Clearance of 25-hydroxyvitamin D3 During Vitamin D3 Supplementation (CLEAR-PLUS)

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.

Study Overview

• Status: Completed
• Conditions: Chronic Kidney Disease
• Intervention / Treatment: Drug: D6-25-hydroxyvitamin D3

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 Type: Interventional
• Enrollment (Actual): 19
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: DIAGNOSTIC
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline, 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline, 6 months
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.	Baseline, 6 months
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.	Baseline, 6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline, 6 months
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.	Baseline, 7 days
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.	Baseline, 7 days
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.	Baseline, 7 days
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.	Baseline, 7 days

Collaborators and Investigators

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

Publications and helpful links

General Publications

• Hsu S, Zelnick LR, Lin YS, Best CM, Kestenbaum B, Thummel KE, Rose LM, Hoofnagle AN, de Boer IH. Differences in 25-Hydroxyvitamin D Clearance by eGFR and Race: A Pharmacokinetic Study. J Am Soc Nephrol. 2021 Jan;32(1):188-198. doi: 10.1681/ASN.2020050625. Epub 2020 Oct 28.

Study record dates

Study Major Dates

• Study Start (ACTUAL): June 1, 2018
• Primary Completion (ACTUAL): July 8, 2019
• Study Completion (ACTUAL): January 1, 2021

Study Registration Dates

• First Submitted: June 22, 2018
• First Submitted That Met QC Criteria: June 22, 2018
• First Posted (ACTUAL): July 3, 2018

Study Record Updates

• Last Update Posted (ACTUAL): May 17, 2022
• Last Update Submitted That Met QC Criteria: May 14, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: chronic kidney disease; vitamin d catabolism
• Additional Relevant MeSH Terms: Urologic Diseases; Renal Insufficiency; Kidney Diseases; Renal Insufficiency, Chronic; Physiological Effects of Drugs; Micronutrients; Vitamins; Bone Density Conservation Agents; Calcifediol; Hydroxycholecalciferols
• Other Study ID Numbers: STUDY00000608; R01DK099199 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Coded individual participant data may be shared with other researchers under mutually agreeable terms.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No