Study Comparing Two Isoforms of Vitamin D Supplements for Infants
Condition: Healthy
Study type: Interventional
Phase: Phase 3

Summary: 
      There are two different types of vitamin D - vitamin D3 (animal source) and vitamin D2 (plant
      source). Almost all the usual vitamin D preparations for infants available in Canadian
      pharmacies contain vitamin D3 which may not be suitable for families who avoid animal
      products for social or religious reasons. The purpose of this study is to learn more about
      the two forms of vitamin D and if blood levels of vitamin D are similar in infants after
      taking them. Forty-eight breastfed infants will be randomly assigned to 400 IU of either
      vitamin D2 or D3 supplement for 3 months starting at 1 month of age. The difference in blood
      vitamin D levels, after 3 months of supplementation, between the two groups will help
      determine if the two supplements are equal.
    

Detailed description: 
      Vitamin D is important to develop strong bones and teeth as well as to prevent rickets, a
      childhood bone disease in which the bones get very soft and bend. the investigators know that
      vitamin D can be produced by cells in our skin during sunny months of the year but there is a
      concern about the safety of sun exposure in infants. As well breast milk contains very little
      vitamin D. It is for this reason that Health Canada recommends all breast fed babies should
      receive 400 IU of vitamin D per day. There are two different types of vitamin D - vitamin D3
      (animal source) and vitamin D2 (plant source). Standard infant preparations in Canada tend to
      be in the vitamin D3 form. To date, there is insufficient information to judge the
      equivalency of 400 IU of vitamin D2 and D3 given daily in very young Canadian infants. In
      view of over 1 million Canadian families practicing vegetarianism, this would appear to be an
      important and not yet answered question. The investigators cannot extrapolate from the adult
      data because the infant physiology is immature relative to adults and absorption, especially
      of fat soluble vitamins differs. This area needs to be better evaluated to emphasize the
      optimal isoform of vitamin D during infancy necessary for the development of adequate bone
      mass.

      This study aims to compare the relative ability of equal daily intakes of vitamin D2 and D3,
      amounts (400 IU/d) currently recommended by Health Canada, to support circulating 25(OH)D
      concentrations after 3 months of supplementation in breastfed newborns. In particular,
      whether both supplements are equally effective in their ability to achieve and sustain
      optimal plasma 25(OH)D concentrations, defined as 25(OH)D values between 75-225 nmol/L.

      Design: Randomized clinical trial in which 48, 1 month old infants, will be randomized to
      either the vitamin D2 or D3 isoform at the standard of care dosage (400 IU daily) for 3
      months; a sufficient time to observe a change of vitamin D status ascribed to the supplement.
      Infant physiology is immature and evolving and the time to stabilize 25-hydroxy vitamin D
      (25(OH)D) is approximately 3 weeks (half-life). Supplements will be double blinded to
      participants, investigators and all staff.

      Recruitment: Infants will be recruited from 1 large primary care center located in the
      greater Montreal area. The goal is for infants to begin the study at 4 weeks of age but a
      range of +/- 2 weeks. Rolling recruitment over a 9 months period with a 3 month follow-up for
      all beginning in May 2010. This covers both the synthesizing and non synthesizing periods of
      vitamin D. This age group has been selected (first month of life) since vitamin D stores
      transferred from the mother begin to decrease owing to the 15 to 30 day half life of 25(OH)D.
      After this point, infants need a source of vitamin D other than breast milk or sunshine.
      Because the majority of Canadian infants are now breastfed for at least 3-6 months of age the
      first 4 months of life appear to be an important time frame to examine the relative potency
      of the 2 isoforms.

