Roche trials database

Protocol number:

MV17117

Title of Study:

Multicenter Open Label Trial on Treatment Efficacy and Safety in Patients with Chronic Hepatitis C Receiving Ribavirin Combination Therapy

Sponsor:

Hoffmann-La Roche

Company division:

Pharmaceutical

Product name:

PEGASYS

Generic name:

peginterferon alfa-2a (40KD)

Therapeutic area:

• Hepatitis C, Chronic

Clinical study summary:

This was a multicenter, open–label, multinational, parallel–group trial. Patients infected with chronic hepatitis C (CHC) were assigned to one of two treatment groups according to the discretion of the investigator: PEGASYS (peginterferon alfa–2a(40KD) combination therapy with ribavirin for 24 or 48 weeks. Patients were followed for 24 weeks after the end of treatment. The sponsor recommended to assign genotype non-1 patients to the 24-week group and genotype 1 patients to the 48-week group.

Study center(s):

60 centers in Bosnia Herzegovina, Czech Republic, Macedonia, Slovakia

Phase of development:

III

Objectives:

Primary objective: to evaluate the effect of ribavirin/PEGASYS combination therapy given for 24 weeks (genotype non-1) or 48 weeks (genotype 1), on the clearance of HCV viremia 24 weeks after treatment end (sustained virological response) in naïve patients with chronic HCV (CHC) infection.
Secondary objectives: to evaluate the effect of ribavirin/PEGASYS combination therapy given for 24 weeks (genotype non-1) or 48 weeks (genotype 1), on the clearance of HCV viremia 24 weeks after treatment end (sustained virological response) in patients with CHC infection who have previously been treated with interferon (IFN) monotherapy or interferon combination therapy with ribavirin (IFN/RBV); to evaluate the efficacy of ribavirin/PEGASYS combination therapy given for 24 (genotype non 1) or 48 weeks (genotype 1) on the reduction/clearance of HCV viremia after 12 weeks of treatment and at the end of treatment in naïve patients with CHC infection; to evaluate the efficacy of ribavirin/PEGASYS combination therapy given for 24 (genotype non 1) or 48 weeks (genotype 1) on the reduction/clearance of HCV viremia after 12 weeks of treatment and at the end of treatment in patients with CHC infection who have previously been treated with IFN or IFN/RBV; to evaluate the safety of ribavirin/PEGASYS combination therapy

Methodology:

All patients were screened between 56 days prior to first dose of trial medication. Patient’s disease status was assessed by monitoring serum HCV RNA titers. Quantitative viral titers (AMPLICOR HCV MONITOR^® Test v2.0) were obtained during screening and at 12 weeks after treatment start. Qualitative HCV RNA results (AMPLICOR^® HCV Test v2.0) were obtained at treatment end, ie, 24 weeks after treatment start for genotype non-1 patients and 48 weeks after treatment start for genotype 1 patients, and 24 weeks post-treatment. For all patients prematurely discontinued after 12 weeks of treatment qualitative HCV RNA was obtained at individual treatment end and, if they exhibited evidence of virological response, 24 weeks post-treatment.
Safety assessments were performed during treatment and the 24-week follow-up. Patients who were prematurely withdrawn from study treatment were followed for safety for 12 weeks after their last dose of trial medication.

Number of patients (planned/analyzed):

1500 planned; 1158 enrolled; 1155 treated

Diagnosis and main criteria for inclusion:

Male or female outpatients ≥18 years of age with serologically and histologically proven CHC, detectable HCV RNA, elevated ALT, and compensated liver disease.

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

800 mg or 1000/1200 mg of ribavirin according to genotype (non-1 or 1) and body weight (1000/1200 mg < or ≥75 kg) administered orally twice daily in split doses (i.e. 2 3 tablets bid) for 24 or 48 weeks.
Basic medication: 180 μg of PEGASYS (peginterferon alfa-2a (40KD)) administered subcutaneously once weekly for 24 or 48 weeks.

