Nutritional Outcomes After Vitamin A Supplementation in Subjects With SCD

Overview

This study establishes the safety and efficacy of vit A supplementation doses (3000 and 6000 IU/d) over 8 weeks in children with SCD-SS, ages 9 and older and test the impact of vit A supplementation on key functional and clinical outcomes. Additionally, vitamin A status is assessed in healthy children ages 9 and older to compare to subjects with SCD-SS.

Full Title of Study: “Vitamin A in Sickle Cell Disease: Improving Sub-optimal Status With Supplementation”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: September 30, 2016

Detailed Description

Suboptimal vitamin A (vit A) status is prevalent in children with type SS sickle cell disease (SCD-SS) and associated with hospitalizations and poor growth and hematological status. Preliminary data in children with SCD-SS show that vit A supplementation at the dose recommended for healthy children failed to improve vit A status, resulting in no change in hospitalizations, growth or dark adaptation. This indicates an increased vit A requirement most likely due to chronic inflammation, low vit A intake and possible stool or urine loss. The dose of vit A needed to optimize vit A status in subjects with SCD-SS is unknown.

Interventions

  • Dietary Supplement: retinyl palmitate
    • The intervention is a daily vitamin A supplement.

Arms, Groups and Cohorts

  • Active Comparator: Lower Dose Vitamin A
    • Subjects with SCD-SS in the lower dose Vitamin A arm receive 3000IU of retinyl palmitate daily for 8 weeks.
  • Active Comparator: Higher Dose Vitamin A
    • Subjects with SCD-SS in the higher dose Vitamin A arm receive 6000IU of retinyl palmitate daily for 8 weeks.
  • No Intervention: Healthy Comparison Arm
    • Healthy subjects receive no intervention and undergo comparisons to the two vitamin A supplementation arms at baseline.

Clinical Trial Outcome Measures

Primary Measures

  • Serum Vitamin A status
    • Time Frame: Change from baseline after supplementation for 8 weeks
    • Serum vitamin A as measured by retinol

