Abstract
CONTROL ID: 1541639 Institutional Author(s): ABSTRACT BODY: Background The ADVANCE study showed that telaprevir (TVR, T) every 8 hours (q8h) combined with peginterferon alfa-2a (P) and ribavirin (R) had superior efficacy to PR alone. Reported here are results from OPTIMIZE, a Phase III, randomized, open-label, international, non-inferiority study comparing twice daily (bid) vs q8h TVR (NCT01241760). Methods Treatment-naive patients with genotype 1 (G1) HCV infection were randomized (stratified by fibrosis stage and IL28B genotype) to 750mg q8h or 1125mg bid TVR plus P 180µg/week and R 1000 or 1200mg/day for 12 weeks (TVR phase), then PR alone for 12 weeks if Week 4 HCV RNA was <25 IU/mL target not detected (RVR) or 36 weeks if detectable. The primary endpoint was SVR12 (HCV RNA <25 IU/mL 12 weeks after the last planned dose of PR). The pre-specified non-inferiority margin was –11%. Secondary objectives included additional efficacy outcomes, safety and tolerability. Methods Treatment-naive patients with genotype 1 (G1) HCV infection were randomized (stratified by fibrosis stage and IL28B genotype) to 750mg q8h or 1125mg bid TVR plus P 180µg/week and R 1000 or 1200mg/day for 12 weeks (TVR phase), then PR alone for 12 weeks if Week 4 HCV RNA was <25 IU/mL target not detected (RVR) or 36 weeks if detectable. The primary endpoint was SVR12 (HCV RNA <25 IU/mL 12 weeks after the last planned dose of PR). The pre-specified non-inferiority margin was –11%. Secondary objectives included additional efficacy outcomes, safety and tolerability. Results 744 patients were randomized and 740 treated. 60% of patients were male, 92% were Caucasian, 15% had bridging fibrosis,14% had compensated cirrhosis, 85% had baseline HCV RNA =800,000 IU/mL, 57% had G1a and 29% had IL28B CC. Outcomes were similar between regimens [Table]. TVR bid vs q8h was non-inferior: difference 1.5% (95% CI: –4.9%, 12.0%). 69% for TVR bid vs 67% for q8h achieved RVR and were eligible for 24 week treatment duration. The adverse event (AE) profile was generally similar between arms. The most frequent AEs during the TVR phase were fatigue (47.3%), pruritus (42.7%), anemia (41.6%), nausea (36.5%) and rash (35.3%). AEs leading to discontinuation of TVR included rash (5.3%), anemia (4.6%), pruritus (2.6%), fatigue (1.2%) and maculopapular rash (1.1%). SAEs were reported in 8.5% of patients (TVR phase). Conclusions In this study, with a high proportion of patients with bridging fibrosis or compensated cirrhosis, the efficacy of 1125mg bid TVR was non-inferior to 750mg q8h offering the potential of simplified dosing to G1 HCV-infected patients. Safety and tolerability were generally similar between regimens and consistent with the known profile of TVR.
CONTROL ID: 1414817 Institutional Author(s): ABSTRACT BODY: Twice daily dosing of TVR in combination with PegIFN+RBV has not been extensively studied in G1 HCV patients. The obvious benefit of twice daily dosing is ease of administration (taken at the same time as RBV) and improved adherence, which could result in better viral clearance rates. The purpose of this study is to assess the effectiveness of TVR dosed at 1125 mg Q12hr in treatment naïve and previously treated patients with genotype 1 chronic HCV infection. We obtained informed consent and treated 118 consecutive patients with TVR 1125mg po Q12 hrs. 103 of these have completed therapy or reached week 12 of treatment with HCV RNA measurements at baseline and monthly thereafter. We collected data on IL28B, RBV dose reduction, use of EPO, AEs, early discontinuations , treatment failures and SVR12/24. Results: Of the 103 evaluable patients 58/103 (56.3%) are treatment naïve (TN) or relapsers and 45/103 (43.6%) are treatment failures (NR). 33/103 (32%) have F0-2 fibrosis and 70/103 (68%) have F3/4 . 70 (71.5%) and 28 (28.5%) patients have genotype 1a and 1b respectively. IL28B genotyping was available in 39/103 patients and was CC in 20.5% and non-CC in 79.5%. 55 of the 58 (94.8%) TN patients were HCV RNA undetectable (UND)or <43 IU/ml at week 4 and UND at week 12 (eRVR=32/55). 30 of these have reached week 24 and all remain UND. 10 patients who completed therapy at week 24 have reached 12 weeks of F/U and all are SVR12. 23 of 45 (51.1%) NR were HCV RNA UND or <43 IU/ml and UND at week 12 and 19 of these have reached week 24; all remain UND. 6 NR patients who DC therapy early have achieved SVR12. 17 of the 22 (77%) patients who failed therapy in the NR group had F3/4. Safety: 27/103 patients stopped therapy prior to week 12 due to hepatic decompensation (4), SAEs (7), viral breakthrough or lack of milestone (12) or other reasons (4). 24/27 early DCs had advanced fibrosis and 2/27 achieved SVR12. The remainder relapsed. 5/103 patients developed hepatic decompensation (ascites, SBP, bleeding or HE) and 4/5 were hospitalized. There were no deaths. RBV dose reductions for anemia (Hgb<10 g) were required in 49/103 (44.7%) patients and EPO was used in 45/49 of these patients. Platelet or neutrophil growth factors were used in 6 and 2 patients respectively. 34/49 (73.5%) of patients requiring growth factor had cirrhosis. Conclusions: This early data demonstrates that on-treatment response rates with Q12 hr dosing of TVR are equivalent to or better than those published to date with Q8 hr dosing in a difficult to- treat population with mostly advanced fibrosis, G1a and unfavorable IL28B genotypes. This is the first study of Q12hr dosing in NR patients. Co-Author Disclosure Status FONTE: AASLD 2012 |
