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

• ClinicalTrials.gov Identifier: NCT04170348
• Recruitment Status: Active, not recruiting
• First Posted: November 20, 2019
• Last Update Posted: March 21, 2023
• Sponsor: Gary M Brittenham, MD
• Information provided by (Responsible Party): Gary M Brittenham, MD, Columbia University

Study Description

Brief Summary:

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).

Condition or disease	Intervention/treatment	Phase
Sickle Cell Disease; Anemia, Sickle Cell; Anemia, Hemolytic, Congenital; Respiratory Tract Diseases; Respiration Disorders; Acute Chest Syndrome; Lung Diseases; Asthma; Respiratory Tract Infections; Nutrition Disorders; Deficiency Diseases Vitamin; Vitamin D Deficiency	Drug: Daily oral vitamin D3, 3,333 IU; Drug: Bolus oral vitamin D3, 100,000 IU; Drug: Placebo oral tablet	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 69 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Controlled, double-masked, randomized Phase 2 clinical trial
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Masking will be performed by the Research Pharmacy; all other research staff and participants will be blinded to allocation.
• Primary Purpose: Prevention
• Official Title: Daily Vitamin D for Sickle-cell Respiratory Complications
• Actual Study Start Date: September 15, 2020
• Estimated Primary Completion Date: June 30, 2024
• Estimated Study Completion Date: February 28, 2025

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures :

1. 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 Outcome Measures :

1. Change in Forced Vital Capacity (FVC) [ Time Frame: Baseline and month 24 ]
   Change forced vital capacity (FVC; % predicted) from baseline
2. Change in Forced Expiratory Volume in 1 second (FEV1) [ Time Frame: Baseline and month 24 ]
   Change in Forced Expiratory Volume in 1 second (FEV1; % predicted) from baseline.
3. Change in Forced Expiratory Volume in 1 second (FEV1)/Forced Vital Capacity ratio [ Time Frame: Baseline and month 24 ]
   Change in Forced Expiratory Volume in 1 second (FEV1; % predicted)/Forced Vital Capacity (FVC) [FEV1/FVC] % predicted from baseline.
4. Change in Forced Expiratory Flow at 25%-75% vital capacity (FEF25-75) [ Time Frame: Baseline and month 24 ]
   Change in Forced Expiratory Flow at 25%-75% vital capacity (FEF25-75) % predicted from baseline.
5. Change in ratio of Residual Lung Volume (RV) to Total Lung Capacity (TLC) [ Time Frame: Baseline and month 24 ]
   Change in per cent of the ratio of Residual Lung Volume (RV) to Total Lung Capacity (RV/TLC) from baseline.
6. Change in Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO) [ Time Frame: Baseline and month 24 ]
   Change in Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO; % predicted) from baseline
7. Change in Fractional Concentration of Exhaled Nitric Oxide (FENO) [ Time Frame: Baseline and month 24 ]
   Change in Fractional Concentration of Exhaled Nitric Oxide (FENO) in parts per billion (ppb) from baseline
8. Change in Maximum Inspiratory Pressure (MIP) [ Time Frame: Baseline and month 24 ]
   Change in Maximum Inspiratory Pressure (MIP; cm H2O) from baseline
9. Change in Maximum Expiratory Pressure (MEP) [ Time Frame: Baseline and month 24 ]
   Change in Maximum Expiratory Pressure (MEP; cm H2O) from baseline
10. 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
11. 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
12. 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
13. 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
14. 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
15. 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
16. 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
17. Change in blood hemoglobin concentration (Hb) [ Time Frame: Baseline up to month 24 ]
    Change in blood hemoglobin concentration (Hb; g/dL) from baseline
18. Change in blood platelet concentration [ Time Frame: Baseline up to month 24 ]
    Change in blood platelet concentration (platelets/mL) from baseline
19. 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
20. 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
21. 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
22. 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
23. 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
24. 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.=

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

United States, New York

Columbia University Medical Center

New York, New York, United States, 10032

Sponsors and Collaborators

Gary M Brittenham, MD

Investigators

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

More Information

Additional Information:

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 

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.

• Responsible Party: Gary M Brittenham, MD, James A. Wolff Professor of Pediatrics and Professor of Medicine, Columbia University
• ClinicalTrials.gov Identifier: NCT04170348
• Other Study ID Numbers: AAAS0396; R01FD006372 ( U.S. FDA Grant/Contract )
• First Posted: November 20, 2019
• Last Update Posted: March 21, 2023
• Last Verified: September 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Gary M Brittenham, MD, Columbia University:

Sickle Cell Disease; Acute Chest Syndrome; Respiratory Complication; Vitamin D Deficiency

Additional relevant MeSH terms:

Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases; Acute Chest Syndrome; Respiration Disorders; Anemia; Anemia, Sickle Cell; Anemia, Hemolytic; Anemia, Hemolytic, Congenital; Vitamin D Deficiency; Nutrition Disorders; Deficiency Diseases; Vitamin A Deficiency; Disease; Pathologic Processes; Hematologic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Avitaminosis; Malnutrition; Infections; Vitamin D; Ergocalciferols; Cholecalciferol; Vitamins; Trientine; Micronutrients; Physiological Effects of Drugs; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents