Prevention of Kidney Graft Dysfunction MedDRA version: 17.1 Level: LLT Classification code 10051366 Term: Kidney graft dysfunction System Organ Class: 100000004863
Conditions
Sponsors
Opsona Therapeutics Ltd
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Inclusion Criteria for Transplant Recipients: Phase 0 & Part A-Adult patients receiving an ECD, DCD, or an SCD (CIT>18h at time of arrival at the hospital (Phase 0) or at randomisation (Part A) kidney transplantation satisfying the following criteria// Part B -Adult patients receiving an ECD kidney transplant satisfying the following criteria: •Provide written informed consent •Accepted for renal transplantation due to end stage renal disease •First or second renal transplant recipient - for second renal transplantations; oThe second transplant should NOT be due to rejection oPanel Reactive Antibody (PRA) should be 18 hours at time of arrival in the recipient’s hospital in Phase 0 or at randomisation in Part A •Kidney allograft maintained in cold storage with or without machine perfusion Inclusion Criteria for Donor Kidney in Part B: •The donor k
Exclusion criteria
Exclusion criteria: Exclusion Criteria for Transplant Recipients: •Use of an investigational drug in the 30 days before surgery •Participation in any other research study (drug or non-drug) without prior approval from the Medical Monitor •Known hypersensitivity to human monoclonal antibodies or any of the study-drug excipients •Previous hypersensitivity to basiliximab and anti-thymocyte globulin (ATG) if induction with one of these agents would normally be required •Part B only- Previous hypersensitivity to basiliximab and/or anti-thymocyte globulin (ATG) depending on induction regimen • Pre-operative serum potassium >6.0mmol/L o Note: Dialysis before surgery to correct hyperkalaemia or hypervolaemia is recommended •History or known HIV or HBV (surface antigens)positive o Note: Patients known to have a positive virology history but current unknown status must be assumed to be still positive at screening. Patients with a positive history who are confirmed to be sero-negative at screening may enter the study. •History of malignancy within the last five years judged to be at risk of relapse within the timeframe of the clinical trial, except excised squamous or basal cell carcinoma of the skin or cervical intraepithelial neoplasia •Scheduled to undergo multi-organ transplantation •Planned dual kidney transplantation •Presence of clinically significant infections requiring continued therapy •Active tuberculosis •Existence of any surgical or medical condition, other than the current transplantation which, in the opinion of the investigator, might significantly alter the distribution, metabolism or excretion of study medication •Presence of uncontrolled diabetes mellitus (defined according to local diagnostic procedures) •Current drug and/or alcohol abuse •History or presence of a medical condition or disease that in the investigator's assessment would place the patient at an unacceptable risk for study participation •Lactating or pregnant woman •Patient institutionalised by administrative or court order (Part B- In the situation that a legal guardian has provided consent this can be considered on a case by case basis) Exclusion Criteria for Donor Kidney (Phase 0 and Part A): • Expected CIT >30h for any kidney type at the start of surgery Note: If the patient is randomised and there are unforeseen delays at the time start of surgery an additional 2 hours will be allowed. If the CIT at the outset of surgery is more than 32 hours the patient should not be dosed with OPN-305/placebo. The start time for measurement of CIT is the time of clamping of the donor kidney. •Terminal creatinine >2mg/dL (176.9µm/L) (ECD>1.5mg/dl (132.6µmol/L) ) • Donor who is known to have received an investigational drug for I-R injury or graft rejection (immunosuppressant) in the 48h before organ recovery • Participation in any other research study (drug or non-drug) without prior approval from the Medical Monitor • Kidney donor 30h for any kidney type at the start of surgery Note: If the patient is randomised and there are unforeseen delays at the time start of surgery an additional 2 hours will be allowed. If the CIT at the outs
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Primary end point(s): • Phase 0: TLR2 receptor occupancy • Part A: Incidence of dDGF • Part B: EGF (dDGF + fDGF) in patients with ECD donors, where dDGF is defined as the initiation of dialysis in the first 7 days following transplantation and fDGF is defined as a failure of serum creatinine to decrease by at least 10% daily on 3 successive days during the first week post transplantation;Timepoint(s) of evaluation of this end point: • Phase 0: TLR2 receptor occupancy evaluated pre t=0, t=2,24,72h, day 7 and 14 • Part A: Incidence of DGF evaluated day 0 to day 7 • Part B: EGF (dDGF + fDGF). dDGF and fDGF evaluated day 0 to day 7 post transplantation ;Main Objective: • Phase 0: To determine the receptor occupancy of OPN-305 1.5mg/kg in patients receiving an ECD, DCD or SCD(CIT>18h) kidney transplantation and to verify the doses of OPN-305 to be used in Part A. • Part A: To select the optimal single IV dose of OPN-305 for Part B of the study in ECD/DCD/SCD(CIT>18h) kidney transplantation patients. The primary endpoint for this objective is the incidence of DGF on Day 7 defined as the initiation of dialysis in the first 7 days post-transplantation (dDGF) in patients receiving an ECD/DCD/SCD(CIT>18h) kidney transplantation • Part B: To evaluate whether 0.5mg/kg OPN-305 can improve early graft function, by measuing the composite endpoint of DGF and fDGF. ;Secondary Objective: Phase 0: PK & safety of single-dose OPN305 1.5mg/kg Part A: Safety & PK of doses of OPN305 in pts undergoing ECD/DCD/SCD(CIT>18h) kidney transplant. PartB: Effect in pts receiving ECD kidney transplant of single-dose 0.5mg/kg OPN305 on: •Graft function o Incidence of SGF (= SCr>3 mg/dL on post-op d5, without dialysis requirement) o Estimated GFR = Cr, Cystatin C, SMDA at d7, d14 and months 1, 3 & 6 o SCr over time •Composite endpoint; graft loss, incidence of biopsy-proven kidney allograft rejection, Pt death, Loss to followup •Time to biopsy-proven kidney allograft rejection •Time to 1st dialysis & | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Phase 0, Parts A and B: Safety •Safety (adverse events and laboratory) data will be recorded for all patients in Phase 0, Part A and Part B who receive the single-dose IV administration, incidence of infections by organism type and specific organism. Phase 0 and Part A: PK and PD •PK variables will include Cmax, Tmax, t½ and AUC – all patients in Phase 0 and up to 12 patients in each dose-group in Part A •Immunogenicity of OPN-305 (re-establishment of the screening cutpoints for anti-drug antibodies [ADA] and confirmatory cut-point of ADA)- Phase 0 •Effect of OPN-305 on pro-inflammatory cytokines •Extent and duration of TLR2 receptor occupancy on monocytes by OPN-305 •Serum amyloid A (SAA) as a marker of acute inflammation •Secreted Phosphoprotein 1 (SPP-1) and Tissue Inhibitor Metallo-Protease 1 (TIMP-1) RNA as markers of acute inflammation – Part A only Part A and Part B •Immunogenicity of OPN-305 (binding and neutralising antibodies) Part A secondary efficacy endpoints were: • dDGF excluding dialysis for hyperkalaemia or hypervolaemia only (based on the DSMB adjudication) •fDGF •Duration of maximal TLR2 receptor occupancy •PK Part B Secondary Efficacy Endpoints. These endpoints are ranked in order of importance with regard to efficacy assessment: • eGFR measured by creatinine, Cystatin C and SDMA and at 7 and 14 days and 1,3 and 6 months • Serum creatinine (over time) •SGF to be assessed over the first 5 days post transplant • Components of the composite endpoint: -Incidence of biopsy-proven kidney allograft rejection (biopsies will be done on a for-cause basis only) - Graft loss - Reports of patient death(s) - Patients lost to follow up • Time to biopsy-proven kidney allograft rejection (biopsies will be done on a for-cause basis only) • Time to first dialysis and DGF duration. DGF Duration is defined as; - For dDGF, it is the time from the end of the transplantation surgery until completion of the final dial | — |
Countries
Austria, Belgium, Czech Republic, France, Germany, Netherlands, Poland, Spain, Switzerland, United Kingdom, United States
Contacts
Public ContactVP Pharmaceutical Dev. & Operations
Opsona Therapeutics Ltd
Outcome results
None listed