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

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

Official Title
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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

Conditions
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Autoimmune Hepatitis

Intervention / Treatment
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* Drug: LCP-Tacro (tacrolimus)
* Drug: Azathioprine


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LCP-Tacro<br>LCP-Tacro tablets(1,2,and 5mg tacrolimus)+ prednisone tablets(5mg) | Drug: LCP-Tacro (tacrolimus)<br>* 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.<br>* Other names: 1,2,and 5mg tacrolimus tablets;|
| Active Comparator: Azathioprine<br>Azathioprine tablets(50mg)+ prednisone tablets(5mg) | Drug: Azathioprine<br>* 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.<br>* Other names: 50mg azathioprine tablets + 5mg prednisone tablets;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Autoimmune hepatitis, Chronic active hepatitis