Acute Chest Syndrome, Anemia, Hemolytic, Congenital, Anemia, Sickle Cell, Asthma, Deficiency Diseases Vitamin, Lung Diseases, Nutrition Disorders, Respiration Disorders, Respiratory Tract Diseases, Respiratory Tract Infections, Sickle Cell Disease, Vitamin D Deficiency
Conditions
Keywords
Sickle Cell Disease, Acute Chest Syndrome, Respiratory Complication, Vitamin D Deficiency
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.
Interventions
DRUGDaily oral vitamin D3, 3,333 IU
Oral vitamin D3, 3,333 IU, will be administered daily.
DRUGMonthly oral vitamin D3, 100,000 IU
Oral vitamin D3, 100,000 IU, will be administered monthly.
DRUGPlacebo oral tablet
Participants randomized to receive once monthly oral bolus of vitamin D3, will receive placebo on all other days of the month.
Sponsors
FDA Office of Orphan Products Development
Columbia University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Masking will be performed by the Research Pharmacy; all other research staff and participants will be blinded to allocation.
Intervention model description
Controlled, double-masked, randomized Phase 2 clinical trial
Eligibility
Sex/Gender
ALL
Age
3 Years to 20 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Annual Rate of Respiratory Events | Month 12, Month 24 | 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
| Measure | Time frame | Description |
|---|---|---|
| Forced Expiratory Volume in 1 Second (FEV1) | Baseline, Month 24 | Forced Expiratory Volume in 1 second (FEV1; % predicted) at baseline and at month 24. |
| Forced Expiratory Volume in 1 Second (FEV1)/Forced Vital Capacity Ratio | Baseline, Month 24 | Forced Expiratory Volume in 1 second (FEV1; % predicted)/Forced Vital Capacity (FVC) \[FEV1/FVC\] % predicted at baseline and month 24 |
| Forced Expiratory Flow at 25%-75% Vital Capacity (FEF25-75, % Predicted) | Baseline, Month 24 | Forced Expiratory Flow at 25%-75% vital capacity (FEF25-75) % predicted at baseline and month 24 . |
| Ratio of Residual Lung Volume (RV) to Total Lung Capacity (TLC) | Baseline, Month 24 | Ratio of Residual Lung Volume (RV) to Total Lung Capacity (RV/TLC) at baseline and month 24. |
| Mean Forced Vital Capacity (FVC % Predicted) | Baseline, Month 24 | This is to measure the forced vital capacity (FVC; % predicted) at baseline and at month 24. Forced Vital Capacity (FVC) is a key measure of lung function that indicates the total volume of air a person can forcefully exhale after taking a deep breath. It is calculated using spirometry, which assesses lung capacity and helps diagnose respiratory conditions. Predicted FVC: The FVC is compared to predicted values based on age, height, and sex to determine if it is within the normal range (80% or more of predicted). Interpretation: A low FVC may indicate obstruction (e.g., asthma or COPD), while a high FVC may suggest restriction in lung function. Baseline Measurement: It is essential to establish a baseline FVC to monitor changes over time and assess the effectiveness of treatments. For accurate interpretation, it is crucial to compare FVC results with other measurements, such as FEV1, to identify the presence of obstructive or restrictive lung disease. |
| Neutrophil Count | Baseline, Month 12, Month 24 | Blood Neutrophil Count in percentage at baseline, month 12 and month 24 |
| Platelet Count | Baseline, Month 12, Month 24 | Blood Platelet Count (Platelets\*10\^3/ per μL) at baseline, month 12 and month 24 |
| Serum C-reactive Protein (CRP) | Baseline, Month 12, Month 24 | Serum C-reactive protein (CRP; mg/L) at baseline, month 12 and month 24 |
| Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO) | Baseline, Month 24 | Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO; % predicted) at baseline and month 24 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Daily Oral Vitamin D3 Oral vitamin D3, 3,333 IU
Daily oral vitamin D3, 3,333 IU: Oral vitamin D3, 3,333 IU, will be administered daily. | 27 |
| Monthly Bolus Oral Vitamin D3 Bolus oral vitamin D3, 100,000 IU
Bolus oral vitamin D3, 100,000 IU: Bolus oral vitamin D3, 100,000 IU, will be administered monthly.
