E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Prevention of Delayed Graft Function (DGF) following renal transplantation |
la prevención del retraso en la función del injerto (RFI) después de un trasplante renal |
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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. |
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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 | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10048747 |
E.1.2 | Term | Renal graft function delayed |
E.1.2 | System Organ Class | 100000004863 |
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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 |
Primary Objective: ? Phase 0: To determine the receptor occupancy of OPN305 1.5mg/kg in patients receiving an ECD, DCD or SCD(CIT>18h) kidney transplantation and to verify the doses of OPN305 to be used in Part A of the study. ? Part A: to select the optimal single IV dose of OPN305 for Part B of the study in ECD/DCD/SCD(CIT>18h) kidney transplantation patients. The primary endpoint for this objective is: o The incidence of DGF on Day 7 defined as the need for dialysis in the 7 days post-transplantation (dDGF) in patients receiving an ECD/DCD/SCD(CIT>18h) kidney transplantation ? Part B: to extend the evaluation whether the optimal dose of OPN305 from Part A can reduce the incidence of DGF ? Parts A and B: to evaluate whether OPN305 can reduce the incidence of DGF defined as the use of dialysis in the 7 days following transplantation (dDGF) o Note that all three active doses may contribute to this endpoint if similar in efficacy in Part A. |
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E.2.2 | Secondary objectives of the trial |
?Phase 0-PK and safety of a single-dose IV administration of OPN305 1.5mg/kg ?Part A-Safety and PK of doses of OPN305 in patients undergoing ECD/DCD/SCD(CIT>18h) kidney transplantation. o Functional DGF (fDGF) o Receptor occupancy. Parts A and B combined Effect in patients receiving an ECD, DCD or SCD(CIT>18h) kidney transplantation of single IV doses of OPN305 on: ?Composite endpoint oGraft function oGraft survival oIncidence of & time to biopsy-proven kidney allograft rejection o Pt death ? fDGF in patients not receiving dialysis in the first 7d following transplantation ? Time free from DGF ? Time to first dialysis and DGF duration. DGF Duration: o dDGF, time from the end of transplantation surgery to completion of final dialysis for DGF o fDGF, time from transplantation to when creatinine starts to fall by >10% without dialysis ?Blood and urine biomarkers for AKI ?Duration of initial hospitalisation and duration & reason for re-admissions ? Safety |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Inclusion Criteria for Transplant Recipients: Adult patients receiving an ECD, DCD, or an SCD (CIT>18h at randomisation) kidney transplantation satisfying the following; ?Provide written informed consent ?Accepted for renal transplantation due to end stage renal disease ?First or second renal transplant recipient ?Recipient of a kidney meeting the inclusion criteria for a donor kidney ?At least 18 years of age ?If 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 site-specific guidelines) 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 ?-HCG will be confirmed as part of screening biochemistry) in the 48 hours before OPN305 administration ?If 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: ?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 randomisation ?Kidney allograft maintained in cold storage with or without machine perfusion |
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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 ?History or known HIV, HBV (core and surface antigens), 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 ?Positive screening for 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 active peptic ulcer disease, or 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
Exclusion Criteria for Donor Kidney: ?Terminal creatinine >1.5mg/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 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 antibody or ABO antibody incompatible kidney ?Donor institutionalised by administrative or court order |
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E.5 End points |
E.5.1 | Primary end point(s) |
? Phase 0: TLR2 receptor occupancy ? Part A: Incidence of dDGF ? Parts A and B (including patients from Part A as described above): Incidence of dDGF; defined as the need for dialysis in the 7 days following renal transplantation (dDGF). |
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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 ? Parts A and B: Incidence of DGF evaluated day 0 to day 7 |
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E.5.2 | Secondary end point(s) |
Part 0, A and B: PK and 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. ?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 OPN305 (re-establishment of the screening cut-points for anti-drug antibodies [ADA] and confirmatory cut-point of ADA) ? Phase 0 ?Immunogenicity of OPN305 (binding and neutralising antibodies) ? Parts A and B ?Effect of OPN305 on pro-inflammatory cytokines ? Phase 0 and Part A ?Extent and duration of TLR2 receptor occupancy on monocytes by OPN305 ? Phase 0 and Part A ?Serum amyloid A (SAA) as a marker of acute inflammation ? Phase 0 and Part A ?Secreted Phosphoprotein 1 (SPP-1) and Tissue Inhibitor Metallo-Protease 1 (TIMP-1) RNA as markers of acute inflammation ? Part A Part A ?fDGF ?Duration of maximal TLR2 receptor occupancy ?PK Secondary Efficacy Endpoints (Parts A and B) These endpoints are ranked in order of importance with regard to efficacy assessment: 1.Components of the composite endpoint: a.Serum creatinine and Iohexol clearance at 7 days and 6 months b.Incidence of, and time to, biopsy-proven kidney allograft rejection (biopsies will be done on a for-cause basis only) c.Rate of primary non-function (permanent lack of function of the allograft) d.Reports of patient death(s) 2.Functional DGF (fDGF) in patients who do NOT receive dialysis in the first 7 days post-transplantation. fDGF Is defined as failure to reduce serum creatinine by 10% per day during 3 consecutive days in the first 7 days following transplant surgery 3.Time free from DGF 4.Time to first dialysis and DGF duration. DGF Duration is defined as; a.For dDGF, it is the time from the end of the transplantation surgery until completion of the final dialysis for DGF b.For fDGF, it is the time from transplantation to the time when creatinine starts to fall by >10% without dialysis 5.Blood and urine biomarkers for acute kidney injury (AKI) 6.Duration of initial hospitalisation and the duration and reasons for hospital re-admissions |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Part 0, A and B: ?Safety at all visits. ?PK pre t=0, t=65 min, 2, 3, 6, 9, 13h, days 2,3,4,7,14,28 ?Immunogenicity of OPN305 at screening, pre t=0, d 7,14,28,56,90,180 ?Pro-inflammatory cytokines pre t=0, t=0,1,3,7,24h ?TLR2 RO pre t=0, t=2,24,72h, day 7,14,28,56,90,180 ?Serum amyloid A pre t=0, t=1,7,24,48h ?Secreted Phosphoprotein 1 and Tissue Inhibitor Metallo-Protease 1 RNA t=0, t=1,7,24,48h ?fDGF all visits Secondary Efficacy Serum creatinine and Iohexol clearance at d 7 and 6 months Allograft rejection, primary non-function, patient death(s), fDGF, time free from DGF, time to first dialysis and DGF duration, hospitalisation/ re-admissions evaluated at all visit AKI at screening, d 2,7,14,28,90,180 |
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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 | 15 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 50 |
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 |
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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
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6 months after last visit. Graft survival at 12 months will be reported by the Investigators in a separate follow-up protocol. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |