Clinical trial NCT01567540: A Pilot Study Evaluating Safety of Sitagliptin Combined With Peg-IFN Alfa-2a + Ribavirin in Chronic Hepatitis C Patients
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Hepatitis C
Keywords: Chronic Hepatitis C
Interferon protein 10
Chemokine gradients
Sitagliptin
Lead sponsor: Institut National de la Santé Et de la Recherche Médicale, France
Sponsor class: OTHER_GOV
First posted: 2012-03-30
Enrollment: 3
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility 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

Primary outcomes:
measure: Safety (Number of adverse events, Toxicity grade > 3)
timeFrame: After Day 1 until the end of the trial, i.e. a duration of 15 weeks for each patient
Secondary outcomes:
measure: Change in Viral Load as compared to baseline
timeFrame: week 1, 2, 3 of sitagliptin monotherapy; week 2, 4, 12 of triple therapy
measure: Metabolic studies: Oral glucose tolerance will be assessed
timeFrame: baseline, week 1 of sitagliptin monotherapy; week 2 of triple therapy
measure: Immunologic study
timeFrame: baseline, week 1 and 3 of sitagliptin monotherapy; week 1, 2, 4, 12 of triple therapy
measure: Immunologic study
timeFrame: baseline; week 1 and 3 of sitagliptin monotherapy; week 1, 2, 4, 12 of triple therapy
measure: Immunologic study
timeFrame: baseline, week 1 and 3 of sitagliptin monotherapy; week 1, 2, 4, 12 of triple therapy.
Other outcomes:
Locations:
city: Argenteuil
country: France
facility: Centre Hospitalier Victor Dupuy
city: Créteil
country: France
facility: Centre Hospitalier Intercommunal Créteil
city: Créteil
country: France
facility: Henri Mondor Hospital
city: Paris
country: France
facility: Cochin Hospital
Study officials:
affiliation: Institut National de la Santé Et de la Recherche Médicale, France
name: Matthew L. ALBERT, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: