Clinical trial NCT02428647: Lao Zinc Study: Effects of Two Forms of Daily Preventive Zinc Versus Therapeutic Zinc Supplementation
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Diarrhea
Keywords: growth
plasma zinc concentration
Lead sponsor: University of California, Davis
Sponsor class: OTHER
Collaborators: name: Lao Tropical and Public Health Institute, Lao PDR
name: USDA, Western Human Nutrition Research Center
name: University of British Columbia
name: Khon Kaen University
name: Nutrition International
name: The Mathile Institute for the Advancement of Human Nutrition
First posted: 2015-04-29
Enrollment: 3433
Sex: ALL
Minimum age (years): 6
Maximum age (years): 23
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

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

Primary outcomes:
measure: Change in length and length-for-age Z-score
timeFrame: 36 weeks
measure: Change in weight and weight-for-age Z-score
timeFrame: 36 weeks
measure: Incidence of diarrhea
timeFrame: 36 weeks
measure: Change in hemoglobin concentration
timeFrame: 32 weeks
measure: Change in micronutrient status
timeFrame: 32 weeks
measure: Innate and adaptive immune defense
timeFrame: 32 weeks
Secondary outcomes:
measure: Change in mid-upper circumference
timeFrame: 36 weeks
measure: Achievement of gross motor developmental milestones
timeFrame: after 4, 8, 12, 16, 20, 24, 32 and 36 weeks
measure: Change in stool calprotectin concentration
timeFrame: 36 weeks
measure: Change in stool neopterin concentration
timeFrame: 36 weeks
measure: Change in hair cortisol concentration
timeFrame: 36 weeks
measure: Intestinal protozoa parasite infection
timeFrame: 36 weeks
measure: Helminths parasite infection
timeFrame: 36 weeks
measure: Acute and chronic sleep pattern
timeFrame: after 4, 8, 12, 16, 20, 24, 32 and 36 weeks
measure: B-vitamin status
timeFrame: 36 weeks
Other outcomes:
measure: Incidence of serious adverse events
timeFrame: 36 weeks
measure: Incidence of any non-serious adverse events
timeFrame: 36 weeks
Locations:
city: Vientiane
country: Lao People's Democratic Republic
facility: Lao Tropical and Public Health Institute
Study officials:
affiliation: University of California, Davis
name: Sonja Y Hess, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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: 10.1177/0379572117742502. Epub 2017 Dec 19.
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 Jun;71(6):532-538. doi: 10.1136/jclinpath-2017-204786. Epub 2017 Dec 2.
citation: Kingchaiyaphum B, Sanchaisuriya K, Fucharoen G, Chaibunruang A, Hess SY, Hinnouho GM, Barffour MA, Wessells KR, Kounnavong S, Fucharoen S. Hemoglobins F, A2 , and E levels in Laotian children aged 6-23 months with Hb E disorders: Effect of age, sex, and thalassemia types. Int J Lab Hematol. 2020 Jun;42(3):277-283. doi: 10.1111/ijlh.13164. Epub 2020 Feb 12.
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 Environmental Enteric Dysfunction among Rural Laotian Children: A Randomized Controlled Trial. Am J Trop Med Hyg. 2020 Feb;102(2):415-426. doi: 10.4269/ajtmh.19-0584.
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 young Lao children in a double-blind randomised trial. Br J Nutr. 2019 Oct 28;122(8):895-909. doi: 10.1017/S0007114519001715.
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 Laotian Children: A Randomized Controlled Trial. Nutrients. 2018 Dec 27;11(1):47. doi: 10.3390/nu11010047.
citation: 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 Diarrhea Prevention on Physical Growth, Anemia, and Micronutrient Status in Rural Laotian Children: A Randomized Controlled Trial. J Pediatr. 2019 Apr;207:80-89.e2. doi: 10.1016/j.jpeds.2018.11.022. Epub 2018 Dec 21.
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: a Randomized Controlled Trial. Biol Trace Elem Res. 2021 Feb;199(2):442-452. doi: 10.1007/s12011-020-02163-2. Epub 2020 Apr 30.
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 Controlled Trial. Am J Trop Med Hyg. 2020 Oct;103(4):1416-1426. doi: 10.4269/ajtmh.20-0106.
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 supplementation regimens on the incidence and duration of diarrhea and acute respiratory tract infections in rural Laotian children: A randomized controlled trial. J Glob Health. 2020 Jun;10(1):010424. doi: 10.7189/jogh.10.010424.
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 Concentrations in Rural Laotian Children from Communities with a High Prevalence of Zinc Deficiency: Results of a Randomized Controlled Trial. J Nutr. 2020 Aug 1;150(8):2204-2213. doi: 10.1093/jn/nxaa037.
citation: Kewcharoenwong C, Sein MM, Nithichanon A, Khongmee A, Wessells KR, Hinnouho GM, Barffour MA, Kounnavong S, Hess SY, Stephensen CB, Lertmemongkolchai G. Daily preventive zinc supplementation increases the antibody response against pathogenic Escherichia coli in children with zinc insufficiency: a randomised controlled trial. Sci Rep. 2022 Sep 27;12(1):16084. doi: 10.1038/s41598-022-20445-8.
citation: Hinnouho GM, Hampel D, Shahab-Ferdows S, Barffour MA, McAnena L, Arnold CD, Ryan Wessells K, Kounnavong S, Allen LH, McNulty H, Hess SY. Daily supplementation of a multiple micronutrient powder improves folate but not thiamine, riboflavin, or vitamin B12 status among young Laotian children: a randomized controlled trial. Eur J Nutr. 2022 Oct;61(7):3423-3435. doi: 10.1007/s00394-022-02890-3. Epub 2022 May 9.