A phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) versus placebo in combination with background methotrexate in patients with active rheumatoid arthritis and an inadequate response to methotrexate alone

Authors

  • Joel M. Kremer,

    Corresponding author
    1. Albany Medical College, Albany, New York
    • Director of Research, The Center for Rheumatology, Albany Medical College, 1367 Washington Avenue, Suite 101, Albany, NY 12206
    Search for more papers by this author
    • Dr. Kremer has received consulting fees from Pfizer (less than $10,000).

  • Stanley Cohen,

    1. Metroplex Clinical Research Center, Dallas, Texas
    Search for more papers by this author
    • Dr. Cohen owns stock in Pfizer.

  • Bethanie E. Wilkinson,

    1. Pfizer, Groton, Connecticut
    Search for more papers by this author
    • Drs. Wilkinson, Connell, French, Gruben, Kanik, Krishnaswami, and Wallenstein own stock or stock options in Pfizer.

  • Carol A. Connell,

    1. Pfizer, Groton, Connecticut
    Search for more papers by this author
    • Drs. Wilkinson, Connell, French, Gruben, Kanik, Krishnaswami, and Wallenstein own stock or stock options in Pfizer.

  • Jonathan L. French,

    1. Pfizer, Groton, Connecticut
    Search for more papers by this author
    • Drs. Wilkinson, Connell, French, Gruben, Kanik, Krishnaswami, and Wallenstein own stock or stock options in Pfizer.

  • Juan Gomez-Reino,

    1. Hospital Clinico Universitario, University of Santiago, Santiago de Compostela, Spain
    Search for more papers by this author
    • Dr. Gomez-Reino has received consulting fees, speaking fees, and/or honoraria from Schering-Plough, Bristol-Myers Squibb, Wyeth, Roche, and UCB (less than $10,000 each).

  • David Gruben,

    1. Pfizer, Groton, Connecticut
    Search for more papers by this author
    • Drs. Wilkinson, Connell, French, Gruben, Kanik, Krishnaswami, and Wallenstein own stock or stock options in Pfizer.

  • Keith S. Kanik,

    1. Pfizer, Groton, Connecticut
    Search for more papers by this author
    • Drs. Wilkinson, Connell, French, Gruben, Kanik, Krishnaswami, and Wallenstein own stock or stock options in Pfizer.

  • Sriram Krishnaswami,

    1. Pfizer, Groton, Connecticut
    Search for more papers by this author
    • Drs. Wilkinson, Connell, French, Gruben, Kanik, Krishnaswami, and Wallenstein own stock or stock options in Pfizer.

  • Virginia Pascual-Ramos,

    1. Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
    Search for more papers by this author
  • Gene Wallenstein,

    1. Pfizer, Groton, Connecticut
    Search for more papers by this author
    • Drs. Wilkinson, Connell, French, Gruben, Kanik, Krishnaswami, and Wallenstein own stock or stock options in Pfizer.

  • Samuel H. Zwillich

    1. Pfizer, Groton, Connecticut
    Search for more papers by this author

  • ClinicalTrials.gov identifier: NCT00413660.

  • Presented in part at the 75th and 76th Annual Scientific Meetings of the American College of Rheumatology/Association of Rheumatology Health Professionals, San Francisco, CA, October 2008 and Philadelphia, PA, October 2009, respectively.

Abstract

Objective

To compare the efficacy, safety, and tolerability of 6 dosages of oral tofacitinib (CP-690,550) with placebo for the treatment of active rheumatoid arthritis (RA) in patients receiving a stable background regimen of methotrexate (MTX) who have an inadequate response to MTX monotherapy.

Methods

In this 24-week, double-blind, phase IIb study, patients with active RA (n = 507) were randomized to receive placebo or tofacitinib (20 mg/day, 1 mg twice daily, 3 mg twice daily, 5 mg twice daily, 10 mg twice daily, or 15 mg twice daily). All patients continued to receive a stable dosage of MTX. The primary end point was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 12.

Results

At week 12, ACR20 response rates for patients receiving all tofacitinib dosages ≥3 mg twice daily (52.9% for 3 mg twice daily, 50.7% for 5 mg twice daily, 58.1% for 10 mg twice daily, 56.0% for 15 mg twice daily, and 53.8% for 20 mg/day) were significantly (P ≤ 0.05) greater than those for placebo (33.3%). Improvements were sustained at week 24 for the ACR20, ACR50, and ACR70 responses, scores for the Health Assessment Questionnaire disability index, the 3-variable Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP), and a 3-variable DAS28-CRP of <2.6. The most common treatment-emergent adverse events occurring in >10% of patients in any tofacitinib group were diarrhea, upper respiratory tract infection, and headache; 21 patients (4.1%) experienced serious adverse events. Sporadic increases in transaminase levels, increases in cholesterol and serum creatinine levels, and decreases in neutrophil and hemoglobin levels were observed.

Conclusion

In patients with active RA in whom the response to MTX has been inadequate, the addition of tofacitinib at a dosage ≥3 mg twice daily showed sustained efficacy and a manageable safety profile over 24 weeks.

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) (1). Intracellular pathways that include JAKs are critical to immune cell activation, proinflammatory cytokine production, and cytokine signaling (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). JAK-1 and JAK-3 are required for signaling via γ-chain cytokine receptors for 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 homodimers. Tofacitinib subsequently modulates adaptive and innate immunity but may also affect hematopoiesis (3,4).

In a 6-week phase IIa monotherapy trial in patients with active RA and an inadequate response or unacceptable toxicity to methotrexate (MTX) or tumor necrosis factor inhibitors, tofacitinib at dosages of 5 mg twice daily, 15 mg twice daily, and 30 mg twice daily was efficacious in treating the signs and symptoms of RA (5). Tofacitinib at a dosage of 30 mg twice daily appeared to offer no increase in efficacy over a dosage of 15 mg twice daily. Clinically meaningful improvements in pain, physical functioning, and health status have also been observed in patients receiving tofacitinib (6).

Combination therapy is often used in the management of RA; novel treatments may be administered in combination with traditional disease-modifying antirheumatic drugs (DMARDs), in particular MTX. The pharmacokinetics of tofacitinib coadministered with MTX were investigated in a phase I, open-label study of patients with RA who were receiving stable dosages of MTX (15–25 mg/week). No clinically significant changes in pharmacokinetics were seen, and dose alterations of either drug were considered unnecessary when the drugs were coadministered (7).

To more fully characterize the efficacy and safety dose-response profile of tofacitinib over a longer period of time, two phase IIb trials of 24 weeks duration were initiated: one to assess tofacitinib as monotherapy (8), and the other (reported here) to assess tofacitinib as an addition to stable background MTX treatment. The primary objective of the current study was to compare the efficacy of 6 dosages of tofacitinib (1 mg twice daily, 3 mg twice daily, 5 mg twice daily, 10 mg twice daily, and 15 mg twice daily, and 20 mg/day) versus placebo, over 12 weeks, for the treatment of signs and symptoms of RA in patients with active RA receiving a stable dosage of MTX who had an inadequate response to MTX alone.

