Activated Vitamin D for the Prevention and Treatment of Acute Kidney Injury

Study Overview
=================
Brief Summary
-----------------
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.

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.

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

Conditions
-----------------
Critically Ill, Acute Kidney Injury

Intervention / Treatment
-----------------
* Drug: Calcifediol
* Drug: Calcitriol
* Drug: Placebos


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

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

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 |