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

• Sponsor: David Leaf (Other)
• Overall Status: Completed
• CT.gov ID: NCT02962102
• Collaborator: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)
• Enrollment: 150
• Location: 1
• Arms: 3
• Actual Duration (Months): 40.1
• Patients Per Site Per Month: 3.7

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Critically Ill; Acute Kidney Injury	Drug: Calcifediol; Drug: Calcitriol; Drug: Placebos	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 150 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Activated Vitamin D for the Prevention and Treatment of Acute Kidney Injury (ACTIVATE-AKI)
• Actual Study Start Date: Apr 3, 2017
• Actual Primary Completion Date: Jul 16, 2020
• Actual Study Completion Date: Aug 6, 2020

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Death Within 7 Days [7 days]

   All-cause mortality within 7 days following randomization

2. Number of Participants Who Received Renal Replacement Therapy Within 7 Days [7 days]

   Number of participants who received renal replacement therapy within 7 days following randomization

3. Relative Average Change in Serum Creatinine From Day 0 to Days 1-7 [7 days]

   Average percentage change in serum creatinine assessed on days 1-7 as compared to day 0

Secondary Outcome Measures

1. Number of Participants With New or Worsening Stage of AKI, Defined by KDIGO Guidelines [7 days]

   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.

2. Peak Serum Creatinine (mg/dl) [7 days]

   Highest serum creatinine value on days 1 to 7

3. 28-day Mortality [28 days]

   All-cause mortality assessed during the 28 days following randomization

4. ICU- and Hospital-free Days [28 days]

   28 minus the number of days in the ICU or hospital, with 0 assigned to patients who die before 28 days

Other Outcome Measures

1. Kidney Injury - Subgroup Analysis Based on Time Zero 25-hydroxyvitamin D Level Above Versus Below the Median [7 days]

   Composite of daily serum creatinine, need for renal replacement therapy (RRT), or death within 7 days

2. Kidney Injury - Subgroup Analysis Based on the Presence or Absence of AKI on Enrollment [7 days]

   Composite of daily serum creatinine, need for renal replacement therapy (RRT), or death within 7 days

3. Kidney Injury - Subgroup Analysis Based on APACHE II Score on Enrollment Above Versus Below the Median [7 days]

   Composite of daily serum creatinine, need for renal replacement therapy (RRT), or death within 7 days

4. Kidney Injury - Subgroup Analysis Based on ICU Type (Medical Versus Surgical) [7 days]

   Composite of daily serum creatinine, need for renal replacement therapy (RRT), or death within 7 days

5. Kidney Injury - Subgroup Analysis Based on the Presence or Absence of Sepsis on Enrollment [7 days]

   Composite of daily serum creatinine, need for renal replacement therapy (RRT), or death within 7 days

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115

Sponsors and Collaborators

• David Leaf
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

• Principal Investigator: David E Leaf, MD, MMSc, Brigham and Women's Hospital

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Dec 25, 2018
• Informed Consent Form - Dec 25, 2018

More Information

Publications

None provided.

• Responsible Party: David Leaf, Assistant Professor of Medicine, Harvard Medical School, Brigham and Women's Hospital
• ClinicalTrials.gov Identifier: NCT02962102
• Other Study ID Numbers: 2016P002527; 5K23DK106448
• First Posted: Nov 11, 2016
• Last Update Posted: Feb 3, 2022
• Last Verified: Jan 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
• Additional relevant MeSH terms: Acute Kidney Injury; Critical Illness; Wounds and Injuries; Calcitriol; Calcifediol

Study Results

Participant Flow

Arm/Group Title	Calcifediol	Calcitriol	Placebo
Arm/Group Description	Calcifediol 400mcg orally x 1, followed by 200mcg orally daily x 4 Calcifediol: Calcifediol 400mcg orally x 1, followed by 200mcg orally daily x 4	Calcitriol 4mcg orally daily x 5 days Calcitriol: Calcitriol 4mcg orally daily x 5	Equal volume of medium chain triglyceride (MCT) oil orally daily x 5 days Placebos: Placebo (medium chain triglyceride oil) orally daily x 5
Period Title: Overall Study
STARTED	51	50	49
COMPLETED	51	50	49
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Calcifediol	Calcitriol	Placebo	Total
Arm/Group Description	Calcifediol 400mcg orally x 1, followed by 200mcg orally daily x 4 Calcifediol: Calcifediol 400mcg orally x 1, followed by 200mcg orally daily x 4	Calcitriol 4mcg orally daily x 5 days Calcitriol: Calcitriol 4mcg orally daily x 5	Equal volume of medium chain triglyceride (MCT) oil orally daily x 5 days Placebos: Placebo (medium chain triglyceride oil) orally daily x 5	Total of all reporting groups
Overall Participants	51	50	49	150
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	64	65	65	65
Sex: Female, Male (Count of Participants)
Female	19 37.3%	21 42%	18 36.7%	58 38.7%
Male	32 62.7%	29 58%	31 63.3%	92 61.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	4 7.8%	4 8%	3 6.1%	11 7.3%
Not Hispanic or Latino	45 88.2%	45 90%	46 93.9%	136 90.7%
Unknown or Not Reported	2 3.9%	1 2%	0 0%	3 2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	1 2%	4 8.2%	5 3.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	5 9.8%	7 14%	3 6.1%	15 10%
White	43 84.3%	40 80%	41 83.7%	124 82.7%
More than one race	2 3.9%	1 2%	0 0%	3 2%
Unknown or Not Reported	1 2%	1 2%	1 2%	3 2%
Baseline estimated glomerular filtration rate (eGFR) (ml/min/1.73m^2) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [ml/min/1.73m^2]	94	98	94	95
APACHE II score (units on a scale) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [units on a scale]	26	25	27	25
Invasive mechanical ventilation (Count of Participants)
Count of Participants [Participants]	41 80.4%	43 86%	41 83.7%	125 83.3%
Vasopressors/inotropes (Count of Participants)
Count of Participants [Participants]	28 54.9%	28 56%	30 61.2%	86 57.3%
Acute kidney injury (Count of Participants)
Count of Participants [Participants]	19 37.3%	18 36%	18 36.7%	55 36.7%
Plasma 25-hydroxyvitamin D (ng/ml) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [ng/ml]	18.8	17.3	14.5	16.5

Outcome Measures

1. Primary Outcome

Title	Death Within 7 Days
Description	All-cause mortality within 7 days following randomization
Time Frame	7 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Calcifediol	Calcitriol	Placebo
Arm/Group Description	Calcifediol 400mcg PO/NGT/OGT x 1, followed by 200mcg PO/NGT/OGT daily x 4 Calcifediol: Calcifediol 400mcg PO/NGT/OGT x 1, followed by 200mcg PO/NGT/OGT daily x 4	Calcitriol 4mcg PO/NGT/OGT daily x 5 days Calcitriol: Calcitriol 4mcg PO/NGT/OGT daily x 5	Equal volume of medium chain triglyceride (MCT) oil daily x 5 days Placebos: Placebo (medium chain triglyceride oil) daily x 5
Measure Participants	51	50	49
Count of Participants [Participants]	4 7.8%	9 18%	6 12.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Calcifediol, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.52
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Calcitriol, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.58
	Comments
	Method	Fisher Exact
	Comments

2. Primary Outcome

Title	Number of Participants Who Received Renal Replacement Therapy Within 7 Days
Description	Number of participants who received renal replacement therapy within 7 days following randomization
Time Frame	7 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Calcifediol	Calcitriol	Placebo
Arm/Group Description	Calcifediol 400mcg PO/NGT/OGT x 1, followed by 200mcg PO/NGT/OGT daily x 4 Calcifediol: Calcifediol 400mcg PO/NGT/OGT x 1, followed by 200mcg PO/NGT/OGT daily x 4	Calcitriol 4mcg PO/NGT/OGT daily x 5 days Calcitriol: Calcitriol 4mcg PO/NGT/OGT daily x 5	Equal volume of medium chain triglyceride (MCT) oil daily x 5 days Placebos: Placebo (medium chain triglyceride oil) daily x 5
Measure Participants	51	50	49
Count of Participants [Participants]	1 2%	1 2%	4 8.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Calcifediol, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.20
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Calcitriol, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.20
	Comments
	Method	Fisher Exact
	Comments

3. Primary Outcome

Title	Relative Average Change in Serum Creatinine From Day 0 to Days 1-7
Description	Average percentage change in serum creatinine assessed on days 1-7 as compared to day 0
Time Frame	7 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Calcifediol	Calcitriol	Placebo
Arm/Group Description	Calcifediol 400mcg PO/NGT/OGT x 1, followed by 200mcg PO/NGT/OGT daily x 4 Calcifediol: Calcifediol 400mcg PO/NGT/OGT x 1, followed by 200mcg PO/NGT/OGT daily x 4	Calcitriol 4mcg PO/NGT/OGT daily x 5 days Calcitriol: Calcitriol 4mcg PO/NGT/OGT daily x 5	Equal volume of medium chain triglyceride (MCT) oil daily x 5 days Placebos: Placebo (medium chain triglyceride oil) daily x 5
Measure Participants	51	50	49
Median (Inter-Quartile Range) [Relative average percent increase]	-2.3	-7.1	-7.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Calcifediol, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.44
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Calcitriol, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.29
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

4. Secondary Outcome

Title	Number of Participants With New or Worsening Stage of AKI, Defined by KDIGO Guidelines
Description	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.
Time Frame	7 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Calcifediol	Calcitriol	Placebo
Arm/Group Description	Calcifediol 400mcg PO/NGT/OGT x 1, followed by 200mcg PO/NGT/OGT daily x 4 Calcifediol: Calcifediol 400mcg PO/NGT/OGT x 1, followed by 200mcg PO/NGT/OGT daily x 4	Calcitriol 4mcg PO/NGT/OGT daily x 5 days Calcitriol: Calcitriol 4mcg PO/NGT/OGT daily x 5	Equal volume of medium chain triglyceride (MCT) oil daily x 5 days Placebos: Placebo (medium chain triglyceride oil) daily x 5
Measure Participants	51	50	49
Count of Participants [Participants]	20 39.2%	23 46%	19 38.8%

5. Secondary Outcome

Title	Peak Serum Creatinine (mg/dl)
Description	Highest serum creatinine value on days 1 to 7
Time Frame	7 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Calcifediol	Calcitriol	Placebo
Arm/Group Description	Calcifediol 400mcg PO/NGT/OGT x 1, followed by 200mcg PO/NGT/OGT daily x 4 Calcifediol: Calcifediol 400mcg PO/NGT/OGT x 1, followed by 200mcg PO/NGT/OGT daily x 4	Calcitriol 4mcg PO/NGT/OGT daily x 5 days Calcitriol: Calcitriol 4mcg PO/NGT/OGT daily x 5	Equal volume of medium chain triglyceride (MCT) oil daily x 5 days Placebos: Placebo (medium chain triglyceride oil) daily x 5
Measure Participants	51	50	49
Median (Inter-Quartile Range) [mg/dl]	1.2	1.3	1.2

6. Secondary Outcome

Title	28-day Mortality
Description	All-cause mortality assessed during the 28 days following randomization
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Calcifediol	Calcitriol	Placebo
Arm/Group Description	Calcifediol 400mcg PO/NGT/OGT x 1, followed by 200mcg PO/NGT/OGT daily x 4 Calcifediol: Calcifediol 400mcg PO/NGT/OGT x 1, followed by 200mcg PO/NGT/OGT daily x 4	Calcitriol 4mcg PO/NGT/OGT daily x 5 days Calcitriol: Calcitriol 4mcg PO/NGT/OGT daily x 5	Equal volume of medium chain triglyceride (MCT) oil daily x 5 days Placebos: Placebo (medium chain triglyceride oil) daily x 5
Measure Participants	51	50	49
Count of Participants [Participants]	10 19.6%	16 32%	10 20.4%

7. Secondary Outcome

Title	ICU- and Hospital-free Days
Description	28 minus the number of days in the ICU or hospital, with 0 assigned to patients who die before 28 days
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Calcifediol	Calcitriol	Placebo
Arm/Group Description	Calcifediol 400mcg PO/NGT/OGT x 1, followed by 200mcg PO/NGT/OGT daily x 4 Calcifediol: Calcifediol 400mcg PO/NGT/OGT x 1, followed by 200mcg PO/NGT/OGT daily x 4	Calcitriol 4mcg PO/NGT/OGT daily x 5 days Calcitriol: Calcitriol 4mcg PO/NGT/OGT daily x 5	Equal volume of medium chain triglyceride (MCT) oil daily x 5 days Placebos: Placebo (medium chain triglyceride oil) daily x 5
Measure Participants	51	50	49
ICU-free days	20	16	11
Hospital-free days	5	4	0

8. Other Pre-specified Outcome

Title	Kidney Injury - Subgroup Analysis Based on Time Zero 25-hydroxyvitamin D Level Above Versus Below the Median
Description	Composite of daily serum creatinine, need for renal replacement therapy (RRT), or death within 7 days
Time Frame	7 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Other Pre-specified Outcome

Title	Kidney Injury - Subgroup Analysis Based on the Presence or Absence of AKI on Enrollment
Description	Composite of daily serum creatinine, need for renal replacement therapy (RRT), or death within 7 days
Time Frame	7 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

10. Other Pre-specified Outcome

Title	Kidney Injury - Subgroup Analysis Based on APACHE II Score on Enrollment Above Versus Below the Median
Description	Composite of daily serum creatinine, need for renal replacement therapy (RRT), or death within 7 days
Time Frame	7 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

11. Other Pre-specified Outcome

Title	Kidney Injury - Subgroup Analysis Based on ICU Type (Medical Versus Surgical)
Description	Composite of daily serum creatinine, need for renal replacement therapy (RRT), or death within 7 days
Time Frame	7 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

12. Other Pre-specified Outcome

Title	Kidney Injury - Subgroup Analysis Based on the Presence or Absence of Sepsis on Enrollment
Description	Composite of daily serum creatinine, need for renal replacement therapy (RRT), or death within 7 days
Time Frame	7 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	7 days for hypercalcemia and 28 days for all-cause mortality
Arm/Group Title	Calcifediol		Calcitriol		Placebo
Arm/Group Description	Calcifediol 400mcg PO/NGT/OGT x 1, followed by 200mcg PO/NGT/OGT daily x 4 Calcifediol: Calcifediol 400mcg PO/NGT/OGT x 1, followed by 200mcg PO/NGT/OGT daily x 4		Calcitriol 4mcg PO/NGT/OGT daily x 5 days Calcitriol: Calcitriol 4mcg PO/NGT/OGT daily x 5		Equal volume of medium chain triglyceride (MCT) oil daily x 5 days Placebos: Placebo (medium chain triglyceride oil) daily x 5
All Cause Mortality
	Calcifediol		Calcitriol		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/51 (19.6%)		16/50 (32%)		10/49 (20.4%)
Serious Adverse Events
	Calcifediol		Calcitriol		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/51 (0%)		0/50 (0%)		0/49 (0%)
Other (Not Including Serious) Adverse Events
	Calcifediol		Calcitriol		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/51 (2%)		1/50 (2%)		0/49 (0%)
Endocrine disorders
Hypercalcemia	1/51 (2%)		1/50 (2%)		0/49 (0%)

Limitations/Caveats

Limited sample size and AKI event rate

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.