concentration technique | 36 weeks | 
| Helminths parasite infection | Helminth parasite infections will be assessed using duplicate Kato-Katz thick smears | 36 weeks | 
| Acute and chronic sleep pattern | Assessed by Brief Infant Child Sleep Questionnaire | after 4, 8, 12, 16, 20, 24, 32 and 36 weeks | 
| B-vitamin status | 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) | 36 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
growth, plasma zinc concentration