Placebo-Controlled Study to Evaluate the Safety and Efficacy of OPN-305 in Preventing Delayed Renal Graft Function

Study Overview
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Brief Summary
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When a patient receives a kidney transplant particularly if the kidney is from an older donor or one who has had the kidney removed after their heart has stopped, there is a risk that the newly transplanted kidney may not function immediately. If the delay in function means that dialysis is needed in the first 7 days after the transplantation then this is known as delayed graft function or dDGF. Also delayed graft function that does not require dialysis but is present because the serum creatinine does not fall sufficiently is known as functional delayed graft function or fDGF. This problem is often due to an excessive inflammatory reaction to not having had a blood supply between the time of donation and transplant. OPN-305 is a monoclonal antibody that blocks Toll-like Receptor 2 which is thought to be partly responsible for increasing the risk of this inflammation. It is hoped that the effects of the inflammation will be reduced and therefore prevent dDGF and fDGF from occurring. The purpose of the study is to explore how effective OPN-305 is in preventing dDGF and fDGF as well as improving other measures of kidney function and the overall safety of the antibody. In the first part of the study, each patient received an Infusion of one of three possible doses of OPN-305 or a placebo and in the second part the most suitable dose of OPN-305 and a placebo would be used. The purpose of this second part of the study is to find out if a dose of OPN-305 which has already been tested in an earlier part of this study can prevent kidney graft dysfunction. For the purposes of this study, kidney function will be assessed using the composite of delayed graft function (dDGF) because dialysis is necessary in the first 7 days and functional delayed graft function that does not require dialysis but is present because the serum creatinine, a key measure of renal function, does not fall sufficiently (fDGF) in the first 7 days post-transplant. Protocol OPN305-103 follows out to 12 months post-transplant the clinical status and graft function of patients who have completed the 6-month post-transplant period under Part A or Part B of OPN305-102.

Official Title
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A Three-Part, Multi-Centre, Randomised, Double-Blind, Placebo-Controlled, Parallel-Group, Sequential Adaptive, Phase II Study to Evaluate the Safety, Tolerability and Efficacy of OPN-305, a Humanised Monoclonal Antibody That Blocks Toll-Like Receptor 2, in Renal Transplant Patients at High Risk of Delayed Graft Function

Conditions
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Delayed Graft Function

Intervention / Treatment
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* Drug: OPN-305
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria INCLUSION CRITERIA FOR TRANSPLANT RECIPIENTS First or second renal transplant recipient - for second renal transplantations; The second transplant should NOT be due to rejection Panel Reactive Antibody (PRA) should be <10% Minimum 3 months since the loss of the first transplanted kidney Dialysis-dependent at the time of transplantation as documented by: Requirement for at least 2 dialysis sessions/week in the 56 days before transplantation INCLUSION CRITERIA FOR DONOR KIDNEY: The donor kidney must be considered compatible according to local transplant guidelines An ECD donor defined as: o Extended Criteria Donor defined as: Donor ≥60 years of age Donor 50-59 years of age with two of three of the following criteria present: Death due to cerebrovascular accident Pre-existing history of systemic hypertension Terminal creatinine > 1.5mg/dL (132.6 µmol/L) Kidney allograft maintained in cold storage with or without machine perfusion Exclusion Criteria EXCLUSION CRITERIA FOR TRANSPLANT RECIPIENTS: Use of an investigational drug in the 30 days before Study Day 1 Participation in any other research Known hypersensitivity to human monoclonal antibodies or any of the study-drug excipients Previous hypersensitivity to basiliximab or anti-thymocyte globulin (ATG) History or known HIV, HBV, or HCV-positive History of malignancy within the last five years, 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. 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 institutionalized by administrative or court order EXCLUSION CRITERIA FOR ALL DONOR KIDNEYS DCD or SCD donor kidney Terminal creatinine >3mg/dL 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 (drug or non-drug) Kidney donor <5 years of age or <20kg body weight Living donor allograft HLA or ABO incompatible kidney as defined by a negative cytotoxic crossmatch Donor institutionalized by administrative or court order

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: OPN-305<br> | Drug: OPN-305<br>* Intravenous infusion for 1 hour at start of transplant procedure<br>|
| Placebo Comparator: Matching placebo<br> | Drug: Placebo<br>* Intravenous infusion for 1 hour at start of transplant procedure<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measure of Early Graft Function EGF | Initiation of dialysis in the first 7 days following renal transplantation and failure of serum creatinine to decrease by at least 10% daily on 3 successive days during the first week post transplantation | First 7 days following renal transplantation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Creatinine at 7 and 14 days and at 1, 3 and 6 months | Measure of creatinine at 7 and 14 days and at 1, 3 and 6 months | 7 and 14 days and at 1, 3 and 6 months | 
| Cystatin C at 7 and 14 days and at 1, 3 and 6 months | Measure of Cystatin C at 7 and 14 days and at 1, 3 and 6 months | 7 and 14 days and at 1, 3 and 6 months | 
| Symmetrical dimethylarginine at 7 and 14 days and at 1, 3 and 6 months | Measure of symmetrical dimethylarginine at 7 and 14 days and at 1, 3 and 6 months | 7 and 14 days and at 1, 3 and 6 months | 
| Incidence of slow graft function | Slow graft function to be assessed over first 5 days post-transplant | 5 days post-transplant | 
| Serum creatinine over time | Measure of Serum creatinine over time | over the duration of follow-up | 
| Composite endpoint | Components of the composite endpoint are: 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 | 6 months | 
| Time to biopsy-proven kidney allograft rejection | Time to biopsy-proven kidney allograft rejection | 6 months | 
| Time to first dialysis or functional delayed graft function and delayed graft function duration | Duration of DGF is defined as either: Time from transplantation to time of completion of final dialysis for DGF Time from transplantation to time when creatinine starts to fall by at least 10% without dialysis | 30 days | 
| Blood and urine biomarkers for acute kidney injury (AKI) | Serum NGAL, urinary NGAL, α-GST, π-GST, KIM-1 and IL-18 | days 2, 7, 14, 28, 90 and 180 | 
| Duration of initial hospitalization | Duration of initial hospitalization | 6 months | 
| Duration of subsequent readmissions | Duration of subsequent readmissions | 6 months | 
| Reason for subsequent readmissions | Reason for subsequent readmissions | 6 months | 
| Number of Adverse events (AEs) | Number of Adverse events (AEs) | 6 months | 
| Nature of Adverse events (AEs) | Nature of Adverse events (AEs) | 6 months | 
| Incidence of infections | Incidence of infections by category and organism | 6 months | 
| Rate of primary non-function (permanent lack of function of the allograft) |  | 6 months | 
| Number of dialysis sessions between 0 and 30 days post-transplantation | Number of dialysis sessions between 0 and 30 days post-transplantation | 30 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Early kidney graft dysfunction, renal transplantation