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| ID | Type | Description | Link |
|---|---|---|---|
| IRB00022171 | Other Identifier | JHSPH IRB |
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| Name | Class |
|---|---|
| International Centre for Diarrhoeal Disease Research, Bangladesh | OTHER |
| Bill and Melinda Gates Foundation | OTHER |
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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.
The primary aims of the study are to:
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| MNs - Placebo | Placebo Comparator | 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 |
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| MNs - Level 1 | Active Comparator | 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 |
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| MNs - Level 2 | Active Comparator | 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 |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Micronutrient Supplement | Dietary Supplement | A packaged food supplement providing calories and protein and fortified with micronutrients provided at an approximate RDA. |
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| 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. |
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Number of participants with side effects | We will report the number of participants who experience any of the following side effects; Nausea, vomiting, fatigue, headache, hemorrhage, blurred vision, rash, tingling sensation in the extremities, brittleness of nail/hair, dark stool or fishy body odor. | Weekly from enrollment up to 1 month postpartum for pregnant women. Weekly from enrollment up to 3 months for non-pregnant women |
Inclusion Criteria:
Either
OR
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Parul Chrisian, DrPH | Johns Hopkins Bloomberg School of Public Health | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| JiVitA Project | Rangpur City | Bangladesh |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 39755576 | Derived | Siddiqua TJ, Schulze KJ, Hasan ST, Ahsan KB, Bandyopadhyay S, Zavala E, Ali H, Haque R, Sujan HM, Rahman MH, Baker S, Stephenson KK, Ge X, Gough EK, Langevin B, Wu LSF, Dyer B, Roy AK, Jubair M, Nishan AA, Rosenblum M, Gopalakrishnan M, Kraemer K, Erchick DJ, Ahmed T, Christian P. Micronutrient dose response (MiNDR) study among women of reproductive age and pregnant women in rural Bangladesh: study protocol for double-blind, randomised, controlled trials. BMJ Open. 2025 Jan 4;15(1):e090108. doi: 10.1136/bmjopen-2024-090108. |
| Label | URL |
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| Trial protocol | View source |
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| MNs - Level 3 | Active Comparator | 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 |
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| 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) |
| 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) |
| Breastmilk Vitamin A concentration | Retinol and retinyl esters will be measured by ultra-performance liquid chromatography (UPLC). These will be expressed as μg/L. | 1 month postpartum |
| Breastmilk Vitamin E concentration | Plasma α and γ tocopherol will be measured by ultra-performance liquid chromatography (UPLC). These will be expressed as μg/L. | 1 month postpartum |
| Breastmilk B vitamin concentration | Vitamin B12, Vitamin B1, B2 and B6 vitamers will be measured by ultra-performance liquid chromatography (UPLC). These will be expressed as μg/L. | 1 month postpartum |
| Breastmilk mineral concentration | Zinc, selenium, copper, manganese, magnesium, phosphorus will be measured by Inductively coupled plasma mass spectrometry (ICP-MS). These will be expressed as μg/L. | 1 month postpartum |
| Change in gut microbiome composition | Measured by changes in bacterial 16S ribosomal ribonucleic acid gene sequencing (16S RNA) and multigenomic sequencing For women in reproductive age, gut microbiome composition will be measured at baseline, and end-line (3 months). For pregnant women, gut microbiome composition will be measured at baseline (10-12 weeks of gestation), and late pregnancy (36 weeks of gestation). | Baseline, end-line up to 36 wks of gestation in pregnancy (Pregnant women). Baseline, end-line up to 3 months (non-pregnant women) |
| Frequency of neonatal deaths across study arms | Number of deaths between 0-28 days | Birth to 28 days of life |
| Frequency of stillbirths across study arms | Number of stillbirths | At birth |
| Frequency of low birth weight infants across study arms | Low birth weight will be defined as birth weight (within <72 h) less than 2500 g | At birth |
| Frequency of preterm birth across study arms | Preterm birth will be defined as babies born alive before 37 weeks of pregnancy are completed | At birth |
| Frequency of gross congenital defects across study arms | Any congenital gross malformations at birth that can be identified by physical examination | At birth |
| Frequency of neonatal morbidity across study arms | Will report number of infants experiencing any of the following; fever, cough, cold, difficulty in breathing or diarrhoea. | At 1 month of age |
| Change in infant gut microbiome composition, functional profile and maturation | Measured by metagenomic sequencing of total fecal DNA | 3-6 months and 6-9 months of infant age |
| Change in human milk oligosaccharide composition | Measured by quantification of the 19 most abundant HMOs - representing 95% of total HMO concentration in milk and all structural features using HPLC with flouresence detection. We aim to examine the impact of the micronutrient interventions on HMOs in human milk. | 1 month, 3-6 months and 6-9 months of infant age |
| Infant length-for-age z-score | Anthropometry taken using length board. We aim to examine difference in infant length-for-age z-score by intervention arm as well effect modification by microbiota maturity on stunting. | 3-6 months and 6-9 months of infant age |
| Infant weight-for-length z-score | Measured using a pediatric digital scale. We will examine the difference in WLZ score by intervention arm and effect modification of microbiota maturity on wasting (WLZ< -2) | 3-6 months and 6-9 months of infant age |