Cystic Fibrosis
Conditions
Keywords
cystic fibrosis, vitamin d catabolism
Brief summary
The goal of this study is to define 25(OH)D3 catabolism in CF patients using gold standard pharmacokinetics studies. Specifically, the investigators will evaluate the metabolic clearance of 25(OH)D3 among participants with CF and matched control subjects. The goal of this work is to provide the first comprehensive characterization of vitamin D metabolism in CF patients and promote novel hypotheses for subsequent studies.
Interventions
intravenous administration of stable isotope-labeled D6-25(OH)D3
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
University of Washington
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Age ≥ 18 years * Serum total 25(OH)D 10-50 ng/mL * Diagnosis of cystic fibrosis in accordance with CF Foundation Guidelines; OR, normal CONTROL
Exclusion criteria
* Primary hyperparathyroidism * Gastric bypass * Tuberculosis or sarcoidosis * Current pregnancy * Child-Pugh Class B or C cirrhosis (i.e. cirrhosis with ascites, hepatic encephalopathy, bilirubin \>=2 mg/dL, serum albumin \<=3.5 g/dL, or PT \>= 4 seconds) * History of kidney transplantation or end stage renal disease treated with dialysis * Use of vitamin D3 or vitamin D2 supplements exceeding a mean daily dose of 400 IU, within 3 months (wash-out allowed) * Use of 1,25(OH)2D3 or an analogue, calcimimetics, or medications known to induce CYP24A1 within 4 weeks (wash-out allowed) * Serum calcium \> 10.1 mg/dL * Hemoglobin \< 9 g/dL
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Metabolic Clearance of D6-25(OH)D3 | 8 weeks | Metabolic clearance is calculated as the administered dose of 25(OH)D3 divided by the area under the plasma concentration-time curve (AUC). AUC is calculated using the linear trapezoidal method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AUC of D6-25(OH)D3 | 8 weeks | AUC is calculated using the linear trapezoidal method. |
| Terminal Half-life of D6-25(OH)D3 | 8 weeks | Terminal half-life is equal to ln2/k, where k is the slope of the terminal regression line estimated using ≥3 plasma concentrations. |
| Volume of Distribution of D6-25(OH)D3 | 8 weeks | Volume of distribution in the central compartment is calculated as dose/C0, where dose is the administered dose of 25(OH)D3 and C0 is the initial (estimated) concentration of drug in plasma. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Metabolic Formation Clearance of D6-25(OH)D3 Metabolites | 8 weeks | Metabolic formation clearance is calculated as the daughter metabolite plasma AUC divided by the AUC of D6-25(OH)D3 (metabolite/parent AUC ratio). AUC is calculated using the linear trapezoidal method. |
| Serum Concentration of ALT | 7 days | Change in the serum concentration of ALT from baseline to 7 days after 25(OH)D3 |
| Serum Concentration of Calcium | 7 days | Change in the serum concentration of calcium from baseline to 7 days after 25(OH)D3 |
| Serum Concentration of Creatinine | 7 days | Change in the serum concentration of creatinine from baseline to 7 days after 25(OH)D3 |
| Serum Concentration of AST | 7 days | Change in the serum concentration of AST from baseline to 7 days after 25(OH)D3 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| CF Group Participants with cystic fibrosis | 5 |
| Healthy Controls Participants without cystic fibrosis | 5 |
| Total | 10 |
Baseline characteristics
| Characteristic | Healthy Controls | Total | CF Group |
|---|---|---|---|
| Age, Continuous | 24.8 years STANDARD_DEVIATION 3.3 | 31.8 years STANDARD_DEVIATION 12.3 | 38.8 years STANDARD_DEVIATION 14.3 |
| 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 | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 10 Participants | 5 Participants |
| Sex: Female, Male Female | 4 Participants | 5 Participants | 1 Participants |
| Sex: Female, Male Male | 1 Participants | 5 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 5 |
| other Total, other adverse events | 2 / 5 | 1 / 5 |
| serious Total, serious adverse events | 0 / 5 | 0 / 5 |
Outcome results
Primary
Metabolic Clearance of D6-25(OH)D3
Metabolic clearance is calculated as the administered dose of 25(OH)D3 divided by the area under the plasma concentration-time curve (AUC). AUC is calculated using the linear trapezoidal method.
