Activated Vitamin D for the Prevention and Treatment of Acute Kidney Injury (ACTIVATE-AKI)

Activated Vitamin D for the Prevention and Treatment of Acute Kidney Injury (ACTIVATE-AKI)

The purpose of this study is to assess the efficacy of calcifediol (25-hydroxyvitamin D) and calcitriol (1,25-dihydroxyvitamin D) in preventing and reducing the severity of acute kidney injury (AKI) in critically ill patients.

Study Overview

• Status: Completed
• Conditions: Acute Kidney Injury; Critically Ill
• Intervention / Treatment: Drug: Calcifediol; Drug: Calcitriol; Drug: Placebos

Detailed Description

Decreased circulating levels of active vitamin D metabolites, including 25-hydroxyvitamin D (25D) and 1,25-dihydroxyvitamin D (1,25D), are common in critically ill patients, and lower levels are independently associated with a higher risk of acute kidney injury (AKI). Further, administration of 25D and 1,25D attenuates AKI in animal models. The purpose of this study is to assess if administration of 25D and 1,25D decreases the incidence and severity of AKI in critically ill patients.

• Study Type: Interventional
• Enrollment (Actual): 150
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age ≥ 18
• Admitted to the ICU within 48h prior to enrollment
• Likely to remain in the ICU (alive) for ≥72h
• Naso/orogastric tube or ability to swallow
• High risk of severe AKI

Exclusion Criteria:

• Serum total calcium > 9.0 mg/dl or phosphate > 6.0 mg/dL within previous 48h
• Currently receiving oral calcium supplementation
• Ingestion of vitamin D3 >1,000 IU/day or any 25-hydroxyvitamin D or 1,25-dihydroxyvitamin D during the previous 7 days
• AKI stage 2 or 3 (based on KDIGO serum creatinine and/or urine output criteria)
• History of transplantation or receiving chronic (>7days) of immunosuppressive medications (not including glucocorticoid steroids at a dose less than or equivalent to prednisone 20 mg/day)
• Neutropenia in the previous 48h
• Active primary parathyroid disease, active granulomatous disease, or symptomatic nephrolithiasis in the previous 3 months
• Receiving cytochrome P450 inhibitors
• Chronic Kidney Disease stage V or End Stage Renal Disease
• Hemoglobin < 7 g/dL
• GI malabsorption
• Prisoner
• Pregnancy or breast feeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Calcifediol; Calcifediol 400mcg orally x 1, followed by 200mcg orally daily x 4	Drug: Calcifediol; Calcifediol 400mcg orally x 1, followed by 200mcg orally daily x 4
Experimental: Calcitriol; Calcitriol 4mcg orally daily x 5 days	Drug: Calcitriol; Calcitriol 4mcg orally daily x 5
Placebo Comparator: Placebo; Equal volume of medium chain triglyceride (MCT) oil orally daily x 5 days	Drug: Placebos; Placebo (medium chain triglyceride oil) orally daily x 5

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Death Within 7 Days	All-cause mortality within 7 days following randomization	7 days
Number of Participants Who Received Renal Replacement Therapy Within 7 Days	Number of participants who received renal replacement therapy within 7 days following randomization	7 days
Relative Average Change in Serum Creatinine From Day 0 to Days 1-7	Average percentage change in serum creatinine assessed on days 1-7 as compared to day 0	7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With New or Worsening Stage of AKI, Defined by KDIGO Guidelines	Any of the following: 1) an increase in serum creatinine ≥50% compared to the immediate pre-randomization value; 2) new or progressive stage of oliguria; or 3) receipt of renal replacement therapy. Oliguria stages 1, 2, and 3 are defined as urine output (UOP) <0.5 ml/kg/h for 6-12h, <0.5 ml/kg/h for >12h, and <0.3 ml/kg/h for ≥24h or anuria for ≥12h, respectively.	7 days
Peak Serum Creatinine (mg/dl)	Highest serum creatinine value on days 1 to 7	7 days
28-day Mortality	All-cause mortality assessed during the 28 days following randomization	28 days
ICU- and Hospital-free Days	28 minus the number of days in the ICU or hospital, with 0 assigned to patients who die before 28 days	28 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Kidney Injury - Subgroup Analysis Based on Time Zero 25-hydroxyvitamin D Level Above Versus Below the Median	Composite of daily serum creatinine, need for renal replacement therapy (RRT), or death within 7 days	7 days
Kidney Injury - Subgroup Analysis Based on the Presence or Absence of AKI on Enrollment	Composite of daily serum creatinine, need for renal replacement therapy (RRT), or death within 7 days	7 days
Kidney Injury - Subgroup Analysis Based on APACHE II Score on Enrollment Above Versus Below the Median	Composite of daily serum creatinine, need for renal replacement therapy (RRT), or death within 7 days	7 days
Kidney Injury - Subgroup Analysis Based on ICU Type (Medical Versus Surgical)	Composite of daily serum creatinine, need for renal replacement therapy (RRT), or death within 7 days	7 days
Kidney Injury - Subgroup Analysis Based on the Presence or Absence of Sepsis on Enrollment	Composite of daily serum creatinine, need for renal replacement therapy (RRT), or death within 7 days	7 days

Collaborators and Investigators

• Sponsor: David Leaf
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: David E Leaf, MD, MMSc, Brigham and Women's Hospital

Publications and helpful links

General Publications

• Leaf DE, Shenoy T, Zinchuk K, Gupta S, Dias JA, Sanchez-Almanzar D, Ginde AA, Athar H, Cheng C, Tamura T, Kim EY, Waikar SS. Randomized trial of activated vitamin D for acute kidney injury prevention in critically ill patients. JCI Insight. 2025 Sep 9:e193523. doi: 10.1172/jci.insight.193523. Online ahead of print.

Study record dates

Study Major Dates

• Study Start (Actual): April 3, 2017
• Primary Completion (Actual): July 16, 2020
• Study Completion (Actual): August 6, 2020

Study Registration Dates

• First Submitted: November 3, 2016
• First Submitted That Met QC Criteria: November 9, 2016
• First Posted (Estimated): November 11, 2016

Study Record Updates

• Last Update Posted (Estimated): September 29, 2025
• Last Update Submitted That Met QC Criteria: September 15, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Pathologic Processes; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Disease Attributes; Renal Insufficiency; Pathological Conditions, Signs and Symptoms; Critical Illness; Acute Kidney Injury; Lipids; Polycyclic Compounds; Steroids; Fused-Ring Compounds; Cholestenes; Cholestanes; Sterols; Vitamin D; Secosteroids; Membrane Lipids; Hydroxycholecalciferols; Cholecalciferol; Dihydroxycholecalciferols; Calcitriol; Calcifediol
• Other Study ID Numbers: 2016P002527; 5K23DK106448 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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