PATIENTS AND METHODS

The study was conducted in 72 centers in the US, Europe, and Latin America, in accordance with the Declaration of Helsinki and in compliance with all International Conference on Harmonisation Good Clinical Practice Guidelines. The study (Pfizer protocol no. A3921025) was approved by the institutional review boards and/or independent ethics committees for each center. All patients provided written, informed consent.

Patients.

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 [9]), and had active disease, defined as ≥6 tender joints based on a 68-joint count and ≥6 painful joints based on a 66-joint count at the screening and baseline visits and either an erythrocyte sedimentation rate above the upper limit of normal (ULN) or a C-reactive protein (CRP) level >7 mg/liter. Patients must have been receiving oral or parenteral MTX continuously for ≥4 months, with a stable dosage of 7.5– 25 mg/week for ≥6 weeks prior to administration of the first dose of study drug. Stable dosages <15 mg/week were permitted if intolerance to or toxicity from higher dosages was documented. Patients continued to receive a stable dosage of MTX throughout the study. All other biologic or nonbiologic DMARDs and immunosuppressive therapy were discontinued ≥4 weeks prior to administration of the first dose of study drug (8 weeks for infliximab and adalimumab; 3 months for abatacept).

Key exclusion criteria included the following: evidence of hematopoietic disorders at the time of screening or within 3 months prior to administration of the first dose of 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) level >1.5× ULN; current or recent history of severe, progressive, or uncontrolled disease other than RA; untreated infection with Mycobacterium tuberculosis or other clinically significant infection; and 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.

Eligible patients were randomized equally to receive oral tofacitinib at a dosage of 1 mg twice daily, 3 mg twice daily, 5 mg twice daily, 10 mg twice daily, 15 mg twice daily, or 20 mg/day or placebo for 24 weeks. Patients randomized to receive tofacitinib at dosages of 1 mg twice daily, 3 mg twice daily, and 20 mg/day and those assigned to receive placebo who failed to achieve ≥20% reduction from baseline in both the swollen and tender/painful joint counts at week 12 were considered to be nonresponders and were automatically reassigned to receive tofacitinib 5 mg twice daily for the remaining 12 weeks of study (blinding maintained). No other dosage adjustments of tofacitinib were permitted. A single dosage reduction of MTX (≤5 mg/week) was allowed for patients with a confirmed elevation of transaminase levels.

Concomitant medications.

Patients continued to receive a stable background regimen of RA therapy, which had to include MTX (supplemented with folic acid) and may have included nonsteroidal antiinflammatory drugs, opioids (total daily dose less 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 daily). CYP3A inducers and CYP3A4, CYP3A5, and CYP3A7 inhibitors were prohibited due to the potential for drug interactions. Also prohibited were vaccinations with live components 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. Injected joints were considered as having their preinjection status for the remainder of the study.

Study assessments.

Efficacy measures.

The primary objective was to compare the efficacy of 6 different dosages of tofacitinib versus placebo over 12 weeks. The primary end point was the response rate according to the ACR 20% improvement criteria (ACR20) (10), based on the 68-joint tender/painful joint count, the 66-joint swollen joint count, and the CRP level at week 12, by nonresponder imputation (NRI). The primary efficacy analysis was conducted during the first 12 weeks; the durability of efficacy with tofacitinib was assessed during weeks 12–24. The secondary efficacy end points analyzed at all time points 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) using the CRP (DAS28-CRP) (11), a DAS28-CRP of <2.6, and change in components of the ACR core set of disease activity measures (12), including the Health Assessment Questionnaire disability index (HAQ DI) (13), the Short Form 36 (SF-36) Health Survey (physical component summary [PCS] score and mental component summary [MCS] score) (14), and the Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F) subscale (15). Efficacy assessments were carried out at baseline and at weeks 2, 4, 6, 8, 12, 16, 20, and 24 or at the time of early termination.

Safety measures.

All adverse events (AEs), their severity, and the investigator's opinion of their relationship to the study drug were recorded. The criterion for drug discontinuation due to elevated transaminase levels was a confirmed increase of >3× ULN that did not resolve promptly with adjustment of the concomitant medication(s). Laboratory evaluations, vital sign assessments, and electrocardiography were carried out at scheduled time points.

Statistical analysis.

The full analysis set included all patients who were randomized and received ≥1 dose of study drug; this was equivalent to the safety population. Efficacy response rates for binary end points (e.g., the ACR20) were analyzed using the normal approximation to the binomial, comparing each dosage of tofacitinib with placebo. For continuous measures (e.g., change from baseline in an SF-36 domain), a longitudinal, mixed-effect, repeated-measures model was used. Treatment group, 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 placebo were formed. All patients who were randomized and received ≥1 dose of study drug were analyzed for efficacy and safety.

To address missing data in calculating response rates, 3 types of imputation were used: 1) NRI, 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, and additional analyses were performed as a measure of robustness of the results. The P values have not been corrected for multiple comparisons.

RESULTS

Patient disposition and study treatment.

Overall, 685 patients were screened; 509 of these patients were randomized, and 507 received ≥1 dose of study drug (Figure 1). Discontinuations in each treatment group ranged from 12% to 22%, and the majority were not attributed to the study drug (Figure 1). There were generally fewer discontinuations after week 12 compared with the period from baseline to week 12. At week 12, 30.0% of patients receiving tofacitinib 1 mg twice daily, 19.1% of patients receiving tofacitinib 3 mg twice daily, 16.3% of patients receiving tofacitinib 20 mg/day, and 26.1% of patients receiving placebo were classified as nonresponders and were reassigned to receive tofacitinib 5 mg twice daily.

Figure 1.

Patient disposition, showing the total number of patients screened, the total number of patients randomized to a treatment group, and the number of evaluable patients. a = 1 patient was withdrawn after being reassigned to receive tofacitinib at a dosage of 5 mg twice daily (bid). qd = once daily.

The baseline demographics and disease characteristics of the patients were similar across the treatment groups (Table 1). The majority of patients were white women, ages 45–64 years. At baseline, the mean duration of RA ranged from 7.5 years to 11.8 years, the mean MTX dosage ranged from 16.0 mg/week to 17.0 mg/week, and the mean number of prior DMARDs (including MTX) ranged from 1.7 per patient to 1.9 per patient.

