Clinical benefit of 1-year certolizumab pegol (CZP) add-on therapy to methotrexate treatment in patients with early rheumatoid arthritis was observed following CZP discontinuation: 2-year results of the C-OPERA study, a phase III randomised trial

Tatsuya Atsumi, Yoshiya Tanaka, Kazuhiko Yamamoto, Tsutomu Takeuchi, Hisashi Yamanaka, Naoki Ishiguro, Katsumi Eguchi, Akira Watanabe, Hideki Origasa, Shinsuke Yasuda, Yuji Yamanishi, Yasuhiko Kita, Tsukasa Matsubara, Masahiro Iwamoto, Toshiharu Shoji, Osamu Togo, Toshiyuki Okada, Désirée van der Heijde, Nobuyuki Miyasaka, Takao Koike, Tatsuya Atsumi, Yoshiya Tanaka, Kazuhiko Yamamoto, Tsutomu Takeuchi, Hisashi Yamanaka, Naoki Ishiguro, Katsumi Eguchi, Akira Watanabe, Hideki Origasa, Shinsuke Yasuda, Yuji Yamanishi, Yasuhiko Kita, Tsukasa Matsubara, Masahiro Iwamoto, Toshiharu Shoji, Osamu Togo, Toshiyuki Okada, Désirée van der Heijde, Nobuyuki Miyasaka, Takao Koike

Abstract

Objectives: To investigate the clinical impact of 1-year certolizumab pegol (CZP) therapy added to the first year of 2-year methotrexate (MTX) therapy, compared with 2-year therapy with MTX alone.

Methods: MTX-naïve patients with early rheumatoid arthritis (RA) with poor prognostic factors were eligible to enter Certolizumab-Optimal Prevention of joint damage for Early RA (C-OPERA), a multicentre, randomised, controlled study, which consisted of a 52-week double-blind (DB) period and subsequent 52-week post treatment (PT) period. Patients were randomised to optimised MTX+CZP (n=159) or optimised MTX+placebo (PBO; n=157). Following the DB period, patients entered the PT period, receiving MTX alone (CZP+MTX→MTX; n=108, PBO+MTX→MTX; n=71). Patients who flared could receive rescue treatment with open-label CZP.

Results: 34 CZP+MTX→MTX patients and 14 PBO+MTX→MTX patients discontinued during the PT period. From week 52 through week 104, significant inhibition of total modified total Sharp score progression was observed for CZP+MTX versus PBO+MTX (week 104: 84.2% vs 67.5% (p<0.001)). Remission rates decreased after CZP discontinuation; however, higher rates were maintained through week 104 in CZP+MTX→MTX versus PBO+MTX→MTX (41.5% vs 29.3% (p=0.026), 34.6% vs 24.2% (p=0.049) and 41.5% vs 33.1% (p=0.132) at week 104 in SDAI, Boolean and DAS28(erythrocyte sedimentation rate) remission. CZP retreated patients due to flare (n=28) showed rapid clinical improvement. The incidence of overall adverse events was similar between groups.

Conclusions: In MTX-naïve patients with early RA with poor prognostic factors, an initial 1 year of add-on CZP to 2-year optimised MTX therapy brings radiographic and clinical benefit through 2 years, even after stopping CZP.

Trial registration number: NCT01451203.

Keywords: Anti-TNF; DMARDs (biologic); Early Rheumatoid Arthritis; Methotrexate.

