Chronic Kidney Disease
Conditions
Keywords
chronic kidney disease, vitamin d catabolism
Brief summary
The goal of this study is to determine how 25(OH)D3 clearance is affected by vitamin D3 supplementation using a gold standard pharmacokinetic approach.
Detailed description
We expect that this study will enhance interpretation of available diagnostic tests, inform the results of ongoing large clinical trials of vitamin D supplements, and help develop new strategies to target vitamin D to improve health.
Interventions
Intravenous administration of a deuterium-labeled 25(OH)D3 to evaluate the metabolic clearance of 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
No
Inclusion criteria
* Successful prior completion of related protocol CLEAR (NCT02937350) or CLEAR-CF (NCT03104855) * Age ≥ 18 years * Self-reported race Caucasian, African American, or African
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 (unless failed transplant now treated with hemodialysis) * 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 \< 10 g/dL
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Metabolic Clearance of D6-25(OH)D3 | Baseline, 6 months | 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. Change in clearance of D6-25(OH)D3 will be calculated as D6-25(OH)D3 clearance measured during CLEAR-PLUS minus D6-25(OH)D3 clearance previously measured during participation in the related study protocol (without vitamin D3 supplementation). Concentration was measured at 5 minutes, 4 hours, and at 1, 4, 7, 14, 21, 28, 42, and 56 days post administration. The change listed is between two timepoints. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in AUC of D6-25(OH)D3 | Baseline, 6 months | AUC is calculated using the linear trapezoidal method. Change in the AUC of D6-25(OH)D3 will be calculated as D6-25(OH)D3 AUC measured during CLEAR-PLUS minus D6-25(OH)D3 AUC previously measured during participation in the related study protocol (without vitamin D3 supplementation). Concentration was measured at 5 minutes, 4 hours, and at 1, 4, 7, 14, 21, 28, 42, and 56 days post administration. The change listed is between two timepoints. |
| Change in Terminal Half-life of D6-25(OH)D3 | Baseline, 6 months | Terminal half-life is equal to ln2/k, where k is the slope of the terminal regression line estimated using ≥3 plasma concentrations. Change in the terminal half-life of D6-25(OH)D3 will be calculated as D6-25(OH)D3 half-life measured during CLEAR-PLUS minus D6-25(OH)D3 half-life previously measured during participation in the related study protocol (without vitamin D3 supplementation). Concentration was measured at 5 minutes, 4 hours, and at 1, 4, 7, 14, 21, 28, 42, and 56 days post administration. The change listed is between two timepoints. |
| Change in Volume of Distribution of D6-25(OH)D3 | Baseline, 6 months | 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. Change in the volume of distribution of D6-25(OH)D3 will be calculated as D6-25(OH)D3 volume of distribution measured during CLEAR-PLUS minus D6-25(OH)D3 volume of distribution previously measured during participation in the related study protocol (without vitamin D3 supplementation). Concentration was measured at 5 minutes, 4 hours, and at 1, 4, 7, 14, 21, 28, 42, and 56 days post administration. The change listed is between two timepoints. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in the Serum Concentration of AST | Baseline, 7 days | Change in the serum concentration of AST from baseline to 7 days after 25(OH)D3 administration. The change listed is between two timepoints. |
| Change in the Serum Concentration of ALT | Baseline, 7 days | Change in the serum concentration of ALT from baseline to 7 days after 25(OH)D3 administration. The change listed is between two timepoints. |
| Changes in Metabolic Formation Clearance of D6-25(OH)D3 Metabolites. | Baseline, 6 months | 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. Changes in the metabolic formation clearance of D6-25(OH)D3 metabolites will be calculated as metabolic formation clearance measured during CLEAR-PLUS minus metabolic formation clearance previously measured during participation in the related study protocol (without vitamin D3 supplementation). Concentration was measured at 5 minutes, 4 hours, and at 1, 4, 7, 14, 21, 28, 42, and 56 days post administration. The change listed is between two timepoints. |
| Change in the Serum Concentration of Calcium | Baseline, 7 days | Change in the serum concentration of calcium from baseline to 7 days after 25(OH)D3 administration. The change listed is between two timepoints. |
| Change in the Serum Concentration of Creatinine | Baseline, 7 days | Change in the serum concentration of creatinine from baseline to 7 days after 25(OH)D3 administration. The change listed is between two timepoints. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Healthy Controls Healthy Controls (n = 10) | 10 |
| CKD Group CKD Group (n = 8) | 8 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Healthy Controls | CKD Group | Total |
|---|---|---|---|
| Age, Continuous | 60 years STANDARD_DEVIATION 6 | 69 years STANDARD_DEVIATION 7 | 64 years STANDARD_DEVIATION 7 |
| Clearance after supplement | 436 ml/d STANDARD_DEVIATION 135 | 322 ml/d STANDARD_DEVIATION 88 | 385 ml/d STANDARD_DEVIATION 128 |
| 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 | 6 Participants | 4 Participants | 10 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 | 4 Participants | 4 Participants | 8 Participants |
| Sex: Female, Male Female | 4 Participants | 2 Participants | 6 Participants |
| Sex: Female, Male Male | 6 Participants | 6 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 18 |
| other Total, other adverse events | 6 / 18 |
| serious Total, serious adverse events | 0 / 18 |
Outcome results
Primary
Change in 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. Change in clearance of D6-25(OH)D3 will be calculated as D6-25(OH)D3 clearance measured during CLEAR-PLUS minus D6-25(OH)D3 clearance previously measured during participation in the related study protocol (without vitamin D3 supplementation). Concentration was measured at 5 minutes, 4 hours, and at 1, 4, 7, 14, 21, 28, 42, and 56 days post administration. The change listed is between two timepoints.
