Phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs

Authors

  • Roy Fleischmann,

    Corresponding author
    1. Metroplex Clinical Research Center and University of Texas Southwestern Medical Center, Dallas
    • Metroplex Clinical Research Center, 8144 Walnut Hill Lane, Suite 800, Dallas, TX 75231

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    • Dr. Fleischmann has received consulting fees from Pfizer and Abbott (less than $10,000 each) and has received study grants from Pfizer and Abbott.

  • Maurizio Cutolo,

    1. University of Genoa, Genoa, Italy
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    • Dr. Cutolo has received consulting fees, speaking fees, and/or honoraria from Actelion and Mundipharma (less than $10,000 each) and has received a study grant from Pfizer.

  • Mark C. Genovese,

    1. Stanford University, Stanford, California
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    • Dr. Genovese has received consulting fees from Pfizer (less than $10,000) and has received a study grant from Pfizer.

  • Eun Bong Lee,

    1. Seoul National University College of Medicine, Seoul, Republic of Korea
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    • Dr. Lee has received consulting fees from Pfizer (less than $10,000).

  • Keith S. Kanik,

    1. Pfizer, New London, Connecticut
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    • Drs. Kanik, Connell, Gruben, Krishnaswami, Wallenstein, Wilkinson, and Zwillich own stock or stock options in Pfizer.

  • Seth Sadis,

    1. Pfizer, New London, Connecticut
    Current affiliation:
    1. Compendia Bioscience, Ann Arbor, Michigan
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    • Dr. Sadis owns stock in Pfizer.

  • Carol A. Connell,

    1. Pfizer, New London, Connecticut
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    • Drs. Kanik, Connell, Gruben, Krishnaswami, Wallenstein, Wilkinson, and Zwillich own stock or stock options in Pfizer.

  • David Gruben,

    1. Pfizer, New London, Connecticut
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    • Drs. Kanik, Connell, Gruben, Krishnaswami, Wallenstein, Wilkinson, and Zwillich own stock or stock options in Pfizer.

  • Sriram Krishnaswami,

    1. Pfizer, New London, Connecticut
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    • Drs. Kanik, Connell, Gruben, Krishnaswami, Wallenstein, Wilkinson, and Zwillich own stock or stock options in Pfizer.

  • Gene Wallenstein,

    1. Pfizer, New London, Connecticut
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    • Drs. Kanik, Connell, Gruben, Krishnaswami, Wallenstein, Wilkinson, and Zwillich own stock or stock options in Pfizer.

  • Bethanie E. Wilkinson,

    1. Pfizer, New London, Connecticut
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    • Drs. Kanik, Connell, Gruben, Krishnaswami, Wallenstein, Wilkinson, and Zwillich own stock or stock options in Pfizer.

  • Samuel H. Zwillich

    1. Pfizer, New London, Connecticut
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    • Drs. Kanik, Connell, Gruben, Krishnaswami, Wallenstein, Wilkinson, and Zwillich own stock or stock options in Pfizer.


  • Presented in part at the Annual European Congress of Rheumatology of the European League Against Rheumatism, Copenhagen, Denmark, June 2009 and at the 73rd Annual Scientific Meeting of the American College of Rheumatology, Philadelphia, PA, October 2009. Previously published in abstract form: Kanik K, Fleischmann R, Cutolo M, Genovese M, Lee EB, Sadis S, et al. Phase 2b dose ranging monotherapy study of the oral JAK inhibitor CPP-690,550 and adalimumab vs placebo in patients with active rheumatoid arthritis with an inadequate response to DMARDs [abstract]. Ann Rheum Dis 2009;68 Suppl 3:123; and Fleischmann R, Genovese MC, Gruben D, Kanik KS, Wallenstein GV, Wilkinson B, et al. Safety and efficacy after 24 week dosing of the oral JAK inhibitor CP-690,550 as monotherapy in patients with active rheumatoid arthritis [abstract]. Arthritis Rheum 2009;60 Suppl 10:1924.

  • ClinicalTrials.gov identifier: NCT00550446.

Abstract

Objective

To compare the efficacy, safety, and tolerability of 5 doses of oral tofacitinib (CP-690,550) or adalimumab monotherapy with placebo for the treatment of active rheumatoid arthritis (RA) in patients with an inadequate response to disease-modifying antirheumatic drugs.

Methods

In this 24-week, double-blind, phase IIb study, patients with RA (n = 384) were randomized to receive placebo, tofacitinib at 1, 3, 5, 10, or 15 mg administered orally twice a day, or adalimumab at 40 mg injected subcutaneously every 2 weeks (total of 6 injections) followed by oral tofacitinib at 5 mg twice a day for 12 weeks. The primary end point was the responder rate according to the American College of Rheumatology 20% improvement criteria (ACR20) at week 12.

Results

Treatment with tofacitinib at a dose of ≥3 mg twice a day resulted in a rapid response with significant efficacy when compared to placebo, as indicated by the primary end point (ACR20 response at week 12), achieved in 39.2% (3 mg; P ≤ 0.05), 59.2% (5 mg; P < 0.0001), 70.5% (10 mg; P < 0.0001), and 71.9% (15 mg; P < 0.0001) in the tofacitinib group and 35.9% of patients in the adalimumab group (P = 0.105), compared with 22.0% of patients receiving placebo. Improvements were sustained at week 24, according to the ACR20, ACR50, and ACR70 response rates as well as classifications of remission according to the 3-variable Disease Activity Score in 28 joints (DAS28) using C-reactive protein and the 4-variable DAS28 using the erythrocyte sedimentation rate. The most common treatment-emergent adverse events (AEs) in patients across all tofacitinib treatment arms (n = 272) were urinary tract infection (7.7%), diarrhea (4.8%), headache (4.8%), and bronchitis (4.8%).

Conclusion

Tofacitinib monotherapy at ≥3 mg twice a day was efficacious in the treatment of patients with active RA over 24 weeks and demonstrated a manageable safety profile.

Intracellular pathways that include the JAK kinases are critical to immune cell activation, proinflammatory cytokine production, and cytokine signaling (1). Tofacitinib (CP-690,550) is a novel, orally administered JAK inhibitor that is being investigated as a targeted immunomodulator and disease-modifying therapy in rheumatoid arthritis (RA) (2). Tofacitinib selectively inhibits JAK-1, JAK-2, and JAK-3 in vitro, with functional cellular specificity for JAK-1 and JAK-3 over JAK-2 (3). Inhibition of JAK-3, in combination with JAK-1, blocks signaling through the common γ-chain–containing cytokines (interleukin-2 [IL-2], IL-4, IL-7, IL-9, IL-15, and IL-21). JAK-1/2 is required for interferon-γ and IL-6 signaling, whereas hematopoietic cytokines signal through JAK-2/2.

In a phase IIa study, patients with active RA who had an inadequate response to, or were intolerant of, treatment with methotrexate (MTX) or tumor necrosis factor (TNF) inhibitors were treated with tofacitinib monotherapy at a dosage of 5, 15, or 30 mg twice a day for 6 weeks. Treatment with tofacitinib resulted in clinically meaningful reductions in the signs and symptoms of RA when compared to the placebo group (4), led to improvements in pain, function, and health status (5), and demonstrated an acceptable safety profile (4).

