Telaprevir clinical studies

# Clinical Studies

## Description of Adult Clinical Trials
The efficacy and safety of INCIVEK in subjects with genotype 1 chronic hepatitis C were evaluated in 4 adequate and well-controlled clinical trials: 3 in treatment-naive subjects and one in previously treated subjects (relapsers, partial responders, and null responders). Subjects in these trials had compensated liver disease, detectable HCV RNA, and liver histopathology consistent with chronic hepatitis C. In the trials, INCIVEK was administered at a total daily dosage of 2250 mg as either 750 mg every 8 hours (Trials 108, 111, C211 and C216) or 1125 mg twice daily (Trial C211); the peginterferon alfa-2a (Peg-IFN-alfa-2a) dose was 180 micrograms per week, and the ribavirin (RBV) dose was 1000 mg per day (subjects weighing less than 75 kg) or 1200 mg per day (subjects weighing greater than or equal to 75 kg). Plasma HCV RNA values were measured during the clinical trials using the COBAS TaqManHCV test (version 2.0), for use with the High Pure System. The assay had a lower limit of quantitation of 25 IU per mL.
For Trials 108, 111, and C216, SVR was defined as HCV RNA less than 25 IU per mL at last observation within the SVR visit window (i.e., weeks 32-78 for patients assigned to 24 weeks of treatment and weeks 56-78 for patients assigned to 48 weeks of treatment).
For Trial C211, SVR was defined as HCV RNA less than 25 IU/mL and assessed 12 weeks after the planned end of treatment, using the last measurement in the visit window.

## Treatment-Naive Adults

### Trial 108 (ADVANCE)
Trial 108 was a randomized, double-blind, parallel-group, placebo-controlled trial conducted in treatment-naive subjects (had received no prior therapy for HCV, including interferon or pegylated interferon monotherapy). INCIVEK was given for the first 8 weeks of treatment (T8/PR regimen) or the first 12 weeks of treatment (T12/PR regimen) in combination with Peg-IFN-alfa-2a/RBV for either 24 or 48 weeks. Subjects who had undetectable HCV RNA (Target Not Detected) at weeks 4 and 12 (extended Rapid Virologic Response ) received 24 weeks of Peg-IFN-alfa-2a/RBV treatment, and subjects who did not have undetectable HCV RNA at weeks 4 and 12 (no eRVR) received 48 weeks of Peg-IFN-alfa-2a/RBV treatment. The control regimen (Pbo/PR48) had a fixed treatment duration, with telaprevir-matching placebo for the first 12 weeks and Peg-IFN-alfa-2a/RBV for 48 weeks.
The 1088 enrolled subjects had a median age of 49 years (range: 18 to 69); 59% of the subjects were male; 23% had a body mass index greater than or equal to 30 kg/m2; 9% were Black; 11% were Hispanic or Latino; 77% had baseline HCV RNA levels greater than 800,000 IU per mL; 15% had bridging fibrosis; 6% had cirrhosis; 59% had HCV genotype 1a; and 40% had HCV genotype 1b.
Table 10 shows the response rates for the T12/PR and Pbo/PR48 groups.
In the T8/PR group, the overall SVR rate was 72%. The eRVR rate was 57% and the SVR rate for eRVR subjects was 86%. The SVR rate for no eRVR subjects was 52%. More subjects in the T8/PR group experienced virologic failure after Week 12 while receiving peginterferon alfa and ribavirin alone, 7% compared to 4% in T12/PR group.
SVR rates were higher (absolute difference of at least 22%) for the T12/PR group than for the Pbo/PR48 group across subgroups by sex, age, race, ethnicity, body mass index, HCV genotype subtype, baseline HCV RNA (less than 800,000, greater than or equal to 800,000 IU per mL), and extent of liver fibrosis. However, there were small numbers of subjects enrolled in some key subgroups. In the T12/PR group:
- Twenty-one subjects had cirrhosis at baseline and the overall SVR in these subjects was 71% (15/21). Among subjects with cirrhosis, 43% (9/21) were assigned to 24 weeks of treatment and of those 78% (7/9) achieved SVR.
- Twenty-six subjects were Black/African Americans. The overall SVR among Black/African American subjects was 62% (16/26). Among these subjects, 35% (9/26) were assigned to 24 weeks of treatment and of those 89% (8/9) achieved SVR.

