TABLE OF CONTENTS

INTRODUCTION ----------------------------------------------------------------------------2

SUMMARY OF CLINICAL STUDIES: PHASE 1 AND 2 --------------------------3

SUMMARY OF CLINICAL STUDIES: PHASE 3

STUDY NV 15801

PROTOCOL AND MAJOR AMENDMENTS------------------------------------- 6

CENTERS, DISPOSITION, DEMOGRAPHY, BASELINE DISEASE -------9

STUDY OUTCOMES: PRIMARY EFFICACY -----------------------------------13

SECONDARY EFFICACY ------------------------------13

SUBGROUPS -----------------------------------------------15

SAFETY ------------------------------------------------------19

CONCLUSIONS -------------------------------------------------------------------------30

STUDY NV 15942

PROTOCOL -----------------------------------------------------------------------------31

CENTERS, DISPOSITION, DEMOGRAPHY, BASELINE DISEASE -----34

STUDY OUTCOMES: PRIMARY EFFICACY ---------------------------------38

SECONDARY EFFICACY -----------------------------39

SAFETY -----------------------------------------------------46

CONCLUSIONS ------------------------------------------------------------------------56

APPENDIX 1 ---------------------------------------------------------------------------------58

 

 

 

 

 

 

 

 

INTRODUCTION

The purpose of this meeting is: 1) to update the Antivirals Advisory Committee on the data supporting the safety and efficacy of PEGASYS (Pegylated Interferon alfa 2a) in combination with COPEGUS(ribavirin) for the treatment of adult patients with chronic hepatitis C infection and 2) to discuss questions about dosing that may result in request for postmarketing studies.

Filing of Application

On -------------------, Hoffman-LaRoche Corporation submitted to FDA a License Application for PEGASYS (peginterferon alfa 2a) and COPEGUS

(ribavirin, USP) combination therapy for the treatment of chronic hepatitis C.

Study Products

Peginterferon alfa-2a (PEG-IFN) 180 mg administered sc qw

Ribavirin 200 mg/tablet administered po daily in split doses (final dose 1000 or 1200 mg depending on body weight) and taken with food.

Comparator product: Interferon alfa-2b 3 (IFN) 3 MIU administered sc tiw

Ribavirin 200 mg/capsule (Schering/ICN brand) administered po

daily in split doses (final dose 1000 or 1200 mg depending on body

weight) and taken with food.

Chronic Hepatitis C

HCV causes 20% of all cases of acute viral hepatitis and 70-90% of all cases of chronic viral hepatitis. The acute infection is asymptomatic in the majority of cases. Recovery from acute infection occurs in approximately 15% of adults with the remainder developing chronic hepatitis C infection. Patients with chronic HCV infection typically have persistent viremia and in most cases abnormal ALT levels.

In the US, approximately 50% of children and 85% of adults infected with HCV develop chronic hepatitis leading to an overall prevalence of 2.7 million individuals in the US with chronic hepatitis C infection. After decades, liver cirrhosis develops in about 20% of adults with chronic HCV infection within 20 years and 30% within 30years. In children with chronic HCV the incidence of cirrhosis is lower compared to adults possibly due to the shorter duration of infection or a slower progression of disease. The development of cirrhosis is associated with liver failure, with portal hypertension with its related complications and with the development of hepatocellular carcinoma. Chronic HCV infection causes approximately12,000 deaths per year and is the primary reason for liver transplantation in the US. Genotype 1 is the most prevalent HCV genotype in the US (approximately 70% overall) and is less likely to respond to treatment compared with HCV genotypes 2 and 3. In addition to genotype 1, other factors associated with diminished response to treatment are: high circulating HCV viral load (>2x 106 copies/ml serum) and the presence of cirrhosis on histology.

 

 

Treatment of Chronic Hepatitis C

Alpha interferons were the first antiviral agents to be licensed for the treatment of patients with chronic hepatitis C. Alpha interferons can induce loss of detection of circulating HCV RNA, normalization of serum transaminase levels, and a modest reduction in liver inflammation. At 6 months following completion of alpha interferon monotherapy, the proportion of patients with undetectable HCV RNA is low (<20%). The addition of ribavirin to alpha interferon treatment roughly doubles the proportion of responders to approximately 40%. At the time the safety and efficacy trials for this submission were undertaken, alpha interferon and ribavirin represented the most efficacious therapy available for chronic hepatitis C. Peginterferon alfa 2b, both as monotherapy and in combination with ribavirin, was approved for the treatment of chronic hepatitis C in 2001.

Arguably, the risk/benefit of interferon alfa monotherapy for chronic HCV is no longer acceptable especially for patients with poor prognostic factors such as genotype 1 or high viral titers. Fewer than 10% of patients with chronic hepatitis C with cirrhosis or genotype 1 achieve sustained viral response with interferon alfa monotherapy.

There is no definitive evidence that the loss of detection of circulating HCV RNA six months after the end of treatment (sustained viral response), which is the primary outcome measure of most studies, will decrease the incidence of serious long-term outcomes including progression of liver disease to cirrhosis and the development of hepatocellular carcinoma.

Alpha interferons adversely affect a number of organ systems and may induce a number of serious toxicities including neuropsychiatric disorders, autoimmune disorders, ischemic disorders and disorders of host defenses. The majority of patients on alpha interferons experience fatigue and flu-like symptoms; alpha interferons also commonly induce nausea, vomiting, anorexia and weight loss. They may induce liver decompensation in patients with chronic liver failure. Interferons are abortifacients.

Toxic effects of ribavirin include hemolytic anemia, teratogenicity, embryocidal activity and mutagenesis. The main dose-limiting toxicity of ribavirin is hemolytic anemia which if severe may induce ischemic cardiac or neurologic events. The anemia is usually reversible following discontinuation of treatment.

CLINICAL STUDIES OF PEGASYS AND COPEGUS

Study Hypothesis: The pegylation of interferon alfa 2a will increase the treatment response and tolerability of that agent against chronic hepatitis C due to the improved pharmacokinetic properties that result from pegylation with increased exposure to more consistent serum concentration for 7 days and the possibility of once a week dosing.

The clinical development program comprised 19 phase 1 clinical pharmacology studies (14 to support PEG-IFN alfa-2a and 5 to support Ribavirin). The 14 clinical pharmacology studies of PEG-IFN alfa-2a were part of the monotherapy development program. Table 1 lists the principal clinical safety and efficacy studies.

Table 1. Clinical Studies of Peginterferon alfa-2a and Ribavirin in CHC

Protocol No. Study Objectives

Treatment Duration N

Treatment Groups

NV15800 Phase 2

Safety and PK study

48 wks (genotype 1) 16

PEG-IFN alfa-2a 180 ìg sc qw ribavirin 1000/1200 mg po qd

 

24 wks (genotype non-1) 4

PEG-IFN alfa-2a 180 ìg sc qw ribavirin 1000/1200 mg po qd

NV15801 Phase 3

Efficacy and safety

48 wks 227

PEG-IFN alfa-2a 180 ìg sc qw placebo po qd

 

465

PEG-IFN alfa-2a 180 ìg sc qw

   

ribavirin 1000/1200 mg po qd

 

457

IFN alfa-2b 3 MIU sc tiw

   

ribavirin 1000/1200 mg po qd

NV15942 Phase 3

Treatment duration (24 vs.48 wks) and ribavirin dose (800 vs. 1000/1200 mg)

24 wks 207

PEG-IFN alfa-2a 180 ìg sc qw

   

ribavirin 800 mg po qd

 

24 wks 280

PEG-IFN alfa-2a 180 ìg sc qw ribavirin 1000/1200 mg po qd

 

48 wks 361

PEG-IFN alfa-2a 180 ìg sc qw

   

ribavirin 800 mg po qd

 

48wks 436

PEG-IFN alfa-2a 180 ìg sc qw

   

ribavirin 1000/1200 mg po qd

Including patients participating in the two pivotal studies to be discussed, a total of 1377 patients have received PEG-IFN alfa 2a alone in a range of doses but predominantly 180mg sc as part of the phase 1 clinical pharmacology studies; 357 patients have been exposed to Roche’s ribavirin alone and 1843 have been exposed to the combination of PEG-IFN-alfa 2a plus Roche’s ribavirin

SUMMARY OF PHASE 2 STUDY

The phase 2 study, NV15800 was a randomized, open label study in patients with chronic hepatitis C without cirrhosis in which all patients received PEG-IFN alfa-2a and ribavirin combination therapy. The major focus of this study was to ascertain the impact of food upon ribavirin absorption as well as the safety of the combination of peginterferon alfa 2a and ribavirin. Given the very few patients studied, the conclusions that can be drawn from this study are very limited. The study will not be considered further here. No dose-ranging studies of PEG-IFN in combination with ribavirin were carried out.

RATIONALE FOR SELECTION OF DOSAGE OF PEGINTERFERON AND RIBAVIRIN FOR PHASE 3

The dose of peginterferon was selected on the basis of analyses of data of peginterferon monotherapy. The efficacy of peginterferon alfa-2a monotherapy in adult patients not previously treated was evaluated in four clinical studies. These trials were comparative, open-label, randomized, with 48-week of therapy followed by 24 weeks of follow-up. A total of 1600 patients were enrolled, 996 patients were treated with PEGASYS.

 

Table 2. Clinical Studies of Peginterferon alfa-2a Monotherapy in CHC

Study Design

Treatment Regimen N

(48 week duration)

Conclusions

NV15489 Phase 2 randomized, open-label, ascending dose

Peginterferon: 45 mg qw (20)

90 mg qw (20)

180 mg qw (45)

270 mg qw (41)

Interferon 3 MIU tiw (33)

90 and 180 mg doses chosen for exploration in phase 3

NV15495 Phase 3 randomized, open-label

Interferon 3 MIU tiw (88)

Peginterferon 90 mg qw (96)

Peginterferon 180 mg qw (87)

Peginterferon 180 mg superior to IFN for virologic response

NV15496 Phase 3 randomized, open-label

Interferon 3 MIU tiw (214)

Peginterferon 135 mg qw (215)

Peginterferon 180 mg qw (210)

Peginterferon 180 mg and 135 mg superior to IFN for virologic response. Responses in the two peginterferon groups similar to each other

NV15497 Phase 3 randomized, open-label

Interferon 6 MIU tiw x12 wks (264)

then 3 MIU tiw x36 wks

Peginterferon 180 mg qw (267)

Peginterferon superior to IFN for virologic and biochemical response

 

The number of responders to peginterferon alfa-2a monotherapy was higher than the number of responders to unpegylated interferon alfa-2a monotherapy. The addition of ribavirin to unpegylated interferon alfa increases the number of responders. The sponsor hypothesized that the addition of ribavirin to peginterferon alfa-2a would further increase the number of responders.

The rationale for dose of peginterferon alfa-2a selected for the phase 3 studies was in part based on the analysis of treatment response and safety in peginterferon monotherapy study NV15496. In that study the sustained viral response achieved by both 135mg and 180mg doses of peginterferon once weekly SC were indistinguishable. The sponsor observed that the histologic responses in the peginterferon 135mg group and the interferon alfa-2a group were not different. However the histologic response of the peginterferon 180mg group appeared to be higher than that of the interferon alfa-2a group. The incidence of adverse events appeared to be similar in the 135mg and 180mg peginterferon dose groups. The sponsor concluded that the 180 mg peginterferon dose should be tested in the pivotal studies.

The dose of ribavirin chosen for study was 1000 or 1200 mg po daily based on body weight < or > 75 kg. This is the recommended dose for interferon alfa-2b and ribavirin combination therapy. Patients were instructed to take ribavirin with food because of evidence that food increases the bioavailability of ribavirin.

 

 

 

SUMMARY OF STUDY NV15801

Study Title

"A Phase III, Randomized, Multicenter Efficacy and Safety Study

Comparing the Combination of Pegylated-Interferon alfa 2a and Ribavirin

to REBETRON in the Treatment of Patients with Chronic HCV Infection"

Study Design

Randomized, multicenter, international, partially blinded, active controlled (REBETRON) phase 3 study of two Peginterferon alfa 2a regimens in 1149 treatment naïve patients with histologically, serologically and virologically documented chronic hepatitis C. Subjects were randomly assigned to one of three treatment arms: Peginterferon alfa 2a monotherapy, peginterferon alfa 2a combined with ribavirin, or Intron A/Rebetol on a 1:2:2 basis. Subjects were treated for 48 weeks and were followed for 24 weeks.

Dosing

Peginterferon alfa-2a (Roche):180 ìg in 1 mL solution administered sc once weekly in combination with Ribavirin (COPEGUS, Roche): 200 mg/tablet, 1000 - 1200 mg administered po daily in split doses. The dose of COPEGUS and REBETOL was based upon body weight, patients <75 kg received 1000mg per day and those >75 kg received 1200 mg per day.

REBETRON: Interferon alfa-2b (Intron A, Schering): 3 MIU in 0.5 mL solution administered sc three times per week in combination with Ribavirin (REBETOL Schering/ICN): 200 mg/capsule: 1000 - 1200 mg administered po daily in split doses based upon body weight.

Placebo: Identical-appearing, equivalent numbers of tablets as ribavirin (Roche) administered po daily in split doses for use in the monotherapy arm.

Dosing Modification Rules

Ribavirin

The dose adjustment guidelines for ribavirin were the same across study groups. Ribavirin was to be reduced to 600 mg per day if (1) a patient without significant cardiovascular disease experienced a fall in hemoglobin to <10 g/dL and >8.5 g/dL or (2) a patient with stable cardiovascular disease experienced a fall in hemoglobin by >2 g/dL during any 4 weeks of treatment. Once a patient’s ribavirin dose was held due to either a lab abnormality or adverse event, the investigator could attempt to increase the dose of ribavirin to 600 mg daily, and further to 800 mg daily. However, it was not recommended that ribavirin be increased to its original assigned dose (1000-1200 mg).

Peginterferon and interferon

If a patient experienced a clinically significant adverse event or a laboratory abnormality, the dose of peginterferon or interferon was lowered to pre-specified levels

based on the degree of severity of the event as shown below.

 

 

Number of Dose Reduction Levels for Adverse Event or Laboratory Abnormality

Severity

Grade

Mild

Moderate Limited

Moderate Persistent

Severe Limited

Severe Persistent

Life-Threatening

Level

0

0

0 - 1

0 - 1

1 - 2

Stop Drug

 

 

 

 

The table below shows the guidelines for lowering the dose of peginterferon when patients experienced neutropenia or thrombocytopenia.

 

Dose Adjustments for Low Absolute Neutrophil and Platelet Counts

     

Parameter

Downward Dose Adjustment

 
 

ANC (cells/mm3)

   

1000

None

 

750 - 999

Week 1 - 2: Immediate 1 Level adjustment

 

Week 3 - 48: None

 

500 - 749

Week 1 - 2: Delay or hold dose until 750 then resume dose with 1 Level adjustment

 

Week 3 - 48: Immediate 1 Level adjustment

250 - 499

Week 1 - 2: Delay or hold dose until 750 then resume dose with 2 Level adjustment

 

Week 3 - 48: Delay or hold dose until 750 then resume dose with 1 Level adjustment

<250

Stop Drug

 

Platelet Count (cells/mm3)

   

50,000

None

 

35,000 - 49,000

Delay or hold dose until

50,000 then resume dose with 1 Level adjustment

25,000 - 34,000

Delay or hold dose until

50,000 then resume dose with 2 Level adjustment

<25,000

Stop Drug

 

 

The dose of interferon was to be reduced to 1.5 MIU tiw if a patient experienced a fall in white blood count to <1.5 X 109/l ( but >1.0x109/l) or a fall in neutrophil count to <.75x109/l (but >.5x109/l) or a platelet count to <50x109/l (but >25x109/l)

 

Dose Reduction Levels for Peginterferon alfa-2a and Interferon alfa-2b

 

Assigned Dose

Dose Reduction Levels

Peginterferon alfa-2a

180 ìg

135 ìg

90 ìg

45 ìg

Interferon alfa-2b

3 x106

2.2x106

1.5x106

----

If four or more consecutive doses of test drug were held or otherwise not administered (i.e. the patient had not received test medication for more than 28 days), the patient was considered intolerant of the test medication or non-compliant.

Study Population

Men and women outpatients 18 years of age with serologically and histologically proven CHC, elevated ALT, and detectable HCV RNA. Excluded were patients with HIV, other forms of hepatitis, a history of severe psychiatric or cardiac disease, severe seizure disorders, severe retinopathy, or previous interferon or ribavirin therapy.

Primary Efficacy Outcome

The primary outcome was a combined endpoint of non-detectable serum HCV-RNA (<100 copies/ml by a commercial PCR assay) and normal serum ALT activity after the 24-week treatment-free follow-up period (nominally 72 weeks).

Secondary Efficacy Outcomes

The following were the principal secondary outcomes:

-End-of-treatment virologic and biochemical responses

-Sustained virological and biochemical responses

-End-of-follow-up histological changes from pretreatment.

Withdrawal for Treatment Failure

In both studies, study subjects who did not demonstrate either a virologic response (HCV negative or 2 log10 decrease ) or a biochemical response(normal ALT) could be withdrawn from the study by 12 weeks of therapy and were to be withdrawn from study if unresponsiveness persisted by 24 weeks.

Clinical and Laboratory Evaluations

One certified laboratory performed all HCV RNA PCR determinations. Local laboratories could be used for repeat testing required for safety assessments.

Patients were assessed for safety at weeks 1, 2, 4, 6 and 8 and then every 4 weeks during treatment and follow-up. Patients who were prematurely withdrawn from treatment were followed for 12 weeks after treatment. Following the initiation of treatment, quantitative viral titers were also obtained at weeks 4, 12 and 24 only if the qualitative titer was positive. Qualitative titers (AMPLICOR) were obtained at weeks 4, 12, 24, 48, 60 and 72. Serum ALT activities were obtained by the same schedule for safety assessments. The liver biopsy at baseline and week 72 was reviewed by one pathologist.

Statistical Analyses

Primary efficacy analysis

o The primary efficacy population was the Intention to Treat population which was defined as all subjects randomized.

o This study analyzed categorical variables using the Cochran-Mantel-Haenszel test. Stratification variables were country and pretreatment HCV genotype. Breslow- Day’s test was used to test the homogeneity of the odds ratio across the strata formed by country and genotype.

o A "closed testing procedure" was planned to allow for all 3 possible pairwise comparisons. First, the global hypothesis of no treatment differences would be tested at a significance level of 0.05. Next, if the global hypothesis was rejected, the three pairwise treatment comparisons among the three treatment groups would be tested at a significance level of 0.05. In addition to hypothesis testing, two-sided 97.5% confidence intervals of odds ratio would be provided.

o Interim analysis: A blinded review of all available week 4 PCR data was conducted after 815 patients had been randomized, it was decided to increase the sample size to 450:450:225 (REBETRON:PEG-IFN plus ribavirin:PEG-IFN plus placebo) for a total 1125 in order to detect a 10% improvement (instead of the 12% planned originally) of PEG-IFN plus ribavirin over REBETRON with at least 80% power. Sustained response rates of 40%:50%:40% were assumed in the calculation. The power to reach statistical significance between PEG-IFN plus ribavirin and PEG-IFN plus placebo was estimated to be 68% with the increased sample size.

MAJOR PROTOCOL AMENDMENTS

Amendment D: Three hundred additional patients were added to protocol to ensure that the study could detect a statistically significant treatment difference of at least 10% improvement of PEG-IFN plus ribavirin over REBETRON. This decision was based on a blinded interim analysis of week 4 virological data. The total study population was raised to 1125 and the 1:2:2 randomization was retained. A liver biopsy at 48 weeks in a portion of patients was added (50 in each arm) to evaluate safety issues. The week 12 discontinuation policy for non-responders was made optional in light of literature reports of success with 24 weeks.

Amendment E, G: Previously, 150 patients (13% of total) were scheduled to have an end of treatment biopsy. To increase concordance with other studies, the numbers and timing of liver biopsies were changed to 225 patients or 20% at end of follow-up. Twenty patients treated with Rebetron would have end-of-treatment liver biopsies.

 

Amendment H: The definition of sustained virologic response was two consecutive HCV RNA measurements 21 days apart measured 408 days with the lower limit of week 60. To be considered a responder, a patient had to have normal serum ALT activity and no detectable virus at the end of untreated-follow-up period

STUDY RESULTS

Study Centers

There were 81 participating study centers in US, Europe, Australia, Taiwan, Mexico, and Brazil. Differences in treatment response between geographic regions have been observed in studies of interferon therapies. These differences are attributable at least in part to differences in the distribution of baseline demographic and disease factors that predict response to treatment. For this reason the distribution of baseline variables, the treatment responses, and the safety data were analyzed by subdividing the study population into U.S., non-US, Europe, and "Other". The centers in the US contributed 41% of the patients participating in the study.

Patient Disposition

1149 patients were randomized; 28 patients were randomized but did not receive any treatment. The two comparison arms had equivalent numbers of individuals randomized but untreated. Table 3 shows that somewhat fewer subjects in the PEG-IFN monotherapy and IFN-alfa 2b+ ribavirin arms completed 48 weeks of treatment compared to the PEG-IFN +ribavirin arm (67% versus 76%). This difference was due to higher numbers of subjects withdrawn from the protocol for futility at 24 weeks in those two arms. The remainder of the withdrawals from the protocol were mostly for adverse events or laboratory abnormalities (See review of safety).

 

Table 3. Disposition of Patients

 

PEG-IFN alfa-2a

PEG-IFN alfa-2a+

IFN alfa-2b +

Ribavirin

Ribavirin

N (%)

N (%)

N (%)

Randomized

227

465

457

Treated

224 (99)

453 (97)

444 (97)

Completed: 12 wks of treatment

217 (96)

435 (94)

426 (93)

24 wks of treatment

197 (87)

414 (89)

402 (88)

48 wks of treatment

152 (67)

353 (76)

304 (67)

24 wks of follow-up

146 (64)

334 (72)

290 (63)

 

Patient Demographics

The mean age of study participants was approximately 43 years and this mean is within the age group (30-49 years of age) with the highest HCV prevalence in the US. The study protocol excluded pediatric patients. There was no upper age limit but very few elderly patients were enrolled. The mean weight of participants was approximately 79 kg in all three arms with the recorded range from 42 to 156 kg. The subjects enrolled in US centers were on average heavier than subjects enrolled in non-US centers (See Table 4). Peginterferon alfa-2a and interferon alfa-2b were administered as fixed doses and the ribavirin was crudely weight-adjusted based on body weight above or below 75 kg. Given the wide range in body weights of study subjects, the differences in body weight between subjects in US and Non-US centers, and the fixed or crude weight-adjusted dosing, the analysis of safety and efficacy by body weight would be an important review objective.

Approximately 2/3 of the participants were men. This gender distribution is consistent with the higher prevalence of HCV in men. Approximately 84% of participants were Caucasian. Overall 5% of participants were black, (11% of US participants). Approximately 5% of participants both in the total population and in the US sites were Hispanic. Since the prevalence of HCV in the US is higher in African Americans and in Hispanics compared to Caucasians, these two ethnic minorities were under-represented in the study. Response to interferon therapy is lower in African Americans and in Hispanics for reasons not fully understood. It should be noted that the sponsor has already undertaken studies to assess the safety and efficacy of peginterferon alfa-2a and ribavirin combination therapy in patients from these ethnic groups.

Table 4 summarizes the patient demographics in the treated population. US patients weigh more, have somewhat higher body mass index and are also older compared to Non-Us patients.

 

 

 

 

Table 4. Population Baseline Characteristics by Geographic Regiona

Factor

All Patients

N %

U.S.

N %

Non-U.S.

N %

Europe

N %

Other

N %

 

1121b (100)c

460 (41)

661 (59)

451 (40)

210 (19)

Age (years)

<35

268 (23)

50 (11)

209 (32)

154 (34)

55 (26)

35-44

405 (36)

185 (40)

220 (33)

142 (31)

78 (37)

45-54

329 (29)

187 (41)

142 (21)

89 (20)

53 (25)

55-64

108 (10)

32 (7)

76 (11)

55 (12)

21 (10)

>65

16 (1)

3 (1)

13 (2)

10 (2)

3 (1)

Gender

Male

800 (71)

333 (72)

467 (71)

314 (70)

153 (73)

Female

321 (29)

127 (28)

194 (29)

137 (30)

57 (27)

Ethnic Group

White

943 (84)

385 (84)

558 (84)

436 (97)

122 (58)

Black

53 (5)

48 (11)

5 (1)

3 (1)

2 (1)

Asian

64 (6)

3 (1)

61 (10)

9 (1)

52 (25)

Other

61 (5)

24 (5)

37 (6)

3 (1)

34 (16)

Body Mass Index

£25

577 (51)

222 (48)

355 (54)

265 (59)

90 (43)

>25

543 (49)

238 (52)

305 (46)

185 (41)

120 (57)

Weight (kg)

<64

75 (16)

 

175 (26)

127 (28)

48 (23)

<74

316 (28)

112 (24)

204 (31)

142 (31)

52 (26)

75-<85

274 (24)

121 (26)

153 (21)

102 (23)

51 (25)

85-98

230 (21)

111 (24)

129 (20)

80 (18)

49 (25)

>98

116 (14)

116 (25)

0

0

0

a Analysis group: Treated patients

The demographic characteristics were reasonably well distributed across the treatment groups (not shown).

Disease Characteristics at Baseline

Source of HCV Infection

The means of acquisition of HCV infection was similar across treatment groups (Table 5). The predominant mode of transmission was injection drug use. The second highest source of HCV in participants was sporadic or unknown and the third most common was transfused blood products.

Table 5. Infection Source and HCV Genotype

PEG-IFN alfa-2a

N = 227

N %

PEG-IFN alfa-2a Ribavirin 1000-1200mg N = 465

N %

IFN alfa-2b

Ribavirin 1000-1200mg N = 457

N %

Infection Source

 

 

 

 

 

 

Injection drug use

82

(36)

197

(42)

182

(40)

Transfusion

47

(21)

87

(19)

101

(22)

Unknown

72

(32)

134

(29)

127

(28)

 

 

Viral Genotype, Viral Load and Severity of Liver Disease at Baseline

Approximately two thirds of participants in the study were infected with genotype 1 (Table 6); the number was somewhat higher in US study patients compared to non-US patients (see Table 7). The distribution of genotype 1 observed in the study patients is consistent with the incidence of this genotype in HCV infected patients in the US population. Among the non-genotype 1, only types 2 and 3 were significantly represented in the study. The proportion of patients with high viral load was evenly distributed across the three study arms for the entire population and in geographic subgroups. No relationship has been established between the rate of disease progression or severity of liver disease and the HCV genotype or the number of circulating HCV-RNA copies. Both viral genotype and viral load predict response to interferon treatment, however, with high viral load genotype 1 having the least likelihood of response to interferon treatment.

Table 6. HCV Genotypes by Treatment Group

 

PEG-IFN alfa-2a

N = 227

N %

PEG-IFN alfa-2a Ribavirin 1000-1200mg N = 465

N %

IFN alfa-2b

Ribavirin 1000-1200mg N = 457

N %

Genotype

           

Type 1

146

(64)

305

(66)

292

(64)

1a

70

(31)

143

(31)

158

(35)

1b

69

(30)

160

(34)

124

(27)

Other

7

(3)

2

(0)

10

(2)

Non-1

81

(36)

160

(34)

165

(36)

2

37

(16)

56

(12)

62

(14)

3

34

(15)

88

(19)

85

(19)

4

9

(4)

13

(3)

12

(3)

5

1

(<1)

 

-

4

(1)

6

 

-

2

(<1)

1

(<1)

It is also established that patients with cirrhosis have a lower likelihood of responding to interferon therapy. The proportion of patients who had cirrhosis at baseline was numerically similar across the study arms with 25 (17%) of PEG-IFN monotherapy, 40 (13%) of PEG-IFN/ribavirin and 32 or (11%) of the Interferon alfa-2b/ribavirin having histologic evidence of cirrhosis at baseline. The incidence of cirrhosis was numerically lower in Non-US centers (Europe in particular) compared to the US centers (Table7).

Table 7. Baseline Disease Characteristics by Geographic Regiona

Factor

All Patients

N %

U.S.

N %

Non-U.S.

N %

Europe

N %

Other

N %

 

1121b(100)c

460 (41)

661 (59)

451 (40)

210 (19)

HCV RNA

<2x106

378 (34)

147 (32)

231 (35)

153 (34)

78 (37)

>2x106

740 (66)

310 (68)

430 (65)

298 (66)

132 (63)

Genotype

1

728 (65)

322 (70)

406 (61)

268 (59)

138 (66)

Non-1

393 (35)

138 (30)

255 (39)

183 (41)

72 (34)

Histology

Cirrhosis

144 (13)

72 (16)

72 (11)

37 (8)

35 (17)

No Cirrhosis

977 (87)

388 (84)

589 (89)

414 (92)

175 (83)

a Analysis group: Treated patients

Primary Efficacy Analysis

The primary comparison in this study was between PEG-IFN alfa 2a plus ribavirin and IFN alfa 2b plus ribavirin. The purpose of the PEG-IFN monotherapy arm was to provide information on the impact of ribavirin on both efficacy and safety when used in combination with PEG-IFN. The intent to treat population was used for the efficacy analysis and was defined as all subjects randomized whether or not they received treatment.

The primary endpoint in this study was the combined sustained (24-weeks post-treatment) virologic and biochemical response. Table 8 shows a numerical difference (6%) that favors peginterferon alfa-2a and ribavirin over interferon alfa-2b and ribavirin. The p value for the difference was 0.057. Peginterferon alfa-2a and ribavirin combination therapy was superior to peginterferon alfa-2a monotherapy.

Table 8. Sustained Virologic and Biochemical Response at 24 wks Post-treatment1

PEG-IFN alfa-2a

--------

N = 227

Group(a)

PEG-IFN alfa-2a ribavirin

N = 465

Group(b)

IFN alfa-2b

ribavirin

N = 457

Group(c)

Sustained Virologic and Biochemical Response

55 (24%)

210 (45%)

180 (39%)

Pairwise comparisons2

Odds ratio

P

b vs. c

1.30 (0.95, 1.78)

0.057

b vs. a

2.70 (1.79, 4.10)

0.001

c vs. a

2.08 (1.37, 3.16)

0.001

1Intent- to-treat population

2Global test of treatment difference: P<0.001

Secondary Efficacy Analyses

Table 9 shows a secondary efficacy analysis using sustained virologic response at 24 weeks post treatment. In this analysis, the treatment difference between PEG-IFN alfa 2a plus ribavirin and IFN-alfa-2b plus ribavirin is 8% and this difference does achieve statistical significance. Both regimens performed better than the PEG-IFN monotherapy which was consistent with expectations. There is a good concordance between biochemical and virologic response. However in a few patients who achieved a sustained virologic response, transaminase levels had not returned to normal by endpoint. The possibility exists that in some of these cases the ALT elevation might be unrelated to CHC.

