Tacrolimus Versus Mycophenolate for Autoimmune Hepatitis Patients With Incomplete Response on First Line Therapy

Study Overview
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Brief Summary
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Rationale: The combination of azathioprine and prednisone is the first-line treatment for autoimmune hepatitis (AIH), a chronic inflammatory disease of the liver. Complete biochemical remission (CR) is the first treatment goal in autoimmune hepatitis. CR is determined by AST and ALT and IgG within the reference range. CR is not reached in a substantial proportion of AIH patients: after one year 50%, after three years around 20% did not achieve CR. Without CR ongoing hepatitis leads to progression towards fibrosis and eventually (decompensated) cirrhosis. Not achieving CR is the most important risk factor for the need for liver transplantation or liver related death, independent of age and presence of cirrhosis. Tacrolimus (TAC) and mycophenolate mofetil (MMF) are frequently used to prevent rejection in kidney and liver transplant patients. In AIH patients with insufficient response or intolerance to first-line therapy in retrospective cohort studies with MMF 0-57% and with TAC 20-95% CR was reached. Objective: The aim of this study is to compare the effectiveness of TAC with MMF as a second line treatment for AIH. Proportion of patients with CR after 12 months of treatment will be the primary outcome parameter to determine effectivity. Study design: Randomized open-label two arm study. Patients will be randomized between treatment with TAC or MMF. Study population: Patients with AIH with an incomplete response (no CR) to first-line treatment are eligible for this study. Intervention: In the TAC group baseline treatment will be replaced by tacrolimus. In the MMF group baseline treatment will be replaced by MMF. The current dose of prednisolone, or at least 5 mg daily, will be continued in both arms. After achieving CR prednisolone will be tapered according to protocol. Main study parameters/endpoints: Difference in proportion of patients with CR at 12 months (normalization of ALT, AST and IgG) between the TAC and MMF treatment group. Secondary parameters: Safety and tolerability of TAC and MMF treatments Difference in proportion of patients with CR at 6 months (normalization of ALT, AST and IgG) between the TAC and MMF treatment group. Difference in ALT, AST and IgG at 6 and 12 months versus baseline Difference in fibrogenesis and fibrosis parameters between groups and before and after treatment Difference in quality of life between groups and before and after treatment

Official Title
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TAILOR Study: Tacrolimus Versus Mycophenolate for Autolmmune Hepatitis Patients With incompLete Response On First Line Therapy: a Randomized Trial

Conditions
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Autoimmune Hepatitis

Intervention / Treatment
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* Drug: Mycophenolate Mofetil
* Drug: Tacrolimus


Participation Criteria
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Eligibility Criteria
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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 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 Malignancy in the medical history

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Mycofenolate Mofetil<br>Patients in the mycophenolate mofetil (MMF) arm will receive MMF for a total of 12 months (if tolerated) | Drug: Mycophenolate Mofetil<br>* Mycophenolate mofetil will be started at a dose 500mg twice daily. When tolerated and an AUC within range, patients will be titrated to 1000mg twice daily at week two.<br>* Other names: Cellcept;|
| Experimental: Tacrolimus (Envarsus)<br>Patients in the tacrolimus (TAC) arm will receive treatment with meltdose TAC for a total of 12 months (if tolerated) | Drug: Tacrolimus<br>* Meltdose tacrolimus will be started at a dose of 0.07 mg/kg/day. The drug will be taken orally once-daily in the morning. Dose will be adjusted to reach target AUC and trough levels.<br>* Other names: Envarsus;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete biochemical remission | The proportion of patients with CR after 12 months of treatment with TAC compared to MMF in patients with AIH with an incomplete response to first-line treatment. | 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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; Number of (opportunistic) infections; tremor; diarrhea | 52 weeks | 
| Proportion of patients with complete biochemical remission after 6 months | Defined as ALT, AST and IgG below the upper limit of normal | 24 weeks | 
| Proportion of patients with partial response | defined as decrease of AST and ALT, but no normalization | 52 weeks | 
| Proportion of patients with insufficient treatment response | less than 25% reduction in ALT after 6 and 12 months treatment | 52 weeks | 
| Dose reduction of prednisone | Difference between dose at inclusion and dose at the end of study | 52 weeks | 
| Cessation rate of prednisone | The number of patients able to completely withdraw from corticosteroids | 52 weeks | 
| Change of AST | at 6 and 12 months versus baseline and between groups at the same time points | 24 and 52 weeks | 
| Change of ALT | at 6 and 12 months versus baseline and between groups at the same time points | 24 and 52 weeks | 
| Change of IgG | at 6 and 12 months versus baseline and between groups at the same time points | 24 and 52 weeks | 
| Liver function | Total bilirubin, albumin, INR and MELD-score after 6 and 12 months between groups | 24 and 52 weeks | 
| Fibrosis | Liver stiffness as measured by elastography and blood fibrosis markers (ELF) | 52 weeks | 
| Influence of liver disease on the quality of life | using the validated liver disease symptom index (LDSI) | 52 weeks | 
| Treatment effect on health status | using the validated EQ5D | 52 weeks | 
| Cost-effectiveness based on empiric data obtained by this study. | Economic evaluation including a cost-effectiveness evaluation | 52 weeks | 
| Cost-effectiveness from a societal perspective | Economic evaluation including a cost-utility evaluation (costs per QALY) | 52 weeks |