Daily Vitamin D for Sickle-cell Respiratory Complications

Study Overview
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Brief Summary
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This study aims to answer the question whether daily oral vitamin D supplementation can reduce the risk of respiratory or lung complications in children and adolescents with sickle cell disease. Respiratory problems are the leading causes of sickness and of death in sickle cell disease. The investigators hypothesize that daily oral vitamin D3, compared to monthly oral vitamin D, will rapidly increase circulating vitamin D3, and reduce the rate of respiratory complications by 50% or more within the first year of supplementation in children and adolescents with sickle cell disease. This study is funded by the FDA Office of Orphan Products Development (OOPD).

Detailed Description
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This is a 2-year controlled, double-blind, randomized Phase 2 clinical trial comparing the efficacy in reducing the rate of respiratory events in sickle-cell disease of daily oral vitamin D3 (3,333 IU/d) with monthly bolus oral vitamin D3, (100,000 IU/mo) as a control. The scientific premise of the clinical trial is that circulating concentrations of vitamin D3, the parent compound, are the principal determinant of the anti-infective and immunomodulatory effects of supplementation. Eligible participants will be initially screened to determine their blood vitamin D levels. Those with 25-hydroxyvitamin D levels between 5 and 60 ng/mL will be assigned by chance to one of the two arms for 24 months. Participants will be checked every month and will have periodic blood and urine tests to monitor for any side effects of the study treatments. Children above 5 y/o who can cooperate and understand the procedure will have lung function test at baseline and at 24 months. Showing that a monthly dose of vitamin D reduces lung infections, asthma and the acute chest syndrome could help establish this simple, low-cost treatment as a way to decrease sickness and deaths in children and adolescents with sickle-cell disease.

Official Title
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Daily Vitamin D for Sickle-cell Respiratory Complications

Conditions
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Asthma, Sickle Cell Disease, Anemia, Sickle Cell, Anemia, Hemolytic, Congenital, Respiratory Tract Diseases, Respiration Disorders, Acute Chest Syndrome, Lung Diseases, Respiratory Tract Infections, Nutrition Disorders, Deficiency Diseases Vitamin, Vitamin D Deficiency

Intervention / Treatment
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* Drug: Daily oral vitamin D3, 3,333 IU
* Drug: Bolus oral vitamin D3, 100,000 IU
* Drug: Placebo oral tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of sickle cell disease (Hb SS, Hb SC, Hb S-Beta-thalassemia) Age 3-20 years old Exclusion Criteria: Patient unwilling or unable to provide written informed consent (and assent, if applicable) Patient unable or unwilling to comply with requirements of the clinical trial Participation in another clinical trial Current diagnosis of rickets History of hypercalcemia or diagnosis of any medical condition associated with hypercalcemia, including primary hyperparathyroidism, malignancy, sarcoidosis, tuberculosis, granulomatous disease, familial hypocalciuric hypercalcemia Current use of corticosteroids, excluding inhaled steroids Current use of anticonvulsants (phenytoin, phenobarbital, carbamazepine) Therapy with thiazide diuretics or lithium carbonate Known liver or renal disease Patients taking medications for pulmonary complications of sickle cell disease not on a stable dose of medications, as defined by a change in medications or doses within the three months prior to study entry Patients on chronic red blood cell transfusion therapy

