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

Diarrhea Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02428647
• Other study ID #: 626187
• Secondary ID: 10-1347-UCALIF-0
• Status: Completed
• Phase: N/A
• Start date: September 2015
• Est. completion date: July 2017

Study information

• Verified date: January 2022
• Source: University of California, Davis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 3433
• Est. completion date: July 2017
• Est. primary completion date: May 2017
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 6 Months to 23 Months

Eligibility

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

Related Conditions & MeSH terms

• Diarrhea

Intervention

Dietary Supplement:
• MNP
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
• preventive zinc supplement
7 mg zinc daily as dispersible tablet
• therapeutic zinc supplement
20 mg zinc per day for 10 days during diarrhea episodes, as dispersible tablet
• preventive placebo supplement
dispersible daily placebo tablet
• therapeutic placebo supplement
dispersible placebo tablet for 10 days during diarrhea episodes
• placebo powder
placebo powder

Locations

Country	Name	City	State
Lao People's Democratic Republic	Lao Tropical and Public Health Institute	Vientiane

Sponsors (7)

Lead Sponsor	Collaborator
University of California, Davis	Khon Kaen University, Lao Tropical and Public Health Institute, Lao PDR, Nutrition International, The Mathile Institute for the Advancement of Human Nutrition, University of British Columbia, USDA, Western Human Nutrition Research Center

Country where clinical trial is conducted

Lao People's Democratic Republic, 

References & Publications (12)

Barffour MA, Hinnouho GM, Kounnavong S, Wessells KR, Ratsavong K, Bounheuang B, Chanhthavong B, Sitthideth D, Sengnam K, Arnold CD, Brown KH, Hess SY. Effects of Daily Zinc, Daily Multiple Micronutrient Powder, or Therapeutic Zinc Supplementation for Diar — View Citation

Barffour MA, Hinnouho GM, Wessells KR, Kounnavong S, Ratsavong K, Sitthideth D, Bounheuang B, Sengnam K, Chanhthavong B, Arnold CD, Brown KH, Larson CP, Hess SY. Effects of therapeutic zinc supplementation for diarrhea and two preventive zinc supplementat — View Citation

Hess SY, Hinnouho GM, Barffour MA, Bounheuang B, Arnold CD, Bell D, Marts TH, Kounnavong S. First Field Test of an Innovative, Wider Tape to Measure Mid-Upper Arm Circumference in Young Laotian Children. Food Nutr Bull. 2018 Mar;39(1):28-38. doi: 10.1177/ — View Citation

Hess SY, Wessells KR, Hinnouho GM, Barffour MA, Sanchaisuriya K, Arnold CD, Brown KH, Larson CP, Fucharoen S, Kounnavong S. Iron status and inherited haemoglobin disorders modify the effects of micronutrient powders on linear growth and morbidity among yo — View Citation

Hinnouho GM, Barffour MA, Wessells KR, Brown KH, Kounnavong S, Chanhthavong B, Ratsavong K, Kewcharoenwong C, Hess SY. Comparison of haemoglobin assessments by HemoCue and two automated haematology analysers in young Laotian children. J Clin Pathol. 2018 — View Citation

Hinnouho GM, Bernstein RM, Barffour MA, Arnold CD, Wessells KR, Ratsavong K, Bounheuang B, Kounnavong S, Hess SY. Impact of Two Forms of Daily Preventive Zinc or Therapeutic Zinc Supplementation for Diarrhea on Hair Cortisol Concentrations Among Rural Lao — View Citation

Hinnouho GM, Wessells KR, Barffour MA, Sayasone S, Arnold CD, Kounnavong S, Hess SY. Impact of Different Strategies for Delivering Supplemental Zinc on Selected Fecal Markers of Environmental Enteric Dysfunction among Young Laotian Children: A Randomized — View Citation

Kewcharoenwong C, Schuster GU, Wessells KR, Hinnouho GM, Barffour MA, Kounnavong S, Brown KH, Hess SY, Samer W, Tussakhon I, Peerson JM, Lertmemongkolchai G, Stephensen CB. Daily Preventive Zinc Supplementation Decreases Lymphocyte and Eosinophil Concentr — View Citation

Kingchaiyaphum B, Sanchaisuriya K, Fucharoen G, Chaibunruang A, Hess SY, Hinnouho GM, Barffour MA, Wessells KR, Kounnavong S, Fucharoen S. Hemoglobins F, A(2) , and E levels in Laotian children aged 6-23 months with Hb E disorders: Effect of age, sex, and — View Citation

Wessells KR, Brown KH, Arnold CD, Barffour MA, Hinnouho GM, Killilea DW, Kounnavong S, Hess SY. Plasma and Nail Zinc Concentrations, But Not Hair Zinc, Respond Positively to Two Different Forms of Preventive Zinc Supplementation in Young Laotian Children: — View Citation

Wessells KR, Brown KH, Kounnavong S, Barffour MA, Hinnouho GM, Sayasone S, Stephensen CB, Ratsavong K, Larson CP, Arnold CD, Harding KB, Reinhart GA, Lertmemongkolchai G, Fucharoen S, Bernstein RM, Hess SY. Comparison of two forms of daily preventive zinc supplementation versus therapeutic zinc supplementation for diarrhea on young children's physical growth and risk of infection: study design and rationale for a randomized controlled trial. BMC Nutr. 2018 Nov 29;4:39. doi: 10.1186/s40795-018-0247-6. eCollection 2018. — View Citation

Wessells KR, Hinnouho GM, Barffour MA, Arnold CD, Kounnavong S, Kewcharoenwong C, Lertmemongkolchai G, Schuster GU, Stephensen CB, Hess SY. Impact of Daily Preventive Zinc or Therapeutic Zinc Supplementation for Diarrhea on Plasma Biomarkers of Environmen — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Incidence of serious adverse events	Serious adverse events, including death and required overnight stay in a health facility	36 weeks
Other	Incidence of any non-serious adverse events	non-serious adverse events that may be detected retrospectively, such as the incidence of diarrhea, vomiting, etc., based on the results of morbidity surveillance	36 weeks
Primary	Change in length and length-for-age Z-score		36 weeks
Primary	Change in weight and weight-for-age Z-score		36 weeks
Primary	Incidence of diarrhea		36 weeks
Primary	Change in hemoglobin concentration		32 weeks
Primary	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
Primary	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	Change in mid-upper circumference		36 weeks
Secondary	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
Secondary	Change in stool calprotectin concentration		36 weeks
Secondary	Change in stool neopterin concentration		36 weeks
Secondary	Change in hair cortisol concentration		36 weeks
Secondary	Intestinal protozoa parasite infection	Intestinal protozoan infections will be assessed by a modified formalin-ethyl acetate concentration technique	36 weeks
Secondary	Helminths parasite infection	Helminth parasite infections will be assessed using duplicate Kato-Katz thick smears	36 weeks
Secondary	Acute and chronic sleep pattern	Assessed by Brief Infant Child Sleep Questionnaire	after 4, 8, 12, 16, 20, 24, 32 and 36 weeks
Secondary	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