Safety and Efficacy Study of Single Doses of TT-034 in Patients With Chronic Hepatitis C

Study Overview
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Brief Summary
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The study is a first in man, dose escalation study that will measure the safety and efficacy of TT-034 in the treatment of patients with chronic hepatitis C. The study is divided into 5 dose levels. Subjects will be given a single dose delivered by IV infusion. The subjects will be monitored and the data analyzed. After a set time, between 6 and 10 weeks depending on the dose level, the next set of subjects will be dosed. The study drug is a gene therapy treatment that produces molecules that destroy the Hepatitis C virus (HCV) in infected cells. Once the study drug is given, it cannot be withdrawn. Additionally, once an individual receives a dose, he or she will not be able to receive a second dose, but will remain eligible to receive most other HCV treatments.

Detailed Description
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This is a first-time use of a method of therapy designed to transfer anti-HCV genetic sequences into the hepatocytes of subjects infected with HCV. The anti-HCV sequences will be comprised of three different short hairpin RNAs (shRNA) that have the ability to directly cleave the RNA genome of HCV by a process known as RNA interference. The transfer of the anti-HCV sequences will be accomplished using a vector that was made from an adenovirus-associated virus (AAV) by removing the viral genes and replacing them with a non-replicating genetic sequence that produces three different shRNA that target three different regions within the HCV genes. This type of vector has been used in other clinical trials in order to transduce the hepatocytes of subjects who suffer from hemophilia.

Official Title
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A Phase I,II Open-Label Dose Escalation Study to Evaluate the Safety and Efficacy of Single Doses of TT-034 for Subjects With Chronic Hepatitis C (CHC) Infection

Conditions
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Hepatitis C

Intervention / Treatment
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* Drug: TT-034


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must a history of chronic HCV infection defined as documented HCV genotype 1 infection for at least 6 months. Subjects must have: Documented failure to respond to prior treatment or relapse with a combination of peg-interferon (peg-IFN), ribavirin (RBV), and either boceprevir or telaprevir, OR a combination of peg-IFN and ribavirin or Subject is ineligible or unwilling to receive a combination of peg-IFN, RBV, and either boceprevir or telaprevir. Female subjects have to be of non-childbearing potential, defined as meeting any of the following criteria: Female subjects over the age 60. Female subjects aged 45-60 years old must be amenorrhoeic for at least 2 years and must have serum follicle stimulating hormone (FSH) levels > 30 IU/L. Female subjects with hysterectomy or bilateral oophorectomy. All female subjects must have a negative serum pregnancy test at Screening and a negative urine pregnancy test at Baseline. Male subjects and their partners must be willing to comply with the following requirements to use 2 methods of effective contraception: Male subjects with a vasectomy must use a condom. Without a vasectomy, male subjects must use a condom. The female must be sterile or willing to use an additional form of contraception. Baseline HCV RNA level of > 100,000 IU/mL and: No evidence of cirrhosis at Screening At least 3 months since prior therapy for HCV A willingness to enroll in a 5 year follow-up safety study Exclusion Criteria: Body mass index < 18.5 or > 30 Total body weight > 80 KG Female subjects of childbearing potential (including females with tubal ligation) or women who are pregnant or nursing Male subjects who are unwilling to provide the required semen samples Presence of nAb levels to AAV8 that abrogate AAV8 transduction Severe Liver disease Hepatocellular carcinoma (HCC) or suspicion of HCC Coronary artery disease Platelet count of < 150 x 109/L or Creatinine ≥ 1.5 mg/dL at Screening Hypertension with systolic blood pressure consistently ≥ 130 mmHg or diastolic blood pressure consistently ≥ 90 mmHg Screening examinations indicative of possible occult malignancy unless cancer has been excluded Family history of colon cancer in any first-degree relative unless ruled out by colonoscopy Positive for human immunodeficiency virus 1 (HIV1) or HIV2 antibody Co-infection with hepatitis B virus History of autoimmune disease Renal impairment Hospitalization for liver disease within 60 days of Screening Use of drugs of abuse in the prior 3 months Other concomitant disease or condition likely to significantly decrease life expectancy or cancer Treatment with an investigational drug within 6 months preceding the first dose of trial medication Received an AAV vector previously or any other gene transfer agent in the previous 6 months History of cardiac abnormalities, as assessed at the Screening Visit Twelve-lead ECG demonstrating QTcB > 465 ms at Screening Chronic hepatic diseases Evidence of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, psychiatric, neurologic, or allergic diseases. Evidence of autoimmune disease or pre-existing autoimmune or antibody-mediated diseases Use of immunosuppressive medications within 6 months before the entry into this study, except for inhaled or topical corticosteroids

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Escalating Dose of TT-034<br>The study contains one dose escalation arm with active drug. | Drug: TT-034<br>* The study drug will be given as a single dose IV infusion on Day 1. 5 different dose levels corresponding to the 5 cohorts of the study will be given.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary objective is to assess the safety and tolerability of single escalating doses of TT-034 administered IV as a single infusion to subjects with CHC. |  | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the activity of TT-034 on the viral load of subjects with CHC receiving single escalating doses of TT-034 |  | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Genotype 1, Chronic Hepatitis C, CHC, HCV, Hepatitis, RNAi, shRNA, ddRNAi, AAV8, AAV, Adeno-associated virus, Adeno-associated viral vectors