A Pilot Study Evaluating Safety of Sitagliptin Combined With Peg-IFN Alfa-2a + Ribavirin in Chronic Hepatitis C Patients

This study has been terminated.
(New treatments available, which prevents additional recruitment.)
Sponsor:
Information provided by (Responsible Party):
Institut National de la Santé Et de la Recherche Médicale, France
ClinicalTrials.gov Identifier:
NCT01567540
First received: March 2, 2012
Last updated: January 17, 2014
Last verified: January 2014
  Purpose

Hepatitis C infection is a major public health problem with nearly 175 million infected individuals worldwide. Although cure is possible, only 20-40% of patients spontaneously resolve infection and 40-80% of chronically infected patients (numbers vary depending on viral genotype) that receive pegylated-interferon-alfa2a/ribavirin therapy clear the virus and are sustained virologic responders (SVR). Still for many, the virus manages to circumvent natural immunity and current therapeutic strategies, resulting in significant morbidity and mortality.

To better define the distinct clinical outcomes of HCV infection many investigators have performed candidate molecules screens or transcriptional profiling in order to identify correlates of viral clearance. One molecule that has gained significant attention is CXCL10 (also known as interferon-gamma induced protein-10 or IP-10) as an important negative prognostic biomarker. Given that CXCL10 is produced by hepatocytes and mediates chemo-attraction of activated lymphocytes expressing the CXCL10-receptor, CXCR3, it is counter-intuitive as to why this chemokine correlates with therapeutic non-responsiveness.

The investigators hypothesized and have now demonstrated that CXCL10 is being cleaved in situ, resulting in the generation of an antagonist form of the chemokine. Based on the use of specific inhibitors, the investigators now propose to test whether protection of the agonist form of CXCL10 will increase responsiveness to peg-IFN-alfa2 / ribavirin therapy. This can be achieved using DPPIV inhibitors, targeting the enzyme responsible for N-terminal truncation of CXCL10. If safety is confirmed, the efficacy of DPPIV-inhibition in HCV patients will be tested in future trials that examine potential clearance benefits.


Condition Intervention Phase
Hepatitis C
Drug: Sitagliptin
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Pilot Study to Evaluate the Clinical and Biological Tolerance of Sitagliptin With Pegylated Interferon alfa2a Plus Ribavirin Combination Therapy in Chronic Hepatitis C Patients

Resource links provided by NLM:


Further study details as provided by Institut National de la Santé Et de la Recherche Médicale, France:

Primary Outcome Measures:
  • Safety (Number of adverse events, Toxicity grade > 3) [ Time Frame: After Day 1 until the end of the trial, i.e. a duration of 15 weeks for each patient ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Change in Viral Load as compared to baseline [ Time Frame: week 1, 2, 3 of sitagliptin monotherapy; week 2, 4, 12 of triple therapy ] [ Designated as safety issue: No ]
  • Metabolic studies: Oral glucose tolerance will be assessed [ Time Frame: baseline, week 1 of sitagliptin monotherapy; week 2 of triple therapy ] [ Designated as safety issue: No ]
  • Immunologic study [ Time Frame: baseline, week 1 and 3 of sitagliptin monotherapy; week 1, 2, 4, 12 of triple therapy ] [ Designated as safety issue: No ]
    Monitoring the short and long form of IP-10 as compared to the total plasma concentration (three distinct ELISA assays).

  • Immunologic study [ Time Frame: baseline; week 1 and 3 of sitagliptin monotherapy; week 1, 2, 4, 12 of triple therapy ] [ Designated as safety issue: No ]
    Plasma concentration and activity of DPPIV (measured using an ELISA and a luciferase-based bioassay, respectively).

  • Immunologic study [ Time Frame: baseline, week 1 and 3 of sitagliptin monotherapy; week 1, 2, 4, 12 of triple therapy. ] [ Designated as safety issue: No ]
    Frequency of CXCR3+ cells in circulation (monitored by FACS).


Enrollment: 3
Study Start Date: March 2013
Study Completion Date: January 2014
Primary Completion Date: January 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: DPPIV Inhibition
The study includes an initial phase of 3 weeks with administration of sitagliptin (100 mg/d) as monotherapy, followed immediately by 12 weeks of triple therapy (sitagliptin 100 mg/d combined with peg-IFN alfa-2a and ribavirin).
Drug: Sitagliptin
100 mg Sitagliptin daily for 15 weeks

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age between 18 and 70 years
  • For women, effective contraception during the trial and a negative pregnancy test (urine) before enrollment
  • Patients naïve to prior hepatitis C treatment
  • Confirmed HCV infection, based on the presence of HCV antibodies and plasma viremia allowing a measure of the circulating viral load
  • Infection with HCV genotype 1 or 4
  • Intent of treatment Alfa2 pegylated IFN-/ ribavirin

Exclusion Criteria:

  • HBV Infection
  • HIV Infection
  • Severe anemia (Hb <7-8 g / dl)
  • Renal failure (creatinine clearance <60 ml / min)
  • Taking digoxin within 6 months of starting treatment.
  • Taking immunosuppressants within 6 months of starting treatment
  • History of serious hypersensitivity reaction (such as anaphylactic shock or angioedema) to sitagliptin
  • Patients with type I and II diabetes
  • Pregnancy or absence of effective contraception
  • A person deprived of liberty by judicial or administrative decision
  • Living conditions-suggesting an inability to track all scheduled visits by the protocol
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01567540

Locations
France
Centre Hospitalier Victor Dupuy
Argenteuil, France, 95100
Henri Mondor Hospital
Créteil, France, 94010
Centre Hospitalier Intercommunal Créteil
Créteil, France, 94010
Cochin Hospital
Paris, France, 75014
Sponsors and Collaborators
Institut National de la Santé Et de la Recherche Médicale, France
Investigators
Principal Investigator: Matthew L. ALBERT, MD, PhD Institut National de la Santé Et de la Recherche Médicale, France
  More Information

No publications provided

Responsible Party: Institut National de la Santé Et de la Recherche Médicale, France
ClinicalTrials.gov Identifier: NCT01567540     History of Changes
Other Study ID Numbers: C10-54, 2011-000823-34
Study First Received: March 2, 2012
Last Updated: January 17, 2014
Health Authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)

Keywords provided by Institut National de la Santé Et de la Recherche Médicale, France:
Chronic Hepatitis C
Interferon protein 10
Chemokine gradients
Sitagliptin

Additional relevant MeSH terms:
Hepatitis
Hepatitis A
Hepatitis, Chronic
Hepatitis C
Hepatitis C, Chronic
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Flaviviridae Infections
Interferon-alpha
Interferons
Ribavirin
Peginterferon alfa-2a
Sitagliptin
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Dipeptidyl-Peptidase IV Inhibitors
Protease Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on July 26, 2014