Acute Chest Syndrome, Asthma, Respiratory Infections, Sickle Cell Disease, Vitamin D Deficiency
Conditions
Keywords
sickle cell disease, acute chest syndrome, respiratory complications, vitamin D
Brief summary
This study aims to answer the question whether oral vitamin D supplementation can decrease lung complications in children and adolescents with sickle cell disease. Lung complications are the leading causes of morbidity and of death in sickle cell disease. Infections and increased inflammation play important roles in the development of the lung problems in sickle cell disease. Emerging evidence shows that vitamin D helps the immune system to fight infection and to control inflammation and could potentially help prevent respiratory complications in patients with sickle cell disease. The investigators hypothesize that oral vitamin D3, 100,000 IU (2.5 mg), given once a month to a group of children and adolescents with sickle cell disease, will reduce the rate of respiratory events (infection, asthma exacerbation and acute chest syndrome) compared to the rate in a group given standard dose oral vitamin D3, 12,000 IU (0.3 mg) given once a month. Funding Source - U.S. Food & Drug Administration, Office of Orphan Products Development
Detailed description
This study will be a Phase 2 double-blind randomized clinical trial in 80 patients with sickle cell disease, ages 3 to 20 years-old, comparing a 2-year monthly oral dose of vitamin D3, 100,000 IU (equivalent to 3,300 IU/day) to a standard monthly dose, 12,000 IU (400 IU/day) in reducing the rate of respiratory events (defined as respiratory infections, acute asthma exacerbation, and the acute chest syndrome) in children and adolescents with sickle cell disease in comparison with the rates of respiratory events over a baseline period of one year. Eligible participants (130 patients) will initially be screened to determine their blood vitamin D levels (serum 25-hydroxyvitamin D). Those with 25-hydroxyvitamin D levels between 5 and 60 ng/mL will be eligible for randomization. At study entry, blood and urine samples will be collected for routine and special blood tests including tests on immune function, inflammation, and bone function. Children above 5 years old will also have lung function and muscle strength tests. Participants will be followed once a month to administer the study medication (oral vitamin D3) and to monitor any side effects from the study medication by history, examination and blood and urine tests. After 12 and 24 months of therapy, the same study procedures at study entry will be repeated. This study could help establish oral vitamin D3 as a simple, low cost treatment to reduce respiratory complications in children and adolescents with sickle cell disease.
Interventions
DRUGExperimental: Vitamin D3 100,000 IU
Oral vitamin D3, 100,000 IU \[2.5 mg\] given once a month
DRUGActive Comparator: Vitamin D3 12,000 IU
Standard dose oral vitamin D3 12,000 IU \[0.3 mg\] given once a month
Sponsors
Gary M Brittenham, MD
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
3 Years to 20 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of sickle cell disease (HbSS, HbSC, HbS Beta-thalassemia) * Age 3 to 20 years old
Exclusion criteria
* Patient (or parent or guardian) unwilling or unable to provide written informed consent (and assent, if applicable) * Patient unable or unwilling to comply with requirements of the clinical trial * Participation in other therapeutic clinical trial * Current diagnosis of rickets * History of hypercalcemia or diagnosis of any medical condition associated with hypercalcemia, including primary hyperparathyroidism, malignancy, sarcoidosis, tuberculosis, granulomatous disease, familial hypocalciuric hypercalcemia * Current use of corticosteroids, excluding inhaled steroids * Current use of anticonvulsants (phenytoin, phenobarbital, carbamazepine) * Therapy with thiazide diuretics or lithium carbonate * Known liver or renal disease * 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 * Patients on chronic red blood cell transfusion therapy * Absence of baseline record of respiratory events (respiratory infections, asthma exacerbations, episodes of acute chest syndrome) for the preceding year * Pregnancy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Annual Rate of Respiratory Events | Up to 2 years | Defined as respiratory infection, acute asthma exacerbation, and acute chest syndrome. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Forced Vital Capacity (FVC) | Up to 2 years | Percent predicted forced vital capacity will be calculated for both groups. |
