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ARD Online First, published on April 14, 2014 as 10.1136/annrheumdis-2013-204807 Clinical and epidemiological research

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Comparison of Tripterygium wilfordii Hook F with methotrexate in the treatment of active rheumatoid arthritis (TRIFRA): a randomised, controlled clinical trial Qian-wen Lv,1 Wen Zhang,1 Qun Shi,1 Wen-jie Zheng,1 Xin Li,1 Hua Chen,1 Qing-jun Wu,1 Wan-lan Jiang,1 Hong-bin Li,2 Lu Gong,3 Wei Wei,3 Hui Liu,4 Ai-jing Liu,5 Hong-tao Jin,5 Jun-xiang Wang,6 Xiu-mei Liu,7 Zhen-bin Li,8 Bin Liu,9 Min Shen,1 Qian Wang,1 Xiang-ni Wu,1 Di Liang,1 Yu-feng Yin,1 Yun-yun Fei,1 Jing-mei Su,1 Li-dan Zhao,1 Ying Jiang,1 Jing Li,1 Fu-lin Tang,1 Feng-chun Zhang,1 Peter E Lipsky,10 Xuan Zhang1 Handling editor Tore K Kvien ▸ Additional material is published online. To view please visit the journal (http:// dx.doi.org/10.1136/ annrheumdis-2013-204807) For numbered affiliations see end of article. Correspondence to Dr Xuan Zhang, Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; [email protected] and Dr Peter E Lipsky, Formerly National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA; [email protected] Q-wL, WZ, QS and W-jZ contributed equally to this manuscript. Received 23 October 2013 Revised 24 February 2014 Accepted 1 March 2014

To cite: Lv Q-wen, Zhang W, Shi Q, et al. Ann Rheum Dis Published Online First: [ please include Day Month Year] doi:10.1136/ annrheumdis-2013-204807

ABSTRACT Objectives To compare the efficacy and safety of Tripterygium wilfordii Hook F (TwHF) with methotrexate (MTX) in the treatment of active rheumatoid arthritis (RA). Methods Design: a multicentre, open-label, randomised controlled trial. All patients were assessed by trained investigators who were unaware of the therapeutic regimen. Intervention: 207 patients with active RA were randomly allocated (1:1:1) to treatment with MTX 12.5 mg once a week, or TwHF 20 mg three times a day, or the two in combination. At week 12, if reduction of the 28-joint count Disease Activity Score (DAS28) was 20 mg/L. Patients were excluded if they had a history of chronic serious infection, any current infection or any type of cancer. Pregnant or lactating women were excluded. All patients were informed of the risk of infertility and patients with a desire to have children were excluded. Patients who had received DMARDs or biological therapy within 3 months before participating in this study were excluded. Patients were allowed to continue to

Figure 1 Patient disposition. MTX, methotrexate; qw, once a week; RA, rheumatoid arthritis; TwHF, Tripterygium wilfordii Hook F. 2

Lv Q-wen, et al. Ann Rheum Dis 2014;0:1–9. doi:10.1136/annrheumdis-2013-204807

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Clinical and epidemiological research receive non-steroidal anti-inflammatory drugs and stable dosage of oral corticosteroids (≤10 mg prednisone or equivalent/day) during the study.

Randomisation and interventions A computer-generated randomised code was used to assign patients with RA in a 1:1:1 ratio to one of three treatment arms to receive oral TwHF pills 20 mg three times a day; or MTX starting from 7.5 mg once a week and increasing to 12.5 mg once a week (0.20–0.25 mg/kg) within 4 weeks, with folic acid 10 mg on the day after each MTX administration; or TwHF plus MTX at the same dosage as above. At week 12, if patients in the MTX or TwHF monotherapy groups showed a reduction of the 28-joint count Disease Activity Score (DAS28) ≥30%, then the monotherapy was continued; otherwise the patients were switched to MTX+TwHF combination therapy. If the patients in the combination therapy group had a reduction of DAS28