To determine the durability of the response and longer-term safety profile, further testing of tofacitinib administered at dosages of ≤15 mg twice a day over a longer study period was required. Therefore, two 24-week phase IIb dose-ranging studies were initiated. One study assessed tofacitinib (1–15 mg twice a day and 20 mg once a day) in combination with stable doses of background MTX in patients with active RA who had an inadequate response to MTX alone (6). The present study assessed tofacitinib monotherapy (1–15 mg twice a day) in patients who had an inadequate response to traditional disease-modifying antirheumatic drugs (DMARDs).

PATIENTS AND METHODS

Patients.

This study was conducted in 63 centers in the United States, Europe, Latin America, and the Republic of Korea. The study was performed in compliance with the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice Guidelines. The study (Pfizer protocol no. A3921035) was approved by the Institutional Review Boards/Independent Ethics Committees at each investigational center. All patients provided their written informed consent.

Eligible patients were ≥18 years of age, had a diagnosis of RA for ≥6 months (meeting the American College of Rheumatology [ACR] 1987 revised criteria for RA [7]), and had active disease, defined as ≥6 tender/painful joints (68 joint count) and ≥6 swollen joints (66 joint count) at the screening and baseline visits and either an erythrocyte sedimentation rate (ESR) above the upper limit of normal (ULN) or a C-reactive protein (CRP) level >7 mg/liter. Other key inclusion criteria included failure of at least one DMARD due to lack of efficacy or toxicity, and washout of all DMARDs except antimalarial agents at stable doses.

Key exclusion criteria included the following: discontinuation of a previous TNF inhibitor due to lack of efficacy or adverse events (AEs); previous adalimumab therapy; evidence of hematopoietic disorders at screening or within 3 months prior to the first dose of the study drug (hemoglobin level <9.0 gm/dl, hematocrit <30%, white blood cell count <3.0 × 109/liter, absolute neutrophil count <1.2 × 109/liter, or platelet count <100 × 109/liter); estimated glomerular filtration rate ≤50 ml/minute (Cockcroft-Gault calculation); total bilirubin, aspartate aminotransferase (AST), or alanine aminotransferase (ALT) levels >2× ULN; untreated infection with Mycobacterium tuberculosis or other clinically significant infection; and a history of malignancy, with the exception of adequately treated nonmetastatic basal cell or squamous cell cancer of the skin or cervical carcinoma in situ.

Study treatment.

The present study was designed as a phase IIb, randomized, double-blind, placebo-controlled, active-comparator, parallel-group study. Patients were randomized equally to receive one of the following treatments: tofacitinib, administered orally at 1, 3, 5, 10, or 15 mg twice a day; adalimumab, injected subcutaneously at 40 mg once every other week for 10 weeks (baseline and weeks 2, 4, 6, 8, and 10) followed by reassignment to receive tofacitinib at week 12, administered orally at 5 mg twice a day, with the reassignment occurring irrespective of the patient's response to adalimumab; or placebo. Patients who were randomized to receive tofacitinib at 1 or 3 mg twice a day or placebo and in whom a ≥20% reduction from baseline in both the swollen and tender/painful joint counts was not achieved at week 12 were reassigned, in a blinded manner, to receive tofacitinib at 5 mg twice a day beginning at week 12; these patients were categorized in the treatment (reassigned) groups. No other dose adjustments were permitted.

Concomitant medications.

Patients could continue on a stable background regimen of RA therapy, which included antimalarial agents, nonsteroidal antiinflammatory drugs, opioids (total daily dose lower than or equal to the equivalent of 30 mg oral morphine), acetaminophen (≤2.6 gm/day), and/or oral corticosteroids (≤10 mg prednisone or equivalent/day). CYP3A inducers and CYP3A4, CYP3A5, and CYP3A7 inhibitors were prohibited, due to the potential for drug interactions. Also prohibited were live-component vaccinations and intravenous/intramuscular administration of corticosteroids. Intraarticular corticosteroids were allowed (cumulative dose ≤40 mg methylprednisolone or equivalent) in ≤2 joints, and were not to be administered during or between the week 6 and week 12 visits. For all injected joints, if a joint was swollen and/or tender before the injection, it was considered swollen and/or tender from that point forward, regardless of the status of the joint after the injection.

Study assessments.

Efficacy measures.

The primary objective was to compare the efficacy of 5 different dosages of tofacitinib (1–15 mg twice a day) by assessing the response rates according to the ACR 20% improvement criteria (ACR20) (8) at week 12, based on the number of tender/painful joints (68 joint count), the number of swollen joints (66 joint count), and the CRP level. Secondary objectives included the durability of the treatment response and safety of the treatment over 24 weeks, efficacy of adalimumab over 12 weeks, and safety of reassignment from adalimumab to tofacitinib (weeks 12–24). The secondary efficacy end points analyzed throughout the study included the following: the ACR20, ACR50, and ACR70 response rates, and the proportions of patients achieving disease remission according to the 3-variable Disease Activity Score in 28 joints (DAS28) (9) using the CRP (DAS28-CRP), the 4-variable DAS28 using the ESR (DAS28-ESR), a DAS28 score of <2.6, and the least squares mean change in components of the ACR core set of disease activity measures, including the Health Assessment Questionnaire disability index (HAQ DI) (10), the Short Form 36 (SF-36) Health Survey (11), and the Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F) subscale (12), as well as patient's assessment of pain and patient's and physician's global assessments of disease activity on 0–100-mm visual analog scales.

Safety measures.

All AEs and the severity of AEs were recorded. Laboratory evaluations, vital sign assessments, physical examinations, and electrocardiography were performed at scheduled time points.

Statistical analysis.

Efficacy response rates for binary end points were analyzed using the normal approximation to the binomial, comparing each dose of study treatment with placebo. For continuous measures, a longitudinal, mixed-effects, repeated-measures model was used. Treatment, week, and treatment-by-week interaction were included as fixed effects, along with patients as a random effect. Estimates of the mean and mean difference from placebo were derived from the model, and contrasts with the values in the placebo group were formed (no comparisons were specified by the protocol for tofacitinib versus adalimumab).

The full analysis data set included all patients who were randomized and received at least one dose of study drug; this was equivalent to the safety population. To address missing data, 3 types of imputation were used: 1) nonresponder imputation (NRI), in which the patient's baseline observation was carried forward for missing values; 2) last observation carried forward (LOCF); and 3) data remaining as-is (no imputation; grouped according to original dose, with post–reassignment visits excluded for reassigned patients). NRI was used for analyses of the ACR20 primary end point at week 12. Additional analyses were performed as a measure of robustness of the results. P values have not been corrected for multiple comparisons.

RESULTS

Disposition and characteristics of the patients.

Overall, 555 patients were screened for inclusion, and 386 were randomized to receive treatment. Of these patients, 384 received a study treatment, and each regimen was evaluated for efficacy and safety (Figure 1). There were generally more treatment discontinuations in patients treated with placebo, those treated with adalimumab, and those treated with lower doses of tofacitinib. There were generally fewer discontinuations post–week 12 (n = 27) compared with the period from baseline to week 12 (n = 44).

