Study on Delayed Graft Function Using Paired Kidneys

• Urine production [ Time Frame: 28 days ] [ Designated as safety issue: No ]
  Median time (days) until production of ≥1 litre urine over a 24-hour period, i.e. median number of days following the first infusion of study drug until the first day (08:00 - 08:00) that urine production was ≥1 litre over a 24-hour period.
• Creatinine clearance [ Time Frame: 28 days ] [ Designated as safety issue: No ]
  Calculated creatinine clearance at days 14 and 28
• Incidence of delayed graft function [ Time Frame: 7 days ] [ Designated as safety issue: No ]
  Incidence of delayed graft function (required dialysis due to inadequate renal function during the first 7 days after transplantation).
• Number of dialysis sessions [ Time Frame: 28 days ] [ Designated as safety issue: No ]
  Number of dialysis sessions through day 7, 14, and 28
• Mean total daily urine output [ Time Frame: 14 days ] [ Designated as safety issue: No ]
  Mean total daily urine output through day 14
• Daily serum creatinine [ Time Frame: 14 days ] [ Designated as safety issue: No ]
  Daily serum creatinine at days 1 to 7 and at days 1 to 14
• Mean serum creatinine [ Time Frame: 28 days ] [ Designated as safety issue: No ]
  Mean serum creatinine at days 4, 7, 10, 14, and 28
• Length of hospitalization following transplantation [ Time Frame: 28 days ] [ Designated as safety issue: No ]
  Length of hospitalization following transplantation
• Follow-up on graft survival and function [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  Results of the 6- and 12-month follow-up on graft survival and function will be summarized as an addendum to the final clinical study report
• adverse and serious adverse events, and acute rejection [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
  number of adverse and serious adverse events, and number of acute rejection periods

The study is designed to evaluate the safety and efficacy of an intravenously administered drug in recipients of kidneys from cardiac death donors who are risk for developing delayed graft function.

Renal transplantation is the most effective and cost-efficient form of renal replacement therapy for a burgeoning population that presents with end-stage renal disease. Although organ donation has become a national priority, the gap between the number of patients awaiting a kidney versus the number of available kidneys continues to widen exponentially. In many countries within the European Union, utilization of "donation after cardiac death" (DCD) kidneys is steadily increasing, expanding the donor pool by > 50%. Given the high incidence of cardiac deaths in the US, aggressive pursuit of the DCD kidney pool could potentially reduce waitlist periods to months, if not days. Risk for delayed graft function (DGF) with the attendant risks for increased recipient morbidity, chronic allograft nephropathy and increased medical costs has however tempered DCD kidney utilization in this country. Development of strategies that limit normothermic reperfusion injury, promote renal repair, reduce the incidence and/or duration of DGF and improve long-term outcome can greatly enhance acceptance and recruitment of DCD kidneys. The study is designed to evaluate the safety and efficacy of an intravenously administered drug in recipients of kidneys from DCD donors who are risk for developing DGF. This trial is unique in that it compares drug versus placebo outcome in kidney recipients from the same donor with direct evaluation of function (creatinine clearance) in the graft.

• Drug: BB3
  Daily intravenous administration of 2mg/kg for 4 days
• Drug: Normal Saline
  Daily intravenous administration for four (4) days. The volume of normal saline will vary by estimated weight.

• Placebo Comparator: Normal saline
  Placebo
  Intervention: Drug: Normal Saline
• Active Comparator: BB3
  Small molecule mimetic of hepatocyte growth factor/scatter factor
  Intervention: Drug: BB3

Inclusion Criteria:

• Subjects must sign the informed consent document prior to performance of any study related procedure including the Screening procedure.
• Males and females ≥ 18 years of age.
• Had renal transplantation due to end stage disease requiring chronic dialysis.
• Study drug can be administered within 6 to 9 hours after transplantation.
• Received kidney from donor after cardiac death.
• DCD kidney fulfills the clinical site's criteria for transplantation.
• Creatinine clearance from the transplanted kidney over a 2-hour collection period is < 10 mL/min.
• Dry weight ≤ 100 kg.
• Women of child bearing potential have a negative serum pregnancy test prior to transplantation.
• Women of child bearing potential (including perimenopausal women who have had a menstrual period within 1 year) must agree to use 2 forms of effective birth control regimen (at least one-barrier method) during the 28-day study period. Men must agree to use condoms during the study period; a condom with spermicide is considered a single barrier.
• In the opinion of the Investigator, the subject is capable of understanding and complying with the protocol.

Exclusion Criteria:

• Mean arterial pressure < 40 mmHg or cardiac index < 1.8 L/min/m2.
• Requires emergency dialysis for reasons other than high plasma creatinine levels, e.g. severe fluid overload or severe metabolic abnormalities.
• Recipient of multiple organ transplantation or scheduled for multiple organ transplantation.
• Recipient of kidney from a paediatric donor age 10 years or less.
• Recipient age > 75 years.
• Patients with ASA 4 or 5
• Patients with chronic obstructive pulmonary disease (COPD) GOLD IV
• Has measurable donor-specific antibody or positive cross-match requiring deviation from standard immunosuppressive therapy.
• Currently participating in or has participated in an investigational drug or medical device study within 30 days or five half-lives, whichever is longer, prior to enrolment into this study.
• Subjects who are currently taking or within 2 weeks prior to Screening have taken medications for Parkinson's disease.
• Subjects who are currently taking or within 2 weeks prior to Screening have taken medications for depression.
• Concurrent sepsis or active bacterial infection.
• Have an active malignancy or history of solid, metastatic or haematologic malignancy with the exception of basal or squamous cell carcinoma of the skin that has been removed.
• Women of child bearing potential who is breast feeding.
• History of positive HIV test.
• History of rheumatoid arthritis.
• History of proliferative retinopathy or laser surgery for retinopathy.
• Subjects who have a penicillin allergy.
• Subjects who require medications metabolized by CYP1A2 (see Chapter 5.2), or are receiving ciprofloxacin and fluvoxamine (Luvox®).
• Subject is unwilling or unable to comply with the protocol or to cooperate fully with the Investigator or the site personnel.
• Subject is not deemed medically stable for the study in the opinion of the Investigator or the subject's primary nephrologist.