Nutritional Outcomes After Vitamin A Supplementation in Subjects With SCD

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Sickle Cell Anemia in Children, Vitamin A Deficiency in Children

Intervention / Treatment
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* Dietary Supplement: retinyl palmitate


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 9 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Subjects in parallel groups will be randomized to one of two doses of vitamin A supplementation.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Lower Dose Vitamin A<br>Subjects with SCD-SS in the lower dose Vitamin A arm receive 3000IU of retinyl palmitate daily for 8 weeks. | Dietary Supplement: retinyl palmitate<br>* The intervention is a daily vitamin A supplement.<br>|
| Active Comparator: Higher Dose Vitamin A<br>Subjects with SCD-SS in the higher dose Vitamin A arm receive 6000IU of retinyl palmitate daily for 8 weeks. | Dietary Supplement: retinyl palmitate<br>* The intervention is a daily vitamin A supplement.<br>|
| No Intervention: Healthy Comparison Arm<br>Healthy subjects receive no intervention and undergo comparisons to the two vitamin A supplementation arms at baseline. | |

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Retinol, Stable isotope dilution, DXA, retinyl palmitate