Placebo oral tablet: Participants randomized to receive once monthly oral bolus of vitamin D3, will receive placebo on all other days of the month. | 31 |
| Total | 58 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Lost to Follow-up | 2 | 2 |
| Overall Study | Non-adherence | 1 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 5 |
Baseline characteristics
| Characteristic | Daily Oral Vitamin D3 | Monthly Bolus Oral Vitamin D3 | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 25 Participants | 30 Participants | 55 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 1 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 17 Participants | 17 Participants | 34 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 12 Participants | 21 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants | 17 Participants | 28 Participants |
| Race (NIH/OMB) More than one race | 8 Participants | 4 Participants | 12 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 4 Participants | 8 Participants |
| Race (NIH/OMB) White | 4 Participants | 6 Participants | 10 Participants |
| Region of Enrollment United States | 27 participants | 31 participants | 58 participants |
| Sex: Female, Male Female | 12 Participants | 16 Participants | 28 Participants |
| Sex: Female, Male Male | 15 Participants | 15 Participants | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 27 | 0 / 31 |
| other Total, other adverse events | 23 / 27 | 19 / 31 |
| serious Total, serious adverse events | 8 / 27 | 3 / 31 |
Outcome results
Primary
Annual Rate of Respiratory Events
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.
Time frame: Month 12, Month 24
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Daily Oral Vitamin D3 | Annual Rate of Respiratory Events | Treatment Year 1 | 3.3 Respiratory events per year | Standard Deviation 2.1 |
| Daily Oral Vitamin D3 | Annual Rate of Respiratory Events | Treatment Year 2 | 3.4 Respiratory events per year | Standard Deviation 1.7 |
| Monthly Bolus Oral Vitamin D3 | Annual Rate of Respiratory Events | Treatment Year 1 | 3.3 Respiratory events per year | Standard Deviation 2.6 |
| Monthly Bolus Oral Vitamin D3 | Annual Rate of Respiratory Events | Treatment Year 2 | 3.2 Respiratory events per year | Standard Deviation 2.4 |
Secondary
Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO)
Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO; % predicted) at baseline and month 24
Time frame: Baseline, Month 24
Population: Due to COVID-19 restrictions, data was only collected/analyzed for 11 out of 27 at baseline and 16 out of 27 at month 24 for DAILY ARM; data was collected/analyzed for 12 out of 31 at baseline and 18 out 31 at month 24 for MONTHLY ARM.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Daily Oral Vitamin D3 | Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO) | Baseline | 87.3 percent predicted | Standard Deviation 10.3 |
| Daily Oral Vitamin D3 | Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO) | Month 24 | 86.5 percent predicted | Standard Deviation 12.5 |
| Monthly Bolus Oral Vitamin D3 | Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO) | Baseline | 85.3 percent predicted | Standard Deviation 15.8 |
| Monthly Bolus Oral Vitamin D3 | Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO) | Month 24 | 90.0 percent predicted | Standard Deviation 14.1 |
Secondary
Forced Expiratory Flow at 25%-75% Vital Capacity (FEF25-75, % Predicted)
Forced Expiratory Flow at 25%-75% vital capacity (FEF25-75) % predicted at baseline and month 24 .
Time frame: Baseline, Month 24
Population: Due to COVID-19 restrictions, data was only collected/analyzed for 13 out of 27 at baseline and 18 out of 27 at month 24 for DAILY ARM; data was collected/analyzed for 14 out of 31 at baseline and 21 out 31 at month 24 for MONTHLY ARM.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Daily Oral Vitamin D3 | Forced Expiratory Flow at 25%-75% Vital Capacity (FEF25-75, % Predicted) | Baseline | 80.9 percent predicted | Standard Deviation 22.3 |
| Daily Oral Vitamin D3 | Forced Expiratory Flow at 25%-75% Vital Capacity (FEF25-75, % Predicted) | Month 24 | 81.1 percent predicted | Standard Deviation 26.5 |
| Monthly Bolus Oral Vitamin D3 | Forced Expiratory Flow at 25%-75% Vital Capacity (FEF25-75, % Predicted) | Baseline | 86.6 percent predicted | Standard Deviation 24.8 |
| Monthly Bolus Oral Vitamin D3 | Forced Expiratory Flow at 25%-75% Vital Capacity (FEF25-75, % Predicted) | Month 24 | 83.7 percent predicted | Standard Deviation 25 |
Secondary
Forced Expiratory Volume in 1 Second (FEV1)
Forced Expiratory Volume in 1 second (FEV1; % predicted) at baseline and at month 24.
Time frame: Baseline, Month 24
Population: Due to COVID-19 restrictions, data was only collected/analyzed for 13 out of 27 at baseline and 18 out of 27 at month 24 for DAILY ARM; data was collected/analyzed for 14 out of 31 at baseline and 21 out 31 at month 24 for MONTHLY ARM.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Daily Oral Vitamin D3 | Forced Expiratory Volume in 1 Second (FEV1) | Baseline | 84.6 percent predicted | Standard Deviation 9.2 |
| Daily Oral Vitamin D3 | Forced Expiratory Volume in 1 Second (FEV1) | Month 24 | 85.5 percent predicted | Standard Deviation 12.6 |
| Monthly Bolus Oral Vitamin D3 | Forced Expiratory Volume in 1 Second (FEV1) | Baseline | 84.4 percent predicted | Standard Deviation 12.5 |
| Monthly Bolus Oral Vitamin D3 | Forced Expiratory Volume in 1 Second (FEV1) | Month 24 | 90.8 percent predicted | Standard Deviation 12.9 |
Secondary
Forced Expiratory Volume in 1 Second (FEV1)/Forced Vital Capacity Ratio
Forced Expiratory Volume in 1 second (FEV1; % predicted)/Forced Vital Capacity (FVC) \[FEV1/FVC\] % predicted at baseline and month 24
Time frame: Baseline, Month 24
Population: Due to COVID-19 restrictions, data was only collected/analyzed for 13 out of 27 at baseline and 18 out of 27 at month 24 for DAILY ARM; data was collected/analyzed for 14 out of 31 at baseline and 21 out 31 at month 24 for MONTHLY ARM.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Daily Oral Vitamin D3 | Forced Expiratory Volume in 1 Second (FEV1)/Forced Vital Capacity Ratio | Baseline | 97.9 ratio | Standard Deviation 6.5 |
| Daily Oral Vitamin D3 | Forced Expiratory Volume in 1 Second (FEV1)/Forced Vital Capacity Ratio | Month 24 | 97.5 ratio | Standard Deviation 8 |
| Monthly Bolus Oral Vitamin D3 | Forced Expiratory Volume in 1 Second (FEV1)/Forced Vital Capacity Ratio | Baseline | 100.1 ratio | Standard Deviation 8 |
| Monthly Bolus Oral Vitamin D3 | Forced Expiratory Volume in 1 Second (FEV1)/Forced Vital Capacity Ratio | Month 24 | 97.7 ratio | Standard Deviation 9.8 |
Secondary
Mean Forced Vital Capacity (FVC % Predicted)
This is to measure the forced vital capacity (FVC; % predicted) at baseline and at month 24. Forced Vital Capacity (FVC) is a key measure of lung function that indicates the total volume of air a person can forcefully exhale after taking a deep breath. It is calculated using spirometry, which assesses lung capacity and helps diagnose respiratory conditions. Predicted FVC: The FVC is compared to predicted values based on age, height, and sex to determine if it is within the normal range (80% or more of predicted). Interpretation: A low FVC may indicate obstruction (e.g., asthma or COPD), while a high FVC may suggest restriction in lung function. Baseline Measurement: It is essential to establish a baseline FVC to monitor changes over time and assess the effectiveness of treatments. For accurate interpretation, it is crucial to compare FVC results with other measurements, such as FEV1, to identify the presence of obstructive or restrictive lung disease.
Time frame: Baseline, Month 24
Population: Due to COVID-19 restrictions, data was only collected/analyzed for 13 out of 27 at baseline and 18 out of 27 at month 24 for DAILY ARM; data was collected/analyzed for 14 out of 31 at baseline and 21 out 31 at month 24 for MONTHLY ARM.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Daily Oral Vitamin D3 | Mean Forced Vital Capacity (FVC % Predicted) | Month 24 | 83.2 percent predicted | Standard Deviation 9.9 |
| Daily Oral Vitamin D3 | Mean Forced Vital Capacity (FVC % Predicted) | Baseline | 86.3 percent predicted | Standard Deviation 9.4 |
| Monthly Bolus Oral Vitamin D3 | Mean Forced Vital Capacity (FVC % Predicted) | Baseline | 84.3 percent predicted | Standard Deviation 13.2 |
| Monthly Bolus Oral Vitamin D3 | Mean Forced Vital Capacity (FVC % Predicted) | Month 24 | 88.7 percent predicted | Standard Deviation 11.8 |
Secondary
Neutrophil Count
Blood Neutrophil Count in percentage at baseline, month 12 and month 24
Time frame: Baseline, Month 12, Month 24
