New Treatment Response in People With and Without Cirrhosis From Chronic Hepatitis C
Condition: Cirrhosis; Chronic Hepatitis C; Hepatitis C; Hepatitis C, Chronic
MeSH terms: Hepatitis A; Hepatitis C; Hepatitis C, Chronic; Hepatitis; Hepatitis, Chronic; Liver Cirrhosis; Fibrosis
Intervention: DUAL; QUAD
Intervention description: Asunaprevir and Daclatsvir; Asunaprevir, daclatsvir, peginterferon and ribavirin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 35.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Hepatitis C; Non-Responders; Direct Acting Antivirals; Interferon Free; Cirrhosis

Summary:

      Background:

      - Some people who have chronic hepatitis C do not respond to the usual treatment with
      peginterferon and ribavirin. New chronic hepatitis treatments are being developed that may
      work better for different people. The treatments will look at how specific genes interact
      with the drugs. Researchers want to see how well these new drugs work in people whose chronic
      hepatitis C has not responded or only partly responded to the usual treatment drugs.

      Objectives:

      - To compare new treatments for people with chronic hepatitis C.

      Eligibility:

      - Individuals at least 18 years of age who have chronic hepatitis C that has not responded to
      standard treatments.

      Design:

        -  Participants will be screened with a physical exam and medical history. Blood and urine
           samples will be collected. Liver scans and a biopsy will be taken before the start of
           treatment.

        -  Participants will be separated into two groups. One group will have the new treatment
           drugs (assunaprevir and daclatasvir). The second group will have these two drugs as well
           as peginterferon and ribavirin. All participants will have an initial 4-day hospital
           stay with regular blood tests to see how the start of the treatment works.

        -  The first group will take the new study drug tablets daily for 24 weeks. Those who do
           not respond to this treatment will also start to take peginterferon and ribavirin, and
           the treatment will continue for 24 weeks after starting the additional drugs.

        -  The second group will take all four drugs according to the standard dosing schedule for
           24 weeks.

        -  Treatment will be monitored with frequent blood tests. Liver scans, biopsies, and other
           tests will be performed as directed by the study doctors.

        -  Participants will have 24 weeks of regular followup visits.
    

Eligibility criteria:

        -INCLUSION CRITERIA:

        INCLUSION CRITERIA FOR BOTH GENOTYPES 1a and 1b:

          1. Adults, ages 18 and above

          2. Chronic hepatitis C (HCV RNA in serum for more than 6 months)

          3. HCV Genotype 1

          4. HCV RNA in serum above 10,000 IU/mL

          5. Non-response to previous therapy with peginterferon and ribavirin categorized as
             null-response as defined by a less than 1 log IU/mL decline in HCV RNA at treatment
             week 4 or a less than 2 log IU/mL decline in HCV RNA at treatment week 12; and partial
             response as defined by a greater than or equal to 2 log decrease in HCV RNA at
             treatment week 12 but continued detection of HCV RNA at treatment week 24

          6. No contraindications to agents being used (asunaprevir, daclatasvir, peginterferon and
             ribavirin).

          7. No evidence or history of hepatic decompensation.

          8. Females of childbearing potential must have a negative serum or urine pregnancy test
             result (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours before
             the first dose of study drug.

          9. Women of childbearing potential (WOCBP) and men must use highly effective methods of
             birth control to minimize the risk of pregnancy. WOCBP must follow instructions for
             birth control for the entire duration of the study including a minimum of 24 weeks
             after the last dose of P/R. Birth control requirements are or WOCBP and men who are
             sexually active with WOCBP

         10. Women must not be breastfeeding

         11. Fully informed, written consent to the study including repeat liver biopsy.

        ADDITIONAL INCLUSION CRITERIA FOR GENOTYPE 1a

        1) Liver biopsy showing Ishak stages 0-2 or 5-6 within 12 weeks of initiating therapy OR a
        prior biopsy performed within 96 weeks of screening visit WITH saved tissue. Up to 10
        subjects who do not fulfill the entry histologic criteria will be allowed to participate in
        the trial at the discretion of the investigator.

        ADDITIONAL INCLUSION CRITERIA FOR GENOTYPE 1b

          1. Baseline sequence analysis of the NS5A region to exclude presence of mutations known
             to confer resistance to daclatasvir.