Figure 1.

Patient disposition, showing the total number of patients screened, total number randomized to a treatment group, and number of evaluable patients. a = 1 patient did not meet the inclusion/exclusion criteria, and 1 patient decided to no longer participate. b = Patients completing treatment through week 24, including reassigned patients. bid = twice a day; qow = once every other week.

Baseline demographic and clinical characteristics were similar between the treatment groups (Table 1). The majority of patients were white and female, with a mean age of 52–55 years. The mean duration of RA was 7.7–10.8 years, and patients had failed treatment with a mean 1.5–1.9 prior DMARDs.

Table 1. Baseline demographic and clinical characteristics of the RA patients in the full analysis data set*
 Placebo (n = 59)TofacitinibAdalimumab, 40 mg qow (n = 53)
1 mg bid (n = 54)3 mg bid (n = 51)5 mg bid (n = 49)10 mg bid (n = 61)15 mg bid (n = 57)
  • *

    RA = rheumatoid arthritis; qow = once every other week; NSAID = nonsteroidal antiinflammatory drug; TNF = tumor necrosis factor; HAQ DI = Health Assessment Questionnaire disability index; ESR = erythrocyte sedimentation rate; CRP = C-reactive protein; DAS28 = Disease Activity Score in 28 joints.

  • Including all patients reassigned to receive tofacitinib at 5 mg twice a day (bid) at week 12.

  • The most common prior disease-modifying antirheumatic drugs (DMARDs) were methotrexate (MTX) (42.7%), hydroxychloroquine (8.6%), and leflunomide (8.3%).

  • §

    Three patients were excluded because information on the MTX dose was not available.

Sex, no. (%) female52 (88.1)46 (85.2)44 (86.3)43 (87.8)53 (86.9)50 (87.7)45 (84.9)
Age, mean ± SD years53 ± 13.755 ± 13.353 ± 12.254 ± 13.552 ± 10.953 ± 13.054 ± 11.9
Race, no. (%)       
 White43 (72.9)44 (81.5)38 (74.5)36 (73.5)44 (72.1)46 (80.7)43 (81.1)
 Black3 (5.1)02 (3.9)03 (4.9)01 (1.9)
 Asian6 (10.2)5 (9.3)5 (9.8)6 (12.2)5 (8.2)4 (7.0)4 (7.5)
 Other7 (11.9)5 (9.3)6 (11.8)7 (14.3)9 (14.8)7 (12.3)5 (9.4)
Duration of RA since diagnosis, mean (range) years10.8 (0.7–44.0)9.4 (0.6–38.0)9.9 (0.8–30.0)8.1 (0.5–38.0)8.6 (0.5–38.0)8.7 (0.8–38.0)7.7 (0.8–50.0)
Prior failed DMARDs, mean no.1.91.51.91.91.81.91.9
NSAID use at screening, %67.877.870.669.477.168.475.5
Prior MTX use, %78858684848181
Prior MTX dosage, mean mg/week§12.713.513.713.811.914.614.7
Previously failed ≥1 TNF inhibitor, %8.51.97.84.18.27.07.5
Concomitant glucocorticoids, %57.661.151.055.154.156.154.7
Concomitant antimalarials, %1011810111411
Rheumatoid factor positive, %74.585.288.277.580.380.774.6
Tender joints, mean (68 count)25.927.024.627.125.725.924.1
Swollen joints, mean (66 count)16.916.715.917.416.316.914.9
HAQ DI, mean (scale 0–3)1.541.571.531.401.491.621.44
ESR, mean mm/hour46.246.541.947.443.843.144.8
CRP, mean mg/liter23.521.416.224.516.721.720.1
4-variable DAS28-ESR, mean6.66.56.46.66.56.56.3
3-variable DAS28-CRP, mean5.65.55.45.65.55.55.4

Efficacy.

The ACR20 response rate at week 12 (primary end point) was significantly higher among patients receiving ≥3 mg tofacitinib twice a day compared with those receiving placebo, with an ACR20 response achieved in 31.5% (1 mg; P = 0.256), 39.2% (3 mg; P ≤ 0.05), 59.2% (5 mg; P < 0.0001), 70.5% (10 mg; P < 0.0001), and 71.9% (15 mg; P < 0.0001) of patients in the tofacitinib groups and in 35.9% of patients in the adalimumab group (P = 0.105), compared with 22.0% of patients in the placebo group (Figure 2A). At week 24, a significant ACR20 response was observed in the tofacitinib groups for doses ≥5 mg twice a day, when compared with placebo (Figure 2B). The time to onset of a significantly higher ACR20 response as compared with placebo was 2 weeks for those receiving tofacitinib at doses of ≥3 mg twice a day (Figure 2C).

Figure 2.

Treatment response rates according to the proportion of patients achieving the American College of Rheumatology 20% improvement criteria (ACR20), ACR50, and ACR70 at week 12 (A) and week 24 (B), and time course of the ACR20 response over 24 weeks (C), in the full analysis data set with nonresponder imputation. Bars show the mean ± SEM. The percentages of ACR responders in each treatment group are shown above the bars. = P ≤ 0.05; ∗∗ = P < 0.001; ∗∗∗ = P < 0.0001 versus placebo. bid = twice a day; ADA = adalimumab; qow = once every other week.

Significant improvement according to the ACR20 response rates was also seen when the data were analyzed using LOCF, with differences seen at week 2 and week 12 for those patients receiving ≥3 mg tofacitinib twice a day, and at week 24 for those receiving ≥5 mg twice a day, when compared with those receiving placebo (see Supplementary Figure 1, available on the Arthritis & Rheumatism web site at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1529-0131). Furthermore, when the data were analyzed by geographic location (in analyses using NRI), the ACR20 response rates at week 12 were consistent with the overall response pattern observed (see Supplementary Figure 4, available on the Arthritis & Rheumatism web site at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1529-0131).

When improvement was measured using the ACR50 response rates, we again observed significant improvements in the tofacitinib dose groups compared with placebo at week 12 (in those receiving ≥5 mg twice a day) and week 24 (in those receiving ≥3 mg twice a day). Similarly, the ACR70 response rates were significantly higher in the tofacitinib dose groups compared with placebo at week 12 (in those receiving 10 mg and 15 mg twice a day) and week 24 (in those receiving ≥5 mg twice a day) (Figures 2A and B). Results from the LOCF analyses supported the findings from the NRI analyses with regard to the ACR50 and ACR70 response rates.

In patients treated with adalimumab (receiving adalimumab up to week 12 and then reassigned to receive tofacitinib at 5 mg twice a day during weeks 12–24) who were classified as nonresponders (no change in the swollen and tender/painful joint count), the response rates (in analyses with no imputation) at week 12 were 4.8% for the ACR20, 0% for the ACR50, and 0% for the ACR70; at week 24 (reassigned group), the rates were 52.6%, 21.1%, and 10.5%, respectively. In patients treated with adalimumab who were classified as responders (≥20% reduction in the swollen and tender/painful joint counts), the response rates were 80.0% for the ACR20, 44.0% for the ACR50, and 8.0% for the ACR70 at week 12; at week 24 (reassigned group), the rates were 71.4%, 42.9%, and 23.8%, respectively. Scores for components of the ACR core criteria set at baseline and week 12, as well as the least squares mean change from baseline to week 12, are presented in Table 2.