Population: Data was collected and analyzed only for the following numbers of study participants out of 27 for DAILY ARM and 31 for MONTHLY ARM at each time point due to some study participants did not complete the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Daily Oral Vitamin D3 | Neutrophil Count | Baseline | 45.8 Percentage of Neutrophils | Standard Deviation 13.5 |
| Daily Oral Vitamin D3 | Neutrophil Count | Month 12 | 47.7 Percentage of Neutrophils | Standard Deviation 13.8 |
| Daily Oral Vitamin D3 | Neutrophil Count | Month 24 | 45.5 Percentage of Neutrophils | Standard Deviation 14.8 |
| Monthly Bolus Oral Vitamin D3 | Neutrophil Count | Baseline | 43.9 Percentage of Neutrophils | Standard Deviation 9.6 |
| Monthly Bolus Oral Vitamin D3 | Neutrophil Count | Month 12 | 43.0 Percentage of Neutrophils | Standard Deviation 11 |
| Monthly Bolus Oral Vitamin D3 | Neutrophil Count | Month 24 | 46.8 Percentage of Neutrophils | Standard Deviation 12 |
Secondary
Platelet Count
Blood Platelet Count (Platelets\*10\^3/ per μL) at baseline, month 12 and month 24
Time frame: Baseline, Month 12, Month 24
Population: Data was collected and analyzed only for the following numbers of study participants out of 27 for DAILY ARM and 31 for MONTHLY ARM at each time point due to some study participants did not complete the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Daily Oral Vitamin D3 | Platelet Count | Baseline | 355.1 Platelets *10^3/ per μL | Standard Deviation 191.1 |
| Daily Oral Vitamin D3 | Platelet Count | Month 12 | 390.0 Platelets *10^3/ per μL | Standard Deviation 125 |
| Daily Oral Vitamin D3 | Platelet Count | Month 24 | 398.9 Platelets *10^3/ per μL | Standard Deviation 157.3 |
| Monthly Bolus Oral Vitamin D3 | Platelet Count | Baseline | 376.2 Platelets *10^3/ per μL | Standard Deviation 242 |
| Monthly Bolus Oral Vitamin D3 | Platelet Count | Month 12 | 387.2 Platelets *10^3/ per μL | Standard Deviation 191.8 |
| Monthly Bolus Oral Vitamin D3 | Platelet Count | Month 24 | 359.9 Platelets *10^3/ per μL | Standard Deviation 150.1 |
Secondary
Ratio of Residual Lung Volume (RV) to Total Lung Capacity (TLC)
Ratio of Residual Lung Volume (RV) to Total Lung Capacity (RV/TLC) at baseline and month 24.
Time frame: Baseline, Month 24
Population: Due to COVID-19 restrictions, data was only collected/analyzed for 11 out of 27 at baseline and 16 out of 27 at month 24 for DAILY ARM; data was collected/analyzed for 12 out of 31 at baseline and 18 out 31 at month 24 for MONTHLY ARM.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Daily Oral Vitamin D3 | Ratio of Residual Lung Volume (RV) to Total Lung Capacity (TLC) | Baseline | 121.0 ratio | Standard Deviation 28.2 |
| Daily Oral Vitamin D3 | Ratio of Residual Lung Volume (RV) to Total Lung Capacity (TLC) | Month 24 | 106.9 ratio | Standard Deviation 34.6 |
| Monthly Bolus Oral Vitamin D3 | Ratio of Residual Lung Volume (RV) to Total Lung Capacity (TLC) | Baseline | 101.2 ratio | Standard Deviation 28.9 |
| Monthly Bolus Oral Vitamin D3 | Ratio of Residual Lung Volume (RV) to Total Lung Capacity (TLC) | Month 24 | 109.1 ratio | Standard Deviation 19 |
Secondary
Serum C-reactive Protein (CRP)
Serum C-reactive protein (CRP; mg/L) at baseline, month 12 and month 24
Time frame: Baseline, Month 12, Month 24
Population: Data was collected and analyzed only for the following numbers of study participants out of 27 for DAILY ARM and 31 for MONTHLY ARM at each time point due to some study participants did not complete the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Daily Oral Vitamin D3 | Serum C-reactive Protein (CRP) | Baseline | 2.1 mg/L | Standard Deviation 2.6 |
| Daily Oral Vitamin D3 | Serum C-reactive Protein (CRP) | Month 12 | 5.9 mg/L | Standard Deviation 13.7 |
| Daily Oral Vitamin D3 | Serum C-reactive Protein (CRP) | Month 24 | 3.0 mg/L | Standard Deviation 2.9 |
| Monthly Bolus Oral Vitamin D3 | Serum C-reactive Protein (CRP) | Baseline | 2.9 mg/L | Standard Deviation 3.7 |
| Monthly Bolus Oral Vitamin D3 | Serum C-reactive Protein (CRP) | Month 12 | 3.6 mg/L | Standard Deviation 5 |
| Monthly Bolus Oral Vitamin D3 | Serum C-reactive Protein (CRP) | Month 24 | 4.6 mg/L | Standard Deviation 7.9 |