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

NCT02723786 | Terminated Phase 2 Results

• 2 other identifiers: 2048242015-002812-33
• Study Type: interventional
• Target: 7
• Locations: 2 countries
• Sites: 4

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.

Conditions

Kidney Transplantation (Status Post)

Keywords

Delayed Graft Function; Renal Transplantation; Prevention; GSK1070806

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (18)

• Serum Creatinine at Baseline and Change From Baseline Over Time Post Transplant

  Baseline and up to 12 months

• Urine Volume at Baseline and Change From Baseline Over Time Post Transplant

  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

  Up to Day 7

• Number of Participants With Episodes of Biopsy-proven Acute Rejection

  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

  Baseline and at 0.75 hours, 4-8 hours, Day 1, Day 2, Day 30, Day 90, 6 months and 12 months post reperfusion

Study Arms (1)

GSK1070806 3 mg/kg IV

EXPERIMENTAL

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; Drug: 1) basiliximab 2) mycophenolate mofetil (MMF) OR azathioprine 3) tacrolimus 4) corticosteroids

Interventions

GSK1070806 BIOLOGICAL

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.

GSK1070806 3 mg/kg IV

1) basiliximab 2) mycophenolate mofetil (MMF) OR azathioprine 3) tacrolimus 4) corticosteroids DRUG

This immunosuppressant regimen may be revised based on the clinical judgment of the investigator including titration of tacrolimus levels.

GSK1070806 3 mg/kg IV

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• 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.
• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (4)

GSK Investigational Site

L'Hospitalet de Llobregat, 08907, Spain

Location

GSK Investigational Site

Cambridge, CB2 0QQ, United Kingdom

Location

GSK Investigational Site

Glasgow, G51 4TF, United Kingdom

Location

GSK Investigational Site

Newcastle upon Tyne, NE7 7DN, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 33684160 DERIVED

MeSH Terms

Conditions

Delayed Graft Function

Interventions

GSK1070806; Mycophenolic Acid; Adrenal Cortex Hormones

Condition Hierarchy (Ancestors)

Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Caproates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids; Lipids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 14, 2016
• First Posted: March 30, 2016
• Study Start: August 27, 2016
• Primary Completion: March 31, 2017
• Study Completion: March 6, 2018
• Last Updated: June 26, 2019
• Results First Posted: June 10, 2019

Record last verified: 2019-05

Data Sharing

• IPD Sharing: Will share

Locations

ES (1); GB (3)