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Study of a Novel Therapeutic Vaccine Against Hepatitis C Using Ad6NSmut and MVA-NSmut in Chronically Infected Patients (HCV004)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01701336
Recruitment Status : Completed
First Posted : October 5, 2012
Last Update Posted : August 29, 2013
European Commission
Information provided by (Responsible Party):
ReiThera Srl

Tracking Information
First Submitted Date  ICMJE August 28, 2012
First Posted Date  ICMJE October 5, 2012
Last Update Posted Date August 29, 2013
Study Start Date  ICMJE March 2012
Actual Primary Completion Date October 2012   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 3, 2012)
Number and severity of adverse events [ Time Frame: 6 months ]
Safety is assessed by the frequency, incidence and nature of adverse events and serious adverse events arising during the study. Abnormal clinical findings from medical history, examination or blood, will be assessed as to their clinical significance. All AEs occurring during the study observed by the investigator or reported by the patient, whether or not attributed to study medication, will be reported in the CRF. All AEs that result in a patient's withdrawal from the study or that are present at the end of the study, will be followed up until a satisfactory resolution occurs, or until a non-study related causality is assigned.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 3, 2012)
IFNγ ELISpot. Unit: IFNγ spot forming cells (SFC)/ million splenocytes [ Time Frame: 6 months ]
The primary assay to monitor vaccine immunogenicity is the IFNγ ELISpot. This is an established immunological assay to measure cell mediated immune response against HCV NS proteins. Immunogenicity data analysis will be based on tabulations of HCV NS-specific responses at times pointed out in the study visit flow chart. Analysis of immunogenicity data collected will be performed at the end of the study.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: October 3, 2012)
HCV-RNA. Unit: viral genomes/ml/ALT [ Time Frame: 6 months ]
Viral dynamics is determined by measuring over time both HCV-RNA levels, by commercially available quantitative assays, and Serum alanino-aminotransferase (ALT). ALT and HCV-RNA data are then fitted into a bio-mathematical model to evaluate the effects of the antiviral therapy regimens on the viral load and the infected cell decline throughout the whole treatment course.
Original Other Pre-specified Outcome Measures Same as current
Descriptive Information
Brief Title  ICMJE Study of a Novel Therapeutic Vaccine Against Hepatitis C Using Ad6NSmut and MVA-NSmut in Chronically Infected Patients
Official Title  ICMJE Phase Ib Study to Assess the Safety and Immunogenicity of a Novel HCV Vaccine, Based on the Sequential Injection of Ad6NSmut and MVA-NSmut, Given in Combination With PEG-Interferon Alfa Plus Ribavirin for Re-treatment of Chronic Hepatitis C
Brief Summary The purpose of this study is to determine whether administration of recombinant IMPs Ad6NSmut and MVA-NSmut (experimental vaccines for hepatitis C) in HCV chronically infected patients in combination with the standard Interferon/ribavirin therapy is safe and induces an immunological response.
Detailed Description

An effective antiviral T cell response can mediate HCV viral control and induce the spontaneous resolution of HCV during primary infection. This observation strongly supports the case for the development of T cell induction strategies as a potential therapy for HCV. A hallmark of persistent HCV infection, when viral loads are high, is a weak and narrowly focused HCV specific T cell response, whereas in resolved infection with undetectable viral loads robust T cell responses are detected. A very potent immunization strategy might overcome this problem and induce a strong and diversified cell mediated immune response against HCV.

The rationale of using HCV vaccine in combination with PEG-IFN/RBV is supported both, by in vitro models and by mathematical models of HCV dynamics under antiviral therapy. Studies of viral dynamics suggested that HCV RNA kinetics result from the sum of two major actions or phases: inhibition of viral production and reduction of infected cells number. The mathematical model, relying on both HCV-RNA and alanine aminotransferase (ALT) measures after PEG-IFN/RBV therapy, suggests that the elimination of infected cells by the immune system could play a major role in sustaining viral reduction. This view is in accordance with the results of a recent study showing that IFN-γ, one of the cytokines secreted by CTLs (Cytotoxic T Lymphocyte) and NK (Natural Killer) cells, is able to inhibit HCV genomic and subgenomic replication in an "in vitro" model. In the mathematical description the parameter that represents the putative "non lytic" control of HCV replication during antiviral therapy is φ, resulting from the difference π-δ0, where π and δ0 are the time constant of the second phase decay of viraemia and of the infected cells, respectively. Interestingly, the median value of parameter φ, which is inversely related to the half-life of HCV-RNA molecules in the infected cells after phase 1, was significantly higher in sustained responders than in transient responders and non responders (NR). In addition, whereas the baseline HCV-RNA production was comparable in all patients regardless of their outcome, the median value of the residual HCV-RNA production during therapy was significantly higher in NR than in responders. This data support the hypothesis that to reach a sustained response and an efficacious control of the infection, the elimination of the infected cells is more relevant than a strong inhibition of viral production. All the above considerations support the hypothesis that vaccination might be a new therapeutic opportunity to a cohort of consecutive HCV genotype 1a and 1b infected patients who failed to respond to PEG-IFN/RBV therapy. Therefore a potent induction of T cell responses in chronically infected patients might be used in combination with the current antiviral therapy in order to achieve sustained response in previously partial responders or relapsers.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Hepatitis C
Intervention  ICMJE Biological: Ad6NSmut, MVA-NSmut
2 doses Ad6NSmut at week 0 and 4, then 2 doses of MVA-NSmut at weeks 8 and 12. PEG-IFN/RBV therapy starts at week 10 after first vaccination
Other Names:
  • Ad6NSmut
  • MVA-NSmut
Study Arms  ICMJE Experimental: Unique Arm
  • Ad6NSmut
  • MVA-NSmut