### Trial 111 (ILLUMINATE)
Trial 111 was a randomized, open-label trial conducted in treatment-naive subjects. The trial was designed to compare SVR rates in subjects achieving eRVR who were treated with INCIVEK for 12 weeks in combination with Peg-IFN-alfa-2a/RBV for either 24 weeks (T12/PR24 regimen) or 48 weeks (T12/PR48 regimen).
The 540 enrolled subjects had a median age of 51 years (range: 19 to 70); 60% were male; 32% had a body mass index greater than or equal to 30 kg/m2; 14% were Black; 10% were Hispanic or Latino; 82% had baseline HCV RNA levels greater than 800,000 IU per mL; 16% had bridging fibrosis; 11% had cirrhosis; 72% had HCV genotype 1a; and 27% had HCV genotype 1b.
The overall SVR rate for all subjects enrolled in the trial was 74%. A total of 352 (65%) subjects achieved eRVR and of those 322 (60%) were randomized to 24 weeks (T12/PR24, n=162) or 48 weeks (T12/PR48, n=160) of treatment. The SVR rates were similar at 92% (T12/PR24) and 90% (T12/PR48), respectively. Again, small numbers of subjects were enrolled in some key subgroups:
Sixty-one (11%) of subjects had cirrhosis at baseline. Among subjects with cirrhosis, 30 (49%) achieved an eRVR: 18 were randomized to T12/PR24 and 12 to T12/PR48. The SVR rates were 61% (11/18) for the T12/PR24 group and 92% (11/12) for the T12/PR48 group.
Blacks/African Americans comprised 14% (73/540) of trial subjects. Thirty-four (47%) Black/African American subjects achieved an eRVR and were randomized to T12/PR24 or T12/PR48. The respective SVR rates were 88% (15/17) and 88% (15/17), compared to 92% (244/266) for Caucasians among randomized subjects.

### Trial C211 (OPTIMIZE)
Trial C211 was a randomized, open-label, Phase 3 trial conducted in treatment-naive subjects. Enrolled subjects received 12 weeks of either INCIVEK 750 mg every 8 hours  or INCIVEK 1125 mg twice daily  in combination with peginterferon alfa-2a and ribavirin. The trial was designed to compare twice-daily dosing  versus q8h dosing  of INCIVEK. At week 12, INCIVEK dosing ended and subjects continued on peginterferon alfa-2a and ribavirin treatment. The total treatment duration was determined based on the subjects' individual on-treatment viral response. If a subject achieved undetectable HCV RNA < 25 IU/mL (target not detected) at week 4, the total treatment duration was 24 weeks. Otherwise, the total treatment duration was 48 weeks.
The 740 enrolled subjects had a median age of 51 years (range: 18 to 70); 60% of the subjects were male; 21% had a body mass index  30 kg/m2; 5% were Black; 2% were Asian; 85% had baseline HCV RNA levels  800,000 IU/ml; 15% had bridging fibrosis; 14% had cirrhosis; 57% had HCV genotype 1a; and 43% had HCV genotype 1b.
Table 11 shows the response rates for the T12(twice daily)/PR group and the T12(q8h)/PR groups by treatment outcomes. The overall SVR rates were similar at 74%  and 73% , respectively.
SVR rates were similar for the T12(twice daily)/PR and T12(q8h)/PR groups across subgroups determined by sex, age, race, ethnicity, body mass index, HCV genotype subtype, IL28B genotype, baseline HCV RNA (less than 800,000, greater than or equal to 800,000 IU per mL), and extent of liver fibrosis. However, there were small numbers of subjects enrolled in some key subgroups.
Fifty-four and 49 subjects in T12(twice daily)/PR and T12(q8h)/PR groups, respectively, had cirrhosis at baseline. The SVR rate in these subjects was 54% (29/54) in the T12(twice daily)/PR group and 49% (24/49) in the T12(q8h)/PR group. In the T12(twice daily)/PR group, 52% (28/54) of subjects with cirrhosis achieved undetectable HCV RNA (target not detected) at week 4; their SVR rate was 68% (19/28). In the T12(q8h)/PR group, 59% (29/49) achieved undetectable HCV RNA (target not detected) at week 4; their SVR was 59% (17/29). The SVR rate for subjects assigned 48 weeks of treatment was 38% (10/26) in the T12(twice daily)/PR group and 35% (7/20) in the T12(q8h)/PR.
Thirty-five subjects were Black/African Americans. The overall SVR among Black/African American subjects was 50% (10/20) in the T12(twice daily)/PR group and 60% (9/15) in the T12(q8h)/PR group. Among these subjects, 46% (16/35) were assigned to 24 weeks of treatment and of those 88% (14/16) achieved SVR.

