Efficacy, Safety, Tolerability and Pharmacokinetic (PK) Study of GSK1070806 for the Prevention of Delayed Graft Function (DGF) in Adult Subjects After Renal Transplantation

A Phase 2 Pilot, Multicenter, Single Arm Study to Evaluate the Efficacy, Safety, Tolerability, and Pharmacokinetics of GSK1070806 Plus Standard of Care for the Prevention of Delayed Graft Function in Adult Subjects After Renal Transplantation

This is a phase 2 study to evaluate the efficacy, safety, tolerability and pharmacokinetics of GSK1070806 in subjects undergoing renal transplantation. GSK1070806 is an anti-interleukin 18 (IL18) monoclonal antibody, which binds to IL-18 and inhibits signaling through the IL-18 receptor. Recipients of donor kidneys, retrieved after circulatory death of the donor, will be administered a single intravenous infusion of GSK1070806 to test whether inhibition of IL-18 can reduce the rate of Delayed Graft Function (DGF) and graft rejection. Subjects will be followed for 12 months post dose/transplant. Up to 40 adult subjects will be enrolled in this study.

Inclusion Criteria:

• Recipient age range: Between 18 and 75 years of age inclusive, at the time of signing the informed consent.

• Dialysis-dependent recipient of first time, single kidney-only, Donation after Circulatory Death (DCD) transplant.

• Eligible for kidney transplantation: Considered eligible after undergoing multidisciplinary evaluation at the institution at which the transplantation will be performed.

• Immunosuppressants (at the time of transplantation): planned to receive a combination of immunosuppressants including basiliximab, mycophenolate mofetil or azathioprine, tacrolimus, and corticosteroids.

• Male and Female:

  1. Males: Male subjects with female partners of child bearing potential must utilize a condom and female partners must comply with use of highly effective contraceptive methods for 180 days post-dose of study medication.

  2. Females:

     • Non-reproductive potential defined as in the protocol. Reproductive potential: Must not be pregnant or lactating, and agrees to follow one of the options listed in the Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP) for 180 days post dose as defined in the protocol.

• Capable of providing signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and in the protocol.

Exclusion Criteria:

• Liver function: Alanine Aminotransferase (ALT) >2xUpper Limit of Normal (ULN) and bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
• QT interval: single or average Corrected QT Interval (QTc)>480 milliseconds (msec) or in subjects with bundle branch block QTc>500 msec (these criteria do not apply to subjects with predominately paced rhythms).
• Concurrent medication: Subjects who receive treatment that is prohibited for safety reasons (e.g. live vaccines, cyclophosphamide or other biologic immunosuppressants) should not receive investigational product without the explicit approval of the Medical Monitor (Sponsor).
• Investigational product: Any within 5 half-lives or twice the duration of the biological effect whichever is longer (investigational product refers to any drug not approved for sale in the country in which it is being used).
• Immunosuppression: Are being considered for steroid-free, anti-thymocyte globulin (ATG) or alemtuzumab induction, which have a much more profound and prolonged immunosuppressive effect than basiliximab.
• Prior biologic immunosuppressives: The subject has received an agent within the following time period prior to the day of dosing in the current study: 30 days, 5 half-lives or twice the duration of the biological effect, whichever is longer.
• Vaccines: A live vaccine within 30 days prior to GSK1070806 administration
• Receiving a DCD kidney allograft from a donor with any of the following characteristics: cold ischemic time >36 hours, age <5 years old, age >75 years old, ABO blood type incompatible against the recipient, T- and/or B-cell positive cross-match by complement dependent cytotoxicity or flow cytometry against the recipient (where positive cross-match is unavailable, virtual cross-match is allowed), serology positive for hepatitis B (except hepatitis B surface antibody and prior vaccination), hepatitis C or human immunodeficiency virus (HIV), Epstein Barr Virus (EBV) positive donor allograft with an EBV negative recipient, donor had acute or chronic bacterial, viral or fungal infection that according to the investigator causes a risk to recipient, particularly if the infection was resistant or systemic, normothermic regional machine perfusion organ retrieval techniques were utilized, surgical damage to donor allograft during organ procurement
• Previous organ transplantation: has previously undergone any other organ transplantation (with the exception of corneal transplantation).
• Malignancy: has a history of malignancy in the past 5 years except for adequately treated cancers of the skin (basal or squamous cell) or carcinoma in situ of the uterine cervix.
• Acute or chronic infection: has required management of acute or chronic infections (excludes prophylaxis of infections), as follows: currently being treated for a chronic infection, which in the opinion of the investigator, could put the subject at undue risk; hospitalized for treatment of infection, or treated for an infection with parenteral antibiotics (includes antibacterials, antivirals, anti-fungals, or anti-parasitic agents) within 30 days before Day 0, which in the opinion of the investigator, could put the subject at undue risk; current evidence, or history within the last 14 days, of an influenza-like illness as defined by fever (>38 degree Celsius) and two or more of the following symptoms: cough, sore throat, runny nose, sneezing, limb / joint pain, headache, vomiting / diarrhoea; subjects with any history of active tuberculosis, recent tuberculosis exposure, or judged by investigators to be at risk of tuberculosis will be excluded from the study.
• Other disease/conditions. Has any of the following: clinical evidence of significant unstable or uncontrolled acute or chronic diseases, which in the opinion of the investigator, could confound the results of the study or put the subject at undue risk; a surgical procedure planned in the 12 months after Day 0, other than kidney transplantation or related procedure; a known history of any other medical disease (e.g., cardiopulmonary), laboratory abnormality, or condition (e.g., poor venous access) that, in the opinion of the investigator, makes the subject unsuitable for the study
• Hepatitis B: subjects will be excluded with any evidence of acute or chronic infection, or if interpretation of their results is unclear. This includes: Hepatitis B surface Antigen (HBsAg)+, Anti- Hepatitis B core (Anti-HBc)+, Hepatitis B Deoxyribose Nucleic Acid (HB DNA)+. It is permissible to enroll subjects who are anti-Hepatitis B (HB)s+ only, when this is attributable to vaccination and there is no history of previous infection.
• Hepatitis C: subjects will be excluded if there is any evidence of past or current hepatitis C infection, including hepatitis C antibody, hepatitis C Recombinant ImmunoBlot Assay (RIBA) or Polymerase Chain Reaction (PCR).
• HIV: known to have a historically positive HIV test.
• Immunodeficiency: recipient with a history of, or laboratory evidence of immunodeficiency.
• Drug Sensitivity: has a history of sensitivity to any of the study medications including: GSK1070806; background immunosuppressive regimen; designated prophylactic anti-infective therapies or components thereof, or a history of drug or other allergy including a previous anaphylactic reaction to parenteral administration or biologic therapy (ie monoclonal antibody) that, in the opinion of the Investigator or Medical Monitor, contraindicates their participation.
• Substance abuse: has clinical evidence of current drug or alcohol abuse or dependence.
• Co enrollment: participating in another interventional study (participation in purely observational or cohort studies is acceptable provided they do not impair feasibility, or involve excessive additional sampling).
• Compliance: is unlikely to comply with scheduled study visits based on investigator judgment or has a history of a psychiatric disorder or condition that may compromise communication with the investigator.