Clinical Trial Result Information
Title of Study:
Efficacy and safety of peginterferon alfa-2a (40KD) (PEGASYS) in patients with HBeAg positive chronic hepatitis B.
Fast Facts:
| Protocol number: | ML17700 |
| Sponsor: | Shanghai Roche Pharmaceutical Ltd. |
| Company division: | Pharmaceutical |
| Product name: | PEGASYS |
| Generic name: | peginterferon alfa-2a (40KD) |
| Phase of development: | IV |
| Therapeutic area, approved indication: | Hepatitis B, Chronic |
| Date of report: | 4/3/2006 |
Clinical study summary:
This was a multicenter, national, non-randomized, open label study conducted in patients with HBeAg positive chronic hepatitis B (CHB). All patients received PEGASYS for 48 weeks, and were evaluated at week 72.
Study center(s) :
46 centers in China.
Objectives:
To evaluate the efficacy and safety of PEGASYS given for 48 weeks in the treatment of Chinese patients with HBeAg positive chronic hepatitis B.
Methodology:
Following screening, eligible patients were stratified into 3 groups according to their pre-treatment history (Group A: naïve patients; Group B : interferon-pre-treated; Group C : lamivudine-pre-treated. All patients received PEGASYS 180μg subcutaneously once weekly for 48 weeks. After 24 weeks of treatment-free follow-up, seroconversion and HBV-DNA response rate were assessed.
Number of patients (planned/analyzed):
307 enrolled; 305 ITT population (≥1 dose, and post-baseline assessment), 255 PP population (≥4 weeks of treatment).
Diagnosis and main criteria for inclusion:
CHB patients 18-65 years of age, HBeAg positive for at least 6 months, HBsAg positive and HBsAb negative for at least 6 months, serum HBV DNA >500000 copies/mL, ALT>ULN but ≤10xULN.
Test product, dose and mode of administration or test procedure:
PEGASYS (peginterferon alfa-2a (40KD)) 180 µg subcutaneously once weekly for 48 weeks.
Duration of treatment:
48 weeks.
Criteria for evaluation (efficacy, safety):
Primary endpoints at week 72:（i）HBeAg seroconversion: loss of HBeAg and presence of anti-HBe（ii）HBV-DNA<105copies/mL
Secondary endpoints both at week 48 and week 72:（i）HBV-DNA<5x102copies/mL,（ii）Loss of HBeAg,（iii）Loss of HBsAg and presence of anti-HBs at week 72,（iv）ALT normalization,（v）combined response of loss of HBeAg, ALT normalization and HBV DNA<105copies/mL.
Statistical methods:
Although an ITT analysis was specified in the protocol, efficacy data were analyzed based on the per-protocol population, i.e. PP analysis, owing to the large number of significant protocol violations. Patients with missing data at week 48 and/or week 72 were defined as non-responders. Response rates for the primary and secondary endpoints were expressed as percentages with their respective 95% confidence intervals. Analysis of variance was used to analyze continuous variables. Incidence of adverse events and laboratory abnormalities were descriptively summarized by group.
Summary (efficacy, safety, other results):
Efficacy: The analysis was based on 255 evaluable patients. At week 72, the HBV-DNA response rate (HBV-DNA <105 copies/mL) was 31.87%, 33.33% and 25.30% in groups A, B, C, respectively. Although the figure was similar between groups A and B, and somewhat lower in group C, there was no significant difference across the groups (p=0.4862).
At week 72, no significant difference was observed on the HBeAg seroconversion among the three groups. The seroconversion rates were 19.78%, 14.81% and 18.07%, respectively (p=0.6899).
All secondary efficacy response variables both at week 48 and week 72 were similar among the 3 groups, with no significant difference observed. Of particular note, only one patient in group A attained HBsAg seroconversion at week 72. The combined response rate at week 72 was slightly higher than at week 48 in each group.
At the end of treatment (48 weeks), there were a total of 219 patients remaining; the HBV-DNA response rate (HBV-DNA<105 copies/mL) was 45.57% (36/79), 42.03% (29/69) and 49.30% (35/71) in group A, B, C, respectively; there was no statistically significant difference across the groups (p=0.6890). Likewise, there was no statistically significant difference observed in the HBeAg seroconversion among the three groups (24.05%, 17.39% and 16.90% respectively (p=0.4647).
At the end of follow up (72 weeks), there were a total of 142 patients remaining; the HBV-DNA response rate (HBV-DNA<105 copies/mL) was 63.04% (29/46), 57.45% (27/47) and 42.86% (21/49) in group A, B, C respectively. The HBeAg seroconversion rate among the three groups was 39.13%, 25.53% and 30.61% respectively (p=0.4647). No statistically significant differences were observed (p>0.05).
Safety: The incidence of adverse events in groups A, B, C was 62%, 56% and 63% respectively. The safety profiles of the three groups were similar, and the common adverse events (defined as those with an incidence of at least 5%) were those known to be associated with interferon therapy including pyrexia (41%), mya-arthralgia (15%), fatigue (14%), dizziness (10%), alopecia (8%), gastrointestinal discomfort (8%), thyroid dysfunction (6%) and weight loss (6%); other less commonly reported were pruritus, rash, asthenia, and gingival bleeding. During the treatment period, only 3 serious adverse events occurred, one in each group. These SAEs were psoriasis (possibly related), paratyphoid C (remotely related) and fever (possibly related). All required additional hospitalization and cessation of study medication, and all were resolved without sequelae. During the treatment period, 7 patients were prematurely withdrawn from the study for adverse events (3 in group A, 2 in group B and 2 in group C), and 3 patients (1 in group A, 2 in group B) were withdrawn due to significant laboratory abnormalities. During the entire study period, the main reasons for withdrawal were loss of contact (patients’ poor compliance) and refusal to return due to insufficient therapeutic response.
In the three groups, similar proportions of patients (25% in group A, 19% in group B and 25% in group C) experienced dose modifications for safety reasons. The majority were due to laboratory abnormalities, of which leucopenia or neutropenia was the most common, followed by thrombocytopenia and ALT disorders.
As was expected from the known safety profile of PEGASYS, abnormalities in leucocytes, platelet counts, hematocrit, haemoglobin and serum triglycerides were observed in all three groups during the treatment period, but gradually returned to normal values after treatment.
Conclusions:
In Chinese patients with HBeAg positive chronic hepatitis B, after receiving PEGASYS 180 μg monotherapy once per week for 48 weeks, followed by a 24-week no treatment observation, 25.3%~33.3% of the patients obtained a viral response at the week 72 visit. The low response rate was thought to be due to the unexpectedly high drop out rate (up to 39% of patients had missing data at the week 72 visit) which made the study results very difficult to interpret. However, as the differences between the 3 groups were not significant, pre-treatment with interferon or lamivudine is not a hurdle for PEGASYS treatment, delivering comparable responses in HBV DNA decline and HBeAg seroconversion compared to those seen in naïve patients.
The safety profile of PEGASYS in this study was consistent with the known safety profile of PEGASYS in CHB patients in previous studies, and no new safety issues were identified. Pretreatment with interferon or lamivudine did not produce a change in the safety profile, compared to that seen in naïve patients. As in previous studies, PEGASYS was safe and tolerable in the Chinese patient population.
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