Full details of the ORAL Scan study design have been reported previously 5. Briefly, ORAL Scan was a phase III, double‐blind, parallel‐group, placebo‐controlled RCT of tofacitinib 5 mg or 10 mg twice daily with background MTX, compared with continued background MTX plus placebo, in adult patients with RA who had an inadequate response to MTX (ClinicalTrials.gov identifier: NCT00847613; see Appendix A for study investigators). Patients were randomized 4:4:1:1 to receive tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, placebo switched to tofacitinib 5 mg twice daily, or placebo switched to tofacitinib 10 mg twice daily. In the placebo treatment sequences, nonresponders (defined as patients with <20% improvement in swollen and tender joint counts) were advanced in a blinded manner to receive tofacitinib at month 3, according to the prespecified randomization schedule. All remaining patients receiving placebo were advanced in a blinded manner to receive tofacitinib at month 6. Prior to the first dose of study drug, patients must have been receiving MTX continuously for ≥4 months and a stable dose for ≥6 weeks. All patients received stable doses of MTX (≤25 mg weekly) throughout the ORAL Scan study. Stable weekly doses of <15 mg were allowed only in the case of intolerance of higher doses, toxicity from higher doses, or where higher doses would violate the local label.
The trial was approved by the institutional review boards (IRBs) and/or independent ethics committees at each investigational center or a central IRB and conducted in accordance with the Declaration of Helsinki and International Conference on Harmonisation Good Clinical Practice Guidelines. All patients provided written informed consent.
Here we report 24‐month data from the completed RCT (final, locked database). Clinical efficacy parameters evaluated included the American College of Rheumatology criteria for 20% improvement (ACR20), ACR50, and ACR70 responses 11; mean changes from baseline in the 4‐variable Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28‐ESR) 12; remission defined as DAS28‐ESR <2.6, Clinical Disease Activity Index (CDAI) ≤2.8, or Simplified Disease Activity Index (SDAI) ≤3.3, or by Boolean remission criteria 13; and low disease activity defined as DAS28‐ESR ≤3.2, CDAI ≤10, or SDAI ≤11.
The mean change from baseline in Health Assessment Questionnaire (HAQ) disability index (DI) was a coprimary end point at month 3. Changes from baseline through month 12, for which a step‐down approach was used with coprimary efficacy end points assessed sequentially, have been reported previously 5. Since this article primarily has a safety and efficacy focus, HAQ DI results are briefly presented here for completeness.
Consistent with the 12‐month interim analysis, inhibition of progression of structural damage was assessed by mean changes from baseline in modified Sharp/van der Heijde score (SHS), including erosion and joint space narrowing (JSN) scores, and proportions of patients without radiographic progression (SHS changes from baseline ≤0.5), evaluated for months 12–24. All radiographs were scored independently by 2 readers who were blinded with regard to treatment, visit, and time; these 2 readers’ SHS scores were then averaged for each time point to provide a single composite score for months 12 and 24. Note that all available radiographs were reread for the 24‐month analysis.
The incidence and severity of all‐cause adverse events (AEs), abnormal clinical laboratory findings, and vital signs were recorded. Treatment‐emergent AEs (TEAEs), serious AEs (SAEs), discontinuations due to AEs, and laboratory evaluations of interest were assessed according to treatment phase: months 0–3, months 3–6, and months 6–24. A Safety End Point Adjudication Committee comprising external independent consultants who were blinded with regard to treatment sequence assignment reviewed all deaths, cardiovascular events, and malignancies. Safety data up to month 12 have been presented previously 5.
Crude exposure‐adjusted incidence rates (with corresponding 95% confidence intervals [95% CIs]) for AEs and serious infections were calculated based on the number of unique patients with events per 100 patient‐years of exposure.
All analyses were based on the full analysis set, which included all patients who received ≥1 dose of study drug and had ≥1 postbaseline assessment. Except where noted, data are presented by the randomized treatment sequences. Patients initially treated with tofacitinib who did not experience a decrease of >20% in tender and swollen joints were “advanced” at month 3 to the same dosage of tofacitinib.
Missing ACR responses and data on remission and low disease activity status were addressed by nonresponder imputation with no advancement penalty, i.e., missing values resulting from patients withdrawing from the study for any reason were set to failure, but in patients continuing the study, values measured after advancement were not set to failure. This was done for all patients who met the criterion for advancement, those receiving tofacitinib as well those receiving placebo. This enabled the assessment of responses for patients who were “advanced” from tofacitinib to tofacitinib, and thus had no true change in medication. Analyses with nonresponder imputation with no advancement penalty are presented; specifically, response rates, with corresponding SEs and 95% CIs, based on Z‐scores formed by the normal approximation to the binomial distribution, compared with baseline values within each sequence. P values were not corrected to control for Type I errors.
To maintain blinding at month 3, radiographs were obtained in all patients who advanced at month 3. For radiographic data only, the radiographic scores for month 6 were imputed by linear extrapolation from baseline and month 3. Note that this includes patients receiving tofacitinib as well as patients receiving placebo, with the linear extrapolation value being the best estimate for each randomized treatment. For patients receiving placebo, radiographic scores for month 12 were imputed by linear extrapolation based on baseline and month 3 (for patients who advanced at month 3) or baseline and month 6 (for patients who advanced at month 6). Linear extrapolation was used to impute any missing data at the month 12 and month 24 visits. That is, baseline and non‐missing month 12 data would be used to estimate progression for a missing month 24 visit (radiographic data only).
Results for the clinical efficacy and structural progression end points are provided by their respective imputation methods (nonresponder imputation with no advancement penalty for efficacy and linear extrapolation for radiographic data), as well as observed, without imputation. Changes from baseline in erosion and JSN scores were computed for each patient, and individual values are presented in cumulative probability plots to show the distribution of the changes in individual patients.
The durability of response was assessed for low disease activity and remission as defined by the DAS28‐ESR, after month 6 in the full analysis set and for patients who completed the study, as observed. A flare was recorded at a visit if the DAS28‐ESR worsened by >1.2 from month 6, or, if the DAS28‐ESR was 5.1 at the visit, the score had worsened by >0.6 from month 6. A total of 6 visits, representing 18 months of study time, occurred after month 6.
Each of the structural progression end points were expressed as changes from baseline and analyzed by analysis of covariance applied to the imputed data set, with treatment, baseline values of the end point, and geographic region included as fixed effects.
All nonstructural continuous end points (efficacy variables such as DAS28‐ESR or patient‐reported outcomes such as patient's global assessment of disease activity) were expressed as changes from baseline. Each was analyzed by a linear mixed‐effects repeated‐measures model. Treatment, visit, treatment‐by‐visit interaction, geographic region, and baseline value were included as fixed effects, and patients were included as random effects. In both approaches, estimates of mean changes from baseline were derived from the model as least squares means, with corresponding SEs and 95% CIs, with t‐statistics and P values comparing tofacitinib with placebo. Rates of nonprogression, based on radiographic scores, were calculated based on linear extrapolation as described above.
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