Nutritional Outcomes After Vitamin A Supplementation in Subjects With SCD

Vitamin A in Sickle Cell Disease: Improving Sub-optimal Status With Supplementation

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.

Study Overview

• Status: Completed
• Conditions: Sickle Cell Anemia in Children; Vitamin A Deficiency in Children
• Intervention / Treatment: Dietary supplement: retinyl palmitate

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.

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19146
      • Children's Hospital of Philadelphia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 9 years and older (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.	Dietary supplement: retinyl palmitate; The intervention is a daily vitamin A supplement.
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.	Dietary supplement: retinyl palmitate; The intervention is a daily vitamin A supplement.
NO_INTERVENTION: Healthy Comparison Arm; Healthy subjects receive no intervention and undergo comparisons to the two vitamin A supplementation arms at baseline.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum Vitamin A status	Serum vitamin A as measured by retinol	Change from baseline after supplementation for 8 weeks

Secondary Outcome Measures

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total body vitamin A status via Stable Isotope Dilution	compartmental modeling of [13C10]-retinyl acetate, measured by high performance liquid chromatography/mass spectroscopy	Change from baseline after supplementation for 8 weeks

Collaborators and Investigators

• Sponsor: Children's Hospital of Philadelphia
• Collaborators: Penn State University; Newcastle University

Publications and helpful links

General Publications

• 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.
• Ribaya-Mercado JD, Maramag CC, Tengco LW, Dolnikowski GG, Blumberg JB, Solon FS. Carotene-rich plant foods ingested with minimal dietary fat enhance the total-body vitamin A pool size in Filipino schoolchildren as assessed by stable-isotope-dilution methodology. Am J Clin Nutr. 2007 Apr;85(4):1041-9. doi: 10.1093/ajcn/85.4.1041.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (ACTUAL): October 2, 2015
• Primary Completion (ACTUAL): September 30, 2016
• Study Completion (ACTUAL): September 30, 2016

Study Registration Dates

• First Submitted: August 1, 2018
• First Submitted That Met QC Criteria: August 13, 2018
• First Posted (ACTUAL): August 16, 2018

Study Record Updates

• Last Update Posted (ACTUAL): August 16, 2018
• Last Update Submitted That Met QC Criteria: August 13, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Keywords: DXA; retinyl palmitate; Retinol; Stable isotope dilution
• Additional Relevant MeSH Terms: Eye Diseases; Hematologic Diseases; Nutrition Disorders; Genetic Diseases, Inborn; Anemia; Avitaminosis; Deficiency Diseases; Malnutrition; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Vision Disorders; Anemia, Sickle Cell; Night Blindness; Vitamin A Deficiency; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Protective Agents; Micronutrients; Vitamins; Antioxidants; Anticarcinogenic Agents; Vitamin A; Retinol palmitate
• Other Study ID Numbers: 13-010081

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data that underlie the results reported will be shared upon request, after deidentification.
• IPD Sharing Time Frame: The data will be available immediately upon publication.
• IPD Sharing Access Criteria: Contact brownellj@email.chop.edu. Requestors will need to sign a data access agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No