Secondary Measures

  • Vitamin A toxicity
    • Time Frame: Change from baseline after supplementation for 8 weeks
    • Retinyl palmitate
  • Height Z-score
    • Time Frame: Change from baseline after supplementation for 8 weeks
    • Measured on a stadiometer, compared to Center for Disease Control (CDC) reference standard to create a z-score
  • Weight Z-score
    • Time Frame: Change from baseline after supplementation for 8 weeks
    • Measured on a standing scale, compared to CDC reference standard to create a z-score
  • BMI Z-score
    • Time Frame: Change from baseline after supplementation for 8 weeks
    • Calculated using kg/m^2 and compared to CDC reference standards
  • Fat-free Mass
    • Time Frame: Change from baseline after supplementation for 8 weeks
    • Calculated from dual-energy x-ray absorptiometry (DEXA) scan
  • Fat-free Mass
    • Time Frame: Change from baseline after supplementation for 8 weeks
    • Calculated from DEXA scan
  • Fat Mass
    • Time Frame: Change from baseline after supplementation for 8 weeks
    • Calculated from DEXA scan
  • Upper arm muscle area
    • Time Frame: Change from baseline after supplementation for 8 weeks
    • Calculated from mid-upper arm circumference
  • Upper arm fat area
    • Time Frame: Change from baseline after supplementation for 8 weeks
    • Calculated from mid-upper arm circumference and triceps skinfold thickness
  • Muscle strength
    • Time Frame: Change from baseline after supplementation for 8 weeks
    • Directly measured with Biodex Multi-Joint System 3 Pro
  • Jump strength
    • Time Frame: Change from baseline after supplementation for 8 weeks
    • Directly measured with Force Plate
  • Upper limb strength
    • Time Frame: Change from baseline after supplementation for 8 weeks
    • Directly measured with hand-grip strength dynamometer
  • Muscle function
    • Time Frame: Change from baseline after supplementation for 8 weeks
    • Directly measured with Bruininks-Oseretsky Test of Motor Proficiency
  • Dietary Intake
    • Time Frame: Change from baseline after supplementation for 8 weeks
    • Analysis of a three-day food record
  • Coefficient of fat absorption
    • Time Frame: Change from baseline after supplementation for 8 weeks
    • Calculated from 72-hour stool collection and dietary fat intake
  • Hemoglobin
    • Time Frame: Change from baseline after supplementation for 8 weeks
    • Direct measurement through spectral absorption
  • Hematocrit
    • Time Frame: Change from baseline after supplementation for 8 weeks
    • Direct measurement through spectral absorption
  • Fetal hemoglobin
    • Time Frame: Change from baseline after supplementation for 8 weeks
    • Direct measurement through quantitative flow cytometry
  • Mean corpuscular volume
    • Time Frame: Change from baseline after supplementation for 8 weeks
    • Direct measurement through quantitative flow cytometry
  • Mean corpuscular hemoglobin
    • Time Frame: Change from baseline after supplementation for 8 weeks
    • Calculated from hemoglobin mass and erythrocyte count
  • Mean corpuscular hemoglobin concentration
    • Time Frame: Change from baseline after supplementation for 8 weeks
    • Calculated from hemoglobin divided by hematocrit
  • Reticulocyte count
    • Time Frame: Change from baseline after supplementation for 8 weeks
    • Direct measurement through quantitative flow cytometry
  • Retinol binding protein, serum
    • Time Frame: Change from baseline after supplementation for 8 weeks
    • Direct measurement through quantitative nephelometry
  • Retinol binding protein, urine
    • Time Frame: Change from baseline after supplementation for 8 weeks
    • Direct measurement through quantitative nephelometry
  • Urine creatinine
    • Time Frame: Change from baseline after supplementation for 8 weeks
    • Direct measurement through quantitative spectrophotometry
  • Serum creatinine
    • Time Frame: Change from baseline after supplementation for 8 weeks
    • Direct measurement through quantitative spectrophotometry
  • Serum alanine aminotransferase
    • Time Frame: Change from baseline after supplementation for 8 weeks
    • Direct measurement through quantitative enzymatic assay
  • Serum aspartate aminotransferase
    • Time Frame: Change from baseline after supplementation for 8 weeks
    • Direct measurement through quantitative enzymatic assay
  • Serum gamma glutamyltransferase
    • Time Frame: Change from baseline after supplementation for 8 weeks
    • Direct measurement through quantitative enzymatic assay
  • Serum alkaline phosphatase
    • Time Frame: Change from baseline after supplementation for 8 weeks
    • Direct measurement through quantitative enzymatic assay
  • Serum bilirubin
    • Time Frame: Change from baseline after supplementation for 8 weeks
    • Direct measurement through quantitative quantitative spectrophotometry
  • High-sensitivity c-reactive protein
    • Time Frame: Change from baseline after supplementation for 8 weeks
    • Direct measurement through quantitative quantitative immunoturbidimetry
  • Tumor necrosis factor alpha
    • Time Frame: Change from baseline after supplementation for 8 weeks
    • Direct measurement through quantitative quantitative multiplex bead assay
  • White blood cell count
    • Time Frame: Change from baseline after supplementation for 8 weeks
    • Direct measurement through automated cell count
  • White blood cell differential
    • Time Frame: Change from baseline after supplementation for 8 weeks
    • Direct measurement through automated cell count
  • Lymphocyte subtypes
    • Time Frame: Change from baseline after supplementation for 8 weeks
    • Direct measurement through quantitative flow cytometry

Participating in This Clinical Trial

Inclusion Criteria

  • Sickle cell disease, SS genotype (subjects with sickle cell disease only) – Usual state of good health (no hospitalizations, emergency room visits, or unscheduled acute illness clinic visits for two weeks prior to screening) – Commitment to a 119-day study (subjects with sickle cell disease only), or a 4-day study (healthy volunteers only) Exclusion Criteria:

  • Hydroxyurea initiated within the previous 6 weeks (subjects with sickle cell disease only) – History of stroke (subjects with sickle cell disease only) – Other chronic conditions that may affect growth, dietary intake or nutritional status – Retinoic acid (topical or oral), weight loss medication and/or lipid lowering medications – Subjects with a BMI greater than 98th percentile for age and sex – Pregnant or lactating females (subjects who become pregnant during the course of the study will not continue participation) – Liver function tests >4 x upper limit of reference range – Participation in another study with impact on vitamin A status (subjects with sickle cell disease only) – Use of multi-vitamin or commercial nutritional supplements containing vitamin A (those who are willing to discontinue these supplements, with the approval of the medical care team, will be eligible for the study after a 1 month washout period. Subjects taking nutritional products without vitamin A will be eligible) – Inability to swallow pills (subjects with sickle cell disease only)

Gender Eligibility: All

Minimum Age: 9 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • Children’s Hospital of Philadelphia
  • Collaborator
    • Penn State University
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Virginia Stallings, MD, Principal Investigator, Children’s Hospital of Philadelphia

References

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Solomons NW. Vitamin A. In: B.Bowman, R.Russell, editors. Present Knowledge in Nutrition, Volume I. 9 ed. Washington DC: International Life Science Institute Press; 2006:157-183

Ross CA. Vitamin A and carotenoids. In: M.E.Shils, M.Shike, C.A.Ross, B.Caballero, R.J.Cousins, editors. Modern Nutrition in Health and Disease. 10 ed. Philadelphia: Lippincott, Williams and Wilkins; 2006:351-375

Schall JI, Zemel BS, Kawchak DA, Ohene-Frempong K, Stallings VA. Vitamin A status, hospitalizations, and other outcomes in young children with sickle cell disease. J Pediatr. 2004 Jul;145(1):99-106. doi: 10.1016/j.jpeds.2004.03.051.

