Enhancing Treatment of Iron Deficiency and Iron Deficiency Anemia With an Antioxidant, Vitamin E
Condition: Iron Deficiency; Iron Deficiency Anemia
MeSH terms: Anemia; Anemia, Iron-Deficiency; Iron Deficiencies; Deficiency Diseases
Study type: Interventional
Phase: Phase 1

Summary: 
      The study addresses treatment of iron deficiency, the most common nutritional deficiency that
      infants and young children encounter. With the knowledge that iron deficiency may
      irreversibly affect a baby's long-term neurodevelopment and behavior, the investigators are
      offering free screening blood draws at Children's Hospital Colorado to older babies and
      toddlers (9-24 months old). If their blood results indicate a serum ferritin of ≤ 15
      micrograms/dL without the presence of an elevated C-reactive protein (CRP), they will be
      invited to continue in the intervention portion of the study, where they will receive iron
      supplements as well as vitamin E (or placebo) for an eight week treatment period. The
      rationale for the study is to test whether addition of Vitamin E, an antioxidant and
      anti-inflammatory agent, improves the treatment response to supplemental iron.
    

Detailed description: 
      Enhancing Treatment of Iron Deficiency and Iron Deficiency Anemia with an Antioxidant,
      Vitamin E

      Synopsis/Abstract Iron Deficiency (ID) and Iron Deficiency Anemia (IDA) are common in older
      breastfed infants and toddlers. Treatment of 3-6 mg iron/kg/day is recommended by the
      American Academy of Pediatrics (AAP), but this regimen often results in only modest changes
      in iron status, despite being a substantially higher dose (relative to body weight) than is
      commonly used for adults. We propose that high therapeutic doses of iron induce an
      inflammatory response, thus increasing hepatic synthesis of a critical regulator of iron
      absorption, hepcidin, which functions to limit iron absorption in the context of
      inflammation. In infants and toddlers found to have ID or IDA, we propose to evaluate the
      efficacy of the addition of Vitamin E to iron therapy compared with the same dose of iron
      alone. Our primary hypothesis is that in infants and toddlers with ID or IDA, 2 months of
      supplemental Vitamin E combined with therapeutic iron supplementation will be more
      efficacious than the same dose of iron alone. The study design is a randomized, double blind
      efficacy trial of 2 months of iron therapy (6 mg/kg/day) with or without Vitamin E (18
      mg/day), in infants and toddlers with ID or IDA from 9 to 24 months of age. Primary outcomes
      include biomarkers of iron status (ferritin, hemoglobin, transferrin saturation, and
      transferrin receptor); secondary outcomes include biomarkers of inflammation and oxidant
      stress. Subjects: We will screen older infants (9-12 months of age) who were predominantly
      breastfed through at least the first 9 months of life, and toddlers (12-24 months of age) who
      were breastfed and/or who have modest dietary iron intakes. Intervention: Sixty-eight
      subjects found to have ID or IDA will be consented and randomized to one of the two treatment
      regimens (34 subjects per group). Liquid supplement preparations of iron (both groups),
      Vitamin E (test) and placebo (control) will be distributed by the research pharmacy at The
      Children's Hospital.Children's Hospital Colorado. Outcomes: Biomarkers of iron status, iron
      homeostasis, oxidant stress, and of systemic and intestinal inflammation will be repeated at
      the end of the intervention. If the hypotheses are supported, the findings would provide a
      simple and effective modification to enhance iron therapy, and to improve the balance between
      adequate iron uptake to meet physiologic needs and excessive iron intake and its potential
      adverse effects.

      I. Goals and objectives:

      The broad goal of this proposal is to improve the health and nutrition of young children by
      improving iron status of infants and toddlers who have developed iron deficiency (ID) or iron
      deficiency anemia (IDA). The specific objective is to test an intervention proposed to
      enhance the efficacy, and minimize potential toxicity, of therapeutic iron for infants and
      young children who have a dietary iron deficiency.

