E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Delayed Graft Function in Adult Subjects After Renal Transplantation. |
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E.1.1.1 | Medical condition in easily understood language |
Delayed Graft Function (DGF) following renal transplantation. |
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E.1.1.2 | Therapeutic area | Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Surgical Procedures, Operative [E04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10074474 |
E.1.2 | Term | Transplantation complications |
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 |
• To assess the frequency of delayed graft function (DGF) in donation after circulatory death (DCD) renal transplant recipients treated with GSK1070806. |
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E.2.2 | Secondary objectives of the trial |
• To assess graft function in DCD renal transplant recipients treated with GSK1070806.
• To assess the effect of GSK1070806 on acute rejection risk, and rejection/PD biomarkers.
• To assess the effect of GSK1070806 on dialysis dependency and graft survival.
• To assess the safety and tolerability of GSK1070806 in renal transplant recipients.
• To assess the pharmacokinetics of GSK1070806 in renal transplant recipients.
• To assess the effect of GSK1070806 administration on serum IL-18 levels.
• To determine immunogenicity of GSK1070806 in renal transplant recipients. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
TITLE: Investigating the role of interleukin 18 in ischemia re-perfusion injury in human kidneys.
Date: 30th Nov 2015 Version 00
This substudy will run concurrently with 204824
•Objectives
•To understand the responses of peripheral blood mononuclear cells (PBMCs) to ischemia reperfusion injury in the transplanted kidney
•To understand how PBMC responses are altered by neutralization of IL-18 cytokine
•To understand how IL-18 cytokine neutralization affects fibrosis of the transplanted kidney
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E.3 | Principal inclusion criteria |
1. Recipient age range: 18 years of age and older, at the time of signing the informed consent.
2. Dialysis-dependent recipient of first time or second time, single kidney-only, Donation after Circulatory Death (DCD) transplant.
-Donor kidney must be 'controlled' meeting either Maastricht Category 3 or 4 criteria:
ď‚§Category 3: Donor awaiting cardiac arrest
ď‚§Category 4: Cardiac arrest in a brain stem dead donor
3. Eligible for kidney transplantation: Considered eligible for transplantation after undergoing multidisciplinary evaluation at the institution at which the transplantation will be performed.
4. Immunosuppressants (at the time of transplantation): planned to receive a combination of immunosuppressants including basiliximab, mycophenolate mofetil or azathioprine, tacrolimus, and corticosteroids.
5. Male and Female:
Males: Male subjects with female partners of child bearing potential must utilize a condom and female partners must comply with use of one of the highly effective contraceptive methods described in Appendix 4 of the protocol for 180 days post-dose of study medication.
Females:
a. Non-reproductive potential defined as:
• Females with one of the following procedures documented and no plans to utilize assisted reproductive techniques (e.g., in vitro fertilization or donor embryo transfer):
- Bilateral tubal ligation or salpingectomy
- Hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion
- Hysterectomy
- Bilateral Oophorectomy (surgical menopause)
• Postmenopausal defined as 12 months of spontaneous amenorrhea.
- In questionable cases (including cases in which amenorrhea is suspected to result from a subject’s poor renal function/dialysis) a blood sample with simultaneous follicle stimulating hormone (FSH) and estradiol levels consistent with menopause are required. If FSH/estradiol results are not available in time subjects are to be initiated on contraceptive methods (see below and Appendix 4 of the protocol).
- Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods if they wish to continue their HRT during the study.
b. Reproductive potential. Must not be pregnant or lactatng, and agrees to follow one of the options listed in the Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP) (see Appendix 4 of the protocol) for 180 days post dose. If a hormonal method of birth control is selected from the list in Appendix 4 of the protocol, then subjects must have been using these methods at least 28 days prior to GSK1070806 administration, or be abstinent, or utilize a condom as a method of contraception until the selected hormonal method has been in place for the 28 day period.
The investigator is responsible for ensuring that subjects understand how to properly use the indicated methods of contraception by providing counsel directly or by referring subjects to health care professionals with expertise in this area.
6. Capable of providing signed informed consent as described in Section 10.2 which includes compliance with the requirements and restrictions listed in the consent form and in this protocol. |
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E.4 | Principal exclusion criteria |
1. Liver function: ALT >2xULN and bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
2. QT interval: single or average QTc > 480 msec or in subjects with bundle branch block QTc > 500 msec (these criteria do not apply to subjects with predominately paced rhythms).
3.Ventricular arrhythmia: History of cardiac arrest or malignant ventricular arrhythmia at any time. Any acute cardiovascular syndrome within six months before screening. These may include acute coronary syndrome (myocardial infarction or unstable angina) or coronary intervention(percutaneous or surgical), or acute stroke.
4. Concurrent medication: Subjects who receive treatment that is prohibited for safety reasons, should not receive investigational product without the explicit approval of the Medical Monitor (Sponsor).
5. Investigational product: Any within 5 half-lives or twice the duration of the biological effect whichever is longer.
6. Immunosuppression: Are being considered for steroid-free, anti-thymocyte globulin (ATG) or alemtuzumab induction, which have a much more profound and prolonged immunosuppressive effect than basiliximab.
7. Prior biologic immunosuppressives: please view protocol for further information.
8. Vaccines: A live vaccine within 30 days prior to GSK1070806 administration.
9. Receiving a DCD kidney allograft from a donor with any of the following characteristics
a. cold ischemic time > 36 hours
b. age < 5 years old
c. ABO blood type incompatible against the recipient.
d. T- and/or B-cell positive crossmatch by complement dependent cytotoxicity or flow cytometry against the recipient.
e. serology positive for hepatitis B (except hepatitis B surface antibody and prior vaccination), hepatitis C or human immunodeficiency virus
(HIV)
f. EBV positive donor allograft with an EBV negative recipient
g. donor had acute or chronic bacterial, viral or fungal infection that according to the investigator causes a risk to recipient, particularly if the infection was resistant or systemic
h. normothermic regional machine perfusion organ retrieval techniques were utilized
I. surgical damage to donor allograft during organ procurement (view protocol for further information)
j. 'Uncontrolled' Maastricht Category 1, Category 2, and Category 5 (view protocol for further information)
10. Previous organ transplantation (view protocol for further information)
11. Malignancy: has a history of malignancy in the past 5 years except for adequately treated cancers of the skin (basal or squamous cell) or carcinoma in situ of the uterine cervix.
12. Acute or chronic infection: has required management of acute or chronic infections (excludes prophylaxis of infections), as follows:
a. currently being treated for a chronic infection, which in the opinion of the investigator, could put the subject at undue risk
b. hospitalized for treatment of infection, or treated for an infection with parenteral antibiotics within 30 days before Day 0, which in the opinion of the investigator, could put the subject at undue risk.
c. current evidence, or history within the last 14 days, of an influenza-like illness as defined by fever (>38°C) and two or more of the following symptoms: cough, sore throat, runny nose, sneezing, limb / joint pain, headache, vomiting / diarrhoea
d. patients with any history of active tuberculosis, view protocol for further information.
13. Other disease/conditions. Has any of the following:
a. clinical evidence of significant unstable or uncontrolled acute or chronic diseases, which in the opinion of the investigator, could confound the results of the study or put the subject at undue risk
b. a surgical procedure planned in the 12 months after Day 0, other than kidney transplantation or related procedure
c. a known history of any other medical disease (view protocol for further information)
14. Hepatitis B: patients will be excluded with any evidence of acute or chronic infection, or if interpretation of their results is unclear. This includes:
a. HBsAg +
b. Anti-HBc +
c. HB DNA+
It is permissible to enrol patients who are anti-HBs+ only, when this is attributable to vaccination and there is no history of previous infection.
15. Hepatitis C: patients will be excluded if there is any evidence of past or current hepatitis C infection, including hepatitis C antibody, hepatitis C RIBA immunoblot or PCR.
16. HIV: known to have a historically positive HIV test.
17. Immunodeficiency: recipient with a history of, or laboratory evidence of immunodeficiency.
18. Drug Sensitivity: has a history of sensitivity to any of the study medications including:
a. GSK1070806
b. background immunosuppressive regimen,
c. designated prophylactic anti-infective therapies please see protocol for further information.
Full exclusion criteria can be found in the protocol Section 5.2 |
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E.5 End points |
E.5.1 | Primary end point(s) |
Proportion of subjects requiring dialysis during the first 7 days post transplant, (excluding requirement for dialysis due to hyperkalemia within first 24 post-operative hours). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
• Serum creatinine at baseline and over time post transplant.
• Urine output at baseline and over time post transplant.
• Proportion of subjects in the first 7 days with:
- Primary Non Function
- Functional DGF
- Intermediate Graft Function
- Immediate Graft Function
• Proportion of subjects with episodes of biopsy-proven acute rejection.
• Rejection biomarkers/ PD markers (including serum IP-10 and Mig) at baseline and over time post transplant.
• Number of dialysis events per patient in the first 30 days post transplant.
• Proportion of subjects who are dialysis-independent at visits up to 12 months post transplant.
• AEs and SAEs
- Clinical laboratory values
- Vital signs
- Frequency, type and severity of infections
• Serum concentrations of GSK1070806 over time, and derived pharmacokinetic parameters if feasible (AUC, Cmax).
• Free, total, and GSK1070806 bound IL-18 at baseline and over time post transplant.
• Frequency of anti-drug antibodies (ADAs) before and after GSK1070806 administration.
• ADA titers.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Bayesian sequential approach |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 6 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
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 | 1 |
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 |