 

 

 

 

 

Table 9. Sustained Virologic Response at 24 wks Post-treatment1

PEG-IFN alfa-2a

-------

N = 227

Group (a)

PEG-IFN alfa-2a ribavirin

N = 465

Group (b)

IFN alfa-2b

ribavirin

N = 457

Group ( c)

Sustained Virologic Response

62 (27%)

234 (50%)

190 (42%)

Pairwise comparisons2

Odds ratios

P

b vs. c

1.49 (1.09, 2.05)

0.004

b vs. a

2.92 (1.94, 4.41)

0.001

c vs. a

1.94 (1.29, 2.92)

0.001

1Intent- to-treat population

2Global test of treatment difference: P<0.001

Other secondary endpoint consider virologic and biochemical response at either the end of follow-up (72 wks) or at the end of therapy (48 wks) and are shown in Table 10. These endpoints provided evidence in support of the superiority of peginterferon alfa-2a and ribavirin, over interferon alfa-2b and ribavirin.

Table 10. Other Secondary Efficacy Analyses1

 

Peg-IFN alfa 2a

----

N=227

Peg-IFN alfa 2a ribavirin

N=465

IFN-alfa 2b

ribavirin

N=457

Sustained Biochemical Response

(WK 72)

72 (32%)

 

233 (50%)

OR: 1.37 (1.01, 1.87)

197 (43%)

End-of-Treatment Virologic Response (WK 48)

132 (58%)

 

314 (68%)

OR: 2.16 (1.58, 2.97)

231 (51%)

End-of-Treatment Biochemical Response (WK 48)

91 (40%)

 

249 (54%)

OR: 1.30 (0.96, 1.77)

217(47%)

1Intent-to-treat population

OR: Odds ratios PEG-IFN/R vs. IFN/R

Efficacy endpoints for pivotal trials of interferon-based therapies for CHC have evolved with the advent of validated assays for HCV RNA. The first interferon therapies were licensed based on demonstration of normalization of serum transaminase levels (biochemical response) supported by improvement in liver histology. Subsequently biochemical response combined with loss of detection of HCV RNA (virologic response) became a standard primary efficacy outcome. The agency’s current thinking is that virologic response alone is appropriate as a primary efficacy endpoint. The Anti-Viral Drugs Advisory Committee on December 12, 2001, endorsed the use of a sustained virologic response 24 weeks after the completion of treatment. While the p value for the pre-specified primary endpoint comparing PEGASYS and COPEGUS with REBETRON was 0.057 , a number of secondary endpoints including virologic response alone or biochemical response alone provided strong support for the superiority of peginterferon alfa-2a and ribavirin over interferon alfa-2b and ribavirin.

Finally, changes in liver histopathology in response to treatment were evaluated in a subset of patients. A liver biopsy with histology consistent with chronic hepatitis C within 12 months of enrollment was required for enrollment in the study. Paired liver biopsies were obtained after treatment in approximately 20% of patients. Response to treatment based on Histologic Activity Score was defined as >2 point decrease in score from baseline. Over 70% of patients in all treatment groups were observed to have a modest reduction in inflammation compared to baseline (Table 11). Approximately 20% of patients had no change in inflammation score and 3-5% had an increase in inflammation score.

When histologic response is compared to sustained viral response it would appear that those patients who had a sustained virologic response are more likely to have a histologic response. Overall, the number of subjects with paired biopsies is small, the improvement in histology from baseline is modest and there are no statistically significant differences between the treatment groups.

 

Table 11. Histologic Responders in Patients with Paired Biopsies

 

Peg-IFN alfa 2a

----

N=39

Peg-IFN alfa 2a ribavirin

N=80

IFN-alfa 2b

ribavirin

N=79

Responders

28/39 (72%)

64/80 (80%)

60/79 (76%)

 

SUBGROUP ANALYSES

Subgroup Analysis: Patients who Relapse in the Post-treatment Period

Patients with HCV RNA negative at the end of treatment but positive at the end of follow-up (24 weeks post-treatment) were considered to have relapsed. The proportion of patients who relapsed (positive or missing HCV-RNA) was highest in the PEG-IFN monotherapy group. As for the two combination therapy groups, the relapse rate in the PEG-IFN alfa 2a/ribavirin group was higher than in the IFN alfa 2b/ribavirin group (see Table 12). It should also be noted that the end of treatment response rate of the PEG-IFN alfa 2a/ ribavirin group was higher than that of the IFN-alfa 2b/ribavirin group.

Table 12. Relapse in Patients with Undetectable HCV-RNA at End of Treatment 1

PEG-IFN alfa 2a

----

N= 227

PEG-IFN alfa 2a ribavirin

N=465

IFN-alfa 2b

ribavirin

N=457

Responder at end-of-treatment (48 wks)

132 (58%)

314 (68%)

231 (51%)

Responder at end-of-follow up (24 wks post-treatment)

60 (26%)

221 (47%)

181 (40%)

Relapsers

72/132 (55%)

93/314 (30%)

50/231 (22%)

1Intent-to-treat population

Subgroup Analysis: Time to First Loss of HCV RNA in Treatment Responders

The majority of individuals who ultimately achieve a sustained virologic response have negative HCV-RNA at 12 weeks of therapy. Those proportions were 75% in the PEG-IFN monotherapy group, 84% in the PEG-IFN/ribavirin group and 78% in the IFN/ribavirin group. By 24 weeks, those numbers had increased to 91% in the PEG-IFN monotherapy group, and 95% in the two combination therapy groups.

The attainment of a negative HCV-RNA at 12 weeks also has predictive value for the success of a subject in achieving a sustained viral response (see Table 13). In the PEG-IFN alfa 2a plus ribavirin group, 205 of the 279 patients who were HCV RNA negative at 12 weeks achieved sustained virologic response for a positive predictive value of 73%. On the other side, 134 of 174 patients who ultimately did not achieve sustained virologic response had a positive HCV-RNA at 12 weeks, a 77% negative predictive value. Those same positive and negative predictive values for the IFN-alfa 2b/ ribavirin were similar with a 74% positive predictive value and 82% negative predictive value. In contrast, the positive predictive value for the monotherapy arm was 54% with a negative predictive value of 88% presumably reflecting the lower efficacy of the monotherapy.

This study allowed for continuation of participation beyond 24 weeks for patients who had either evidence of virologic response (negative HCV RNA or 2 log 10 drop in viral titer) or evidence of a biochemical response (normalization of ALT). Expanding the definition of viral response to include subjects who have a positive HCV RNA but whose viral titer has decreased 2 log 10 permits even greater negative predictive value. As shown in Table 14, of the subjects receiving PEG-IFN alfa 2a/ribavirin only two not meeting this definition ultimately had a sustained viral response for a negative predictive value of 97%.

Table 13. Correlation between In-Treatment and Post-Treatment (>12 weeks) Virologic Response

Treatment Duration

 

Peg-IFN alfa 2a

----

N= 227

Peg-IFN alfa 2a ribavirin

N=465

IFN-alfa 2b

ribavirin

N=457

   

yes

no

yes

no

yes

no

Week 4

yes

29

12

96

24

63

17

 

no

36

147

149

184

135

229

Week 12

yes

49

41

205

74

155

55

 

no

16

118

40

134

43

191

Week 24

yes

59

66

232

105

188

76

 

no

6

93

13

103

10

170

Week 48

yes

62

66

225

75

185

38

 

no

3

93

20

133

13

208

 

 

 

 

 

 

Table 14. Correlation Between Reduction in HCV RNA > 2 log at Week 12 and Sustaineda Response

Sustained Response

yes

no

Week 12 HCV RNA negative or decreased 2- log (base 10) from baseline titer

yes

243

147

Sustained Response

no

2

73

a2 consecutive HCV RNA negative at >12 wks post-treatment

Subgroup Analysis: Treatment Response by Viral Genotype and Viral Load at Baseline

Patients with viral genotype 1, regardless of viral load, had a lower response rate compared to patients with other genotypes (Table 15). Patients with high viral load (>2x106 copies of HCV RNA/ml serum) also had lower responses compared to patients with low viral load.

Patients with both genotype 1 and high viral load were least likely to respond both in the PEG-IFN alfa 2a/ribavirin group (39%) and in the IFN/ribavirin group (32%). The influence of viral load appeared to be less in non-genotype 1 patients in the PEG-IFN/ ribavirin group.

Table 15. Sustained Virologic Response by HCV Genotype and Viral Titers1

 

Peg-IFN alfa 2a

N % Response

Peg-IFN alfa 2a ribavirin

N %Response

IFN-alfa 2b ribavirin

N % Response

ALL PATIENTS

62/227 (27)

234/465 (50)

190/457 (42)

Genotype 1

27/146 (18)

129/305 (42)

100/292 (34)

Genotype non-1

35/81 (43)

105/160 (66)

90/165 (55)

Type 1 –low titer

15/44 (34)

58/114 (51)

39/92 (42)

–high titer

12/101 (12)

71/181 (39)

61/188 (32)

-missing

1 --

10 --

12 --

Non 1 -low titer

15/25 (60)

31/44 (70)

36/56 (64)

-high titer

20/54 (37)

71/108 (66)

54/103 (52)

- missing

2 --

8 --

6 --

1Intent-to-treat population

Subgroup Analysis: Response to Treatment by Age, Gender, Ethnic Group, Cirrhosis and Geographic Region

The effect of age, gender, ethnicity, cirrhosis on treatment response was examined in the three study groups. The effects were consistent across groups and were also consistent with previous observations (see Table 16). The effect of these factors on treatment response was also examined by geographic region and did not yield notable new hypotheses (not shown).

 

 

 

Age

In general, younger patients had higher treatment responses with all three regimens compared to older patients (Table 16). The efficacy in US patients was lower than in non-US at most age categories.


Table 16. Virologic Responsea by Age, Gender, Ethnic Group, Cirrhosis, and Geographic Region

 

Peg-IFN alfa 2a

N %SVR

Peg-IFN alfa 2a ribavirin

N %SVR

IFN alfa 2b ribavirin

N %SVR

All Patients

224 (29)

453 (53)

444 (44)

Age (yrs): <35

43 (42)

109 (68)

107 (54)

35-44

91 (31)

154 (56)

165 (47)

45-54

70 (23)

136 (43)

123 (36)

55-64

20 (10)

48 (35)

40 (33)

>65

0

8 (50)

8 (50)

Gender: Men

151 (33)

324 (53)

325 (43)

Women

73 (30)

129 (54)

119 (47)

Ethnic Group: White

186 (29)

372 (54)

385 (46)

Black

13 (15)

27 (22)

13 (23)

Asian

12 (75)

28 (82)

24 (54)

Other

13 (15)

26 (38)

22 (18)

Cirrhosis: Present

34 (21)

56 (41)

54 (35)

Not-Present

190 (30)

397 (55)

390 (46)

Geography: U.S.

93 (26)

184 (42)

183 (36)

Non-U.S.

131 (31)

269 (61)

261 (50)

atreated population

Gender:

Overall there was little difference between the SVR rate of men and women in this study.

Racial and Ethnic Background:

Response rates were lower in Black and Hispanic patients compared with the response rate in Caucasians. African Americans made up the vast majority of Black patients enrolled (48/53). The response rate in Asian patients on the other hand was higher than Caucasians. The validity of these observations is somewhat questionable due to the very low numbers of minority patients that were enrolled in this study.

Cirrhosis at Baseline

The unfavorable effect of cirrhosis on treatment response was observed in all three treatment arms. In each arm, individuals with cirrhosis had a 9-14 point lower percentage of viral response. PEG-IFN alfa-2a and ribavirin combination therapy induced higher responses than IFN alfa 2b and ribavirin combination therapy (41% versus 35%). The US versus non-US trends favoring the latter are seen again in these subgroups.

