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

Sponsor

Tacere Therapeutics, Inc. (Industry)

Overall Status

Completed

CT.gov ID

NCT01899092

Collaborator

(none)

Enrollment

Locations

Arm

Duration (Months)

2.3

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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 Once the study drug is given, it cannot be withdrawn.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.

Condition or Disease	Intervention/Treatment	Phase
Hepatitis C	Drug: TT-034	Phase 1/Phase 2

Detailed Description

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

9 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Jan 1, 2014

Actual Primary Completion Date :

Sep 1, 2016

Actual Study Completion Date :

Nov 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Escalating Dose of TT-034 The study contains one dose escalation arm with active drug.	Drug: TT-034 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.

Arm

Intervention/Treatment

Experimental: Escalating Dose of TT-034

The study contains one dose escalation arm with active drug.

Drug: TT-034

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.

Outcome Measures

Primary Outcome Measures

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

To assess the activity of TT-034 on the viral load of subjects with CHC receiving single escalating doses of TT-034 [6 months]

Other Outcome Measures

To determine the maximum tolerable dose or the optimal efficacy dose (whichever comes first) [6 months]
To determine the viral load [6 months]
To assess the presence of viral escape mutants in subjects with detectable viral load after receiving TT-034 [6 months]
To monitor TT-034 vector DNA levels and shRNA expression in the target organ (liver) after dosing with TT-034 [3 weeks]
To monitor TT-034 vector DNA levels and shRNA expression peripherally (in blood) after dosing with TT-034 [6 months]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCSD Antiviral Research Center	San Diego	California	United States	92103
2	Duke Clinical Research Institute	Durham	North Carolina	United States	27710
3	The Liver Institute at Methodist Dallas	Dallas	Texas	United States	75203
4	The Texas Liver Institute	San Antonio	Texas	United States	78215