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

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ClinicalTrials.gov Identifier: NCT02723786
Recruitment Status : Terminated (Lack of efficacy)
First Posted : March 30, 2016
Results First Posted : June 10, 2019
Last Update Posted : June 26, 2019
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Kidney Transplantation (Status Post) Biological: GSK1070806 Drug: 1) basiliximab 2) mycophenolate mofetil (MMF) OR azathioprine 3) tacrolimus 4) corticosteroids Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 7 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : August 27, 2016
Actual Primary Completion Date : March 31, 2017
Actual Study Completion Date : March 6, 2018

Resource links provided by the National Library of Medicine


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.




Primary Outcome Measures :
  1. Number of Participants Requiring Dialysis During the First 7 Days Post Transplant [ Time Frame: Up to Day 7 ]
    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.


Secondary Outcome Measures :
  1. Serum Creatinine at Baseline and Change From Baseline Over Time Post Transplant [ Time Frame: Baseline and up to 12 months ]
    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.

  2. Urine Volume at Baseline and Change From Baseline Over Time Post Transplant [ Time Frame: Baseline (Pre-operative) and up to Day 28 ]
    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.

  3. Number of Participants in the First 7 Days With: Primary Non Function, Functional DGF, Intermediate Graft Function, Immediate Graft Function [ Time Frame: Up to Day 7 ]
    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.

  4. Number of Participants With Episodes of Biopsy-proven Acute Rejection [ Time Frame: Up to 12 months ]
    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.

  5. 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 [ Time Frame: Baseline and at 0.75 hours, 4-8 hours, Day 1, Day 2, Day 30, Day 90, 6 months and 12 months post reperfusion ]
    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.

  6. Number of Participants With Dialysis Events in the First 30 Days Post-transplant [ Time Frame: Up to 30 days ]
    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.

  7. Number of Participants Who Are Dialysis Independent at Visits up to 12 Months Post-transplant [ Time Frame: Up to 12 months ]
    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.

  8. Number of Participants With Adverse Event (AE) and Serious Adverse Event (SAE) [ Time Frame: Up to 12 months ]
    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.

  9. Number of Participants Having Any Abnormality in Hematology Results of Potential Clinical Importance [ Time Frame: Up to 12 months ]
    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).

  10. Number of Participants Having Any Abnormal Clinical Chemistry Results of Potential Clinical Importance [ Time Frame: Up to 12 months ]
    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).

  11. Number of Participants Having Any Abnormality of Potential Clinical Importance of Vital Signs Results [ Time Frame: Up to 12 months ]
    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).

  12. Number of Participants Having Infections [ Time Frame: Up to 12 months ]
    Number of participants having infections were summarized.

  13. Serum Concentrations of GSK1070806 [ Time Frame: Pre-operative, 0.75 hours, 4-8 hours, 24 hours, 168 hours, Day 30, Day 90, 6 months and 12 months after kidney reperfusion ]
    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.

  14. Maximum Plasma Concentration (Cmax) of GSK1070806 [ Time Frame: Pre-operative, 0.75 hours, 4-8 hours, 24 hours, 168 hours, Day 30, Day 90, 6 months and 12 months after kidney reperfusion ]
    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.

  15. 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 [ Time Frame: Pre-operative, 0.75 hours, 4-8 hours, 24 hours, 168 hours, Day 30, Day 90, 6 months and 12 months after kidney reperfusion ]
    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.

  16. Baseline and Change From Baseline in Serum Levels of Free, Total, and GSK1070806 Bound Interleukin 18 (IL-18) Over Time Post-transplant [ Time Frame: Baseline and at 0.75 hours, 4-8 hours, Day 1, Day 2, Day 30, Day 90, 6 months and 12 months post reperfusion ]
    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.

  17. Number of Participants With Positive Result in Anti-GSK1070806 Antibodies (ADAs) [ Time Frame: 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 ]
    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.

  18. ADA Titer Before and After GSK1070806 Administration [ Time Frame: 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 ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02723786


Locations
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Spain
GSK Investigational Site
L'Hospitalet de Llobregat, Spain, 08907
United Kingdom
GSK Investigational Site
Cambridge, United Kingdom, CB2 0QQ
GSK Investigational Site
Glasgow., United Kingdom, G51 4TF
GSK Investigational Site
Newcastle upon Tyne., United Kingdom, NE7 7DN
Sponsors and Collaborators
GlaxoSmithKline
Investigators
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Study Director: GSK Clinical Trials GlaxoSmithKline
  Study Documents (Full-Text)

Documents provided by GlaxoSmithKline:
Statistical Analysis Plan  [PDF] May 24, 2017
Study Protocol  [PDF] May 4, 2017


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Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT02723786     History of Changes
Other Study ID Numbers: 204824
2015-002812-33 ( EudraCT Number )
First Posted: March 30, 2016    Key Record Dates
Results First Posted: June 10, 2019
Last Update Posted: June 26, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by GlaxoSmithKline:
Delayed Graft Function
Renal Transplantation
Prevention
GSK1070806

Additional relevant MeSH terms:
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Delayed Graft Function
Pathologic Processes
Tacrolimus
Azathioprine
Basiliximab
Mycophenolic Acid
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Calcineurin Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antibiotics, Antineoplastic
Antineoplastic Agents
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents
Antimetabolites
Antimetabolites, Antineoplastic
Antirheumatic Agents