Table 1. Baseline demographics and clinical characteristics of the randomized and treated patients*
CharacteristicPlacebo (n = 69)Tofacitinib
1 mg bid (n = 70)3 mg bid (n = 68)5 mg bid (n = 71)10 mg bid (n = 74)15 mg bid (n = 75)20 mg/day (n = 80)
  • *

    Except where indicated otherwise, values are the number (%). bid = twice daily; DMARDs = disease-modifying antirheumatic drugs; NSAIDs = nonsteroidal antiinflammatory drugs; MTX = methotrexate; TNF = tumor necrosis factor; TJC68 = tender joint count in 68 joints; SJC66 = swollen joint count in 66 joints; HAQ DI = Health Assessment Questionnaire disability index; DAS28-ESR = Disease Activity Score in 28 joints using the erythrocyte sedimentation rate; DAS28-CRP = DAS28 using the C-reactive protein (CRP) level.

Female sex56 (81.2)57 (81.4)52 (76.5)57 (80.3)55 (74.3)66 (88.0)63 (78.8)
Age, mean ± SD years53 ± 13.452 ± 11.651 ± 14.952 ± 12.856 ± 10.454 ±11.154 ± 10.8
Race       
 White58 (84.1)61 (87.1)54 (79.4)63 (88.7)64 (86.5)65 (86.7)72 (90.0)
 Black3 (4.3)1 (1.4)1 (1.5)2 (2.8)1 (1.4)1 (1.3)2 (2.5)
 Asian001 (1.5)0000
 Other8 (11.6)8 (11.4)12 (17.6)6 (8.5)9 (12.2)9 (12.0)6 (7.5)
Disease duration, years       
 Mean9.211.89.49.07.510.89.8
 Range0.5–39.00.5–40.80.5–43.30.5–46.00.5–30.00.6–65.00.6–46.0
No. of prior failed DMARDs, mean1.71.91.91.71.71.91.7
Prior NSAIDs, %78.374.382.471.875.778.767.5
Prior MTX dosage, mean mg/week17.016.616.916.016.716.616.4
Prior failed ≥1 TNF inhibitors, %2.02.09.15.66.810.76.0
Concomitant glucocorticoids, %44.961.460.357.756.864.061.3
Rheumatoid factor positive, %83.079.389.882.867.787.175.0
TJC68, mean21.623.622.821.524.823.723.1
SJC66, mean15.716.515.714.114.715.315.2
HAQ DI, mean (scale 0–3)1.201.581.361.441.331.411.46
CRP, mean mg/liter18.916.315.918.014.417.214.7
4-variable DAS28-ESR, mean6.16.46.16.16.46.26.3
3-variable DAS28-CRP, mean5.35.55.35.15.35.45.3

Efficacy.

The ACR20 response rate at week 12 (primary end point) was significantly higher among patients receiving ≥3 mg of tofacitinib twice daily compared with the response rate in those receiving placebo. An ACR20 response was achieved in 45.7% (1 mg twice daily), 52.9% (3 mg twice daily), 50.7% (5 mg twice daily), 58.1% (10 mg twice daily), 56.0% (15 mg twice daily), and 53.8% (20 mg/day) of patients in the tofacitinib group compared with 33.3% of patients in the placebo group (P ≤ 0.05 for all tofacitinib doses ≥3 mg) (Figure 2A). The time to onset of a significantly higher ACR20 response as compared with placebo was 2 weeks for patients receiving tofacitinib at a dosage of ≥3 mg twice daily (Figure 2B); efficacy was sustained at week 24, with significantly higher ACR20 response rates in patients receiving dosages of 3 mg twice daily, 10 mg twice daily, 15 mg twice daily, and 20 mg/day (P ≤ 0.05 versus placebo) (Figure 2A). These results were supported by the LOCF analyses performed for the ACR20 over 24 weeks, with statistical significance achieved for all dosages ≥3 mg twice daily compared with placebo at weeks 12 and 24 (Figure 2C). Logistic regression analysis demonstrated a significant dose-response for the ACR20 (P ≤ 0.05).

Figure 2.

A, Treatment response rates according to the American College of Rheumatology 20% improvement criteria (ACR20), ACR50, and ACR70 at week 12 and week 24 in the full analysis set, using nonresponder imputation. B, ACR20 response rates from baseline to week 24 in the full analysis set, using nonresponder imputation. C, ACR20 response rates from baseline to week 24 in the full analysis set, using the last observation carried forward. Values are the mean ± SEM. ∗ = P ≤ 0.05; ∗∗ = P < 0.001; ∗∗∗ = P < 0.0001, versus placebo. bid = twice daily; qd = once daily.

Among patients treated with tofacitinib at a dosage of ≥5 mg twice weekly, 45.3% were classified as nonresponders (failed to achieve an ACR20 response) at week 12; at week 24, an ACR20 response was achieved by 29.0% (5 mg twice daily), 22.6% (10 mg twice daily), and 27.3% (15 mg twice daily) of these patients.

When the ACR20 response rates at week 12 were analyzed according to geographic location, the results were consistent with the overall results, with patients receiving tofacitinib dosages ≥3 mg twice daily achieving the highest rates. With the exception of the 3 mg twice daily dosage, response rates were higher in Latin America and Europe compared with the US (see Supplementary Figure 1, available on the Arthritis & Rheumatism Web site at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1529-0131).

Greater ACR50 response rates were observed for all tofacitinib groups compared with placebo (Figure 2A). At weeks 12 and 24, the ACR50 response rate was significantly greater for patients receiving tofacitinib at dosages of 15 mg twice daily and 20 mg/day compared with placebo (P ≤ 0.05); at week 12, patients receiving 5 mg of tofacitinib twice daily exhibited a significantly greater response compared with patients receiving placebo (P ≤ 0.05). Similarly, significant improvements in the ACR70 response rate at week 12 were observed for patients receiving tofacitinib at dosages of 3 mg twice daily, 5 mg twice daily, 15 mg twice daily, and 20 mg/day (P ≤ 0.05 versus placebo); such improvements were also observed at week 24 for patients receiving tofacitinib at dosages of 1 mg twice daily, 3 mg twice daily, 5 mg twice daily, 15 mg twice daily, and 20 mg/day (P < 0.001 for 15 mg twice daily versus placebo; P ≤ 0.05 for all other comparisons with placebo).

Scores for components of the ACR core criteria set at baseline and the change from baseline to week 12 are presented in Table 2 (no imputation). At 12 weeks, significant improvements from baseline were seen for patients receiving tofacitinib dosages ≥3 mg twice daily for all measures except the physician's global assessment (not significant for 1 mg twice daily, 3 mg twice daily, or 10 mg twice daily). These improvements were sustained to week 24. Scores for components of the ACR core criteria at week 24 for the patients receiving tofacitinib dosages of 5, 10, and 15 mg twice daily are shown in Supplementary Table 2, available on the Arthritis & Rheumatism Web site at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1529-0131.

