AKI
Conditions
Brief summary
The purpose of this study is to evaluate the effect of RBT-1 (stannous protoporphyrin \[SnPP\]/iron sucrose \[FeS\]) on preconditioning response biomarkers in subjects who are at risk for AKI following cardiac surgery.
Interventions
DRUGLow Dose RBT-1
intravenous administration
DRUGHigh Dose RBT-1
intravenous administration
DRUGPlacebo
intravenous administration
Sponsors
Renibus Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Caregiver, Investigator)
Intervention model description
Subjects will be randomized 1:1:1 to low dose RBT-1, high dose RBT-1, and placebo
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female subjects ≥18 years of age at Screening. 2. Able and willing to comply with all study procedures. 3. Stable kidney function per Investigator assessment and no known episodes of AKI during the preceding 4 weeks. 4. Scheduled to undergo non-emergent coronary and/or valve surgery(ies) requiring cardiopulmonary bypass, including: * CABG alone; * Combined CABG surgery/repair of 1 or more cardiac valves; * Cardiac valve(s) replacement or repair alone. 5. Females and males of childbearing potential must agree to use 2 forms of contraception, with at least 1 being a barrier method, or abstain from sexual activity for 30 days following study drug administration. 6. Male subjects must agree not to donate or sell sperm for 30 days following study drug administration.
Exclusion criteria
1. Presence of AKI (KDIGO criteria) at the time of Screening. 2. Surgery to be performed without cardiopulmonary bypass. 3. Surgery to be performed under conditions of circulatory arrest or hypothermia with rectal temperature \<28°C (82.4°F). 4. eGFR ≤20 mL/min/1.73m2 or need for dialysis. 5. Surgery for aortic dissection or to correct a major congenital heart defect. 6. Administration of iodinated contrast media within 24 hours prior to cardiac surgery or evidence of contrast-induced nephropathy prior to cardiac surgery. 7. Cardiogenic shock or hemodynamic instability within the 24 hours prior to surgery and requirement for inotropes or vasopressors or other mechanical devices, such as intra-aortic balloon counter-pulsation. 8. Requirement for any of the following within 7 days prior to cardiac surgery: * Defibrillator or permanent pacemaker; * Mechanical ventilation; * Intra-aortic balloon counter-pulsation; * Left ventricular assist device; * Other forms of mechanical circulatory support. 9. Known history of cancer within the past 2 years, except for carcinoma in situ of the cervix or adequately treated basal cell carcinoma of the skin. 10. Known or suspected sepsis at time of Screening or confirmed or treated endocarditis within 30 days prior to cardiac surgery. 11. Other current active infection requiring systemic antibiotic treatment. 12. Inadequate hepatic function, defined as total bilirubin or alanine aminotransferase or aspartate aminotransferase \>2X the upper limit of normal at time of Screening or Child Pugh Class C liver disease or higher. 13. Any congenital coagulation disorder. 14. Asplenia (anatomic or functional). 15. History of photosensitivity or active skin disease that, in the opinion of the Investigator, could be worsened by RBT-1. 16. Known hypersensitivity or previous anaphylaxis to SnPP or any tin-based product. 17. Serum ferritin \>500 ng/mL or those who have received IV iron within 28 days of Screening. 18. Pregnancy or lactation. 19. Treatment with an investigational drug or participation in an interventional study within 30 days prior to administration of study drug. 20. In the opinion of the Investigator, any disease processes or confounding variables that would inappropriately alter the outcome of the study. 21. Inability to comply with the requirements of the study protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Evaluate the Efficacy of RBT-1 in Generating a Preconditioning Response as Measured by a Composite of Biomarkers | Baseline through Pre-Surgery | Composite of the geometric mean of the ratios of the maximum PreOp value over Baseline for plasma heme oxygenase-1 (HO-1), ferritin, and interleukin-10 (IL-10) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Renal Tubular Injury Biomarkers | Baseline through Day 3 post-cardiac surgery | Geometric mean of the ratios of the maximum PostOp value over Baseline for urine KIM-1, NGAL, and cystatin C. |
| Number of Subjects With Reduction in Urine Output | Baseline through post-cardiac surgery through Day 5 | Documented AE of sustained reduction in urine output, oliguria, or anuria post-cardiac surgery through Day 5 |
| Number of Subjects With Acute Kidney Injury (AKI) | Baseline through Day 5 post-cardiac surgery | AKI is defined using the KDIGO criteria (ie, an absolute increase in serum creatinine of ≥1.5 × Baseline; or documented AE of sustained reduction in urine output, oliguria, or anuria; or initiation of dialysis). |
Countries
Australia, Canada, United States
