| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Immunosuppression withdrawal in liver transplantation |
|
| E.1.1.1 | Medical condition in easily understood language |
| Withdrawal of drugs which lower the immune system after a liver transplant |
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| E.1.1.2 | Therapeutic area | Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Diagnosis [E01] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10024716 |
| E.1.2 | Term | Liver transplantation |
| E.1.2 | System Organ Class | 100000004865 |
|
| 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 |
| To determine if the use of a liver tissue transcriptional test of tolerance to stratify liver recipients prior to immunosuppression (IS) withdrawal accurately identifies operationally tolerant recipients and reduces the incidence of rejection, as compared with a control group in whom IS withdrawal is performed without stratification. |
|
| E.2.2 | Secondary objectives of the trial |
1) To establish the safety of biomarker-guided IS withdrawal.
2) To determine the health-economic impact of withdrawing IS in liver transplant recipients and to assess how much this cost is influenced by the use of a diagnostic test of operational tolerance.
3) To assess the effect of IS withdrawal on the quality of life of liver transplant recipients.
4) To determine the extent to which IS withdrawal improve drug-related co-morbidities.
5) To investigate if liver transplant recipients under IS become operationally tolerant over time.
6) To determine if the presence of donor-specific anti-HLA antibodies influence the success of IS withdrawal, and whether IS withdrawal promotes the development of anti-HLA antibodies in liver transplant recipients.
7) To explore the association between operational liver transplant tolerance, iron metabolism,immunosenescence, and specific gut microbiome profiles |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) consented adult liver transplant recipients >3 years post-transplant if aged >50 years or ≥6 years post-transplant if aged 18-49 years;
2) deceased or living donor liver transplant;
3) single transplanted organ;
4) direct bilirubin ≤17.1 umol/L and ALT ≤60 IU/L;
5) on calcineurin inhibitor based immunosuppression and no more than one of the following: low dose mycophenolic acid, mycophenolate mofetil, or azathioprine; or on mycophenolic/mycophenolate monotherapy;
6) ability to sign informed consent;
7) Women without childbearing potential defined as one or more of following:
• Women at least 6 weeks after surgical sterilization by bilateral tubal ligation or bilateral oophorectomy with or without hysterectomy or with hysterectomy or uterine agenesis at the day of inclusion
• women ≥ 55 years of age at the day of inclusion who have been postmenopausal since at least 1 year
• women < 50 years of age at the day of inclusion who have been postmenopausal since at least 1 year and who have serum FSH levels > 40 mIU/mL, as well as serum estrogen levels < 30 pg/ml or a negative estrogen test.
OR
Women of childbearing potential who have a negative hCG serum or urine pregnancy test (in case of treatment with mycophenolate or mycophenolate acid two urine or serum pregnancy tests with a sensitivity of at least 25 mIU/ml at a time lag of 8-10 days between them are necessary) and agree to meet one of the following criteria [from the time of baseline and during the study and for a period of 6 weeks (IMPs containing mycophenolate or mycophenolic acid) or 6 months (IMPs containing azathioprine) following discontinuation of therapy]:
• Correct use of reliable contraception methods according to the latest version of the summary of product characteristics (SmPC).
• True abstinence (if this is already the preferred lifestyle of the person; periodic abstinence and withdrawal are not acceptable methods of contraception)
• Sexual relationship only with female partners and/or sterile male partners (a vasectomy of the male partner is not sufficient in case of treatment with IMPs containing mycophenolate or mycophenolic acid)
Sexually active (including vasectomized) men taking mycophenolate or mycophenolate acid have to use condoms for sex during treatment and for 90 days thereafter; their partners of childbearing potential have to use highly effective contraception for the same period.
Sexually active men taking azathioprine have to use condoms for sex during treatment and for 6 months thereafter; their partners of childbearing potential have to use effective contraception for the same period.
This applies also to patients with impaired fertility due to chronic uraemia, since that usually returns to normal after transplantation.
|
|
| E.4 | Principal exclusion criteria |
1) serum positivity for HCV-RNA;
2) serum positivity for HIV-1 infection, HBV surface antigen or HBV-DNA;
3) autoimmune liver disease;
4) rejection within the previous year;
5) GFR<40 ml/min;
6) need for chronic anticoagulation that cannot be safely discontinued;
7) baseline liver biopsy showing rejection, advanced fibrosis or moderate-severe inflammation;
8) age <18 years at the time of transplant;
9) pregnant females and females of childbearing age not using effective/highly effective contraception ;
10) curent illicit drug or alcohol use;
11) inability to attend frequent follow-up visits;
12) inability to comply with study directed treatment;
13) medical conditions interfering with safe completion of the trial;
14) participation in another clinical trial. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is defined as the successful discontinuation of IS with maintainance of normal allograft status as assessed by liver biopsy and liver tests 12 months after IS withdrawal (operational tolerance). For the purposes of validating the clinical usefulness of the tolerance biomarker, successful IS withdrawal is considered the Gold Standard. Since this outcome is strictly restricted to the IS withdrawal process and by definition cannot be observed in Arm B-, the analysis of the primary outcome will be restricted to Arms A and B+. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 12 months after IS withdrawal |
|
| E.5.2 | Secondary end point(s) |
Rejection (incidence, severity, timing, steroid resistant rejection, chronic rejection).
Reasons for failure of IS withdrawal.
Progression of graft fibrosis in tolerant participants and those on maintenance IS.
Graft loss.
All–cause mortality.
Proportion of tolerant participants remaining free of rejection at 3 years post IS withdrawal.
Renal function at 1, 2 and 3 years after enrollment.
Change in co-morbidities associated with IS use (hypertension, cardiovascular risk profile, diabetes mellitus, hyperlipidemia, malignancy).
Development of anti-HLA antibodies (before and after initiation of IS withdrawal).
HrQOL changes associated with IS withdrawal.
Pharmacoeconomic impact of IS withdrawal.
The secondary mechanistic endpoints of the trial are:
Mechanistic and clinical mediators and/or moderators: Intra-hepatic and systemic iron parameters. Time post-transplant, age, sex and type of IS. Markers of immune-exhaustion in blood and liver tissue. Gut microbiome profile. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| 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 | No |
| 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) | 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 | Yes |
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
| Immunosuppression withdrawal performed without the guidance of the stratifying biomarker test |
|
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 4 |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| 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 | 6 |
| 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 |
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