Daily Vitamin D for Sickle-cell Respiratory Complications (ViDAS-2)

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 Overview

• Status: Active, not recruiting
• Conditions: Respiratory Tract Infections; Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; Nutrition Disorders; Vitamin D Deficiency; Asthma; Sickle Cell Disease; Anemia, Sickle Cell; Anemia, Hemolytic, Congenital; Acute Chest Syndrome; Deficiency Diseases Vitamin
• Intervention / Treatment: Drug: Daily oral vitamin D3, 3,333 IU; Drug: Bolus oral vitamin D3, 100,000 IU; Drug: Placebo oral tablet

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 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.

• Study Type: Interventional
• Enrollment (Actual): 69
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 20 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Daily oral vitamin D3; Oral vitamin D3, 3,333 IU	Drug: Daily oral vitamin D3, 3,333 IU; Oral vitamin D3, 3,333 IU, will be administered daily.; Other Names: Cholecalciferol for oral administration; 10-secocholeta-5,7,10(19)-trien-3B-ol for oral administration
Active Comparator: Monthly bolus oral vitamin D3; Bolus oral vitamin D3, 100,000 IU	Drug: Bolus oral vitamin D3, 100,000 IU; Bolus oral vitamin D3, 100,000 IU, will be administered monthly.; Other Names: Cholecalciferol for oral administration; 10-secocholeta-5,7,10(19)-trien-3B-ol for oral administration; 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Gary M Brittenham, MD
• Investigators: Principal Investigator: Gary M Brittenham, MD, Columbia University; Principal Investigator: Margaret T Lee, MD, Columbia University

Publications and helpful links

General Publications

• 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.
• De A, Anekwe CV, Kattan M, Yao Y, Jin Z, Brittenham GM, Lee MT. Validation of a Questionnaire to Identify Respiratory Tract Infections in Children With Sickle Cell Disease. J Pediatr Hematol Oncol. 2021 Jul 1;43(5):e661-e665. doi: 10.1097/MPH.0000000000002164.

Helpful Links

• Response to Long-term Vitamin D Therapy for Bone Disease in Children With Sickle Cell Disease.
• Randomized phase 2 trial of monthly vitamin D to prevent respiratory complications in children with sickle cell disease

Study record dates

Study Major Dates

• Study Start (Actual): September 15, 2020
• Primary Completion (Estimated): June 30, 2024
• Study Completion (Estimated): February 28, 2025

Study Registration Dates

• First Submitted: October 1, 2019
• First Submitted That Met QC Criteria: November 18, 2019
• First Posted (Actual): November 20, 2019

Study Record Updates

• Last Update Posted (Actual): March 27, 2024
• Last Update Submitted That Met QC Criteria: March 26, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Sickle Cell Disease; Vitamin D Deficiency; Acute Chest Syndrome; Respiratory Complication
• Additional Relevant MeSH Terms: Infections; Hematologic Diseases; Genetic Diseases, Inborn; Avitaminosis; Malnutrition; Hemoglobinopathies; Lung Diseases; Vitamin D Deficiency; Anemia; Anemia, Sickle Cell; Respiratory Tract Infections; Vitamin A Deficiency; Nutrition Disorders; Respiration Disorders; Respiratory Tract Diseases; Deficiency Diseases; Acute Chest Syndrome; Anemia, Hemolytic; Anemia, Hemolytic, Congenital; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Micronutrients; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Chelating Agents; Sequestering Agents; Vitamin D; Cholecalciferol; Vitamins; Ergocalciferols; Trientine
• Other Study ID Numbers: AAAS0396; R01FD006372 (U.S. FDA Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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