Clinical Trial Result Information

Protocol number
WV16240

Title of Study
A Phase III Partially Double-Blinded Study Evaluating the Efficacy and Safety of Peginterferon Alfa-2a (40KD) (PEGASYS) Combined With Placebo or Lamivudine Versus Lamivudine in HBeAg-Positive Patients With Chronic Hepatitis B

Sponsor
F Hoffman-La Roche Ltd

Company division
Pharmaceutical

Product name
PEGASYS

Generic name
peginterferon alfa-2a (40KD)

Therapeutic area
Hepatitis B, Chronic

Clinical study summary
This was a phase III, multicenter, randomized study in HBeAg-positive patients with chronic hepatitis B. Patients were randomized 1:1:1 to PEGASYS/placebo, PEGASYS / lamivudine, or lamivudine monotherapy, and the efficacy and safety of PEGASYS monotherapy or PEGASYS/ lamivudine was compared to that of lamivudine monotherapy.

Study center(s)
67 centers in Australia, Brazil, Canada, China, France, Germany, Hong Kong, Israel, Korea, New Zealand, Poland, Singapore, Switzerland, Taiwan, Thailand and the United States.

Phase of development
III

Objectives
Primary: To compare the efficacy and safety of PEGASYS with and without lamivudine with lamivudine monotherapy in the treatment of HbeAg-positive patients with chronic hepatitis B (CHB).

Secondary: To explore sustained outcomes by reference to decreases in alanine aminotransferase (ALT) levels and comparison of paired biopsies.

Methodology
Patients were randomized to one of 3 treatment groups to receive PEGASYS/placebo, PEGASYS/lamivudine or lamivudine monotherapy. PEGASYS was administered weekly, and lamivudine or placebo were administered daily. Patients were evaluated at treatment Weeks 1, 2, 4, 6, 8, and 12 and every 6 weeks thereafter for a total of 48 weeks. Virologic and immunologic response was assessed at the end of 24 weeks of untreated follow-up (ie Week 72). Safety was assessed throughout the study, and blood samples were taken from a limited number of patients to assess the effect of lamivudine on the pharmacokinetics (PK) of pegylated interferon alfa-2a (40KD), and vice versa.

Number of patients (planned/analyzed)
820 randomized; 814 treated.

Diagnosis and main criteria for inclusion
CHB patients >=18 years of age; positive HBeAg; positive HBsAg and negative HBsAb; serum HBV-DNA >500,000 copies/mL; ALT greater than the upper limit of normal (ULN) but ≤10 x ULN; liver biopsy performed within previous 12 months and results consistent with CHB infection.

Test product, dose and mode of administration or test procedure
PEGASYS, 180 µg/sc/qw/48 weeks, with placebo or lamivudine, 100 mg/po/qd/48 weeks.

Duration of treatment
48 weeks, followed by 24 weeks of untreated follow-up.

Reference therapy, dose and mode of administration or reference procedure
Lamivudine 100 mg/po/qd/48 weeks

Criteria for evaluation (efficacy, safety)
Primary efficacy parameters): (1) HBeAg seroconversion defined as the absence of HBeAg and presence of anti-HBe at week 72; (2) HBV-DNA response defined as the HBV-DNA <105 copies/mL at week 72.

Secondary efficacy parameters (Week 72): (1) loss of HBeAg; (2) loss of HBsAg and loss of HBsAg with presence of anti-HBs; (3) combined endpoint of HBeAg seroconversion, normalization of ALT, and HBV-DNA <105 copies/mL; (4) serum ALT.

PK parameters: peginterferon alfa-2a (40KD): tmax, Cmax, AUC0-168h Ctrough. lamivudine: Ctrough.

Safety parameters: Adverse events, laboratory abnormalities and vital signs.

Statistical methods
Response rate variables were tested using the Cochran-Mantel-Haenszel test and with conditional logistic regression. The continuous variables were analyzed with analysis of covariance.

Summary (efficacy, safety, other results)
Efficacy - Patients treated with PEGASYS had significantly higher end of follow-up HBeAg seroconversion and HBV-DNA responses than patients treated with lamivudine monotherapy. The combination of lamivudine with PEGASYS offered no additional efficacy benefits compared with PEGASYS alone.

All secondary efficacy response variables except histologic response were significantly higher at the end of follow-up in patients receiving PEGASYS than in patients receiving lamivudine monotherapy. Sixteen patients (3%) treated with PEGASYS attained HBsAg seroconversion at Week 72, compared with no patients treated with lamivudine monotherapy (P=0.016).

Major efficacy results are summarized below:

