Article Figures & Data
- Figure 1.
Patient disposition, weeks 24–128. Reasons for discontinuation include adverse event, lack of efficacy, investigator decision, protocol violation, entry criteria not met, and patient decision. One hundred patients did not enter the first open-label extension (OLE): 42 patients who discontinued during the double-blind period (weeks 0–24) and 58 patients who completed Week 24. Of the 58 eligible patients who did not enter the first OLE, 55 were from sites not participating in the OLE and 3 elected not to participate. Fifty-seven patients did not continue to the second OLE: 32 who discontinued during the first OLE and 25 who completed the first OLE (19 patients from sites not participating in the second OLE and 6 who elected not to participate).
- Table 1.
Baseline characteristics and disease activity at Week 0, Week 24, and Week 76. Data are reported as mean values ± SD unless otherwise indicated.
Characteristics Week 0 All Groups, n = 301 Week 24 All Groups, n = 201 Week 76 All Groups, n = 144 Age, yrs 51 ± 12 51 ± 12 53 ± 11 Female, % 83 83 83 Duration of RA, yrs 5.6 ± 4.4 5.9 ± 4.5 5.9 ± 4.4 ACPA-positivea, % 69 67 69 RF-positiveb, % 71 70 74 Prednisone use, % 49 51 46 Background DMARD use MTX monotherapy, % 69 79 75 MTX + other DMARD, % 29 20 24 Tender joints, of 68 22 ± 12 7 ± 9 6 ± 8 Swollen joints, of 66 16 ± 8 5 ± 6 4 ± 4 HAQ-DIc 1.16 ± 0.67 0.78 ± 0.64 0.74 ± 0.63 High-sensitivity CRPd, mg/l 13 ± 19 6 ± 12 5 ± 12 ESR, mm/h 39 ± 18 27 ± 19 26 ± 18 DAS28-CRP 5.5 ± 0.9 3.3 ± 1.2 2.9 ± 1.2 DAS28-ESR 6.3 ± 0.8 4.0 ± 1.3 3.6 ± 1.3 CDAI 37 ± 12 14 ± 11 11 ± 9 SDAI 39 ± 12 15 ± 11 11 ± 9 ↵a ACPA positivity (ULN = 5 U/ml).
↵b RF positivity (ULN = 14 IU/ml).
↵c Scores on the HAQ-DI range from 0 to 3, with higher scores indicating greater disability.
↵d High-sensitivity C-reactive protein (ULN = 3 mg/l). ACPA: anticyclic citrullinated peptide antibody; CDAI: Clinical Disease Activity Index; CRP: C-reactive protein; DAS28-CRP: Disease Activity Score for 28 joints based on the CRP level; DAS28-ESR: DAS for 28 joints based on the erythrocyte sedimentation rate; DMARD: disease-modifying antirheumatic drugs; HAQ-DI: Health Assessment Questionnaire–Disability Index; MTX: methotrexate; RA: rheumatoid arthritis; RF: rheumatoid factor; SDAI: Simplified Disease Activity Index; ULN: upper limit of normal.
- Table 2.
Safety summary for weeks 0–24, weeks 24–76, and weeks 76–128. Data are n (%) [IR].
Blinded Period, Weeks 0–24 Randomized Dose First OLE, Weeks 24–76 (4 mg or 8 mg) Second OLE, Weeks 76–128 (4 mg throughout) 4:8 mg 2 mg 4 mg 8 mg 4 mg Pre-rescue Post-rescue 8 mg 4/4 mg 4:8/4 mg 8/4 mg n = 52, PYE = 23.6 n = 52, PYE = 23.2 n = 50, PYE = 22.4 n = 108, PYE = 102.8 n = 61, PYE = 6.1 n = 61, PYE = 50.7 n = 32, PYE = 27.5 n = 79, PYE = 78.1 n = 47, PYE = 43.0 n = 18, PYE = 17.3 SAE 3 (6) [12.7] 0 4 (8) [17.7] 17 (16) [16.5] 1 (2) [16.5] 6 (10) [11.8] 6 (19) [21.8] 5 (6) [6.4] 3 (6) [7.0] 0 TEAE 31 (60) [131.6] 32 (62) [138.6] 36 (72) [159.0] 68 (63) [66.1] 14 (23) [230.6] 42 (69) [82.9] 20 (63) [72.7] 41 (52) [52.5] 25 (53) [58.2] 10 (56) [57.8] Study discontinuations due to AE 1 (2) [4.2] 1 (2) [4.3] 1 (2) [4.4] 8 (7) [7.8] 1 (2) [16.5] 1 (2) [2.0] 3 (9) [10.9] 1 (1) [1.3] 2 (4) [4.7] 0 Infections 14 (27) [59.4] 13 (25) [56.3] 14 (28) [61.8] 38 (35) [37.0] 8 (13) [131.7] 25 (41) [49.3] 12 (38) [43.6] 24 (30) [30.7] 13 (28) [30.3] 5 (28) [28.9] Herpes zoster* 0 0 0 6 (6) [5.8] 0 1 (2) [2.0] 2 (6) [7.3] 1 (1) [1.3] 0 0 Serious infections 2 (4) [8.5] 0 1 (2) [4.4] 5 (5) [4.9] 1 (2) [16.5] 1 (2) [2.0] 2 (6) [7.3] 2 (3) [2.6] 2 (4) [4.7] 0 4/4 mg = 4 mg baricitinib for weeks 24–76 and weeks 76–128. 4:8/4 = 4 mg baricitinib through Week 28 or 32, then 8 mg through Week 76 and 4 mg for weeks 76–128. 8/4 mg = 8 mg baricitinib for weeks 24–76 and 4 mg for weeks 76–128. Pre-rescue includes all AE that began or worsened on or before the date of dose escalation. Post-rescue includes all AE that began or worsened after the date of dose escalation.
