Diarrhea
Conditions
Keywords
growth, plasma zinc concentration
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.
Interventions
DIETARY_SUPPLEMENTMNP
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
DIETARY_SUPPLEMENTpreventive zinc supplement
7 mg zinc daily as dispersible tablet
DIETARY_SUPPLEMENTtherapeutic zinc supplement
20 mg zinc per day for 10 days during diarrhea episodes, as dispersible tablet
DIETARY_SUPPLEMENTpreventive placebo supplement
dispersible daily placebo tablet
DIETARY_SUPPLEMENTtherapeutic placebo supplement
dispersible placebo tablet for 10 days during diarrhea episodes
DIETARY_SUPPLEMENTplacebo powder
placebo powder
Sponsors
Lao Tropical and Public Health Institute, Lao PDR
USDA, Western Human Nutrition Research Center
University of British Columbia
Khon Kaen University
Nutrition International
The Mathile Institute for the Advancement of Human Nutrition
University of California, Davis
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
6 Months to 23 Months
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 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 |
| 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 | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Intestinal protozoa parasite infection | 36 weeks | Intestinal protozoan infections will be assessed by a modified formalin-ethyl acetate concentration technique |
| Acute and chronic sleep pattern | after 4, 8, 12, 16, 20, 24, 32 and 36 weeks | Assessed by Brief Infant Child Sleep Questionnaire |
| 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) |
| Helminths parasite infection | 36 weeks | Helminth parasite infections will be assessed using duplicate Kato-Katz thick smears |
| Change in hair cortisol concentration | 36 weeks | — |
| Change in mid-upper circumference | 36 weeks | — |
| 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 stool calprotectin concentration | 36 weeks | — |
| Change in stool neopterin concentration | 36 weeks | — |
Other
| Measure | Time frame | Description |
|---|---|---|
| Incidence of serious adverse events | 36 weeks | Serious adverse events, including death and required overnight stay in a health facility |
| Incidence of any non-serious adverse events | 36 weeks | non-serious adverse events that may be detected retrospectively, such as the incidence of diarrhea, vomiting, etc., based on the results of morbidity surveillance |
Countries
Laos
Outcome results
None listed