Effectiveness of a Micronutrient Supplement to Lower Plasma Homocysteine MDEG2 Pilot Supplementation Trial
Condition: Micronutrient Deficiencies; Hyperhomocysteinemia
MeSH terms: Hyperhomocysteinemia
Study type: Interventional
Phase: Phase 2

Summary: 
      This micronutrient supplementation study is a 3-arm randomized controlled trial, unblinded,
      with 125 women per arm. Non-pregnant, non-lactating healthy women of reproductive age in West
      Kiang, The Gambia, will be randomized to 12 weeks of daily supplementation of either a) novel
      micronutrient supplement, b) a United Nations International Multiple Micronutrient
      Preparation (UNIMMAP) tablet or c) no intervention (control). The novel micronutrient
      supplement is a drink powder providing 800 µg folic acid, 5.2 µg cyanocobalamin (B12), 2.8 mg
      Riboflavin-5'-phosphate (B2), and 4g trimethylglycine (betaine). UNIMMAP contains 15
      micronutrients at the Recommended Daily Allowance level. The aim is to test the effectiveness
      of the supplements on correcting micronutrient deficiencies in the dry season and to reduce
      homocysteine levels. The hypothesis is that the new drink powder will be the most effective
      supplement, causing a reduction in 1 µmol/L compared to the control group after
      supplementation.

      The supplements will be supplied to participants on a daily basis by Community-based Birth
      Attendants (CBCs). The CBCs will observe consumption of the supplement. The novel
      micronutrient supplement will be provided in powder form with instructions to dissolve one
      sachet in a cup of 200ml water. UNIMMAP will be provided in capsule form to be taken with
      water. Women will provide one 10ml fasted venous blood sample at baseline and another after 6
      and 12 weeks of supplementation. At each time point they will also have their blood pressure
      and anthropometry assessed and provide a urine pregnancy test.

      Correcting micronutrient deficiencies is extremely important for the long-term health of
      women, and in particular around the time of conception and throughout pregnancy since
      micronutrients are needed for the proper physical and cognitive development of the baby.
      Certain micronutrients are required for adding a methyl group to places on DNA ('DNA
      methylation'). The pattern of these methyl groups can help determine whether a gene is
      switched on or off. Correct functioning of DNA methylation processes is therefore of critical
      importance for fetal development. High levels of homocysteine can impede DNA methylation,
      therefore supplements that reduce homocysteine may not only be beneficial for the mother but
      also for the developing child. The most effective supplement in this trial will be considered
      for testing in larger pregnancy trials.
    

Detailed description: 
      In rural Gambia women experience considerable variation in their diet by season. In the dry
      season women have particular micronutrient deficiencies that can disrupt one-carbon
      metabolism pathways. In the dry season women have lower levels of most of the B vitamins and
      higher levels of homocysteine compared to the rainy season. The goal of this trial is to test
      two nutritional interventions to see which one works best in providing micronutrients in the
      ratio and quantity necessary for optimal 1-carbon metabolism in the dry season. The primary
      end point is to assess which supplement is most effective in reducing plasma homocysteine.

      This is a 3-arm randomized controlled trial, unblinded, with 125 women per arm. Non-pregnant,
      non-lactating healthy women of reproductive age in West Kiang will be randomized to 12 weeks
      of daily supplementation of either a) novel micronutrient drink powder supplement, b)
      existing available micronutrient supplement (UNIMMAP) or c) no intervention (control). The
      novel drink powder provides 800 µg folic acid, 5.2 µg cyanocobalamin (B12), 2.8 mg
      Riboflavin-5'-phosphate (B2), and 4g trimethylglycine (betaine). This dose is twice the
      Recommended Daily Allowance for folic acid, B12 and B2. The UNIMMAP tablet provides 15
      micronutrients (vitamins A, D, E, B1, B2, B6, B12, C, Niacin, Folic Acid, Iron, Zinc, Copper,
      Iron, Selenium) at the Recommended Daily Allowance level.

      Potentially eligible participants will be identified through the Keneba Health and
      Demographic Surveillance System in all 35 villages of West Kiang region of The Gambia. Field
      assistants will visit the homes of potentially eligible participants to provide full
      information about the purpose and methods of the study, potential risks and benefits, and
      participants' rights. Full inclusion and exclusion criteria will be assessed. Participants
      will then be asked to provide a signed or thumb-printed informed consent before being
      enrolled into the study.

      The supplements will be supplied to participants on a daily basis by Community-based Birth
      Companions (CBCs). The novel drink powder will be provided in daily sachets and dissolved in
      200ml water. UNIMMAP will be provided in capsule form to be taken with water. The CBCs will
      observe consumption of the supplement. Participants will be given 7 coloured cards at the
      start of each week. Every day they will give the CBC one card and receive their supplement.
      Each week a field assistant will collect data on compliance by recording card collection in
      liaison with the CBC.

      Women will provide one 10mL fasted venous blood sample at baseline and another after 6 and 12
      weeks of supplementation. At each time point they will also have their blood pressure and
      anthropometry (weight and height) assessed and provide a urine pregnancy test. Women will be
      brought to the Medical Research Council Gambia (MRCG) field station at Keneba for the
      baseline, 6 week (mid-line) and 12 week (end-line) data collection visits. Participants will
      be followed-up after the intervention period for a further 3 weeks to monitor any adverse
      effects.

      The fasted 10mL baseline, 6 week and 12 week blood samples will be taken by venepuncture into
      EDTA monovettes and kept on ice. Within one hour of collection the samples will be processed
      by the laboratory in Keneba to centrifuge the samples, separate the plasma and store plasma
      and red blood cell aliquots at -70°C. One plasma aliquot will be analysed in Keneba to
      measure homocysteine using the Cobas Integra 400 Plus analyser.

      The hypothesis is that the novel micronutrient supplement will reduce plasma by at least 1
      µmol/L compared to the control group after 12 weeks of daily supplementation. It will be more
      effective in reducing plasma homocysteine than existing UNIMMAP tablets.

      This trial is powered to study to detect a decrease of 1 µmol/L homocysteine with 80% power
      and 95% confidence. The trial statistician will use a linear regression model to determine
      the mean difference between intervention and control homocysteine at 12 weeks adjusted for
      baseline homocysteine, week 12 age and week 12 body mass index.
    

Intervention name(s): novel micronutrient; existing micronutrient supplement, UNIMMAP
Intervention type(s): Dietary Supplement; Dietary Supplement
Intervention description(s): The supplements will be supplied to participants on a daily basis. The novel micronutrient supplement will be provided in powder form with instructions to dissolve one sachet in 250ml of clean water; UNIMMAP will be provided in tablet form and given one daily
Intervention MeSH terms: Micronutrients; Trace Elements
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: 3-arm randomized controlled trial, unblinded, with 125 women per arm.
Masking: None (Open Label)
Primary purpose: Treatment