Micronutrient Dose Response Study in Bangladesh

Study Overview
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Brief Summary
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The recommended daily amounts of vitamins and minerals, referred to as micronutrients, are based on data from high income settings and for healthy populations do not fully correct nutritional deficiencies in undernourished settings. This study will determine the minimum acceptable doses across a range of nutrients at which sufficiency is achieved with supplementation using biochemical indicators of nutritional status in non-pregnant (non-lactating) women of reproductive age and pregnant women in Bangladesh. In this double-masked randomized controlled trial, a dose response study will be undertaken using increasing levels of doses provided as supplements to women (pregnant or non-pregnant) with nutritional indicators as outcomes.

Detailed Description
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The primary aims of the study are to: To characterize the time-course of in vivo exposures (dose response) of several micronutrients in pregnant and non-pregnant and non-lactating women of reproductive age (WRA) in a real-life situation. To characterize any clinically meaningful prognostic factors that can explain the between-subject variability. To investigate whether the micronutrients follow dose-proportional pharmacokinetics.

Official Title
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Micronutrient Dose Response (MiNDR) Study in Bangladesh

Conditions
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Micronutrient Status

Intervention / Treatment
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* Dietary Supplement: Micronutrient Supplement


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Either Women (non-pregnant and non-lactating) and not planning a pregnancy in the next 6 months OR Pregnant women (gestational age at enrollment of 12-14 weeks) Exclusion Criteria: Eligible women not consenting to participate Based on point-of-care clinical indicators after enrollment and prior to starting the intervention that is indicative of pre-existing liver or kidney conditions and severe anemia

