Study design and treatment
ORAL Standard (A3921064; NCT00853385) was a double-blind, phase 3 trial  in which patients were randomly assigned to one of five regimens, all with stable background MTX: tofacitinib 5 mg BID, tofacitinib 10 mg BID, ADA 40 mg Q2W (subcutaneous injection), placebo for 3 or 6 months followed by tofacitinib 5 mg BID, and placebo for 3 or 6 months followed by tofacitinib 10 mg BID for a total of 12 months.
ORAL Sequel (A3921024; NCT00413699) is an open-label long-term extension study  in which all patients from ORAL Standard were eligible to receive tofacitinib 10 mg BID with or without conventional synthetic DMARDs. Exclusion criteria included treatment-related serious AEs and serious or recurrent infections (including serious or recurrent herpes zoster) in the index study. Patients with latent tuberculosis were allowed to continue in the extension study if they had received an adequate course of therapy. Patients from certain countries (e.g., Korea, Croatia, Denmark, Czech Republic, Germany, Spain, Sweden, Ireland and the United Kingdom) who enrolled in the extension study ≥14 days after their final index study visit were excluded if their absolute lymphocyte count (ALC) values were <750 cells/mm3. Patients from the remaining countries were excluded if their ALC values were <500 cells/mm3.
The current post-hoc analyses included patients who were randomized at baseline to treatment with blinded ADA 40 mg Q2W + MTX or blinded tofacitinib 10 mg BID + MTX in ORAL Standard and subsequently received open-label tofacitinib 10 mg BID (with or without MTX) in the extension study. Although the patients initiated treatment in the long-term extension with tofacitinib 10 mg BID, this could be reduced to 5 mg BID for safety reasons. Additionally, dose adjustments, including tapering and discontinuation (DC) of permitted concomitant RA medications (such as MTX, prednisone and non-steroidal anti-inflammatory drugs) were allowed in response to inadequate efficacy, disease improvement, or for safety reasons.
Each study was performed in compliance with the Declaration of Helsinki and Good Clinical Practice Guidelines established by the International Conference on Harmonization. The final protocols, amendments, and informed consent documentation were reviewed and approved by the institutional review board and the independent ethics committee of each investigational center (Additional file 1: Table S1).
Patients in this analysis included those who were initially enrolled in the phase 3, ORAL Standard study  and subsequently elected to enroll in the extension study . Eligible patients in the phase 3 study were ≥18 years of age and had received a diagnosis of active RA, as classified according to the American College of Rheumatology (ACR) 1987 Revised Criteria  and had not failed or had an AE to a TNFi in the past. Additional inclusion and exclusion criteria have been described previously . Patients who completed participation in the study or discontinued for reasons other than treatment-related serious AEs and who met other inclusion/exclusion criteria were invited to enroll in the long-term extension . For patients enrolling in the long-term extension study within 2 weeks of their last dose in the blinded study, baseline values were obtained from the blinded study.
Post-hoc descriptive statistics are reported (data cutoff date 19 April 2012). As the extension study is ongoing, the study database has not yet been locked (i.e., some values may change for the final, locked study database).
Safety and tolerability assessments
The incidence of treatment-emergent AEs (TEAEs) was calculated at scheduled visits of the blinded study (baseline, and months 1, 3, 6, 9, and 12) and extension study (baseline, months 1, 2, 3, and every 3 months thereafter).
In the current analyses, the incidence of TEAEs was compared during the last 3 months of blinded therapy and the first 3 months of open-label treatment.
Exposure-adjusted incidence rates (and corresponding 95 % confidence intervals) of DCs due to AEs, serious AEs and serious infections per 100 patient-years from baseline were calculated for patients who completed treatment with ADA 40 mg Q2W + MTX or tofacitinib 10 mg BID + MTX in the blinded study for patients, (1) regardless of whether they entered the extension study, and (2) who then enrolled in the extension study. These analyses were performed for 3-month (months 0 − 3, 3 − 6, 6 − 9, and 9 − 12) and 12-month (months 0 − 12) periods for both the blinded study and the first 12 months of the extension study. Of note, there were two study visits in the last 3 months of the blinded study (visits 5 and 6 at months 9 and 12, respectively), and four study visits in the first 3 months of the extension study (visits 1 − 4, for baseline and months 1, 2, and 3).
The following efficacy parameters were measured in patients who completed treatment with ADA + MTX or tofacitinib 10 mg + MTX in the blinded study (or discontinued for reasons other than a treatment-related serious AE) and then switched to the tofacitinib 10 mg group in the extension study: ACR response rates (20 %, 50 %, and 70 % improvement), mean change in Health Assessment Questionnaire-Disability Index (HAQ-DI) scores from the baseline of the blinded study, and Disease Activity Score for 28-joint counts based on the erythrocyte sedimentation rate (DAS28-4(ESR)) <2.6 response rates at: (1) month 9 (visit 5) of the blinded study (“-3 months” relative to the switch); (2) the time of switching from the blinded to the extension study (“switch”), and (3) month 3 (visit 4) of the extensions study (“+3 months”) allowing visit windows of ±1.5 months to capture all efficacy and safety data.