Study to Investigate the Efficacy of Elbasvir/Grazoprevir Fixed-Dose Combination for 8 Weeks in Treatment-Naïve, HCV GT1b-Infected Patients, With Non-severe Fibrosis
Condition: Chronic HCV Infection
MeSH terms: Hepatitis C; Fibrosis
Intervention: Elbasvir/Grazoprevir Fixed Dose Combination
Intervention description: Evaluate the efficacy of Elbasvir/Grazoprevir Fixed-Dose Combination for 8 Weeks in Treatment-Naïve, HCV GT1b-Infected Patients, with non- severe fibrosis as measured by the proportion of subjects with sustained viral response 12 weeks after cessation of treatment (SVR 12).
Intervention MeSH terms: Grazoprevir; Elbasvir-grazoprevir drug combination
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 117.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Hepatitis C; Genotype 1B; Non Severe Fibrosis; Treatment Naïve; 8 Weeks of Treatment; Elbasvir/Grazoprevir Combination

Summary:

      A Phase 3, Global, Multicenter, Open-Label Study to Investigate the Efficacy of
      Elbasvir/Grazoprevir Fixed-Dose Combination for 8 Weeks in Treatment-Naïve, HCV GT1b-Infected
      Patients, with non-severe fibrosis

      The primary objectives of this study are as follows:

        -  To evaluate the efficacy of Elbasvir/Grazoprevir Fixed-Dose Combination for 8 Weeks in
           Treatment-Naïve, HCV GT1b-Infected Patients, with non- severe fibrosis as measured by
           the proportion of subjects with sustained viral response 12 weeks after cessation of
           treatment (SVR 12).

        -  To evaluate the safety and tolerability of EBV/GZR treatment

      The secondary objectives of this study are as follows:

        -  To determine the proportion of subjects who attain SVR at 4 and 24 weeks after cessation
           of treatment (SVR4 and SVR24)

        -  To evaluate the proportion of subjects with virologic failure

        -  To evaluate the kinetics of circulating HCV RNA during treatment and after cessation of
           treatment.

        -  To evaluate the emergence of viral resistance to EBV/GZR during treatment and after
           cessation of treatment
    

Eligibility criteria:

        Inclusion Criteria:

          -  Willing and able to provide written informed consent

          -  Male or female, age ≥ 18 years

          -  Body Mass Index (BMI) ≥ 18 kg/m2

          -  HCV RNA ≥ 100 000 IU/mL at Screening

          -  Chronic HCV infection (≥ 6 months) documented by prior medical history or liver
             biopsy, only genotype 1b virus. (Positive for anti HCV antibody, HCV RNA, or an HCV
             genotype)

          -  Treatment-naïve with no prior exposure to any IFN, RBV, or approved or experimental
             HCV-specific DAA

          -  Non severe fibrosis (F<2) according to combination of this two tests :

        Fibroscan lower than 9.5kPa and Fibrotest lower than 0.59

          -  Females of childbearing potential (as defined in protocol Appendix 4) must have a
             negative serum pregnancy test at screening and a negative urine pregnancy test on Day
             1 prior to enrollment

          -  Male subjects and female subjects of childbearing potential who engage in heterosexual
             intercourse must agree to use 2 effective method(s) of contraception from at least two
             weeks prior to Day 1 through 14 days after the last dose of study drugs.

               -  If acceptable by local regulatory agencies, methods of birth control allowed in
                  the study are: intrauterine device (IUD), diaphragm with spermicide, hormonal
                  contraceptives (e.g., birth control pills, transdermal patch, or injectables),
                  contraceptive sponge, female condom, male condom with spermicide or vasectomy.

               -  Note: Periodic abstinence (e.g., abstinence only on certain calendar days,
                  abstinence only during ovulation period, use of symptothermal methods, use of
                  post-ovulation methods and withdrawal) are not acceptable methods of
                  contraception.

          -  A female subject who is not of reproductive potential is eligible without requiring
             the use of contraception. A female subjects who is not of reproductive potentials is
             defined as one who has either 1) reached natural menopause (defined as 12 months with
             no menses without an alternative medical cause), 2) 6 weeks post surgical bilateral
             oophorectomy with or without hysterectomy, or 3) bilateral tubal ligation.

          -  A male subject who is not of reproductive potential is eligible without requiring the
             use of contraception. A male subject who is not of reproductive potential is defined
             as: one who has undergone a successful vasectomy. A successful vasectomy is defined
             as: (1) microscopic documentation of azoospermia, or (2) a vasectomy more than 2 years
             ago with no resultant pregnancy despite sexual activity post vasectomy.

          -  Lactating females must agree to discontinue nursing before starting study drug

          -  Subject must be of generally good health, with the exception of chronic HCV infection,
             as determined by the Investigator

          -  Subject must be able to comply with the dosing instructions for study drug
             administration and able to complete the study schedule of assessments

        Exclusion Criteria:

          -  Is under the age of legal consent, is mentally or legally incapacitated, has
             significant emotional problems at the time of pre-study screening visit or expected
             during the conduct of the study or has a history of a clinically significant
             psychiatric disorder which, in the opinion of the investigator, would interfere with
             the study procedures.

          -  Current or prior history of any of the following:

               -  Clinically significant illness (other than HCV) or any other major medical
                  disorder that may interfere with subject treatment, assessment or compliance with
                  the protocol; subjects currently under evaluation for a potentially clinically
                  significant illness (other than HCV) are also excluded

               -  Gastrointestinal disorder or post-operative condition that could interfere with
                  the absorption of the study drug

               -  Difficulty with blood collection and/or poor venous access for the purposes of
                  phlebotomy

               -  History of decompensation (e.g., clinical ascites, encephalopathy, and/or
                  variceal hemorrhage)

               -  Solid organ transplantation (including hematopoietic stem cell transplants) other
                  than kidney, cornea and hair.

               -  Significant cardiac disease

               -  Unstable psychiatric condition including hospitalization, suicidal attempt,
                  and/or a period of disability as a result of their psychiatric illness within 2
                  years prior to Screening

               -  Malignancy within the 5 years prior to Screening, with the exception of specific
                  cancers that have been cured by surgical resection (e.g., basal cell skin cancer,
                  etc.). Subjects under evaluation for possible malignancy are not eligible

               -  Significant drug allergy (e.g., hepatotoxicity)

          -  Subject has the following laboratory parameters at Screening:

               -  ALT > 10 x the upper limit of normal (ULN)

               -  AST > 10 x ULN

               -  Direct bilirubin > 1.5 x ULN

               -  Platelets < 75,000/μL

               -  HbA1c > 8.5%

               -  Creatinine clearance < 50 mL/min as calculated by the Cockcroft-Gault equation

               -  Hemoglobin < 10 g/dL

               -  Albumin < 3 g/dL

               -  INR > 1.5 x ULN unless subject has known hemophilia or is stable on an
                  anticoagulant regime affecting INR

          -  Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson's disease,
             alfa-1 antitrypsin deficiency, cholangitis)

          -  Infection with hepatitis B virus (HBV) or human immunodeficiency virus (HIV)

          -  Clinically-relevant alcohol or drug abuse within 12 months of Screening.

               -  Alcohol, intravenous drugs, inhalational (not including marijuana), psychotropic,
                  narcotics, cocaine use, prescription or over-the-counter drugs: within 1 year of
                  the screening visit, or if shorter, is judged by investigator to be capable of
                  complying with study procedures

               -  receiving opiate agonist substitution therapy within 1 year of screening visit,
                  or if shorter, is judged by investigator to be capable of complying with study
                  procedures

               -  history of marijuana use if deemed excessive by a physician investigator or
                  interferes with the subject's daily function. If subject's marijuana use is not
                  deemed excessive and does not interfere with daily function, subject must agree
                  to discontinue any current use of recreational marijuana prior to entry into
                  trial and throughout the trial period

                    -  A positive drug screen will exclude subjects unless it can be explained by a
                       prescribed medication; the diagnosis and prescription must be approved by
                       the investigator

          -  Use of any prohibited concomitant medication listed in Section 5.5 of this protocol
             within 2 weeks prior to day 1.

          -  Known hypersensitivity to the study drug, the metabolites, or formulation excipient

          -  is currently participating or has participated in a study with an investigational
             compound within 30 days of signing informed consent and is not willing to refrain from
             participating in another study. Collection of additional blood, urine, or tissue
             samples or additional data, beyond that specified in this protocol, is prohibited
             (other than that related to subject's medical care).

          -  (female) is pregnant, lactating, expecting to conceive or donate eggs, or is of
             childbearing potential and unwilling to commit to two methods of birth control
             throughout treatment and after the completion of all treatment (see Inclusion
             Criteria); or male subject is planning to impregnate or provide sperm donation or has
             a female sexual partner of childbearing potential and is unwilling to commit to using
             a two methods of birth control throughout treatment and after the completion of all
             treatment (see Inclusion Criteria).

          -  had a life-threatening SAE during the screening period. 2. is a member or a family
             member of the investigational study staff or sponsor staff directly involved with this
             study.

          -  has evidence or history of chronic hepatitis not caused by HCV, including but not
             limited to nonalcoholic steatohepatitis (NASH), drug-induced hepatitis, and autoimmune
             hepatitis.

               -  NOTE: Subjects with history of acute non-HCV-related hepatitis, which resolved >
                  6 months before study entry, may be enrolled.

          -  For subjects diagnosed with diabetes mellitus, documented HbA1c >8.5% (to exclude
             uncontrolled diabetes).

          -  Has any of the following conditions:.

               -  Subject with a history of gastric surgery (e.g., stapling, bypass) or subject
                  with a history of malabsorption disorders (e.g., celiac sprue disease).

               -  Any medical condition requiring, or likely to require, chronic systemic
                  administration of corticosteroids during the course of the trial.

          -  Has exclusionary laboratory values as listed below (see Table 5 for unit conversions
             of some laboratory values specified below):

               -  Note: If any of the laboratory exclusion criteria below are met, the site may
                  have the abnormal value retested one time.

        Table 5: Exclusionary laboratory values:

          -  Laboratory Assessment

          -  hemoglobin < LLN (lower limit of normal) of laboratory reference range

          -  neutrophils <1.5 x 103/μL (<1.2 x 103/μL for Blacks)

          -  platelets <75 x 103/μL

          -  direct bilirubin >1.5 x ULN

          -  Total Bilirubin >1.6 mg/dL unless history of Gilbert's disease. (If Gilbert's disease
             is the proposed etiology, this must be documented in the subject's chart)

          -  Serum Albumin < 3.0 g/dL (lower limit of normal) of laboratory reference range

          -  creatinine clearance <50 mL/min

          -  INR >1.5

          -  ALT >350

          -  AST >350