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Clinical Trial Result Information
Protocol number
NR15997
Title of Study
A randomized, open-label, multicenter, efficacy and safety study of Pegasys for the treatment of hepatitis C virus infection administered to patients 6 to 60 months post liver transplantation
Sponsor
Roche Laboratories Inc.
Company division
Pharmaceutical
Product name
PEGASYS
Generic name
peginterferon alfa-2a(40KD)
Therapeutic area
Hepatitis C, Chronic
Clinical study summary
This was a prospective, multicenter, open-label, multiple-dose study to assess the efficacy and safety of peginterferon alfa-2a(40KD)(PEGASYS). Patients with liver transplant and chronic hepatitis C (CHC) were randomized to receive either subcutaneous (sc) PEGASYS 180 μg/week for 48 weeks, or no treatment, followed by a 24 week treatment-free follow-up period. After 72 weeks, sustained virologic response (SVR) was measured.
Study center(s)
13 centers in United States and Austria
Phase of development
IV
Objectives
Primary: To investigate the sustained response rate at week 72( ie 24 weeks after 48 weeks of treatment) of PEGASYS based on viral load for the treatment of CHC in liver transplant recipients.
Secondary: To investigate the effect of PEGASYS on: (1) Viral load (2) HCV-RNA titers, based on a 2 log10 decrease from baseline;(3) Serum alanine transaminase (ALT) levels ;(4) Histologic changes, based on the histology activity index (HAI) as measured by comparison of liver biopsy findings ; (5) Graft survival; (6) To evaluate the safety of PEGASYS.
Methodology
Following screening, patients were randomized either to receive PEGASYS or no treatment. Randomization was centralized and stratified by study enter and viral load (low viral load ≤1 x 106IU/mL vs high viral load >1 x 106IU/mL).
Number of patients (planned/analyzed)
Approximately 67 with liver transplant
Diagnosis and main criteria for inclusion
Male and female outpatients ≥18 years of age with documented CHC by an anti-HCV antibody test who underwent liver transplantation. Main inclusion criteria were: detectable HCV-RNA quantifiable at ≥1000 IU/mL by the Roche AMPLICOR HCV MONITOR test, version 2.0; elevated serum ALT ≥1.5 times the upper limit of normal (ULN); results of a liver biopsy obtained within the last 8 weeks prior to initiation of study medication showing histologic evidence of hepatitis without evidence of mild, moderate, or severe acute allograft rejection; and liver transplant ≥6 months and ≤60 months before the baseline visit.
Test product, dose and mode of administration or test procedure
PEGASYS 180 µg/sc/week.
Duration of treatment
Once weekly for a total of 48 weeks.
Reference therapy, dose and mode of administration or reference procedure
Not applicable.
Criteria for evaluation (efficacy, safety)
Primary efficacy parameter: SVR at the conclusion of the treatment-free follow-up period (Week 72).
Secondary efficacy parameter: Virologic response (VR) at Weeks 4, 12, 24, and 48; biochemical response (BR) at Weeks 4, 12, 24, 48, and 72; 2 log10 decrease in HCV-RNA at Weeks 4, 12, 24, 48, and 72; and change in HAI scores from baseline to the end of 48 weeks of therapy and from baseline to the end of the 24-week treatment-free follow-up period.
Statistical methods
Efficacy: All efficacy analyses were performed using a modified intent-to-treat (MITT) population and included all patients randomized 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)
Efficacy – Primary efficacy parameter: For the MITT population, the SRV at the end of the 24 week treatment-free period (Week 72) was 12% (95% confidence interval [CI], 4%–29%) in the PEGASYS® group and 0% in the untreated group.
Secondary efficacy parameters:
Virologic Response Over Time. In the MITT population, for the PEGASYS group, the VR peaked at Weeks 12 and 24, with 33% of patients having an HCV-RNA titer of <50 IU/mL. At the end of 48 weeks of treatment with PEGASYS, the VR was 30% (10/33). Of the 10 patients in the PEGASYS group with an end-of-treatment response, 4 (40%) continued to have undetectable HCV-RNA titers at Week 72. No patient in the untreated group had a VR. Results for VR in the standard analysis population were similar.
2 Log10 Decrease in HCV-RNA Over Time. In the MITT population, for the PEGASYS group, the proportion of patients having a 2 log10 decrease from baseline in HCV-RNA peaked at Week 24 (17 patients, 52%). Included in this group of 17 patients were all 7 patients with non–type 1 genotype. At the end of 48 weeks of treatment with PEGASYS, 15 patients (45%) had a 2 log10 decrease from baseline in HCV-RNA, and at Week 72, 4 patients (12%) had a 2 log10 decrease from baseline in HCV-RNA. No patient in the untreated group had a 2 log10 decrease from baseline in HCV-RNA at any time during the study. Results of this analysis in the standard analysis population were similar.
Biochemical Response. The sustained BR at Week 72 was 33% in the PEGASYS group and 22% in the untreated group.
Serum ALT Levels Over Time. At all time points for both groups, the trend for serum ALT over time was downward, except for the untreated group at Week 24, in 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-values range from 0.169 to 0.865).
Viral Load Stratum Over Time. At each scheduled post-baseline assessment, patients in the PEGASYS group had a lower viral load than patients in the untreated group (P<0.001 at each time point except Week 72, where P=0.048).
Mean HCV-RNA Titers Over Time. At all time points for both groups, HCV-RNA titers decreased over time. 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, 12, 24, and 48 (each was P<0.001). By Week 72, the difference between groups in terms of change in mean HCV-RNA titers from baseline was not statistically significant (P=0.103).
Histologic Response. Of the 41 patients having paired biopsies (baseline-Week 72), the proportion of patients demonstrating an histologic response (defined as =2-point decrease in total HAI score from baseline to end of study) at Week 72 was 33% (7/21 patients) in the PEGASYS group and 25% (5/20 patients) in the untreated group. Mean total HAI scores at baseline were 6.1 and 4.8 in the PEGASYS and untreated groups, respectively. Mean change from baseline at Week 72 was 0 (standard error [SE], 0.84) in the PEGASYS group and 1.6 (SE, 0.94) in the untreated group.
Histologic Grade and Stage of Disease. Of the 21 patients in the PEGASYS group and 20 patients in the untreated group with a paired biopsy (baseline-Week 72), 8 (38%) and 6 (30%), respectively, showed improvement in necroinflammation, defined as =1-point decrease in total score for Knodell Parts I, II, and III. Among patients with paired biopsies, an improvement in fibrotic stage (Knodell Part IV) was apparent for 1 (5%) patient in the PEGASYS group and 1 (5%) patient in the untreated group.
Of the 21 patients with paired biopsies (baseline-Week 72) in the PEGASYS group, 6 (29%) and 5 (24%), respectively, experienced a worsening in the histologic grade (necroinflammatory changes) or stage (fibrosis) of disease. Of the 20 patients with paired biopsies in the untreated group, 10 (50%) and 9 (45%), respectively, experienced a worsening in the histologic grade (necroinflammatory changes) or stage (fibrosis) of disease. A statistically significant difference between groups was observed in mean change from baseline to Week 48 in total HAI score (PEGASYS group, –2.0; untreated group, +0.8; P=.005). However, no statistically significant differences between groups in mean change from baseline to Week 72 in HAI score were observed, indicating that the positive effect observed at Week 48 was not sustained to Week 72. Safety:
Adverse Events. Consistent with previous experience with CHC in this population, all patients in each group experienced =1 AE during the study. The most frequent treatment AEs were those well-characterized and known to occur with PEGASYS therapy and included diarrhea, peripheral edema, headache, fatigue, rigors, insomnia, nausea, myalgia, arthralgia, pyrexia, cough, nasopharyngitis, depression, dizziness, appetite decreased, hypertension, and injection-site erythema. No unexpected single AEs were reported during this study, nor were any unusual patterns of AEs noted.
Incidence rates of AEs for the various body systems were consistently higher in the PEGASYS group compared with the untreated group, with the largest differences noted for the following disorders (respectively): general (88% vs 50%), nervous system (70% vs 34%); psychiatric (52% vs 22%); renal and urinary (33% vs 6%); and gastrointestinal (82% vs. 59%).
The majority (87.6%) of AEs in each group were rated as mild or moderate in intensity. The proportion of AEs rated as severe or life-threatening was similar in the PEGASYS (65/500 AEs, 13.0%) and untreated (28/250 AEs, 11.2%) groups. There were 3 life-threatening AEs in the PEGASYS group, including multi-organ failure, hepatic failure, and metastases to the lung.
The majority of severe AEs had an individual incidence of 1 patient each. The most common severe AE was nausea, which was reported by 4 patients in the PEGASYS group. Additional severe AEs reported by =2 patients in the PEGASYS group included diarrhea,, vomiting, fatigue, pain in limb, renal failure, dysuria, and abnormal liver function tests.. Abdominal pain, arthralgia, and back pain were the only additional AEs reported as severe for =2 patients in the untreated group. In the PEGASYS group, 43.4% of the 500 AEs were considered to be possibly or probably related to study treatment. The most frequent AEs considered to be probably related to study treatment were those known to be associated with interferon therapy, and included fatigue, rigors, injection-site erythema, thrombocytopenia, insomnia, and pyrexia.
Deaths. Two patients in the PEGASYS group died during this study, 1 as a result of hepatic and renal insufficiency and 1 as a result of pulmonary metastases. Both deaths were considered to be unrelated to treatment.
Serious Adverse Events. A total of 26 patients experienced 48 serious adverse events (SAEs) during this study, including the 2 fatal events in the PEGASYS group. A total of 34 SAEs were reported in the PEGASYS group and 14 in the untreated group. Pyrexia, angina pectoris, ascites, and peritoneal hemorrhage were the only individual SAEs experienced by >1 patient across both groups. Pyrexia was reported by 3 patients in the PEGASYS group and 1 patient in the untreated group, while angina pectoris, ascites, and peritoneal hemorrhage were each reported by 1 patient in each of the groups. Six of the 34 SAEs in the PEGASYS group were assessed as treatment-related, and consisted of infection, pyrexia, cholestasis, hepatic failure, jaundice, and convulsions. All of these were considered possibly related to study treatment. Two of the remaining SAEs in the PEGASYS group were considered remotely related to study treatment, and 26 SAEs were considered unrelated to study treatment.
Dose Modifications and Early Discontinuations. The dose of PEGASYS was modified as a result of an SAE in 6 patients. Treatment was discontinued prematurely as a result of an SAE in 4 patients. Eight patients in the Pegasys group and one patient in the untreated group withdrew prematurely for AEs or laboratory abnormalities. All but 4 patients (PEGASYS, 3; untreated, 1) who withdrew prematurely did so within the first 24 weeks of the study.
Hematology Laboratory Tests. Mean values for all hematology parameters (except neutrophils, monocytes, prothrombin time, and partial thromboplastin time) were decreased from baseline at Week 48 for patients in the PEGASYS group. Mean values for hematocrit were decreased from baseline at Week 48 for patients in the untreated group. Three patients, all in the PEGASYS group, had neutrophil counts below 0.5 x 109/L during the first 48 weeks of the study.and nine patients in the PEGASYS group had a platelet count between 20 and 49.9 x 109/L. For all 9 patients, platelet counts remained low throughout most or all of the study. One of these patients reported an AE of epistaxis (severe, possibly related).
Chemistry Laboratory Tests. Mean baseline values of ALT, aspartate aminotransferase (AST) alkaline phosphatase, blood urea nitrogen (BUN), glucose, and triglycerides were above the normal range. Mean values for ALT, AST, alkaline phosphatase, and triglycerides improved over the course of the study. The improvement was greater in the PEGASYS group for ALT (baseline mean, 89.5 U/L; Week 72 mean, 41.0 U/L) and AST (baseline mean, 63.2 U/L; Week 72 mean, 27.6 U/L), and in the untreated group for alkaline phosphatase (baseline mean, 113.9 U/L; Week 48 mean, 95.4 U/L) and triglycerides (baseline mean, 2.71 mmol/L; Week 72 mean, 2.22 mmol/L). Mean values for BUN and glucose worsened slightly over the course of the study in both groups. Mean values for total bilirubin and creatinine were within the normal range in both groups at baseline, but worsened during the study in patients in the PEGASYS group. In this group, total bilirubin (normal range, 0–17.1 µmol/L) worsened from a mean baseline value of 15.6 µmol/L to 19.3 µmol/L at Week 12. It improved to 11.9 µmol/L by the next assessment at Week 24, and remained near that level until end of study. Mean values for creatinine increased from baseline during the study in both groups. In the PEGASYS group, creatinine (normal range, 0–133 µmol/L) increased from a mean baseline value of 122.5 µmol/L to a mean value at Week 48 of 171.7 µmol/L, then to a mean value at Week 72 of 182.8 µmol/L. The increase in creatinine for the untreated group was only marginal, increasing from a mean baseline value of 115.8 µmol/L to 121.5 µmol/L at Week 48 and 123.8 µmol/L at Week 72.
Vital Signs. Some patients had occasional instances of abnormal vital sign measurements; however, none of these occurrences raised new safety concerns about the use of PEGASYS.
Organ Rejection. Four patients, all in the PEGASYS group, had either biopsy-proven or presumptive acute rejection (P=0.114). No patient had graft loss. Median time to rejection could not be calculated because only 4 acute rejection events occurred. Time to first biopsy-proven or presumptive acute rejection was statistically significantly shorter for the PEGASYS group (P=0.040, log-rank test).
Malignancies. Five patients in the PEGASYS group and 1 patient in the untreated group developed a malignancy during the study. The malignancies in the PEGASYS group were basal cell carcinoma (1 patient), lipoma (1), and oropharyngeal cancer stage (1; this patient also developed pulmonary metastases, which counted as a second malignancy), and benign prostatic hyperplasia (2). The malignancy in the untreated group was benign prostatic hyperplasia (1).
Opportunistic Infections. Four patients in the PEGASYS group had 9 opportunistic infections and 2 patients in the untreated group had 2 opportunistic infections.
Survival Time. There was no significant difference in the survival time between the 2 groups (P=0.143, log-rank test).
Conclusions
In patients with CHC who have undergone liver transplantation, PEGASYS therapy was effective in inducing a SVR (24 weeks after completion of a 48-week treatment period) in 12% of patients. A VR was achieved in 30% of patients after 48 weeks of treatment. No patient in the untreated group had a VR. No statistically significant difference between groups was observed in the proportion of patients with biopsy-proven or presumptive rejection. No patient in either group had graft loss. There was no significant difference in survival time between the 2 groups. No new safety concerns regarding PEGASYS therapy emerged among these patients.
Publications (references, if available)
Chalasani N et al. Prospective, randomized trial of peginterferon alfa-2a for recurrence of hepatitis c after liver transplantation. Hepatology 2005; 41(2): 289-298
Date of report
12/22/2003
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