E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Discontinuation of immunosuppression in liver transplantation |
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E.1.1.1 | Medical condition in easily understood language |
Discontinuation of anti-rejection medication in liver transplantation |
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E.1.1.2 | Therapeutic area | Body processes [G] - Immune system processes [G12] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10024714 |
E.1.2 | Term | Liver transplant |
E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective is to determine the capacity of a short course of low-dose IL-2 to facilitate the complete discontinuation of immunosuppressive drugs in liver recipients 2-6 years after transplantation. |
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E.2.2 | Secondary objectives of the trial |
1) To determine the capacity of low-dose IL-2 to expand endogenous regulatory T cells (Tregs) in patients under calcineurin inhibitor immunosuppression; 2) to assess the safety of low-dose IL-2 administration in liver transplantation; 3) to investigate the sequential changes in Treg function, immunophenotype, and molecular profile following low-dose IL-2 treatment and calcineurin inhibitor discontinuation; 4) to determine if the baseline Treg function, immunophenotype, and molecular profile predict the response to low-dose IL-2; 5) to assess the changes in the blood and liver tissue inflammatory microenvironment; 6) to evaluate the development of anti-HLA antibodies. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Adult liver transplant recipients 2-6 years post-transplant and age ≤50 years; 2. Recipient of single organ transplant only; 3. Liver function tests: direct bilirubin and ALT <2 x ULN at the screening visit; 4. On calcineurin inhibitor (CNI) based IS; with or without one of the following: Low dose mycophenolic acid (≤ 1080 mg daily), mycophenolate mofetil (MMF ≤ 1500 mg daily), or azathioprine (≤ 150 mg daily); 5. Provision of written informed consent. |
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E.4 | Principal exclusion criteria |
1. Serum positivity for HCV-RNA at screening; 2. Serum positivity for HIV-1 infection, HBV surface antigen or HBV-DNA at screening; 3. Active liver or systemic immune-mediated disease in which IS discontinuation is inadvisable (autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis); 4. Acute or chronic rejection within the 52 weeks prior to screening; 5. GFR <40 mL/min (to mitigate the risk of worsening renal failure should rejection occur and high level of CNI be required); 6. The need for chronic anti-coagulation that cannot be safely discontinued to safely perform for a liver biopsy; 7. Screening liver biopsy showing signs of clinically significant histological damage will preclude continuation in the trial; 8. Maintenance immunosuppressive therapy with a mTOR inhibitor (sirolimus or everolimus); 9. Active infection or malignancy; 10. Inability to comply with study directed treatment; 11. Any medical condition that in the opinion of the principal investigator would interfere with safe completion of the trial (including severe cardiac disease, severe respiratory disease with O2 blood saturation <92%, any other major organ dysfunction, and Eastern Cooperative Oncology Group (ECOG) performance status of ECOG > 1). 12. Participation in another IMP study within 3 months from consent; 13. Any known allergy or intolerance to the IMP components; 14. Any contraindication to Proleukin administration as per SmPC; 15. Pregnancy or lactation; 16. Lack of effective methods of contraception for women and men of childbearing potential (as per section 7.6 of the Protocol); 17. Hypersensitivity to Proleukin or to any of the excipients. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is defined as the proportion of subjects who achieve successful immunosuppression withdrawal as defined by the absence of rejection and a rejection free biopsy at 1 year following discontinuation of immunosuppression. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1 year following discontinuation of immunosuppression |
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E.5.2 | Secondary end point(s) |
Clinical: • Rejection (incidence, severity, timing, steroid resistant rejection, chronic rejection); • Patient survival; • Graft loss; Mechanistic: • IL-2-related adverse events; • Effect of IL-2 on blood and liver Treg numbers; • Sequential immunophenotypic changes in blood and liver tissue; • Sequential changes in Treg function, immunophenotype, and molecular profile following low-dose IL-2 treatment and calcineurin inhibitor discontinuation; • Sequential changes in the inflammatory microenvironment in blood and liver tissue; • Development of serum anti-HLA antibodies. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Clinical: 1 year following the discontinuation of immunosuppression Mechanistic: at the time points of sample collection specified in Table 3 of the LITE protocol. |
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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 | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
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 | Yes |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
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 | No |
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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
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 | 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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End of the trial will be defined by the database lock. |
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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 | 9 |
E.8.9.1 | In the Member State concerned days | 0 |