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 count in 68 jointsSwollen joint count in 66 jointsPatient'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
nMean ± SEMnMean ± SEMnMean ± SEMnMean ± SEMnMean ± SEMnMean ± SEMnMean ± SEM
  • *

    Values are the least squares means from the full analysis data set, in analyses with no imputation. P values are versus placebo. VAS = visual analog scale; HAQ DI = Health Assessment Questionnaire disability index; CRP = C-reactive protein; bid = twice daily.

Placebo              
 Baseline6921.59 ± 1.596915.72 ± 1.066951.19 ± 3.346958.30 ± 1.846951.88 ± 3.18691.20 ± 0.096918.88 ± 2.35
 Week 126113.77 ± 1.90618.79 ± 1.176141.02 ± 3.356135.70 ± 3.186039.85 ± 3.32611.08 ± 0.106019.69 ± 2.59
 Change −7.63 ± 1.18 −6.35 ± 0.79 −13.03 ± 2.84 −22.75 ± 2.30 −15.07 ± 2.80 −0.16 ± 0.06 3.04 ± 1.68
Tofacitinib 1 mg bid              
  Baseline7023.64 ± 1.397016.51 ± 0.997059.96 ± 3.077062.66 ± 1.917062.47 ± 2.96701.58 ± 0.077016.30 ± 2.16
  Week 126412.84 ± 1.60648.31 ± 1.056435.92 ± 2.816333.65 ± 2.536438.78 ± 2.86641.19 ± 0.08618.53 ± 1.23
  Change −10.68 ± 1.16 −7.37 ± 0.78 −22.30 ± 2.78 −27.59 ± 2.26 −20.91 ± 2.74 −0.34 ± 0.06 −7.42 ± 1.67
  P 0.064 0.36 ≤0.05 0.13 0.14 ≤0.05 <0.0001
 3 mg bid              
  Baseline6822.79 ± 1.286815.68 ± 1.046655.05 ± 3.056857.50 ± 2.246858.91 ± 2.78661.36 ± 0.096815.85 ± 2.35
  Week 12598.83 ± 1.25595.36 ± 0.865730.90 ± 3.185926.17 ± 2.785934.42 ± 3.27580.92 ± 0.10579.54 ± 1.79
  Change −13.95 ± 1.18 −10.07 ± 0.79 −24.39 ± 2.88 −32.25 ± 2.30 −22.61 ± 2.79 −0.48 ± 0.08 −6.50 ± 1.71
  P <0.001 <0.001 ≤0.05 ≤0.05 0.06 ≤0.05 <0.0001
 5 mg bid              
  Baseline7121.46 ± 1.547114.06 ± 0.887154.87 ± 3.177156.51 ± 2.257154.62 ± 2.81711.44 ± 0.087118.03 ± 2.96
  Week 126410.09 ± 1.46646.13 ± 0.856428.88 ± 2.856424.77 ± 2.356429.66 ± 2.71640.94 ± 0.08606.54 ± 1.25
  Change 12.06 ± 1.15 −8.73 ± 0.77 −27.37 ± 2.76 −33.84 ± 2.25 −27.13 ± 2.72 −0.49 ± 0.06 −10.11 ± 1.67
  P ≤0.05 ≤0.05 <0.001 <0.001 ≤0.05 <0.001 <0.0001
 10 mg bid              
  Baseline7424.84 ± 1.457414.74 ± 0.877456.66 ± 2.967460.77 ± 1.957458.35 ± 2.69741.33 ± 0.077414.42 ± 2.07
  Week 126610.88 ± 1.57665.50 ± 0.726533.78 ± 3.166626.47 ± 2.426535.05 ± 3.06650.95 ± 0.08639.11 ± 2.53
  Change −12.83 ± 1.13 −9.48 ± 0.76 −22.14 ± 2.72 −33.91 ± 2.19 −22.42 ± 2.67 −0.39 ± 0.06 −6.55 ± 1.63
  P ≤0.05 ≤0.05 ≤0.05 <0.001 0.06 ≤0.05 <0.0001
 15 mg bid              
  Baseline7523.68 ± 1.477515.33 ± 0.817555.83 ± 2.647560.51 ± 1.657556.09 ± 2.47751.41 ± 0.077517.21 ± 1.96
  Week 126610.18 ± 1.56664.85 ± 0.746631.48 ± 3.066523.28 ± 2.226632.53 ± 3.01660.96 ± 0.08625.81 ± 0.92
  Change −13.46 ± 1.12 −10.52 ± 0.76 −24.19 ± 2.70 −36.68 ± 2.20 −24.09 ± 2.66 −0.43 ± 0.06 −10.44 ± 1.64
  P <0.001 <0.001 ≤0.05 <0.0001 ≤0.05 ≤0.05 <0.0001
 20 mg/day              
  Baseline8023.11 ± 1.428015.21 ± 0.908059.61 ± 2.648058.75 ± 2.008057.24 ± 2.88791.46 ± 0.068014.68 ± 1.92
  Week 127011.27 ± 1.00706.80 ± 1.067031.09 ± 3.187028.93 ± 2.806930.76 ± 3.06680.90 ± 0.08659.53 ± 1.87
  Change −12.43 ± 1.09 −8.70 ± 0.73 −25.65 ± 2.62 −30.06 ± 2.12 −27.11 ± 2.60 −0.53 ± 0.06 −5.10 ± 1.59
  P ≤0.05 ≤0.05 ≤0.05 ≤0.05 ≤0.05 <0.0001 <0.001

Compared with the mean change in the DAS28-CRP from baseline to week 12 in the placebo group (−0.84), the mean changes in the tofacitinib groups were significantly greater: −1.42 (1 mg twice daily [P ≤ 0.05]), −1.79 (3 mg twice daily [P < 0.0001]), −1.69 (5 mg twice daily [P < 0.0001]), −1.83 (10 mg twice daily [P < 0.0001]), −2.03 (15 mg twice daily [P < 0.0001]), and −1.69 (20 mg/day [P < 0.0001]). At week 24, significant improvements in the mean DAS28-CRP were observed for patients receiving tofacitinib dosages ≥3 mg twice daily (P ≤ 0.05 for 3 mg twice daily and 20 mg/day versus placebo; P < 0.001 for 5 mg twice daily and 10 mg twice daily versus placebo; and P < 0.0001 for 15 mg twice daily versus placebo). DAS28-CRP scores from baseline to week 24 are shown in Supplementary Figure 2A (available on the Arthritis & Rheumatism Web site at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1529-0131).

At week 12, the percentage of patients achieving a DAS28-CRP of <2.6 (see Supplementary Figure 2B, available on the Arthritis & Rheumatism Web site at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1529-0131) was significantly higher in the groups receiving tofacitinib at dosages of 3 mg twice daily (23.1% [P ≤ 0.05]), 10 mg twice daily (27.5% [P < 0.001]), 15 mg twice daily (29.2% [P < 0.001]), and 20 mg/day (20.8% [P ≤ 0.05]) compared with the percentage in the group assigned to receive placebo (6.1%). By week 24, all groups receiving tofacitinib at a dosage ≥3 mg twice daily exhibited significantly higher proportions of patients with a DAS28-CRP of <2.6 (P ≤ 0.05 versus placebo). In addition, a post hoc analysis demonstrated European League Against Rheumatism “good” responses (a DAS28-CRP of ≤3.2 at the current visit and a decline >1.2 from baseline at the current visit) (16) in 35.4% (3 mg twice daily [P ≤ 0.05]), 29.4% (5 mg twice daily [P ≤ 0.05]), 35.7% (10 mg twice daily [P ≤ 0.05]), 41.7% (15 mg twice daily [P < 0.001]), and 31.2% (20 mg/day [P ≤ 0.05]) of patients receiving tofacitinib compared with 15.2% in the placebo group. This improvement was maintained to week 24 for patients assigned to the following dosage groups: 3 mg twice daily, 5 mg twice daily, 20 mg/day (P ≤ 0.05); 10 mg twice daily (P < 0.001); and 15 mg twice daily (P < 0.0001).

By week 4, the mean change from baseline in the HAQ DI (no imputation) was significantly improved for patients receiving tofacitinib dosages ≥3 mg twice daily (P ≤ 0.05 versus placebo). At week 12, changes in the HAQ DI for all treatment groups were significantly different from those for the placebo group; improvements were maintained to week 24, and changes in the groups receiving tofacitinib at dosages of 5 mg twice daily and 20 mg/day remained significantly different from those in the placebo group. At week 2, there were significantly (P ≤ 0.05) more HAQ DI responders (improvement of ≥0.22 units; NRI) in patients receiving tofacitinib at dosages of 5 mg twice daily (42.3%), 10 mg twice daily (46.0%), 15 mg twice daily (48.0%), and 20 mg/day (46.3%) compared with patients receiving placebo (23.5%). At week 12, significantly more HAQ DI responders were observed in the group receiving 10 mg of tofacitinib twice daily (52.7%) and the group receiving tofacitinib 20 mg/day (48.8%); by week 24, no significant difference compared with placebo was seen in any tofacitinib group.

Improvements in the PCS score of the SF-36 (mean change from baseline; no imputation) were observed at week 12 in the groups receiving tofacitinib dosages of 15 mg twice daily and 20 mg/day (P ≤ 0.05 versus placebo) and at week 24 in the group receiving a dosage of 20 mg/day (P ≤ 0.05 versus placebo). Improvements in the MCS score of the SF-36 were observed at week 12 in the groups receiving tofacitinib dosages of 1 mg twice daily, 15 mg twice daily, and 20 mg/day (P ≤ 0.05 versus placebo) and at week 24 in the groups receiving 5 mg twice daily and 15 mg twice daily (P ≤ 0.05 versus placebo). No improvements or a dose response in the FACIT-F subscale was apparent (data not shown).

Safety.

Treatment-emergent adverse events.

Across all groups of patients receiving tofacitinib (n = 438), 66.7% of patients (n = 292) had a total of 801 treatment-emergent AEs from baseline to week 24 (see Supplementary Table 1, available on the Arthritis & Rheumatism Web site at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1529-0131). AEs occurring in ≥5% and ≥2 patients in any treatment group are shown in Table 3. Most AEs were mild in severity. Patients assigned to receive tofacitinib at a dosage of 15 mg twice daily reported the highest number of AEs. From baseline to week 12, the most frequently reported AEs (≥5%; all causality, all treatment groups) were headache, diarrhea, nausea, urinary tract infection, upper respiratory tract infection, nasopharyngitis, influenza, cough, elevated ALT level, and elevated AST level. Twenty-one patients reported serious AEs overall throughout the entire study period, with the highest incidence in the group receiving tofacitinib at a dosage of 15 mg twice daily.

Table 3. Treatment-emergent all-cause adverse events occurring in ≥5% and ≥2 patients in any group over 24 weeks*
System organ class/preferred term (MedDRA)Tofacitinib
Placebo1 mg bid3 mg bid5 mg bid, Bl to W24 (n = 71)10 mg bid, Bl to W24 (n = 74)15 mg bid, Bl to W24 (n = 75)20 mg/day
Bl to W12 (n = 69)Post 12Bl to W12 (n = 70)Post W12Bl to W12 (n = 68)Post W12Bl to W12 (n = 80)Post W12
O (n = 51)R (n = 18)O (n = 49)R (n = 21)O (n = 55)R (n = 13)O (n = 67)R (n = 13)
  • *

    Values are the number (%). bid = twice daily; Bl = baseline; W12 = week 12; O = original assignment; R = reassigned after week 12 to tofacitinib 5 mg twice daily; MedDRA = Medical Dictionary for Regulatory Activities; ALT = alanine aminotransferase; AST = aspartate aminotransferase; RA = rheumatoid arthritis.

Gastrointestinal disorders               
 Diarrhea2 (2.9)005 (7.1)3 (6.1)02 (2.9)009 (12.7)1 (1.4)3 (4.0)1 (1.3)01 (7.7)
 Upper abdominal pain3 (4.3)01 (5.6)2 (2.9)1 (2.0)02 (2.9)001 (1.4)2 (2.7)1 (1.3)1 (1.3)01 (7.7)
 Dyspepsia1 (1.4)1 (2.0)1 (5.6)1 (1.4)1 (2.0)000003 (4.1)2 (2.7)1 (1.3)00
 Flatulence1 (1.4)001 (1.4)0000002 (2.7)0001 (7.7)
 Nausea1 (1.4)003 (4.3)004 (5.9)003 (4.2)5 (6.8)4 (5.3)2 (2.5)00
General disorders and  administration-site  conditions               
 Chest pain00001 (2.0)03 (4.4)0001 (1.4)2 (2.7)1 (1.3)01 (7.7)
Infections and infestations               
 Gastroenteritis1 (1.4)000000002 (2.8)4 (5.4)2 (2.7)1 (1.3)00
 Nasopharyngitis2 (2.5)001 (1.4)1 (2.0)1 (4.8)1 (1.5)1 (1.8)1 (7.7)5 (7.0)2 (2.7)6 (8.0)3 (4.3)2 (3.0)1 (7.7)
 Pharyngitis2 (2.5)001 (1.4)003 (4.4)1 (1.8)02 (2.8)01 (1.3)2 (2.9)01 (7.7)
 Sinusitis0001 (1.4)1 (2.0)01 (1.5)0003 (4.1)1 (1.3)001 (7.7)
 Upper respiratory tract  infection2 (2.9)02 (11.1)01 (2.0)03 (4.4)005 (7.0)5 (6.8)2 (2.7)4 (5.0)2 (3.0)1 (7.7)
 Urinary tract infection0001 (1.4)01 (4.8)4 (5.9)1 (1.8)1 (7.7)5 (7.0)4 (5.4)5 (6.7)5 (6.3)2 (3.0)0
 Influenza01 (2.0)01 (1.4)01 (4.8)1 (1.5)002 (2.8)5 (6.8)3 (4.0)1 (1.3)01 (7.7)
Liver enzymes               
 ALT increased1 (1.4)001 (1.4)01 (4.8)1 (1.5)00005 (6.7)1 (1.3)01 (7.7)
 AST increased0000001 (1.5)00005 (6.7)2 (2.5)00
Metabolism and nutrition disorders               
Hypercholesterolemia0002 (2.9)001 (1.5)00004 (5.3)2 (2.5)00
Musculoskeletal and  connective tissue  disorders               
 Arthralgia0000002 (2.9)1 (1.8)1 (7.7)1 (1.4)2 (2.7)2 (2.7)000
 Worsening RA1 (1.4)01 (5.6)2 (2.9)01 (4.8)001 (7.7)2 (2.8)1 (1.4)0000
Nervous system disorders               
 Headache1 (1.4)003 (4.3)002 (2.9)002 (2.8)3 (4.1)4 (5.3)10 (12.5)2 (3.0)1 (7.7)
 Somnolence0001 (1.4)000002 (2.8)00001 (7.7)
Respiratory, thoracic and  mediastinal disorders               
 Cough0001 (1.4)002 (2.9)003 (4.2)6 (8.1)2 (2.7)3 (3.8)00
Skin and subcutaneous  tissue disorders               
 Rash1 (1.4)001 (1.4)002 (2.9)002 (2.8)4 (5.4)2 (2.7)1 (1.3)00

