Pilot Study of Betaine + Combination Antiviral Therapy for Chronic Hepatitis C Genotype 1 Non-responder/Relapsers
Pilot Study of Betaine + Combination Antiviral Therapy for Chronic Hepatitis C Genotype 1 Non-responder/Relapsers
This is a non-randomized, open-label study examining the safety and efficacy of betaine in
 addition to standard anti-viral therapy in genotype 1 hepatitis C non-responders or relapsers
 to previous pegylated interferon plus ribavirin. Betaine (20 gm/day) in 2 divided doses will
 be added to Peginterferon alpha 2a (180 mcg) plus weight-based Ribavirin (1000 or 1200
 mg/day, for body weight < or > 75 kg, respectively, for 48 weeks. Patients must be diagnosed
 with chronic hepatitis C, genotype I, and have undergone therapy for hepatitis C with
 pegylated interferon plus ribavirin. Subjects will be followed for safety, tolerability,
 hepatitis C viral response and the effect on interferon gene signaling in peripheral blood
 mononuclear cells during therapy.
The primary objective is to examine the safety and efficacy of the betaine when combined with
 standard anti-viral therapy in previously treated adult subjects with chronic hepatitis C
 infected with genotype 1. The efficacy will be determined through comparison of the sustained
 viral response (SVR) to our protocol three-drug regimen (Betaine, Peginterferon plus
 Ribavirin) to that historically seen in relapsers and non-responders when retreated with
 standard therapy (Peginterferon and Ribavirin alone).

 Secondary objectives include: (1) the comparison of the occurrence of rapid and early
 virologic response in the first 4 (Rapid Virologic Response, RVR) and 12 (Early Virologic
 Response, EVR) weeks of therapy, respectively, between the study regimen and historically
 treated patients. (2) the comparison of ALT normalization between the two groups. and (3) the
 effect on interferon gene signaling in peripheral blood mononuclear cells (PBMCs) between the
 two groups in the first 12 weeks of therapy and 6 months following the end of therapy..
Inclusion Criteria:

 -  Subject must be willing to give informed consent and be able to adhere to dose and
 visit schedules.

 -  History of chronic hepatitis C, genotype 1, non-responders or relapsers as documented
 by genotype testing and HCV RNA levels at 12 weeks ( < 2 log change) during therapy or
 at 3 - 12 months post therapy, respectively.

 -  Adult subjects 18-70 years of age, of either gender

 -  Liver biopsy within 3 years prior to the screening 1 visit with a pathology report
 confirming that the histological diagnosis is consistent with chronic hepatitis C.

 -  Compensated liver disease with the following maximum hematologic, biochemical and
 serologic criteria at the Screening visit (WNL=within normal limits) Hemoglobin > 12
 g/dl for females and >13 g/dl for males, WBC > 3000/mm3, Platelets > 80,000/mm3,
 Direct Bilirubin - WNL. Indirect bilirubin - WNL, Albumin - WNL, Serum Creatinine -
 WNL.

 -  Fasting glucose should be 70 -140 mg/dl, results between 116-140 require a HbA1c <
 8.5%

 -  TSH - WNL

 -  Subjects with a history of mild depression may be considered for entry in to this
 study provided that a pretreatment assessment of the subject's affective status
 supports that the subject is clinically stable.

 -  Subjects with a history of substance abuse must have abstained from using the
 substance for at least one year prior to the Screening visit.

 -  Antinuclear antibodies (ANA) < 1:320

 -  No radiologic evidence of a focal mass suggestive of hepatoma and/or ascites.

 Exclusion Criteria:

 -  Pregnant or nursing subjects. Subjects who intend to become pregnant during the study
 period. Subjects with partners who intend to become pregnant during the study period.

 -  Prior response to therapy and failure to achieve SVR which may have been due to
 treatment non-compliance, in the assessment of the investigator based upon subject's
 medical history.

 -  Participation in any clinical trial of a HCV protease inhibitor of any duration.
 Subjects may have received other investigational agents for the treatment of HCV, as
 long as they have also received an adequate course of Peg-IFN/RBV [i.e., the
 investigational agent could not have replaced either Peg-IFN (such as Albuferon) or
 RBV (viramidine)].

 -  History of new hepatitis C exposure within the last 6 months

 -  Current or intended use of G-CSF and/or GM-CSF during the stud period is prohibited.
 Current use of erythropoietin (EPO) is prohibited.

 -  Suspected hypersensitivity to any interferon product or ribavirin

 -  Participation in any other clinical trial within 30 days of Screening visit 1

 -  Treatment with any investigational drug within 30 days of Screening visit 1.

 -  Any other cause for liver disease other than CHC, including but not limited to:
 hemachromatosis, Alpha-1 antitrypsin deficiency, Wilson's disease, Autoimmune
 hepatitis, Alcoholic liver disease, Non-alcoholic steatohepatitis (NASH), Drug-related
 liver disease

 -  Known coagulopathies including hemophilia

 -  Known hemoglobinopathies

 -  Known G6PD deficiency

 -  Known coinfection with HIV and/or HBV

 -  Evidence of active or suspected malignancy or a history of malignancy within the last
 five years (with the exception of adequately treated basal cell carcinoma of the
 skin).

 -  Evidence of decompensated liver disease such as history or presence of ascites,
 bleeding varices or hepatic encephalopathy

 -  Subjects with organ transplants other than cornea or hair transplant

 -  Any Known preexisting medical condition, that could interfere with the subject's
 participation in and completion of the study including, but not limited to moderate to
 severe depression, or a history of severe psychiatric disorder, such as psychosis,
 suicidal ideation and/or suicidal attempt; Subjects with a past history or current use
 of lithium and/or antipsychotic drugs; CNS trauma or seizure disorder; Clinically
 significant ECG abnormalities and/or significant cardiovascular dysfunction within the
 past 2 years prior to Screening ; Poorly controlled diabetes mellitis; Chronic
 pulmonary disease (COPD); Immunologically mediated disease such as inflammatory bowel
 disease, rheumatoid arthritis, idiopathic thrombocytopenia purpura, systemic lupus
 erythematosus, autoimmune hemolytic anemia, scleroderma, severe psoriasis or
 symptomatic thyroid disorder; Any medical condition requiring, or likely to require
 during the course of the study, chronic systemic administration of steroids: History
 of, or active clinical gout.

 -  Substance abuse, such as alcohol (>80 g/day), IV drugs and inhaled drugs. Subjects
 with a history of substance abuse must have abstained from the abuse substance for at
 least one year. Subjects with clinically significant retinal abnormalities

 -  Any other condition which in the opinion of the investigator would make the subject
 unsuitable for enrollment, or could interfere with the subject participating in and
 completing the protocol

 -  Subjects who are part of the staff personnel directly involved with the study

 -  Subjects who are immediate family members of the investigational study staff