## Previously Treated Adults

### Trial C216 (REALIZE)
Trial C216 was a randomized, double-blind, placebo-controlled trial conducted in subjects who did not achieve SVR with prior treatment with Peg-IFN-alfa-2a/RBV or Peg-IFN-alfa-2b/RBV. The trial enrolled prior relapsers (subjects with HCV RNA undetectable at end of treatment with a pegylated interferon-based regimen, but HCV RNA detectable within 24 weeks of treatment follow-up) and prior non-responders (subjects who did not have undetectable HCV RNA levels during or at the end of a prior course of at least 12 weeks of treatment). The nonresponder population included 2 subgroups: prior partial responders (greater than or equal to 2-log10 reduction in HCV RNA at week 12, but not achieving HCV RNA undetectable at end of treatment with peginterferon alfa and ribavirin) and prior null responders (less than 2-log10 reduction in HCV RNA at week 12 of prior treatment with peginterferon alfa and ribavirin).
Subjects were randomized in a 2:2:1 ratio to one of 2 INCIVEK combination treatment groups (with and without a Peg-IFN-alfa-2a/RBV lead-in) or a control group. The T12/PR48 group received INCIVEK and Peg-IFN-alfa-2a/RBV for 12 weeks (without a lead-in), followed by placebo and Peg-IFN-alfa-2a/RBV for 4 weeks, followed by Peg-IFN-alfa-2a/RBV for 32 weeks. The T12(DS)/PR48 group had a lead-in (delayed start of INCIVEK) with placebo and Peg-IFN-alfa-2a/RBV for 4 weeks, followed by INCIVEK and Peg-IFN-alfa-2a/RBV for 12 weeks, followed by Peg-IFN-alfa-2a/RBV for 32 weeks. The Pbo/PR48 group received placebo and Peg-IFN-alfa-2a/RBV for 16 weeks, followed by Peg-IFN-alfa-2a/RBV for 32 weeks.
The 662 enrolled subjects had a median age of 51 years (range: 21 to 70); 70% of the subjects were male; 26% had a body mass index greater than or equal to 30 kg/m2; 5% were Black; 11% were Hispanic or Latino; 89% had baseline HCV RNA levels greater than 800,000 IU per mL; 22% had bridging fibrosis; 26% had cirrhosis; 54% had HCV genotype 1a, and 46% had HCV genotype 1b. Null and partial responders had higher baseline HCV RNA levels and more advanced liver disease (cirrhosis) than relapsers; other characteristics were similar across these populations.
The lead-in and immediate start regimens produced comparable SVR and no SVR rates, so data from these 2 groups were pooled (Table 12).
Among prior relapsers, 76% (218/286) achieved an eRVR and of those 95% (208/218) achieved an SVR. In an earlier, dose-finding clinical trial, 78% (52/67) of prior relapsers achieved an eRVR and were treated with 24 weeks of peginterferon alfa and ribavirin (T12/PR24); of those 94% (49/52) achieved an SVR.
For all populations in the trial (prior relapsers, prior partial responders, and prior null responders), SVR rates were higher for the T12/PR group than for the Pbo/PR48 group across subgroups by sex, age, ethnicity, body mass index, HCV genotype subtype, baseline HCV RNA level, and extent of liver fibrosis.
Twenty-six percent (139/530) of subjects treated with INCIVEK had cirrhosis at baseline. SVR rates among cirrhotic subjects who received INCIVEK combination treatment compared to Pbo/PR48 were: 84% (48/57) compared to 7% (1/15) for prior relapsers, 34% (11/32) compared to 20% (1/5) for prior partial responders, and 14% (7/50) compared to 10% (1/10) for prior null responders.
Four percent (19/530) of treatment experienced subjects who received INCIVEK combination treatment were Black/African Americans; the SVR rate for these subjects was 63% (12/19) compared to 66% (328/498) for Caucasians.