New Treatment Response in People With and Without Cirrhosis From Chronic Hepatitis C

Exclusion Criteria

• •1. Medical History and Concurrent Diseases
• •1. Liver or any other organ transplant (including hematopoietic stem cell transplants) other than cornea and hair;
• •2. Current or known history of cancer (except in situ carcinoma of the cervix or adequately treated basal or squamous cell carcinoma of the skin) within 5 years prior to enrollment
• •3. Documented or suspected HCC, as evidenced by previously obtained imaging studies or liver biopsy (or on a screening imaging study/liver biopsy if this was performed)
• •4. Evidence of decompensated liver disease including, but not limited to, radiologic criteria, a history or presence of ascites, bleeding varices, or hepatic encephalopathy
• •5. Evidence of a medical condition contributing to chronic liver disease other than HCV (such as, but not limited to: hemochromatosis, autoimmune hepatitis, metabolic liver disease, alcoholic liver disease, toxin exposures)
• •6. History of chronic hepatitis B virus (HBV) as documented by HBV serologies (eg, HBsAg-seropositive). Subjects with resolved HBV infection may participate (eg, HBsAb-seropositive with concurrent HBsAg-seronegative)
• •7. Any gastrointestinal disease or surgical procedure that may impact the absorption of study drug. (Subjects who have had cholecystectomy are permitted to enter the study)
• •8. History of HIV infection
• •9. Hemophilia
• •10. Uncontrolled diabetes (any subject with a confirmed screening HgA1c greater than or equal to 8.5 must be excluded)
• •11. Confirmed, uncontrolled hypertension (any screening systolic blood pressure greater than or equal to 160 mmHg or diastolic blood pressure greater than or equal to 100 mmHg should be excluded unless discussed with the central medical monitor)
• •12. Any other medical and/or social reason, including active substance abuse as defined by DSM-IV, Diagnostic Criteria for Drug and Alcohol Abuse, which in the opinion of the investigator would make the candidate inappropriate for participation in this study
• •13. History of severe psychiatric disorders including but not limited to, schizophrenia, psychosis, bipolar disorder, post-traumatic stress disorder, mania, etc.
• •14. Inability to tolerate oral medication;
• •15. Poor venous access
• •2\. Physical and Laboratory Test Findings
• •Note: Growth factors must not be used to achieve eligibility criteria.
• •1. ALT greater than or equal to 10 times ULN
• •2. Total bilirubin greater than or equal to 34 micromoles per liter (greater than or equal to 2 mg/dL) unless the subject has documented history of Gilbert s disease
• •3. Albumin \< 3.5 g/dL (35 g/L)
• •4. Creatinine clearance (CrCl) less than or equal to 50 ml/min (as estimated by Cockcroft and Gault)
• •5. Platelets \< 50 times 10(9) cells/L
• •6. ANC \< 0.5 times 10(9) cells/L
• •7. Hemoglobin \< 8.5 g/dL
• •8. INR greater than or equal to 1.7
• •9. Alpha-fetoprotein (AFP):
• •i) AFP \> 100 ng/mL OR
• •ii) AFP greater than or equal to 50 ng/mL and less than or equal 100 ng/mL requires a liver ultrasound and subjects with findings suspicious for HCC are excluded
• •j) QTcF or QTcB \> 500 msec
• •3\. Allergies and Adverse Drug Reaction
• •a) History of hypersensitivity to drugs with a similar biochemical structure to asunaprevir
• •or daclatasvir.