Geographic Region

Roughly 40% of study patients were enrolled in the US; 40% of the other patients were enrolled in Europe, and roughly 20% were enrolled in Australia, Taiwan, Mexico, Brazil. Table 16 shows that overall the proportion of virologic responders in each of the treatment arms was higher in patients enrolled at non-US centers compared to patients enrolled at US centers. Various prognostic factors were explored to examine this treatment difference. The difference in response was attributable to a higher proportion in US compared to non-US in poor prognostic baseline variables including older age, higher body weight, higher proportion of HCV1 or cirrhosis.

Exploratory analyses were conducted to analyze treatment effect in US and non-US populations in subgroups defined by body weight, genotype, and baseline viral titer. These analyses are provided in Appendix 1 (see Tables 17 and 18). A logistic regression analysis including genotype, viral titer, geographic region, and weight found that the geographic region was not a significant factor contributing to treatment response. Thus, the differences in sustained virological response for the overall population observed between US and non-US patients appear to be largely due to imbalance in other important prognostic factors for response.

 

SAFETY ANALYSES

Overview of Adverse Events

Nearly all patients experienced one or more adverse events (Table 19). The incidence of severe adverse events was similar across groups. Serious adverse events were numerically higher in the peginterferon groups (12%) compared to the interferon/ribavirin group (9%). The incidence of treatment discontinuation for adverse events or laboratory abnormalities was 10-11% in the combination therapy groups and 7% in the peginterferon monotherapy group overall. The incidence of dose modification of the interferon therapy for adverse event or laboratory abnormality was higher for peginterferon (27-32%) compared to interferon (18%). The most common reason for dose modification was neutropenia and/or thrombocytopenia. The incidence of withdrawal from treatment was not different between the interferon combination arms. Also, the incidence of treatment discontinuation or modification was not different in the US centers compared to non-US centers. The higher rates of SAEs and dose modification suggest the potential for greater toxicity of PEG-IFN and ribavirin compared to IFN and ribavirin.

Taken together the serious adverse events and the treatment discontinuation and dose modification data suggest the potential for greater toxicity of peginterferon/ribavirin compared to interferon/ribavirin.

Table 19. Overview of Adverse Events

 

Peg-IFN alfa 2a

N %

Peg-IFN alfa 2a ribavirin

N %

IFN alfa 2b ribavirin

N %

Adverse Events: Any severity

212 (95)

446 (99)

435 (98)

Severe

63 (28)

131 (29)

127 (29)

Serious

26 (12)

53 (12)

38 (9)

Death

2

0

1

Withdrawalsa

15 (7)

44 (10)

47 (11)

Dose modificationa : PEG-IFN or IFN

61 (27)

145 (32)

81 (18)

Ribavirin

----

181 (40)

164 (37)

adue to adverse event or laboratory abnormality

Most Common Adverse Events

The incidence of new adverse events was summarized for the treatment period, the post-treatment period and the treatment and post-treatment periods combined

Table 20 shows that the incidence of the most common adverse events for the treatment plus post-treatment period was not higher in the peginterferon/ribavirin group compared to the interferon/ribavirin group.

Most Commonly Affected Body Systems

The most common adverse event was a systemic reaction consisting of fatigue/weakness/asthenia with or without headache, fever, chills/rigors. The second most common group of adverse events was neuropsychiatric with irritability, insomnia, impaired concentration/memory impairment, depression, anxiety/nervousness. The musculoskeletal system was commonly affected with myalgias and arthralgia. GI manifestations were also prominent (nausea, vomiting, anorexia, weight loss, abdominal pain, diarrhea). Finally skin manifestations included alopecia, dermatitis, pruritus, and injection site reactions.

Table 20. Common Adverse Events: In-Treatment and 24 Weeks Post-treatment a

 

PEG-IFN alfa-2a

PEG-IFN alfa-2a ribavirin

IFN alfa-2b ribavirin

 

N = 223

N = 451

N = 443

ADVERSE EVENT

No. (%)

No. (%)

No. (%)

Fatigue

98 (44)

242 (54)

244 (55)

Headache

115 (52)

211 (47)

230 (52)

Pyrexia

85 (38)

195 (43)

247 (56)

Myalgia

94 (42)

189 (42)

220 (50)

Insomnia

52 (23)

168 (37)

174 (39)

Nausea

58 (26)

130 (29)

145 (33)

Alopecia

48 (22)

128 (28)

151 (34)

Rigors

52 (23)

106 (24)

157 (35)

Arthralgia

64 (29)

121 (27)

112 (25)

Irritability

56 (25)

109 (24)

123 (28)

Depression

44 (20)

95 (21)

131 (30)

Pruritus

41 (18)

101 (22)

88 (20)

Appetite decreased

24 (11)

96 (21)

98 (22)

Dermatitis

29 (13)

95 (21)

80 (18)

Diarrhoea

54 (24)

77 (17)

68 (15)

Dizziness

31 (14)

81 (18)

70 (16)

Asthenia

26 (12)

69 (15)

72 (16)

Dyspnoea

20 (9)

70 (16)

72 (16)

Cough

23 (10)

73 (16)

51 (12)

Dry skin

20 (9)

50 (11)

64 (14)

Anxiety

18 (8)

51 (11)

60 (14)

Back pain

29 (13)

52 (12)

46 (10)

Abdominal pain upper

35 (16)

41 (9)

50 (11)

Injection site inflammation

26 (12)

56 (12)

44 (10)

Concentration impairment

28 (13)

41 (9)

53 (12)

Vomiting

17 (8)

52 (12)

51 (12)

Weight decrease

18 (8)

52 (12)

49 (11)

Abdominal pain

28 (13)

44 (10)

34 (8)

Sore throat

18 (8)

42 (9)

30 (7)

Dry mouth

14 (6)

33 (7)

37 (8)

Pain

14 (6)

36 (8)

30 (7)

Dyspepsia

9 (5)

35 (8)

30 (7)

Sinusitis

12 (5)

35 (8)

23 (5)

Nasopharyngitis

17 (8)

28 (6)

20 (5)

Sweating increased

10 (4)

30 (7)

23 (5)

Constipation

4 (2)

24 (5)

33 (7)

Dyspnoea exertional

8 (4)

22 (5)

31 (7)

URI

13 (6)

23 (5)

25 (6)

Influenza

18 (8)

18 (4)

22 (5)

Herpes simplex

15 (7)

22 (5)

20 (5)

Weakness

10 (4)

24 (5)

23 (5)

Eczema

3 (1)

30 (7)

23 (5)</