The First, Multicenter, Double-Blind, Randomized, Parallel-Group Study of Certolizumab Pegol in Early Rheumatoid Arthritis Demonstrates Inhibition of Joint Damage Progression

Tatsuya Atsumi¹, Kazuhiko Yamamoto², Tsutomu Takeuchi³, Hisashi Yamanaka⁴, Naoki Ishiguro⁵, Yoshiya Tanaka⁶, Katsumi Eguchi⁷, Akira Watanabe⁸, Hideki Origasa⁹, Toshiharu Shoji¹⁰, Osamu Togo¹¹, Toshiyuki Okada¹², Désirée M. van der Heijde¹³, Nobuyuki Miyasaka¹⁴ and Takao Koike^15,16, ¹Division of Rheumatology, Endocrinology and Nephrology, Hokkaido University Graduate School of Medicine, Sapporo, Japan, ²Department of Allergy and Rheumatology, The University of Tokyo, Tokyo, Japan, ³Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Kitakyushu, Japan, ⁴Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan, ⁵Department of orthopedics, Nagoya University Graduate School and Faculty of Medicine, Nagoya, Japan, ⁶The First Department of Internal Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan, ⁷Department of Rheumatology, Sasebo City General Hospital, Nagasaki, Japan, ⁸Division of Rheumatology, Department of Internal Medicine, School of Medicine, Tohoku University, Tokyo, Japan, ⁹Division of Biostatistics and Clinical Epidemiology, University of Toyama School of Medicine, Toyama, Japan, ¹⁰Department of Clinical Research and Development, UCB Pharma, Tokyo, Japan, ¹¹Biometrics Group, UCB Pharma, Tokyo, Japan, ¹²Astellas Pharma Inc, Tokyo, Japan, ¹³Department of Rheumatology, Leiden University Medical Center, Leiden, Netherlands, ¹⁴Department of Rheumatology, Tokyo Medical and Dental University, Tokyo, Japan, ¹⁵NTT Sapporo Medical Center, Sapporo, Japan, ¹⁶Hokkaido University Graduate School of Medicine, Sapporo, Japan

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: anti-TNF therapy, Biologics, certolizumab pegol and joint damage, Early Rheumatoid Arthritis

Session Information

Title: Rheumatoid Arthritis - Small Molecules, Biologics and Gene Therapy: Therapeutic Strategies, Biomarkers and Predictors of Outcomes in Rheumatoid Arthritis

Session Type: Abstract Submissions (ACR)

Background/Purpose

The efficacy and safety of certolizumab pegol (CZP)+methotrexate (MTX) therapy compared to MTX alone, in Japanese MTX-naïve early rheumatoid arthritis (RA) patients (pts) with poor prognostic factors from the C-OPERA trial, have not been previously reported.

Methods

Pts with ≤12 months persistent arthritis fulfilling 2010 ACR/EULAR classification criteria¹were enrolled in this multicenter, double-blind, randomized study (NCT01451203). Eligible pts were MTX-naïve, with at least moderate disease activity (DAS28[ESR]≥3.2), high-positive anti-CCP (>3xULN), and were either rheumatoid factor positive or had bone erosion on radiographs of hands/feet. Pts were randomized 1:1 to CZP+MTX or placebo (PBO)+MTX. Unless precluded by tolerability, MTX dose was rapidly escalated to 16mg by Week (Wk) 8. The primary endpoint was change from baseline (CFB) in van der Heijde modified total Sharp score (mTSS) at Wk52. Secondary endpoints were CFB in mTSS at Wk24, and clinical remission rates by DAS28[ESR], ACR/EULAR (SDAI), and ACR/EULAR (Boolean) at Wk24 and 52. Post-hoc analyses assessed whether higher radiographic progression amongst PBO+MTX treated pts occurred within certain categories of baseline (BL) factors (eg. CRP, HAQ-DI, MMP-3).

Results

A total of 316 pts (CZP+MTX: n=159, PBO+MTX: n=157) were randomized and received ≥1 dose of study drug. Groups were well-balanced at BL, with mean (±SD) age: 49.2±10.5 yrs, symptom duration: 4.1±2.9 months, DAS28[ESR]: 5.45±1.15 and mTSS: 5.55±12.43. Average MTX dose was 11.6±2.8 mg/wk. CFB in mTSS at Wk52 and 24 for CZP+MTX were, on average, 0.36 and 0.26, and for PBO+MTX were 1.58 and 0.86, respectively (Figure). Statistical comparison of CFB in mTSS by nonparametric approach (ANCOVA on ranks) was significantly greater for CZP+MTX than PBO+MTX at Wk52 (p<0.001) and Wk24 (p=0.003) (Figure). CZP+MTX remission rates were significantly greater than for PBO+MTX at Wk52 (SDAI: 57.9% vs 33.8% [p<0.001]; Boolean: 45.3% vs 28.0% [p=0.002]; DAS28[ESR]: 57.2% vs 36.9% [p<0.001]) and at Wk24 (SDAI: 48.4% vs 29.3% [p<0.001]; Boolean: 36.5% vs 22.3% [p=0.007]; DAS28[ESR]: 52.8% vs 30.6% [p<0.001] Fisher's Exact test). Higher BL DAS28[ESR], CRP, mTSS, HAQ-DI and serum MMP-3 seemed associated with more radiographic progression in the PBO+MTX group, whereas CZP+MTX still inhibited progression of structural damage in these pts despite this higher risk of progression (Table). CZP+MTX was well tolerated, with no unexpected safety signals observed.

Conclusion

CZP+MTX was significantly more effective than PBO+MTX in inhibiting disease progression, as well as in achieving clinical remission, in MTX-naïve Japanese early RA pts with poor prognostic factors.

Reference 1. Aletaha D. Ann Rheum Dis 2010;69:1580–8

Disclosure:

T. Atsumi,

Astellas,Bistol-Myers,Chugai and Mitsubishi-Tanabe ,

K. Yamamoto,

UCB Pharma, Pfizer, Abbott, BMS, Roche, Chugai, Mitsubishi-Tanabe and Eisa,

UCB Pharma, Pfizer, Abbott, Santen, Mitsubishi-Tanabe and Eisai.,

T. Takeuchi,

AstraZeneca, Eli Lilly, Novartis, Mitsubishi-Tanabe and Asahi Kasei,

Abott, Astellas, BMS, Chugai, Daiichi-Sankyo, Eisai, Janssen, Mitsubishi-Tanabe, Nippon Shinyaku, Otsuka, Pfizer, Sanofi-Aventis, Santen, Takeda and Teijin,

UCB Pharma, Abbott, BMS, Chugai, Eisai, Janssen, Mitsubishi-Tanabe, Pfizer and Takeda,

H. Yamanaka,

UCB Pharma, Abbott, Astellas, BMS, Chugai, Eisai, Janssen, Mitsubishi-Tanabe, Pfizer and Takeda,

N. Ishiguro,

Takeda, Mitsubishi-Tanabe, Astellas, Chugai, Abbott, BMS, Eisai, Janssen, Kaken and Pfizer,

Takeda, Mitsubishi-Tanabe, Astellas, Chugai, Abbott, BMS, Eisai, Janssen, Kaken, Pfizer, Taisho-Toyama and Otsuka,

Y. Tanaka,

BMS, MSD, Chugai, Mitsubishi-Tanabe, Astellas, Abbvie, Daiichi-Sankyo,

UCB Pharma, Mitsubishi-Tanabe, Abbott, Abbvie, Eisai, Chugai, Janssen, Pfizer, Takeda, Astellas, Daiichi-Sankyo, GSK, AstraZeneca, Eli Lilly, Quintiles, MSD, Asahi Kasei,

UCB, Mitsubishi-Tanabe, Abbott, Abbvie, Eisai, Chugai, Janssen, Pfizer, Takeda, Astellas, Daiichi-Sankyo, GSK, AstraZeneca, Eli Lilly, Quintiles, MSD, Asahi Kasei,

K. Eguchi,

UCB Pharma,

A. Watanabe,

Daiichi-Sankyo, Kyorin, Shionogi, Taisho, Dainippon-Sumitomo, Taiho, Toyama Chemical and Meiji Seika,

MSD, GSK, Shionogi, Daiichi-Sankyo, Taisho-Toyama, Dainippon-Sumitomo, Mitsubishi-Tanabe, Pfizer,

H. Origasa,

UCB Pharma and Astellas,

T. Shoji,

UCB Pharma,

O. Togo,

UCB Pharma,

T. Okada,
None;

D. M. van der Heijde,

AbbVie, Amgen, AstraZeneca, Augurex, BMS, Celgene, Centocor, Chugai, Covagen, Daiichi, Eli-Lilly, Galapagos, GSK, Janssen Biologics, Merck, Novartis, Novo-Nordisk, Otsuka, Pfizer, Roche, Sanofi-Aventis, Schering-Plough, UCB Pharma, Vertex,

Director of Imaging Rheumatology bv,

N. Miyasaka,

Pfizer, Takeda, Mitsubishi-Tanabe, Chugai, Abbott, Eisai and Astellas,

T. Koike,

Abbvie, Astellas, BMS, Chugai, Daiichi-Sankyo, Eisai, Mitsubishi-Tanabe, Pfizer, Santen, Taisho-Toyama, Takeda, Teijin, UCB Pharma,

UCB Pharma, Pfizer, Chugai, Abbott, Mitsubishi-Tanabe, Takeda, Eisai, Santen, Astellas, Taisho-Toyama, BMS, Teijin and Daiichi-Sankyo,

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