E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
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 |
Difference in proportion of patients with CR at 12 months (normalization of ALT, AST and IgG) between the TAC and MMF treatment group. |
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E.2.2 | Secondary objectives of the trial |
Safety and Tolerability: Number and severity of side effects; Rate of stopping treatment due to side effects; serum creatinin & potassium; Blood pressure; Blood glucose levels and incidence of new onset diabetes; (opportunistic) infections; tremor; diarrhea Proportion of patients with complete biochemical remission at 6 months Proportion of patients with partial response, (decrease of AST and ALT, but no normalization) Proportion of patients with insufficient treatment response, defined as less than 25% reduction in ALT after 6 and 12 months treatment Dose reduction and cessation rate of prednisone Change of AST, ALT and IgG at 6 and 12 months vs baseline and between groups at the same time points Liver function: Total bilirubin, albumin, INR and MELD-score after 6 and 12 months between groups Fibrosis: Liver stiffness as measured by elastography and blood fibrosis markers (ELF) Quality of life: using the validated liver disease symptom index and EQ5D Cost-effectiveness |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Patient is older than 18 years old • Probable or definite auto immune hepatitis according to the original or simplified IAIHG criteria (>10 points pre-treatment on the original criteria or >6 points on the simplified criteria)(2, 3) • Incomplete responder on at least a half year of first-line treatment, with at least last 6 months azathioprine / 6-MP) / 6-TG and prednisolone or budesonide, and ALT 1.5 – 10x ULN for at least 2 months • Patient is capable of understanding the purpose and risks of the study, has been fully informed and has given written informed consent to participate in the study
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E.4 | Principal exclusion criteria |
• Presence of decompensated liver disease, defined as ascites, coagulopathy (INR >1.5), encephalopathy, variceal bleed, hepatopulmonal syndrome, hepatorenal syndrome or HCC in the past 6 months • Signs of other liver diseases as NAFLD, Wilson disease, hemochromatosis, alcoholic liver disease or hepatitis B/C/D • Clinical diagnosis of overlap / variant syndrome with PBC or PSC • Liver transplantation in the medical history or currently on the waiting list for liver transplantation • Incompliance with therapy during the last 12 months • Active infections during inclusion including latent tuberculosis and HIV co-infection • Allergic or hypersensitive to tacrolimus or MMF • An estimated glomerular filtration rate (eGFR) of <60 mL/min • Pregnancy or intention to become pregnant in the next 12 months • Use of TAC or MMF in the past 6 months • Intolerance to AZA
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E.5 End points |
E.5.1 | Primary end point(s) |
Difference in proportion of patients with CR at 12 months (normalization of ALT, AST and IgG) between the TAC and MMF treatment group. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
52 weeks (i.e. 12 months) |
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E.5.2 | Secondary end point(s) |
Safety and Tolerability: Number and severity of side effects; Rate of stopping treatment due to side effects; serum creatinin & potassium; Blood pressure; Blood glucose levels and incidence of new onset diabetes; (opportunistic) infections; tremor; diarrhea Proportion of patients with complete biochemical remission at 6 months Proportion of patients with partial response, (decrease of AST and ALT, but no normalization) Proportion of patients with insufficient treatment response, defined as less than 25% reduction in ALT after 6 and 12 months treatment Dose reduction and cessation rate of prednisone Change of AST, ALT and IgG at 6 and 12 months vs baseline and between groups at the same time points Liver function: Total bilirubin, albumin, INR and MELD-score after 6 and 12 months between groups Fibrosis: Liver stiffness as measured by elastography and blood fibrosis markers (ELF) Quality of life: using the validated liver disease symptom index and EQ5D Cost-effectiveness |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Patients will be seen at screening, week 0, week 2, week 12, week 24, week 36 and week 52 |
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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 | 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 | Yes |
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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
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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The trials end when all patients have had their last study visit. |
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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 | |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |