Clinical Trial Result Information
Title of Study:
A Phase III Partially Double-Blind Study Evaluating the Efficacy and Safety of Peginterferon Alfa-2a (40KD) (PEGASYS) Combined With Placebo or Lamivudine Versus Lamivudine in HBeAg-Negative Patients With Chronic Hepatitis B (CHB)
Fast Facts:
| Protocol number: | WV16241 |
| Sponsor: | F Hoffman-La Roche Ltd |
| Company division: | Pharmaceutical |
| Product name: | PEGASYS |
| Generic name: | peginterferon alfa-2a (40KD) |
| Phase of development: | III |
| Therapeutic area, approved indication: | Hepatitis B, Chronic |
| Date of report: | 2/1/2004 |
Clinical study summary:
This was a phase III, multicenter, randomized study in HBeAg-negative 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) :
53 centers in Canada, China, France, Germany, Greece, Hong Kong, Italy, New Zealand, Poland, Spain, Switzerland, Taiwan, Thailand and Turkey.
Objectives:
Primary: To compare the efficacy and safety of PEGASYS with and without lamivudine to that of lamivudine monotherapy in the treatment of HBeAg-negative patients with chronic hepatitis B (CHB).
Secondary: To explore sustained outcomes by reference to decreases in viral load and alanine aminotransferase (ALT) levels during therapy.
Methodology:
Patients were randomized to one of 3 treatment groups, to receive PEGASYS/placebo, PEGASYS/lamivudine or lamivudine monotherapy. PEGASYS was administered weekly, 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. Biochemical and virologic 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 to assess pharmacokinetic parameters of pegylated interferon alfa-2a (40KD).
Number of patients (planned/analyzed):
552 randomized; 537 treated.
Diagnosis and main criteria for inclusion:
CHB patients >=18 years of age; anti-HBe–positive for >=6 months; HBeAg-negative; HBsAg-positive; anti-HBs–negative; detectable HBV DNA (>100,000 copies/mL), ALT greater than the upper limit of normal (ULN) but <=10 x ULN; liver biopsy within the previous 24 months, with results consistent with CHB viral 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) Normal ALT levels at end of follow-up; (2) HBV DNA <20,000 copies/mL at end of follow-up.
Secondary efficacy parameters: Paired biopsy comparison, quantitative serum ALT/DNA, loss of HBsAg, and presence of HBsAb.
Pharmacokinetic (PK) parameters: Cmax, Tmax, AUC0-168h Ctrough
Safety parameters: Adverse events, vital signs, and clinical laboratory parameters.
Statistical methods:
Response rate variables were tested using the Cochran-Mantel-Haenszel test (primary analysis) and with conditional logistic regression (secondary analysis). Analysis of covariance was used to analyze the continuous variables.
Summary (efficacy, safety, other results):
Efficacy - PEGASYS treatment had statistically significantly superior efficacy over lamivudine monotherapy with respect to the co-primary endpoints of sustained biochemical response (59% and 60% vs 44%) and virologic response (43% and 44% vs 29%). The combination of lamivudine with PEGASYS offered no additional efficacy benefits compared with PEGASYS alone.
In the PEGASYS treatment arms, 12 patients (3% and 4%) cleared HBsAg, and 8 of these patients (2% and 3%) also developed anti-HBs (ie, HBsAg seroconversion) by Week 72 (see summary below).
|
Respond at end of follow-up |
PEG-IFN/ placebo N=177 |
PEG-IFN/ lamivudine N=179 |
Lamivudine N=181 |
p-value overall* |
|
Serum ALTa |
105(59%) |
107(60%) |
80(44%) |
0.003 |
|
HBV-DNAb |
76(43%) |
79(44%) |
53(29%) |
0.005 |
|
HBsAg loss |
7(4%) |
5(3%) |
0 |
0.029 |
|
HBsAg seroconversion |
5(3%) |
3(2%) |
0 |
0.086 |
|
Histologicalc |
85/143 (59%) |
68/143 (48%) |
72/125 (58%) |
0.101 |
|
a <ULN, b <2000 copies/mL, c decrease in HAI score >=2 points (patients with paired biopsies only)
* p-value overall - from the Cochran-Mantel Haenszel test for differences in responses between the treatment groups, controlling for region and ALT strata |
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). Steady state was achieved within 8 weeks of treatment, with no unpredictable drug accumulation during 48 weeks of treatment.
Safety - The overall safety experience is summarized in the following table:
|
PEG/IFN/ placebo N=177 n(%) |
PEG/IFN/ lamivudine N=179 n(%) |
Lamivudine N=181 n(%) |
|
Any AEs (during and up to 8 weeks post-treatment) |
Any event |
155(88) |
155(87) |
86(48) |
Severe events |
13(7) |
21(12) |
5(3) |
| Serious AEs
|
During treatement and up to 8 weeks post treatment |
9(5) |
12(7) |
5(3) |
Beyond 8 weeks post treatment |
2(1) |
4(2) |
2(1) |
| Premature withdrawls for safety reasons
|
AEs |
9(5) |
7(4) |
0 |
Lab Abnormalities |
3(2) |
0 |
0 |
Death |
1(<1) |
|
|
| Dose modifications/interruptions
|
AEs |
13(7) |
23(13) |
0 |
Laboratory abnormalities |
65(37) |
64(36) |
0 |
The overall tolerability and safety profile in the PEGASYS/placebo arm was similar to that in the PEGASYS/lamivudine arm. The adverse events profile was as expected from previous experience with PEGASYS treatment, and no new or unexpected safety signals were identified.
Serious adverse events included infections (1% and 2% of patients in each treatment arm), thyroid abnormalities (2 cases in PEGASYS-treated patients), and single cases of a variety of other types of events, with no clear pattern across treatment groups. One death due to thrombotic thrombocytopenic purpura occurred in the PEGASYS monotherapy arm.
Temporary or permanent dose modifications for safety reasons (mainly for neutropenia and thrombocytopenia) were common in PEGASYS-treated patients; however, few patients withdrew for these reasons. Approximately 3% of PEGASYS-treated patients developed grade 4 neutropenia (<0.5 x 109/L); however, none was temporally associated with serious or severe infection or led to treatment withdrawal. Grade 3 or 4 thrombocytopenia (~18% of PEGASYS-treated patients versus 2% in the lamivudine group) was managed mainly with permanent dose reduction.
In the PEGASYS/placebo and PEGASYS/lamivudine groups, 34% and 37% of patients, respectively, had grade 3 or higher flares in ALT (ie, >5 x ULN) ,versus 18% in the lamivudine arm, during treatment. These elevations were not associated with hepatic decompensation, and no patient required treatment discontinuation. The majority of events were managed by observation and continuing therapy unchanged; about one fifth of cases were managed with reduction or temporary withholding of dosing.
Post-therapy flares (>5 and >10 x ULN, respectively) were less common in the PEGASYS/placebo arm (20%, 7%) than in the PEGASYS/lamivudine (31%, 15%) and lamivudine monotherapy (33%, 14%) arms.
Conclusions:
PEGASYS treatment resulted in significantly higher end of follow-up responses (both virologic and biochemical) than lamivudine monotherapy in HBeAg-negative patients with CHB viral infection. Addition of lamivudine to PEGASYS therapy did not provide additional efficacy benefit, or alter the safety or PK profile of PEGASYS.
Post-therapy ALT flares were more common in patients treated with lamivudine (monotherapy or in combination with PEGASYS) than in patients treated with PEGASYS monotherapy.
No new or unexpected safety signals arose with PEGASYS treatment during this study, and the majority (>90%) of patients were able to complete the 48 weeks planned duration of treatment.
Publications (references, if available):
Peginterferon Alfa-2a Alone, Lamivudine Alone, and the Two in Combination in Patients with HBeAg-Negative Chronic Hepatitis B. NEJM 351 (12): 1206-1217, (2004)
