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 |
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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 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 of the study.
• 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:
o 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 extend the evaluation whether the optimal dose of OPN-305 from Part A can reduce the incidence of DGF
• Parts A and B: to evaluate whether OPN-305 can reduce the incidence of DGF defined as the initiation of dialysis in the first 7 days following transplantation (dDGF) |
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E.2.2 | Secondary objectives of the trial |
Phase 0: PK & safety of single-dose OPN-305 1.5mg/kg
Part A; Safety & PK of doses of OPN-305 in pts undergoing ECD/DCD/SCD(CIT>18h) kidney transplantation, fDGF & RO.
Parts A & B comb; Effect in pts receiving ECD, DCD or SCD (CIT>18h) kidney transplantation of OPN305 doses on:
•Graft function
•Composite endpoint; graft loss, incidence of biopsy-proven kidney allograft rejection, Pt death, Loss to followup
•Time to biopsy-proven kidney allograft rejection
•fDGF in pts not receiving dialysis in first 7d following transplant
•Time to 1st dialysis & DGF duration (dDGF=time from end of transplant
surgery to completion of final dialysis for DGF, fDGF=time from transplant to when creatinine starts to fall by at least 10% without dialysis)
•Incidence of dialysis between d7 & d30
•Incidence of primary non-function
•Blood & urine biomarkers for AKI
•Duration of initial hospitalisation & duration & reason for subsequent re-admissions
•Safety-Incidence of infections by type & organism |
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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 time of arrival at the hospital in Phase 0 or at randomisation in Parts A and B) 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 - 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
•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 recorded 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:
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 Parts A and B
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 or anti-thymocyte globulin (ATG)
• Known hypersensitivity to iohexol or iodine or patients with manifest thyrotoxicosis
• Pre-operative serum potassium >6.0mmol/L
o Note: Dialysis before surgery to correct hyperkalaemia or hypervolaemia is recommended
•History or known HIV, HBV (surface antigens), or HCV-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, 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 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:
• Expected CIT >30h for any kidney type at the start of surgery
•Terminal creatinine >2mg/dL (ECD>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 or ABO incompatible kidney defined as a positive cytotoxic crossmatch
•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 on the selected OPN-305 dose and placebo as described above): Incidence of dDGF; defined as the initiation of dialysis in the first 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, incidence of infections by organism type and specific
organism.
•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:
•Immunogenicity of OPN-305 (binding and neutralising antibodies) –
Parts A and B
•Effect of OPN-305 on pro-inflammatory cytokines – Phase 0 and Part A
•Extent and duration of TLR2 receptor occupancy on monocytes by OPN-
305 – 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:
• dDGF excluding dialysis for hyperkalaemia or hypervolaemia only
(based on the DSMB adjudication)
•fDGF
•Duration of maximal TLR2 receptor occupancy
•PK
Secondary Efficacy Endpoints (Parts A&B). These endpoints are ranked
in order of importance with regard to efficacy assessment:
1. Serum creatinine and Iohexol clearance at 7 days and 6 months
2. Components of the composite endpoint:
a.Incidence of biopsy-proven kidney allograft rejection (biopsies will be
done on a for-cause basis only)
b. Graft loss
c. Reports of patient death(s)
d. Patients lost to follow up
Note: the components of this composite endpoint will be combined with
graft function in a separate analysis.
3. Time to biopsy-proven kidney allograft rejection (biopsies will be done
on a for-cause basis only)
4. 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 at least 10% per day during 3 consecutive days in the first 7 days following transplant surgery
5. 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 at least 10% without dialysis
6. Incidence of the initiation of dialysis between 7 and 30 days posttransplantation
7. Rate of primary non-function (permanent lack of function of the
allograft)
8. Blood and urine biomarkers for acute kidney injury (AKI)
9. 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 OPN-305 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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
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 |
Spain |
Poland |
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 | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |