Mycophenolate Mofetil Versus Azathioprine in Treatment Naive Autoimmune Hepatitis (CAMARO)

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Autoimmune Hepatitis
• Intervention / Treatment: Drug: Mycophenolate mofetil; Drug: Azathioprine

• Study Type: Interventional
• Enrollment (Estimated): 70
• Phase: Phase 4

Contacts and Locations

Study Locations

• Belgium
  • Antwerpen, Belgium
    • University Hospital Antwerpen
• Netherlands
  • Amsterdam, Netherlands, 1081 HV
    • Vrije Universiteit Medisch Centrum
  • Amsterdam, Netherlands
    • Amsterdam UMC, location AMC
  • Arnhem, Netherlands
    • Rijnstate Ziekenhuis
  • Den Bosch, Netherlands
    • Jeroen Bosch ziekenhuis
  • Enschede, Netherlands
    • Medisch Spectrum Twente
  • Groningen, Netherlands
    • University Medical Center Groningen
  • Leiden, Netherlands, 2333ZA
    • Leiden University Medical Centre
  • Maastricht, Netherlands
    • Maastricht UMC+
  • Nieuwegein, Netherlands, 3430 EM
    • Sint Antonius Hospital
  • Nijmegen, Netherlands, 6525GA
    • Radboud University Medical Centre
  • Rotterdam, Netherlands
    • Erasmus MC
  • Uden, Netherlands
    • Bernhoven
  • Limburg
    • Heerlen, Limburg, Netherlands, 6419 PC
      • Zuyderland

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Mycophenolate mofetil; 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
Active Comparator: Azathioprine; . 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

What is the study measuring?

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	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

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Collaborators: Leiden University Medical Center
• Investigators: Principal Investigator: Joost PH Drenth, MD, PhD, Radboud University Medical Center; Principal Investigator: Bart van Hoek, MD, PhD, Leiden University Medical Center

Study record dates

Study Major Dates

• Study Start: January 1, 2017
• Primary Completion (Estimated): June 1, 2023
• Study Completion (Estimated): June 1, 2023

Study Registration Dates

• First Submitted: August 17, 2016
• First Submitted That Met QC Criteria: September 8, 2016
• First Posted (Estimated): September 14, 2016

Study Record Updates

• Last Update Posted (Actual): June 22, 2023
• Last Update Submitted That Met QC Criteria: June 18, 2023
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Immune System Diseases; Autoimmune Diseases; Liver Diseases; Hepatitis, Viral, Human; Enterovirus Infections; Picornaviridae Infections; Hepatitis, Chronic; Hepatitis; Hepatitis A; Hepatitis, Autoimmune; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antitubercular Agents; Antibiotics, Antitubercular; Azathioprine; Mycophenolic Acid
• Other Study ID Numbers: NL57115.058.16

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED