Relative Bioavailability of Iron and Folic Acid in New Test Supplement
Condition: Iron Deficiency; Folic Acid Deficiency
MeSH terms: Iron Deficiencies; Folic Acid Deficiency
Study type: Interventional
Phase: Phase 1

Summary: 
      Deficiencies of iron and folic acid during pregnancy can lead to adverse outcomes for the
      fetus, thus supplements are recommended. Adherence to current tablet-based supplements is
      documented to be poor. Recently a powdered form of micronutrients has been developed which
      may decrease side-effects and thus improve adherence. However, before testing the efficacy of
      the supplement as an alternate choice for supplementation during pregnancy, the
      bioavailability of the iron needs to be determined. The objective of this study is to measure
      the relative bioavailability of iron and folic acid from a powdered supplement that can be
      sprinkled on semi-solid foods or beverages versus a traditional tablet supplement in pregnant
      women.
    

Detailed description: 
      Background:

      The proposal addresses the issue of the bioavailability of the supplement SuppleFem as
      compared to the current standard supplement Materna during pregnancy in Canadian women. In
      recognition of the difficulties Canadian women face in order to meet their iron (27 mg/day)
      and folic acid (600 µg/day) requirements from dietary sources alone during pregnancy, Health
      Canada currently recommends that an iron/folic acid supplement be taken by all women during
      pregnancy. However, because of issues related to adherence, many pregnant women do not
      fulfill the Health Canada recommendation. Adherence is largely influenced by the
      gastrointestinal side-effects associated with the use of iron tablets or pills, as well as
      the nausea and vomiting common during the first trimester. It is estimated that
      approximately10% of women discontinue the use of iron because of adverse effects while others
      use less than a daily dose. Women suffering from indigestion and heart-burn
      (gastro-esophageal acid reflux) associated with the use of iron supplements commonly
      discontinue their use and many find it difficult to swallow pills when nauseated.

      The bioavailabilities of iron and folic acid in supplements may be an area of concern,
      primarily due to the higher requirements during pregnancy. Materna® contains a large quantity
      of calcium (250 mg), whereas Sprinkles contains none. A study by Hallberg, et al. (1991)
      showed that adding as little as 165 mg of calcium to a meal reduced the absorption of iron by
      50-60% in wheat rolls. In addition, a study by Koren, et al. (2004) showed that after
      adjusting for dose, the iron absorbed from one maternal iron supplement containing calcium
      was statistically less as compared to one without calcium. A study by Rossander-Hultén et al
      (1991, as cited by Sandröm, 2001) found that zinc has the potential to inhibit iron
      absorption in supplements but not when zinc is added to food . The iron supplement contains
      25mg of zinc whereas SuppleFem contains only 5.5mg. There are no reported interactions
      between folate and other nutrients. However, there is evidence that folate bioavailability
      may be influenced by the amount ingested. While pregnancy does increase the demand for
      folate, the amount in SuppleFem is compliant with the current DRI guidelines at 600µg,
      whereas the iron supplement contains 1000 µg. Currently, there is not enough research to
      indicate whether unmetabolized folic acid poses any health risks .

      Rationale:

      A new natural health product, "SuppleFem Sprinkles", was designed to address the issues with
      adherence. Sprinkles are single-dose sachets (like small packets of sugar) containing
      micronutrients in a powder form (iron as ferric pyrophosphate, folic acid and other
      micronutrients), which are easily sprinkled onto any foods or liquids prepared in the
      household. Any semi-solid food or liquid can be fortified by their addition. Sprinkles are
      meant to be added once daily to any semi-solid foods eaten in the home (eg: pureed fruits,
      orange juice or oatmeal), or mixed into a liquid. The efficacy of Sprinkles to prevent anemia
      in pregnant women has not previously been demonstrated, however, in the past five years,
      seven community-based trials in four different countries have examined the efficacy of
      Sprinkles in both infants and young children in developing countries xii, xiv, , , , , Before
      adherence can be measured as a primary outcome, however, it must be shown that there is no
      significant difference in the bioavailability of the ferric pyrophosphate in the SuppleFem®
      compared to the iron in the leading iron supplement thus showing that SuppleFem is as
      efficacious as standard treatments. If the new delivery system proves to be non-inferior to
      the leading iron tablets, then adherence to this new natural health product can be examined
      at a later date.

      Trial Objectives:

      Primary objective- The primary objective of this study is to determine whether or not the
      powdered formulation of micronized ferric pyrophosphate in SuppleFem® (to be mixed with
      liquids or food) is as bioavailable as the iron in the standard recommended pregnancy
      supplement.

      Secondary Objective- The secondary objective of this study is to compare the relative
      bioavailability (ratio of AUCs for serum folate over an 8 hour period) of folic acid
      following a single dose of Materna® or Sprinkles.

      Study Design & Duration:

      The crossover design of the study will allow each subject to act as their own control. Since
      the interventions will be given in therapeutic dosage rather than a larger pharmaceutical
      dose it is anticipated that there should be no carryover effect to the next intervention. The
      washout periods between treatments will be one week each. It is anticipated that the study
      will begin September 1, 2005 and would last for a period of 6 to 9 weeks. Duration of study
      for each subject will be 3 weeks. Patients will be enrolled in the trial upon their answering
      of a posted advertisement. During the initial encounter, the prospective subjects will be
      informed as to the purpose of the trial, how the trial will be conducted, what their time
      commitment will be and any possible potential for harm This information will be explained by
      the study coordinator and informed consent will be obtained if the patient is agreeable.
      Subjects will fill out a baseline questionnaire detailing their supplement use as well as
      other demographic information before commencing the study. Prior supplement use should not
      impact on the relative bioavailability of either supplement since the crossover design will
      ensure prior use will impact on both treatments equally. Visit number one will determine
      diurnal variation values for the serum iron as well as establish iron status. Individuals in
      each of the groups will then be randomly allocated to either SuppleFem® or Materna® by
      selecting coloured poker chips from a bag to assign equal probability for each subject to
      fall into either of the two treatments. Two colors will be chosen to represent the two
      interventions. The chips will be placed in an opaque bag by the study coordinator and
      subjects will be asked at the commencement of the second visit (first intervention) to
      withdraw a chip from the bag as part of the randomization process. The colour will identify
      which intervention group the subject will be placed in. For visit number three, subjects will
      receive the opposite treatment from the one they took in visit two. Subject blinding is not
      possible due to the physical forms of the interventions; Materna is a large pill whereas
      Sprinkles are a granular powder. This study will be highly controlled and subjects will be
      closely observed while ingesting the supplements to ensure that the entire precisely measured
      amount is consumed. Further, serum measurements are objective in nature and cannot be
      influenced by the subject.
    

Intervention name(s): Daminaide 995 - SuppleFem Sprinkles; Materna
Intervention type(s): Dietary Supplement; Dietary Supplement
Intervention description(s): The study agent SuppleFem will be a preblend manufactured by Acatris in Oakville Ontario and will be repackaged into 1 gram aliquots in white plastic Tamper Seal Vials.1 ram to be taken with test meal; Materna is a pregnancy supplement available on the Canadian market and is manufactured by Wyeth. Dose is 1 tablet per day
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Keywords: pregnancy; relative bioavailability; iron; folic acid; ferric pyrophosphate; Study focus is to compare the relative bioavailability of SuppleFem Sprinkles to the current tradtional tablet Materna in pregnant women