LCP-Tacro vs. Azathioprine for the Treatment of Autoimmune Hepatitis

A Phase II, Open-Label, Multi-Center, Prospective, Randomized Study of LCP-Tacro Tablets vs. Azathioprine, in Combination With Corticosteroids, for the Treatment of Autoimmune Hepatitis

An open-label, multi-center, prospective, randomized study to evaluate the efficacy, safety and tolerability of LCP-Tacro tablets given once daily vs. azathioprine, each in combination with prednisone, for the treatment of autoimmune hepatitis (AIH).

Study Overview

• Status: Terminated
• Conditions: Autoimmune Hepatitis
• Intervention / Treatment: Drug: LCP-Tacro (tacrolimus); Drug: Azathioprine

Detailed Description

An open-label, multi-center, prospective, randomized study to evaluate the efficacy, safety and tolerability of LCP-Tacro tablets given once daily vs. azathioprine for the treatment of autoimmune hepatitis (AIH).

Patients with histologically confirmed chronic hepatitis who fulfill criteria established by the International Autoimmune Hepatitis Group (IAIHG) and Inclusion and Exclusion criteria will be enrolled after having signed an informed consent document.

Up to 60 patients will be randomized (1:1) to receive treatment with LCP-Tacro + prednisone vs. azathioprine (AZA) + prednisone.

• LCP-Tacro will be started at 2 mg once daily (q.d.) with weekly measurement of tacrolimus whole blood trough levels and adjustment of the daily dose of LCP-Tacro to achieve target tacrolimus levels of 3 - 6 ng/mL. Patients with histological evidence of cirrhosis and a Model for End-Stage Liver Disease (MELD) score ≤ 8 will commence LCP-Tacro at a fixed dose of 1 mg once daily, with subsequent dosage adjustments to maintain tacrolimus trough levels at 3 - 6 ng/mL.
• AZA will be started at 50 - 100 mg (approximately 1 mg/kg) once daily (q.d.).

Patients will also commence treatment with prednisone 30 mg/day for one week, then 20 mg/day for one week, then 15 mg/day for two weeks, then 10 mg/day through Month 6.

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N1
      • Heritage Medical Research Clinic
    • Edmonton, Alberta, Canada, T6G 2X8
      • Zeildler Ledcor Centre
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3E 3P4
      • John Buhler Research Centre, University of Manitoba Health Sciences Centre
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 2Y9
      • Queen Elizabeth Ii Health Sciences Centre
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic - Phoenix
  • Florida
    • Jacksonville, Florida, United States, 32216
      • Mayo Clinic - Jacksonville
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • New York
    • New York, New York, United States, 10029
      • Mount Sinai Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • St. Luke's Advanced Liver Therapies
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Men and women at least 18 years of age with a diagnosis of definite or probable AIH defined by the revised International Autoimmune Hepatitis Group (IAIHG) criteria
• Elevation of serum ALT ≥ 1.5 times the upper limit of normal
• Liver biopsy showing chronic hepatitis consistent with AIH
• Patients able to swallow the study medication
• Patients capable of understanding the purposes and risks of the study, who can give written informed consent and who are willing to participate in and comply with the study
• Women of childbearing potential must have a negative serum pregnancy test within seven days prior to receiving study medication and agree to use contraceptive measures to avoid pregnancy during participation in the trial.

Exclusion Criteria:

• Patients with other concurrent liver disease
• Patients with cirrhosis on liver biopsy with a MELD score > 15
• Patients with a history or presence of decompensated liver disease
• Patients with serum creatinine ≥ 1.5 mg/dL prior to enrollment
• Patients positive for HCV RNA or Hepatitis B surface antigen (HBsAg)
• Patients with a history of alcohol intake > 25 g/day within the past six months
• Patients with TSH outside normal range accompanied by an abnormal T4
• Patients with alpha-fetoprotein ≥ 20 ng/mL
• Patients with severe anemia (hemoglobin < 8 g/dL), leukopenia (WBC < 4000/mm3), or thrombocytopenia (platelet count < 100,000/mm3)
• Patients with a history of recent exposure to hepatotoxic drugs
• Patients who require therapy with any immunosuppressive agent other than those prescribed in the study
• Patients unable or unwilling to provide informed consent
• Pregnant or nursing women
• Patients with reproductive potential who are unwilling/unable to use a double barrier method of contraception
• Patients who have been treated with another investigational agent in the three months prior to enrollment
• Patients receiving any drug interfering with tacrolimus metabolism
• Patients with current malignancy or a history of malignancy (within the past 5 years), except basal or non-metastatic squamous cell carcinoma of the skin that has been treated successfully
• Patients with uncontrolled concomitant infection, a systemic infection requiring treatment, or any other unstable medical condition that could interfere with the study objectives
• Patients with severe diarrhea, vomiting, active peptic ulcer or gastrointestinal disorder that may affect the absorption of tacrolimus
• Patients with a known hypersensitivity to azathioprine, corticosteroids or tacrolimus
• Patients with any form of current substance abuse, psychiatric disorder or a condition that, in the opinion of the Investigator, may invalidate communication with the Investigator
• Patients who are recipients of an organ transplant or who require treatment with immunosuppressives or corticosteroids for any disease other than AIH.

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: LCP-Tacro; LCP-Tacro tablets(1,2,and 5mg tacrolimus)+ prednisone tablets(5mg)	Drug: LCP-Tacro (tacrolimus); LCP-Tacro(tacrolimus)tablets starting at 2 mg once daily, then adjusted to achieve and maintain target whole blood tacrolimus levels of 3 - 6 ng/mL, plus prednisone 30 mg/day for one week, then 20 mg/day for one week, then 15 mg/day for two weeks, then 10 mg/day through Month 6.; Other Names: 1,2,and 5mg tacrolimus tablets
Active Comparator: Azathioprine; Azathioprine tablets(50mg)+ prednisone tablets(5mg)	Drug: Azathioprine; Azathioprine tablets 50 - 100 mg (approximately 1 mg/kg) once daily, plus prednisone 30 mg/day for one week, then 20 mg/day for one week, then 15 mg/day for two weeks, then 10 mg/day through Month 6.; Other Names: 50mg azathioprine tablets + 5mg prednisone tablets

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biochemical Remission of (AIH) at Month 6.	Percent of patients that achieve biochemical remission of (AIH) at Month 6 during treatment with LCP-Tacro + prednisone or azathioprine + prednisone. Biochemical remission is defined as ALT, total bilirubin and gamma globulin within normal limits.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biochemical Remission by Month 3.	Percent of patients who achieve biochemical remission by Month 3 during treatment with LCP-Tacro + prednisone or azathioprine + prednisone. Biochemical remission is defined as ALT, total bilirubin and gamma globulin within normal limits.	3 months
Incomplete Response, Treatment Failure, or a Case of Relapse at 6 Months	Percents of patients in each treatment group classified as having an incomplete response (defined as some or no improvement during therapy), a treatment failure (defined as permanent discontinuation of the regimen originally randomized to), or a case of relapse (recurrence following achievement of remission)	6 months

Collaborators and Investigators

• Sponsor: Veloxis Pharmaceuticals
• Investigators: Principal Investigator: Gerald Y Minuk, M.D., University of Manitoba Health Sciences Centre, Winnipeg; Principal Investigator: Andrew Mason, MD, University of Alberta, Edmonton; Principal Investigator: Russell H Wiesner, MD, Mayo Clinic, Rochester, MN; Principal Investigator: John M Vierling, MD, Baylor College of Medicine; Principal Investigator: Velimir A Luketic, MD, Virginia Commonwealth University, Richmond, VA; Principal Investigator: Joseph A Odin, MD, PhD, Mount Sinai Medical Center, New York, NY; Principal Investigator: Elizabeth Carey, MD, Mayo Clinic; Principal Investigator: John R Lake, MD, University of Minnesota; Principal Investigator: Barry G Rosser, MD, Mayo Clinic; Principal Investigator: Steven L Flamm, MD, Northwestern University; Principal Investigator: Kevork M Peltekian, MD, Queen Elizabeth Ii Health Sciences Centre; Principal Investigator: Mark G Swain, MD, University of Calgary

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2007
• Primary Completion (Actual): April 1, 2009
• Study Completion (Actual): July 1, 2009

Study Registration Dates

• First Submitted: January 23, 2008
• First Submitted That Met QC Criteria: January 23, 2008
• First Posted (Estimate): February 6, 2008

Study Record Updates

• Last Update Posted (Actual): March 17, 2020
• Last Update Submitted That Met QC Criteria: March 6, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Keywords: Autoimmune hepatitis; Chronic active hepatitis
• 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; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Calcineurin Inhibitors; Prednisone; Azathioprine; Tacrolimus
• Other Study ID Numbers: LCP-Tacro Study 2016