Clinical Trial Result Information

Title of Study:
A randomized, open-label, multi-center, efficacy and safety study of Pegasys as a prophylaxis against hepatitis C virus infection recurrence after liver transplantation.

Fast Facts:

Protocol number:	NR15996
Sponsor:	Roche Laboratories 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:	1/5/2004

Clinical study summary:
This prospective, multi-center, open-label, multiple-dose study evaluated the efficacy and safety of PEGASYS given once weekly for 48 weeks to prevent recurrence of hepatitis C virus (HCV) infection following liver transplantation.

Study center(s) :
17 centers: 13 throughout the United States and 4 in Canada.

Objectives:
Primary: To evaluate PEGASYS as prophylaxis against recurrence of HCV infection in liver transplant recipients as measured by the sustained response of PEGASYS following 48 weeks of therapy and 24 weeks of treatment-free follow-up based on viral load.

Secondary: To investigate the effect of PEGASYS on: (1) Viral load after 4, 12, 24, and 48 weeks of therapy; (2) Decrease of 2-log10 from baseline of HCV-RNA measured at 4, 12, and 24 weeks of therapy; (3) Serum alanine aminotransferase (ALT) levels after 4, 12, 24, and 48 weeks of therapy, and after 24 weeks of treatment-free follow-up; (4) Histologic changes based on the histology activity index (HAI), as measured by comparison of liver biopsy findings pretreatment, Week 48 (end of treatment), and at the end of the 24-week treatment-free follow-up period.

Safety: The safety of PEGASYS was evaluated by monitoring (1) Vital signs, laboratory values, adverse events (AEs), electrocardiograms, and chest x-ray films; (2) Dose adjustments of study medication and immunosuppressive regimen; (3) Malignancies; (4) Opportunistic infections; and (5) Premature withdrawals for safety reasons.

Graft survival was evaluated by monitoring: (1) Incidence and severity of allograft rejection based on the rejection activity index score; (2) Proportion of patients with biopsy-proven or presumptive acute rejection within 6 and 12 months post-liver transplantation; and (3) Time to first biopsy-proven or presumptive acute rejection episode.

Methodology:
Screening began prior to liver transplantation, within 6 months of the first dose of study drug. Patients were randomized to receive either PEGASYS or no treatment for 48 weeks, followed by 24 weeks of treatment-free follow-up.

Number of patients (planned/analyzed):
54 patients were enrolled.

Diagnosis and main criteria for inclusion:
Male or female patients >18 years of age with a history of HCV infection, who have undergone a liver transplant without allograft rejection within 3 weeks prior to initiation of PEGASYS. Prior to liver transplantation, patients must have had documented >1000 IU/mL HCV-RNA and abnormal levels of ALT. Additionally, the liver ex-plant must have had histologic signs of cirrhosis compatible with HCV infection. Patients should not have had prior treatment with an interferon (IFN) or ribavirin (ie, naïve patients). Patients who were HBsAg-positive or who had active cytomegalovirus infection, human immunodeficiency virus or hepatocellular carcinoma were excluded.

Test product, dose and mode of administration or test procedure:
PEGASYS 180 µg/sc.

Duration of treatment:
Once weekly for 48 weeks.

Reference therapy, dose and mode of administration or reference procedure:
Not applicable.

Criteria for evaluation (efficacy, safety):
Efficacy parameter: Sustained viral response (SVR; non-detectable serum HCV-RNA [<50 IU/mL] response by the AMPLICOR HCV PCR assay) at the conclusion of the 24-week treatment-free follow-up period.

Secondary efficacy parameters: (1) Non-detectable serum HCV-RNA after 4, 12, 24, and 48 weeks of therapy; (2) Decease of 2-log10 from baseline of HCV-RNA measured at 4, 12, and 24 weeks of therapy; (3) Evaluation of serum ALT levels after 4, 12, 24, and 48 weeks of therapy and after 24 weeks of treatment-free follow-up; (4) Evaluation of histologic differences between treated and untreated patients based on the HAI as measured by comparison of findings pre-treatment (post-liver transplantation), Week 48 (end of treatment) and at the end of the 24-week treatment-free follow-up period.

