The primary objective is to study the effect of a 16-week treatment with a PPAR-* agonist versus placebo on effectiveness of subsequent standard treatment with PEG-IFN and RBV, measured as SVR, in previously non-responders or relapsers with CHC…
ID
Source
Brief title
Condition
- Hepatic and hepatobiliary disorders
- Viral infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Outcome is presented as non-detectable hepatitis C virus, 6 months after
finishing PEG-IFN/RBV therapy.
Secondary outcome
Prior to randomisation, at 16 weeks and at 28 weeks, patients will undergo
liver biopsies to assess disease activity and histomorphology, and 1H-MRS to
non-invasively quantify liver fat accumulation. In addition, insulin resistance
will be assessed by an oral glucose tolerance test (OGTT). Finally, various
metabolic parameters and markers of inflammation and oxidative stress will be
measured
Background summary
Currently, hepatic steatosis or non-alcoholic fatty liver disease (NAFLD) is
regarded as a key pathogenic factor and component of the metabolic syndrome.
Hepatocellular steatosis in chronic hepatitis C (CHC) has been described in all
hepatitis C virus (HCV) genotypes. Whereas in genotype 3 hepatic steatosis
seems a consequence of a direct toxic effect of HCV on hepatocytes, in genotype
1, metabolic derangements, in particular insulin resistance may contribute to
liver fat accumulation. Thus, steatosis and insulin resistance may negatively
impact on the liver, thereby adversely influencing treatment efficacy and
enhance progression to fibrosis. A yet it is unknown whether prior delipidation
of the liver and improvement of insulin sensitivity would improve the
responsiveness to subsequent anti-viral therapy.
Peroxisome-proliferator-activator-receptor (PPAR)-* agonists or
thiazolidinediones (TZD) are a new class of drugs for the treatment of type 2
diabetes. In addition to their insulin sensitizing effects, TZD have been shown
to significantly reduce hepatic steatosis. The state-of-the-art noninvasive
method for quantification of hepatic fat in vivo is proton (1H) magnetic
resonance spectroscopy (MRS).
We hypothesize that (hepatic) insulin resistance and liver fat accumulation
underlie the decreased/absent responsiveness to antiviral therapy in a subgroup
of CHC patients. Pre-treatment with PPAR-* agonists, through amelioration of
insulin resistance and decrease in hepatic steatosis, may result in an increase
of sustained viral response (SVR) to subsequent standard antiviral therapy with
PEG-IFN and RBV in patients with CHC previously non-responding or relapsing to
PEG-IFN containing antiviral therapy.
Study objective
The primary objective is to study the effect of a 16-week treatment with a
PPAR-* agonist versus placebo on effectiveness of subsequent standard treatment
with PEG-IFN and RBV, measured as SVR, in previously non-responders or
relapsers with CHC genotype 1.
Secondary objectives are to study associations of disease activity, liver fat
content, liver function, liver histomorphology, insulin sensitivity and
response to antiviral therapy.
Study design
Monocenter double-blind randomized placebo-controlled trial.
Intervention
Patients will be randomized for treatment with either PPAR-* agonist
(pioglitazone; daily dose of 45 mg) or corresponding placebo during 16 weeks,
prior to the start of PEG-IFN/RBV therapy.
Study burden and risks
The risk to and burden for the subject will be in proportion to the potential
value of the research. Subjects have a CHC infection, which opposes them with a
serious health risk. The subjects in this study did not respond to standard
previous treatment for this disease. Thus, there are no further validated
established treatment options for these patients. We hypothesize that
pre-treatment with pioglitazone may result in an increased and sustained
response to antiviral treatment. This benefit outweighs the extra efforts and
minor extra risks a subject is exposed to. Extra risk will be kept to a
minimum.
Boelelaan 1115
1081 HV Amsterdam
Nederland
Boelelaan 1115
1081 HV Amsterdam
Nederland
Listed location countries
Age
Inclusion criteria
* CHC genotype 1 infected men and women * 21 and * 65 yrs of age
* Previously non-responders or relapsers to any PEG-IFN-containing treatment
* Patients requiring a liver biopsy before treatment
* Fasting plasma glucose *7.0 mmol/l
* Hepatic steatosis
* Written informed consent
Exclusion criteria
* Exclusion criteria for MRI
* ALT levels * 150 IU/ml
* Co-infection with HIV or hepatitis B
* Present excessive alcohol use defined as > 2 units/day
* Cardiovascular co-morbidity
* Any type of diabetes mellitus
* Use of glucocorticosteroids, hormonal substitution, pagitaxel, theofyllin, myelosuppresive agents.
* A psychiatric, addictive or any other disorder that compromises the subjects ability to understand the study content and to give written informed consent for participation in the study
* Present abuse of i.v. drugs (including methadon)
* Subject no longer available for follow-up assessment
* Standard contraindication for treatment with PEG-IFN and RBV
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
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In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2007-007075-16-NL |
| CCMO | NL18763.029.07 |
| Other | volgt |