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: MNs - Placebo<br>Placebo powder, daily in the form of a powdered flavored drink. Plus, a daily fortified balanced energy and protein food supplement containing 400 kcals and 14 g of protein and 1 recommended daily allowance (RDA) of 18 micronutrients will be given daily including 90 ug of vitamin K, 400 ug of folic acid, 1 mg of copper and 500 mg of calcium | Dietary Supplement: Micronutrient Supplement<br>* A packaged food supplement providing calories and protein and fortified with micronutrients provided at an approximate RDA.<br>* Other names: Balanced Energy and Protein Supplement (BEP);|
| Active Comparator: MNs - Level 1<br>Dose 1 of micronutrients (MNs) listed provided daily in the form of a powdered drink. Micronutrients: Vitamin A -0.355 mg Vitamin D - 0.02 mg Vitamin E - 34 mg Vitamin B1 - 1.4 mg Vitamin B2 - 1.4 mg Vitamin B3 - 17 mg Vitamin B6 - 2.1 mg Vitamin B12 - 0.0034 mg Vitamin C - 20 mg Selenium - 0.035 mg Choline - 550 mg Pantothenic acid - 7mg Biotin - 0.035 mg Potassium - 1000 mg Manganese - 2.6 mg Magnesium - 145 mg Plus, a daily fortified balanced energy and protein supplement containing 400 kcals and 14 g of protein and 1 RDA of 18 micronutrients will be given simultaneously including 90 ug of vitamin K, 400 ug of folic acid, 1 mg of Copper and 500 mg of calcium | Dietary Supplement: Micronutrient Supplement<br>* A packaged food supplement providing calories and protein and fortified with micronutrients provided at an approximate RDA.<br>* Other names: Balanced Energy and Protein Supplement (BEP);|
| Active Comparator: MNs - Level 2<br>Dose 2 of micronutrients listed below provided daily in the form of a powdered flavored drink. Micronutrients: Vitamin A -0.93 mg Vitamin D - 0.04 mg Vitamin E - 109 mg Vitamin B1 - 2.8 mg Vitamin B2 - 2.8 mg Vitamin B3 - 47 mg Vitamin B6 - 4.1 mg Vitamin B12 - 0.0094 mg Vitamin C - 20 mg Iron - 10 mg Zinc - 5 mg Selenium - 0.135 mg Choline - 750 mg Pantothenic acid - 7mg Biotin - 0.035 mg Potassium - 1000 mg Manganese - 2.6 mg Magnesium - 145 mg Plus, a daily fortified balanced energy and protein food supplement containing 400 kcals and 14 g of protein and 1 RDA of 18 micronutrients will be given daily including 90 ug of vitamin K, 400 ug of folic acid, 1 mg of copper and 500 mg of calcium | Dietary Supplement: Micronutrient Supplement<br>* A packaged food supplement providing calories and protein and fortified with micronutrients provided at an approximate RDA.<br>* Other names: Balanced Energy and Protein Supplement (BEP);|
| Active Comparator: MNs - Level 3<br>Dose 3 of micronutrients listed below provided daily in the form of a powdered drink. Micronutrients: Vitamin A - 1.48 mg Vitamin D - 0.06 mg Vitamin E - 184 mg Vitamin B1 - 4.2 mg Vitamin B2 - 4.2 mg Vitamin B3 - 82 mg Vitamin B6 - 8.1 mg Vitamin B12 - 0.0154 mg Vitamin C - 20 mg Iron - 10 mg Zinc - 5 mg Selenium - 0.235 mg Choline - 900 mg Pantothenic acid - 7mg Biotin - 0.035 mg Potassium - 1000 mg Manganese - 2.6 mg Magnesium - 145 mg Plus, a daily fortified balanced energy and protein food supplement containing 400 kcals and 14 g of protein and 1 RDA of 18 micronutrients will be given daily including 90 ug of vitamin K, 400 ug of folic acid, 1 mg of copper and 500 mg of calcium | Dietary Supplement: Micronutrient Supplement<br>* A packaged food supplement providing calories and protein and fortified with micronutrients provided at an approximate RDA.<br>* Other names: Balanced Energy and Protein Supplement (BEP);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in vitamin A status | Plasma retinol (μmol/L), retinyl esters (μmol/L), and serum retinol binding protein (μmol/L) For women in reproductive age, these biomarkers will be measured at baseline, midline (1.5 months), and end-line (3 months). For pregnant women, the biomarkers will be measured at baseline (10-12 weeks of gestation), mid-pregnancy (22 weeks or 30 weeks of gestation), late pregnancy (36 weeks of gestation), and 1 month postpartum. | Baseline, midline, end-line, up to 1 month post-partum (Pregnant women). Baseline, midline, end-line, up to 3 months (non-pregnant women) | 
| Change in vitamin D status | Serum 25(hydroxy)D (nmol/L) For women in reproductive age, these biomarkers will be measured at baseline, midline (1.5 months), and end-line (3 months). For pregnant women, the biomarkers will be measured at baseline (10-12 weeks of gestation), mid-pregnancy (22 weeks or 30 weeks of gestation), late pregnancy (36 weeks of gestation), and 1 month postpartum. | Baseline, midline, end-line, up to 1 month post-partum (Pregnant women). Baseline, midline, end-line, up to 3 months (non-pregnant women) | 
| Change in vitamin E status | Plasma α and γ tocopherol (μmol/L) For women in reproductive age, these biomarkers will be measured at baseline, midline (1.5 months), and end-line (3 months). For pregnant women, the biomarkers will be measured at baseline (10-12 weeks of gestation), mid-pregnancy (22 weeks or 30 weeks of gestation), late pregnancy (36 weeks of gestation), and 1 month postpartum. | Baseline, midline, end-line, up to 1 month post-partum (Pregnant women). Baseline, midline, end-line, up to 3 months (non-pregnant women) | 
| Change in B-vitamin static indicators | Vitamin B12 (plasma homocysteine, methylmalonic acid, and holo-transcobalamin, and serum B12); Folic acid (serum folate, and whole blood folate); Vitamin B1 (urinary B1 excretion), Vitamin B2 (urinary B2 excretion), Vitamin B3 (urinary N-methylnicotinamide and 2-pyridone), Vitamin B6 (plasma pyridoxal 5' phosphate and other B6 vitamers, urinary B6 excretion). All the indicators will be expressed as pg/ml. For women in reproductive age, these biomarkers will be measured at baseline, midline (1.5 months), and end-line (3 months). For pregnant women, the biomarkers will be measured at baseline (10-12 weeks of gestation), mid-pregnancy (22 weeks or 30 weeks of gestation), late pregnancy (36 weeks of gestation), and 1 month postpartum. | Baseline, midline, end-line, up to 1 month post-partum (Pregnant women). Baseline, midline, end-line, up to 3 months (non-pregnant women) | 
| Change in B-vitamin enzymatic activity | Vitamin B1 (erythrocyte transketolase activity), Vitamin B2 (erythrocyte Glutathione reductase activity, urinary B2 excretion), Vitamin B3 (erythrocyte nicotinamide adenine dinucleotide (NAD) and NAD/nicotinamide-adenine dinucleotide phosphate (NADP) ratio. All the indicators will be presented as ratio or activity coefficient. For women in reproductive age, these biomarkers will be measured at baseline, midline (1.5 months), and end-line (3 months). For pregnant women, the biomarkers will be measured at baseline (10-12 weeks of gestation), mid-pregnancy (22 weeks or 30 weeks of gestation), late pregnancy (36 weeks of gestation), and 1 month postpartum. | Baseline, midline, end-line, up to 1 month post-partum (Pregnant women). Baseline, midline, end-line, up to 3 months (non-pregnant women) | 
| Change in iron status | Serum ferritin and soluble transferrin receptor (μg/L) For women in reproductive age, these biomarkers will be measured at baseline, midline (1.5 months), and end-line (3 months). For pregnant women, the biomarkers will be measured at baseline (10-12 weeks of gestation), mid-pregnancy (22 weeks or 30 weeks of gestation), late pregnancy (36 weeks of gestation), and 1 month postpartum. | Baseline, midline, end-line, up to 1 month post-partum (Pregnant women). Baseline, midline, end-line, up to 3 months (non-pregnant women) | 
| Change in iodine status | Urinary iodine (μg/L), and thyroglobulin (μg/L) For women in reproductive age, these biomarkers will be measured at baseline, midline (1.5 months), and end-line (3 months). For pregnant women, the biomarkers will be measured at baseline (10-12 weeks of gestation), mid-pregnancy (22 weeks or 30 weeks of gestation), late pregnancy (36 weeks of gestation), and 1 month postpartum. | Baseline, midline, end-line, up to 1 month post-partum (Pregnant women). Baseline, midline, end-line, up to 3 months (non-pregnant women) | 
| Change in selenium static indicator | Serum selenium (μg/L) For women in reproductive age, these biomarkers will be measured at baseline, midline (1.5 months), and end-line (3 months). For pregnant women, the biomarkers will be measured at baseline (10-12 weeks of gestation), mid-pregnancy (22 weeks or 30 weeks of gestation), late pregnancy (36 weeks of gestation), and 1 month postpartum. | Baseline, midline, end-line, up to 1 month post-partum (Pregnant women). Baseline, midline, end-line, up to 3 months (non-pregnant women) | 
| Change in selenium enzymatic indicator | Plasma Glutathione peroxidase-3 (U/L) For women in reproductive age, these biomarkers will be measured at baseline, midline (1.5 months), and end-line (3 months). For pregnant women, the biomarkers will be measured at baseline (10-12 weeks of gestation), mid-pregnancy (22 weeks or 30 weeks of gestation), late pregnancy (36 weeks of gestation), and 1 month postpartum. | Baseline, midline, end-line, up to 1 month post-partum (Pregnant women). Baseline, midline, end-line, up to 3 months (non-pregnant women) | 
| Change in zinc status | Serum Zinc (μg/L) For women in reproductive age, these biomarkers will be measured at baseline, midline (1.5 months), and end-line (3 months). For pregnant women, the biomarkers will be measured at baseline (10-12 weeks of gestation), mid-pregnancy (22 weeks or 30 weeks of gestation), late pregnancy (36 weeks of gestation), and 1 month postpartum. | Baseline, midline, end-line, up to 1 month post-partum (Pregnant women). Baseline, midline, end-line, up to 3 months (non-pregnant women) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in inflammation | Serum Alpha glycoprotein (AGP) and plasma C-reactive protein (CRP). These will be expressed as mg/L. For women in reproductive age, these biomarkers will be measured at baseline, midline (1.5 months), and end-line (3 months). For pregnant women, the biomarkers will be measured at baseline (10-12 weeks of gestation), mid-pregnancy (22 weeks or 30 weeks of gestation), late pregnancy (36 weeks of gestation), and 1 month postpartum. | Baseline, midline, end-line, up to 1 month post-partum (Pregnant women). Baseline, midline, end-line, up to 3 months (non-pregnant women) | 
| Change in hormonal markers | Plasma hepcidin (μg/L), erythropoietin (μg/L), and serum parathyroid hormone (μg/L) For women in reproductive age, these biomarkers will be measured at baseline, midline (1.5 months), and end-line (3 months). For pregnant women, the biomarkers will be measured at baseline (10-12 weeks of gestation), mid-pregnancy (22 weeks or 30 weeks of gestation), late pregnancy (36 weeks of gestation), and 1 month postpartum. | Baseline, midline, end-line, up to 1 month post-partum (Pregnant women). Baseline, midline, end-line, up to 3 months (non-pregnant women) | 
