Clinical Trial Result Information

Protocol number
ML17619

Title of Study
A pilot study assessing efficacy and safety of peginterferon alfa-2a (PEGASYS) versus continuation of lamivudine (LAM) and/or adefovir dipivoxil (ADV) in patients with chronic hepatitis B pre-treated with LAM and/or ADV for >6 months. An open label, multi-center, randomized, national study.

Sponsor
F. Hoffmann-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 randomized, open label trial comparing continuing treatment with adefovir dipivoxil (ADV) and/or lamivudine (LAM), or switching to treatment with PEGASYS, in patients with chronic hepatitis B. Patients who had been treated with ADV and/or LAM for >6 months were randomized either to a further 72 weeks of continuous therapy with ADV and/or LAM, or to 48 weeks' therpy with PEGASYS followed by a 24-week follow-up without antiviral therapy. The study was prematurely terminated after 11 months, since only 14 patients had been randomized at this point. Due to this premature termination, data were available only up to week 52.

Study center(s)
7 centers in France.

Phase of development
III

Objectives
Primary: To explore the efficacy of new-onset therapy with PEGASYS compared to that of continued therapy with ADV and/or LAM in patients with chronic hepatitis B pre-treated with ADV and/or LAM for >6 months.
Secondary: To explore the safety profile of PEGASYS compared to that of continued therapy with ADV and/or LAM in patients with chronic hepatitis B pre-treated with ADV and/or LAM for >6 months.

Methodology
Patients with chronic hepatitis B were to be treated with weekly PEGASYS, 180μg sc for 48 weeks, followed by 24 treatment-free weeks, or with oral adefovir dipivoxil 10mg + oral lamivudine 100mg daily for 72 weeks. At the end of 48 and 72 weeks, viral load and serum ALT were to be measured. Adverse events and laboratory parameters were measured at intervals throughout the study.

Number of patients (planned/analyzed)
Planned: 140. Actual: 14.

Diagnosis and main criteria for inclusion
Adults with chronic hepatitis B (HBeAg-positive or HBeAg-negative) pre-treated with ADV and/or LAM for >6 months, with HBV DNA <10,000 copies/mL at screening and no virologic indication of resistance to lamivudine and/or adefovir, with ALT ≤10x ULN.

Test product, dose and mode of administration or test procedure
PEGASYS (peginterferon alfa-2a (40KD)): 180μg sc once weekly, subcutaneous injection for 48 weeks (planned).

Duration of treatment
72 weeks (planned)

Reference therapy, dose and mode of administration or reference procedure
Adefovir dipivoxil: 10mg once daily, orally, and/or lamivudine: 100mg once daily, orally for 72 weeks (planned).

Criteria for evaluation (efficacy, safety)
Efficacy: Primary: Loss of HbsAG 72 weeks after start of randomized treatment.
Secondary: Loss of HBsAg 48 weeks after start of randomized treatment; HBsAg seroconversion (HBsAg loss and presence of anti-HBs) at 48  and 72 weeks after start of randomized treatment; HBV DNA <200, <400, ≤10,000 copies/mL, (Roche TaqMan Assay) at 48 and 72 weeks after start of randomized treatment; normal serum ALT at 48 and 72 weeks after start of randomized treatment; combined response (HBV DNA <10,000 copies/mL and normal ALT) at 48 and 72 weeks after start of randomized treatment.

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

Statistical methods
The primary objective was to demonstrate the efficacy superiority of PEGASYS (group A) versus continuous treatment (group B).
The primary analysis was to have been conducted on the Intention-to-treat (ITT) population, including all randomized patients. All patients receiving at least one dose of study medication and having a subsequent safety assessment were to be considered for analyses of safety.

Summary (efficacy, safety, other results)
αDue to the premature termination of the study, at which point only 14 patients had been randomized (6 in the PEGASYS group, and 8 in the ADV/LAM group), and 1 patient in the PEGASYS group had withdrawn consent, only a descriptive analysis of the data was conducted.
The primary efficacy parameter was the change observed in the HBsAg status at 72 weeks. Due to the premature termination of the study, data were available only until week 52: HBsAg loss was not identified in any patient during this period.
Secondary efficacy parameters: HBsAg loss was not observed during the treatment period in patients with data up to week 48.
After 24 weeks of PEGASYS treatment, one patient had a positive anti-HBs ab test. At week 48, a second PEGASYS patient had a positive anti-HBs ab test. In the ADV/LAM group, 2 patients had a positive test at week 48. No HBsAg seroconversion (defined by the loss of HBsAg and the presence of anti-Hbs antibody) was observed. All the patients remained HBsAg positive during this period.
Only one patient (in the ADV/LAM group) had an HBeAg positive and anti-HBe ab negative test at inclusion. HBeAg loss was not observed for this patient but data were available only up to 24 weeks. No seroconversion (defined by the loss of HBeAg and the presence of anti-HBe antibody) was observed for this patient.
In the PEGASYS group, the median HBV DNA remained unchanged during the 48 week treatment period. An increase of median HBV DNA was observed in the ADV/LAM group after week 12.
The median ALT remained unchanged in the ADV/LAM group. An increase was observed in the PEGASYS group during the first 4 weeks of the treatment period, then ALT decreased but stayed 10U/L above the baseline level at the end of treatment.
Because of the small number of patients per group and the number of non documented patients at each study period, interpretation of the efficacy data is difficult.

Safety: Mean patient exposure to study treatments was 42 week, the ADV/LAM patients having a slightly longer treatment than the PEGASYS group (43 weeks vs. 41 weeks).
Among the 13 patients analysed for safety, the total number of reported adverse events was 52. Seventeen AEs were reported in the ADV/LAM group and 35 AEs in the PEGASYS group. These proportions are consistent with previous studies with both treatments in this pathology.
Most of the AEs (94%) were mild or moderate in intensity. In the PEGASYS group, mild AEs were the most frequently experienced (mild: 49%; moderate: 43%) while moderate AEs were more frequent in the ADV/LAM group (59% vs. 41%). Three severe AEs were reported in the PEGASYS group. In the overall population, the most frequent AEs were psychiatric events (33%) followed by digestive (13%) and hematologic (13%) events.
Approximately half of the adverse events (25/52) were related to treatment. All the related AEs were reported by 4 patients in the PEGASYS group, with the most common AEs being psychiatric (9 events) and hematologic abnormalities (7 events).
One patient (PEGASYS group) reported a serious adverse event not related to study drug (broken leg).
A total of 20% of the AEs in the PEGASYS group were hematological abnormalities, neutropenia and thrombopenia, whereas no hematological abnormalities were reported in the ADV/LAM group. Most of the neutropenic events (79%) in the PEGASYS group were grade 1 or 2, and all the thrombopenic events were grade 1. A total of 18% of the AEs in the ADV/LAM group were incidences of hypercreatinemia, which was not seen in any patients in the PEGASYS group. Digestive events were more frequent in the ADV/LAM group (24% vs. 9%) and dermatogical events more frequent in the PEGASYS group (11% vs. 6%).
Thus, in this limited number of patients, the safety profile of PEGASYS was as expected and that of ADV/LAM was consistent with the known good tolerability of the two drugs.

Conclusions
No conclusions can be drawn from the study, due to its premature termination and the small number or patients enrolled.

Date of report
2/2/2007

Click here for the protocol registry listing of this trial.