CLEAR-PLUS: Clearance of 25-hydroxyvitamin D3 During Vitamin D3 Supplementation

• Sponsor: University of Washington (Other)
• Overall Status: Completed
• CT.gov ID: NCT03576716
• Collaborator: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)
• Enrollment: 19
• Location: 1
• Arm: 1
• Actual Duration (Months): 31
• Patients Per Site Per Month: 0.6

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Chronic Kidney Disease	Drug: D6-25-hydroxyvitamin D3	Phase 1

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 19 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Diagnostic
• Official Title: Clearance of 25-hydroxyvitamin D3 During Vitamin D3 Supplementation
• Actual Study Start Date: Jun 1, 2018
• Actual Primary Completion Date: Jul 8, 2019
• Actual Study Completion Date: Jan 1, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Study Population D6-25-hydroxyvitamin D3 with vitamin D3	Drug: D6-25-hydroxyvitamin D3; Intravenous administration of a deuterium-labeled 25(OH)D3 to evaluate the metabolic clearance of 25(OH)D3; Other Names: stable isotope deuterium-labeled 25(OH)D3

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Washington	Seattle	Washington	United States	98195

Sponsors and Collaborators

• University of Washington
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

• Principal Investigator: Ian de Boer, MD, MS, University of Washington

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - May 18, 2018

More Information

Publications

None provided.

• Responsible Party: Ian deBoer, Professor, Medicine/Nephrology, University of Washington
• ClinicalTrials.gov Identifier: NCT03576716
• Other Study ID Numbers: STUDY00000608; R01DK099199
• First Posted: Jul 3, 2018
• Last Update Posted: May 17, 2022
• Last Verified: May 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Ian deBoer, Professor, Medicine/Nephrology, University of Washington: chronic kidney disease; vitamin d catabolism
• Additional relevant MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic; Hydroxycholecalciferols; Calcifediol

Study Results

Participant Flow

Arm/Group Title	Healthy Controls	CKD Group
Arm/Group Description	Healthy controls defined as normal eGFR (>60 ml/min per 1.73m2)	CKD group defined as those with eGFR (<60 ml/min per 1.73 m2)
Period Title: Overall Study
STARTED	10	9
COMPLETED	10	8
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	Healthy Controls	CKD Group	Total
Arm/Group Description	Healthy Controls (n = 10)	CKD Group (n = 8)	Total of all reporting groups
Overall Participants	10	8	18
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60 (6)	69 (7)	64 (7)
Sex: Female, Male (Count of Participants)
Female	4 40%	2 25%	6 33.3%
Male	6 60%	6 75%	12 66.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	6 60%	4 50%	10 55.6%
White	4 40%	4 50%	8 44.4%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Clearance after supplement (ml/d) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [ml/d]	436 (135)	322 (88)	385 (128)

Outcome Measures

1. Primary Outcome

Title	Change in Metabolic Clearance of D6-25(OH)D3
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Healthy Controls	CKD Group
Arm/Group Description	Healthy controls defined as normal eGFR (>60 ml/min per 1.73m2)	CKD group defined as those with eGFR (<60ml/min per 1.73m2)
Measure Participants	10	8
Mean (95% Confidence Interval) [ml/d]	21	5

2. Secondary Outcome

Title	Change in AUC of D6-25(OH)D3
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Healthy Controls	CKD Group
Arm/Group Description	Healthy controls defined as normal eGFR (>60ml/min per 1.73m2)	CKD group defined as those with eGFR (<60ml/min per 1.73m2)
Measure Participants	10	8
Mean (Standard Deviation) [ng x day/mL]	0.07 (11.2)	-2.58 (7.51)

3. Secondary Outcome

Title	Change in Terminal Half-life of D6-25(OH)D3
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Healthy Controls	CKD Group
Arm/Group Description	Healthy controls defined as normal eGFR (>60ml/min per 1.73m2)	CKD group defined as those with eGFR (<60ml/min per 1.73m2)
Measure Participants	10	8
Mean (95% Confidence Interval) [d]	-1.3	1.2

4. Secondary Outcome

Title	Change in Volume of Distribution of D6-25(OH)D3
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Healthy Controls	CKD Group
Arm/Group Description	Healthy controls defined as normal eGFR (>60ml/min per 1.73m2)	CKD group defined as those with eGFR (<60ml/min per 1.73m2)
Measure Participants	18	8
Mean (Standard Deviation) [L]	0.28 (4.13)	0.55 (0.94)

5. Other Pre-specified Outcome

Title	Changes in Metabolic Formation Clearance of D6-25(OH)D3 Metabolites.
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Healthy Controls	CKD Group
Arm/Group Description	Healthy controls defined as normal eGFR (>60ml/min per 1.73m2)	CKD group defined as those with eGFR (<60ml/min per 1.73m2)
Measure Participants	10	8
Mean (95% Confidence Interval) [ratio]	0.01	-0.02

6. Other Pre-specified Outcome

Title	Change in the Serum Concentration of Calcium
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Healthy Controls	CKD Group
Arm/Group Description	Healthy controls defined as normal eGFR (>60ml/min per 1.73m2)	CKD group defined as those with eGFR (<60ml/min per 1.73m2)
Measure Participants	10	8
Mean (Standard Deviation) [mg/dl]	0.20 (0.20)	0.28 (0.33)

7. Other Pre-specified Outcome

Title	Change in the Serum Concentration of Creatinine
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Healthy Controls	CKD Group
Arm/Group Description	Healthy controls defined as normal eGFR (>60ml/min per 1.73m2)	CKD group defined as those with eGFR (<60ml/min per 1.73m2)
Measure Participants	10	8
Mean (Standard Deviation) [mg/dl]	0.03 (0.10)	-0.02 (0.15)

8. Other Pre-specified Outcome

Title	Change in the Serum Concentration of AST
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Healthy Controls	CKD Group
Arm/Group Description	Healthy controls defined as normal eGFR (>60ml/min per 1.73m2)	CKD group defined as those with eGFR (<60ml/min per 1.73m2)
Measure Participants	10	8
Mean (Standard Deviation) [units/L]	1.30 (4.60)	-0.13 (1.36)

9. Other Pre-specified Outcome

Title	Change in the Serum Concentration of ALT
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Healthy Controls	CKD Group
Arm/Group Description	Healthy controls defined as normal eGFR (>60ml/min per 1.73m2)	CKD group defined as those with eGFR (<60ml/min per 1.73m2)
Measure Participants	10	8
Mean (Standard Deviation) [units/L]	1.56 (2.83)	0.50 (2.98)

Adverse Events

Time Frame	8 weeks
Adverse Event Reporting Description	Everyone had the same treatment, so it's most appropriate to summarize AEs for the whole group.
Arm/Group Title	All Participants
Arm/Group Description	All Participants (N = 18). AEs were not collected by arm but altogether.
All Cause Mortality
	All Participants
	Affected / at Risk (%)	# Events
Total	0/18 (0%)
Serious Adverse Events
	All Participants
	Affected / at Risk (%)	# Events
Total	0/18 (0%)
Other (Not Including Serious) Adverse Events
	All Participants
	Affected / at Risk (%)	# Events
Total	6/18 (33.3%)
General disorders
Sensation in arm during infusion	5/18 (27.8%)
Infections and infestations
Diverticulitis	1/18 (5.6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.