| Change in clinical markers of liver enzymes | Plasma alanine transaminase (U/L), and Aspartate aminotransferase (U/L) For women in reproductive age, these biomarkers will be measured at baseline, midline (1.5 months), and end-line (3 months). For pregnant women, the biomarkers will be measured at baseline (10-12 weeks of gestation), mid-pregnancy (22 weeks or 30 weeks of gestation), late pregnancy (36 weeks of gestation), and 1 month postpartum. | Baseline, midline, end-line, up to 1 month post-partum (Pregnant women). Baseline, midline, end-line, up to 3 months (non-pregnant women) | 
| Change in clinical markers of lipid profile | Plasma triglyceride, total cholesterol, high density lipoprotein, low density lipoprotein. These will be expressed as mg/dL. For women in reproductive age, these biomarkers will be measured at baseline, midline (1.5 months), and end-line (3 months). For pregnant women, the biomarkers will be measured at baseline (10-12 weeks of gestation), mid-pregnancy (22 weeks or 30 weeks of gestation), late pregnancy (36 weeks of gestation), and 1 month postpartum. | Baseline, midline, end-line, up to 1 month post-partum (Pregnant women). Baseline, midline, end-line, up to 3 months (non-pregnant women) | 
| Change in clinical markers of renal function | Plasma creatinine (mg/dL), and blood urea nitrogen (mg/dL) For women in reproductive age, these biomarkers will be measured at baseline, midline (1.5 months), and end-line (3 months). For pregnant women, the biomarkers will be measured at baseline (10-12 weeks of gestation), mid-pregnancy (22 weeks or 30 weeks of gestation), late pregnancy (36 weeks of gestation), and 1 month postpartum. | Baseline, midline, end-line, up to 1 month post-partum (Pregnant women). Baseline, midline, end-line, up to 3 months (non-pregnant women) | 
| Change in clinical markers of electrolytes | Plasma sodium, calcium, potassium, and chloride. These will be expressed as mmol/L. For women in reproductive age, these biomarkers will be measured at baseline, midline (1.5 months), and end-line (3 months). For pregnant women, the biomarkers will be measured at baseline (10-12 weeks of gestation), mid-pregnancy (22 weeks or 30 weeks of gestation), late pregnancy (36 weeks of gestation), and 1 month postpartum. | Baseline, midline, end-line, up to 1 month post-partum (Pregnant women). Baseline, midline, end-line, up to 3 months (non-pregnant women) | 
| Change in glucose | Plasma glucose (mg/dL) For women in reproductive age, these biomarkers will be measured at baseline, midline (1.5 months), and end-line (3 months). For pregnant women, the biomarkers will be measured at baseline (10-12 weeks of gestation), mid-pregnancy (22 weeks or 30 weeks of gestation), late pregnancy (36 weeks of gestation), and 1 month postpartum. | Baseline, midline, end-line, up to 1 month post-partum (Pregnant women). Baseline, midline, end-line, up to 3 months (non-pregnant women) | 
| Change in hemoglobin | Whole blood hemoglobin (g/L) For women in reproductive age, these biomarkers will be measured at baseline, midline (1.5 months), and end-line (3 months). For pregnant women, the biomarkers will be measured at baseline (10-12 weeks of gestation), mid-pregnancy (22 weeks or 30 weeks of gestation), late pregnancy (36 weeks of gestation), and 1 month postpartum. | Baseline, midline, end-line, up to 1 month post-partum (Pregnant women). Baseline, midline, end-line, up to 3 months (non-pregnant women) | 
| Change in serum minerals | Serum copper, manganese, magnesium, phosphorus, and iron. These will be expressed as μg/L. For women in reproductive age, these biomarkers will be measured at baseline, midline (1.5 months), and end-line (3 months). For pregnant women, the biomarkers will be measured at baseline (10-12 weeks of gestation), mid-pregnancy (22 weeks or 30 weeks of gestation), late pregnancy (36 weeks of gestation), and 1 month postpartum. | Baseline, midline, end-line, up to 1 month post-partum (Pregnant women). Baseline, midline, end-line, up to 3 months (non-pregnant women) | 
| Change in bone turnover biomarker | Pyrilinks-D urine test (nmol/L) For women in reproductive age, these biomarkers will be measured at baseline, midline (1.5 months), and end-line (3 months). For pregnant women, the biomarkers will be measured at baseline (10-12 weeks of gestation), mid-pregnancy (22 weeks or 30 weeks of gestation), late pregnancy (36 weeks of gestation), and 1 month postpartum. | Baseline, midline, end-line, up to 1 month post-partum (Pregnant women). Baseline, midline, end-line, up to 3 months (non-pregnant women) | 
| Change in urinary metabolite of vitamin E | Urinary alpha-carboxy ethyl hydroxy chromanol (nmol/L) will be measured only in pregnancy. For pregnant women, the biomarkers will be measured at baseline (10-12 weeks of gestation), mid-pregnancy (22 weeks or 30 weeks of gestation), late pregnancy (36 weeks of gestation), and 1 month postpartum. | Baseline, midline, end-line, up to 1 month post-partum (Pregnant women). Baseline, midline, end-line, up to 3 months (non-pregnant women) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Biochemical indicators, protein, Pregnancy, Micronutrients, Energy, Supplements