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.

Study Overview

• Status: Terminated
• Conditions: Kidney Transplantation (Status Post)
• Intervention / Treatment: Biological: GSK1070806; Drug: 1) basiliximab 2) mycophenolate mofetil (MMF) OR azathioprine 3) tacrolimus 4) corticosteroids

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Phase 2

Contacts and Locations

Study Locations

• Spain
  • L'Hospitalet de Llobregat, Spain, 08907
    • GSK Investigational Site
• United Kingdom
  • Cambridge, United Kingdom, CB2 0QQ
    • GSK Investigational Site
  • Glasgow., United Kingdom, G51 4TF
    • GSK Investigational Site
  • Newcastle upon Tyne., United Kingdom, NE7 7DN
    • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: GSK1070806 3 mg/kg IV; Subjects received a single dose of 3 milligram per kilogram (mg/kg) intravenous (IV) infusion of GSK1070806 administered prior to kidney allograft reperfusion. Subjects also received a combination immunosuppression comprized of basiliximab; mycophenolate mofetil (MMF) or aziothioprine; tacrolimus; and corticosteroids based on the clinical judgment of the investigator.

Biological: GSK1070806; Injectable solution of 100 milligram/millilitre (mg/mL), administered as a single dose of 3 milligram/kilogram (mg/kg) (maximum of 10 mg/kg) diluted in 100 mL sterile IV infusion bag of 0.9% Sodium Chloride.; Drug: 1) basiliximab 2) mycophenolate mofetil (MMF) OR azathioprine 3) tacrolimus 4) corticosteroids; This immunosuppressant regimen may be revised based on the clinical judgment of the investigator including titration of tacrolimus levels.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Requiring Dialysis During the First 7 Days Post Transplant	The requirement of dialysis (except as needed for hyperkalaemia during the first 24 hours [hrs]) were used to assess the frequency of delayed graft function (DGF) in donation after circulatory death (DCD) renal transplant recipients treated with GSK1070806. The 'Analysis Population' (AP) is defined as participants in the 'All Subjects' Population who have been declared to have DGF or have reached 7 days.	Up to Day 7