Trumbo P, Yates AA, Schlicker S, Poos M. Dietary reference intakes: vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. J Am Diet Assoc. 2001 Mar;101(3):294-301. doi: 10.1016/S0002-8223(01)00078-5. No abstract available.

Dougherty KA, Schall JI, Kawchak DA, Green MH, Ohene-Frempong K, Zemel BS, Stallings VA. No improvement in suboptimal vitamin A status with a randomized, double-blind, placebo-controlled trial of vitamin A supplementation in children with sickle cell disease. Am J Clin Nutr. 2012 Oct;96(4):932-40. doi: 10.3945/ajcn.112.035725. Epub 2012 Sep 5.

Haskell MJ, Handelman GJ, Peerson JM, Jones AD, Rabbi MA, Awal MA, Wahed MA, Mahalanabis D, Brown KH. Assessment of vitamin A status by the deuterated-retinol-dilution technique and comparison with hepatic vitamin A concentration in Bangladeshi surgical patients. Am J Clin Nutr. 1997 Jul;66(1):67-74. doi: 10.1093/ajcn/66.1.67. Erratum In: Am J Clin Nutr 1999 Mar;69(3):576.

Ribaya-Mercado JD, Solon FS, Solon MA, Cabal-Barza MA, Perfecto CS, Tang G, Solon JA, Fjeld CR, Russell RM. Bioconversion of plant carotenoids to vitamin A in Filipino school-aged children varies inversely with vitamin A status. Am J Clin Nutr. 2000 Aug;72(2):455-65. doi: 10.1093/ajcn/72.2.455.

Olson JA. Serum levels of vitamin A and carotenoids as reflectors of nutritional status. J Natl Cancer Inst. 1984 Dec;73(6):1439-44.

Kawchak DA, Schall JI, Zemel BS, Ohene-Frempong K, Stallings VA. Adequacy of dietary intake declines with age in children with sickle cell disease. J Am Diet Assoc. 2007 May;107(5):843-8. doi: 10.1016/j.jada.2007.02.015.

Garcia OP. Effect of vitamin A deficiency on the immune response in obesity. Proc Nutr Soc. 2012 May;71(2):290-7. doi: 10.1017/S0029665112000079. Epub 2012 Feb 28.

Cantorna MT, Nashold FE, Hayes CE. In vitamin A deficiency multiple mechanisms establish a regulatory T helper cell imbalance with excess Th1 and insufficient Th2 function. J Immunol. 1994 Feb 15;152(4):1515-22.

Esteban-Pretel G, Marin MP, Cabezuelo F, Moreno V, Renau-Piqueras J, Timoneda J, Barber T. Vitamin A deficiency increases protein catabolism and induces urea cycle enzymes in rats. J Nutr. 2010 Apr;140(4):792-8. doi: 10.3945/jn.109.119388. Epub 2010 Feb 24.

Kennedy KA, Porter T, Mehta V, Ryan SD, Price F, Peshdary V, Karamboulas C, Savage J, Drysdale TA, Li SC, Bennett SA, Skerjanc IS. Retinoic acid enhances skeletal muscle progenitor formation and bypasses inhibition by bone morphogenetic protein 4 but not dominant negative beta-catenin. BMC Biol. 2009 Oct 8;7:67. doi: 10.1186/1741-7007-7-67.

Dougherty KA, Schall JI, Rovner AJ, Stallings VA, Zemel BS. Attenuated maximal muscle strength and peak power in children with sickle cell disease. J Pediatr Hematol Oncol. 2011 Mar;33(2):93-7. doi: 10.1097/MPH.0b013e318200ef49.

Zemel BS, Kawchak DA, Ohene-Frempong K, Schall JI, Stallings VA. Effects of delayed pubertal development, nutritional status, and disease severity on longitudinal patterns of growth failure in children with sickle cell disease. Pediatr Res. 2007 May;61(5 Pt 1):607-13. doi: 10.1203/pdr.0b013e318045bdca.

Allen LH, Haskell M. Estimating the potential for vitamin A toxicity in women and young children. J Nutr. 2002 Sep;132(9 Suppl):2907S-2919S. doi: 10.1093/jn/132.9.2907S.

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