Evaluation of Safety, Tolerability, and Antiviral Activity of Chlorcyclizine HCl Alone or in Combination With Ribavirin in Patients With Chronic Hepatitis C

Up to 50 patients with chronic hepatitis C, who are treatment na(SqrRoot) ve or relapsers to
any interferon/ribavirin regimen will be enrolled into this pilot study evaluating
chlorcyclizine HCl with or without ribavirin (RBV) as antiviral therapy. Adult patients
(greater than or equal to18 years of age) with evidence of active chronic hepatitis C
infection (all genotypes) with detectable HCV RNA in serum >10,000 IU/mL without
contraindications to chlorcyclizine HCl or ribavirin or evidence/history of hepatic
decompensation will be enrolled. Patients will be monitored for at least two months with
regular testing for ALT and HCV RNA quantitative levels before treatment and will undergo
admission to start therapy, which includes a thorough medical evaluation and timed blood
sampling. Patients will be randomized to one of two treatment groups; one with chlorcyclizine
HCl (75 mg twice daily) and the other with RBV+ chlorcyclizine HCl (75 mg twice daily). For
all genotypes, RBV will be dosed based on weight (1000 mg daily <75 kg and 1200 mg daily
greater than or equal to 75 kg). At each clinic visit, patients will be questioned about side
effects and symptoms, undergo a focused physical examination, and have blood taken for
complete blood counts, HCV RNA, PT/INR and routine liver tests (ALT, AST, alkaline
phosphatase, direct and total bilirubin, and albumin). At the end of 28 days of treatment,
patients will undergo a repeat thorough medical evaluation inclusive of a complete physical
exam, symptom scale evaluation, complete blood counts, routine liver tests, and HCV serology
panels. The primary endpoint of therapy will be a decline in quantitative HCV RNA viral
levels after 28 days of treatment as compared to baseline viral titers and between groups.
Several secondary endpoints will be measured, including side effects of therapy, ALT levels,
quantification of chlorcyclizine HCl and its metabolites in serum, and quality of life.
Therapy will be stopped for intolerance to RBV and/or chlorcyclizine HCl (which will be
carefully defined).

- INCLUSION CRITERIA:

- Adults, ages 18 and above;

- Chronic hepatitis C (HCV RNA in serum for more than 6 months);

- HCV RNA in serum at or above 10,000 IU/mL;

- Treatment naive patients defined as individuals whom have never undergone any form of
interferon and ribavirin therapy for chronic HCV infection or relapsers defined as
reappearance of HCV RNA in serum after treatment (with any form of interferon and
ribavirin therapy) was discontinued and an end-of-treatment response was achieved;

- No major contraindications to agents being used (chlorcyclizine HCl and ribavirin);

- 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;

- Women of childbearing potential and men, participants and partners, must use highly
effective methods of birth control to minimize the risk of pregnancy and must follow
instructions for birth control for the entire duration of the study including a
minimum of 24 weeks after the last dose of ribavirin. Two forms of birth control are
required from the time of screening throughout the duration of the on-treatment study
period and for at least 24 weeks after the last dose of ribavirin. Examples of
effective birth control include: condom with spermicide; diaphragm with spermicide;
cervical cap with spermicide; female condom; intrauterine devices (IUDs); vasectomy in
men;

EXCLUSION CRITERIA:

- Liver or any other organ transplant (including hematopoietic stem cell transplants)
other than cornea and hair;

- 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;

- 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);

- Evidence of decompensated liver disease including, but not limited to, bilirubin >4
mg/dL, albumin <3.0 gm/dL, prothrombin time >2 sec prolonged or a history or presence
of ascites, bleeding varices, or hepatic encephalopathy. Patients with ALT levels >500
U/L will not be enrolled but may be followed until three determinations are below this
level;

- Evidence of a medical condition contributing to chronic liver disease other than
chronic HCV infection (such as, but not limited to: acute hepatitis C infection,
hemochromatosis, autoimmune hepatitis, metabolic liver disease, alcoholic liver
disease, toxin exposures);

- 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);

- Any prior exposure to direct-acting antiviral therapies for chronic HCV infection;

- History of HIV infection;

- History of hemoglobinopathies (eg. thalassemia major or sickle cell anemia), diagnoses
associated with an increased baseline risk for anemia (eg, spherocytosis), hemolytic
anemia, or diseases in which anemia would be medically problematic, or hemophilia;

- 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);

- 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;

- Significant systemic or major illnesses other than liver disease, including, but not
limited to, clinically significant emphysema or chronic bronchitis, symptomatic benign
prostatic hypertrophy, glaucoma, gastrointestinal motility related illnesses,
congestive heart failure, renal failure (eGFR <50 mL/min), and active coronary artery
disease;

- Significant prior history suggestive of cardiovascular instability, including but not
limited to evidence of significant myocardial ischemia, unstable re-entry phenomena,
other significant dysarrhythmias and/or uncontrolled hypertension;

- Inability to tolerate oral medication;

- For relapsers: exposure to interferon based therapy with ribavirin within 12 weeks
prior to screening;

- Allergy or hypersensitivity to chlorcyclizine HCl or ribavirin;

- Any known contraindication to ribavirin, not otherwise specified;

- Inability to refrain from operating heavy machinery while on therapy;

- Breastfeeding women;

- Inability to understand or sign informed consent;

- Active use of chlorcyclizine HCl or another piperazine class antihistamine within 6
months of enrollment;

- Inability to abstain from piperazine class antihistamines during enrollment in the
clinical trial period.