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Controlled, double-masked, randomized Phase 2 clinical trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Daily oral vitamin D3<br>Oral vitamin D3, 3,333 IU | Drug: Daily oral vitamin D3, 3,333 IU<br>* Oral vitamin D3, 3,333 IU, will be administered daily.<br>* Other names: 10-secocholeta-5,7,10(19)-trien-3B-ol for oral administration;|
| Active Comparator: Monthly bolus oral vitamin D3<br>Bolus oral vitamin D3, 100,000 IU | Drug: Bolus oral vitamin D3, 100,000 IU<br>* Bolus oral vitamin D3, 100,000 IU, will be administered monthly.<br>* Other names: 10-secocholeta-5,7,10(19)-trien-3B-ol for oral administration;Drug: Placebo oral tablet<br>* Participants randomized to receive once monthly oral bolus of vitamin D3, will receive placebo on all other days of the month.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Respiratory Events | Annual rate of respiratory events will be calculated as the sum of respiratory infection, asthma exacerbation, and acute chest syndrome, as ascertained by use of a validated questionnaire. | Screening up to month 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Forced Vital Capacity (FVC) | Change forced vital capacity (FVC; % predicted) from baseline | Baseline and month 24 | 
| Change in Forced Expiratory Volume in 1 second (FEV1) | Change in Forced Expiratory Volume in 1 second (FEV1; % predicted) from baseline. | Baseline and month 24 | 
| Change in Forced Expiratory Volume in 1 second (FEV1)/Forced Vital Capacity ratio | Change in Forced Expiratory Volume in 1 second (FEV1; % predicted)/Forced Vital Capacity (FVC) [FEV1/FVC] % predicted from baseline. | Baseline and month 24 | 
| Change in Forced Expiratory Flow at 25%-75% vital capacity (FEF25-75) | Change in Forced Expiratory Flow at 25%-75% vital capacity (FEF25-75) % predicted from baseline. | Baseline and month 24 | 
| Change in ratio of Residual Lung Volume (RV) to Total Lung Capacity (TLC) | Change in per cent of the ratio of Residual Lung Volume (RV) to Total Lung Capacity (RV/TLC) from baseline. | Baseline and month 24 | 
| Change in Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO) | Change in Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO; % predicted) from baseline | Baseline and month 24 | 
| Change in Fractional Concentration of Exhaled Nitric Oxide (FENO) | Change in Fractional Concentration of Exhaled Nitric Oxide (FENO) in parts per billion (ppb) from baseline | Baseline and month 24 | 
| Change in Maximum Inspiratory Pressure (MIP) | Change in Maximum Inspiratory Pressure (MIP; cm H2O) from baseline | Baseline and month 24 | 
| Change in Maximum Expiratory Pressure (MEP) | Change in Maximum Expiratory Pressure (MEP; cm H2O) from baseline | Baseline and month 24 | 
| Change in interleukin 2 (IL 2) concentration | Change in serum interleukin 2 concentration (IL 2; pg/mL ) from baseline | Baseline up to month 24 | 
| Change in interleukin 4 (IL 4) concentration | Change in serum interleukin 4 concentration (IL 4; pg/mL ) from baseline | Baseline up to month 24 | 
| Change in interleukin 5 (IL 5) concentration | Change in serum interleukin 5 concentration (IL 5; pg/mL ) from baseline | Baseline up to month 24 | 
| Change in interleukin 13 (IL 13) concentration | Change in serum interleukin 13 concentration (IL 13; pg/mL ) from baseline | Baseline up to month 24 | 
| Change in interferon gamma (IFN gamma). concentration | Change in serum interferon gamma concentration (IFN gamma; pg/mL ) from baseline | Baseline up to month 24 | 
| Change in interleukin 10 (IL 10) concentration | Change in serum interleukin 10 concentration (Iinterleukin 10; pg/mL ) from baseline | Baseline up to month 24 | 
| Change in Transforming Growth Factor beta (TGF beta) | Change in serum Transforming Growth Factor beta (TGF beta; pg/mL ) from baseline | Baseline up to month 24 | 
| Change in blood hemoglobin concentration (Hb) | Change in blood hemoglobin concentration (Hb; g/dL) from baseline | Baseline up to month 24 | 
| Change in blood platelet concentration | Change in blood platelet concentration (platelets/mL) from baseline | Baseline up to month 24 | 
| Change in serum C-reactive protein (CRP) | Change in serum C-reactive protein (CRP; mg/L) from baseline | Baseline up to month 24 | 
| Change in interleukin 1alpha (IL 1alpha) concentration | Change in serum interleukin 1alpha (IL 1alpha; pg/mL) from baseline | Baseline up to month 24 | 
| Change in interleukin 1beta (IL 1beta) concentration | Change in serum interleukin 1beta (IL 1beta; pg/mL) from baseline | Baseline up to month 24 | 
| Change in Tumor Necrosis Factor alpha (TNF alpha) concentration | Change in serum Tumor Necrosis Factor alpha (TNF alpha; pg/mL) from baseline | Baseline up to month 24 | 
| Change in C-terminal telopeptides of Type I collagen (CTX) | Change in serum C-terminal telopeptides of Type I collagen (CTX; ng/mL) from baseline | Baseline up to month 24 | 
| Change in intact N-terminal propeptide of type I procollagen (P1NP) | Chang in serum intact N-terminal propeptide of type I procollagen (P1NP; µg/L) from baseline.= | Baseline up to month 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sickle Cell Disease, Acute Chest Syndrome, Respiratory Complication, Vitamin D Deficiency