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum Creatinine at Baseline and Change From Baseline Over Time Post Transplant	Blood samples were collected to measure serum creatinine at the indicated timepoints to assess graft function in DCD renal transplant recipients treated with GSK1070806. Baseline value was the latest pre-dose assessment value. Change from Baseline was post Baseline value minus Baseline value. NA indicates data is not available as standard deviation could not be calculated due to n=1. The AP Population is defined as participants having Baseline and at least one post-Baseline assessment.	Baseline and up to 12 months
Urine Volume at Baseline and Change From Baseline Over Time Post Transplant	Urine volume at Baseline and over time post transplant was measured to assess graft function in DCD renal transplant recipients treated with GSK1070806. Baseline value was the latest pre-dose assessment value. Change from Baseline was post Baseline value minus Baseline value. All Subjects Population comprised of participants who received the dose of study medication.	Baseline (Pre-operative) and up to Day 28
Number of Participants in the First 7 Days With: Primary Non Function, Functional DGF, Intermediate Graft Function, Immediate Graft Function	Number of participants in the first 7 days with primary non function, functional DGF, intermediate graft function and immediate graft function were evaluated to access graft function in DCD renal transplant recipients treated with GSK1070806. The AP Population is defined as participants in the 'All Subjects' Population who have been declared to have DGF or have reached 7 days.	Up to Day 7
Number of Participants With Episodes of Biopsy-proven Acute Rejection	Number of participants with episodes of biopsy-proven acute rejection were evaluated to assess the effect of GSK1070806 on acute rejection risk, and rejection/Pharmacodynamic (PD) biomarkers.	Up to 12 months
Serum Interferon Gamma-induced Protein 10 (IP-10) and Serum Monokine Induced Gamma Interferon (Mig) Levels at Baseline and Change From Baseline Over Time Post Transplant	The interferon-gamma -inducible chemokine IP10 and the interferon-gamma -inducible chemokine Mig have been identified as an early predictive marker of antibody-mediated kidney graft rejection. Baseline value was the latest pre-dose assessment value. Change from Baseline was calculated as post Baseline value minus Baseline value.	Baseline and at 0.75 hours, 4-8 hours, Day 1, Day 2, Day 30, Day 90, 6 months and 12 months post reperfusion
Number of Participants With Dialysis Events in the First 30 Days Post-transplant	Number of participants with dialysis events in the first 30 days post transplant was evaluated to assess the effect of GSK1070806 on dialysis dependency and graft survival. The AP Population is defined as participants having Baseline and at least one post-Baseline assessment.	Up to 30 days
Number of Participants Who Are Dialysis Independent at Visits up to 12 Months Post-transplant	Number of participants who are dialysis independent at visits up to 12 months post transplant was evaluated to assess the effect of GSK1070806 on dialysis dependency and graft survival.	Up to 12 months
Number of Participants With Adverse Event (AE) and Serious Adverse Event (SAE)	AE is any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment were categorized as SAE.	Up to 12 months
Number of Participants Having Any Abnormality in Hematology Results of Potential Clinical Importance	Blood samples were collected to evaluate hematology parameters. Number of participants with abnormality in any hematology parameter results of potential clinical importance (high or low) observed at any time post Baseline are presented. PCI (high or low) was considered if hematocrit (high:>0.54;low:change from baseline [CFB] 0.075 decrease), hemoglobin (high:180; low: CFB 25 decrease), lymphocytes (low: 0.8), neutrophil count (low: 1.5), platelet count (low: 100; high: 550), White blood cells (low: 3; high:20).	Up to 12 months
Number of Participants Having Any Abnormal Clinical Chemistry Results of Potential Clinical Importance	Blood samples were collected to evaluate clinical chemistry parameters. Number of participants with abnormal chemistry results of potential clinical importance (high or low) in any of these parameters at any time post Baseline visit have been presented. PCI (high or low) was considered if albumin (low<30), calcium (low<2, high>2.75), creatinine (high: CHB>44.2 increase), glucose (low<3, high>9), magnesium (low<0.5, high>1.23), phosphorus (low<0.8, high>1.6), potassium (low<3, high>5.5), sodium (low: 130, high>150), Total carbon dioxide (CO2) (low:18, high>32), Alanine aminotransferase (ALT) (high>=2*upper limit of normal [ULN]), Aspartate aminotransferase (AST) (high: >=2*ULN), Alkaline phosphatase (ALP) (high:>=2*ULN), Total bilirubin (high: >2*ULN), Total bilirubin+ALT (high: 1.5*ULN total bilirubin with >=2*ULN ALT).	Up to 12 months
Number of Participants Having Any Abnormality of Potential Clinical Importance of Vital Signs Results	Vital signs parameters included analysis of systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR) and body temperature. Number of participants with any abnormality of potential clinical importance (high or low) in any of these vitals signs at any time post Baseline visit have been presented. PCI (high or low) was considered if SBP (low: <85, high:>160), DBP (low: <45, high>100), HR (low: <40, high: >110) and temperature (low: <35.5, high: >37.5).	Up to 12 months
Number of Participants Having Infections	Number of participants having infections were summarized.	Up to 12 months
Serum Concentrations of GSK1070806	Serial blood samples were collected to evaluate PK of GSK1070806 at Pre-operative, 0.75 hours, 4-8 hours, 24 hours, 168 hours, Day 30, Day 90, 6 months and 12 months after kidney reperfusion. PK Population included participants in the 'All Subjects' Population for whom a serum PK sample is obtained and analyzed for GSK1070806.	Pre-operative, 0.75 hours, 4-8 hours, 24 hours, 168 hours, Day 30, Day 90, 6 months and 12 months after kidney reperfusion
Maximum Plasma Concentration (Cmax) of GSK1070806	Serial blood samples were collected to evaluate PK of GSK1070806 at Pre-operative, 0.75 hours, 4-8 hours, 24 hours, 168 hours, Day 30, Day 90, 6 months and 12 months after kidney reperfusion. Log-transformed geometric mean and 95% confidence interval have been presented.	Pre-operative, 0.75 hours, 4-8 hours, 24 hours, 168 hours, Day 30, Day 90, 6 months and 12 months after kidney reperfusion
Area Under the Plasma Concentration Time Curve (AUC) From Time 0 to the Last Measurable Concentration (AUC[0-t]) and AUC From Time 0 to Infinite Time (AUC[0-inf]) of GSK1070806	Blood samples were collected to evaluate PK of GSK1070806 at Pre-operative, 0.75 hours, 4-8 hours, 24 hours, 168 hours, Day 30, Day 90, 6 months and 12 months after kidney reperfusion. Log-transformed geometric mean and 95% confidence interval have been presented.	Pre-operative, 0.75 hours, 4-8 hours, 24 hours, 168 hours, Day 30, Day 90, 6 months and 12 months after kidney reperfusion
Baseline and Change From Baseline in Serum Levels of Free, Total, and GSK1070806 Bound Interleukin 18 (IL-18) Over Time Post-transplant	IL-18 is itself rapidly secreted from intracellular stores following inflammasome mediated-activation. The appearance of IL-18 marks the initiation of the inflammatory response leading to further injury. Blood samples were collected at indicated time points to assess serum levels of free, total, and GSK1070806 bound IL-18. Baseline value was the latest pre-dose assessment value. Change from Baseline was post Baseline value minus Baseline value.	Baseline and at 0.75 hours, 4-8 hours, Day 1, Day 2, Day 30, Day 90, 6 months and 12 months post reperfusion
Number of Participants With Positive Result in Anti-GSK1070806 Antibodies (ADAs)	Serum samples were to be collected to test for the presence of antibodies against GSK1070806 at indicated time points. The presence of anti-GSK1070806 binding antibodies were to be assessed using a validated electrochemiluminescent (ECL) immunoassay.	0.75 hour and 4-8 hour on Day 0, Day 1, Day 2, Day 30, Day 90, 6 months and 12 months post reperfusion
ADA Titer Before and After GSK1070806 Administration	Serum samples were to be collected to test for the presence of antibodies against GSK1070806 at indicated time points. The presence of ADA titre was to be assessed using a validated ECL immunoassay.	0.75 hour and 4-8 hour on Day 0, Day 1, Day 2, Day 30, Day 90, 6 months and 12 months post reperfusion

