Effect of RBT-1 on Preconditioning Response Biomarkers in Subjects Undergoing CABG and/or Cardiac Valve Surgery

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 2, Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Effect of RBT-1 on Preconditioning Response Biomarkers in Subjects Undergoing Coronary Artery Bypass Graft (CABG) and/or Cardiac Valve Surgery (The START Study)

Conditions
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AKI

Intervention / Treatment
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* Drug: Low Dose RBT-1
* Drug: High Dose RBT-1
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects ≥18 years of age at Screening. Able and willing to comply with all study procedures. Stable kidney function per Investigator assessment and no known episodes of AKI during the preceding 4 weeks. 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. 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. Male subjects must agree not to donate or sell sperm for 30 days following study drug administration. Exclusion Criteria: Presence of AKI (KDIGO criteria) at the time of Screening. Surgery to be performed without cardiopulmonary bypass. Surgery to be performed under conditions of circulatory arrest or hypothermia with rectal temperature <28°C (82.4°F). eGFR ≤20 mL/min/1.73m2 or need for dialysis. Surgery for aortic dissection or to correct a major congenital heart defect. Administration of iodinated contrast media within 24 hours prior to cardiac surgery or evidence of contrast-induced nephropathy prior to cardiac surgery. 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. 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. 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. Known or suspected sepsis at time of Screening or confirmed or treated endocarditis within 30 days prior to cardiac surgery. Other current active infection requiring systemic antibiotic treatment. 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. Any congenital coagulation disorder. Asplenia (anatomic or functional). History of photosensitivity or active skin disease that, in the opinion of the Investigator, could be worsened by RBT-1. Known hypersensitivity or previous anaphylaxis to SnPP or any tin-based product. Serum ferritin >500 ng/mL or those who have received IV iron within 28 days of Screening. Pregnancy or lactation. Treatment with an investigational drug or participation in an interventional study within 30 days prior to administration of study drug. In the opinion of the Investigator, any disease processes or confounding variables that would inappropriately alter the outcome of the study. Inability to comply with the requirements of the study protocol.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Subjects will be randomized 1:1:1 to low dose RBT-1, high dose RBT-1, and placebo
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low Dose RBT-1<br>Single IV infusion prior to cardiac surgery | Drug: Low Dose RBT-1<br>* intravenous administration<br>|
| Experimental: High Dose RBT-1<br>Single IV infusion prior to cardiac surgery | Drug: High Dose RBT-1<br>* intravenous administration<br>|
| Placebo Comparator: Placebo<br>Single IV infusion prior to cardiac surgery | Drug: Placebo<br>* intravenous administration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the efficacy of RBT-1 in generating a preconditioning response as measured by a composite of biomarkers | Plasma heme oxygenase-1 (HO-1), ferritin, and interleukin-10 (IL-10) | Baseline through Day 3 post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in renal tubular injury biomarkers | KIM-1, NGAL, cystatin C | Baseline through Day 3 post-cardiac surgery | 
| Reduction in urine output | Documented oliguria of <0.5 mL/kg/hour for more than 6 hours post-cardiac surgery | Baseline through Day 3 post-cardiac surgery | 
| Incidence of acute kidney injury (AKI) | AKI is defined using the KDIGO criteria (ie, an absolute increase in serum creatinine by 0.5 mg/dL, which is present over 2 laboratory measurements at least 12 hours apart; or an increase in serum creatinine ≥1.5 × Baseline. | Baseline through Day 5 post-cardiac surgery |