Table 2. American College of Rheumatology disease activity core component scores at baseline and week 12, and mean change from baseline to week 12*
 Tender/painful joint countSwollen joint countPatient's assessment of pain, 0–100 mm VASPatient's global assessment of disease activity, 0–100 mm VASPhysician's global assessment of disease activity, 0–100 mm VASHAQ DICRP, mg/liter
No.Mean ± SEMNo.Mean ± SEMNo.Mean ± SEMNo.Mean ± SEMNo.Mean ± SEMNo.Mean ± SEMNo.Mean ± SEM
  • *

    Values are the least squares means from the full analysis data set, in analyses with no imputation. VAS = visual analog scale; HAQ DI = Health Assessment Questionnaire disability index; CRP = C–reactive protein; bid = twice a day; qow = once every other week.

Placebo              
 Baseline5925.92 ± 1.685916.90 ± 1.275960.29 ± 3.025961.41 ± 2.785963.02 ± 2.44581.54 ± 0.095923.53 ± 3.52
 Week 124615.50 ± 1.944611.85 ± 1.424643.93 ± 3.564644.85 ± 3.484644.76 ± 3.67451.24 ± 0.114537.00 ± 7.85
 Change −10.98 ± 1.57 −4.87 ± 1.15 −16.56 ± 3.19 −16.45 ± 3.21 −19.60 ± 2.86 −0.25 ± 0.08 14.06 ± 2.56
Tofacitinib 1 mg bid              
  Baseline5427.02 ± 2.095416.70 ± 1.215459.74 ± 3.215460.74 ± 3.385462.13 ± 2.27541.57 ± 0.095421.39 ± 3.02
  Week 124418.32 ± 2.534411.39 ± 1.694447.25 ± 3.894445.39 ± 3.944341.72 ± 3.52441.28 ± 0.114316.89 ± 3.25
  Change −9.58 ± 1.60 −5.98 ± 1.17 −13.92 ± 3.25 −15.51 ± 3.28 −19.61 ± 2.93 −0.25 ± 0.08 −3.88 ± 2.61
 3 mg bid              
  Baseline5124.55 ± 1.585115.90 ± 1.195161.25 ± 3.355159.76 ± 3.195062.10 ± 2.60511.53 ± 0.095116.22 ± 2.73
  Week 124612.33 ± 1.90469.26 ± 1.584642.30 ± 3.964640.78 ± 3.854636.65 ± 3.46461.09 ± 0.11469.23 ± 1.86
  Change −12.65 ± 1.60 −6.55 ± 1.18 −17.91 ± 3.25 −18.96 ± 3.28 −26.77 ± 2.95 −0.44 ± 0.08 −10.41 ± 2.58
 5 mg bid              
  Baseline4927.14 ± 2.094917.35 ± 1.474964.14 ± 3.364967.55 ± 3.214865.85 ± 2.07491.40 ± 0.104924.51 ± 4.34
  Week 124611.52 ± 1.82467.33 ± 1.054632.70 ± 3.724633.52 ± 3.584529.80 ± 2.82460.94 ± 0.11458.13 ± 1.79
  Change −16.24 ± 1.63 −9.53 ± 1.20 −30.76 ± 3.29 −31.15 ± 3.32 −35.56 ± 3.01 −0.51 ± 0.08 −14.56 ± 2.61
 10 mg bid              
  Baseline6125.70 ± 1.786116.33 ± 1.066162.92 ± 2.406162.41 ± 2.556061.05 ± 2.04601.49 ± 0.106116.66 ± 2.16
  Week 12578.09 ± 1.59575.58 ± 1.045728.14 ± 3.025729.02 ± 3.065625.37 ± 2.65560.81 ± 0.09543.12 ± 0.47
  Change −17.87 ± 1.46 −10.70 ± 1.07 −34.28 ± 2.95 −33.17 ± 2.97 −38.33 ± 2.69 −0.66 ± 0.07 −16.54 ± 2.37
 15 mg bid              
  Baseline5725.88 ± 1.775716.93 ± 1.205663.46 ± 3.385762.77 ± 3.615767.19 ± 2.38571.62 ± 0.095721.70 ± 4.37
  Week 12548.44 ± 1.53545.11 ± 0.975427.26 ± 3.525426.93 ± 3.615424.20 ± 2.55540.78 ± 0.09523.62 ± 0.54
  Change −17.80 ± 1.50 −11.73 ± 1.10 −35.79 ± 3.05 −35.77 ± 3.06 −41.65 ± 2.75 −0.82 ± 0.07 −18.06 ± 2.42
Adalimumab, 40 mg qow              
  Baseline5324.11 ± 1.905314.91 ± 1.125364.36 ± 2.955362.15 ± 3.005362.77 ± 2.09531.44 ± 0.095320.09 ± 3.22
  Week 124614.74 ± 2.17467.41 ± 1.154642.87 ± 3.804644.04 ± 3.724638.22 ± 3.44461.13 ± 0.114514.53 ± 3.03
  Change −11.22 ± 1.60 −8.49 ± 1.17 −20.85 ± 3.24 −18.66 ± 3.26 −29.96 ± 2.91 −0.35 ± 0.08 −7.43 ± 2.59

When improvement was assessed as a DAS28-ESR score of <2.6, the response rates at week 12 were significantly higher in patients treated with tofacitinib at dosages of ≥10 mg twice a day compared with placebo (P ≤ 0.05). The response rates in the different groups were as follows: for tofacitinib 1 mg, 7.7%; for tofacitinib 3 mg, 5.9%; for tofacitinib 5 mg, 12.5%; for tofacitinib 10 mg, 14.8%; for tofacitinib 15 mg, 19.3%; for adalimumab, 3.9%; for placebo, 3.6%. At week 24, these response rates were maintained for dosages of ≥10 mg twice a day, and significantly higher response rates were also observed for tofacitinib dosages of 3 mg twice a day and 5 mg twice a day.

In patients receiving adalimumab, a significant response according to a DAS28-ESR score of <2.6 was not seen at either week 12 (see Supplementary Figure 2, available on the Arthritis & Rheumatism web site at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1529-0131) or week 24 (response rate of 3.9% in the reassigned group). When disease remission was defined as a DAS28-CRP score of <2.6, the response rates at week 12 showed a similar trend as that assessed with the DAS28-ESR score in patients receiving tofacitinib compared with those receiving placebo.