Time frame: Baseline, 6 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Healthy Controls | Change in Metabolic Clearance of D6-25(OH)D3 | 21 ml/d |
| CKD Group | Change in Metabolic Clearance of D6-25(OH)D3 | 5 ml/d |
Secondary
Change in AUC of D6-25(OH)D3
AUC is calculated using the linear trapezoidal method. Change in the AUC of D6-25(OH)D3 will be calculated as D6-25(OH)D3 AUC measured during CLEAR-PLUS minus D6-25(OH)D3 AUC previously measured during participation in the related study protocol (without vitamin D3 supplementation). Concentration was measured at 5 minutes, 4 hours, and at 1, 4, 7, 14, 21, 28, 42, and 56 days post administration. The change listed is between two timepoints.
Time frame: Baseline, 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Controls | Change in AUC of D6-25(OH)D3 | 0.07 ng x day/mL | Standard Deviation 11.2 |
| CKD Group | Change in AUC of D6-25(OH)D3 | -2.58 ng x day/mL | Standard Deviation 7.51 |
Secondary
Change in 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. Change in the terminal half-life of D6-25(OH)D3 will be calculated as D6-25(OH)D3 half-life measured during CLEAR-PLUS minus D6-25(OH)D3 half-life previously measured during participation in the related study protocol (without vitamin D3 supplementation). Concentration was measured at 5 minutes, 4 hours, and at 1, 4, 7, 14, 21, 28, 42, and 56 days post administration. The change listed is between two timepoints.
Time frame: Baseline, 6 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Healthy Controls | Change in Terminal Half-life of D6-25(OH)D3 | -1.3 d |
| CKD Group | Change in Terminal Half-life of D6-25(OH)D3 | 1.2 d |
Secondary
Change in 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. Change in the volume of distribution of D6-25(OH)D3 will be calculated as D6-25(OH)D3 volume of distribution measured during CLEAR-PLUS minus D6-25(OH)D3 volume of distribution previously measured during participation in the related study protocol (without vitamin D3 supplementation). Concentration was measured at 5 minutes, 4 hours, and at 1, 4, 7, 14, 21, 28, 42, and 56 days post administration. The change listed is between two timepoints.
Time frame: Baseline, 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Controls | Change in Volume of Distribution of D6-25(OH)D3 | 0.28 L | Standard Deviation 4.13 |
| CKD Group | Change in Volume of Distribution of D6-25(OH)D3 | 0.55 L | Standard Deviation 0.94 |
Other Pre-specified
Change in the Serum Concentration of ALT
Change in the serum concentration of ALT from baseline to 7 days after 25(OH)D3 administration. The change listed is between two timepoints.
Time frame: Baseline, 7 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Controls | Change in the Serum Concentration of ALT | 1.56 units/L | Standard Deviation 2.83 |
| CKD Group | Change in the Serum Concentration of ALT | 0.50 units/L | Standard Deviation 2.98 |
Other Pre-specified
Change in the Serum Concentration of AST
Change in the serum concentration of AST from baseline to 7 days after 25(OH)D3 administration. The change listed is between two timepoints.
Time frame: Baseline, 7 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Controls | Change in the Serum Concentration of AST | 1.30 units/L | Standard Deviation 4.6 |
| CKD Group | Change in the Serum Concentration of AST | -0.13 units/L | Standard Deviation 1.36 |
Other Pre-specified
Change in the Serum Concentration of Calcium
Change in the serum concentration of calcium from baseline to 7 days after 25(OH)D3 administration. The change listed is between two timepoints.
Time frame: Baseline, 7 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Controls | Change in the Serum Concentration of Calcium | 0.20 mg/dl | Standard Deviation 0.2 |
| CKD Group | Change in the Serum Concentration of Calcium | 0.28 mg/dl | Standard Deviation 0.33 |
Other Pre-specified
Change in the Serum Concentration of Creatinine
Change in the serum concentration of creatinine from baseline to 7 days after 25(OH)D3 administration. The change listed is between two timepoints.
Time frame: Baseline, 7 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Controls | Change in the Serum Concentration of Creatinine | 0.03 mg/dl | Standard Deviation 0.1 |
| CKD Group | Change in the Serum Concentration of Creatinine | -0.02 mg/dl | Standard Deviation 0.15 |
Other Pre-specified
Changes in 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. Changes in the metabolic formation clearance of D6-25(OH)D3 metabolites will be calculated as metabolic formation clearance measured during CLEAR-PLUS minus metabolic formation clearance previously measured during participation in the related study protocol (without vitamin D3 supplementation). Concentration was measured at 5 minutes, 4 hours, and at 1, 4, 7, 14, 21, 28, 42, and 56 days post administration. The change listed is between two timepoints.
Time frame: Baseline, 6 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Healthy Controls | Changes in Metabolic Formation Clearance of D6-25(OH)D3 Metabolites. | 0.01 ratio |
| CKD Group | Changes in Metabolic Formation Clearance of D6-25(OH)D3 Metabolites. | -0.02 ratio |