Clinical Trial Result Information

Title of Study:
Randomized, multicenter, double-blind, pilot study evaluating the effect of PEGASYS doses of 180 µg or 270 µg in combination with Copegus doses of 1200 mg or 1600 mg on viral kinetics, virological response, pharmacokinetics, and safety in interferon-naïve patients with chronic hepatitis C genotype 1 virus infection of high viral titer and body weight greater than 85 kg.

Fast Facts:

Protocol number:	NV17318
Sponsor:	Hoffmann-La Roche, 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:	10/1/2006

Clinical study summary:
This was a randomized, multicenter, double-blind, parallel-group study comparing the efficacy, pharmacokinetics, and safety of the combination of higher doses of PEGASYS, 270 µg sc once weekly, and ribavirin, 1600 mg po daily, with that of the approved doses of PEGASYS, 180 µg sc once weekly, and ribavirin, 1200 mg po daily, in patients with HCV genotype 1 infection, high viral titer, and body weight >85 kg.

Study center(s) :
Total of 23 centers in the United States.

Objectives:
Primary: To evaluate the effect of treatment with PEGASYS doses of 180 or 270 µg weekly in combination with ribavirin doses of 1200 or 1600 mg daily on HCV viral kinetics from baseline to week 24 in patients with HCV genotype 1 virus infection of high viral titer and body weight >85kg .
Secondary: To compare the efficacy and safety of the combination of higher doses of PEGASYS (270 µg once weekly) and ribavirin (1600 mg daily) to that of the approved doses of PEGASYS (180 µg once weekly) and ribavirin (1200 mg daily) in the target population. To evaluate the pharmacokinetics of PEGASYS doses of 180 or 270 µg weekly and ribavirin doses of 1200 or 1600 mg daily when given for 24 weeks as combination therapy.

Methodology:
Patients were screened within 35 days before the first dose of study drug. Virological response was assessed at 72 hours and at intervals up to week 72. Patients were evaluated for safety at intervals until the end of treatment and at weeks 48, 60 and 72 after start of treatment. Patients who exhibited evidence of a virological response (serum HCV RNA <50 IU/mL) but were prematurely withdrawn from treatment for other reasons were followed to week 72.

Number of patients (planned/analyzed):
188 enrolled and randomized; 187 treated.

Diagnosis and main criteria for inclusion:
Male and female patients ≥18 years of age weighing >85 kg with serologically and histologically confirmed CHC, elevated ALT, HCV genotype 1 infection, HCV RNA >800,000 IU/mL, and compensated liver disease.

Test product, dose and mode of administration or test procedure:
PEGASYS (peginterferon alfa-2a (40KD) 180 µg or 270 µg. Copegus (ribavirin) 1200 mg or 1600 mg.
Group A: (control): 180 µg of PEGASYS administered sc once weekly + 1200 mg ribavirin po daily for 48 weeks.
Group B: 180 µg of PEGASYS administered sc once weekly + 1600 mg of ribavirin administered po daily for 48 weeks.
Group C: 270 µg of PEGASYS administered sc once weekly + 1200 mg of ribavirin administered po daily for 48 weeks.
Group D: 270 µg of PEGASYS administered sc once weekly + 1600 mg of ribavirin administered po daily for 48 weeks.

Duration of treatment:
48 weeks.

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

Criteria for evaluation (efficacy, safety):
Efficacy: Primary: Viral kinetics from baseline to week 24 of treatment including patterns of viral decline during the initial 24 weeks, virological response (serum HCV RNA <50 IU/mL) at individual clinical visits, and prediction of sustained virological response. Secondary: Sustained virological response, virological response at the end of the treatment period (week 48), and virological response at 12 weeks after the end of treatment period. Pharmacokinetics: Peginterferon alfa-2a (40KD) serum trough concentrations; ribavirin plasma trough concentrations. Safety: Clinical and laboratory adverse events, Beck Depression Inventory scores, dose adjustments and premature withdrawal for safety reasons, laboratory test results and vital signs.

Statistical methods:
Efficacy: A repeated measures linear mixed effects analysis of covariance appropriate for unbalanced data was used to compare the HCV RNA profile across treatment arms over the initial 24 weeks of treatment. For the multiple linear logistic regression analyses, stepwise and backward linear regression models were used. Virological responses and their corresponding 95% confidence limits were summarized by treatment group at each visit. Probability of a sustained virological response was predicted using log10-transformed viral load at week 4 and virological response status at week 12. Pharmacokinetics: Peginterferon alfa-2a (40KD) serum trough concentrations and ribavirin plasma trough concentrations were summarized using descriptive statistics. Safety: Descriptive statistics were used to summarize safety parameters by treatment group.

Summary (efficacy, safety, other results):
In the week 24 analysis, the two treatment regimens using 270μg of PEGASYS appeared to have an efficacy advantage over the two treatment regimens using the approved 180μg dose of PEGASYS. The p-value for the pairwise comparison of the higher vs the lower dose of PEGASYS (270μg vs 180μg) in patients receiving the higher ribavirin dose (1600mg) was significant (p=0.036), and in patients receiving the lower ribavirin dose (1200mg) was of borderline significance (p=0.061). The predicted sustained virological responses of 48% and 50% in the two groups receiving the 270μg dose of PEGASYS were higher than in the two groups receiving the 180μg dose of PEGASYS (41% and 31%). The percentages of patients who achieved a virological response at week 12 and at week 24 were numerically higher in the groups receiving the 270μg dose than in those receiving the 180μg dose (53% and 51% vs 48% and 38% at week 12, and 60% and 68% vs 57% and 55% at week 24).
Except for virological response at week 24, which was numerically higher in the group receiving 1600mg ribavirin (68%) than in the group receiving 1200mg ribavirin (60%), in combination with the 270μg dose of PEGASYS, the ribavirin dose did not appear to play an important role in decreasing the viral titer or on sustained virological response.
The three experimental regimens appeared to have some efficacy advantage over the control regimen when sustained virological response was evaluated. Increasing either the PEGASYS dose to 270 µg or the ribavirin dose to 1600 mg resulted in an improvement of only 4% to 8% in sustained virological response. The improvement in sustained virological response was 19% when the doses of both drugs were increased.
The highest sustained virological response (47%) was achieved by the group receiving the higher doses of both PEGASYS and ribavirin, and the lowest sustained virological response (28%) was seen in the control group, which received the currently approved doses of PEGASYS and ribavirin. The sustained virological responses in the other two experimental groups were 32% and 36%. The results were similar for virological response at 12 weeks after the end of treatment.
Increasing only the PEGASYS dose to 270 µg or increasing only the ribavirin dose to 1600 mg improved virological response at the end of treatment (55% and 57%, respectively) relative to the control group (46%), but these responses were not maintained between weeks 48 and 72. In contrast, simultaneously increasing the doses of both PEGASYS and ribavirin improved end-of-treatment response (55%) as well as relapse rate, 19% compared with 40% in the control group.

Pharmacokinetics: PEGASYS mean trough concentrations reached steady state between week 8 and week 12, and accumulation from week 4 to week 24 was approximately 1.1-fold to 1.3-fold across the four treatment groups. The average steady-state serum trough concentrations in patients receiving weekly doses of 270μg PEGASYS represented a 1.5-fold increase in exposure level from the 180μg dose, indicating a linear dose response for this dose range. Linear regression analysis showed an association between PEGASYS serum trough concentrations and body weight across the body weight range evaluated in this study; PEGASYS serum trough concentrations decreased with increasing body weight.
Ribavirin plasma exposure in patients weighing more than 85 kg was equivalent to the exposure reported from previous studies at the same dose level. AUC 0-12 values were similar to the mean AUC 0-12 values in a general population of HCV patients receiving 1000 or 1200mg daily doses of ribavirin based on a 75kg body weight cutoff. The mean AUC 0-12, 24 week dose at week 24 in the two groups assigned to the 1600mg daily dose of ribavirin was 35 μg.h/mL. This is 15% lower than the expected mean value (41μg.h/mL) based on a linear dose-exposure response, because patients in the 1600mg dose group had relatively more dose reductions.

Safety: The most intensified treatment regimen, the 270 µg PEGASYS dose in combination with the 1600 mg ribavirin dose, was associated with a less favorable safety and tolerability profile than the approved treatment regimen of 180 µg of PEGASYS plus 1200 mg of ribavirin (control arm). The 270 µg PEGASYS dose in combination with the 1200 mg ribavirin dose was associated with a safety and tolerability profile that was closer to that of the control arm.

	PEGASYS 180 µg Ribavirin 1200 mg (N=46)	PEGASYS 180 µg Ribavirin 1600 mg (N=47)	PEGASYS 270 µg Ribavirin 1200 mg (N=47)	PEGASYS 270 µg Ribavirin 1600 mg (N=47)
Serious AEs	4 ( 9%)	6 ( 13%)	6 ( 13%)	5 ( 11%)
Related Serious AEs	2 ( 4%)	2 ( 4%)	2 ( 4%)	4 ( 9%)
Deaths	0	0	0	0
Dose modification for AEs
or lab abnormalities
PEGASYS	9 ( 20%)	12 ( 26%)	8 ( 17%)	13 ( 28%)
Ribavirin	11 ( 24%)	21 ( 45%)	21 ( 45%)	28 ( 60%)
Premature withdrawals for
AEs or lab abnormalities
PEGASYS	6 ( 13%)	3 ( 6%)	8 ( 17%)	11 ( 23%)
Ribavirin	5 ( 11%)	3 ( 6%)	8 ( 17%)	13 ( 28%)
Neutrophil Count
<0.75 x 109.L	7 ( 15%)	7 ( 15%)	4 ( 9%)	11 ( 23%)
<0.50 x 109/L	2 ( 4%)	1 ( 2%)	0	3 ( 6%)
Lymphocytes <0.5 x 109/L	3 ( 7%)	4 ( 9%)	10 ( 21%)	13 ( 28%)
Hemoglobin
<10 g/dL	9 ( 20%)	16 ( 34%)	11 ( 23%)	13 ( 28%)
<8.5 g/dL	2 ( 4%)	3 ( 6%)	1 ( 2%)	8 ( 17%)

Note: Values in this table represent the number and percentage of patients who experienced the event.

No new safety signals were observed in the cirrhotic patients, and the safety profile in cirrhotic patients was similar to that in the overall population.

Conclusions:
The results of this pilot study suggest that the benefit-risk assessment for each of the three experimental arms was somewhat equivocal. The experimental arms that intensified treatment by increasing the dose of just one component of the combination regimen were associated with acceptable risk but only modest benefit. The experimental arm that intensified treatment by increasing the dose of both components of the regimen (PEGASYS 270μg plus ribavirin 1600mg) was associated with meaningful benefit but an increase in risk. The overall results of the trial support the hypothesis that treatment intensification can improve response in this difficult to treat population but suggest that further modification of the experimental arm should be considered in an attempt to optimize the benefit-risk profile.

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