Improvement was also assessed as the mean change in the DAS28-ESR score from baseline to week 12. In the tofacitinib groups, mean score changes of −1.17 (1 mg), −1.58 (3 mg), −2.19 (5 mg; P < 0.001 versus placebo), −2.59 (10 mg; P < 0.0001 versus placebo), and −2.78 (15 mg; P < 0.0001 versus placebo) were observed, as compared with mean changes of −1.43 in the adalimumab group and −1.21 in the placebo group. At week 24, the mean changes from baseline in the DAS28-ESR score were −1.04 (1 mg), −2.02 (3 mg), −2.35 (5 mg; P < 0.01 versus placebo), −2.85 (10 mg; P < 0.0001 versus placebo), and −2.83 (15 mg; P < 0.0001 versus placebo) in the tofacitinib groups, as compared with mean changes of −2.03 in the adalimumab group and −1.43 in the placebo group. (Data on the mean changes from baseline in the DAS28-CRP score at weeks 12 and 24 are presented in Supplementary Table 2, available on the Arthritis & Rheumatism web site at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1529-0131).

With regard to scores on the HAQ DI, there were statistically significant improvements in the scores from baseline through week 24 in the tofacitinib groups compared with the placebo group (in analyses with no imputation), with mean changes from baseline to week 12 of −0.51 (5 mg; P ≤ 0.05 versus placebo), −0.66 (10 mg; P < 0.0001 versus placebo), and −0.82 (15 mg; P < 0.0001 versus placebo) in the tofacitinib groups compared with a mean change of −0.25 in the placebo group. Improvements in the HAQ DI were maintained at week 24 in patients receiving either 10 mg tofacitinib twice a day (mean change from baseline −0.72; P ≤ 0.05 versus placebo) or 15 mg tofacitinib twice a day (mean change from baseline −0.82; P < 0.001 versus placebo), compared with a mean change of −0.37 in the placebo group. For patients treated with adalimumab, no significant improvement in the HAQ DI was seen at either week 12 (mean change from baseline −0.35; P = 0.344 versus placebo) or week 24 (mean change from baseline −0.46 [reassigned group]; P = 0.512 versus placebo).

By week 2 of treatment, there were significantly more patients classified as HAQ DI responders (defined as improvement in the HAQ DI of ≥0.22 units) in the groups receiving tofacitinib at dosages of 1, 3, 10, and 15 mg twice a day as compared with the placebo group. By week 12, significantly more HAQ DI responders were observed in the 3 mg (39.2%), 5 mg (44.9%), 10 mg (60.0%), and 15 mg (71.9%) tofacitinib dose groups compared with the placebo group (19.0%). By week 24, significantly more HAQ DI responders were observed in the treatment groups receiving ≥5 mg tofacitinib twice a day compared with those receiving placebo.

Analysis of self-reported health status using the SF-36 showed significant improvements in the physical component score at week 12 (measured as the mean change from baseline, in analyses with no imputation) in patients receiving tofacitinib at dosages of 5 mg twice a day (mean change 7.0; P ≤ 0.05 versus placebo), 10 mg twice a day (mean change 10.1; P < 0.0001 versus placebo), and 15 mg twice a day (mean change 10.9; P < 0.0001 versus placebo), compared with a mean change of 2.8 in the placebo group. These improvements in the SF-36 physical component score were sustained at week 24, with a mean change from baseline of 11.5 in those receiving 10 mg tofacitinib twice a day (P < 0.0001 versus placebo) and a mean change of 11.0 in those receiving 15 mg tofacitinib twice a day (P < 0.0001 versus placebo), compared with a mean change of 3.1 in the placebo group. No significant change from baseline in the SF-36 physical component score was seen in patients receiving adalimumab, either at week 12 (mean change 3.9) or week 24 (mean change 6.1 [reassigned group]). No significant improvements were seen in the SF-36 mental component score for any treatment group at week 12 or week 24.

A statistically significant improvement in the FACIT-F subscale scores at week 12 was observed in patients receiving tofacitinib at dosages of 5 mg twice a day (P ≤ 0.05 versus placebo), 10 mg twice a day (P < 0.001 versus placebo), and 15 mg twice a day (P ≤ 0.05 versus placebo), when compared with patients receiving placebo. Scores on the FACIT-F subscale were not significantly different in the adalimumab group compared with the placebo group.

Safety.

Treatment-emergent adverse events.

Table 3 provides a summary of AEs, infections, discontinuations due to AEs, and deaths. Across all tofacitinib treatment arms (n = 272 patients), 146 patients (53.7%) experienced a total of 366 treatment-emergent AEs. The most frequent all-causality treatment-emergent AEs occurring in ≥8 patients (across the tofacitinib groups) over the 24-week study period were urinary tract infection (7.7%), diarrhea (4.8%), headache (4.8%), bronchitis (4.8%), nausea (4.0%), upper respiratory tract infection (3.7%), dizziness (2.9%), and nasopharyngitis (2.9%). In the placebo group, the most common AE was urinary tract infection (3.4%); in the adalimumab group (from baseline to week 12), the most common AEs were bronchitis and pruritis (both 5.7%) (see Supplementary Table 1, available on the Arthritis & Rheumatism web site at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1529-0131).

Table 3. Safety summary over 24 weeks*
 PlaceboTofacitinibAdalimumab
Placebo (n = 34)Placebo (reassigned) (n = 25)1 mg bid (n = 37)1 mg bid (reassigned) (n = 17)3 mg bid (n = 34)3 mg bid (reassigned) (n = 17)5 mg bid (n = 49)10 mg bid (n = 61)15 mg bid (n = 57)40 mg qow baseline– week 12 (n = 53)40 mg qow weeks 0–11/tofacitinib 5 mg bid weeks 12–24 (reassigned) (n = 44)
  • *

    Values are the number (%) of patients. Serious infections were defined as any infection (viral, bacterial, or fungal) requiring hospitalization or treatment with parenteral antimicrobial agents. qow = once every other week; AEs = adverse events.

  • Patients were reassigned to receive tofacitinib 5 mg twice a day (bid) from week 12 to week 24.

AEs16 (47.1)13 (52.0)19 (51.4)5 (29.4)18 (52.9)6 (35.3)27 (55.1)36 (59.0)35 (61.4)27 (50.9)28 (63.6)
Serious AEs2 (5.9)02 (5.4)01 (2.9)001 (1.6)4 (7.0)1 (1.9)4 (9.1)
Severe AEs2 (5.9)01 (2.7)02 (5.9)01 (2.0)05 (8.8)00
Infections and infestations6 (17.6)6 (24.0)11 (29.7)2 (11.8)7 (20.6)3 (17.6)17 (34.7)21 (34.4)19 (33.3)10 (18.9)11 (25.0)
Serious infections1 (2.9)02 (5.9)000001 (1.8)01 (2.3)
Discontinuations due to AEs1 (2.9)04 (10.8)03 (8.8)01 (2.0)1 (1.6)3 (5.3)4 (7.5)3 (6.8)
Deaths000000001 (1.8)00

Serious AEs occurred in 2.9% of patients treated with tofacitinib compared with 5.9% of patients in the placebo group. Moreover, 3.3% of patients treated with tofacitinib had severe AEs compared with 5.9% of patients in the placebo group. Fifteen patients reported experiencing serious AEs; the incidence of serious AEs and severe AEs was highest in the patients receiving 15 mg tofacitinib twice a day.

Discontinuations due to AEs occurred in 5.2% of patients (Figure 1). The majority of these AEs were classified as mild or moderate and occurred in 5.4% (1 mg twice a day), 2.0% (5 mg twice a day), 1.6% (10 mg twice a day), and 3.5% (15 mg twice a day) of patients receiving tofacitinib, and in 5.7% of those receiving adalimumab. One death, attributed to cerebrovascular accident, was reported in a patient receiving 15 mg tofacitinib twice a day. No other deaths were reported in patients after exit from the study (in a safety followup analysis).

Infections.

The proportions of patients reporting development of infections over 24 weeks of treatment were 29.7% (1 mg twice a day), 20.6% (3 mg twice a day), 34.7% (5 mg twice a day), 34.4% (10 mg twice a day), and 33.3% (15 mg twice a day) among patients in the tofacitinib groups, compared with 17.6% of patients in the placebo group. Infections were reported by 18.9% of patients treated with adalimumab during the first 12 weeks and by 25.0% of patients treated with tofacitinib at 5 mg twice a day post–week 12 after initial adalimumab therapy. The most common significant infections across the tofacitinib groups were urinary tract infection (3.7%), pneumonia (1.5%), and sinusitis (0.7%). There were no opportunistic infections. Serious infections were observed in 5 patients: pneumonia in 2 patients receiving 1 mg tofacitinib twice a day, pneumococcal sepsis in 1 patient receiving 15 mg tofacitinib twice a day, acute pyelonephritis in 1 patient receiving adalimumab (occurrence after reassignment to receive tofacitinib 5 mg twice a day at week 12), and infection of the ankle joint in 1 patient receiving placebo.

Abnormal laboratory findings.

Changes from baseline to week 24 in key laboratory variables are presented in Table 4. Dose-related changes in the neutrophil count were observed; there were no discontinuations due to neutropenia. One instance of severe neutropenia (classified according to the Outcome Measures in Rheumatology [OMERACT] proposed rheumatology common toxicity criteria [13] as a neutrophil level of 0.5–0.9 × 103 neutrophils/mm3) was observed in 1 patient each in the tofacitinib 1 mg twice a day and adalimumab groups. The incidence of confirmed (occurrence at 2 consecutive visits) mild neutropenia (1.5–1.9 × 103 neutrophils/mm3) was 9.1% (tofacitinib 5 mg twice a day), 6.5% (tofacitinib 10 mg twice a day), and 6.7% (tofacitinib 15 mg twice a day); the incidence of confirmed moderate neutropenia (1.0–1.4 × 103 neutrophils/mm3) was 2.2% (in those receiving tofacitinib 15 mg twice a day). All of these incidents resolved spontaneously during treatment, and none was classified as severe or life-threatening. Thrombocytopenias were also rare, with 4 mild cases in the ≥5 mg tofacitinib twice a day group. One case of moderate thrombocytopenia was reported in the tofacitinib 10 mg twice a day group (lowest platelet count 62.2 × 109/liter), which resolved during treatment.

Table 4. Summary of changes in laboratory data through week 24*
 PlaceboTofacitinibAdalimumab
Placebo (n = 34)Placebo (reassigned) (n = 25)1 mg bid (n = 37)1 mg bid (reassigned) (n = 17)3 mg bid (n = 34)3 mg bid (reassigned) (n = 17)5 mg bid (n = 49)10 mg bid (n = 61)15 mg bid (n = 57)40 mg qow baseline– week 12 (n = 53)40 mg qow weeks 0–11/tofacitinib 5 mg bid weeks 12–24 (reassigned) (n = 44)
  • *

    The full analysis data set was used, in analyses with no imputation. qow = once every other week; HDL = high-density lipoprotein; LDL = low-density lipoprotein.

  • Patients were reassigned to receive tofacitinib 5 mg twice a day (bid) from week 12 to week 24.

  • Abnormal findings after baseline for alanine aminotransferase (ALT) and aspartate aminotransferase (AST), among patients who had normal values at baseline, were defined as single-unit elevations above the upper limit of normal (ULN).

Change from baseline, mean ± SEM           
 Hemoglobin, gm/dl0 ± 1.010.22 ± 0.920.16 ± 0.700.15 ± 0.86−0.39 ± 1.550.20 ± 1.400.26 ± 1.13−0.24 ± 0.99−0.25 ± 0.89−0.07 ± 0.86−0.02 ± 0.89
 Neutrophils, 103/mm3−0.44 ± 1.77−0.51 ± 1.71−0.11 ± 3.13−0.03 ± 3.050.31 ± 2.06−0.44 ± 2.23−0.37 ± 2.15−1.02 ± 2.44−1.62 ± 2.38−0.84 ± 2.29−1.68 ± 2.78
 Serum creatinine, mg/dl0.01 ± 0.090.03 ± 0.070.01 ± 0.100.01 ± 0.090.04 ± 0.170.03 ± 0.080.04 ± 0.010.03 ± 0.090.07 ± 0.11−0.01 ± 0.120.11 ± 0.02
 HDL cholesterol, mg/dl0.16 ± 11.3713.06 ± 7.124.35 ± 11.876.09 ± 12.592.50 ± 13.4414.73 ± 12.229.46 ± 11.489.76 ± 13.668.04 ± 13.301.85 ± 11.444.65 ± 11.72
 LDL cholesterol, mg/dl8.66 ± 22.1616.37 ± 18.575.38 ± 22.4918.16 ± 27.1713.69 ± 17.1923.66 ± 22.6421.83 ± 27.2826.00 ± 32.5933.96 ± 29.61−5.31 ± 35.8213.66 ± 50.15
 Apolipoprotein A-I0.09 ± 0.240.28 ± 0.150.12 ± 0.260.14 ± 0.310.10 ± 0.320.32 ± 0.210.21 ± 0.310.24 ± 0.300.27 ± 0.280.20 ± 0.28
 Apolipoprotein B0.01 ± 0.090.01 ± 0.11−0.02 ± 0.120.06 ± 0.130.07 ± 0.140.05 ± 0.190.06 ± 0.190.08 ± 0.200.11 ± 0.18−0.01 ± 0.29
Abnormality after baseline, no. (%)           
 ALT           
  Normal at baseline292535153216486155842
  Abnormal after baseline           
   >1× ULN5 (17)7 (28)2 (6)2 (13)7 (22)2 (13)6 (13)8 (13)13 (24)1 (13)9 (21)
   >2× ULN00001 (3)1 (6)1 (2)1 (2)2 (4)1 (13)2 (5)
   >3× ULN000000002 (4)1 (13)1 (2)
   >1× ULN sustained until end of study01 (4)1 (3)01 (3)02 (4)1 (2)3 (5)3 (38)1 (2)
 AST           
  Normal at baseline292533153217485956843
  Abnormal after baseline           
   >1× ULN3 (10)4 (16)3 (9)1 (7)6 (19)3 (18)9 (19)13 (22)12 (21)1 (13)9 (21)
   >2× ULN000001 (6)1 (2)1 (2)2 (4)1 (13)2 (5)
   >3× ULN000001 (6)1 (2)02 (4)00
   >1× ULN sustained until end of study01 (4)001 (3)03 (6)2 (3)4 (7)2 (25)2 (5)

Mean changes from baseline in the hemoglobin level were small across all treatment groups. There were no discontinuations due to decreased hemoglobin levels (defined as <8.0 gm/dl or a decrease from baseline of ≥30%). Confirmed severe anemia (defined by the OMERACT criteria as a hemoglobin level of 7–8 gm/dl or a decrease from baseline of ≥2 gm/dl to ≤3 gm/dl) was reported in 2.8% (3 mg twice a day), 4.2% (10 mg twice a day), and 6.5% (15 mg twice a day) of patients receiving tofacitinib. Two of these cases did not resolve during treatment (1 in the 3-mg group and 1 in the 10-mg group). In 1 of these 2 cases (a patient receiving 3 mg twice a day), the study drug was temporarily discontinued due to gastrointestinal bleeding. (Mean changes in the hemoglobin level from baseline to week 24 are shown in Supplementary Figure 3, available on the Arthritis & Rheumatism web site at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1529-0131.)