Collaborators and Investigators

• Sponsor: GlaxoSmithKline

Publications and helpful links

General Publications

• Wlodek E, Kirkpatrick RB, Andrews S, Noble R, Schroyer R, Scott J, Watson CJE, Clatworthy M, Harrison EM, Wigmore SJ, Stevenson K, Kingsmore D, Sheerin NS, Bestard O, Stirnadel-Farrant HA, Abberley L, Busz M, DeWall S, Birchler M, Krull D, Thorneloe KS, Weber A, Devey L. A pilot study evaluating GSK1070806 inhibition of interleukin-18 in renal transplant delayed graft function. PLoS One. 2021 Mar 8;16(3):e0247972. doi: 10.1371/journal.pone.0247972. eCollection 2021.

Study record dates

Study Major Dates

• Study Start (Actual): August 27, 2016
• Primary Completion (Actual): March 31, 2017
• Study Completion (Actual): March 6, 2018

Study Registration Dates

• First Submitted: March 14, 2016
• First Submitted That Met QC Criteria: March 24, 2016
• First Posted (Estimate): March 30, 2016

Study Record Updates

• Last Update Posted (Actual): June 26, 2019
• Last Update Submitted That Met QC Criteria: June 18, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Keywords: Renal Transplantation; Prevention; Delayed Graft Function; GSK1070806
• Additional Relevant MeSH Terms: Pathologic Processes; Delayed Graft Function; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Azathioprine; Tacrolimus; Mycophenolic Acid; Basiliximab
• Other Study ID Numbers: 204824; 2015-002812-33 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No