Background

Baricitinib is an oral, reversible inhibitor of the Janus kinases JAK1 and JAK2 that may have therapeutic value in patients with rheumatoid arthritis.

Methods

We conducted a 52-week, phase 3, double-blind, placebo- and active-controlled trial in which 1307 patients with active rheumatoid arthritis who were receiving background therapy with methotrexate were randomly assigned to one of three regimens in a 3:3:2 ratio: placebo (switched to baricitinib after 24 weeks), 4 mg of baricitinib once daily, or 40 mg of adalimumab (an anti–tumor necrosis factor α monoclonal antibody) every other week. End-point measures evaluated after adjustment for multiplicity included 20% improvement according to the criteria of the American College of Rheumatology (ACR20 response) (the primary end point), the Disease Activity Score for 28 joints (DAS28), the Health Assessment Questionnaire–Disability Index, and the Simplified Disease Activity Index at week 12, as well as radiographic progression of joint damage as measured by the van der Heijde modification of the total Sharp score (mTSS) (range, 0 to 448, with higher scores indicating greater structural joint damage) at week 24.

Results

More patients had an ACR20 response at week 12 with baricitinib than with placebo (primary end point, 70% vs. 40%, P<0.001). All major secondary objectives were met, including inhibition of radiographic progression of joint damage, according to the mTSS at week 24 with baricitinib versus placebo (mean change from baseline, 0.41 vs. 0.90; P<0.001) and an increased ACR20 response rate at week 12 with baricitinib versus adalimumab (70% vs. 61%, P=0.014). Adverse events, including infections, were more frequent through week 24 with baricitinib and adalimumab than with placebo. Cancers were reported in five patients (two who received baricitinib and three who received placebo). Baricitinib was associated with reductions in neutrophil counts and increases in levels of creatinine and low-density lipoprotein cholesterol.

Conclusions

In patients with rheumatoid arthritis who had had an inadequate response to methotrexate, baricitinib was associated with significant clinical improvements as compared with placebo and adalimumab. (Funded by Eli Lilly and Incyte; ClinicalTrials.gov number, NCT01710358.)

Supported by Eli Lilly and Incyte.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

We thank Stephanie Colvin, Ph.D., at Eli Lilly for assistance with tables and figures and with manuscript preparation and process support.

Source Information

From the Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences and the Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom (P.C.T.); the Rebecca MacDonald Centre, Mount Sinai Hospital, University of Toronto, Toronto (E.C.K.); Leiden University Medical Center, Leiden, the Netherlands (D.H.); Brigham and Women’s Hospital, Boston (M.E.W.); Instituto Reumatológico Strusberg, Córdoba, Argentina (L.C.M.); Centro de Investigacion Clinica Especializada, Mexico City (J.R.G.); Ryazan Regional Clinical Cardiology Dispensary, Ryazan, Russia (S.Y.); Eli Lilly, Indianapolis (T.I., S. Beattie, V.A., C.G., T.R., D.S., W.L.M., S. de Bono); and AstraZeneca K.K., Osaka (K.E.), and the First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu (Y.T.) — both in Japan.

Address reprint requests to Dr. Taylor at the Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, Kennedy Institute of Rheumatology, University of Oxford, Windmill Rd., Headington, Oxford OX3 7LD, United Kingdom, or at .

Media in This Article

Figure 1Primary and Secondary Efficacy End Points.Panel A shows the percentage of patients who had 20% improvement according to the criteria of the American College of Rheumatology (ACR20 response). The vertical line at 12 weeks indicates the primary efficacy time point. Panel B shows the least squares mean (LSM) change from baseline in the 28-joint Disease Activity Score, based on the level of high-sensitivity C-reactive protein (DAS28-CRP). For data that were missing because of receipt of rescue therapy or premature discontinuation of the study or study treatment, a modified last-observation-carried-forward (mLOCF) method was used to incorporate the last observation before rescue or discontinuation. Panel C shows the LSM change from baseline in the Health Assessment Questionnaire–Disability Index (HAQ-DI) score, calculated with the use of the mLOCF method; negative changes from baseline indicate improvement. Panel D shows the percentage of patients with a Simplified Disease Activity Index (SDAI) score of 3.3 or less (scores range from 0.1 to 86.0, with higher scores indicating greater disease activity and a score of 3.3 or less indicating remission) at weeks 12, 24, and 52. The DAS28-CRP and HAQ-DI were analyzed at week 12 by means of the modified baseline-observation-carried-forward method, which substituted the baseline observation for patients who had left the study because of an adverse event. Panels A through D include all the patients in the modified intention-to-treat efficacy analysis set (i.e., all the patients who underwent randomization and were treated), which included 1305 patients. Three asterisks denote P<0.001 for supportive analyses comparing baricitinib at the 4-mg dose or adalimumab with placebo, without adjustment for multiple comparisons. One plus sign denotes P≤0.05, two plus signs P≤0.01, and three plus signs P<0.001 for supportive analyses comparing 4 mg of baricitinib with adalimumab, without adjustment for multiple comparisons. A dagger denotes comparisons of baricitinib with placebo and baricitinib with adalimumab for the primary and key secondary end points that are statistically significant as calculated with the graphical method for multiple testing, with the studywise error rate strongly controlled at an alpha level of 0.05 for multiple comparisons.
Figure 2Inhibition of Radiographic Progression of Structural Joint Damage at Week 24.The least squares mean (LSM) change from baseline in structural progression was evaluated with the use of the van der Heijde modification of the total Sharp score (mTSS), with scores ranging from 0 to 448, with higher scores indicating greater structural joint damage. Also shown are scores for erosion and joint-space narrowing. This evaluation included all the patients with a baseline measurement and at least one postbaseline radiograph for the assessment of progression of structural joint damage, which totaled 1234 patients at week 24. Scores that were missing or acquired subsequent to rescue treatment or to a treatment switch as defined in the protocol were imputed with the use of linear extrapolation from baseline and the most recent postbaseline data obtained before or at the initiation of rescue or switch therapy. T bars denote the standard error. Two asterisks denote P≤0.01 and three asterisks P<0.001 for 4 mg of baricitinib or adalimumab versus placebo. A dagger indicates that comparisons between baricitinib and placebo and between baricitinib and adalimumab with respect to the primary and key secondary end points are statistically significant as calculated with the graphical method for multiple testing, with the studywise error rate strongly controlled at an alpha level of 0.05 for multiple comparisons.