    15 subjects receiving 2 doses Ad6NSmut at week 0 and 4, then 2 doses of MVA-NSmut at weeks 8 and 12. PEG-IFN/RBV therapy starts at week 10 after first vaccination

Intervention: Biological: Ad6NSmut, MVA-NSmut
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: August 28, 2013)
Original Estimated Enrollment  ICMJE
 (submitted: October 3, 2012)
Actual Study Completion Date  ICMJE February 2013
Actual Primary Completion Date October 2012   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • HCV infected with genotype-1 infection, previously treated with PEG-IFN/RBV and belonging to one of the 2 categories (partial responder and relapsers) as described above
  • Having terminated previous treatment at least 6 months before enrolment
  • Adults aged 18 to 65 years (inclusive)
  • Resident in or near the trial sites for the duration of the vaccination study
  • Able and willing (in the Investigator's opinion) to comply with all study requirements
  • For women of fertile age (with the exception of those not having heterosexual intercourses and of women with vasectomised partners) and for sexually active men (unless vasectomised), partners of sexually active women, to practice continuous effective contraception, adopting two effective contraceptive methods. Une of these methods must be a barrier contraception method (condom with spermicide, diaphragm or cervical cap). In this study oral contraceptive, considered as one of the two effective forms of contraception, may be used. These contraceptive methods must be used from the screening visit for the whole duration of study and for the 24 weeks following the latest dose of Ribavirin.
  • For women of fertile age a negative pregnancy test on the days of vaccination.
  • Elevated serum ALT, defined as higher than ULN (41 U/L for males and 33 U/L for females) and not exceeding 10x ULN.
  • Written informed consent

Exclusion Criteria:

  • Participation in another research study involving an investigational product in the 30 days preceding enrolment, or planned use during the study period
  • Prior recipients of a recombinant simian or human adenoviral vaccine
  • Serum ALT lower than ULN (41 U/L for males and 33 U/L for females) or exceeding 10x ULN
  • Advanced liver fibrosis
  • Clinical, biochemical, ultrasonographic, or liver biopsy (histology) evidence of cancer or portal hypertension
  • Any confirmed or suspected immunosuppressive or immunodeficient state, including HIV infection; asplenia; recurrent, severe infections and chronic (more than 14 days) immunosuppressant medication within the past 6 months (inhaled and topical steroids are allowed)
  • History of allergic disease or reactions likely to be exacerbated by any component of the vaccine, e.g., Kathon
  • History of clinically significant contact dermatitis
  • Any history of anaphylaxis in reaction to vaccination
  • Pregnancy, lactation or willingness/intention to become pregnant during the study
  • History of cancer (except basal cell carcinoma of the skin and cervical carcinoma in situ)
  • Suspected or known current alcohol abuse as defined by an alcohol intake of greater than 42 units every week
  • Current suspected or known injecting drug abuse
  • In case of history of drug and/or alcool abuse, it is necessary the abuse was terminated at least two years before the enrollment.
  • Seropositive for hepatitis B surface antigen (HBsAg)
  • Seropositive for HIV (antibodies to HIV) at screening
  • Any other significant disease, disorder or finding, which, in the opinion of the Investigator, may either put the patient at risk because of participation in the study, or may influence the result of the study, or the patient's ability to participate in the study
  • Seropositive for human adenovirus 6 (Ad6) neutralising antibodies at titres >200 at screening
  • Any other finding which in the opinion of the investigators would significantly increase the risk of having an adverse outcome from participating in the protocol
  • Individuals who have had a temperature >38°C in the 3 days preceding vaccination.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Italy
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT01701336
Other Study ID Numbers  ICMJE HCV004
2010-022700-49 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party ReiThera Srl
Study Sponsor  ICMJE ReiThera Srl
Collaborators  ICMJE European Commission
Investigators  ICMJE
Study Chair: Ferruccio Bonino, Prof. Azienda Ospedaliera Universitaria. Università di Pisa. Italy
Principal Investigator: Maurizia Brunetto, Dr. Azienda Ospedaliera Universitaria. Università di Pisa. Italy
PRS Account ReiThera Srl
Verification Date August 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP