Mycophenolate Mofetil Versus Azathioprine in Treatment Naive Autoimmune Hepatitis

Study Overview
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Brief Summary
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Rationale: Current standard therapy of autoimmune hepatitis consists of a combination of prednisolone and azathioprine. However, a significant proportion of patients does not respond to, or is intolerant for, azathioprine. Mycophenolate mofetil (MMF) has surpassed azathioprine as therapy to prevent organ transplant rejection and is sometimes used as an alternative option for autoimmune hepatitis. Several case series and one prospective study have documented the efficacy and safety of mycophenolate mofetil as induction therapy for autoimmune hepatitis. Robust evidence from a formal randomized clinical trial is lacking. Objective: To assess the efficacy and safety of mycophenolate mofetil as induction therapy in patients with treatment naive autoimmune hepatitis. Study design: Multicenter, randomised, open-label intervention study Study population: Patients with newly diagnosed autoimmune hepatitis who are in need of induction therapy according to current guidelines. Intervention: The intervention group will receive oral mycophenolate mofetil for 24 weeks. The control group will be treated with azathioprine for 24 weeks. Both groups will be treated with steroid induction which will closely follow the schedule from the recent Clinical Practice Guidelines by the European Association for Study of the Liver (EASL). Main study parameters/endpoints: The primary outcome is the proportion of patients in biochemical remission, defined as normalization of serum alanine transaminase (ALT) and immunoglobulin G (IgG) levels after 24 weeks of treatment, per treatment group. Secondary endpoints include safety and tolerability of mycophenolate mofetil, time to remission, changes in Model For End-Stage Liver Disease (MELD) -score (and its components bilirubin, INR, creatinine), albumin, pseudocholinesterase and N-terminal procollagen-III-peptide, ELF (Enhanced Liver Fibrosis) -score and aspects of quality of life.

Official Title
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A Randomised, Open-label Clinical Trial Assessing the Efficacy and Safety of Mycophenolate Mofetil Versus Azathioprine for Induction of Remission in Treatment Naive Autoimmune Hepatitis

Conditions
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Autoimmune Hepatitis

Intervention / Treatment
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* Drug: Mycophenolate mofetil
* Drug: Azathioprine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Probable or definite diagnosis of autoimmune hepatitis according to the International Autoimmune Hepatitis Study Group criteria First presentation of AIH requiring treatment according to the current EASL guidelines Age ≥ 18 years Must provide informed consent and agree to comply with the trial protocol Exclusion Criteria: Overlap syndrome with Primary Sclerosing Cholangitis (PSC) or Primary Biliary Cholangitis (PBC) (Paris criteria, strong positive Anti-Mitochondrial Antibodies (AMA), past liver biopsy or cholangiographic findings compatible with PBC or PSC). Presentation with acute liver failure, defined as presence of hepatic encephalopathy and coagulopathy (INR > 1.5) Current treatment with prednisone/prednisolone and/or immunosuppressive medication for an indication other than autoimmune hepatitis Current systemic infection Other clinically significant medical conditions that could interfere with the trial If female of childbearing potential: known pregnancy, or unwilling to practice anticontraceptive measures. History of noncompliance with medical regimens, or patients who are considered to be potentially unreliable or unable to participate Mental instability or incompetence, such that the validity of informed consent or compliance with the trial is uncertain

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: Mycophenolate mofetil<br>The intervention group will receive oral mycophenolate mofetil for 24 weeks. Both groups will be treated with steroid induction which will closely follow the schedule from the recent EASL Clinical Practice Guidelines. | Drug: Mycophenolate mofetil<br> <br> |
| Active Comparator: Azathioprine<br>. The control group will be treated with azathioprine (standard of care) for 24 weeks. Both groups will be treated with steroid induction which will closely follow the schedule from the recent EASL Clinical Practice Guidelines. | Drug: Azathioprine<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biochemical remission | The percentage of patients in biochemical remission, defined as normalization of serum ALT and IgG levels after 24 weeks of treatment, per treatment group. | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to biochemical remission |  | 24 weeks | 
| Biochemical remission at any time |  | Up to 24 weeks | 
| Complete biochemical response, defined as normalization of AST, ALT and IgG at 6 months after initiation of treatment |  | Up to 24 weeks | 
| Insufficient response, defined as lack of complete biochemical response determined at 6 months |  | Up to 24 weeks | 
| Non-response at 4 weeks: defined as <50% decrease of serum transaminases within 4 weeks after initiation of treatment |  | Up to 4 weeks | 
| Changes in MELD score (and its components bilirubin, international normalized ratio (INR), creatinine) and in albumin |  | Up to 24 weeks | 
| Changes in liver stiffness, measured by transient elastography |  | Up to 24 weeks | 
| N-terminal procollagen-III-peptide, ELF score |  | 24 weeks | 
| Changes in quality of life measured with SF-36 |  | Up to 24 weeks | 
| Difference in side-effects, adverse events and serious adverse events |  | Up to 24 weeks | 
| The level of ALT, AST, GGT in both groups |  | Up to 24 weeks | 
| Percentage of patients with biochemical remission |  | Up to 24 weeks | 
| Ratio of ALT to lowest ALT ever |  | Up to 24 weeks | 
| Extrahepatic AIH manifestations (e.g. arthralgia) |  | Up to 24 weeks | 
| Patient survival |  | Up to 24 weeks | 
| Fatigue index |  | Up to 24 weeks | 
| Pruritis VAS score |  | Up to 24 weeks | 
| Difference in cumulative corticosteroid dose between MMF and azathioprine |  | Up to 24 weeks |