Discontinuation rates due to AEs are shown in Figure 1. Discontinuations due to treatment-emergent AEs (all causalities) occurred at frequencies of 6.1% (tofacitinib 1 mg twice daily), 3.6% (tofacitinib 3 mg twice daily), 4.2% (tofacitinib 5 mg twice daily), 6.8% (tofacitinib 10 mg twice daily), 13.3% (tofacitinib 15 mg twice daily), 9.0% (tofacitinib 20 mg/day), and 5.9% (placebo). Two deaths were reported; one occurred prior to randomization and the other is described below.

Infections.

The proportion of infections was higher in the tofacitinib groups than in the placebo group; however, no dose effect for infections was demonstrated in this study (see Supplementary Table 1, available on the Arthritis & Rheumatism Web site at http://onlinelibrary.wiley.com/journal/10.1002(ISSN)1529-0131). The most common treatment-related infections were bronchitis (1.6%), nasopharyngitis (1.4%), upper respiratory tract infection (1.4%), urinary tract infection (1.4%), and oral herpesvirus infection (1.4%). Serious infectious events, all of which were considered to be treatment related, were reported by 5 patients receiving tofacitinib: 3 patients had pneumonia (1 each in the 3 mg twice daily, 5 mg twice daily, and 20 mg/day groups); 1 patient had a urinary tract infection (15 mg twice daily group); and 1 patient had a respiratory tract infection (10 mg twice daily group). None of these serious infectious events were associated with neutropenia, and all except 1 patient recovered. A 39-year-old patient receiving tofacitinib 3 mg twice daily developed pneumonia (etiology not determined) followed by respiratory failure and cardiac failure and subsequently died.

Abnormal laboratory findings.

The mean changes from baseline to week 24 in laboratory values are presented in Table 4. Dose-related decreases in neutrophil counts were observed. Neutrophil counts fell by week 2 and did not decrease below 500/mm3 in any patient; events of Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT)–defined neutropenia occurred infrequently and sporadically, and no patient in whom neutropenia developed experienced a serious infectious event. As defined by the OMERACT Proposed Rheumatology Common Toxicity criteria (17), no patients had confirmed (at least 2 consecutive visits) severe neutropenia (0.5–0.9 × 103 neutrophils/mm3), 1 patient in the 15 mg twice daily treatment group had confirmed moderate neutropenia (1.0–1.4 × 103 neutrophils/mm3) (first visit of confirmed event: week 16), and 1 patient each in the 3 mg twice daily (week 8), 5 mg twice daily (week 8), 10 mg twice daily (week 4), and 15 mg twice daily (week 16) groups had confirmed mild neutropenia (1.5–1.9 × 103 neutrophils/mm3). There were no treatment discontinuations due to neutropenia. All abnormal laboratory results of clinical significance, including neutropenia, were monitored until the laboratory values returned to normal or baseline values or were deemed clinically stable.

Table 4. Safety summary according to laboratory values at week 24*
 PlaceboPlacebo (reassigned)Tofacitinib
1 mg bid1 mg bid (reassigned)3 mg bid3 mg bid (reassigned)5 mg bid10 mg bid15 mg bid20 mg/day20 mg/day (reassigned)
  • *

    Except where indicated otherwise, values are the mean ± SEM change from baseline. Values are from the full analysis data set, in analyses with no imputation. bid = twice daily; HDL = high-density lipoprotein; LDL = low-density lipoprotein; APO A-I = apolipoprotein A-I; ALT = alanine aminotransferase; ULN = upper limit of normal; AST = aspartate aminotransferase.