Mean serum creatinine levels increased from baseline (up to 0.11 mg/dl) in all treatment groups throughout the 24 weeks. Sustained creatinine elevations were uncommon; elevations were within the normal reference range, typically a range of 0.5–0.7 mg/dl. Sixteen patients experienced a confirmed increase in the creatinine level of >30% and >0.2 mg/dl from baseline (highest incidence in the tofacitinib 10 mg twice a day and adalimumab groups); in 7 of these patients, this did not resolve during treatment (1 patient in the adalimumab group, 1 receiving tofacitinib 1 mg twice a day, 2 receiving tofacitinib 3 mg twice a day, 1 receiving tofacitinib 5 mg twice a day, and 2 receiving tofacitinib 10 mg twice a day). In 5 of these 7 patients, the increase was related to the fact that their baseline value was lower than their screening value; increases from the screening values in these patients did not meet the outlier criteria. The remaining 2 instances were unexplained; no dose response was noted.

Six patients experienced a confirmed serum creatinine elevation of >50%, corresponding to an absolute increase from baseline of 0.3–0.4 mg/dl (1 patient each in the 3 mg tofacitinib, 3 mg tofacitinib [reassigned], 5 mg tofacitinib, 10 mg tofacitinib, adalimumab, and adalimumab [reassigned] groups); in 4 of these patients, this resolved during treatment, and the other 2 patients discontinued treatment. The maximum confirmed creatinine elevation in a patient receiving tofacitinib was a serum creatinine level of 1.1 mg/dl at week 16 in a patient who had a baseline level of 0.57 mg/dl; this returned to 0.66 mg/dl at week 24 during treatment with tofacitinib, and no cause was identified.

Dose-related increases in the levels of total cholesterol, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) were observed in all tofacitinib treatment groups (Table 4). Among the patients analyzed for LDL cholesterol, the proportions with an LDL level <130 mg/dl at baseline were 82.9% (1 mg tofacitinib), 75.0% (3 mg tofacitinib), 73.9% (5 mg tofacitinib), 66.1% (10 mg tofacitinib), 73.2% (15 mg tofacitinib), and 80.6% (placebo). Among these patients, the proportions with an LDL level >130 mg/dl at any time during the study were 20.7% (1 mg tofacitinib), 33.3% (3 mg tofacitinib), 41.2% (5 mg tofacitinib), 56.4% (10 mg tofacitinib), 51.2% (15 mg tofacitinib), and 24.0% (placebo).

Only a few patients in the tofacitinib groups experienced liver enzyme elevations, and the levels were similar to those in patients treated with placebo or adalimumab. In patients with a normal baseline ALT level, most of the sustained elevations of >1× ULN for the entire study were seen in the tofacitinib 15 mg twice a day and adalimumab groups (n = 3 each). With regard to AST levels, the greatest proportions of patients with sustained elevations were in the tofacitinib 15 mg twice a day and adalimumab groups.

ALT levels >3× ULN were observed in 3.6% of patients receiving 15 mg tofacitinib twice a day, 13.0% of patients receiving adalimumab, and 2.0% of patients in the adalimumab (reassigned) group. AST levels >3× ULN were observed in 5.9% of patients receiving 3 mg tofacitinib (reassigned), 2.1% of patients receiving 5 mg tofacitinib, and 3.6% of patients receiving 15 mg tofacitinib.

In addition, elevations in the ALT and AST levels that were sustained at >1× ULN until the end of the study are shown in Table 4. No patient who experienced an increase in the AST or ALT level of >3× ULN also experienced an increase in the total bilirubin level of >2× ULN (normal being 2 mg/dl), and none of these patients discontinued treatment due to transaminase increases. The majority of liver enzyme elevations resolved spontaneously during treatment.

At week 24, the range of values for the mean systolic blood pressure in all tofacitinib treatment groups was 119–127 mm Hg (compared with 123 mm Hg in the placebo group), and for the mean diastolic blood pressure, the range was 77–79 mm Hg (78 mm Hg in the placebo group). Changes from baseline in these values were minimal, and none were clinically significant; no dose-related trend was apparent. Development of hypertension during treatment was reported in 2.0% of patients receiving tofacitinib 5 mg twice a day, 4.9% of patients receiving tofacitinib 10 mg twice a day, and 3.5% of patients receiving tofacitinib 15 mg twice a day, compared with 2.9% of patients receiving placebo; none were classed as severe.

Safety of switching from adalimumab to tofacitinib 5 mg twice a day.

Initially, 53 patients were randomized to receive adalimumab; 9 of these patients discontinued treatment prior to week 12, and 44 patients were reassigned to receive tofacitinib 5 mg twice a day for the remainder of the study. Four patients discontinued due to AEs (increased hepatic enzyme levels, urinary tract infection, acute pyelonephritis, and renal cell carcinoma) after reassignment to tofacitinib.

From baseline to week 12, 50.9% of patients in the adalimumab group reported experiencing AEs, and 1.9% of patients reported having serious AEs; none were classified as severe. After week 12, following reassignment to tofacitinib 5 mg twice a day, 63.6% of patients reported experiencing AEs, and 9.9% reported having serious AEs; none were classified as severe (Table 3). For comparison, the proportion of patients originally assigned to receive tofacitinib 5 mg twice a day who reported the occurrence of an AE during the post–week 12 to week 24 period was 32.7%; none of these patients reported having a serious AE.

Up to week 12, 40.7% of patients in the placebo group reported experiencing AEs, and 1.7% reported having serious AEs. During the post–week 12 to week 24 period, the proportions were 8.8% for the occurrence of AEs and 2.9% for the occurrence of serious AEs among patients remaining on placebo (not reassigned). The incidence of infections and infestations was 18.9% in the adalimumab group (up to week 12) and 25.0% (after week 12); all were moderate in severity. Increases in the levels of total cholesterol, HDL cholesterol, and LDL cholesterol were seen at week 24, when compared with the levels at week 12, in the adalimumab (reassigned) group.

DISCUSSION

In this phase IIb study, 5 dosages of oral tofacitinib (1, 3, 5, 10, and 15 mg twice a day) and adalimumab monotherapy (40 mg subcutaneously once every other week) were investigated for the treatment of patients with active RA who demonstrated an inadequate response to DMARDs. Tofacitinib was found to be efficacious in treating the signs and symptoms of active RA over 24 weeks at dosages of ≥3 mg twice a day, substantiating and expanding on a previous report of its efficacy and safety as monotherapy (5, 15, and 30 mg twice a day) over 6 weeks (4).

Improvements, as measured by ACR20 response rates, were seen by week 2 and maintained throughout the 24-week study period, demonstrating the sustained efficacy of tofacitinib in the treatment of active RA. Efficacy of tofacitinib was also demonstrated over 24 weeks, when compared with placebo, by improvement in the ACR50 and ACR70 response rates and in the HAQ DI scores, and significant changes from baseline in the DAS28-ESR and DAS28-CRP scores as well as in the proportions of patients with a DAS28-ESR or DAS28-CRP score of <2.6 were also observed. Physical functioning also improved in patients treated with tofacitinib, as demonstrated by the change from baseline in the SF-36 physical component score, consistent with findings from previous reports (5).

The 24-week safety and tolerability profile of tofacitinib was also consistent with results reported in a previous 6-week study in patients with active RA (4). The number of patients discontinuing from this study was low overall, and was similar between all tofacitinib groups and placebo. The incidence of infections was lower (8–12%) than has been previously reported in patients receiving tofacitinib at 5 mg twice a day (25%), those receiving tofacitinib at 15 mg twice a day (30%), and those receiving tofacitinib at 30 mg twice a day (30%) (4). Serious infections occurred but did not appear to be dose-related, and were not associated with neutropenia. Confirmed episodes of OMERACT-defined neutropenia, thrombocytopenia, or anemia were usually infrequent and mild, and resolved spontaneously. Confirmed laboratory abnormalities associated with tofacitinib were rare, and there were no episodes of neutropenia, anemia, or transaminase elevation that required discontinuation.

At tofacitinib dosages of <5 mg twice a day, decreases in the hemoglobin level were noted, which may reflect, in part, a lack of beneficial effect on the anemia in chronic disease. At tofacitinib dosages >5 mg twice a day, decreases in the hemoglobin level may reflect effects on hematopoiesis due to JAK-2 inhibition. When tofacitinib was administered at a dosage of 5 mg twice a day, the hemoglobin level tended to increase, which may reflect a balanced effect, conferring sufficient efficacy to reverse the anemia due to chronic inflammation and having a limited effect on hematopoiesis due to JAK-2 inhibition. However, individual differences in pharmacokinetics, pharmacodynamics, and disease states may be associated with events related to anemia at any dose.

A dose-related increase in the level of LDL cholesterol was observed. Longer studies involving more patients will be needed to determine whether this increase would affect the overall cardiovascular risk. Too few patients were taking lipid-lowering medication at baseline, or had it introduced during the study, to enable any conclusions to be drawn regarding the effects of tofacitinib on lipid changes. This question should also be addressed in future studies.

In 9 of the 16 patients who had confirmed elevations in the serum creatinine level (increase of >30% and 0.2 mg/dl), the condition resolved spontaneously during treatment, and 5 of these instances were attributable to variability between the screening and baseline values. Creatinine elevations will continue to be addressed in the tofacitinib RA clinical trial program, including phase III and long-term extension studies.

Cancer is often a potential concern with immunomodulatory therapy. In this 24-week study, renal cell carcinoma was diagnosed in 1 patient after reassignment from adalimumab to tofacitinib.

Adalimumab was included in this study for 12 weeks as an active comparator and to provide an insight into the safety of switching from a representative standard-of-care TNF inhibitor to tofacitinib. Patients treated with adalimumab monotherapy had ACR20, ACR50, and ACR70 response rates similar to those reported previously (14); however, the placebo response in this study was higher than previously reported. This may explain the lack of statistically significant improvement seen with adalimumab treatment when compared with placebo in the NRI analyses, and also suggests a lower treatment effect for adalimumab in the present study. After the patients were switched to tofacitinib at week 12, they had similar ACR20, ACR50, and ACR70 response rates at week 24 as those observed at week 12 among patients initially treated with tofacitinib at 5 mg twice a day, which strongly suggests that these patients are able to respond to an effective monotherapy medication. Reassignment from adalimumab to tofacitinib 5 mg twice a day was generally well tolerated.

Thus, our study shows that tofacitinib was efficacious at dosages of ≥3 mg twice a day at week 12 and at dosages of ≥5 mg twice a day at week 24, as measured by the ACR20 response rates. Tofacitinib monotherapy has an acceptable safety profile and is efficacious over 24 weeks for the treatment of the signs and symptoms of active RA in patients in whom previous traditional DMARD therapy had failed. This study supports the decision to investigate tofacitinib at dosages of 5 mg and 10 mg twice a day as monotherapy in ongoing phase III trials in patients with active RA.

AUTHOR CONTRIBUTIONS

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Fleischmann had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Fleischmann, Cutolo, Genovese, Lee, Kanik, Connell, Gruben, Krishnaswami, Wallenstein, Wilkinson, Zwillich.

Acquisition of data. Fleischmann, Cutolo, Genovese, Lee, Kanik, Sadis, Wallenstein, Wilkinson.

Analysis and interpretation of data. Fleischmann, Genovese, Lee, Kanik, Sadis, Connell, Gruben, Krishnaswami, Wallenstein, Wilkinson, Zwillich.

ROLE OF THE STUDY SPONSOR

Pfizer developed the study design with external author input, collected and analyzed the data, provided editorial assistance for the manuscript (provided by Jennie Frain, PhD and Gary Dever, PhD of Complete Medical Communications), and reviewed and approved the manuscript prior to submission. The authors (internal and external) interpreted the results, wrote the manuscript, and had the final decision to submit the manuscript for publication. Publication of this article was contingent upon approval by Pfizer.

Acknowledgements

Editorial support was provided by Jennie Frain, PhD and Gary Dever, PhD of Complete Medical Communications. We would like to thank the staff and patients involved in this study. We would also like to thank the following study investigators: C. Baerwald, F. Ballesteros, D. Bichovska, J. Brenol, M. Brooks, R. Bustamante-Gonzalez, R. Chirieac, B. Curkovic, L. Espinoza, M. Fairfax, S. Forejtova, S. Grazio, G. Holuigue, A. Hou, R. Ionescu, A. Kivitz, J. Kochen, Z. Kolarov, P. Kopsa, A. Kovacs, R. Lies, C. Lue, B. Malik, A. Martinovic, M. Matucci Cerinic, P. Miranda, R. Misischia, O. Nadashkevich, P. Nemec, R. Olson, B. Oparanov, J. Orozco-Alcala, D. Payne, J. Poiley, P. Polak, V. Povoroznyuk, M. Robles-San Roman, J. Rosa, I. Rybar, P. Schuette, L. Settas, J. Silverfield, A. Singhal, M. Stanislavchuk, M. Suta, S. Tisheva, V. Tseluyko, S. Udani, L. Unger, P. Vitek, V. Vizir, P. Vlachoyiannopoulos, U. von Hinueber, S. Wolfe, J. Wollenhaupt, D. Xibille-Friedmann, and D. Yoo.

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