Hepatitis C Treatment Naive Genotype 1 Consensus Interferon Trial
Hepatitis C Treatment Naive Genotype 1 Consensus Interferon Trial
Data have suggested that consensus interferon (CIFN) has greater antiviral activity in vitro
 compared with interferon alfa-2a or alfa-2b. Several clinical studies also suggest that CIFN
 has greater antiviral activity in patients with genotype 1 hepatitis C infection,
 particularly if given as a daily injection. These data indicate that the use of a regimen of
 daily CIFN and ribavirin will lead to greater virologic response rates compared with
 pegylated interferon alfa-2b and ribavirin in patients with genotype 1 infection, with
 comparable adverse events. Emerging data indicate that HCV genotype 1 patients with a delayed
 virologic response to initial therapy may benefit from an extended duration of therapy.
 Therefore, the goals of this pilot study are to determine the tolerability and efficacy of
 daily CIFN plus ribavirin when given for 52 weeks or an extended duration of therapy. The
 target population will consist of "difficult-to-treat" patients, defined as having the
 following characteristics: genotype 1, a North American patient population, predominantly
 male gender, and no specific exclusions for pre-existing psychiatric or substance abuse
 co-morbidities.
Current treatment for hepatitis C is a pegylated interferon alfa plus ribavirin. This
 treatment is inadequate for patients with HCV genotype 1, since the majority of patients do
 not respond (termed non-responders) or respond but relapse (termed relapsers) following
 termination of these treatments. Data from the Veterans Health Administration (VHA) Hepatitis
 C Registry and community hospitals indicate that the large majority of patients identified
 with hepatitis C have characteristics associated with a poor treatment response and remain
 untreated at this time. Data have suggested that consensus interferon (CIFN, CIFN or
 interferon alfacon-1) has greater antiviral activity in vitro compared with interferon
 alfa-2a or alfa-2b. Preliminary data indicate that more patients with genotype 1 can respond
 to CIFN and ribavirin than current standard treatments, due to the fact that approximately
 25% of patients who are nonresponders to pegylated interferon and ribavirin may have a
 sustained response to a regimen of daily CIFN and ribavirin. Furthermore, difficult to treat
 patients may benefit from a longer duration of therapy than the standard 48 week regimen
 based on when an initial virologic response to therapy occurs.

 Aims: To determine the safety and efficacy of (A) daily CIFN (15 mcg/d sq) and ribavirin
 (1-1.2 gm/d PO) given for 52 weeks, vs (B) daily CIFN (15 mcg/d sq) and ribavirin (1-1.2 gm/d
 PO) given for 52 to 72 weeks for treatment-naïve patients with hepatitis C genotype 1, with
 treatment duration based on the virologic response during the initial 24 weeks.

 Methods: Patients who meet eligibility criteria will be stratified by race and randomized to
 one of two treatment arms, and all patients will have viral kinetics measured by quantitative
 PCR at weeks 4,8,12,16,20 and 24. Patients in treatment arm A will follow "standard" stopping
 rules, i.e., if there is not a 2-log drop in viremia by 12 weeks the treatment will be
 discontinued, otherwise they will all receive 52 weeks of treatment if they also are
 qualitative PCR negative by week 24. In treatment arm B the patients will be monitored
 monthly until they have a virologic response (defined as >2 log drop in viral levels from
 baseline) by quantitative PCR for up to 24 weeks. Once they have a virologic response by
 quantitative PCR their treatment will be continued for an additional 48 weeks. In both
 groups, treatment will be stopped if the patients do not become negative for HCV RNA by
 qualitative PCR by 24 weeks on therapy. A total of 192 patients at up to 10-20 sites will be
 recruited. The primary endpoint would be the number who achieve a sustained virologic
 response; secondary endpoints are the percentage of patients who complete therapy, have
 significant adverse events, and the relationship of early virologic response at each 4 week
 period between 4 and 24 weeks and those who achieve a sustained virologic response.

 Sample size determination: To detect an absolute difference of 20% or more in sustained
 virologic response between treatment arms A and B; the Log-rank test is performed at the
 alpha level of .05 and the test is maintained at least 80 percent statistical power; it is
 estimated that a total of 96 patients in each treatment arm will be required.

 Analysis: Univariate and multivariate analysis will be used to determine factors associated
 with final endpoints. Subgroup analyses will be done based on time to early virologic
 response and duration of therapy each stratification. The primary and secondary endpoints
 will be determined on an intention-to-treat basis starting with all patients that receive at
 least one dose of study medications. The primary and secondary endpoints will also be
 determined in a per-protocol analysis on those patients who take 80% of the prescribed CIFN
 and 80% of the prescribed ribavirin for 80% of the time.

 Significance: The current initial treatment of pegylated interferon alfa and ribavirin for
 patients with hepatitis C who are genotype 1 and have other "difficult-to-treat"
 characteristics is inadequate. The results of this trial are needed to demonstrate the safety
 and efficacy of two regimens of daily CIFN and ribavirin. Since the large majority of
 hepatitis C patients in VA and other community hospitals fall into this category, the results
 of this trial may influence the potential treatments recommended for these patients.
Inclusion Criteria:

 1. Chronic hepatitis C. This is defined as the documentation of the presence of circulating
 hepatitis C virus by a positive hepatitis C PCR test and a positive HCV genotype test for
 genotype 1, and a liver biopsy (within the previous 5 years) that is compatible with
 chronic hepatitis. In the case of patients that have refused liver biopsies a clinical
 diagnosis of chronic hepatitis C is required.

 2. Positive HCV RNA by PCR, Genotype 1, treatment naive 3. Age 18-65 years. 4. Patient must
 be able to give informed consent. 5. Eligible for interferon alfa and ribavirin-based
 antiviral treatment:

 1. Reconfirmation and documentation that sexually active female patients of childbearing
 potential are practicing adequate contraception. A urine pregnancy test obtained at
 entry prior to the initiation of treatment must be negative.

 2. Reconfirmation that sexually active male subjects are practicing acceptable methods of
 contraception during the treatment period and for six months following the last dose
 of study medication.

 3. For patients with cirrhosis or stage 4 fibrosis on liver biopsy, they must have an
 alpha fetoprotein (AFP) value < 80 ng/mL obtained within 3 months prior to entry.
 Cirrhotics with an alpha fetoprotein value >30 ng/mL but <80ng/mL may be enrolled
 after a normal ultrasound or triphasic CT scan within the previous 3 months.
 Cirrhotics with alpha fetoprotein levels up to 30 ng/ml must have an ultrasound or CT
 scan within 6 months of enrolling that is negative for hepatocellular cancer. Patients
 with an AFP > 80 ng/mL may not be enrolled.

 5) Compensated liver disease with the following laboratory results at entry:

 -  Hemoglobin >=to 12 gm/dL for females and >= 13gm/dl for males

 -  WBC >= 2,000/mm3

 -  Neutrophil >=1,500/mm3

 -  Platelets >=75,000/mm3

 -  Albumin > 3.0 g/dL

 -  Total bilirubin <2.0

 -  Serum creatinine < 1.4 mg/dL

 -  INR <1.8

 -  If diabetic, must have glycosylated Hgb test that demonstrates adequate control of
 diabetes in the opinion of the investigator

 -  TSH within normal limits

 Exclusion Criteria:

 1. Patient unable or unwilling to participate.

 2. Liver disease in addition to chronic hepatitis C (HBsAg positive, autoimmune liver
 disease, hemochromatosis, PBC, PSC, alpha-1 antitrypsin deficiency, Wilson's disease,
 etc.)

 3. Decompensated liver disease, with history of encephalopathy, variceal bleeding, or
 ascites or CHILD-PUGH class B or C.

 4. Baseline BDI > 19 or current suicidal or homicidal ideation. (Note: if baseline BDI is
 > 19 pt. will require a psychiatric evaluation and treatment; if deemed stable after
 this he may be considered according to site PI clinical judgment.)

 5. Current substance use disorder (Must be evaluated and demonstrate engagement and
 compliance with care before they will be eligible).

 6. Patients with active or uncontrolled psychiatric disease including patients who have
 had recent prior severe psychiatric disease (hospitalized) within the last 2 years.

 7. Accepted and reasonable exclusion criteria for interferon alfa and ribavirin based
 treatments:

 1) CNS trauma or active seizure disorders requiring medication. 2) Significant
 cardiovascular dysfunction within the past 12 months 3) Poorly controlled diabetes mellitus
 (in the opinion of the site PI). 4) Moderate or severe chronic pulmonary disease 5)
 Clinically significant immunologically mediated disease 6) Hemoglobinopathies (e.g.,
 Thalassemia) or any other cause of hemolytic anemia.

 7) Any medical condition requiring, or likely to require during the course of the study,
 chronic systemic administration of steroids.

 8) Hypersensitivity to interferon alfa or ribavirin 9) Known anti-HIV positive 10)
 Clinically significant retinopathy 11) Previous solid organ transplantation 12) Any
 condition that, in the opinion of the investigator, will prevent the patient from being
 compliant with study medications or appointments.