Hemoglobin, gm/dl−0.25 ± 0.17−0.48 ± 0.270.24 ± 0.130.04 ± 0.200.22 ± 0.140.08 ± 0.22−0.02 ± 0.11−0.34 ± 0.13−0.38 ± 0.150.01 ± 0.130.18 ± 0.26
Neutrophils, 103/mm3−0.06 ± 0.36−0.48 ± 0.32−0.75 ± 0.45−0.66 ± 0.32−1.20 ± 0.300.04 ± 0.43−0.80 ± 0.32−1.20 ± 0.28−1.67 ± 0.45−0.43 ± 0.27−0.11 ± 0.69
Serum creatinine, mg/dl0.01 ± 0.010.08 ± 0.030.04 ± 0.010.04 ± 0.020.07 ± 0.020.04 ± 0.030.06 ± 0.010.04 ± 0.030.08 ± 0.010.03 ± 0.010.04 ± 0.03
Total cholesterol, mg/dl−6.19 ± 3.9812.62 ± 8.5720.96 ± 4.1126.98 ± 6.1411.45 ± 3.9623.17 ± 6.8019.14 ± 4.5327.69 ± 5.4727.71 ± 4.8221.52 ± 5.8019.97 ± 7.50
HDL cholesterol, mg/dl−2.55 ± 1.402.71 ± 2.971.37 ± 1.759.48 ± 2.084.05 ± 1.763.30 ± 2.705.07 ± 1.584.37 ± 1.576.08 ± 1.615.72 ± 1.466.58 ± 3.02
LDL cholesterol, mg/dl−1.72 ± 3.25−0.89 ± 6.4915.89 ± 3.8517.71 ± 4.867.20 ± 2.8618.26 ± 6.1410.98 ± 3.9520.04 ± 4.6917.18 ± 4.0513.53 ± 4.418.79 ± 4.61
Apo A-I, mg/dl−0.02 ± 0.03−0.04 ± 0.040.06 ± 0.030.06 ± 0.040.03 ± 0.020.07 ± 0.030.01 ± 0.030.06 ± 0.030.05 ± 0.030.03 ± 0.030.04 ± 0.04
Apo B, mg/dl−0.03 ± 0.050.07 ± 0.050.08 ± 0.030.25 ± 0.070.06 ± 0.040.01 ± 0.070.10 ± 0.030.08 ± 0.030.13 ± 0.030.13 ± 0.030.14 ± 0.06
ALT
 Abnormal baseline   value, no. (%)4 (6)6 (9)8 (12)5 (7)3 (4)2 (3)8 (10)
  >1× ULN11 (17)10 (16)8 (13)16 (24)19 (27)27 (37)19 (26)
  >2× ULN1 (2)002 (3)1 (1)6 (8)5 (7)
  >3× ULN1 (2)0001 (1)4 (5)1 (1)
  >1× ULN sustained    until end of study3 (6)01 (2)1 (6)002 (3)4 (6)6 (8)3 (5)0
AST
 Abnormal baseline   value, no. (%)2 (3)4 (6)3 (4)3 (4)5 (7)3 (4)7 (9)
  >1× ULN11 (16)9 (14)9 (14)15 (22)14 (21)28 (39)19 (26)
  >2× ULN2 (3)1 (2)03 (4)1 (1)4 (6)4 (5)
  >3× ULN00001 (1)2 (3)2 (3)
  >1× ULN sustained    until end of study2 (3)001 (5)002 (3)04 (6)2 (3)0

From baseline through week 24, mean increases in the hemoglobin concentration of ≤0.24 gm/dl were observed for patients receiving lower dosages of tofacitinib, and mean decreases of ≤0.48 gm/dl were observed for patients receiving placebo and those receiving tofacitinib dosages of 5 mg twice daily, 10 mg twice daily, and 15 mg twice daily (Table 4); there were no treatment discontinuations due to decreased hemoglobin concentrations (<8 gm/dl or a decrease from baseline of ≥30%). There were 14 cases of confirmed severe anemia (OMERACT criteria: 7–8 gm/dl or ≥2 to ≤3 gm/dl decrease from baseline). Thirteen of these patients were receiving tofacitinib, and 1 patient was receiving placebo; none of these patients had a decrease in the hemoglobin level below 8 gm/dl. Although anemia developed as early as week 2, no pattern of emergence or a tofacitinib dose relationship was observed.

Small increases from baseline in the mean serum creatinine levels (<0.07 mg/dl) were observed in all treatment groups; increases were generally greater in the tofacitinib groups than in the placebo group. Five patients receiving tofacitinib and one patient receiving placebo had a confirmed 50% increase in serum creatinine levels from baseline; none of these patients discontinued treatment. In 4 of these patients, serum creatinine levels stabilized or returned to within 10% of baseline levels at followup, and the other 2 patients were lost to followup. Confirmed serum creatinine level increases of >30% and >0.2 mg/dl from baseline at any time during the study were observed in 8.7%, 11.8%, 20.0%, 20.5%, 21.6%, 10.1%, and 6.0% of patients receiving tofacitinib at dosages of 1 mg twice daily, 3 mg twice daily, 5 mg twice daily, 10 mg twice daily, 15 mg twice daily, 20 mg/day, and patients receiving placebo, respectively; for those patients reassigned to receive tofacitinib at a dosage of 5 mg twice daily at week 12, the proportions were 0%, 0%, 8.3%, and 23.5% for the 1 mg twice daily, 3 mg twice daily, 20 mg/day, and placebo groups, respectively.

Dose-dependent increases in low-density lipoprotein (LDL), high-density lipoprotein (HDL), and total cholesterol levels were observed in all tofacitinib groups. On average, elevations in lipid levels occurred at week 2, peaked at weeks 6–8, and appeared to plateau. In those patients with an elevated LDL cholesterol level (>130 mg/dl) at baseline, the changes from baseline to week 24 ranged from −2.3 mg/dl (tofacitinib 3 mg twice daily) to 14.2 mg/dl (tofacitinib 15 mg twice daily); this pattern was similar to that observed in patients with normal LDL levels at baseline. Lipid level elevations were similar in ACR20 responders and nonresponders. The proportions of patients with an LDL level <130 mg/dl at baseline were 82.2% (tofacitinib 1 mg twice daily), 79.2% (tofacitinib 3 mg twice daily), 77.9% (tofacitinib 5 mg twice daily), 70.8% (tofacitinib 10 mg twice daily), 62.2% (tofacitinib 15 mg twice daily), 65.2% (tofacitinib 20 mg/day), and 80.0% (placebo). The proportions of patients with an LDL level <130 mg/dl at baseline that increased to >130 mg/dl were 37.8% (tofacitinib 1 mg twice daily), 21.4% (tofacitinib 3 mg twice daily), 43.4% (tofacitinib 5 mg twice daily), 60.8% (tofacitinib 10 mg twice daily), 47.8% (tofacitinib 15 mg twice daily), 46.5% (tofacitinib 20 mg/day), and 15% (placebo).

Transaminase level elevations did not have any pattern of emergence but were slightly increased in the higher-dosage tofacitinib groups. Four patients (3 receiving 15 mg twice daily and 1 receiving placebo) permanently discontinued treatment due to transaminase level increases, and 2 patients temporarily discontinued treatment (1 patient receiving 15 mg twice daily and 1 patient receiving placebo). AST levels >3× ULN were observed in 1, 2, and 2 patients in the groups receiving tofacitinib at dosages of 10 mg twice daily, 15 mg twice daily, and 20 mg/day, respectively, compared with no patients in the placebo group. ALT levels >3× ULN were observed in 1, 4, and 1 patients in the tofacitinib 10 mg twice daily, 15 mg twice daily, and 20 mg/day groups, respectively, compared with 1 patient in the placebo group. Increases of >1× ULN in the ALT and AST levels that were sustained to study end are shown in Table 4. No patient who experienced an elevation in the AST or ALT level >3× ULN also experienced an increase in the total bilirubin concentration of >2× ULN or 2 mg/dl.

The mean changes from baseline to week 12 in diastolic or systolic blood pressure were small; no dose-related trend was apparent. AEs of hypertension were reported in patients assigned to receive tofacitinib 1 mg twice daily (4.1%), patients assigned to receive tofacitinib 1 mg twice daily who were reassigned to 5 mg twice daily at week 12 (4.8%), those assigned to receive tofacitinib 3 mg twice daily (3.6%), 5 mg twice daily (1.4%), 10 mg twice daily (2.7%), 15 mg twice daily (2.7%), and 20 mg/day (3.0%), and those reassigned to placebo (5.6%).