| Forced Expiratory Volume (FEV) in 1 Second (FEV1) | Up to 2 years | Percent predicted forced expiratory volume in 1 second will be calculated for both groups. |
| FEV1/FVC Ratio | Up to 2 years | The ratio of FEV1 to FVC will be calculated (in percentage). |
| FEF 25-75 | Up to 2 years | Percent predicted forced expiratory flow (FEF) during expiration of 25 to 75% of the FVC will be calculated. |
| RV/TLC Ratio | Up to 2 years | The ratio of residual volume (RV) to total lung capacity (TLC) will be calculated (in percentage). |
| DLCO | Up to 2 years | Percent predicted of the diffusing capacity for carbon monoxide in the lungs (DLCO) will be measured. |
| Mean 25-Hydroxyvitamin D (25-OHD) | 2 years | The overall mean serum 25-OHD concentration will be measured for both groups. |
| MIP | Up to 2 years | Maximum inspiratory pressure (MIP) will be measured. |
| MEP | Up to 2 years | Maximum expiratory pressure (MEP) will be measured. |
| Hand-grip, Right | Up to 2 years | Muscle strength was measured by looking at hand-grip strength in the right hand. |
| Hand-grip, Left | Up to 2 years | Muscle strength was measured by looking at hand-grip strength in the left hand. |
| Hand-grip, Dominant | Up to 2 years | Muscle strength was measured by looking at hand-grip strength in the dominant hand. |
| FeNO | Up to 2 years | Fractional exhaled nitric oxide (FeNO) will be measured in parts per billion (ppb). |
Countries
United States
Participant flow
Recruitment details
Participants were consented and then randomized. Only individuals who were randomized were included in the data analysis, so demographics are only available for the 62 randomized.
Pre-assignment details
Only participants who were randomized (62) were included in the analysis of data.
Participants by arm
| Arm | Count |
|---|---|
| Vitamin D3 100,000 IU Oral vitamin D3, 100,000 IU \[2.5 mg\] given once a month
Experimental: Vitamin D3 100,000 IU: Oral vitamin D3, 100,000 IU \[2.5 mg\] given once a month | 31 |
| Vitamin D3 12,000 IU Standard dose oral vitamin D3 12,000 IU \[0.3 mg\] given once a month
Active Comparator: Vitamin D3 12,000 IU: Standard dose oral vitamin D3 12,000 IU \[0.3 mg\] given once a month | 31 |
| Total | 62 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 |
| Overall Study | Lost to Follow-up | 2 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Vitamin D3 100,000 IU | Vitamin D3 12,000 IU | Total |
|---|---|---|---|
| Age, Continuous | 9.9 years STANDARD_DEVIATION 4 | 9.9 years STANDARD_DEVIATION 3.8 | 9.9 years STANDARD_DEVIATION 3.9 |
| Sex: Female, Male Female | 16 Participants | 16 Participants | 32 Participants |
| Sex: Female, Male Male | 15 Participants | 15 Participants | 30 Participants |
| Sickle-cell Type Sb0 thalassemia | 1 Participants | 1 Participants | 2 Participants |
| Sickle-cell Type Sb1 thalassemia | 1 Participants | 0 Participants | 1 Participants |
| Sickle-cell Type SC | 3 Participants | 2 Participants | 5 Participants |
| Sickle-cell Type SS | 26 Participants | 28 Participants | 54 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 26 / 31 | 24 / 31 |
| serious Total, serious adverse events | 11 / 31 | 6 / 31 |
Outcome results
Primary
Mean Annual Rate of Respiratory Events
Defined as respiratory infection, acute asthma exacerbation, and acute chest syndrome.
Time frame: Up to 2 years
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Vitamin D3 100,000 IU | Mean Annual Rate of Respiratory Events | Baseline | 3.91 events per year | Standard Deviation 0.35 |
| Vitamin D3 100,000 IU | Mean Annual Rate of Respiratory Events | Year 1 | 3.34 events per year | Standard Deviation 0.37 |
| Vitamin D3 100,000 IU | Mean Annual Rate of Respiratory Events | Year 2 | 1.54 events per year | Standard Deviation 0.37 |
| Vitamin D3 12,000 IU | Mean Annual Rate of Respiratory Events | Baseline | 4.34 events per year | Standard Deviation 0.35 |
| Vitamin D3 12,000 IU | Mean Annual Rate of Respiratory Events | Year 1 | 4.28 events per year | Standard Deviation 0.36 |
| Vitamin D3 12,000 IU | Mean Annual Rate of Respiratory Events | Year 2 | 1.49 events per year | Standard Deviation 0.37 |
Secondary
DLCO
Percent predicted of the diffusing capacity for carbon monoxide in the lungs (DLCO) will be measured.