Safety: (1) AEs; (2) Clinical laboratory tests, vital signs, electrocardiograms, and chest x-ray films; (3) Dosage adjustments of study medication and immunosuppressive regimen; (4) Malignancies; (5) Opportunistic infections; and (6) Premature withdrawals for safety reasons.

Statistical methods:
Efficacy: All efficacy analyses were performed using a modified intent-to-treat (MITT) population and included all randomized patients who had ≥1 post-baseline observation and who received ≥1 dose of study medication (for patients randomized to the PEGASYS group). Additionally, the primary efficacy parameter was analyzed on the standard analysis population and included patients in the MITT population unless the patient met any of the exclusion criteria.

Safety: The population included patients who were randomized and received ≥1 post-baseline safety assessment.

Summary (efficacy, safety, other results):
For the MITT population, the SVR at the end of the 24-week treatment-free period (Week 72) was 8% (95% CI, 1.3%–26.6%) in the PEGASYS group and 0% in the untreated group In the MITT population, the viral response in the PEGASYS group peaked at Week 24, with 19% of patients having a HCV-RNA titer of <50 IU/mL. At the end of 48 weeks of treatment the viral response was 15%. Of the 4 patients in the PEGASYS group with an end-of-treatment response, 2 continued to have undetectable HCV-RNA titers at Week 72. No patient in the untreated group had a viral response. Results for viral response in the standard analysis population were similar up to Week 48; however, no patient in the standard analysis population had a SVR at Week 72. In the MITT population, the proportion of patients in the PEGASYS group having a decrease of 2-log10 from baseline in HCV-RNA peaked at Weeks 4 and 24 ( 27%). At the end of 48 weeks of treatment, 23% of patients had a decrease of 2-log10 from baseline in HCV-RNA, and at Week 72, 8% had a decrease of 2-log10 from baseline in HCV-RNA. One patient in the untreated group had a decrease of 2-log10 from baseline in HCV-RNA at Week 48. Results of this analysis in the standard analysis population were similar.

The sustained biochemical response at Week 72 was 15% in the PEGASYS group and 21% in the untreated group. At all time points for both groups, the trend for serum ALT over time was downward, except for the untreated group at Week 24 for which the serum ALT was essentially unchanged from baseline. No difference between groups in change of mean serum ALT from baseline was observed at Weeks 4, 12, 24, 48, or 72 (P-value range 0.321–0.742).

At each scheduled post-baseline assessment, patients in the PEGASYS group had a lower viral load than patients in the untreated group at each scheduled post-baseline assessment (P-value range <0.001–0.030) except Week 72 (P=0.209). The difference between groups in change of mean HCV-RNA titers from baseline was statistically significant in favor of the PEGASYS group at Weeks 4 and 24 (P=0.003 and P=0.031, respectively). For the untreated group, HCV-RNA titers increased over baseline values at each assessment.

A total of 22 patients, 11 in the PEGASYS group and 11 in the untreated group, had paired biopsies at week 72. The HAI activity scores at baseline and at week 72 were 0.8+ 0.4 and 3.5+ 0.9, respectively, in the PEGASYS group, and 1.2 + 0.4 and 5.2 + 1.0, respectively, in the untreated group.. The increase in HAI score over the 72 week period seemed to be lower in the PEGASYS group than in the untreated group, but this difference was not statistically significant (2.7 + 0.8 vs 4.0 + 1.0, respectively; P=0.3). Fibrosis scores at baseline and at week 72 were 0.2 + 0.1 and 0.6 + 0.2, respectively, in the PEGASYS group, and 0.1 + 0.1 and 1.1 + 0.3, respectively, in the untreated group. The increase in fibrosis score over the 72 week study period seemed to be lower than in the untreated group, but again this difference was not statistically significant (0.4 + 0.2 vs 1.0 + 0.3, respectively; P =0.3).

Safety – The most frequent AEs during treatment were those well-characterized and known to occur with PEGASYS therapy and included headache, pyrexia, diarrhea, fatigue, and peripheral edema. No unexpected single AEs were reported during this study nor were there any unusual patterns of AEs. In 11 body-system categories the incidence of AEs was higher in the untreated group, in 10 body-system categories the incidence of AEs was higher in the PEGASYS group and in 1 body-system category, the incidence of AEs was equal. The investigators rated the majority of AEs (90.4%) in each group as mild or moderate in intensity. The proportion of AEs rated as severe or life-threatening was similar for the PEGASYS (9.1%) and untreated ( 10.1%) groups. Five AEs were judged by the investigator as life-threatening: 2 in the PEGASYS group and 3 in the untreated group. The life-threatening events in the PEGASYS group included hypoglycemia and transplant rejection, and in the untreated group included acute respiratory failure, anemia, and hepatic failure. The most frequent AEs considered probably related to study treatment were those known to be associated with IFN therapy and included fatigue, leucopenia and thrombocytopenia, each occurring in 2 patients. All other AEs considered probably related to study treatment were reported by 1 patient each.

