Autoimmune Hepatitis
Conditions
Brief summary
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.
Interventions
DRUGMycophenolate mofetil
DRUGAzathioprine
Sponsors
Leiden University Medical Center
Radboud University Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Biochemical remission | 24 weeks | The percentage of patients in biochemical remission, defined as normalization of serum ALT and IgG levels after 24 weeks of treatment, per treatment group. |
Secondary
| Measure | Time frame |
|---|---|
| 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 |
| Time to biochemical remission | 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 |
| Difference in side-effects, adverse events and serious adverse events | Up to 24 weeks |
Countries
Belgium, Netherlands
Outcome results
None listed