Duration of treatment:

24 or 48 weeks

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

N/A

Criteria for evaluation (efficacy, safety):

Primary Efficacy Parameter: The primary efficacy parameter was sustained virological response (SVR) rate in naïve patients, defined as percentage of patients with non-detectable HCV RNA as measured by Roche AMPLICOR^® HCV Test, v2.0:(qualitative test with a lower detection limit of 50 IU/mL) at 24 weeks post-completion of the treatment period.
Secondary Efficacy Parameters: 1) SVR rate in pretreated patients, defined as percentage of patients with non-detectable HCV RNA (as measured by Roche AMPLICOR^® HCV Test, v2)at 24 weeks post-completion of the treatment period; 2) percentage of naïve patients with a non-detectable HCV RNA at the end of treatment (as measured by Roche AMPLICOR^® HCV Test, v2.0); 3) percentage of pretreated patients with a non-detectable HCV RNA at the end of treatment (as measured by Roche AMPLICOR^® HCV Test, v2.0); 4) percentage of naïve patients with at least a 2 log drop of HCV RNA at study week 12 as compared to baseline, or an unquantifiable test result (as measured by Roche AMPLICOR^® Monitor HCV Test, v2.0: quantitative test with a lower detection limit of 600 IU/mL) or non-detectable HCV RNA (as measured by Roche AMPLICOR^® HCV Test, v2.0); 5) percentage of pretreated patients with at least a 2-log drop of HCV RNA at study week 12 as compared to baseline, or an unquantifiable test result (as measured by Roche AMPLICOR^® Monitor HCV Test, v2.0) or non-detectable HCV RNA (as measured by Roche AMPLICOR^® HCV Test, v2.0).
Safety: Serious adverse events; non-serious adverse events of special interest, which were defined as adverse events leading to dose reduction or discontinuation of trial medication, neutropenia (neutrophil count <750cells/mm³), thrombocytopenia (platelet count <50,000cells/mm³), and anemia (hemoglobin <10g/dL), ALT elevation leading to dose modification, and unknown or unexpected adverse events; dose modifications of trial medication; and treatment withdrawals for safety reasons.

Statistical methods:

The primary analysis had an intent-to-treat (ITT) approach.
In contrast to the recommendation, the 24-week group did not only comprise genotype non-1 patients but also some genotype 1 patients. In addition, several genotype non-1 patients were assigned to the 48-week group. Therefore the efficacy and safety analysis was structured by the following groups:
24 weeks of treatment (assigned at baseline):1) genotype non-1 naïve patients; 2) other patients (genotype 1, unknown genotype, HCV pre-treated, more than 28 weeks of study treatment); 3) all patients
48 weeks of treatment (assigned at baseline):1) genotype 1 naïve patients; 2) genotype 1 IFN/RBV pretreated patients; 3) other patients (genotype non-1, unknown genotype, IFN monotherapy as pre-treatment, more than 52 weeks of study treatment); 4) all patients
Exact 95% (2-sided) confidence intervals (CI) from the binomial distribution were provided for all primary and secondary efficacy variables in the individual groups. A logistic regression analysis was performed to examine the effects of various prognostic factors on the sustained virological response rate.
Descriptive statistics were used to summarize safety parameters by treatment group.

Summary (efficacy, safety, other results):

In the ITT-population sustained viral response (SVR) rate was 63.2% (CI 55.7%; 70.2%) in the 24-week group and 49.1% (CI 45.9%; 52.3%) in the 48-week group. In the 24-week group genotype non-1 treatment naïve patients presented with an SVR rate of 70%; in the 48-week group genotype 1 naïve patients had an SVR of 55%. Genotype 1 IFN/RBV pretreated patients of the 48-week group had an SVR rate of 31%.
At the end of study treatment 79% of patients were responders in the 24-week group and 57% in the 48-week group. In the 24-week group genotype non-1 treatment naïve patients presented with an end-of-treatment virological response of 80%, genotype 1 naïve patients of the 48-week group with 61%. Genotype 1 IFN/RBV pretreated patients in the 48-week group had a virological response at end of treatment of 47%.
Early virological response (EVR) rate at 12 weeks post-treatment was 69% in the 24-week group. This EVR was lower than the end of treatment response. This was due mainly to absence of week 12 values for several patients which were then counted as non-responders at week 12 but were responders at end of treatment. In the 24-week group, in genotype non-1 naïve patients EVR rate was 72%. In the 48-week group EVR rate was 63% in total, 69% in genotype 1 naïve patients and 56% in genotype 1 IFN/RBV pretreated patients.
EVR was a positive predictive factor for SVR in both treatment groups (24 weeks and 48 weeks treatment). The positive predictive value of achieving EVR for SVR was higher in the 24-week group than in the 48-week group (72% versus 60%). Comparing genotypes, the positive predictive value of achieving EVR for SVR was higher in genotype non-1 naïve patients than in genotype 1 naïve patients (77% versus 63%). For genotype 1 IFN/RBV pretreated patients the positive predictive value was low (47%).
In the 48-week group, not achieving EVR was a negative predictor for not achieving SVR. The negative predictive value of not achieving EVR at week 12 for not achieving SVR was 85% in the 48-week group in total, 78% in genotype 1 naïve patients and 97% in genotype 1 IFN/RBV pretreated patients. In the 24-week group, the numbers of patients not achieving EVR and not achieving SVR were so low that no general conclusion can be drawn as to the negative predictability of not achieving EVR.