      Iron deficiency is the most common micronutrient deficiency in the world and negatively
      impacts health in several ways 1, 2. ID and IDA contribute to stunting and impaired growth,
      increased behavioral problems, and delayed mental and motor development 3, 4, 5-7. Studies
      have also shown that some of the behavioral and developmental consequences of ID and IDA in
      young children are not reversible with treatment 8. Despite the fortification of infant and
      toddler foods in the United States, a significant number of children still develop ID or IDA
      9. Current treatment recommendations include a wide dosage range (3-6 mg/kg/day), which
      represents amounts that are higher than routine supplementation levels for adults (typically
      equivalent to < 1 mg/kg/day), reflecting the challenge and imprecision of effective treatment
      for ID and IDA in children. Iron excess is not without risk, and studies in adults have shown
      local (intestinal) and systemic inflammatory changes within days of iron therapy initiation
      10, 11. Recent advances in the understanding of the regulation of iron homeostasis and
      metabolism indicate that systemic inflammation induces a protein called hepcidin, which
      blocks the uptake of iron into the body12, 13. Thus, stimulation of inflammation by high dose
      iron supplements may actually counteract the intended beneficial effect of the increase in
      iron intake.

      Vitamin E is an essential nutrient that functions as an antioxidant and anti-inflammatory
      agent, and has been studied for many potentially beneficial facets of human health, including
      potential for protection against heart disease14; accelerated aging mediated through DNA
      damage; and impaired immunity 15. Research in adults giving antioxidants along with iron
      therapy was associated with reduced oxidative potential. In this study, a palm oil extract
      containing approximately 7 mg of Vitamin E was supplemented along with iron therapy and was
      associated with reduced fecal oxidation 16 Alpha-tocopherol is the most studied form of
      Vitamin E, and has been shown to decrease biomarkers of total body oxidative stress and
      inflammation 15, 17. We propose to accomplish our primary specific objective by testing the
      effect on treatment outcomes of administration of Vitamin E along with iron supplements.

      II. Hypotheses:

      Our central hypothesis is that in infants and toddlers with ID or IDA, 2 months of
      supplemental Vitamin E combined with therapeutic iron supplementation at 6 mg/kg/day will be
      more efficacious than the same dose of iron alone. The specific hypotheses to be tested by
      the intervention are:

      Hypothesis 1: Subjects receiving both iron and vitamin E supplements will have significantly
      greater changes in serum ferritin (reflecting greater improvement in their iron status), than
      subjects receiving iron alone after eight weeks of supplementation.

      Hypothesis 2: Significantly more subjects receiving both iron and vitamin E supplements will
      have an improved iron status profile, including ferritin, transferrin saturation, and serum
      transferrin receptor, than subjects receiving iron alone.

      Hypothesis 3 Subjects receiving both iron and vitamin E supplements will have significantly
      lower levels of inflammatory and oxidant stress biomarkers than subjects receiving iron
      alone.

      Hypothesis 4: (exploratory): The exposure to two months of iron therapy will be associated
      with significantly altered intestinal bacterial profiles compared to baseline, and at the end
      of therapy, the placebo group will have a greater predominance of potentially pathogenic
      bacterial phyla.
    

Intervention name(s): Vitamin E; Placebo
Intervention type(s): Drug; Other
Intervention description(s): A commercial Vitamin E preparation (Aqueous Vitamin E®, 15 IU/0.3 ml; SilaRx, Inc, Spring Valley, NY) will be used for the study, also on the recommendation of the Children's Hospital Colorado (CHC) research pharmacist. The Vitamin E dose will be 18 mg/day for all subjects randomized to the Vitamin E group.; The control group will receive an indistinguishable placebo preparation, which will be compounded by the CHC research pharmacy using the following inactive ingredients: purified water, polysorbate 80, sorbital, and propylene glycol. This suspension is stable for 6 months.
Other intervention name(s): Aqueous Vitamin E®, 15 IU/0.3 ml
Intervention MeSH terms: Vitamins; Vitamin E; Tocopherols; Tocotrienols; alpha-Tocopherol
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Iron Deficiency; Iron Deficiency Anemia