Conflict of interest statement

Competing interests: TA has taken part in speakers' bureaus for Astellas, Bristol-Myers, Chugai and Mitsubishi-Tanabe. KY has received consultancy fees from Abbott, BMS, Chugai, Eisai, Mitsubishi-Tanabe, Pfizer, Roche and UCB Pharma; and has received research grants from Abbott, Eisai, Mitsubishi-Tanabe, Pfizer, Santen and UCB Pharma. TT has received consultancy fees from AstraZeneca, Asahi Kasei, Eli Lilly, Mitsubishi-Tanabe and Novartis; research grants from Abbott, Astellas, BMS, Chugai, Daiichi-Sankyo, Eisai, Janssen, Mitsubishi-Tanabe, Nippon Shinyaku, Otsuka, Pfizer, Sanofi-Aventis, Santen, Takeda and Teijin; and has taken part in speakers' bureaus for Abbott, BMS, Chugai, Eisai, Janssen, Mitsubishi-Tanabe, Pfizer and Takeda and UCB Pharma. HY has received consultancy fees from Abbott, Astellas, BMS, Chugai, Eisai, Janssen, Mitsubishi-Tanabe, Pfizer, Takeda and UCB Pharma; and has received research grants from Abbott, Astellas, BMS, Chugai, Eisai, Janssen, Mitsubishi-Tanabe, Pfizer, Takeda and UCB Pharma. NI has received research grants from Abbott, Astellas, BMS, Takeda, Chugai, Eisai, Janssen, Kaken Mitsubishi-Tanabe and Pfizer; and has taken part in speakers' bureaus for Abbott, Astellas, BMS, Chugai, Eisai, Janssen, Kaken, Mitsubishi-Tanabe, Otsuka, Pfizer, Taisho-Toyama and Takeda. YT has received research grants from Astellas, Abbvie, BMS, Chugai, Daiichi-Sankyo, Mitsubishi-Tanabe, MSD; has received consultancy fees from Abbott, Abbvie, Asahi Kasei, Astellas, AstraZeneca, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, GSK, Janssen, Mitsubishi-Tanabe, MSD, Pfizer, Quintiles, Takeda and UCB Pharma; and has taken part in speakers' bureaus for Abbott, Abbvie, Asahi Kasei, Astellas, AstraZeneca, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, GSK, Janssen, Mitsubishi-Tanabe, MSD, Pfizer, Quintiles, Takeda and UCB Pharma. KE has received consultancy fees from UCB Pharma. AW has received research grants from Daiichi-Sankyo, Dainippon-Sumitomo, Kyorin, Meiji Seika; Shionogi, Taiho, Taisho and Toyama Chemical; and has taken part in speakers' bureaus for Daiichi-Sankyo, Dainippon-Sumitomo, GSK, Mitsubishi-Tanabe, MSD, Pfizer, Shionogi and Taisho-Toyama. HO has received consultancy fees from Astellas and UCB Pharma. SY has received research grant from BMS and taken part in speakers' bureaus for Abbvie, Astellas, Chugai, Eizai, Pfizer, Mitsubishi-Tanabe and Takeda. YY has no competing interests to disclose. YK has received speakers' bureau from Astellas, Chugai and Ono. TM has received speaker honoraria from Pfizer Japan, Janssen Pharmaceutical Co.. and Astellas Pharma; and research grants form Quintiles Transnational Japan K.K, Janssen Pharmaceutical Co., Takeda Chemical Industries, Daiichi Sankyo Co., Astellas Pharma, Eli Lilly Japan K.K., MSD Co., Nippon Kayaku Co., Parexel International, Pfizer Japan and Bristol-Myers Squibb. MI has received payment for lectures from Astellas, Chugai, Ono and Tanabe-Mitsubishi; has received research grants from Pfizer and a royalty fee from Chugai. TS is an employee of UCB Pharma; TO is an employee of Astellas. DvdH has received consultancy fees from Abbvie, Amgen, AstraZeneca, Augurex, BMS, Boehringer Ingelheim, Celgene, Centocor, Chugai, Covagen, Daiichi-Sankyo, Eli-Lilly, Galapagos, GSK, Janssen Biologics, Merck, Novartis, Novo-Nordisk, Otsuka, Pfizer, Roche, Sanofi-Aventis, Schering-Plough, UCB Pharma and Vertex; and is the Director of Imaging Rheumatology bv. NM has received research grants from Abbott, Astellas, Chugai, Eisai, Mitsubishi-Tanabe, Pfizer and Takeda. TK has received consultancy fees from Abbvie, Astellas, BMS, Chugai, Daiichi-Sankyo, Eisai, Mitsubishi-Tanabe, Pfizer, Santen, Taisho-Toyama, Takeda, Teijin and UCB Pharma, and has taken part in speakers' bureaus for Abbott, Astellas, BMS, Chugai, Daiichi-Sankyo, Eisai, Mitsubishi-Tanabe, Pfizer, Santen, Taisho-Toyama, Takeda, Teijin and UCB Pharma.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Figures

Figure 1
Figure 1
Patient disposition in the Certolizumab-Optimal Prevention of joint damage for Early rheumatoid arthritis trial. CZP, certolizumab pegol; FAS, full analysis set; MTX, methotrexate; PBO, placebo.
Figure 2
Figure 2
(A) Change from baseline in modified total Sharp score (mTSS) at week 104. (B) Cumulative probability plot of mTSS change from baseline at week 104 for both PBO+MTX→MTX and CZP+MTX→MTX groups. Change from baseline in mTSS was analysed using an analysis of covariance model in which actual scores were converted to rank scores, using the treatment group as a factor and baseline rank score as a covariate. Rate of mTSS non-progression (mTSS change from baseline ≤0.5) was compared using Fisher's exact test. CZP, certolizumab pegol; LOCF, last observation carried forward; MTX, methotrexate; PBO, placebo.
Figure 3
Figure 3
The proportion of patients achieving (A) SDAI remission, (B) Boolean remission and (C) DAS28(ESR) remission during the Certolizumab-Optimal Prevention of joint damage for Early rheumatoid arthritis study in both the PBO+MTX→MTX and CZP+MTX→MTX groups. Remission rates at weeks 52 and 104 were compared using Fisher's exact test. CZP, certolizumab pegol; DB, double blind; ESR, erythrocyte sedimentation rate; MTX, methotrexate; PBO, placebo; PT, post treatment.
Figure 4
Figure 4
(A) Retention rate after discontinuation of CZP (Kaplan-Meier plot), (B) clinical remission at weeks 52 and 104, (C) DAS28(ESR) over time during DB period and after CZP restart in patients who were retreated with CZP (n=28), (D) modified total Sharp score non-progression rate during and after 52-week CZP therapy for patients who entered the PT period from CZP+MTX group. CZP, certolizumab pegol; DB, double blind; ESR, erythrocyte sedimentation rate; MTX, methotrexate; PT, post treatment.

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