        INCLUSION CRITERIA FOR GT 1b SUBJECTS WHO RECEIVE RESCUE THERAPY AT THE DISCREATION OF THE
        INVESTIGATOR (THESE CRITERIA MUST BE ASSESSED PRIOR TO INITIATIONOF PEG INFa/RBV THERAPY):

        Important: In addition to the Inclusion Criteria listed above, the following

        Inclusion Criteria apply to all Rescue Subjects:

        a) Subject met a definition of virologic breakthrough or treatment futility, defined

        as:

        i) Any confirmed > 1 log10 increase in HCV RNA from nadir, OR;

        ii) Any confirmed HCV RNA greater than or equal to Lower Limit of quantification (LLOQ)
        after confirmed HCV RNA <LLOQ Target Not Detected while on treatment, OR;

        iii) Any confirmed HCV RNA greater than or equal to LLOQ at Week 8. Measurements should be
        confirmed within 2 weeks of the Week 8 result;

        b) HCV RNA < 400,000 IU/mL at the last assessment; This cut-off was chosen because it is
        felt that peginterferon and ribavirin would be ineffective at higher viral loads in prior
        non-responders to peginterferon and ribavirin with viral breakthrough.

        c) Women of childbearing potential (WOCBP)1 and men must use highly effective methods of
        birth control to minimize the risk of pregnancy. WOCBP must follow instructions for birth
        control for the entire duration of the study including a minimum of 24 weeks after the last
        dose of P/R. Birth control requirements are or WOCBP (see Section C.5 for the definition of
        WOCBP) and men who are sexually active with WOCBP;

        i) Two (2) forms of birth control are required from time of screening throughout the
        duration of the on-treatment study period and for at least 24 weeks after the last dose of
        RBV (or the duration specified by the country-specific RBV label, whichever is longer), in
        such a manner that the risk of pregnancy is minimized. Examples of highly effective birth
        control include:

        -condom with spermicide;

        -diaphragm and spermacide;

        -cervical cap and spermacide

          -  female condom;

          -  intrauterine devices (IUDs);

        Oral contraceptive pills (OCPs) may be used in this study but cannot be considered as an
        effective form of contraception for WOCBP subjects.

        ii) Exceptions include:

          1. WOCBP who are not heterosexually active or who have male partners who have been
             vasectomized for a minimum of 6 months with a history of confirmed azoospermia;

          2. Sexually active men who are vasectomized for a minimum of 6 months with a history of
             confirmed azoospermia.

             d) WOCBP must have a negative serum or urine pregnancy test [minimum sensitivity 25
             IU/L or equivalent units of human chorionic gonadotropin (HCG)] within 24 hours prior
             to the start of P/R. Female subjects must agree to the pregnancy testing requirements
             of this protocol;

             e) Women must not be breastfeeding;

             f) Male Subjects: Requirements (based on RBV label):

             i) Male subjects (unless vasectomized for at least 6 months with a history of
             confirmed azoospermia) with female partners who are WOCBP must agree to inform their
             female partners of the protocol-specified effective birth control methods requirement
             and pregnancy testing recommendations during treatment and post-treatment (i.e., two
             forms of effective methods of birth control and monthly pregnancy testing while the
             subject is enrolled in the study and 6 months following discontinuation of RBV [or for
             the post-treatment duration specified in the country-specific RBV label]), and agree
             to adhere to these recommendations both on-treatment and during the post-treatment
             follow-up period;

        ii) Male subjects must confirm that their female sexual partners are not pregnant at the
        time of screening.

        EXCLUSION CRITERIA:

        Exclusion Criteria for Genotypes 1b:

          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

             6. OTHER EXCLUSION CRITERIA

        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

        C.5 Exclusion Criteria for Gt 1a subjects and 1b subjects who receive rescue therapy at
        discretion of the investigator (Prior to initiation of PegIFN /ribavirin therapy):

        Important: In addition to the Exclusion Criteria listed above WITH THE EXCEPTION OF THE
        LABORATORY TESTS INDICATED IN SECTION C.4.2 A-H, the following

        Exclusion Criteria apply to all Gt 1a and rescue subjects:

        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;