Time frame: Up to 2 years
Population: Only includes participants who completed the assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Vitamin D3 100,000 IU | DLCO | Baseline | 68.0 Percentage predicted DLCO | Standard Deviation 3.2 |
| Vitamin D3 100,000 IU | DLCO | Year 1 | 62.9 Percentage predicted DLCO | Standard Deviation 3.2 |
| Vitamin D3 100,000 IU | DLCO | Year 2 | 68.1 Percentage predicted DLCO | Standard Deviation 3.8 |
| Vitamin D3 12,000 IU | DLCO | Baseline | 72.3 Percentage predicted DLCO | Standard Deviation 3.9 |
| Vitamin D3 12,000 IU | DLCO | Year 1 | 67.8 Percentage predicted DLCO | Standard Deviation 2.4 |
| Vitamin D3 12,000 IU | DLCO | Year 2 | 72.9 Percentage predicted DLCO | Standard Deviation 2.9 |
Secondary
FEF 25-75
Percent predicted forced expiratory flow (FEF) during expiration of 25 to 75% of the FVC will be calculated.
Time frame: Up to 2 years
Population: Only includes participants who completed the assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Vitamin D3 100,000 IU | FEF 25-75 | Baseline | 69.8 Percentage of predicted FEF | Standard Deviation 5.2 |
| Vitamin D3 100,000 IU | FEF 25-75 | Year 1 | 62.9 Percentage of predicted FEF | Standard Deviation 4.4 |
| Vitamin D3 100,000 IU | FEF 25-75 | Year 2 | 62.8 Percentage of predicted FEF | Standard Deviation 4.4 |
| Vitamin D3 12,000 IU | FEF 25-75 | Baseline | 68.8 Percentage of predicted FEF | Standard Deviation 4.9 |
| Vitamin D3 12,000 IU | FEF 25-75 | Year 1 | 64.8 Percentage of predicted FEF | Standard Deviation 4.3 |
| Vitamin D3 12,000 IU | FEF 25-75 | Year 2 | 65.6 Percentage of predicted FEF | Standard Deviation 4.3 |
Secondary
FeNO
Fractional exhaled nitric oxide (FeNO) will be measured in parts per billion (ppb).
Time frame: Up to 2 years
Population: Only includes participants who completed the assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Vitamin D3 100,000 IU | FeNO | Baseline | 19.3 parts per billion | Standard Deviation 2.7 |
| Vitamin D3 100,000 IU | FeNO | Year 1 | 20.5 parts per billion | Standard Deviation 3.5 |
| Vitamin D3 100,000 IU | FeNO | Year 2 | 18.1 parts per billion | Standard Deviation 2.7 |
| Vitamin D3 12,000 IU | FeNO | Baseline | 16.9 parts per billion | Standard Deviation 2.1 |
| Vitamin D3 12,000 IU | FeNO | Year 1 | 16.1 parts per billion | Standard Deviation 2.1 |
| Vitamin D3 12,000 IU | FeNO | Year 2 | 16.4 parts per billion | Standard Deviation 2.4 |
Secondary
FEV1/FVC Ratio
The ratio of FEV1 to FVC will be calculated (in percentage).
Time frame: Up to 2 years
Population: Only includes participants who completed the assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Vitamin D3 100,000 IU | FEV1/FVC Ratio | Year 2 | 82.2 ratio | Standard Deviation 1.5 |
| Vitamin D3 100,000 IU | FEV1/FVC Ratio | Year 1 | 82.6 ratio | Standard Deviation 1 |
| Vitamin D3 100,000 IU | FEV1/FVC Ratio | Baseline | 84.0 ratio | Standard Deviation 1.5 |
| Vitamin D3 12,000 IU | FEV1/FVC Ratio | Year 1 | 81.7 ratio | Standard Deviation 1.3 |
| Vitamin D3 12,000 IU | FEV1/FVC Ratio | Year 2 | 81.6 ratio | Standard Deviation 1.2 |
| Vitamin D3 12,000 IU | FEV1/FVC Ratio | Baseline | 83.3 ratio | Standard Deviation 1.5 |
Secondary
Forced Expiratory Volume (FEV) in 1 Second (FEV1)
Percent predicted forced expiratory volume in 1 second will be calculated for both groups.
