chronic Hepatitis C

The primary efficacy objective for this study is as follows: • To evaluate the safety, tolerability, pharmacokinetics, and antiviral activity of ritonavirboosted danoprevir (DNVr) fixed-dose combination (FDC) in combination with peginterferon α-2a plus ribavirin in treatment-naïve patients of East Asian or Southeast Asian origin who have chronic hepatitis C (CHC) genotype (GT) 1 with or without compensated cirrhosis.

Danoprevir (DNV) plus ritonavir (RTV)

Danoprevir/ritonavir

coat-filled tablet

Danoprevir 125 mg, ritonavir 100 mg

PRIMARY OBJECTIVE
The primary objective for this study is as follows:
• To evaluate the safety, tolerability, pharmacokinetics, and antiviral activity of DNVr FDC in combination with P/R in treatment-naïve patients of East Asian or Southeast Asian origin who have CHC GT 1 with or without compensated cirrhosis.
2.2 SECONDARY OBJECTIVES
The secondary objectives for this study are as follows:
• To monitor and characterize potential emergence of DNV resistance.
• To evaluate rapid virologic response (RVR), complete early virologic response
(cEVR), and SVR of this regimen.

Patients must meet the following criteria for study entry:
1. Male and female patients of East Asian and Southeast Asian origin aged 18 years and older.
2. Body mass index (BMI) between 18.0 kg/m2 and 30.0 kg/m2.
[BMI (kg/m2) = body weight (kg)/height2 (m2)].
3. History of CHC GT 1, documented with HCV GT, and serum HCV RNA
of ≥ 1 × 105 IU/mL at Screening.
4. Never received prior-treatment for HCV with IFN, RBV, or other direct-acting or host-targeting antivirals.
5. Chronic liver disease consistent with CHC infection as determined by biopsy
obtained within the past calendar 24 months (no time limit if patient has cirrhosis)
using one of the liver biopsy methods in Appendix 2 (cirrhosis is defined as: Metavir
score = 4, Knodell score= 4, Batts and Ludwig score = 4, or Ishak modified Histology
Activity Index score ≥ 5), or, as determined by Fibroscan within the past 12 calendar
months (cirrhosis is defined as: ≥ 14.5 kPa). Patients with an “intermediate reading”
(9.5 − 14.4 kPa) require a liver biopsy to confirm fibrosis score.
6. Patients with cirrhosis must be compensated (Child-Pugh A), using the scoring
methods in Appendix 3.
7. Patients with cirrhosis (Appendix 2) must have an abdominal ultrasound, computed
tomography scan, or magnetic resonance imaging scan without evidence of HCC
(within 6 months prior to screening).
8. Negative serum or urine pregnancy test (sensitivity of 25 mIU or better) for females
of childbearing potential within the 24-hour period prior to the first dose of study
drugs.
9. Female patients of childbearing potential must agree to use two reliable forms of effective nonhormonal contraception (i.e., condoms, cervical barriers, intrauterine device, spermicides, or sponge), at least 1 of which must be a physical barrier method, during treatment and for at least 6 months following the last dose of treatment in accordance with the locally approved label for Copegus. A hormonal contraception (in lieu of nonhormonal) plus a physical barrier method can be used after end of treatment with DNVr. All males with female partners of childbearing potential must use two reliable forms of effective contraception (combined) during treatment and for 6 months following the last dose of Copegus in accordance with the locally approved label for Copegus.
10. Ability to participate and willingness to give written informed consent and to comply with the study restrictions.

Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:
1. Pregnant or lactating women or male partners of women who are pregnant.
2. History or presence of decompensated liver disease (history of ascites, hepatic encephalopathy, HCC, or bleeding esophageal varices).
3. Presence or history of non-hepatitis C chronic liver disease, including but not limited to, autoimmune hepatitis, α-1-antitrypsin deficiency, C282Y homozygous hemochromatosis, Wilson’s disease, drug- or toxin-induced liver disease, alcohol-related liver disease, primary biliary cirrhosis, sclerosing cholangitis, and porphyria cutanea tarda causing liver pathology or requiring phlebotomy.
4. Positive Hepatitis B surface antigen (HBsAg) or HIV antibody at screening.
5. Any patient with a history of severe psychiatric disease, including psychosis and/or depression, characterized by a suicide attempt, hospitalization for psychiatric disease, or a period of disability as a result of psychiatric disease, who does not agree to have a psychiatric evaluation at screening and who does not agree to have
continued monitoring by a mental health specialist at least every 4 weeks during the study.
6. History of active malignancy within the last 5 years, with the exception of localized or in situ carcinoma (e.g., basal or squamous cell carcinoma of the skin).
7. History of severe cardiac disease (e.g., New York Heart Association Functional Class III or IV, myocardial infarction within 6 months, ventricular tachyarrhythmias requiring ongoing treatment, unstable angina or other unstable, uncontrolled or significant cardiovascular disease within 6 months). Patients with stable coronary
artery disease (e.g., 6 months after by-pass surgery, angioplasty with or without stent placement, etc.) as confirmed by a cardiologist will be permitted. In addition, patients with documented or presumed unstable coronary artery disease, cardiovascular disease, or cerebrovascular disease should not be enrolled.
8. Patients with higher potential for corrected QT interval (QTc) prolongation as defined by QT interval corrected using Fridericia’s method (QTcF) ≥ 450 ms in males or QTcF≥ 470 ms in females, or notable resting bradycardia (< 45 beats/min), or notable resting tachycardia (> 100 beats/min) at screening, or personal or family
history of congenital long QT syndrome or sudden death.
9. Any patient with an increased risk for anemia (e.g., thalassemia, sickle cell anemia, or spherocytosis) or for whom anemia would be medically problematic.
10. History of uncontrolled severe seizure disorder.
11. History or other evidence of chronic pulmonary disease associated with clinically relevant functional limitation.
12. History of pre-existing renal disease. Patients with a history of nephrolithiasis will be allowed.
13. History of ophthalmologic disorders due to diabetes or hypertension, or history of other severe retinopathy (e.g., cytomegalovirus, macular degeneration).
14. Poorly controlled thyroid function.
15. History of any disease known to cause a significant alteration in immunologic function, including hematologic malignancy or autoimmune disorder or immunologically mediated disease (e.g., inflammatory bowel disease, idiopathic thrombocytopenic purpura, lupus erythematosus, autoimmune hemolytic anemia,
scleroderma, severe psoriasis [defined as affecting > 10% of the body, where one palm of one hand equals 1%, or if the hands and feet are affected] or rheumatoid arthritis).
16. Use of blood transfusion growth factors (including, but not limited to, granulocyte colony stimulating factor [G-CSF] or erythropoietin) or any other therapeutic agents to elevate hematology parameters to facilitate patient entry into the study within 3 months before screening.
17. Any of the following laboratory parameters at screening:
a) Hemoglobin A1c (HgA1c) value ≥ 8.5%.
b) Total bilirubin ≥ 1.5 ×ULN or ≥ 47 µmol/L (2.75 mg/dL) for Gilbert’s syndrome.
c) Hemoglobin < 120 g/L (< 12 g/dL) for females or <130 g/L (< 13 g/dL) for males.
d) ANC≤ 1.5 × 109
/L (1500/µL).
e) Platelet count ≤ 90 × 109
/L (90,000/µL).
f) Serum amylase or lipase levels > 1.5 ×ULN.
g) Any other abnormal screening laboratory result that is considered to be
clinically significant by the investigator.
18. Current enrollment or participation in a clinical trial of an experimental medication or
medical device within 3 months of Screening unless agreed upon by the Sponsor.
19. Use of the following concomitant medications or herbal supplements:
a) Inducers of metabolic enzymes (e.g., rifampin, rifabutin, phenobarbital, phenytoin, carbamazepine, and St. John’s wort) within 14 days or 5 half-lives (whichever is longer) before the first dose of DNVr and while on treatment with DNVr.
b) “Potent” inhibitors of CYP3A (e.g., ketoconazole) within 7 days or 5 half-lives (whichever is longer) before the first dose of DNVr and while on treatment with DNVr.
c) Inhibitors of organic anion transporting polypeptide (OATP transporters) (e.g., cyclosporine, rifampicin) within 7 days before the first dose of DNVr and while on treatment with DNVr.
d) Medications that are contraindicated with RTV, including, but not limited to,alfuzosin, amiodarone, bepridil, flecainide, propafenone, quinidine, voriconazole,astemizole, terfenadine, dihydroergotamine, ergonovine, ergotamine,methylergonovine, cisapride, pimozide, sildenafil (for treatment of pulmonary arterial hypertension), midazolam, triazolam, atorvastatin, lovastatin, and simvastatin.
e) Medications with a narrow therapeutic window that are extensively metabolized
by CYP3A and/or substrates of the P-glycoprotein (P-gp) transporter.
20. Evidence of excessive alcohol, drug or substance abuse (excluding marijuana use) within 1 year of first dose.
21. History of allergy to RBV, PEG-IFN, other IFNs, or RTV or any of their ingredients.