Clinical Trial Result Information

Title of Study:
A prospective, multicenter, open-label, comparative efficacy study of PEGASYS plus Copegus in treatment-naïve Latino patients with chronic hepatitis C-genotype 1, as compared to treatment-naïve non-Latino White patients with chronic hepatitis C-genotype 1

Fast Facts:

Protocol number:	ML18179
Sponsor:	Roche Laboratories Inc.
Company division:	Pharmaceutical
Product name:	PEGASYS
Generic name:	peginterferon alfa-2a (40KD)
Phase of development:	IV
Therapeutic area, approved indication:	Hepatitis C, Chronic
Date of report:	4/22/2008

Clinical study summary:
This non-randomized, open-label, two-arm study was designed to demonstrate non-inferiority of efficacy with respect to virologic response of PEGASYS plus Copegus in treatment-naive Latino patients with chronic hepatitis C, genotype 1, as compared to treatment naive non-Latino White patients with chronic hepatitis C genotype 1, both over 48 weeks of treatment.

Study center(s) :
52 centers in the United States.

Objectives:
Primary: To demonstrate that the sustained virologic response (SVR) rate of PEGASYS (peginterferon alfa-2a (40KD)) in combination with Copegus (ribavirin) in treatment-naive genotype-1 Latino patients was not lower than the SVR of non-Latino white patients.
Secondary: To investigate on-treatment virologic response rate of PEGASYS in combination with Copegus at weeks 4, 12, 24, 48, and at 12 and 24 weeks post-treatment; to investigate the biochemical response rate by serum alanine aminotransferase (ALT) normalization at study weeks 4, 12, 24, 48, and at 12 and 24 weeks post-treatment; to investigate histological activity and liver fibrosis score between pretreatment (within 18 months prior to study drug initiation) and at the end of 24 weeks post-treatment; to evaluate the impact of treatment on patients’ quality of life at end of treatment and 24 weeks post-treatment as compared to baseline; to investigate, safety and tolerability of PEGASYS and Copegus in Latino and non-Latino patients, laboratory abnormalities, vital signs, dose adjustments and premature withdrawals for safety data.

Methodology:
Patients were assessed for virologic and biochemical responses at weeks 4, 12, 24, and 48 on treatment and 12 and 24 weeks post-treatment (weeks 60 and 72). Patients who completed the treatment period were followed-up for 24 weeks post-treatment and had a liver biopsy at week 72. Patients who terminated the study early continued to be assessed for an additional 12 weeks for safety evaluation. Patients who had at least 12 weeks of study drug and who terminated the study early due to therapeutic intolerance or adverse events had an HCV-RNA, serum ALT, and a liver biopsy 24 weeks post-treatment. Quality of life assessments (FSS and SF-36 questionnaire) were performed at baseline, end of treatment, and 24 weeks post-treatment. Depression was monitored throughout the study using the Beck Depression Inventory (BDI). Clinical adverse events, laboratory values, vital signs, and study drug dose adjustments were monitored throughout the study. Fertile or potentially fertile patients were tested monthly for pregnancy throughout the study and monthly for 6 months following therapy completion.

Number of patients (planned/analyzed):
540 planned; 569 enrolled; 568 dosed

Diagnosis and main criteria for inclusion:
Treatment-naive, Latino and non-Latino white patients, 18 to 65 years of age with chronic hepatitis C (HCV) genotype-1. The definition for Latino used in the study was: Hispanic cultural background, Spanish as primary language and parents and all grandparents with Hispanic background. Patients had to have quantifiable HCV-RNA ≥28 IU/mL as demonstrated by Roche High Pure System/COBAS TaqMan Monitor Test, elevated (above the upper limit of normal) ALT within 12 months prior to screening, and compensated liver disease with or without cirrhosis.
Approximately 10% of the patients in each group were to be cirrhotic, and the percentage of cirrhotic patients was to be balanced between the 2 groups.

Test product, dose and mode of administration or test procedure:
PEGASYS (peginterferon alfa-2a (40KD)) 180 μg/0.5 mL subcutaneous injection once a week for 48 weeks PLUS Copegus (ribavirin) 1000 or 1200 mg/day orally (PO) in split doses for 48 weeks. Patients <75 kg (165 lbs) body weight received 1000 mg/day (400 mg in the morning and 600 mg in the evening); patients ≥75 kg (165 lbs) body weight received 1200 mg/day (600 mg in the morning and 600 mg in the evening).

Duration of treatment:
48 weeks

Reference therapy, dose and mode of administration or reference procedure:
N/A.

Criteria for evaluation (efficacy, safety):
Primary Efficacy Endpoint: Proportion of patients with a sustained virologic response (SVR) at the end of 24 weeks post-treatment (week 72).
Secondary Efficacy Endpoints: 1) Proportion of patients with an undetectable HCV-RNA measurement at the end of weeks 4, 12, 24, and 48, and at 12 and 24 weeks post-treatment (end of weeks 60 and 72); 2) Proportion of patients with an early response at week 4; 3) Proportion of patients with an early response at week 12; 4) Change from baseline for HCV-RNA at weeks 4, 12, 24, 48, and at 12 and 24 weeks post-treatment (end of weeks 60 and 72); 5) proportion of patients with a biochemical response (normal serum ALT) at weeks 4, 12, 24, and 48, and at 12 and 24 weeks post-treatment (end of weeks 60 and 72); 6) Proportion of patients with ISHAK Histological Activity Index (HAI) response; 7) Change in ISHAK HAI activity (necroinflammatory) score: baseline vs. end of study (week 72); 8) Change in fibrosis score based on ISHAK: baseline vs. end of study (week 72); 9) Proportion of patients with stable, worsening, and improvement in ISHAK fibrosis score; 10) Change in activity and fibrosis scores based on METAVIR: baseline vs. end of study (week 72); 11) Proportion of patients with stable, worsening, and improvement in METAVIR activity score; 12) Proportion of patients with stable, worsening, and improvement in METAVIR fibrosis score; 13) Change in fat score: baseline vs. end of study (week 72); 14) Proportion of patients with stable, worsening, and improvement in fat score; 15) Proportion of patients with non-zero nonalcoholic steatohepatitis (NASH) score; 16) Change from baseline in Fatigue Severity Scale (FSS) score and FSS item 10 visual analog scale (VAS) score at end of treatment (week 48) and 24 weeks post-treatment (week 72); 17) Change from baseline in SF-36 total score and domain scores at baseline, end of treatment (week 48), and 24 weeks post-treatment (week 72).

Safety Endpoints: Frequency of adverse events (AEs), abnormal laboratory test results, change in vital signs, frequency of study drug dose modifications, and treatment withdrawals for safety reasons.

Statistical methods:
Primary Analysis: Non-inferiority could be concluded if the lower limit of 95% confidence interval (CI) (equivalent to a 1-sided 97.5% CI) of the difference between the ethnic groups was greater than 15%. The 2-sided 95% CI and associated P value for the difference in proportion of patients with an SVR at the end of 24 weeks post-treatment (PL – PNL) were calculated using normal approximation to the binomial distribution. The effect of selected demographic and baseline factors on the probability of SVR was analyzed using multiple logistic regression analysis.

Secondary Analyses: Secondary efficacy variables were summarized by study group using descriptive statistics. Comparisons between the 2 study groups were analyzed using normal approximation to the binomial or analysis of covariance (ANCOVA) for categorical and continuous variables, respectively. Multiple logistic regression procedures were used to evaluate the effects of demographic and baseline variables on selected secondary variables.
Safety data were summarized by study group using descriptive statistics.

Summary (efficacy, safety, other results):
Efficacy: In the primary efficacy analysis, 33.5% of patients in the Latino group and 49.3% of patients in the non-Latino white group had an SVR (P<0.0001). Since the protocol-specified non-inferiority criteria for the between-group difference, -15% (95% CI = -24%, -8%), was not met, it could be concluded that the SVR rate for the Latino group was inferior to that of the non-Latino white group. A post hoc test of the difference between the 2 ethnic groups was conducted to evaluate whether the 95% CI included zero. Since the CI did not contain zero, it could be concluded that the SVR rates for Latino and non-Latino white patients were significantly different (P=0.0001). Mutliple logistic regression on the whole populations showed that non-Latino white is a strong predictor of response. Multiple logistic regression analysis showed that, for Latino patients, baseline ALT ≤3 x ULN, baseline HCV-RNA ≤400,000 IU/mL, and non-cirrhotic status were significant predictors of SVR. For non-Latino white patients, male gender, baseline ALT >3 x ULN and baseline HCV-RNA ≤400,000 IU/mL were significant predictors.
The virologic response rate (HCV-RNA measurement of <28 IU/mL) was significantly higher in non-Latino white patients than Latino patients at all time points during treatment and up to 24 weeks post-treatment. A significantly higher percentage of patients in the non-Latino white group than the Latino-white group had an early virologic response. Non-Latino white patients also had a greater decrease from baseline in HCV-RNA Log10 titers compared with Latino patients at all study weeks (P <0.0001 at all time points). Biochemical and histological results were consistent with virologic response data. Patients reported an increase in fatigue severity from baseline at the end of treatment, with a greater increase in the non-Latino white group relative to the Latino group. Patients reported a decrease in physical and mental functioning from baseline to the end of treatment with a greater decrease in physical functioning in the non-Latino white group (P <0.0001).

Safety: During the 72-week study, 98% of patients in the Latino group and 98% of patients in the non-Latino white group reported at least 1 AE. The most common AEs (occurring in >40% of patients) in decreasing order of frequency were: fatigue, headache, insomnia, nausea, rash, pyrexia, influenza-like illness, depression, anemia, irritability, diarrhea, myalgia, arthralgia, and cough. For most of the common AEs, incidence was higher in the non-Latino group than the Latino group. One non-Latino white patient died due to worsening liver failure secondary to underlying cirrhosis and continued alcohol abuse. The death was judged by the investigator to be unrelated to trial medication. Forty two (16%) patients in the Latino group and 48 (16%) patients in the non-Latino white group reported at least 1 serious adverse event (SAE). Treatment-related (remote, possible, probable as assessed by the investigator) SAEs were reported by 7% of patients in the Latino group and 9% of patients in the non-Latino white group. The most common treatment-related SAEs were suicidal ideation, depression, anemia, suicide attempt, and pneumonia. Twenty-five (9%) patients in the Latino group and 43 (14%) patients in the non-Latino white group discontinued trial treatment due to AEs. The most common AEs resulting in withdrawal were depression, suicidal ideation, drug abuse, and fatigue. Mean and median hematology values, hematocrit, hemoglobin, WBCs, lymphocytes, neutrophils, and platelets, decreased from baseline during weeks 1 and 8, stabilized during the remainder of the treatment period, and then returned to near baseline values after the end of treatment. Mean and median ALT, AST, and total protein values were decreased from baseline throughout the assessment period. Changes in laboratory parameters were generally similar in the 2 study groups.

Conclusions:
The sustained virologic response rate, defined as an undetectable HCV-RNA measurement (<28 IU/mL) 24 weeks post-treatment with PEGASYS + ribavirin for 48 weeks, was lower in treatment-naïve Latino versus non-Latino white patients infected with chronic hepatitis C genotype-1 (33.5% vs. 49.3%, P <0.0001). Secondary efficacy variables, including early virologic response, biochemical response, and histologic response, support the results of the primary SVR analysis, demonstrating that Latino patients respond less well than non-Latino white patients to PEGASYS + ribavirin combination therapy. The predictors of response were different for Latino and non-Latino white patients, indicating a need for further study in Latinos. Combination PEGASYS + ribavirin therapy was generally well tolerated. The type and frequency of adverse events and laboratory abnormalities were consistent with interferon-based therapies. There were no unexpected or unusual safety results.

Publications (references, if available):
Rodriguez-Torres M, Jeffers LJ, Sheikh MY, Rossaro L, Ankoma-Sey V, Hamzeh FM, Martin P. Virologic responses to peginterferon alfa-2a/ribavirin in treatment naïve Latino vs non-Latino Caucasians infected with HCV genotype 1: The Latino study. J Hepatol. 2008 48 (Sup 2): S311.

Rodriguez-Torres M, Jeffers LJ, Sheikh MY, Rossaro L, Ankoma-Sey V, Hamzeh FM, Martin P. Virologic response to peginterferon alfa-2a/ribavirin in treatment-naive Latino vs non-Latino Caucasians infected with HCV genotype 1: the LATINO study. Gastroenterology. 2008;134:A-755. [#161]

Click here for the protocol registry listing of this trial.