Daily Vitamin D for Sickle-cell Respiratory Complications

Overview

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).

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Prevention
    • Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: March 15, 2023

Detailed Description

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 once a year. 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.

Interventions

  • Drug: Daily oral vitamin D3, 3,333 IU
    • Oral vitamin D3, 3,333 IU, will be administered daily.
  • Drug: Bolus oral vitamin D3, 100,000 IU
    • Bolus oral vitamin D3, 100,000 IU, will be administered monthly.
  • Drug: Placebo oral tablet
    • Participants randomized to receive once monthly oral bolus of vitamin D3, will receive placebo on all other days of the month.

Arms, Groups and Cohorts

  • Experimental: Daily oral vitamin D3
    • Oral vitamin D3, 3,333 IU
  • Active Comparator: Monthly bolus oral vitamin D3
    • Bolus oral vitamin D3, 100,000 IU

Clinical Trial Outcome Measures

Primary Measures

  • Rate of Respiratory Events
    • Time Frame: Screening up to month 24
    • 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.

Secondary Measures

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

Participating in This Clinical Trial

Inclusion Criteria

1. Diagnosis of sickle cell disease (Hb SS, Hb SC, Hb S-Beta-thalassemia) 2. Age 3-20 years old Exclusion Criteria:

1. Patient unwilling or unable to provide written informed consent (and assent, if applicable) 2. Patient unable or unwilling to comply with requirements of the clinical trial 3. Participation in another clinical trial 4. Current diagnosis of rickets 5. History of hypercalcemia or diagnosis of any medical condition associated with hypercalcemia, including primary hyperparathyroidism, malignancy, sarcoidosis, tuberculosis, granulomatous disease, familial hypocalciuric hypercalcemia 6. Current use of corticosteroids, excluding inhaled steroids 7. Current use of anticonvulsants (phenytoin, phenobarbital, carbamazepine) 8. Therapy with thiazide diuretics or lithium carbonate 9. Known liver or renal disease 10. 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 11. Patients on chronic red blood cell transfusion therapy

Gender Eligibility: All

Minimum Age: 3 Years

Maximum Age: 20 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Gary M Brittenham, MD
  • Provider of Information About this Clinical Study
    • Sponsor-Investigator: Gary M Brittenham, MD, James A. Wolff Professor of Pediatrics and Professor of Medicine – Columbia University
  • Overall Official(s)
    • Gary M Brittenham, MD, Principal Investigator, Columbia University
    • Margaret T Lee, MD, Principal Investigator, Columbia University
  • Overall Contact(s)
    • Gary M Brittenham, MD, 212 305 7005, gmb31@cumc.columbia.edu

References

Lee MT, Kattan M, Fennoy I, Arpadi SM, Miller RL, Cremers S, McMahon DJ, Nieves JW, Brittenham GM. Randomized phase 2 trial of monthly vitamin D to prevent respiratory complications in children with sickle cell disease. Blood Adv. 2018 May 8;2(9):969-978. doi: 10.1182/bloodadvances.2017013979.

Williams KM, Lee MT, Licursi M, Brittenham GM, Fennoy I. Response to Long-term Vitamin D Therapy for Bone Disease in Children With Sickle Cell Disease. J Pediatr Hematol Oncol. 2018 Aug;40(6):458-461. doi: 10.1097/MPH.0000000000001155.

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