The Role of FGL2-FcgammaRIIB Inhibitory Pathway in Human Viral Hepatitis

November 28, 2016 updated by: University Health Network, Toronto
Viral hepatitis is a serious world health problem affecting over 1 billion people worldwide. Presently the lack of highly effective treatments results in many patients requiring liver transplantation or death. The investigators have defined the role of a unique molecule FGL2 and its receptor fc-gammaR and its role in the pathogenesis of both experimental and human hepatitis. The studies proposed in the present proposal will test the hypothesis that measuring levels of fgl2 in plasma will identify individuals that will go on to develop chronic disease and inhibition of binding of fgl2 to its receptor will allow the host with both acute and chronic disease to develop an appropriate immune response and clear the virus. The studies will provide rationale for generation of new therapies to improve the treatment of patients with acute and chronic viral hepatitis by targeting fgl2.

Study Overview

Status

Completed

Conditions

Detailed Description

Hepatitis C Virus (HCV) infection affects more than 200 million individuals worldwide. Only a fraction of infected individuals clear the virus, whereas the majority (70%) develops chronic infection. The current standard of care, pegylated interferon/ ribavirin (pegIFN/rib) is effective in only 50% of patients. Patients who fail anti-viral therapy gradually progress to end-stage liver disease and hepatocellular cancer; which can only be cured by a liver transplant. The reasons for treatment failure are unclear but involve both viral and host factors. One significant factor may be impaired T cell function. Chronic HCV infection is associated with functionally impaired or exhausted cytotoxic T lymphocytes (CTLs), with decreased anti-viral cytokine production, cytotoxicity and proliferative capacity. The investigators recently showed that many patients who fail treatment have elevated frequencies of CD4+CD25+Foxp3+regulatory T cells (Tregs) producing the novel fibrinogen-like-protein 2 (FGL2/fibroleukin) which appears to impair HCV specific immune responses. Binding of FGL2 to the FcγRIIB receptor leads to inhibition of dendritic cell (DC) maturation, B cell apoptosis and inhibition of development of effective CD4+and CD8+T and B cell anti-viral responses. In HCV, increased levels of secreted FGL2 may suppress anti-viral immune responses and promote disease progression.

Hypothesis: HCV suppresses innate and adaptive anti-viral immune responses through the FGL2-FcγRIIB inhibitory pathway. Inhibition of this pathway will restore effective virus-specific immunity and lead to successful viral eradication.

Significance: These studies will establish the importance of FGL2-FcγRIIB inhibitory pathway in the pathogenesis of HCV chronic infection and provide a novel therapeutic approach to improve virus eradication and long term patient outcomes.

Study Type

Observational

Enrollment (Actual)

106

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • Ontario
      • Toronto, Ontario, Canada, M4G 2C4
        • University Health Network

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 70 years (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

Patients being followed by hepatologists and considering treatment of Hepatitis C vs controls derived from potential live liver donors (for transplant)

Description

Inclusion Criteria:

  1. Able and willing to give written informed consent
  2. Willing to follow the study protocol
  3. Between >18 and <70 years of age, both gender
  4. No history of active alcohol or drug abuse
  5. Adequate contraception for both gender
  6. Diagnosis of chronic HCV infection based on two positive serology tests.
  7. Pre- and post treatment viral load data must be available
  8. Naïve to antiviral treatment
  9. A pre treatment liver biopsy should be available for all patients

Exclusion Criteria:

  1. All other genotypes than genotype 1
  2. Less than 18 or greater than 70 years of age
  3. Pregnancy
  4. Co-infection with HBV (hepatitis B virus), HDV (Hepatitis Delta virus) or HIV co-infection
  5. Coexistence of liver disease of other etiology (autoimmune, alcohol)
  6. Evidence of hepatocellular carcinoma

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
patients
Chronic HCV patients who undergo antiviral therapy
Healthy controls
healthy controls who are willing to give blood and liver tissue samples

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
To correlate plasma levels of FGL2 in patients who undergo antiviral therapy for chronic HCV infection with clinical outcome
Time Frame: 6 months after end of antiviral treatment
6 months after end of antiviral treatment

Secondary Outcome Measures

Outcome Measure
Time Frame
to correlate levels of FGL2 to numbers and immune function of CD4+ and CD8+ T cells, and DC activity
Time Frame: at all timepoints; pre-treatment, at wks 4, 12 and 48 of treatment and 6 months after end of treatment
at all timepoints; pre-treatment, at wks 4, 12 and 48 of treatment and 6 months after end of treatment

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Health Network, Toronto

Investigators

  • Principal Investigator: Nazia Selzner, MD PhD, University Health Network, Toronto

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2014

Primary Completion (Actual)

May 1, 2016

Study Completion (Actual)

September 1, 2016

Study Registration Dates

First Submitted

October 12, 2012

First Submitted That Met QC Criteria

October 17, 2012

First Posted (Estimate)

October 22, 2012

Study Record Updates

Last Update Posted (Estimate)

November 29, 2016

Last Update Submitted That Met QC Criteria

November 28, 2016

Last Verified

November 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 12-5129-BE

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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