Efficacy and Safety of SANGUINATE™ for Reduction of Delayed Graft Function in Patients Receiving a Kidney Transplant

Study Overview
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Brief Summary
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Safety and efficacy study of SANGUINATE on reduction of delayed graft function (DGF) in patients who will be recipients of a donation after brain death (DBD) donor kidney.

Detailed Description
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Phase 2: Sixty (60) adult subjects who will be recipients of a donation after brain death (DBD) donor kidney and who meet all eligibility criteria will be randomized 1:1 within 48 hours prior to transplant surgery to receive: two infusions of SANGUINATE at a dose of 320 mg/kg or placebo on the day of surgery and approximately 24 hours after surgery. Patients will be hospitalized for up to 5 days and the study duration will be 30 days. Results will be used to inform the study design characteristics for Phase III, including sample size. Phase III: The same inclusion/exclusion requirements, dosing schedule, hospitalization stay and outpatient visits as in Phase II with additional visits scheduled at Day 90, Day 180 and Day 365. Study duration will be 365 days.

Official Title
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A Randomized, Placebo-controlled, Prospective, Double-blind, Multicenter Phase 2/3 Study of the Efficacy and Safety of SANGUINATE™ for Reduction of Delayed Graft Function in Recipients of a Donation After Brain Death Kidney Transplant

Conditions
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Delayed Function of Renal Transplant

Intervention / Treatment
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* Drug: SANGUINATE
* Drug: Normal Saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able to understand and provide written informed consent. Male or female subject at least 18 years of age. Dialysis-dependent renal failure initiated at least 3 months prior to transplantation. Subject is to be the recipient of a first kidney transplant from a deceased donor (brain death criteria). Is able to receive intravenous infusions of study drug. Anticipated donor organ cold ischemia time < 30 hours. A calculated prediction of DGF risk of least 25%. Females of childbearing potential must agree to use 2 forms of effective birth control regimen (at least one-barrier method) during the initial 30-day study period. Male subjects must agree to use condoms or other suitable means of pregnancy prevention. Exclusion Criteria: Has received a blood transfusion of packed red blood cells (PRBC), other than with leukocyte-poor blood, within the 90-day period prior to screening. Recipient of a live donor kidney or a kidney from a donation after cardiac death (DCD) donor. Recipient of donor kidney preserved with normothermic machine perfusion. Is scheduled to undergo multi-organ transplantation. Has planned transplant of kidney(s) from a donor < 6 years of age. Has planned transplant of kidneys that are implanted en bloc (dual kidney transplant). Has planned transplant of dual kidneys (from the same donor) transplanted not en bloc. Body Mass Index (BMI) > 38 kg/m2 Is scheduled for transplantation of a kidney from a donor who is known to have received an investigational therapy (under another Investigational New Drug) for ischemic/reperfusion injury immediately prior to organ recovery. Is scheduled to receive an blood type-incompatible donor kidney. Has undergone desensitization to remove antibodies prior to transplantation. Total bilirubin > 1.5 mg per dL, transaminase more than twice the upper limit of normal or evidence of hepatic insufficiency Has participated in an investigational study within the last 30 days or received an investigational product within 5 half-lives of the study drug administration, whichever is longest. Potential subjects participating in a strictly observational study or a study involving approved treatments should be discussed with the Medical Monitor. Has a history of human immunodeficiency virus (HIV) History or presence of active substance abuse (illicit drugs or alcohol) in the previous 6 months, as believed by the Investigator Presence of ECG-based evidence of acute myocardial infarction, unstable angina, decompensated heart failure, third degree heart block or cardiac arrhythmia associated with hemodynamic instability History or presence of any disease or psychiatric condition that in the Investigator's assessment that would increase the risk to subjects associated with study participation, drug administration or interpretation of results History of biopsy-confirmed malignancy within 5 years of randomization, with the exception of adequately treated basal cell or squamous cell carcinoma in situ skin lesions, carcinoma of the cervix in situ, or early detected prostate cancer. Female subject who is pregnant or breast feeding.

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SANGUINATE<br>Two (2) infusions of SANGUINATE | Drug: SANGUINATE<br>* Two (2) infusions of 320 mg/kg of SANGUINATE at Baseline and Day 1<br>* Other names: pegylated carboxyhemoglobin bovine;|
| Placebo Comparator: Normal Saline<br>Two (2) infusions of Normal Saline | Drug: Normal Saline<br>* Two (2) infusions of Normal Saline at an equal volume to SANGUINATE at Baseline and Day 1.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reduction of delayed graft function (DGF) | Reduction of delayed draft function will be measured by the number of dialysis sessions. | 30 Days | 
| Participants With at Least One Occurrence of Safety Composite Endpoint by Treatment Group | Composite endpoint defined by changes in vital signs, electrocardiographic, biochemical, hematological, and urinalysis, graft loss, death and other reported adverse events | Phase 2 - 30 Days; Phase 3: Safety - 90 days; Serious Adverse Events and Adverse Events of Special Interest - 180 Days; Graft Survival - 365 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects requiring dialysis for any reason in the first 7 days post-transplant |  | 7 Days | 
| Proportion of subjects requiring dialysis only in the first 5 days post-transplant |  | 5 Days | 
| Number of days of dialysis therapy. |  | 30 Days | 
| Proportion of subjects with a fall in serum creatinine. |  | 7 Days | 
| Proportion of subjects with a serum creatinine greater than 3 mg/dL, but who did not require dialysis by Day 5 post-transplant |  | 5 Days | 
| Rate of change in estimated creatinine clearance and estimated glomerular filtration rate over time |  | Phase 2: 30 Days |