Tofacitinib (CP-690,550) in combination with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors: a randomised phase 3 trial

Background Rheumatoid arthritis is a heterogeneous chronic disease, and no therapeutic agent has been identified which is universally and persistently effective in all patients. We investigated the effectiveness of tofacitinib (CP-690,550), a novel oral Janus kinase inhibitor, as a targeted immunomodulator and disease-modifying therapy for rheumatoid arthritis. Methods We did a 6-month, double-blind, parallel-group phase 3 study at 82 centres in 13 countries, including North America, Europe, and Latin America. 399 patients aged 18 years or older with moderate-to-severe rheumatoid arthritis and inadequate response to tumour necrosis factor inhibitors (TNFi) were randomly assigned in a 2: 2: 1: 1 ratio with an automated internet or telephone system to receive twice a day treatment with: tofacitinib 5 mg (n=133); tofacitinib 10 mg (n=134); or placebo (n=132), all with methotrexate. At month 3, patients given placebo advanced to either tofacitinib 5 mg twice a day (n=66) or 10 mg twice a day (n=66). Primary endpoints included American College of Rheumatology (ACR) 20 response rate, mean change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI), and rates of disease activity score (DAS) 28-4(ESR) less than 2.6 (referred to as DAS28<2.6), all at month 3. The full analysis set for the primary analysis included all randomised patients who received at least one dose of study medication and had at least one post-baseline assessment. This trial is registered with www.ClinicalTrials.gov, number NCT00960440. Findings At month 3, ACR20 response rates were 41.7% (55 of 132 [95% CI vs placebo 6.06-28.41]; p=0.0024) for tofacitinib 5 mg twice a day and 48.1% (64 of 133; [12.45-34.92]; p<0.0001) for tofacitinib 10 mg twice a day versus 24.4% (32 of 131) for placebo. Improvements from baseline in HAQ-DI were -0.43 ([-0.36 to -0.15]; p<0.0001) for 5 mg twice a day and -0.46 ([-0.38 to -0.17]; p<0.0001) for 10 mg twice a day tofacitinib versus -0.18 for placebo; DAS28<2.6 rates were 6.7% (eight of 119; [0-10.10]; p=0.0496) for 5 mg twice a day tofacitinib and 8.8% (11 of 125 [1.66-12.60]; p=0.0105) for 10 mg twice a day tofacitinib versus 1.7% (two of 120) for placebo. Safety was consistent with phase 2 and 3 studies. The most common adverse events in months 0-3 were diarrhoea (13 of 267; 4.9%), nasopharyngitis (11 of 267; 4.1%), headache (11 of 267; 4.1%), and urinary tract infection (eight of 267; 3.0%) across tofacitinib groups, and nausea (nine of 132; 6.8%) in the placebo group. Interpretation In this treatment-refractory population, tofacitinib with methotrexate had rapid and clinically meaningful improvements in signs and symptoms of rheumatoid arthritis and physical function over 6 months with manageable safety. Tofacitinib could provide an effective treatment option in patients with an inadequate response to TNFi.