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

Tracking Information

• First Submitted Date: October 1, 2019
• First Posted Date: November 20, 2019
• Last Update Posted Date: March 21, 2023
• Actual Study Start Date: September 15, 2020
• Estimated Primary Completion Date: June 30, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 18, 2019)

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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: June 21, 2022)

• Change in Forced Vital Capacity (FVC) [ Time Frame: Baseline and month 24 ]
  Change forced vital capacity (FVC; % predicted) from baseline
• 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.
• 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.
• 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.
• 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.
• 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
• 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
• Change in Maximum Inspiratory Pressure (MIP) [ Time Frame: Baseline and month 24 ]
  Change in Maximum Inspiratory Pressure (MIP; cm H2O) from baseline
• Change in Maximum Expiratory Pressure (MEP) [ Time Frame: Baseline and 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.=

Original Secondary Outcome Measures (submitted: November 18, 2019)

• 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.=

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Daily Vitamin D for Sickle-cell Respiratory Complications
• Official Title: Daily Vitamin D for Sickle-cell Respiratory Complications

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).

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
• Study Phase: Phase 2

Study Design

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

Condition

• 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

Intervention

• 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
• 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.

Study Arms

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

  • Drug: Bolus oral vitamin D3, 100,000 IU
  • Drug: Placebo oral tablet

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.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: September 29, 2022): 69
• Original Estimated Enrollment (submitted: November 18, 2019): 130
• Estimated Study Completion Date: February 28, 2025
• Estimated Primary Completion Date: June 30, 2024 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 3 Years to 20 Years (Child, Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04170348
• Other Study ID Numbers: AAAS0396; R01FD006372 ( U.S. FDA Grant/Contract )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Gary M Brittenham, MD, Columbia University
• Original Responsible Party: Same as current
• Current Study Sponsor: Gary M Brittenham, MD
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

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

• PRS Account: Columbia University
• Verification Date: September 2022