Time frame: 8 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CF Group | Metabolic Clearance of D6-25(OH)D3 | 397 mL/day | Standard Deviation 73 |
| Healthy Controls | Metabolic Clearance of D6-25(OH)D3 | 342 mL/day | Standard Deviation 41 |
Secondary
AUC of D6-25(OH)D3
AUC is calculated using the linear trapezoidal method.
Time frame: 8 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CF Group | AUC of D6-25(OH)D3 | 58.3 ng x day/mL | Standard Deviation 9.7 |
| Healthy Controls | AUC of D6-25(OH)D3 | 67.2 ng x day/mL | Standard Deviation 8.3 |
Secondary
Terminal Half-life of D6-25(OH)D3
Terminal half-life is equal to ln2/k, where k is the slope of the terminal regression line estimated using ≥3 plasma concentrations.
Time frame: 8 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CF Group | Terminal Half-life of D6-25(OH)D3 | 16.2 day | Standard Deviation 3.3 |
| Healthy Controls | Terminal Half-life of D6-25(OH)D3 | 15.8 day | Standard Deviation 1.6 |
Secondary
Volume of Distribution of D6-25(OH)D3
Volume of distribution in the central compartment is calculated as dose/C0, where dose is the administered dose of 25(OH)D3 and C0 is the initial (estimated) concentration of drug in plasma.
Time frame: 8 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CF Group | Volume of Distribution of D6-25(OH)D3 | 8.4 Liters | Standard Deviation 1.4 |
| Healthy Controls | Volume of Distribution of D6-25(OH)D3 | 7.2 Liters | Standard Deviation 1.1 |
Other Pre-specified
Metabolic Formation Clearance of D6-25(OH)D3 Metabolites
Metabolic formation clearance is calculated as the daughter metabolite plasma AUC divided by the AUC of D6-25(OH)D3 (metabolite/parent AUC ratio). AUC is calculated using the linear trapezoidal method.
Time frame: 8 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CF Group | Metabolic Formation Clearance of D6-25(OH)D3 Metabolites | 0.10 ratio | Standard Deviation 0.02 |
| Healthy Controls | Metabolic Formation Clearance of D6-25(OH)D3 Metabolites | 0.08 ratio | Standard Deviation 0.01 |
Other Pre-specified
Serum Concentration of ALT
Change in the serum concentration of ALT from baseline to 7 days after 25(OH)D3
Time frame: 7 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CF Group | Serum Concentration of ALT | 0.00 Units/L | Standard Deviation 0 |
| Healthy Controls | Serum Concentration of ALT | 0.00 Units/L | Standard Deviation 0 |
Other Pre-specified
Serum Concentration of AST
Change in the serum concentration of AST from baseline to 7 days after 25(OH)D3
Time frame: 7 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CF Group | Serum Concentration of AST | 0.60 Units/L | Standard Deviation 5.03 |
| Healthy Controls | Serum Concentration of AST | -1.00 Units/L | Standard Deviation 2.55 |
Other Pre-specified
Serum Concentration of Calcium
Change in the serum concentration of calcium from baseline to 7 days after 25(OH)D3
Time frame: 7 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CF Group | Serum Concentration of Calcium | 0.00 mg/dL | Standard Deviation 0.37 |
| Healthy Controls | Serum Concentration of Calcium | 0.14 mg/dL | Standard Deviation 0.27 |
Other Pre-specified
Serum Concentration of Creatinine
Change in the serum concentration of creatinine from baseline to 7 days after 25(OH)D3
Time frame: 7 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CF Group | Serum Concentration of Creatinine | 0.00 mg/dL | Standard Deviation 0.03 |
| Healthy Controls | Serum Concentration of Creatinine | 0.00 mg/dL | Standard Deviation 0.07 |