Efficacy Endpointa	PEG-IFN/Plac n= 271	PEG-IFN/Lam n= 271	Lam Mono n = 272	Overall p valueb
Primary Efficacy Endpoints
HBeAg seronconversion	87(32.1%)*	74(27.3%)	52(19.1%)	0.003
HBV-DNA <105 copies/mL	86(31.7%)*	91(33.6%)*	60(22.1%)	0.007
Secondary Efficacy Endpoints
Response variables
Loss of HBeAg	91(33.6%)*	77(28.4%)*	57(21.0%)	0.004
Loss of HBsAg	9(3.3%)*	11(4.1%)*	2(0.7%)	0.043
HBsAg seroconversion	8(3.0%)*	8(3.0%)*	0(0%)	0.016
Normalization of ALT activity	111(41.0%)*	106(39.1%)*	76(27.9%)	0.003
Paired liver biopsy responsec	102(49.3%)	112(52.1%)	93(50.5%)	0.786
Triple endpoint response	62(22.9%)*	56(20.7%)*	28(10.3%)	<0.001
Quantitative variablesc,d
Adjusted mean log10 ALT	1.59	1.61	1.67	0.107
Adjusted mean log10 HBV-DNA	7.98*	7.84*	8.58	0.030
Adjusted mean log10 (HBeAg+1)	1.49	1.51	1.64	0.284
Adjusted mean total HAI score	7.41	6.86	7.00	0.195
Note: plac = placebo; lam = lamivudine; mono = monthereapy *Significantly different from the lamivudine montherapy group. a For primary efficacy endpoints, p <0.0125 was considered statisically significant; for secondary efficacy endpoints, p<0.05 was considered statisically significant. b Differences among three treatment groups were based on Cochran-Mantel-Haenszel test or ANCOVA as appropriate. c Sample size may differ from the number of patients in the intent-to-treat population for a given group. d Units of the quantitative variables: log10 ALT = U/L, log10 HBV-DNA = copies/mL; log10 (HBeAg+1) = IU/mL.

PK - The PK profiles for peginterferon alfa-2a (40KD) as monotherapy and in combination with lamivudine were similar, indicating that lamivudine treatment did not alter the PK of peginterferon alfa-2a (40KD). A steady state was achieved within about 12 weeks of treatment with no unpredictable accumulation of peginterferon alfa-2a (40KD) during 48 weeks of treatment. The effects of peginterferon alfa-2a (40KD) on lamivudine pharmacokinetics could not be assessed because of high variations of lamivudine trough concentration.

Safety - More adverse events and laboratory abnormalities were reported in patients treated with PEGASYS than in those treated with lamivudine alone. No new safety concerns of PEGASYS were identified.

The most common adverse events reported in the PEGASYS groups were the well-known flu-like symptoms. A total of 24 patients treated with PEGASYS (with or without lamivudine) experienced depression, 3 additional patients had depressed mood, and 1 patient had suicidal ideation. Infections occurred similarly in frequency in the three treatment groups (20% to 22%), with serious infections in a total of 15 patients.

The incidence of serious adverse events, deaths and premature withdrawals is shown in the table below. Two patients treated with lamivudine monotherapy had hepatic decompensation after discontinuation of lamivudine, which led to liver transplantation in 1 patient and death in the other patient. None of the 3 deaths in the PEGASYS/lamivudine group was considered treatment related; the death in the lamivudine monotherapy group was considered partly related to discontinuation of lamivudine.

In the PEGASYS treatment groups, laboratory abnormalities such as neutropenia, thrombocytopenia, and elevation of ALT levels were the major reasons for safety-related PEGASYS dose reductions. A total of 26 patients treated with PEGASYS experienced a decrease in neutrophil count to < 0.5 × 109/L and 49 patients experienced a decrease in platelet count to < 50 × 109/L. Neutropenia and thrombocytopenia usually returned to baseline level on completion of treatment and were clinically manageable by dose reduction in most cases. Treatment discontinuations were uncommon. No close associations were found between severe neutropenia and infection and between severe thrombocytopenia and bleeding disorders.

Increases in ALT to > 50 U/L during treatment were more common in the PEGASYS treatment groups (45%) than in the lamivudine monotherapy group (35%). In contrast, the incidence of increase in ALT to >150 U/L during follow-up was slightly lower in the PEGASYS/placebo group (27.7%) than in the lamivudine monotherapy group (33.5%). Treatment withdrawals for ALT flares were rare.

In general, the safety profile of the 2 PEGASYS treatment groups was similar.

Safety Parameters	PEG-IFN/Lam N = 271 n(%)	PEG-IFN/Lam N = 271 n(%)	Lam Mono N = 272 n(%)
AEs during trt and up to 8 weeks post-trt
Any events	240(89)	240(89)	152(56)
Severe events	25(9)	27(10)	15(6)
Serious AEs
During trt and up to 8 weeks post-trt	12(4)	16(6)	5(2)
Beyond 8 weeks post trt	4(1)	5(2)	6(2)
Deaths
During trt and up to 8 weeks post-trt	0	3	0
Beyon 8 weeks post trt	0	0	1
Premature withdrawals for AEs
Withdrawals from both PEG-IFN and lam/plac	6(2)	5(2)	-
Withdrawals from PEG-IFN trt only	1(<1)	1(<1)	-
Withdrawals from lam mono	-	-	2(<1)
PEG-IFN dose modifications for AEs	20(7)	23(8)	2
Note: trt = treatment; Plac = Placebo; Lam = lamivudine; mono = monotherapy

Conclusions
PEGASYS was more efficacious than lamivudine monotherapy in the treatment of patients with HbeAg-positive CHB, as demonstrated by significantly higher end-of-follow-up HBeAg seroconversion response and HBV-DNA response. The combination of lamivudine with PEGASYS did not provide additional efficacy benefits over PEGASYS alone.

The safety profile of PEGASYS in patients with HBeAg-positive CHB was consistent with the known safety profile of PEGASYS in CHC patients, and no new safety issues were identified. The majority of patients (≥90%) were able to receive the planned duration of 48 weeks of study treatment.

Publications (references, if available)
Lau G, Piratvisuth T, Luo KX et al; Peginterferon Alfa-2a, Lamivudine, and the Combination for HBeAg-Positive Chronic Hepatitis B. NEJM 352 (26):2682-2695 (2005)

Date of report
6/1/2004