Safety: The overall reporting rate (ie percentage of patients who reported at least one adverse event) was 20% in the 24 week group and 35% in the 48 week group. In genotype 1 naïve patients, adverse events were reported with the same frequency as in genotype 1 IFN/RBV pretreated patients. The majority of the reported adverse events were assessed by the investigator as related to trial medication. The most frequently reported types of adverse events were blood and lymphatic system disorders (13% in the 24-week group, 27% in the 48-week group), mainly neutropenia, anemia, and thrombocytopenia, which represented the majority of adverse events of special interest. Depression was reported by 3 patients (1.6%) in the 24-week group and 8 patients (0.8%) in the 48-week group.
Serious adverse events were reported by 8 patients (4%) in the 24-week group and 7% in the 48-week group.. In genotype 1 naïve patients and genotype 1 IFN/RBV pretreated patients the frequency of serious adverse events was very similar. Approximately half of all serious adverse events were considered related to trial medication by the investigator. Blood and lymphatic system disorders were the most frequent serious adverse events in the 48 week group, occurring in 1.5% of patients. A total of 11 patients (1 in the 24-week group and 10 in the 48-week group) experienced serious infections.
Four patients died during the study, all of them in the 48 week group. In two patients the adverse event leading to death (hepatocellular carcinoma and cardiac failure, respectively) occurred during study treatment and in the other two, the adverse events leading to death (cerebral hemorrhage and hepatic failure, respectively) occurred about 6 weeks after premature discontinuation of study treatment due to anemia. All deaths were considered unrelated to study treatment by the investigator.
The percentage of patients who prematurely withdrew from PEGASYS for safety reasons in the 48-week group was more than double that in the 24-week group (7% versus 3%). Somewhat more genotype 1 naïve patients prematurely withdrew from PEGASYS for safety reasons than genotype 1 IFN/RBV pretreated patients (8% versus 6%). In the 48-week group, the most frequent reason for premature discontinuation of PEGASYS was blood and lymphatic system disorders (2.7%), mainly consisting of neutropenia (1.1%), anemia (1.0%), and thrombocytopenia (0.5%). In the 24-week group, the majority (3 out of 5 patients) prematurely stopped PEGASYS for depression.
Dose reductions of PEGASYS for safety reasons occurred in 7% of the patients in the 24-week group and in 12% of the 48-week group. No difference was observed between genotype 1 naïve patients and genotype 1 IFN/RBV pretreated patients concerning the rate of dose reductions of PEGASYS for safety reasons. The majority of these modifications were for neutropenia (3% in the 24-week group, 7.0% in the 48-week group). Dose reductions of ribavirin occurred in 4% of the patients in the 24-week group and in 15% of the 48-week group. The most frequent reason was anemia (4% and 11%). In genotype 1 naïve patients and genotype 1 IFN/RBV pretreated patients the same pattern for dose modification of ribavirin was observed.
In patients with liver cirrhosis the safety profile was less favorable. A higher occurrence of adverse events was observed than in the general population. The pattern of adverse events was otherwise very similar.

Conclusions:

This study confirms the efficacy of PEGASYS/ribavirin combination therapy observed in randomized controlled studies in everyday clinical practice. The recommended therapy regimens were highly efficacious in daily routine treatment.
In this study, only the non serious adverse events of special interest were captured, which limits the scope of the safety events reviewed. Therefore, keeping in mind this limitation for the analysis, the safety profile of PEGASYS given in combination with ribavirin for 24 weeks or 48 weeks was similar to that previously reported, and no new safety concerns were identified either in the overall population or in those patients with underlying liver cirrhosis.

Date of report:

01.09.2008

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