Participant flow
Pre-assignment details
17 participants were excluded after signing informed consent (11 did not meet eligibility criteria, 5 withdrew consent prior to treatment, 1 had surgery changed to another location)
Participants by arm
| Arm | Count |
|---|---|
| High Dose RBT-1 Single IV infusion of high dose RBT-1 within 1-2 days prior to scheduled cardiac surgery | 46 |
| Low Dose RBT-1 Single IV infusion of low dose RBT-1 within 1-2 days prior to scheduled cardiac surgery | 45 |
| Placebo Single IV infusion of placebo within 1-2 days prior to scheduled cardiac surgery | 44 |
| Total | 135 |
Baseline characteristics
| Characteristic | High Dose RBT-1 | Total | Placebo | Low Dose RBT-1 |
|---|---|---|---|---|
| Age, Continuous | 66.04 years | 65.21 years | 65.70 years | 63.87 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 5 Participants | 1 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 45 Participants | 129 Participants | 43 Participants | 41 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants | 4 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 2 Participants | 8 Participants | 2 Participants | 4 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 41 Participants | 120 Participants | 41 Participants | 38 Participants |
| Region of Enrollment Australia | 5 participants | 12 participants | 3 participants | 4 participants |
| Region of Enrollment Canada | 8 participants | 27 participants | 10 participants | 9 participants |
| Region of Enrollment United States | 33 participants | 96 participants | 31 participants | 32 participants |
| Sex: Female, Male Female | 10 Participants | 33 Participants | 12 Participants | 11 Participants |
| Sex: Female, Male Male | 36 Participants | 102 Participants | 32 Participants | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 46 | 1 / 45 | 3 / 44 |
| other Total, other adverse events | 42 / 46 | 40 / 45 | 40 / 44 |
| serious Total, serious adverse events | 22 / 46 | 13 / 45 | 18 / 44 |
Outcome results
Primary
Evaluate the Efficacy of RBT-1 in Generating a Preconditioning Response as Measured by a Composite of Biomarkers
Composite of the geometric mean of the ratios of the maximum PreOp value over Baseline for plasma heme oxygenase-1 (HO-1), ferritin, and interleukin-10 (IL-10)
Time frame: Baseline through Pre-Surgery
Population: Values were missing from 3 subjects in the low dose RBT-1 treatment group.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| High Dose RBT-1 | Evaluate the Efficacy of RBT-1 in Generating a Preconditioning Response as Measured by a Composite of Biomarkers | 3.60 composite ratio |
| Low Dose RBT-1 | Evaluate the Efficacy of RBT-1 in Generating a Preconditioning Response as Measured by a Composite of Biomarkers | 2.63 composite ratio |
| Placebo | Evaluate the Efficacy of RBT-1 in Generating a Preconditioning Response as Measured by a Composite of Biomarkers | 1.00 composite ratio |
p-value: <0.0001ANCOVA
p-value: <0.0001ANCOVA
Secondary
Change in Renal Tubular Injury Biomarkers
Geometric mean of the ratios of the maximum PostOp value over Baseline for urine KIM-1, NGAL, and cystatin C.
Time frame: Baseline through Day 3 post-cardiac surgery
Population: Biomarker samples were missing from 2 subjects in the Low Dose RBT-1 group and 1 subject in the Placebo group.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| High Dose RBT-1 | Change in Renal Tubular Injury Biomarkers | 7.89 Composite ratio |
| Low Dose RBT-1 | Change in Renal Tubular Injury Biomarkers | 10.84 Composite ratio |
| Placebo | Change in Renal Tubular Injury Biomarkers | 6.10 Composite ratio |
p-value: 0.3954ANCOVA
p-value: 0.0682ANCOVA
Secondary
Number of Subjects With Acute Kidney Injury (AKI)
AKI is defined using the KDIGO criteria (ie, an absolute increase in serum creatinine of ≥1.5 × Baseline; or documented AE of sustained reduction in urine output, oliguria, or anuria; or initiation of dialysis).
Time frame: Baseline through Day 5 post-cardiac surgery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| High Dose RBT-1 | Number of Subjects With Acute Kidney Injury (AKI) | 7 Participants |
| Low Dose RBT-1 | Number of Subjects With Acute Kidney Injury (AKI) | 7 Participants |
| Placebo | Number of Subjects With Acute Kidney Injury (AKI) | 8 Participants |
p-value: >0.9999Fisher Exact
p-value: >0.9999Fisher Exact
Secondary
Number of Subjects With Reduction in Urine Output
Documented AE of sustained reduction in urine output, oliguria, or anuria post-cardiac surgery through Day 5
Time frame: Baseline through post-cardiac surgery through Day 5
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| High Dose RBT-1 | Number of Subjects With Reduction in Urine Output | 2 Participants |
| Low Dose RBT-1 | Number of Subjects With Reduction in Urine Output | 2 Participants |
| Placebo | Number of Subjects With Reduction in Urine Output | 4 Participants |
p-value: 0.6755Fisher Exact
p-value: 0.6758Fisher Exact