Critically Ill, Acute Kidney Injury
Conditions
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.
Interventions
DRUGCalcifediol
Calcifediol 400mcg orally x 1, followed by 200mcg orally daily x 4
DRUGCalcitriol
Calcitriol 4mcg orally daily x 5
DRUGPlacebos
Placebo (medium chain triglyceride oil) orally daily x 5
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
David Leaf
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Death Within 7 Days | 7 days | All-cause mortality within 7 days following randomization |
| 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 |
| 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Peak Serum Creatinine (mg/dl) | 7 days | Highest serum creatinine value on days 1 to 7 |
| 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. |
| 28-day Mortality | 28 days | All-cause mortality assessed during the 28 days following randomization |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Calcifediol 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 | 51 |
| Calcitriol Calcitriol 4mcg orally daily x 5 days
Calcitriol: Calcitriol 4mcg orally daily x 5 | 50 |
| Placebo Equal volume of medium chain triglyceride (MCT) oil orally daily x 5 days
Placebos: Placebo (medium chain triglyceride oil) orally daily x 5 | 49 |
| Total | 150 |
Baseline characteristics
| Characteristic | Calcifediol | Total | Placebo | Calcitriol |
|---|---|---|---|---|
| Acute kidney injury | 19 Participants | 55 Participants | 18 Participants | 18 Participants |
| Age, Continuous | 64 years | 65 years | 65 years | 65 years |
| APACHE II score | 26 units on a scale | 25 units on a scale | 27 units on a scale | 25 units on a scale |
| Baseline estimated glomerular filtration rate (eGFR) | 94 ml/min/1.73m^2 | 95 ml/min/1.73m^2 | 94 ml/min/1.73m^2 | 98 ml/min/1.73m^2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 11 Participants | 3 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 45 Participants | 136 Participants | 46 Participants | 45 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 3 Participants | 0 Participants | 1 Participants |
| Invasive mechanical ventilation | 41 Participants | 125 Participants | 41 Participants | 43 Participants |
| Plasma 25-hydroxyvitamin D | 18.8 ng/ml | 16.5 ng/ml | 14.5 ng/ml | 17.3 ng/ml |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 5 Participants | 4 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 15 Participants | 3 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 3 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 3 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 43 Participants | 124 Participants | 41 Participants | 40 Participants |
| Sex: Female, Male Female | 19 Participants | 58 Participants | 18 Participants | 21 Participants |
| Sex: Female, Male Male | 32 Participants | 92 Participants | 31 Participants | 29 Participants |
| Vasopressors/inotropes | 28 Participants | 86 Participants | 30 Participants | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 10 / 51 | 16 / 50 | 10 / 49 |
| other Total, other adverse events | 1 / 51 | 1 / 50 | 0 / 49 |
| serious Total, serious adverse events | 0 / 51 | 0 / 50 | 0 / 49 |
Outcome results
Primary
Death Within 7 Days
All-cause mortality within 7 days following randomization
Time frame: 7 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Calcifediol | Death Within 7 Days | 4 Participants |
| Calcitriol | Death Within 7 Days | 9 Participants |
| Placebo | Death Within 7 Days | 6 Participants |
p-value: 0.52Fisher Exact
p-value: 0.58Fisher Exact
Primary
Number of Participants Who Received Renal Replacement Therapy Within 7 Days
Number of participants who received renal replacement therapy within 7 days following randomization
Time frame: 7 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Calcifediol | Number of Participants Who Received Renal Replacement Therapy Within 7 Days | 1 Participants |
| Calcitriol | Number of Participants Who Received Renal Replacement Therapy Within 7 Days | 1 Participants |
| Placebo | Number of Participants Who Received Renal Replacement Therapy Within 7 Days | 4 Participants |
p-value: 0.2Fisher Exact
p-value: 0.2Fisher Exact
Primary
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
Time frame: 7 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Calcifediol | Relative Average Change in Serum Creatinine From Day 0 to Days 1-7 | -2.3 Relative average percent increase |
| Calcitriol | Relative Average Change in Serum Creatinine From Day 0 to Days 1-7 | -7.1 Relative average percent increase |
| Placebo | Relative Average Change in Serum Creatinine From Day 0 to Days 1-7 | -7.4 Relative average percent increase |
p-value: 0.44Wilcoxon (Mann-Whitney)
p-value: 0.29Wilcoxon (Mann-Whitney)
Secondary
28-day Mortality
All-cause mortality assessed during the 28 days following randomization
Time frame: 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Calcifediol | 28-day Mortality | 10 Participants |
| Calcitriol | 28-day Mortality | 16 Participants |
| Placebo | 28-day Mortality | 10 Participants |
Secondary
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
Time frame: 28 days
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Calcifediol | ICU- and Hospital-free Days | ICU-free days | 20 Days |
| Calcifediol | ICU- and Hospital-free Days | Hospital-free days | 5 Days |
| Calcitriol | ICU- and Hospital-free Days | ICU-free days | 16 Days |
| Calcitriol | ICU- and Hospital-free Days | Hospital-free days | 4 Days |
| Placebo | ICU- and Hospital-free Days | Hospital-free days | 0 Days |
| Placebo | ICU- and Hospital-free Days | ICU-free days | 11 Days |
Secondary
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.
Time frame: 7 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Calcifediol | Number of Participants With New or Worsening Stage of AKI, Defined by KDIGO Guidelines | 20 Participants |
| Calcitriol | Number of Participants With New or Worsening Stage of AKI, Defined by KDIGO Guidelines | 23 Participants |
| Placebo | Number of Participants With New or Worsening Stage of AKI, Defined by KDIGO Guidelines | 19 Participants |
Secondary
Peak Serum Creatinine (mg/dl)
Highest serum creatinine value on days 1 to 7
Time frame: 7 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Calcifediol | Peak Serum Creatinine (mg/dl) | 1.2 mg/dl |
| Calcitriol | Peak Serum Creatinine (mg/dl) | 1.3 mg/dl |
| Placebo | Peak Serum Creatinine (mg/dl) | 1.2 mg/dl |
Other Pre-specified
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
Time frame: 7 days
Other Pre-specified
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
Time frame: 7 days
Other Pre-specified
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
Time frame: 7 days
Other Pre-specified
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
Time frame: 7 days
Other Pre-specified
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
Time frame: 7 days