• •4\. Prohibited Treatments and /or Therapies
• •1. Exposure to any investigational drug or placebo within 4 weeks of study drug administration;
• •2. Prior exposure to any HCV DAA;
• •3. Prior exposure to pegIFN or RBV within 12 weeks prior to screening;
• •4. Subjects receiving all tricyclic anti-depressants (TCAs) including amitriptyline, clomipramine, desiprmine, dosepin, imipramine, nortriptyline, protriptyline; OR selective serotonin reuptake inhibitors (SSRIs) including fluoxetine, fluvoxamine, paroxetine and
• •sertraline; OR additional agents including venlafaxine, duloxetine, aripiprazole and mirtazapine within 2 weeks prior to Day 1; (subjects may switch to non-prohibited antidepressant therapies (eg citalopram, escitalopram and bupropion) within 2 weeks prior to
• •Day 1). The study eligibility of subjects on any anti-depressant not listed above, may be considered after a consultation with the central medical monitor, prior to Day 1;
• •5\. Sex and Reproductive Status
• •1. Sexually active men whose partners are pregnant at screening are excluded from this study
• •a) Prisoners or subjects who are involuntarily incarcerated
• •b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness
• •a) Severe psychiatric disease that would prohibit use of peg-IFN -2a as judged by the investigator including but not limited to:
• •i) Moderate or severe depression; Beck Depression Score greater than or equal to 15 during screening
• •ii) History of depression associated with hospitalized for depression,
• •electroconvulsive therapy, or depression resulting in a prolonged absence from work and/or significant disruptions from daily functions;
• •iii) Suicidal or homicidal ideation and/or attempt;
• •iv) History of severe psychiatric disorders including but not limited to,
• •schizophrenia, psychosis, bipolar disorder, post-traumatic stress disorder, mania, etc.;
• •b) History of hemoglobinopathies (e.g., thalassemia major or sickle cell anemia), diagnoses associated with an increased baseline risk for anemia (e.g., spherocytosis), hemolytic anemia, or diseases in which anemia would be medically problematic, or hemophilia;
• •c) Pre-existing ophthalmologic disorders considered clinically significant on eye exam, including retinal, examination. Note: all subjects with a history of diabetes or hypertension must have a documented eye exam within 12 months prior to initiation of P/R;
• •d) Thyroid-stimulating hormone (TSH) \< 0.8 times LLN or \> 1.2 times ULN of the laboratory reference range, unless
• •i) The subject is clinically euthyroid as determined by the investigator, AND
• •ii) Free T4 is greater than or equal to 0.8 times LLN and less than or equal to 1.2 times ULN
• •e) History of chronic pulmonary disease associated with functional limitation such as clinically significant chronic obstructive pulmonary disease, interstitial lung disease, pulmonary fibrosis, sarcoidois, etc;
• •f) History of cardiomyopathy, coronary artery disease (including angina), interventional procedure for coronary artery disease (including angioplasty, stent procedure, or cardiac bypass surgery), ventricular arrhythmia, congestive heart failure, pulmonary hypertension, cardiomyopathy, or other clinically significant cardiac disease;
• •g) Historical or current ECG findings indicative of cardiovascular instability, including but not limited to evidence of significant myocardial ischemia, unstable re-entry phenomena, other significant dysarrhythmias and/or uncontrolled hypertension;
• •h) Immunologically-mediated disease (eg, inflammatory bowel disease \[Crohn s disease, ulcerative colitis\], celiac disease, rheumatoid arthritis, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, autoimmune hemolytic anemia, scleroderma,
• •sarcoidosis, severe psoriasis requiring oral or injected treatment, or symptomatic thyroid disorder).
• •i) Any known contraindication to peg-IFN -2a or ribavirin, not otherwise specified.
• •j) Alanine aminotransferase (ALT) greater than 10 times ULN;
• •k) Total Bilirubin greater than or equal to 34 mol/L (greater than or equal to 2 mg/dL), unless subject has a documented history of Gilbert s disease;
• •l) INR greater than or equal to 1.7;
• •m) Albumin \< 3.5 g/dL (35 g/L);
• •n) Platelets \< 70 times 10(9) cells/L;
• •o) ANC \< 1,500 cells/mm3 (confirmed ANC \< 1,200 cells/mm3 for Black/African-Americans);
• •p) Hemoglobin \< 12 g/dL (120 g/L) for women and \< 13 g/dL (130 g/L) for men;
• •q) Creatinine Clearance (CrCl) less than or equal to 50 mL/min (as estimated by Cockcroft and Gault);
• •r) History of hypersensitivity to drugs with similar biochemical structure to pegIFN alpha or ribavirin
• •s) QTcF or QTcB \> 500 msec;