Efficacy and Safety of All-Oral Combination of Narlaprevir/Ritonavir and Daclatasvir in Treatment-Naїve Patients With Chronic Hepatitis C Genotype 1b

Multicenter, Open-label, Phase II Safety and Efficacy Study of All-oral Combination Narlaprevir/Ritonavir and Daclatasvir Administered for 12 Weeks in Patients With Genotype 1b Chronic Hepatitis C

The purpose of this study is to confirm that combination of Narlaprevir, Ritonavir and Daclatasvir is safe and highly effective regimen in treatment-naїve patients with chronic hepatitis C (HCV) genotype 1b infection.

To evaluate effectiveness and safety of treatment with Narlaprevir, Ritonavir and Daclatasvir combination will be selected 105 treatment-naїve patients with chronic HCV genotype 1b without genetic variants coding for the NS5A-Y93 С/H/N/S and/or L31 F/M/V/I amino acid substitutions, eligible as per protocol criteria.

Each patient will participate in the trial approximately up to 38 weeks:

• 2 weeks are expected for screening
• up to 12 weeks for treatment period
• 24 weeks for follow-up period

During treatment period all patient will receive equal drug combination.

Efficacy and safety parameters will be assessed as per primary and secondary endpoints. Also Ctrough for Narlaprevir and Daclatasvir on day 14 will be evaluated as pharmacokinetic objective.

The results of this study will provide new information about treatment of patients with chronic hepatitis C genotype 1 with Narlaprevir/Ritonavir in combination with Daclatasvir during 12 weeks.

Inclusion Criteria -

Subjects who meet all of the following criteria are eligible for participation in the study:

• Are willing and able to provide written informed consent.

• Have confirmed chronic HCV infection as documented by:

  1. positive anti-HCV antibody (Ab) test or
  2. positive HCV RNA or
  3. positive HCV genotyping test at least 6 months prior to the Baseline/Day 1 visit.

• Have HCV genotype 1b at screening as determined by the Central Laboratory. Any non definitive results must exclude the subject from study participation.

• Minimum HCV-RNA level of ≥10,000 IU at baseline.

• No evidence of cirrhosis; availability at Baseline of at least one of the following tests, negative results:

  1. Liver biopsy within 2 years of screening showing absence of cirrhosis;
  2. Fibroscan with a result of ≤ 12.5 kPa within 6 months of baseline/Day1;
  3. FibroTest score of ≤ 0.48 AND APRI of ≤ 1 performed during screening. In the absence of a definitive diagnosis of the presence or absence of cirrhosis by the above criteria, a liver biopsy was required. Liver biopsy results supersede the results obtained by Fibroscan or FibroTest.

• Have a screening electrocardiogram (ECG) without clinically significant abnormalities (P wave < 0.1 s; PQ interval 0,12-0,2 s; QRS complex 0,06-0,1 s; QT interval 0,35-0,49 s).

• Must have the following laboratory parameters at screening:

  1. alanine aminotransferase (ALT) ≤ 10 x the upper limit of normal (ULN);
  2. aspartate aminotransferase (AST) ≤ 10 x ULN;
  3. Hemoglobin ≥ 12g/dL for male, ≥ 11g/dL for female subjects;
  4. Platelets ≥ 50,000cells/mm3;
  5. International normalized ratio (INR) ≤ 1.5 x ULN unless subject has known hemophilia or is stable on an anticoagulant regimen affecting INR;
  6. Albumin ≥ 3g/dL;
  7. Direct bilirubin ≤ 1.5 x ULN;
  8. Hemoglobin A1c (HbA1c) ≤ 10%;
  9. Creatinine clearance (CLcr) ≥ 60 mL/min, as calculated by the Cockcroft-Gault equation;
  10. Have not been treated with any investigational drug or device within 30 days of the screening visit.

• A female subject is eligible to enter the study if it is confirmed that she is:

  1. Not pregnant or nursing;

  2. Of non-childbearing potential (i.e., women who have had a hysterectomy, both ovaries removed, or medically documented ovarian failure, or are postmenopausal women >50 years of age with cessation [for ≥12 months] of previously occurring menses), or

  3. Of childbearing potential (i.e., women who had not had a hysterectomy, both ovaries removed, or medically documented ovarian failure). Women ≤ 50 years of age with amenorrhea are considered to be of childbearing potential. These women must have a negative serum pregnancy test at screening and a negative urine pregnancy test on the baseline/Day 1 visit prior to enrollment. They must also agree to one of the following from 3 weeks prior to baseline/Day 1 until 6 months after last dose of the investigational drugs:

     1. Complete abstinence from intercourse. Periodic abstinence from intercourse (e.g., calendar, ovulation, sympto thermal, post-ovulation methods) is not permitted Or

     2. Consistent and correct use of 1 of the following methods of birth control listed below in addition to a male partner who correctly uses a condom from the date of screening until 6 months after the last dose of the investigational drugs:

        • intrauterine device (IUD) with a failure rate of < 1% per year;
        • female barrier method: cervical cap or diaphragm with spermicidal agent;
        • tubal sterilization;
        • vasectomy in male partner; Women of childbearing potential must not rely on hormone-containing contraceptives as a form of birth control during the study. Female subjects using a hormone-containing contraceptive prior to screening must stop their contraceptive regimen use from the date of screening until 6 months after their last dose of investigational drugs.

• All male study participants must agree to consistently and correctly use a condom, while their female partner agrees to use either 1 of the non hormonal methods of birth control listed above or a hormone-containing contraceptive listed below, from the date of screening until 6 months after their last dose of investigational drugs:

  • implants of levonorgestrel;
  • injectable progesterone;
  • oral contraceptives (either combined or progesterone only);
  • contraceptive vaginal ring;
  • transdermal contraceptive patch;

• Male subjects must agree to refrain from sperm donation for at least 6 months after the last dose of investigational drugs.

• Are in generally good health as determined by the investigator.

• Are able to comply with the dosing instructions for study drug administration and are able to complete the study schedule of assessments.

Exclusion Criteria -

Subjects with any of the following are not eligible for participation in the study:

• Had prior exposure to IFN, RBV, or other approved or experimental DAA targeting the HCV.
• Had prior exposure to amiodarone within 24 months before the screening
• Are pregnant or nursing female or male with pregnant female partner.
• Сhronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson's disease, α1-antitrypsin deficiency, cholangitis).
• Are infected with hepatitis B virus (HBV) or human immunodeficiency virus (HIV).
• Have history of malignancy diagnosed or treated within 5 years; subjects under evaluation for malignancy are not eligible.
• Have chronic use of systemically administered immunosuppressive agents (e.g., prednisone equivalent > 10 mg/day).
• Have clinically relevant drug or alcohol abuse within 12 months of screening. A positive drug screen must exclude subjects unless it can be explained by a prescribed medication; the diagnosis and prescription must be approved by the investigator.
• Have excessive alcohol consumption, defined as more than 3 drinks on any single day and more than 7 drinks per week for females, and > than 4 drinks on any single day and more than 14 drinks per week for males.
• Have history of solid organ transplantation.
• Have history of clinically significant illness or any other major medical disorder that may interfere with subject treatment, assessment, or compliance with the protocol by Investigators' opinion.
• Have history of a gastrointestinal disorder (or postoperative condition) that can interfere with the absorption of the study drug.
• Have history of difficulty with blood collection and/or poor venous access for the purposes of phlebotomy.
• Usage of any prohibited concomitant medications as described in the protocol (list of drugs with expected drug-drug interactions due to concomitant ritonavir usage)
• Have known hypersensitivity to the study investigational medicinal product, the metabolites, or formulation excipients.
• Chronic HCV genotype 1b-infected participant who has the presence of genetic variants coding for the NS5A-Y93 С/H/N/S and/or L31 F/M/V/I amino acid substitutions at Screening.