Time frame: Up to 2 years
Population: Only includes participants who completed the assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Vitamin D3 100,000 IU | Forced Expiratory Volume (FEV) in 1 Second (FEV1) | Baseline | 80.4 Percentage of predicted FEV1 | Standard Deviation 2.4 |
| Vitamin D3 100,000 IU | Forced Expiratory Volume (FEV) in 1 Second (FEV1) | Year 1 | 79.1 Percentage of predicted FEV1 | Standard Deviation 2.7 |
| Vitamin D3 100,000 IU | Forced Expiratory Volume (FEV) in 1 Second (FEV1) | Year 2 | 78.9 Percentage of predicted FEV1 | Standard Deviation 2.8 |
| Vitamin D3 12,000 IU | Forced Expiratory Volume (FEV) in 1 Second (FEV1) | Baseline | 84.9 Percentage of predicted FEV1 | Standard Deviation 2.3 |
| Vitamin D3 12,000 IU | Forced Expiratory Volume (FEV) in 1 Second (FEV1) | Year 1 | 85.3 Percentage of predicted FEV1 | Standard Deviation 2.1 |
| Vitamin D3 12,000 IU | Forced Expiratory Volume (FEV) in 1 Second (FEV1) | Year 2 | 84.5 Percentage of predicted FEV1 | Standard Deviation 2 |
Secondary
Forced Vital Capacity (FVC)
Percent predicted forced vital capacity will be calculated for both groups.
Time frame: Up to 2 years
Population: Only includes participants who completed the assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Vitamin D3 100,000 IU | Forced Vital Capacity (FVC) | Baseline | 85.5 Percentage of predicted FVC | Standard Deviation 2.8 |
| Vitamin D3 100,000 IU | Forced Vital Capacity (FVC) | Year 1 | 85.2 Percentage of predicted FVC | Standard Deviation 2.7 |
| Vitamin D3 100,000 IU | Forced Vital Capacity (FVC) | Year 2 | 85.0 Percentage of predicted FVC | Standard Deviation 2.5 |
| Vitamin D3 12,000 IU | Forced Vital Capacity (FVC) | Baseline | 90.2 Percentage of predicted FVC | Standard Deviation 2.3 |
| Vitamin D3 12,000 IU | Forced Vital Capacity (FVC) | Year 1 | 92.4 Percentage of predicted FVC | Standard Deviation 2.3 |
| Vitamin D3 12,000 IU | Forced Vital Capacity (FVC) | Year 2 | 92.1 Percentage of predicted FVC | Standard Deviation 2.5 |
Secondary
Hand-grip, Dominant
Muscle strength was measured by looking at hand-grip strength in the dominant hand.
Time frame: Up to 2 years
Population: Only includes participants who completed the assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Vitamin D3 100,000 IU | Hand-grip, Dominant | Baseline | 21.2 pounds of force | Standard Deviation 3.2 |
| Vitamin D3 100,000 IU | Hand-grip, Dominant | Year 1 | 20.8 pounds of force | Standard Deviation 3 |
| Vitamin D3 100,000 IU | Hand-grip, Dominant | Year 2 | 23.8 pounds of force | Standard Deviation 4.1 |
| Vitamin D3 12,000 IU | Hand-grip, Dominant | Baseline | 17.1 pounds of force | Standard Deviation 2.2 |
| Vitamin D3 12,000 IU | Hand-grip, Dominant | Year 1 | 17.3 pounds of force | Standard Deviation 2.4 |
| Vitamin D3 12,000 IU | Hand-grip, Dominant | Year 2 | 18.1 pounds of force | Standard Deviation 3.1 |
Secondary
Hand-grip, Left
Muscle strength was measured by looking at hand-grip strength in the left hand.
Time frame: Up to 2 years
Population: Only includes participants who completed the assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Vitamin D3 100,000 IU | Hand-grip, Left | Baseline | 19.9 pounds of force | Standard Deviation 3.4 |
| Vitamin D3 100,000 IU | Hand-grip, Left | Year 1 | 19.0 pounds of force | Standard Deviation 3.4 |
| Vitamin D3 100,000 IU | Hand-grip, Left | Year 2 | 19.6 pounds of force | Standard Deviation 3.6 |
| Vitamin D3 12,000 IU | Hand-grip, Left | Baseline | 16.0 pounds of force | Standard Deviation 2.1 |
| Vitamin D3 12,000 IU | Hand-grip, Left | Year 1 | 13.6 pounds of force | Standard Deviation 2.4 |
| Vitamin D3 12,000 IU | Hand-grip, Left | Year 2 | 15.8 pounds of force | Standard Deviation 2.8 |
Secondary
Hand-grip, Right
Muscle strength was measured by looking at hand-grip strength in the right hand.
