Clinical Trial Result Information

Title of Study:
A Randomized, Open-Label, Multicenter, Phase III Study Evaluating the Efficacy and Safety of Peginterferon alfa-2a (40KD) in Combination With Ribavirin Given for 24 Weeks Versus 48 Weeks Versus No Treatment in Patients With Chronic Hepatitis C and Persistently Normal ALT Levels

Fast Facts:

Protocol number:	NR16071
Sponsor:	F Hoffmann-La Roche Ltd
Company division:	Pharmaceutical
Product name:	PEGASYS
Generic name:	peginterferon alfa-2a (40KD)
Phase of development:	III
Therapeutic area, approved indication:	Hepatitis C, Chronic
Date of report:	10/1/2003

Clinical study summary:
This multicenter, open-label, randomized, parallel-group trial evaluated peginterferon alfa-2a (40KD) (PEGASYS) (180 µg) once weekly (qw) plus ribavirin(Copegus)(800 mg) daily for a treatment period of 24 weeks or 48 weeks, versus .no treatment, in patients with chronic hepatitis C (CHC) and normal ALT levels.

Study center(s) :
A total of 70 sites in Australia, Austria, Brazil, Canada, France, Germany, Italy, Mexico, New Zealand, Portugal, Spain, Switzerland and the United States.

Objectives:
Primary: To evaluate the effect of PEGASYS in combination with ribavirin given for 24 or 48 weeks on the clearance of hepatitis C virus (HCV) viremia 24 weeks after the end of the scheduled treatment (sustained virologic response) versus that seen in an untreated control group.

Secondary: (1) To evaluate the effect of PEGASYS plus ribavirin combination therapy on the reduction of HCV viremia after 4, 12, 24, and 48 weeks (48-week treatment group only) of treatment; (2) To compare the efficacy of PEGASYS and ribavirin combination therapy according to HCV genotype and viral load; (3) To compare the quality of life among the treatment arms and between treatment responders versus nonresponders measured by the Short Form 36 of the Medical Outcome Study and the Fatigue Severity Scale; (4) To monitor serum ALT activity during and after therapy; (5) To evaluate the safety of PEGASYS plus ribavirin combination therapy in patients with CHC and persistently normal ALT activity.

Methodology:
After screening, patients were randomized in a ratio of 1:3:3 to one of the 3 treatment groups (untreated control, 24 weeks treatment, or 48 weeks treatment).During treatment and follow-up, monitoring of HCV RNA titers was used to assess patients’ disease status, and adverse events and laboratory data were collected for assessment of safety.

Number of patients (planned/analyzed):
514 randomized; 491 in safety population

Diagnosis and main criteria for inclusion:
Males or females ≥18 years of age with serologic evidence of HCV infection; histologic evidence of compensated liver disease; detectable serum HCV RNA; persistently normal ALT activity; negative for other forms of hepatitis, cirrhosis, or transition to cirrhosis, and for human immunodeficiency virus (HIV).

Test product, dose and mode of administration or test procedure:
PEGASYS, 180 µg/sc/qw/24 or 48 weeks, and Copegus (ribavirin), 800 mg/po/day with meals/24 or 48 weeks.

Duration of treatment:
24 or 48 weeks.

Reference therapy, dose and mode of administration or reference procedure:
Not applicable

Criteria for evaluation (efficacy, safety):
Primary efficacy parameters: Sustained virologic response defined as undetectable HCV RNA (<50 IU/mL) based on a single HCV RNA determination 24 weeks after completion of treatment (ie Week 48 or Week 72) or at completion of untreated observation period (Week 72).

Secondary efficacy parameters: (1) Sustained virologic response based on 2 HCV RNA determinations performed ≥21 days apart at the end of the 24-week untreated follow-up period or at the end of 72 weeks of untreated observation; (2) virologic response (undetectable HCV RNA) at study Weeks 4, 12, 24, and 48; (3) sustained virologic response by HCV genotype and viral load; (4) maintenance of virologic response. Safety parameters: Adverse events, laboratory test results, and vital signs.

Statistical methods:
Primary analysis population: All randomized patients who received >= dose of study medication (24- and 48-week treatment groups) or who had >=1 post-baseline assessment (untreated control group).

Efficacy: Pairwise comparisons of sustained virologic responses were made between the 24- or 48-week treatment group and the untreated control group and between the 24- and 48-week treatment groups. Categorical variables were analyzed using the Cochran-Mantel-Haenszel test. Odds ratios and the corresponding 95% confidence intervals were given for pairwise treatment comparisons. Continuous variables were analyzed using analysis of variance.

Safety: Descriptive statistics were used to summarize safety parameters by study group.

Summary (efficacy, safety, other results):
Efficacy - Sustained virologic response was significantly higher with treatment for 48 weeks (52%) compared with treatment for 24 weeks (30%) (odds ratio, 3.13; P<.001). No untreated patient in the control group achieved a sustained virologic response.

For patients infected with HCV genotype 1, 48-week treatment resulted in a significantly higher sustained virologic response (40%) compared with 24-week treatment (13%) (odds ratio, 4.47; P<.001). The highest sustained virologic response was obtained in patients with a low baseline viral load (<800,000 IU/mL) treated for 48 weeks (47%).

