| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Prevention of Kidney Graft Dysfunction |
|
| E.1.1.1 | Medical condition in easily understood language |
| Prevention of ‘reperfusion injury’ (tissue damage) occurring within the first few days of transplantation with a consequential lack of proper functioning of the transplanted kidney. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Symptoms and general pathology [C23] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10051366 |
| E.1.2 | Term | Kidney graft dysfunction |
| E.1.2 | System Organ Class | 100000004863 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
• 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. |
|
| E.2.2 | Secondary objectives of the trial |
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 & DGF duration (=dDGF=time from end of
transplant surgery to end of final dialysis for DGF & fDGF=time from transplant to Cr starting to fall by ≥10% without dialysis)
• Number of dialysis sessions between d0 & d30
•Incidence of primary non-function
•Blood & urine biomarkers for AKI
•Duration of initial hospitalisation & subsequent re-admissions
•Safety-Incidence of infections |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 <10%
oMinimum 3 months since the loss of the first transplanted kidney
•Recipient of a kidney meeting the inclusion criteria for a donor kidney
•Eligible for induction of immunosuppression with basiliximab or ATG (rabbit formulation only) [Part B patients]
•At least 18 years of age
•If sexually active female, patient must be/have:
oPost-menopausal defined as the absence of menses for at least one year (serum FSH ≥20IU/L can also be measured according to local practice), OR
oSurgically sterile defined as a bilateral tubal ligation at least 6 months prior to administration of study drug, bilateral oophorectomy, or complete hysterectomy, OR
oUsing an effective means of contraception (per Appendix 1) that is planned to continue for the duration of the study (6 months), AND
oNegative urine pregnancy test if the patient is capable of providing a urine sample (serum β-HCG will be confirmed as part of screening biochemistry) in the 48 hours before OPN-305 administration
Female patients of childbearing potential who are anuric must have a serum pregnancy test. If the result of that test is not, or will not be available before the start of the study-drug administration then the Investigators must ensure, to the best of their knowledge that the patient is not or could not be pregnant. The result of the serum pregnancy test should be confirmed as soon as possible.
•If sexually active male, patient must:
oAgree to use an effective means of contraception (per site-specific guidelines) that is planned to continue for the duration of the study (6 months)
oAgree not to donate sperm until 6 months after dosing
•Dialysis-dependent (including peritoneal dialysis) at the time of transplantation as documented by:
oRequirement for at least 2 dialysis sessions/week in the 56 days before transplantation
•Willingness to comply with the protocol procedures for the duration of the study, including scheduled follow-up visits and examinations
Inclusion Criteria for Donor Kidney in Part A:
•The donor kidney must be considered compatible according to local transplant guidelines
•A donor kidney from one of the following categories;
oDonation after Circulatory Death (only classification Maastricht 3)
oExtended Criteria Donor (to a maximum of 50% of patients in each dose- or placebo-group in Parts A and B) defined as:
•Donor ≥60 years of age
•Donor 50-59 years of age with all three of the following criteria present:
-Death due to cerebrovascular accident
-Pre-existing history of systemic hypertension
-Terminal creatinine ≤ 1.5mg/dL
oStandard Criteria Donor with a cold ischaemic time >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 kidney must be considered compatible according to local transplant guidelines
•An ECD donor kidney defined as:
oExtended 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 - note: maximum terminal creatinine ≤ 3mg/dL (265.25µmol/L)
•Kidney allograft maintained in cold storage with or without machine perfusion
|
|
| E.4 | Principal 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 <5 years of age or <20kg body weight
• Living donor allograft
• HLA or ABO incompatible kidney defined as a positive cytotoxic crossmatch
•Donor institutionalised by administrative or court order if forbidden by local laws or regulations
Exclusion Criteria for Donor Kidney (Part B):
•DCD or SCD donor kidney
• 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 >3mg/dL (265.25μm/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 <5 years of age or <20kg body weight
• Living donor allograft
• HLA or ABO incompatible kidney defined as a positive cytotoxic crossmatch
•Donor institutionalised by administrative or court order if forbidden by local laws or regulations |
|
| E.5 End points |
| E.5.1 | 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 |
|
| E.5.1.1 | 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
|
|
| E.5.2 | 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 dialysis for DGF
- For fDGF, it is the time from transplantation to the time when
creatinine starts to fall by at least 10% without dialysis
• Incidence of the number of dialysis sessions between day 0 and 30 post-transplantation
• Rate of primary non-function (permanent lack of function of the allograft)
• Blood and urine biomarkers for acute kidney injury (AKI)
• Duration of initial hospitalisation and the duration and reasons for hospital re-admissions |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Phase 0, Parts A and B:
•Safety at all visits.
Phase 0 & Part A
•PK :pre t=0, t=65 min, 2, 3, 6, 9, 13h, days 2,3,4,7,14,28
•Pro-inflammatory cytokines: pre t=0, t=0,1,3,7,24h
•Serum amyloid A: pre t=0, t=1,7,24,48h
•TLR2 RO: pre t=0, t=2,24,72h, day 7,14,28,56,90,180
•SPP-1 & TIMP- 1 RNA: t=0, t=1,7,24,48h
Part B
•Creatinine and Cystatin C and SDMA at d 7, d14 and 1,3 & 6 months
Phase 0, Parts A and B
•Immunogenicity of OPN-305: at screening (Phase 0 & Part A), pre t=0, d 7,14,28,56,90,180
•fDGF: all visits
•Allograft rejection, primary non-function, patient death(s), fDGF, time free from DGF, time to first dialysis & DGF duration, hospitalisation/ readmissions: at all visits
•AKI: screening, d 2,7,14,28,90,180, withdrawal. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Austria |
| Belgium |
| Czech Republic |
| France |
| Germany |
| Netherlands |
| Poland |
| Spain |
| Switzerland |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| 6 months after last visit. Graft survival at 12 months will be reported by the Investigators in a separate follow-up protocol. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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