Time frame: Up to 2 years
Population: Only includes participants who completed the assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Vitamin D3 100,000 IU | Hand-grip, Right | Baseline | 21.2 pounds of force | Standard Deviation 3.2 |
| Vitamin D3 100,000 IU | Hand-grip, Right | Year 1 | 20.6 pounds of force | Standard Deviation 3 |
| Vitamin D3 100,000 IU | Hand-grip, Right | Year 2 | 23.8 pounds of force | Standard Deviation 4.1 |
| Vitamin D3 12,000 IU | Hand-grip, Right | Baseline | 16.9 pounds of force | Standard Deviation 2.2 |
| Vitamin D3 12,000 IU | Hand-grip, Right | Year 1 | 16.6 pounds of force | Standard Deviation 2.4 |
| Vitamin D3 12,000 IU | Hand-grip, Right | Year 2 | 17.4 pounds of force | Standard Deviation 2.9 |
Secondary
Mean 25-Hydroxyvitamin D (25-OHD)
The overall mean serum 25-OHD concentration will be measured for both groups.
Time frame: 2 years
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Vitamin D3 100,000 IU | Mean 25-Hydroxyvitamin D (25-OHD) | 36.1 ng/mL |
| Vitamin D3 12,000 IU | Mean 25-Hydroxyvitamin D (25-OHD) | 19.1 ng/mL |
Secondary
MEP
Maximum expiratory pressure (MEP) will be measured.
Time frame: Up to 2 years
Population: Only includes participants who completed the assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Vitamin D3 100,000 IU | MEP | Baseline | 66.3 cm of water | Standard Deviation 3.9 |
| Vitamin D3 100,000 IU | MEP | Year 1 | 60.4 cm of water | Standard Deviation 3.3 |
| Vitamin D3 100,000 IU | MEP | Year 2 | 58.7 cm of water | Standard Deviation 3.4 |
| Vitamin D3 12,000 IU | MEP | Baseline | 66.3 cm of water | Standard Deviation 5.4 |
| Vitamin D3 12,000 IU | MEP | Year 1 | 57.3 cm of water | Standard Deviation 3.1 |
| Vitamin D3 12,000 IU | MEP | Year 2 | 56.2 cm of water | Standard Deviation 4 |
Secondary
MIP
Maximum inspiratory pressure (MIP) will be measured.
Time frame: Up to 2 years
Population: Only includes participants who completed the assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Vitamin D3 100,000 IU | MIP | Baseline | 69.1 cm of water | Standard Deviation 5.6 |
| Vitamin D3 100,000 IU | MIP | Year 1 | 78.7 cm of water | Standard Deviation 6.1 |
| Vitamin D3 100,000 IU | MIP | Year 2 | 77.4 cm of water | Standard Deviation 5 |
| Vitamin D3 12,000 IU | MIP | Baseline | 59.9 cm of water | Standard Deviation 5.3 |
| Vitamin D3 12,000 IU | MIP | Year 1 | 80.4 cm of water | Standard Deviation 6.3 |
| Vitamin D3 12,000 IU | MIP | Year 2 | 74.6 cm of water | Standard Deviation 4.7 |
Secondary
RV/TLC Ratio
The ratio of residual volume (RV) to total lung capacity (TLC) will be calculated (in percentage).
Time frame: Up to 2 years
Population: Only includes participants who completed the assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Vitamin D3 100,000 IU | RV/TLC Ratio | Baseline | 26.9 Percent ratio | Standard Deviation 1.3 |
| Vitamin D3 100,000 IU | RV/TLC Ratio | Year 1 | 25.4 Percent ratio | Standard Deviation 1.8 |
| Vitamin D3 100,000 IU | RV/TLC Ratio | Year 2 | 22.8 Percent ratio | Standard Deviation 1.6 |
| Vitamin D3 12,000 IU | RV/TLC Ratio | Baseline | 25.1 Percent ratio | Standard Deviation 1.6 |
| Vitamin D3 12,000 IU | RV/TLC Ratio | Year 1 | 22.6 Percent ratio | Standard Deviation 1.9 |
| Vitamin D3 12,000 IU | RV/TLC Ratio | Year 2 | 21.8 Percent ratio | Standard Deviation 1.9 |