Sustained virologic response in patients infected with genotype non-1 was also higher with 48-week treatment (75%) compared with 24-week treatment (65%), although this difference was not statistically significant (odds ratio, 1.69; P=.177). This was partly due to the response pattern of patients infected with HCV genotype 4, in whom sustained virologic response was only 13% with 24 weeks of treatment compared with 56% after 48 weeks of treatment. Sustained virologic response was similar in patients with HCV genotype 2 or 3 infection whether these patients were treated for 24 weeks (72%) or 48 weeks (78%).

The percentage of patients who maintained their virologic response was higher in patients infected with genotypes 2 or 3 than in patients infected with genotypes 1 or 4. Maintenance of response was not dependent on treatment duration in patients infected with genotypes 2 or 3 (80% and 88% of patients maintained their response in the 24-week and 48-week treatment groups, respectively). In contrast, in patients infected with genotypes 1 or 4, the percentage of patients who maintained their response was higher after 48 weeks of treatment than after 24 weeks of treatment.

The negative predictive value of not achieving an early virologic response by week 12 for sustained virologic response was ~100% regardless of treatment duration, HCV genotype, or baseline viral load. Of a total of 66 treated patients who did not have a virologic response by Week 12, only 1 patient achieved a sustained virologic response at the end of follow-up.

Safety - The safety profile seen in this study is consistent with that of the general CHC patient population receiving PEGASYS and ribavirin combination therapy. No unexpected safety issues were identified. Overall, 24-week treatment was better tolerated than 48-week treatment, as demonstrated by the lower incidence in the 24-week treatment group of serious, severe or life-threatening adverse events, premature withdrawals from treatment and dose modification due to adverse events and laboratory abnormalities (see table below).

The incidence of the most common adverse events in the 24-week treatment group, such as fatigue, headache, myalgia, pyrexia, and insomnia, was similar to or slightly lower than that in the 48-week treatment group. The incidence of depression was similar in the 24- and 48-week treatment groups (26% vs 27%). Depression was mild to moderate in most patients, and predominantly occurred in the first 12 weeks of treatment. Four patients (6%) in the untreated control group reported depression.

The only death occurred in a patient in the untreated control group, who died of an accidental head injury. The incidence of serious adverse events in the 24-week treatment group (8%) was similar to that in the untreated control group (6%) but lower than that in the 48-week treatment group (16%). Serious infections were the most frequent serious adverse events and occurred in 2%, 4%, and 3% of patients in the 24-week treatment group, 48-week treatment group, and untreated control group, respectively. Except in 1 patient, these serious infections were not associated with a concomitant decrease in neutrophil count to <0.5 × 10⁹/L.

Fewer patients in the 24-week treatment group than in the 48-week treatment group were withdrawn from treatment prematurely, or had their dose of PEGASYS or ribavirin modified, because of adverse events or laboratory abnormalities. In both treatment groups, low neutrophil count and low hemoglobin concentration were the most common laboratory abnormalities leading to modification of the PEGASYS and ribavirin doses, respectively.

During the study, 5% of patients in each treatment group experienced a decrease in neutrophil count to <0.5 ×10⁹/L. Fewer patients experienced a decrease in hemoglobin concentration to <10 g/dL in the 24-week treatment group (6%) than in the 48-week treatment group (12%). A higher percentage of female patients than male patients, especially those with a low body weight, experienced a decrease in hemoglobin concentration to <10 g/dL. No patient developed a platelet count of <20 x10⁹/L during the study.

Approximately half of patients in each study group experienced an elevation in ALT activity to greater than the upper limit of the normal (ULN) (30 U/L). In most cases, the highest ALT value was <2 x ULN. ALT flares (ALT >5 x ULN) were rare. Thyroid dysfunction occurred in 38 patients, 14 patients (7%) in the 24-week treatment group and 24 patients (11%) in the 48-week treatment group, mostly women (87%).

Conclusions:
More than 50% of patients with persistently normal ALT enrolled in this study achieved a sustained virologic response following 48 weeks of combination therapy. These results are comparable with responses reported for patients with elevated ALT receiving similar treatment regimens. No patient in the untreated control group spontaneously cleared HCV during the untreated observation period. In patients with HCV genotype non-1 infection (predominantly genotypes 2 or 3), 24-week treatment was as efficacious as 48-week treatment. In patients with HCV genotype 1 infection, 48 weeks of treatment resulted in a significantly higher sustained virologic response than 24 weeks of treatment.

The safety profile of CHC patients with persistently normal ALT activity is consistent with that of the general CHC patient population receiving PEGASYS and ribavirin combination therapy. As expected, 24-week treatment was generally better tolerated than 48-week treatment, but no unexpected safety issues were identified. Compared with no treatment, PEGASYS and ribavirin combination therapy did not increase ALT flares in patients with CHC and persistently normal ALT activity.

Publications (references, if available):
Zeuzem S et al. Peginterferon Alfa-2a(40 Kilodaltons) and Ribavirin in Patients with Chronic Hepatitis C and Normal Aminotransferse Levels. Gstroenterology 127: 1724-1732 (2004).