One patient in the PEGASYS group died during this study (post-transplant lympho-proliferative disorder and chronic rejection). Two patients in the untreated group died (liver failure and respiratory failure). All deaths were considered unrelated to treatment by the investigators. A total of 30 serious adverse events (SAEs) (including 1 fatal event) in 17 patients (65%) were reported in the PEGASYS group and 32 SAEs (including 2 fatal events) were reported in 16 patients (57%) in the untreated group. In the PEGASYS group, 3 of 30 SAEs were assessed as treatment-related and consisted of 1 episode of pneumonia (probably related to study treatment) and 2 episodes of thrombocytopenia (1 probably related and 1 possibly related to study treatment). The remaining 27 SAEs in the PEGASYS group were considered unrelated to study treatment. The dose of PEGASYS was modified as a result of a SAE in 3 patients. Treatment was discontinued prematurely as a result of a SAE in 1 patient. During the 48-week treatment period, the proportion of patients who withdrew prematurely for AEs or laboratory abnormalities was 11.5% (n=3) in the PEGASYS group and 3% (n=1, a death) in the untreated group.

During the study period, hemoglobin values <11 g/dL were recorded for 27% and 36% of patients in the PEGASYS and untreated groups, respectively; absolute neutrophil counts <1.5 x 109/L in 54% and 36% of patients,; and platelet counts <100 x 109/L in 69% and 36% of patients.. Platelet counts <50 x 109/L were observed in 38.5% of patients receiving PEGASYS and 14.3% of untreated patients. Marked laboratory abnormalities occurring in >=10% of patients in either group included the following: high concentrations of ALT, AST, total bilirubin, alkaline phosphatase, blood urea nitrogen, creatinine, uric acid, glucose, and potassium; high urine concentrations of protein and glucose; low concentrations of total protein, albumin, and calcium; high and low concentrations of chloride and phosphorus; high triglyceride levels; high T4 levels; and high and low T3 uptake.

Four patients had vital sign values that fulfilled the criteria for being abnormal. In the PEGASYS group, 1 had an abnormal elevation in systolic blood pressure (BP) and 1 an abnormal decrease in systolic BP. In the untreated group, 1 had an abnormal elevation in systolic BP and 1 an abnormal elevation in diastolic BP.

Three patients in the PEGASYS group and 6 patients in the untreated group had either biopsy-proven or presumptive acute rejection (P=0.047). No difference was observed between groups for time to first biopsy-proven or presumptive acute rejection either overall or for any demographic or baseline characteristic. 
One patient in the PEGASYS group had a malignant neoplasm during the trial (lymphoproliferative disorder).Seven patients had 9 opportunistic infections in the PEGASYS group, and 9 patients had 18 opportunistic infections in the untreated group. There was no significant difference in the survival time between the 2 groups (P=0.635, log-rank test).

Conclusions:
In patients receiving therapy with PEGASYS as prophylaxis against HCV infection recurrence after liver transplantation, treatment induced a SVR (24 weeks treatment-free after completion of a 48-week treatment period) in 8% of patients. A viral response was achieved in 15% of patients after 48 weeks of treatment. No patient in the untreated group had a viral response. No statistically significant difference between groups was observed in the proportion of patients with biopsy-proven or presumptive rejection. No statistically significant difference was observed between groups for time to first biopsy-proven or presumptive acute rejection either overall or for any demographic or baseline characteristic. There was no statistically significant difference in the survival time between the 2 groups. No new safety concerns regarding PEGASYS therapy emerged among these patients.

Publications (references, if available):
Chalasani et al. Prospective, randomized trials of Peginterferon alfa-2a for recurrence of hepatitis C after liver transplantation. Hepatology 2005; 41 (2): 289-298