TG4040 in Patients With Chronic HCV
TG4040 in Patients With Chronic HCV
The purpose of this study is to evaluate the safety and effectiveness of an investigational
 vaccine (TG4040) to prevent hepatitis C virus (HCV) infection. The primary goal of this study
 is to determine the safety of increasing doses of TG4040 versus placebo (an inactive
 substance) in subjects chronically infected with HCV. Approximately 85 patients, ages 18-65
 years, with chronic HCV infection will be enrolled in this study at two sites, Saint Louis
 University and Cincinnati Children's Hospital. Volunteers will receive doses of TG4040 and
 placebo by injections into the thigh on different days, depending on which study group they
 belong to. Safety will be checked before doses are increased, and each participant will
 receive the study vaccine, TG4040, at some point during the study. Each subject will
 participate in the study for 8 months. This study may help produce a new vaccine that would
 improve control of HCV.
The purpose of this study is to assess the safety, immunogenicity, and efficacy of the
 hepatitis C virus (HCV) vaccine, TG4040, in outpatients with chronic hepatitis C. The study
 will be conducted in two parts at two DMID Vaccine Treatment and Evaluation Unit (VTEU)
 Centers: Saint Louis University and Cincinnati Children's Hospital. Up to 85 subjects with
 chronic hepatitis C will receive the test vaccine via subcutaneous injection into the thigh.
 In Part I of this study, 18 subjects will be randomized to 1 of 3 groups. At the initial
 dosing time point, Group One will receive 10 to the 6th power particle-forming units (PFU)
 and Groups Two & Three will receive saline placebo in 3 doses on Days 0, 7, and 14. After
 Safety Monitoring Committee (SMC) review, Group Two will receive a higher dose of TG4040 (10
 to the 7th power PFU) and Groups One & Three will receive saline placebo. After a further SMC
 review, Group Three will receive a higher dose of TG4040 (10 to the 8th power PFU) and Groups
 One & Two will receive saline placebo. (Each subject will therefore be treated with one
 course of TG4040 and receive two courses of placebo). In Part II of this study, 60 subjects
 (30 non-responders or relapse subjects-Part IIa, and 30 treatment naïve, Part IIb) will be
 randomized into two groups to receive either 10 to the 8th power PFU (or the highest
 tolerated dose) of TG4040 or saline placebo at two dosing time points with a crossover
 design. (Each subject will therefore be vaccinated with the same dose of TG4040 and also
 receive a course of placebo.) Subjects enrolled in either Part I or Part II of the study will
 participate for 8 months. The primary objective for Part I of the study is to assess the
 safety of escalating doses of TG4040 versus placebo administered to non-responders or relapse
 subjects with chronic hepatitis C. The secondary objective for Part I of the study is to
 assess immunogenicity of escalating doses of TG4040 versus placebo administered to
 non-responders or relapse subjects with chronic hepatitis C. The primary safety objective for
 Part II of the study is to assess the safety of the dose of TG4040 selected from Part I
 versus placebo when administered to subjects with chronic hepatitis C, either non-responders
 or relapse subjects or treatment- naïve subjects. The primary efficacy objective for Part II
 of the study is to assess antiviral activity against HCV of TG4040 versus placebo in subjects
 with chronic hepatitis C, non-responders or relapse subjects or treatment-naïve subjects,
 assessed as a 1 log reduction in serum level of HCV RNA. The secondary objective for Part II
 of the study is to assess immunogenicity of TG4040 versus placebo in subjects with chronic
 hepatitis C, non-responders or relapse subjects or treatment-naïve subjects, and correlate
 this with reductions in serum levels of HCV RNA. For Part I, the primary outcome measures are
 related to safety and include measures of reactogenicity, changes in blood counts and hepatic
 panel. For Part II, the primary outcome variable is a change in serum levels of HCV RNA
 compared to baseline. A decrease in more than 1 log from baseline will be considered a
 significant effect. In addition to this, other primary outcome measures will also include
 safety and include measures of reactogenicity, changes in blood counts and hepatic panel.
 Secondary outcomes measures include those tests aimed at assessing immunogenicity of the
 vaccine candidate and include, but are not limited to, development of anti-HCV using standard
 commercial assays and research assays, developed of enhanced in vitro T cell reactivity when
 stimulated with HCV antigens.
Inclusion Criteria:

 Part I and Part II:

 1. Informed consent obtained and signed;

 2. Male or female patients, age 18-65 years old (inclusive)

 3. Female patients will be menopausal for at least 12 months, surgically sterile or agree
 not to become pregnant from the time of study enrollment until at least 28 days after
 the administration of vaccine or placebo. A woman is considered of childbearing
 potential unless post-menopausal or surgically sterilized.

 If the volunteer is female, of childbearing potential, and sexually active, she agrees
 to use acceptable contraception. (Acceptable contraception methods are restricted to
 effective intrauterine devices (IUDs) or licensed hormonal products with use of method
 for a minimum of 30 days prior to vaccination and for the entire study period
 post-vaccination).

 Note: A woman is eligible if she is monogamous with a vasectomized male or abstinent,
 without the additional need for hormonal or barrier birth control methods upon review
 of a reproductive history.

 4. With chronic hepatitis C evidenced by:

 -  HCV RNA detectable in blood, and

 -  A liver biopsy compatible with chronic hepatitis C;

 5. Infected with HCV genotype 1;

 6. Non-cirrhotic patients, i.e. liver biopsy available within one year prior to baseline,
 excluding stage 4 fibrosis; otherwise, if no liver biopsy of less than one year is
 available, it will be performed at baseline;

 7. Patients participating in:

 -  Part I will be non-responder patients: patients having received at least 3 months
 of pegylated IFN-alpha (IFN-alpha) plus ribavirin, with currently detectable HCV
 RNA (whether or not they reach, Early Virologic Response (EVR, defined as a
 reduction of HCV RNA by at least 2 logs from baseline or negative at 12 weeks)
 and/or SVR) with > 6 months between the end of PEG IFN-alpha treatment and the
 first TG4040 injection;

 -  Part IIa will be either non-responder or relapser patients. Part IIb will be
 treatment-naïve patients: patients who have never received IFN-based treatment

 8. Patients must have compensated liver disease, defined through use of the Child-Pugh
 scoring system with:

 -  Features of low serum albumin, prolonged prothrombin time, raised bilirubin,
 ascites and hepatic encephalopathy are scored and patients assigned to Child-Pugh
 class A, B or C, the later two being decompensated. Only patients with
 compensated liver disease will be enrolled.

 -  No history of ascites, hepatic encephalopathy or bleeding from esophageal varices
 laboratory tests values:

 -  Serum bilirubin and international normalized ratio (INR) values <1.2 (except in
 patients with Gilbert syndrome where serum bilirubin may be as high as 3.0 mg/dL)

 -  Serum alanine aminotransferase (ALT) < 5 fold the upper limits of normal (ULN)
 and

 -  Other laboratory parameters of grade 0 or 1 (CTC criteria)

 Exclusion Criteria:

 Part I and Part II:

 1. Co-infection with HBV (indicated by the presence of hepatitis B surface antigen
 (HBsAg) in serum) or HIV (anti-HIV in serum); patients with HIV positive sexual
 partner (by history) will not be included;

 2. Current HCV therapies through out the trial period

 3. Current alcohol abuse or drug addiction that in the opinion of the investigator may
 interfere with the subject's ability to comply with trial procedures.

 4. History of immunodeficiency

 5. Known or suspected impairment of immunologic function including moderate to severe
 kidney impairment

 6. Malignancy within the last 5 years, not including squamous cell skin cancer or basal
 cell skin cancer unless at the vaccination site or history of skin cancer at the
 vaccination site

 7. Significant cardiac disease, evidenced by:

 -  History of myocardial infarction, angina, congestive heart failure,
 cardiomyopathy, stroke or transient ischemic attack, chest pain or shortness of
 breath on activity, or other heart conditions under the care of a physician

 -  Baseline ECG showing clinically significant abnormalities (e.g., all kinds of
 advanced atrioventricular block or intraventricular block with QRS >120msec, QTc
 >460 msec, or frequent premature atrial contractions, atrial fibrillation or
 other atrial arrhythmias, > ventricular couplets or ST-T wave abnormalities
 diagnostic of myocardial ischemia or prior myocardial infarction. EKGs will be
 interpreted by an identified cardiologist at Saint Louis University prior to
 enrollment.

 -  Baseline echocardiogram showing clinically significant abnormalities including
 valvular disease or contractile dysfunction.

 -  Ten percent or greater risk of developing a myocardial infarction or coronary
 death within the next 10 years using the National Cholesterol Education Program's
 risk assessment tool (http://hin.nhlbi.nih.gov/atpiii/calculator.asp)

 NOTE: This criterion applies only to subjects 20 years of age and older AND only if at
 least one of the following apply:

 A) have smoked a cigarette in the past month, and/or B) have hypertension (defined as
 systolic blood pressure >140 mm Hg) or are on antihypertensive medication, and/or C)
 have a family history of coronary heart disease in male first-degree relative (father
 or brother) < 55 years of age or a female first-degree relative (mother or sister) <
 65 years of age.

 8. Current use of immunosuppressive medication; Corticosteroid nasal sprays, Inhaled
 steroids for asthma and/or topical steroids are permissible. Persons taking short
 courses of oral steroids for conditions such as poison ivy will need to wait a period
 of 2 weeks after completion of the steroids to begin vaccination.

 9. History of any one of the following:

 -  Suicide attempt or hospitalization for depression within the past five years.

 -  Any current (within 6 months) severe or poorly-controlled psychiatric disorder
 (e.g., depression, schizophrenia, bipolar illness, obsessive-compulsive disorder,
 severe anxiety, personality disorder).

 -  The following patients must be excluded unless they are assessed and followed by
 a psychiatrist or other mental health professional who pre-approves their study
 participation:

 -  Patients who have had a suicide attempt and/or hospitalization for depression
 more than 5 years ago.

 -  Patients who have had a severe or poorly-controlled psychiatric disorder (e.g.,
 depression, schizophrenia, bipolar illness, obsessive-compulsive disorder, severe
 anxiety, personality disorder) more than 6 months ago but less than 5 years ago.

 10. Receipt of any inactivated vaccine 14 days prior to vaccination or for the duration of
 the study

 11. Receipt of any live attenuated vaccine within 30 days prior to vaccination or for the
 duration of the study

 12. Receipt of any MVA vaccine in the last five years

 13. Use of any experimental agent within 30 days prior to vaccination or for the duration
 of the study

 14. Receipt of blood products or immunoglobulin within six months prior to vaccination

 15. Donation of a unit of blood within 56 days prior to vaccination or for the duration of
 the study following the first vaccination

 16. Acute febrile illness (>100.5 degrees F) on the day of vaccination

 17. Pregnant or lactating women

 18. Any condition that, in the opinion of the investigator, might interfere with study
 objectives

 19. Known allergy to MVA vaccine

 20. Receipt of antiviral drugs such as alpha interferon or ribavirin

 21. Other laboratory parameters of grade 2 or more

 22. Study personnel engaged in the blinding of this study