A Pilot Study Evaluating Safety of Sitagliptin Combined With Peg-IFN Alfa-2a + Ribavirin in Chronic Hepatitis C Patients
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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 |
- 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).
| Estimated Enrollment: | 10 |
| Study Start Date: | March 2013 |
| Estimated Study Completion Date: | December 2015 |
| Estimated Primary Completion Date: | February 2015 (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 |
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| Contact: Matthew L. ALBERT, MD, PhD | +33 (0) 1 45 68 85 52 | matthew.albert@pasteur.fr |
| France | |
| Centre Hospitalier Victor Dupuy | Not yet recruiting |
| Argenteuil, France, 95100 | |
| Contact: Philippe RENARD, MD +33 (0) 1 34 23 16 74 philippe.renard@ch-argenteuil.fr | |
| Principal Investigator: Philippe RENARD, MD | |
| Henri Mondor Hospital | Not yet recruiting |
| Créteil, France, 94010 | |
| Contact: Christophe HEZODE, MD +33 (0) 1 49 81 23 25 christophe.hezode@hmn.aphp.fr | |
| Principal Investigator: Christophe HEZODE, MD | |
| Centre Hospitalier Intercommunal Créteil | Recruiting |
| Créteil, France, 94010 | |
| Contact: Isabelle ROSA, MD +33 (0) 1 45 17 54 80 isabelle.rosa@chicreteil.fr | |
| Principal Investigator: Isabelle ROSA, MD | |
| Cochin Hospital | Recruiting |
| Paris, France, 75014 | |
| Contact: Stanislas POL, MD, PhD +33 (0) 1 58 41 30 01 stanislas.pol@cch.aphp.fr | |
| Principal Investigator: Stanislas POL, MD, PhD | |
| Sub-Investigator: Vincent MALLET, MD, PhD | |
| 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: | May 14, 2013 |
| 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 May 21, 2013