      Frequency and duration of follow up: Infants will be followed for 3 months with 2 visits, at
      baseline (~1 month) and the end of the study (~4 months). Visits will include anthropometric
      assessment and blood collection for the assessment of 25(OH)D and parathyroid hormone (PTH)
      concentrations. Bottles of supplement will be weighed upon receipt and return for compliance.
      As well, parents will be asked to self-report compliance at each visit. In order to encourage
      continued supplementation during the 3 month intervention, the investigators plan to a
      schedule a reminder phone call at approximately 1½ months post the baseline visit. Vitamin D
      supplementation of infants prior to the initial visit (birth to visit 1) will be documented,
      but considered as systematic error. Maternal baseline information will be collected at the
      first visit including demographics, ethnicity, pregnancy history and sun exposure during
      pregnancy. This data will be used to characterize the study population. At each visit, the
      health status and sun exposure and sunscreen use of the infants will be assessed. A
      computerized narrow band reflectometer will be utilized to measure skin pigmentation on
      unexposed skin of the inner upper arm and forehead. Procedures will be performed using
      guidelines established by the European Society of Contact Dermatitis. This test estimates
      melanin content of the skin which influences vitamin D status.

      Sample procurement: At both visits, blood will be collected from infants using a capillary
      blood sample and from mothers by venipuncture. All samples will be taken between 8 and 10 am
      to control for diurnal variation. Approximately 1 ml of heparinized blood will be collected
      from infants via heel/finger prick and 5 ml from mothers.

      Plasma 25(OH)D and PTH concentrations: Response to supplementation will be evaluated by the
      change in plasma 25(OH)D and PTH. Mothers 25(OH)D status will also be obtained to determine
      that both groups are similar as mother's vitamin D status can affect infant's vitamin stores
      and risk of hypovitaminosis. Mother's vitamin D status will also allow us to better establish
      total infant vitamin D exposure through maternal placental transfer of vitamin D. If there is
      no change, the proportion with 25(OH)D below target will be examined. Both vitamin D and PTH
      will be measured using an automated chemiluminescent assay system (Liaison, Diasorin). All
      analyses will be completed in a laboratory meeting the performance targets set by the Vitamin
      D External Quality Assessment Scheme (DEQAS).

      Anthropometry: Infant's weight, length and head circumference will be taken at each visit.
      Gestational age will be documented from the vaccination booklet. Growth will be assessed
      using triplicate measurements of weight (to nearest g without clothing/diaper using a digital
      infant scale) and head circumference (to the nearest 0.1 cm using non-stretchable tape). Data
      will be expressed in absolute units and z-scores using data from the World Health
      Organization growth charts at each age. Mother's weight, height and body composition (% body
      fat using bioelectrical impendence will be measured to accurately describe the population.

      Infant nutrition: Information of infant feeding status (exclusively, predominately breastfed
      or formula fed) will be collected at each visit as well as the reminder telephone call
      (approximately 1½ most post supplementation). If formula is consumed, information about
      specific amounts consumed, frequency, brands as well as additional multivitamins/minerals
      will also be collected.

      Mother's nutrition: Mother's vitamin D intake from diet and supplements will be assessed
      during lactation using a 24 hour recall, using the US Department of Agriculture 5-step
      multiple-pass method for dietary recall, conducted with a registered dietitian at each visit.
      The correct assessment of 25(OH)D from dietary food records is limited as current food
      sources of vitamin D (such as fish) are consumed weekly or a few times/month. 24-hours
      recalls will likely miss important food sources thus, the Canadian adapted Harvard Food
      Frequency Questionnaire will be completed to assess last 3 months of usual food intake.

      Safety: Participants found to be below the optimal range of vitamin D [25(OH)D ≤ 75 nmol/L,
      30 ng/ml] or any value exceeding 225 nmol/L [90 ng/ml] after the 3-month supplementation
      period, upon participant consent, will be contacted and referred to their pediatrician for
      appropriate treatment. If permitted by the participant, the physician will be contacted
      directly with the results. Both maternal and infant 25(OH)D values collected at the visit 2
      will be made available to all participants.
    

Intervention name(s): Cholecalciferol (D3) or ergocalciferol (D2)
Intervention type(s): Dietary Supplement
Intervention description(s): 400 IU administered as 1 drop daily for 3 months
Other intervention name(s): Baby D Drops
Intervention MeSH terms: Cholecalciferol; Vitamin D; Ergocalciferols
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Optimal vitamin D status; 25-hydroxy vitamin D; Rickets and bone mineralization; Breast fed infants; Cholecalciferol and ergocalciferol