A Pilot Study Evaluating Safety of Sitagliptin Combined With Peg-IFN Alfa-2a + Ribavirin in Chronic Hepatitis C Patients
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.
|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|
- 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 ]
- 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).
|Study Start Date:||March 2013|
|Study Completion Date:||January 2014|
|Primary Completion Date:||January 2014 (Final data collection date for primary outcome measure)|
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).
100 mg Sitagliptin daily for 15 weeks
Please refer to this study by its ClinicalTrials.gov identifier: NCT01567540
|Centre Hospitalier Victor Dupuy|
|Argenteuil, France, 95100|
|Henri Mondor Hospital|
|Créteil, France, 94010|
|Centre Hospitalier Intercommunal Créteil|
|Créteil, France, 94010|
|Paris, France, 75014|
|Principal Investigator:||Matthew L. ALBERT, MD, PhD||Institut National de la Santé Et de la Recherche Médicale, France|