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Insulin Sensitivity and Hepatic Steatosis in Hepatitis C

Specific Aims
Determine site and severity of insulin resistance (IR) in treatment-naïve patients with hepatitis C infection (genotype 1) by stepped insulin-euglycemic clamp before and after anti-viral therapy compared to matched controls and those with nonalcoholic fatty liver disease (NAFLD).

Study Design
3 categories - 43 HCV patients, 15 NAFLD patients, 15 controls

Screening Visit: (All Pts)
Oral glucose tolerance test (OGTT), ultrasound (done only in controls to rule out NAFLD), lifetime alcohol survey, review of medications.

Initial Assessment – Visit 1:

• Liver biopsy (only performed in HCV and NAFLD subjects)
• MRI – (in 15 NAFLD subjects and 20 randomly selected HCV subjects)

Initial Assessment – Visit 2: (All Pts)

• IR assessment by stepped insulin-euglycemic clamp:
• Blood draws

Combination antiviral therapy: (HCV pts only)

• HCV subjects will then undergo antiviral therapy pegylated interferon (IFN) - either pegylated IFN alfa-2b (Peg-Intron) or pegylated IFN alfa-2a (Pegasys) along with ribavirin through U of M Gastroenterology Clinic while seeing a member of the study team every 12 weeks at the General Clinical Research Center for follow-up.

Follow-up procedures: (HCV pts only)

• HCV subjects will then undergo antiviral therapy, the IR assessment, and liver biopsy similar to the Initial Assessments – Visits 1 and 2.

Eligibility

Main exclusion criteria:

• Evidence of cirrhosis on liver biopsy
• Diabetes mellitus
• BMI > 30
• HCV genotype other than 1
• History of alcohol abuse > 20 g per day in past 6 months
• Previous HCV antiviral therapy

Costs for the Patient
Subjects will be paid for clamp procedure, liver biopsy, and periodic return visits to the General Clinical Research Center. The study will not cover costs of antiviral therapy, labs, or procedures that are part of a patient’s standard medical care.

Contact Persons
Please contact Dr. Charles Burant at (734) 615-3481 [e-mail: burantc@umich.edu] if you have any questions.

ENABLE 1 (Eltrombopag to Initiate and Maintain Interferon Antiviral Treatment to Benefit Subjects with Hepatitis C-Related Liver Disease) (HUM 16060)

The purpose of the study is to assess the ability of eltrombopag to maintain a platelet count sufficient to initiate antiviral therapy (platelets ≥ 90,000/uL), to minimize antiviral therapy dose reductions and to avoid permanent discontinuation of antiviral therapy.  The clinical benefit of eltrombopag will be measured by the proportion of subjects who are able to achieve SVR.

Study Design

This is a multi-center two-part study, consisting of an open-label, Pre-Antiviral Treatment Phase (Part 1) and a randomized, double-blind, placebo controlled, Antiviral Treatment Phase (Part 2).

Main Inclusion Criteria

• Adult males and females > 18 years of age
• Chronic HCV infection (quantifiable HCV RNA)
• Subjects who are appropriate candidates for pegIFN + ribavirin
• Baseline platelet count < 75,000/uL
• Hemoglobin concentrations ≥ 11.0 g/dL for men or ≥ 10.0 g/dL for women
• Absolute neutrophil count (ANC) ≥ 750/mm3
• Creatinine clearance ≥ 50/mL/min

Main Exclusion Criteria

• Non-responders to previous treatment with peginterferon and ribavirin who failed to achieve a SVR for reasons other than thrombocytopenia.
• Decompensated liver disease or HCC
• Known hypersensitivity, intolerance or allergy to IFN, ribavirin, eltrombopag or any other ingredients.
• Serious cardiac, cerebrovascular, or pulmonary disease
• Any current severe or poorly controlled psychiatric or seizure disorder that has not been well controlled.
• Documented history of esophageal bleeding varices or any condition associated with active bleeding or requires anticoagulation with warfarin or heparin.
• Pre-existing cardiac disease (CHF NYHA Grade III/IV), or arrhythmias know to involve of thromboembolic events (e.g. A-fib), or subjects with a QTc > 450 msec.
• Laboratory evidence of active Hepatitis B or HIV.
• History of alcohol/drug abuse or dependence within the past 6 months..
• Major organ Transplant
• Thyroid dysfunction that is not adequately controlled
• Subjects planning on having cataract surgery.

Study Visits

• Part 1 (Pre-Antiviral Treatment):  Open label eltrombopag weekly until patient achieves platelet count > 90,000 uL.
• Part 2 (Antiviral Treatment Phase): Randomized to eltrombopag vs. placebo, all patients receive pegIFN + ribavirin, bi-weekly visits up to week 12 and then monthly visits with post-treatment FU for 24 weeks
• Medications (including pegIFN + ribavirin) and all study related tests and procedures covered by the study.

Contact: For questions or referrals please contact Diane White: (734) 763-6647 or dfwhite@umich.edu or Anna Lok, MD: aslok@med.umich,edu.

A Phase 3, Safety and Efficacy Study of Boceprevir in Previously Untreated Subjects with Chronic Hepatitis C Genotype 1

Primary Objective

To compare the efficacy of 2 regimens (28 vs. 48 wk) of boceprevir (BOC) 800 mg tid in combination with PegIntron (PEG) 1.5 μg/kg QW subcutaneously (SC) plus weight-based dosing (WBD) of ribavirin (RBV) (600 mg/day to 1400 mg/day) PO to PEG + RBV WBD alone in previously untreated adult subjects with hepatiotis C virus (HCV) genotype 1.

Study Design

Randomized, multi-center, double-blind study of boceprevir or placebo PLUS open-label PEG + RBV in previously untreated subjects with HCV genotype 1.

Subjects will be randomized 1:1:1
Arm 1: Control: Placebo + PEG + RBV x 48 wk
Arm 2: PEG + RBV x 4 wk then BOC + PEG + RBV x 24 wk
Arm 3: PEG + RBV x 4 wk then BOC + PEG + RBV for 44 wk

Main Inclusion Criteria

1. HCV positive
2. Genotype 1

Main Exclusion Criteria

1. Prior treatment with interferon and ribaviron
2. Hgb<12 for females and <13 for males
3. ANC<1500 (for African Americans <1200)
4. Platelet count<100,000
5. Contraindications to use of PEG or RBV
6. Decompensated liver disease, major comorbid medical or psychiatric conditions

Costs for the Patient

All costs for study drug and tests will be covered by the sponsor and provided free of charge to the patient.

Contact: Tess Bonham at (734) 615-0158 (fax: 734-615-3655) or tbonham@umich.edu or Anna Lok, MD, Principal Investigator at aslok@med.umich.edu.