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

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ClinicalTrials.gov Identifier: NCT02900443
Recruitment Status : Recruiting
First Posted : September 14, 2016
Last Update Posted : April 19, 2018
Sponsor:
Collaborator:
Leiden University Medical Center
Information provided by (Responsible Party):
Radboud University

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 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. In a sub-study, drug levels will be measured.


Condition or disease Intervention/treatment Phase
Autoimmune Hepatitis Drug: Mycophenolate mofetil Drug: Azathioprine Phase 4

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 70 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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 Start Date : January 2017
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : December 2019


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



Primary Outcome Measures :
  1. Biochemical remission [ Time Frame: 24 weeks ]
    The percentage of patients in remission, defined as normalization of serum ALT and IgG levels after 24 weeks of treatment, per treatment group.


Secondary Outcome Measures :
  1. Time to biochemical remission [ Time Frame: 24 weeks ]
  2. Biochemical remission at any time [ Time Frame: Up to 24 weeks ]
  3. Partial remission, defined as alanine aminotransferase (ALT) or aspartate aminotransferase (AST) serum levels >1x Upper Limit of Normal (ULN) and <2x ULN [ Time Frame: Up to 24 weeks ]
  4. Minimal response, defined as decrease of ALT or AST serum levels but still >2x ULN [ Time Frame: Up to 24 weeks ]
  5. Treatment failure, defined as no improvement or increase of ALT or AST serum levels [ Time Frame: Up to 24 weeks ]
  6. Changes in liver stiffness, measured by transient elastography [ Time Frame: Up to 24 weeks ]
  7. N-terminal procollagen-III-peptide, ELF score [ Time Frame: Up to 24 weeks ]
  8. Changes in quality of life measured with Short Form Health survey 36 (SF-36) [ Time Frame: Up to 24 weeks ]
  9. Number of patients with treatment related adverse events per treatment group [ Time Frame: Up to 24 weeks ]
  10. The level of liver enzymes in both groups [ Time Frame: Up to 24 weeks ]
  11. Steroid and other side-effects scores consisting of Visual Analogue Scores (VAS) scores (0 - 10) by the physician for Cushing-face, buffalo hump, acne, striae, bruising and hirsutism. [ Time Frame: Up to 24 weeks ]
  12. Percentage of patients with biochemical remission [ Time Frame: Up to 24 weeks ]
  13. Ratio of ALT to lowest ALT ever [ Time Frame: Up to 24 weeks ]
  14. De novo onset of diabetes mellitus (requiring medication) [ Time Frame: Up to 24 weeks ]
  15. Hypertension (requiring medication) [ Time Frame: Up to 24 weeks ]
  16. Glaucoma [ Time Frame: Up to 24 weeks ]
  17. Number of infections [ Time Frame: Up to 24 weeks ]
  18. Extrahepatic AIH manifestations (e.g. arthralgia) [ Time Frame: Up to 24 weeks ]
  19. Patient survival [ Time Frame: Up to 24 weeks ]
  20. Fatigue index [ Time Frame: Up to 24 weeks ]
  21. Pruritis VAS score [ Time Frame: Up to 24 weeks ]
  22. Bone fractures [ Time Frame: Up to 24 weeks ]
  23. Osteoporosis (confirmed by bone densitometry) [ Time Frame: Up to 24 weeks ]


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02900443


Contacts
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Contact: Simon Pape, MD +31652621030 Simon.Pape@radboudumc.nl

Locations
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Netherlands
Vrije Universiteit Medisch Centrum Recruiting
Amsterdam, Netherlands, 1081 HV
Contact: Karin MJ van Nieuwkerk, MD, PhD         
Principal Investigator: Karin MJ van Nieuwkerk, MD, PhD         
Leiden University Medical Centre Recruiting
Leiden, Netherlands, 2333ZA
Contact: Lida Beneken Kolmer    071-526 1188    A.Beneken_Kolmer@lumc.nl   
Principal Investigator: Bart van Hoek, MD, PhD         
Sint Antonius Hospital Recruiting
Nieuwegein, Netherlands, 3430 EM
Contact: Robert C Verdonk, MD, PhD         
Principal Investigator: Robert C Verdonk, MD, PhD         
Radboud University Medical Centre Recruiting
Nijmegen, Netherlands, 6525GA
Contact: Simon Pape, MD    +31-6-52621030    Simon.Pape@radboudumc.nl   
Principal Investigator: Joost PH Drenth, MD, PhD         
Sub-Investigator: Simon Pape, MD         
Sponsors and Collaborators
Radboud University
Leiden University Medical Center
Investigators
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Principal Investigator: Bart van Hoek, MD, PhD Leiden University Medical Center
Principal Investigator: Joost PH Drenth, MD, PhD Radboud University

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Responsible Party: Radboud University
ClinicalTrials.gov Identifier: NCT02900443     History of Changes
Other Study ID Numbers: NL57115.058.16
First Posted: September 14, 2016    Key Record Dates
Last Update Posted: April 19, 2018
Last Verified: April 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Additional relevant MeSH terms:
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Hepatitis A
Hepatitis
Hepatitis, Autoimmune
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Hepatitis, Chronic
Autoimmune Diseases
Immune System Diseases
Mycophenolic Acid
Azathioprine
Antibiotics, Antineoplastic
Antineoplastic Agents
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antimetabolites
Antimetabolites, Antineoplastic
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents