Roche trials database

Protocol number:

ML21301

Title of Study:

A randomized, open-label study of the effect of PEGASYS ® plus COPEGUS® with or without concomitant pioglitazone (Actos®) on early viral kinetics in treatment-naive patients with chronic hepatitis C, genotype-1, and insulin resistance

Sponsor:

Hoffmann-La Roche

Company division:

Pharmaceutical

Product name:

peginterferon alfa-2a [Pegasys]

Generic name:

peginterferon alfa-2a

Therapeutic area:

• Hepatitis C, Chronic

Clinical study summary:

This multicenter, randomized, open-label, controlled study was designed to evaluate the effect of treatment with Pegasys (peginterferon (PEG-IFN) alfa-2a) and Copegus (ribavirin) with and without concomitant pioglitazone in treatment-naïve patients with chronic hepatitis C (genotype-1 HCV infection) and insulin resistance. Patient were randomized to two treatment arms: Arm A: Pegasys plus Copegus and pioglitazone; Arm B: Pegasys plus Copegus.

Study center(s):

48 centers in U.S.A.

Phase of development:

IV

Objectives:

The primary objective was to evaluate the effect of treatment with Pegasys once weekly plus daily Copegus according to body weight with and without concomitant pioglitazone on hepatitis C virus (HCV) titers during the first 12 weeks of anti-HCV therapy in treatment-naïve patients with chronic hepatitis C (genotype-1 HCV infection) and insulin resistance.

The secondary objectives were as follows: to evaluate the effects of pioglitazone on virological response, sustained virological response (SVR), and relapse rates; to evaluate the effect of pioglitazone pretreatment on HCV titers prior to initiation of anti-HCV treatment; to compare the effects of anti-HCV therapy plus pioglitazone vs anti-HCV therapy alone on insulin resistance; to assess the safety of pioglitazone and concomitant anti-HCV therapy in patients with pre-existing liver disease; to evaluate the temporal relationship between virological response and changes in specific cytokines and adipokines in patients on or not on pioglitazone

Methodology:

The study consisted of an optional prescreen, a screen, randomization, a 48-week anti-HCV treatment (AHT) period, and a 24-week post-AHT follow-up. Randomization to treatment arm (with or without pioglitazone) was stratified by HOMA score (< 4, ≥ 4). Patients randomized to pioglitazone participated in a 16-week pioglitazone run-in, during which pioglitazone was initiated and stabilized.

Patients randomized to pioglitazone were discontinued after 16 weeks of pioglitazone treatment if, for safety reasons, starting anti-HCV therapy was contraindicated. Patients in the without-pioglitazone arm started anti-HCV treatment immediately following randomization. For both study arms, baseline was at randomization (prior to receipt of any study treatment), and anti HCV treatment (Pegasys plus Copegus) started at Week 0. Patients who did not achieve a ≥ 2-log₁₀ decrease or undetectable HCV RNA after 12 weeks or detectable HCV RNA after 24 weeks of anti-HCV therapy, or had a BDI-II score ≥ 31 at any time had study treatment discontinued. Premature discontinuation of Copegus treatment was allowed, if necessary, but premature discontinued discontinuation of Pegasys required discontinuation from the study.

Anti-HCV treatment was stopped after 48 weeks, and patients were followed-up for safety and sustained efficacy for 24 weeks. Patients on pioglitazone remained on pioglitazone throughout the study uninterrupted until the final study assessment during follow-up. Patients were followed for efficacy and safety throughout the study, but the primary evaluation of efficacy was over the first 12 weeks of anti-HCV treatment.

Number of patients (planned/analyzed):

240 patients planned; 155 patients enrolled

Diagnosis and main criteria for inclusion:

Adult patients > 18 years of age with chronic hepatitis C, insulin resistance, and a liver biopsy consistent with CHC without cirrhosis and inspected for steatosis within the last 2 years who had not been previously treated with anti-HCV therapy or insulin (within the previous 2 weeks) and a fasting plasma glucose < 240 mg/dL.

Test product, dose and mode of administration or test procedure:

Run-in: daily pioglitazone administered orally (po) for 16 weeks (30 mg daily for 8 weeks, then 45 mg daily for 8 weeks)

AHT period: Peginterferon alfa-2a 180 μg administered subcutaneously (sc) once weekly plus daily ribavirin po according to body weight* administered in divided doses (morning/evening), and concomitant pioglitazone 45 mg daily po for 48 weeks.

Follow-up: pioglitazone 45 mg daily po for 24 weeks

*The ribavirin dose was determined based on body weight: 1000 mg/day if < 75 kg, 1200 mg/day if 75 to < 85 kg, 1400 mg/day if 85 to 95 kg, 1600 mg/day if > 95 kg

Duration of treatment:

48 weeks

Reference therapy, dose and mode of administration or reference procedure:

AHT period: peginterferon alfa-2a 180 μg once weekly sc plus daily ribavirin po according to body weight (same as above) in divided doses (morning/evening) for 48 weeks.

Criteria for evaluation (efficacy, safety):

Efficacy

Primary

Change in log₁₀ HCV RNA from randomization to Week 12 of anti-HCV treatment

Secondary

• Change in log₁₀ HCV RNA from randomization to 12 weeks of anti-HCV treatment and to all other time points
• Proportion of patients with undetectable HCV RNA (< 28 IU/mL) at each time point assessed
• Proportion of patients with ≥ 2-log₁₀ decrease in HCV RNA from randomization to 12 weeks of anti-HCV treatment and to all other time points
• Proportion of patients with a virological relapse at Week 72 (24 weeks after the end of anti-HCV treatment)
• Proportion of patients with a confirmed virological breakthrough (i.e., detectable HCV RNA at any time during anti-HCV treatment up to Week 48 after the attainment of undetectable HCV RNA) and proportion of non-responders (i.e., patients who did not achieve undetectable HCV RNA during anti-HCV treatment)
• Viral kinetics (change in HCV RNA titer) at all assessments from randomization to 16 weeks of pioglitazone pretreatment (pioglitazone arm only)
• Measurements of glycemic control (fasting plasma glucose, insulin, and HbA1c concentrations and HOMA scores) at each time point assessed
• Measurements of lipid control (fasting serum triglycerides, total cholesterol, low- and high-density lipoprotein cholesterol) at each time point assessed
• Measurements of specific cytokines and adipokines associated with changes in insulin resistance (fasting serum tumor necrosis factor [TNF]-α, transforming growth factor [TGF]-β, adiponectin, leptin, free fatty acids) at each time point assessed
• Proportions of patients with Fast Screen Beck Depression Inventory (BDI-FS) score ≥ 4 at each time point

Safety

Pegasys + Copegus: clinical adverse events, laboratory tests, anemia, neutropenia, thrombocytopenia, and vital signs.

Pioglitazone: laboratory tests, fasting glucose, liver enzymes, B-type natriuretic peptide, weight gain, and physical examination for edema.

Statistical methods:

The study size was estimated assuming a common standard deviation (SD) of 1.37 log₁₀ in the change in HCV RNA from randomization to Week 12; 120 patients per arm would provide at least 80% power to detect a 0.5 log₁₀ difference in the two arms using a two-sided t test at alpha = 0.05.

The changes from randomization to each time point in log transformed (base 10) HCV-RNA titers were summarized by treatment arm. Last observation carried forward (LOCF) was used for missing assessments. A mixed-model repeated measures analysis (with covariates baseline HCV RNA and HOMA score < 4 and ≥ 4) was used to compare the two arms up to Week 12 (intent-to-treat [ITT] population), with the best fit variance covariance structure selected for the final model and treatment-by-time interaction effect used for testing.

Estimated treatment difference was provided with standard error, 95% confidence interval (CI), and p-value based on the normal approximation of the binomial. Supportive analyses were performed without imputing for dropouts and using the Per-protocol (PP) Population. Similar analyses were performed in an exploratory manner across all time points up to Week 48 without correction for multiple comparisons.

Response rates and estimated treatment differences with 95% CI were summarized at each visit. Additional analyses were performed on only those patients who received ≥ one dose of anti-HCV treatment. Other secondary endpoints were summarized descriptively as were safety and baseline data.

Safety and baseline data were summarized descriptively.

Summary (efficacy, safety, other results):

Efficacy

Due to dropouts during the pioglitazone run-in, only 80.5% of patients in the with-pioglitazone arm (ITT Population) received anti-HCV treatment. Similar decreases from baseline to Week 12 in mean (± SD) log₁₀ HCV-RNA titers in the two treatment groups (−3.5 ± 1.71 and −3.7 ± 1.62 IU/mL with and without pioglitazone, respectively) resulted in a treatment difference that was not statistically significant (0.21 IU/mL, P = 0.4394, LOCF, primary endpoint). Analyses on the PP Population and using observed data showed similar results as did analyses at all other time points. Virological response rates for undetectable (< 28 IU/mL), ≥ 2-log₁₀ decrease, and ≥ 2-log₁₀ decrease or undetectable HCV RNA were smaller with pioglitazone than without at several time points (numerically smaller at all time points) when patients who did not receive anti-HCV treatment were counted as non-responders. When these patients were omitted from analysis, response rates were still numerically smaller with pioglitazone than without, but the two treatment groups were not considered different at any time point assessed. SVR (undetectable HCV RNA at Week 72) was not different between treatments in either analysis (26.0% and 38.4% with and without pioglitazone, respectively, P = 0.1021, main analysis), and no treatment differences could be detected in exploratory subgroup analyses. Multivariate logistic regression analysis identified age ≤ 40 years and HCV-RNA titers < 800,000 IU/mL as significant predictors of SVR (treatment included in the model), and rapid virological response (RVR, HCV RNA < 28 IU/mL at Week 4) was a positive predictor of SVR in 60.0% and 50.0% of patients, respectively. Virological relapse and breakthrough rates were similar in the two treatment groups, as were the proportions of non-responders (when patients who did not receive anti-HCV therapy were omitted).

Pioglitazone treatment had no effect on HCV-RNA titers but was associated with decreases in glycemic control variables, cytokines, leptin, and free fatty acids and an increase in adiponectin during the run-in. During anti-HCV treatment, these changes were generally larger with pioglitazone than without. Triglycerides and cholesterol variables changed little during the run-in, but during anti-HCV treatment, triglycerides increased and cholesterol decreased, with values returning towards pre-AHT values during the post-AHT follow-up in both treatment arms. The decreases in cholesterol variables were generally smaller with pioglitazone than without.

Safety

Exposure to anti-HCV treatment was similar in the two treatment arms (only patients who received anti-HCV treatment included). Safety data primarily reflected the known safety profiles of the three drugs. There were no deaths. Most patients experienced an adverse event, with the most frequent events those previously associated with anti-HCV treatment (fatigue, anemia, nausea, insomnia, headache, and depression), and only nausea more frequent (> 5% difference) with than without pioglitazone. Serious adverse events occurred to a similar extent in the two groups (13% and 12%, respectively) as did severe events (25% and 24%, respectively). In both groups, a marked increase in alanine aminotransferase occurred in about 10% of patients, and the increases in mean serum triglycerides and decreases in cholesterol variables seen during anti-HCV treatment reversed during the post-AHT follow-up. Pioglitazone treatment was associated with higher incidences of hemoglobin < 10 g/dL (40% vs 20%) and marked decreases in platelets (25% vs 16%) and lymphocytes (44% vs 36%), but not neutrophils compared with anti-HCV treatment alone. A higher incidence of suicidal ideation was observed with pioglitazone than without (8% vs 1%), and the three life-threatening events (suicide attempt, acute respiratory distress, spinal cord injury cervical) occurred in the pioglitazone arm. Few events led to discontinuation of anti-HCV treatment, but the incidence was higher with than without pioglitazone (13% vs 7%) as was the incidence of dose modification of Pegasys (32.3% vs 18.7%, only patients who received anti-HCV treatment included) but not Copegus.

Pioglitazone appeared to be well tolerated as there were no cases of heart failure and few of increased brain natriuretic peptide, increased body weight, or edema, none of which required discontinuation of study treatment. Patients on pioglitazone had a lower incidence of fasting plasma insulin > 100 IU/L and HOMA score ≥ 4 than those on anti-HCV treatment alone but a higher incidence of fasting plasma glucose > 6.94 mmol/L (41.6% vs 31.5%).

Conclusions:

Insulin sensitization using pioglitazone treatment prior to and during anti-HCV therapy in patients with chronic hepatitis C genotype 1 and insulin resistance improved several indices of insulin sensitivity but did not improve virological response compared with anti-HCV therapy alone. Both treatment groups responded to anti-HCV treatment. Safety data reflected the known safety profiles of the three drugs, with most findings typical of combination interferon and ribavirin treatment. Pioglitazone was generally well tolerated, but when added to anti-HCV treatment was associated with increased incidences of decreased hemoglobin, platelets, and lymphocytes compared with anti-HCV treatment alone, all of which were usually manageable with specific treatment and dose reduction.

Publications (references, if available):

Vierling JM, et al. Abstract for American Association for the Study of Liver Diseases Annual Meeting, 2009.

Harrison S, et al. Abstract for International Liver Congress Annual Meeting, 2010.

Harrison S, et al. Abstract for Digestive Disease Week Annual Meeting, 2010.

Vierling JM, et al. Abstract for American Association for the Study of Liver Diseases Annual Meeting, 2010.

Date of report:

15.12.2011

Click here for the protocol registry listing of this trial.