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

Primary Purpose

Chronic Hepatitis C

Status
Completed
Phase
Phase 2
Locations
Switzerland
Study Type
Interventional
Intervention
Pioglitazone
Interferon Alfa-2a
Ribavirin
Sponsored by
University Hospital, Geneva
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Chronic Hepatitis C focused on measuring Chronic hepatitis C, Insulin resistance, Pioglitazone, Non-responders

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Service de Gastroentérologie et d'Hépatologie, University Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Intervention

Arm Description

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

Outcomes

Primary Outcome Measures

Early virological response

Secondary Outcome Measures

Undetectable serum HCV RNA after 4, 24 weeks and 48 weeks 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
Improvement (vs. baseline) of glucose tolerance parameters after 12 and 48 weeks of therapy and after 24 weeks of follow-up

Full Information

First Posted
February 8, 2007
Last Updated
May 27, 2015
Sponsor
University Hospital, Geneva
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1. Study Identification

Unique Protocol Identification Number
NCT00433069
Brief Title
Retreatment of Chronic Hepatitis C Non-responders With Pegylated Interferon Alpha Plus Ribavirin Plus Pioglitazone
Official Title
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)
Study Type
Interventional

2. Study Status

Record Verification Date
May 2015
Overall Recruitment Status
Completed
Study Start Date
January 2007 (undefined)
Primary Completion Date
December 2007 (Actual)
Study Completion Date
January 2008 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University Hospital, Geneva

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Hepatitis C
Keywords
Chronic hepatitis C, Insulin resistance, Pioglitazone, Non-responders

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
5 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Intervention
Arm Type
Experimental
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
Pioglitazone
Other Intervention Name(s)
Actos
Intervention Description
Increase early virological response to pegylated interferon alpha plus ribavirin by increasing insulin sensitivity
Intervention Type
Drug
Intervention Name(s)
Interferon Alfa-2a
Other Intervention Name(s)
Pegasys
Intervention Description
Standard of care for chronic hepatitis C
Intervention Type
Drug
Intervention Name(s)
Ribavirin
Other Intervention Name(s)
Copegus
Intervention Description
Standard of care for chronic hepatitis C
Primary Outcome Measure Information:
Title
Early virological response
Time Frame
Week 12 of triple combined therapy
Secondary Outcome Measure Information:
Title
Undetectable serum HCV RNA after 4, 24 weeks and 48 weeks of therapy
Time Frame
Week 2, 24 and 48 of therapy
Title
Changes (vs. baseline) of body weight, HOMA score, after 4, 12 and 48 weeks of therapy and after 24 weeks of follow-up
Time Frame
Weeks 4, 12 and 48 of therapy
Title
Improvement (vs. baseline) of glucose tolerance parameters after 12 and 48 weeks of therapy and after 24 weeks of follow-up
Time Frame
Weeks 12 and 48 of therapy; week 24 of FU

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Francesco Negro, Prof
Organizational Affiliation
University of Geneva, Switzerland
Official's Role
Principal Investigator
Facility Information:
Facility Name
Service de Gastroentérologie et d'Hépatologie, University Hospital
City
Geneva
State/Province
GE
ZIP/Postal Code
1211
Country
Switzerland

12. IPD Sharing Statement

Citations:
PubMed Identifier
15765399
Citation
Romero-Gomez M, Del Mar Viloria M, Andrade RJ, Salmeron J, Diago M, Fernandez-Rodriguez CM, Corpas R, Cruz M, Grande L, Vazquez L, Munoz-De-Rueda P, Lopez-Serrano P, Gila A, Gutierrez ML, Perez C, Ruiz-Extremera A, Suarez E, Castillo J. Insulin resistance impairs sustained response rate to peginterferon plus ribavirin in chronic hepatitis C patients. Gastroenterology. 2005 Mar;128(3):636-41. doi: 10.1053/j.gastro.2004.12.049.
Results Reference
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Retreatment of Chronic Hepatitis C Non-responders With Pegylated Interferon Alpha Plus Ribavirin Plus Pioglitazone

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