Clinical trial NCT02900443: Mycophenolate Mofetil Versus Azathioprine in Treatment Naive Autoimmune Hepatitis
Official title: 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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Autoimmune Hepatitis
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
Collaborators: name: Leiden University Medical Center
First posted: 2016-09-14
Enrollment: 70
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Biochemical remission
timeFrame: 24 weeks
Secondary outcomes:
measure: Time to biochemical remission
timeFrame: 24 weeks
measure: Biochemical remission at any time
timeFrame: Up to 24 weeks
measure: Complete biochemical response, defined as normalization of AST, ALT and IgG at 6 months after initiation of treatment
timeFrame: Up to 24 weeks
measure: Insufficient response, defined as lack of complete biochemical response determined at 6 months
timeFrame: Up to 24 weeks
measure: Non-response at 4 weeks: defined as <50% decrease of serum transaminases within 4 weeks after initiation of treatment
timeFrame: Up to 4 weeks
measure: Changes in MELD score (and its components bilirubin, international normalized ratio (INR), creatinine) and in albumin
timeFrame: Up to 24 weeks
measure: Changes in liver stiffness, measured by transient elastography
timeFrame: Up to 24 weeks
measure: N-terminal procollagen-III-peptide, ELF score
timeFrame: 24 weeks
measure: Changes in quality of life measured with SF-36
timeFrame: Up to 24 weeks
measure: Difference in side-effects, adverse events and serious adverse events
timeFrame: Up to 24 weeks
measure: The level of ALT, AST, GGT in both groups
timeFrame: Up to 24 weeks
measure: Percentage of patients with biochemical remission
timeFrame: Up to 24 weeks
measure: Ratio of ALT to lowest ALT ever
timeFrame: Up to 24 weeks
measure: Extrahepatic AIH manifestations (e.g. arthralgia)
timeFrame: Up to 24 weeks
measure: Patient survival
timeFrame: Up to 24 weeks
measure: Fatigue index
timeFrame: Up to 24 weeks
measure: Pruritis VAS score
timeFrame: Up to 24 weeks
measure: Difference in cumulative corticosteroid dose between MMF and azathioprine
timeFrame: Up to 24 weeks
Other outcomes:
Locations:
city: Antwerpen
country: Belgium
facility: University Hospital Antwerpen
city: Heerlen
country: Netherlands
facility: Zuyderland
state: Limburg
city: Amsterdam
country: Netherlands
facility: Vrije Universiteit Medisch Centrum
city: Amsterdam
country: Netherlands
facility: Amsterdam UMC, location AMC
city: Arnhem
country: Netherlands
facility: Rijnstate Ziekenhuis
city: Den Bosch
country: Netherlands
facility: Jeroen Bosch Ziekenhuis
city: Enschede
country: Netherlands
facility: Medisch Spectrum Twente
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
city: Leiden
country: Netherlands
facility: Leiden University Medical Centre
city: Maastricht
country: Netherlands
facility: Maastricht UMC+
city: Nieuwegein
country: Netherlands
facility: Sint Antonius Hospital
city: Nijmegen
country: Netherlands
facility: Radboud University Medical Centre
city: Rotterdam
country: Netherlands
facility: Erasmus MC
city: Uden
country: Netherlands
facility: Bernhoven
Study officials:
affiliation: Leiden University Medical Center
name: Bart van Hoek, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Radboud University Medical Center
name: Joost PH Drenth, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: