The combination of elbasvir and grazoprevir for the treatment of chronic HCV infection in Japanese patients: a randomized phase II/III study

Abstract

Background: Elbasvir (EBR) in combination with grazoprevir (GZR) has demonstrated efficacy in patients with hepatitis C virus (HCV) infections in trials primarily conducted in the USA and Europe. We investigated the safety and efficacy of EBR in combination with GZR in Japanese patients with chronic HCV infection, with or without cirrhosis.

Methods: The study was conducted in two parts. In part 1, noncirrhotic patients were randomized 1:1 to receive EBR (50 mg) in combination with GZR (50 or 100 mg) once daily for 12 weeks. In part 2, noncirrhotic patients were randomized 3:1 to receive immediate or deferred treatment with EBR (50 mg) and GZR (100 mg, determined in part 1) for 12 weeks; cirrhotic patients received open-label immediate treatment. The primary efficacy end point was the rate of sustained virologic response 12 weeks after completion of the study treatment.

Results: In part 1, 63 patients were randomized to receive EBR in combination with GZR at a dose of 50 mg (n = 31) or 100 mg (n = 32). The SVR12 rates were 100% with GZR at a dose of 50 mg and 96.8% with GZR at a dose of 100 mg. Tolerability was similar in both arms. In part 2, 301 noncirrhotic patients were randomized to receive immediate treatment (n = 227) or deferred treatment (n = 74), and 35 cirrhotic patients were enrolled. The SVR12 rates were 96.5% and 97.1% after immediate treatment in noncirrhotic and cirrhotic patients respectively. Safety was generally similar between immediate and deferred treatment.

Conclusion: Treatment with EBR in combination with GZR for 12 weeks is effective and well tolerated in Japanese patients with chronic HCV infection. CLINICALTRIALS.

Gov identifier: NCT02203149.

Keywords: Clinical trial; Efficacy; Genotype; Sustained virologic response; Therapy.

Conflict of interest statement

Conflict of interest

Hiromitsu Kumada has received lecture fees from AbbVie, Bristol-Myers Squibb, Dainippon Sumitomo, Gilead, GlaxoSmithKline, and Merck Sharp & Dohme. Yoshiyasu Karino has received lecture fees from AbbVie, Bristol-Myers Squibb, Gilead, and Merck Sharp & Dohme. Kazuaki Chayama has received lecture fees from Ajinomoto, Astellas, AstraZeneca, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Dainippon Sumitomo, Eisai, Gilead, GlaxoSmithKline, Janssen, Kowa, Kyorin, Merck Sharp & Dohme, Mitsubishi Tanabe, Miyarisan, Nippon Kayaku, Nippon Shinyaku, Nippon Siyaku, Otsuka, Roche, Takeda, Toray, Torii, Tsumura, and Zeria, and research grants/contracts from Abbott, AbbVie, Ajinomoto, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Dainippon Sumitomo, Eisai, Gilead, GlaxoSmithKline, Janssen, Kyorin, Merck Sharp & Dohme, Mitsubishi Tanabe, Miyarisan, Olympus, Otsuka, Sysmex, Takeda, Toray, Torii, Tsumura, and Zeria. Norifumi Kawada has received lecture fees from Janssen and Merck Sharp & Dohme, and research grants/contracts from Chugai. Yoshito Itoh has received lecture fees from AbbVie, Ajinomoto, Astellas, AstraZeneca, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Dainippon Sumitomo, Eisai, Fujifilm Medical, Gilead, GlaxoSmithKline, Janssen, Merck Sharp & Dohme, Mitsubishi Tanabe, Otsuka, Taiho, Takeda, and Zeria, and research grants/contracts from AbbVie, Ajinomoto, Astellas, AstraZeneca, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Dainippon Sumitomo, Eisai, Fujifilm Medical, Gilead, GlaxoSmithKline, Kyorin, Kyowa Hakko Kirin, Merck Serono, Merck Sharp & Dohme, Mitsubishi Tanabe, Nippon Kayaku Takeda, Ono, Otsuka, Shionogi, Taiho, and Zeria. Satoshi Mochida discloses intellectual property rights with SRL, has received lecture fees from AbbVie, Ajinomoto, Bristol-Myers Squibb, Dainippon Sumitomo, Merck Sharp & Dohme, and Toray Medical, and has received research grants/contracts from A2 Healthcare, AbbVie, Bristol-Myers Squibb, Chugai, Dainippon Sumitomo, Eisai, Merck Sharp & Dohme, Mitsubishi Tanabe, and Toray Medical. Naoyoshi Yatsuzuka, Etsuo Yodoya, Go Fujimoto, and Luzelena Caro are employees of Merck. Takashi Iwasa, Michael N. Robertson, Stuart Black, and Janice Wahl are employees of and own stock in Merck. The other authors declare that they have no conflict of interest.

Funding

This research was funded by Merck & Co. Inc.

Figures

Fig. 1

Patient disposition. AE adverse event, DTG deferred-treatment group, EBR elbasvir, GZR grazoprevir, ITG immediate-treatment group

Fig. 2

Rate of sustained virologic response at 12 weeks (SVR12) in patients receiving elbasvir (EBR; 50 mg) plus grazoprevir (GZR; 50 or 100 mg) in part 1 and in noncirrhotic and cirrhotic patients receiving EBR at a dose of 50 mg plus GZR at a dose of 100 mg (immediate-treatment group, ITG, only) in part 2 (full analysis set). SVR12 rates are not yet available for the deferred-treatment group. CI confidence interval

Fig. 3

Subgroup analysis of rate of sustained virologic response at 12 weeks (SVR12): immediate-treatment group (part 2; full analysis set). ALT alanine aminotransferase, CI confidence interval, eGFR estimated glomerular filtration rate, HCV hepatitis C virus