Retreatment of Chronic Hepatitis C Non-responders With Pegylated Interferon Alpha Plus Ribavirin Plus Pioglitazone

Study Overview
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Brief Summary
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The aim of this study is to investigate the efficacy and safety of an insulin-sensitizer (Actos) added to a standard Pegasys/Copegus combination therapy of chronic hepatitis C in patients who have previously failed a pegylated-interferon-alpha / ribavirin combination without the insulin sensitizer. The primary endpoint is the initial virological response (level of HCV RNA in serum) as evaluated after 12 weeks of triple therapy.

Detailed Description
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Insulin resistance and diabetes are major disease modifiers in chronic hepatitis C, as they increase liver fibrogenesis and reduce the rate of response to antivirals. Regarding the latter, a previous study showed that a sustained virological response (SVR) occurred in about one third of patients with genotype 1 and insulin resistance (measured as homeostasis assessment of insulin resistance, HOMA-IR > 2) vs. two thirds of genotype 1 patients without insulin resistance. These findings were independently confirmed by other studies and extended to non-responders with genotypes 2, 3 and 4. Thus, we suggested that insulin resistance should be corrected in patients with chronic hepatitis C not responding to currently available antiviral treatment, in order to improve response to retreatment. The modalities of this intervention, however, have not been established. In addition, the optimal HOMA-IR score to be attained has not been identified. To assess this point, we planned a prospective, multicenter study to investigate the efficacy and safety of the insulin-sensitizer pioglitazone (ActosTM, Takeda Pharma AG, Lachen, Switzerland) 15 mg QD, added to the pegylated interferon-α2a (PEG-IFN-α2a) (PegasysTM, Roche Pharma Schweiz AG, Reinach, Switzerland) 180 μg QW/ribavirin (CopegusTM, Roche) 1000-1200 mg QD combination therapy in chronic hepatitis C patients who had previously failed to respond (i.e. had detectable serum HCV RNA after 12 weeks of therapy) to a pegylated interferon-α/ribavirin combination without the insulin-sensitizer. All patients had a baseline HOMA-IR score >2 as additional inclusion criterion, because this was the threshold discriminating responders from non-responders in previous works. Diabetic patients were excluded.

Official Title
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A Pilot Study of Treatment With Pegylated Interferon-Alpha2a, Ribavirin and Insulin Sensitizer Pioglitazone of Insulin Resistance (With the Exception of Diabetes) in Hepatitis C Virus Infection (The INSPIRED HCV Study)

Conditions
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Chronic Hepatitis C

Intervention / Treatment
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* Drug: Pioglitazone
* Drug: Interferon Alfa-2a
* Drug: Ribavirin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed chronic hepatitis C as per liver biopsy performed during the 12 months prior to enrollment (except patients with histologically proven cirrhosis or a Actitest/Fibrotest assay, or a Fibroscan performed during the 12 months prior to enrollment) HCV RNA in serum >600 IU/ml elevated ALT HCV genotypes 1, 2, 3 or 4 failure to respond to a prior treatment with a pegylated interferon alpha + ribavirin HOMA score > 2.00 documentation that sexually active female patients of childbearing potential are practicing adequate contraception (intrauterine device, oral contraceptives, progesterone implanted rods, medroxyprogesterone acetate, surgical sterilization plus a barrier method [diaphragm + spermicide] or monogamous relationship with a male partner who has had a vasectomy or is using a condom + spermicide) during the treatment period and for 6 months after discontinuation of therapy. A serum pregnancy test obtained at entry prior to the initiation of treatment must be negative. Female patients must not be breast feeding documentation that sexually active male patients are practicing acceptable methods of contraception (vasectomy, use of a condom + spermicide, monogamous relationship with a female partner who practices an acceptable method of contraception) during the treatment period and for 6 months after discontinuation of therapy willingness and capability to give written informed consent and to comply with the requirements of the trial Exclusion Criteria: history of diabetes (ADA definition) history of significant cardiovascular disease (NYHA III) including but not limited to uncontrolled hypertension, angina pectoris, myocardial infarction, coronary artery surgery and congestive heart failure HBsAg and/or HIV auto-immune disease, including auto-immune hepatitis alcohol consumption exceeding 40 grams per day hepatocellular carcinoma renal insufficiency (serum creatinine levels above 200 micromol/l) unconjugated bilirubin blood level > 100 micromol/l glutamyl transferase > 20 times the ULN prothrombin time < 60% of control (except in case of oral anti-coagulant therapy) neutrophil count < 1.5 G/L platelet count < 70 G/L hemoglobin <120 g/L organ or bone marrow transplantation current neoplasm and/or anti-tumor chemotherapy current hepatic arterial thrombosis pregnant or breast feeding women; child bearing potential women without adequate contraception throughout the course of therapy psychosis or anti-depressant therapy for uncontrolled clinical depression epilepsy clinically significant retinal abnormalities thyroid dysfunction drug abuse or substitution therapy during the 12 months prior to inclusion interstitial pneumonitis previous auto-immune hemolysis and all causes of chronic hemolysis

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention<br>Pioglitazone 15 mg QD + pegylated interferon Alfa-2a 180 μg QW + ribavirin 1000-1200 mg QD for 12 weeks, to be continued to a total of 48 weeks in case of complete early virological response, defined as undetectable serum HCV RNA after 12 weeks of triple therapy | Drug: Pioglitazone<br>* Increase early virological response to pegylated interferon alpha plus ribavirin by increasing insulin sensitivity<br>* Other names: Actos;Drug: Interferon Alfa-2a<br>* Standard of care for chronic hepatitis C<br>* Other names: Pegasys;Drug: Ribavirin<br>* Standard of care for chronic hepatitis C<br>* Other names: Copegus;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Early virological response |  | Week 12 of triple combined therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Undetectable serum HCV RNA after 4, 24 weeks and 48 weeks of therapy |  | Week 2, 24 and 48 of therapy | 
| Changes (vs. baseline) of body weight, HOMA score, after 4, 12 and 48 weeks of therapy and after 24 weeks of follow-up |  | Weeks 4, 12 and 48 of therapy | 
| Improvement (vs. baseline) of glucose tolerance parameters after 12 and 48 weeks of therapy and after 24 weeks of follow-up |  | Weeks 12 and 48 of therapy; week 24 of FU | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic hepatitis C, Insulin resistance, Pioglitazone, Non-responders