Immunotherapy With TG4040 in Treatment-naïve Patients Chronically Infected With Hepatitis C Virus

Open-label, Dose-escalating, Phase I Study of TG4040 (MVA-HCV) in Treatment-naïve Patients Chronically Infected With Hepatitis C Virus (HCV Genotype 1)

The primary objective is to determine the safety of sub-cutaneous (SC) injections of TG4040 in non-cirrhotic, treatment-naïve patients chronically infected with HCV (genotype 1).

Patients will be sequentially treated at an escalting dose of TG4040. All patients will be followed up to at least 6 months after his/her first injection. In addition, all patients treated at the highest dose will receive a TG4040 boost injection 6 months after the first injection, and will be followed up during an additional 6-month period.

Study Overview

• Status: Completed
• Conditions: Hepatitis C, Chronic
• Intervention / Treatment: Biological: MVA-HCV (Immunotherapy)

Detailed Description

The first nine patients will be sequentially treated in three cohorts of three patients, i.e. they will receive 3 SC injections of TG4040 on Days 1, 8 and 15, at the dose of 10e6 pfu (first cohort), 10e7 pfu (second cohort), or 10e8 pfu (third cohort).

There will be a one-week safety interval between the first injection of the patients of a given cohort, and a two-week safety interval between the last injection of the last patient of a given cohort and the first injection of the first patient of the next one. There will be also a two-week safety observation period after the last injection of the last patient of the third cohort. If the dose of 10e8 pfu does not raise safety problems, then 6 patients will be further enrolled, without safety intervals between patients. They will receive 3 SC injections of TG4040 at the dose of 10e8 pfu, on Days 1, 8 and 15.

All patients will be followed up to at least 6 months after his/her first injection. In addition, all patients treated at the dose of 10e8 pfu will receive a TG4040 boost injection 6 months after the first injection, and will be followed up during an additional 6-month period.

Three additional cohorts of 9 patients will receive a boost injection either at 2, 4 or 6 months.

• Study Type: Interventional
• Enrollment (Anticipated): 42
• Phase: Phase 1

Contacts and Locations

Study Locations

• France
  • Créteil, France, 94010
    • Hôpital Henri Mondor
  • La Tronche, France, 38700
    • Hôpital A. MICHALLON
  • Lyon, France, 69288
    • Hôpital de l'Hôtel-Dieu
  • Nantes, France, 44000
    • Hôpital de l'Hôtel Dieu
  • Strasbourg, France, 67091
    • Hôpital Civil
  • Vandoeuvre, France, 54500
    • Hôpital de Brabois

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Informed consent obtained and signed;
• Male or female patients;
• With chronic hepatitis C (genotype 1) evidenced by HCV positive serology detectable for more than 6 months;
• Patients with fibrosis status graded F0 or F1 according to the METAVIR grading system; patients with a F2 fibrosis stage could be enrolled on a case-by-case basis after being sure that they have a contraindication to be treated with an IFN-based standard HCV treatment; patients with F3 or F4 fibrosis stage will not be enrolled; this will be assessed either on the liver biopsy performed less than 18 months prior to baseline or on a FibroTest® and a FibroScan® performed within 2 months prior to first TG4040 injection; in case of discordant results, a liver biopsy will be performed prior to TG4040 treatment;;
• Treatment-naïve patients: patients who have never received IFN-based treatment;

• Patients must have compensated liver disease, with:

  • No history of ascites, hepatic encephalopathy or bleeding from esophageal varices;

  • Laboratory tests values:

    • Serum alanine aminotransferase (ALT)less then 2 folds the Upper Limit of Normal (ULN);
    • Serum bilirubin and international normalized ratio (INR) values within normal range (except in patients with Gilbert syndrome where serum bilirubin may be as high as 3.0 mg/dL); and
    • Other laboratory parameters of grade 0 or 1 (CTC criteria);
• For women of child-bearing potential, i.e. with no history of hysterectomy or tubal ligation, a negative pregnancy test at study entry and adequate protection against pregnancy during the conduct of the study and until 3 months after last TG4040 injection.

Additionnal cohorts:

• Patients with high ALT level (2 folds ULN<ALT<5 folds ULN in the 2 months before inclusion) and fibrosis not higher than F2.

Exclusion Criteria:

Patients will be excluded from the study for any of the following reasons:

• Co-infection with HBV (indicated by the presence of Hepatitis B Surface Antigen (HBsAg) in serum; patients with anti-hepatitis B core antibody response (anti-HBc) will not be excluded) or HIV (anti-HIV antibodies in serum); patients with HIV positive sexual partner (by history) will not be included;
• Current HCV therapies;
• Active IV drug or alcohol abuse;

• Serious, concomitant disorder, including:

  • primary biliary cirrhosis or sclerosing cholangitis;
  • auto-immune disease such as symptomatic cryoglobulinemia, polyarthritis, multiple sclerosis; a broad auto-immune testing will be performed at baseline;
  • proven or suspected immunosuppressive disorder;
  • active systemic infection; if the patient has acute febrile illness ( > 38°C) on the day of vaccination, it will be delayed by at least one week after complete recovery;
• Malignancy within the last 5 years; patients with history of squamous cell skin cancer or basal cell skin cancer will be enrolled, unless the history of skin cancer is at the vaccination site;
• Systemic corticosteroid therapy or other immunosuppressive/immunomodulating drugs (e.g. Cyclosporine) within 2 months prior to first study drug injection; corticosteroid nasal sprays, inhaled steroids for asthma and/or topical steroids are permissible;
• Participation in another experimental protocol during the study period (last intake of investigational drug within 6 months prior to baseline);
• Breast-feeding women;
• Receipt of any inactivated vaccine 14 days prior to vaccination or for the duration of the study; receipt of any live attenuated vaccine within 30 days prior to vaccination or for the duration of the study;
• Allergy to eggs;
• Patient unable to comply with the protocol requirements;
• Any condition that, in the opinion of the investigator, might interfere with study objectives.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Safety (adverse events, vital signs, physical examination, standard laboratory tests)	regularly

Secondary Outcome Measures

Outcome Measure	Time Frame
Virology (quantification of HCV-RNA), immunology (cellular-mediated and humoral immune responses)	regularly

Collaborators and Investigators

• Sponsor: Transgene
• Investigators: Principal Investigator: Christian TREPO, MD, Hôpital de l'Hôtel-Dieu

Publications and helpful links

General Publications

• Habersetzer F, Honnet G, Bain C, Maynard-Muet M, Leroy V, Zarski JP, Feray C, Baumert TF, Bronowicki JP, Doffoel M, Trepo C, Agathon D, Toh ML, Baudin M, Bonnefoy JY, Limacher JM, Inchauspe G. A poxvirus vaccine is safe, induces T-cell responses, and decreases viral load in patients with chronic hepatitis C. Gastroenterology. 2011 Sep;141(3):890-899.e1-4. doi: 10.1053/j.gastro.2011.06.009. Epub 2011 Jun 13.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: December 1, 2006
• Primary Completion (Actual): September 1, 2009
• Study Completion (Actual): September 1, 2010

Study Registration Dates

• First Submitted: September 7, 2007
• First Submitted That Met QC Criteria: September 12, 2007
• First Posted (Estimate): September 14, 2007

Study Record Updates

• Last Update Posted (Estimate): September 3, 2010
• Last Update Submitted That Met QC Criteria: September 2, 2010
• Last Verified: September 1, 2010

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Flaviviridae Infections; Hepatitis, Viral, Human; Enterovirus Infections; Picornaviridae Infections; Hepatitis, Chronic; Hepatitis; Hepatitis A; Hepatitis C; Hepatitis C, Chronic
• Other Study ID Numbers: TG4040.01