DISCUSSION

In this phase IIb study, 6 dosages of tofacitinib were investigated for the treatment of patients with active RA receiving a stable background regimen of MTX who had an inadequate response to MTX alone. Over 24 weeks, tofacitinib at dosages ≥3 mg twice daily was efficacious for the treatment of the signs and symptoms of RA. A significant dose response was observed for the ACR20, and statistically significant dose-related improvements were seen across all dosages ≥3 mg twice daily compared with placebo for the primary efficacy measure of the ACR20 response rate at week 12 and for the secondary measures of the ACR50 and ACR70 response rates. Efficacy was established as early as week 2 and was sustained to week 24. These results confirm the earlier findings from a phase IIa study (5), which indicated that tofacitinib dosages of 5, 15, and 30 mg twice daily were efficacious as monotherapy over 6 weeks.

The efficacy of tofacitinib was also demonstrated by improvement in the DAS28-CRP over 24 weeks, with significant improvements at weeks 12 and 24 for patients receiving all dosages ≥3 mg twice daily. At week 12, the percentage of patients achieving a DAS28-CRP <2.6 was significantly higher in the groups receiving tofacitinib at dosages of 3 mg twice daily, 10 mg twice daily, 15 mg twice daily, and 20 mg/day compared with the percentage in the group assigned to placebo; at week 24, the percentage was higher for all dosages except 1 mg twice daily. A higher proportion of patients exhibited a DAS28-CRP of <2.6 at week 24 compared with week 12, indicating that disease activity continued to decrease over time with tofacitinib treatment.

Improvements were seen in each of the individual components of the ACR core set of disease activity measures. Clinically significant improvements in physical functioning and health-related quality of life were demonstrated by dose-related changes and decreases over time in the HAQ DI in patients treated with tofacitinib as well as significant improvements in the SF-36 PCS and MCS scores from baseline. These results support those of a previous phase IIa study that demonstrated short-term improvements in pain, physical functioning, and health-related quality of life in patients with moderate-to-severely active RA following 6 weeks of treatment with tofacitinib at dosages of 5 mg twice daily, 15 mg twice daily, and 30 mg twice daily (6).

In the current study, tofacitinib administered on a background of MTX demonstrated an acceptable safety and tolerability profile over 24 weeks in patients with active RA, which was consistent with previously reported results (5). Although all dosages of tofacitinib were associated with AEs, the majority were mild in severity. Furthermore, most AEs were treatable or resolved following drug discontinuation. One death was reported postrandomization in a patient receiving tofacitinib 3 mg twice daily in whom pneumonia developed followed by respiratory and cardiac failure. This patient had a history of tobacco use and underlying interstitial lung disease at baseline. Overall, tofacitinib was associated with an increased rate of infection compared with placebo; however, the incidence of serious infectious events was not dose dependent and was not associated with neutropenia.

Changes from baseline in the hemoglobin concentration and the neutrophil count were generally dose related, as were increases in the HDL, LDL, and total cholesterol levels. The mechanisms for lipid level elevations are under investigation. Elevations in transaminase levels were most frequent in the group assigned to receive tofacitinib 15 mg twice daily but were generally transient. In practice, a dose adjustment of tofacitinib, MTX, or both may be recommended in order to maintain transaminase levels within the normal range. Many therapies elicit improvements in anemia in patients with RA. In the present study, no such improvement was confirmed. Some patients experienced a decrease or a severe reduction in the hemoglobin level. In addition, despite improvement in disease activity, increases in the hemoglobin concentration were observed only in a few patients receiving higher doses of tofacitinib, which may relate to inhibition of JAK-2 signaling by the drug. The incidence of severe anemia with tofacitinib, therefore, will need to be assessed in larger phase III trials.

In conclusion, the results of this phase IIb study demonstrated that statistically significant and clinically meaningful reductions in the signs and symptoms of RA were achieved early and were sustained throughout 24 weeks of treatment with tofacitinib at dosages ≥3 mg twice daily added to a background regimen of MTX, with a predictable and generally manageable safety profile. This study supports the decision to use tofacitinib at dosages of 5 mg twice daily and 10 mg twice daily in ongoing phase III trials in patients with active RA receiving background MTX treatment.

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. Kremer 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. Kremer, Wilkinson, Connell, French, Gomez-Reino, Gruben, Kanik, Krishnaswami, Pascual-Ramos, Wallenstein, Zwillich.

Acquisition of data. Kremer, Wilkinson, Gruben, Pascual-Ramos, Wallenstein.

Analysis and interpretation of data. Kremer, Cohen, Wilkinson, Connell, French, Gomez-Reino, Gruben, Kanik, Krishnaswami, Pascual-Ramos, Wallenstein, Zwillich.

ROLE OF THE STUDY SPONSOR

Pfizer facilitated the study design, provided editorial assistance for the manuscript (provided by Clemence Hindley, PhD and Gary Dever, PhD of Complete Medical Communications), and reviewed and approved the manuscript prior to submission. The authors independently collected the data, interpreted the results, and had the final decision to submit the manuscript for publication. Publication of this article was not contingent upon approval by Pfizer.

Acknowledgements

We thank the staff and patients involved in this study. We gratefully acknowledge the contributions of the following individuals to this study: N. Akkoc, M. Aliste, S. Augustinova, J. Badurski, D. Bichovska, S. Bookbinder, J. Box, M. Cardiel-Rios, C. Danning, F. Dietz, P. Dura, R. Ettlinger, S. Forejtova, E. Fudman, M. Ghirlanda, R. Griffin Jr., V. Hamuryudan, G. Hill, A. Hou, A. Insperger, R. Jimenez, S. Kapil, G. Keser, S. Kiraz, Z. Kolarov, P. Kopsa, A. Kovacs, J. Lukac, J. Marcinkiewicz, F. Marcolino, P. Mease, O. Messina, D. Michel, P. Miranda, E. Mola, J. Molina, O. Neira, E. Nemeth, M. Niemer, R. Olson, B. Oparanov, J. Poiley, I. Pokrzywnicka-Gajek, P. Polak, W. Porawska, L. Prochazkova, A. Racewicz, S. Radominski, S. Rantapaa-Dahlqvist, I. Revayova, O. Rillo, P. Rocca, I. Rosa, Z. Ruzga, J. Sanchez Burson, J. Silverfield, A. Singhal, K. Strader, M. St. John, I. Szombati, G. Tate, S. Transo, P. Vitek, N. Wei, S. Wolfe, A. Ximenes, and C. Zerbini.

Ancillary