↵* Among the cases of herpes zoster, 5 patients were receiving concomitant steroid and 5 patients were not receiving concomitant steroid. IR: incidence rate; AE: adverse event; OLE: open-label extension; PYE: patient-years of exposure; n: no. patients treated with stated dose regimen in the study period or no. patients with event; TEAE: treatment-emergent AE; SAE: serious AE.
- Table 3.
Change from each OLE baseline for selected laboratory analytes. Data represented as mean change from baseline ± SD. Baseline in the blinded period is Week 0, baseline in the first OLE is Week 24, and baseline in the second OLE is Week 76.
Blinded Period, Weeks 0–24 Randomized Dose First OLE, Weeks 24–76 Second OLE, Weeks 76–128 4:8 mg 2 mg, n = 52 4 mg, n = 52 8 mg, n = 50 4 mg, n = 108 Pre-rescue, n = 61 Post-rescue*, n = 61 8 mg, n = 32 4/4 mg, n = 79 4:8/4 mg, n = 47 8/4 mg, n = 18 Neutrophil count, 103 cells/mm3 −0.25 ± 2.18 −0.21 ± 2.02 −1.37 ± 2.33 0.32 ± 2.09 0.11 ± 1.70 0.29 ± 2.08 0.83 ± 2.06 −0.03 ± 1.59 −0.42 ± 1.94 −0.34 ± 1.68 Lymphocyte count, 103 cells/mm3 −0.01 ± 0.50 −0.03 ± 0.66 0.10 ± 0.61 −0.17 ± 0.54 0.10 ± 0.69 −0.23 ± 0.72 −0.43 ± 0.58 −0.06 ± 0.61 0.03 ± 0.50 −0.02 ± 0.59 Platelet count, 103 cells/mm3 19 ± 37 34 ± 66 49 ± 60 −1 ± 66 4 ± 66 8 ± 60 11 ± 74 8 ± 47 −12 ± 62 −33 ± 45 Hemoglobin, g/dl −0.28 ± 1.10 −0.24 ± 0.91 −0.44 ± 1.04 0.04 ± 0.73 −0.02 ± 1.07 0.12 ± 0.92 0.06 ± 0.99 0.08 ± 0.62 0.24 ± 0.69 0.23 ± 1.23 ALT, IU/l 2.2 ± 14.6 2.5 ± 12.7 2.8 ± 23.0 4.8 ± 36.4 −1.3 ± 8.4 5.1 ± 15.7 83.4 ± 466.7 −0.7 ± 19.0 3.0 ± 19.8 −7.7 ± 16.5 HDL-C, mg/dl 3.5 ± 10.0 5.7 ± 12.6 10.0 ± 11.5 −1.4 ± 10.4 0.4 ± 12.4 −0.1 ± 15.1 −3.7 ± 15.3 1.4 ± 9.4 1.0 ± 13.7 0.2 ± 11.7 LDL-C, mg/dl 11.5 ± 22.8 8.8 ± 32.6 14.0 ± 30.9 5 ± 27 −2 ± 19 7 ± 29 4 ± 35 −4 ± 34 5 ± 36 −1 ± 26 Creatinine, mg/dl 0.04 ± 0.10 0.05 ± 0.08 0.07 ± 0.13 0.001 ± 0.115 −0.006 ± 0.093 −0.010 ± 0.119 −0.008 ± 0.120 0.000 ± 0.081 0.000 ± 0.104 −0.016 ± 0.078 Creatine phosphokinase, U/l 25 ± 66 41 ± 81 70 ± 89 39 ± 171 24 ± 93 −6 ± 139 18 ± 108 −33 ± 204 −26 ± 97 24 ± 99 4/4 mg = 4 mg baricitinib through Week 128. 4:8/4 = 4 mg baricitinib through Week 28 or 32 then 8 mg through Week 76 and 4 mg for weeks 76–128. 8/4 mg = 8 mg baricitinib through Week 76 and 4 mg for weeks 76–128. “n” mean no. patients treated with stated dose regimen in the study period. Pre-rescue includes all laboratory results obtained prior to dose escalation. Post-rescue includes all laboratory results obtained after dose escalation.
↵* For patients with dose escalation, the value obtained at the dose escalation visit is used instead of baseline at Week 24 for the post-rescue time period. ALT: alanine aminotransferase; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; OLE: open-label extension.
- Table 4.
Changes in laboratory results (patients who worsened to that grade from baseline). Data are n (%) and indicate no. patients treated with stated dose regimen in the study period.
Blinded Period, Weeks 0–24 Randomized Dose First OLE, Weeks 24–76 Second OLE, Weeks 76–128 4:8 mg 2 mg, n = 52 4 mg, n = 52 8 mg, n = 50 4 mg, n = 108 Pre-rescue, n = 61 Post-rescue, n = 61 8 mg, n = 32 4/4 mg, n = 79 4:8/4 mg, n = 47 8/4 mg, n = 18 Decreased neutrophils Grade 1: ≥ 1500 cells/mm3 to < LLN 4 (8) 1 (2) 5 (10) 17 (16) 2 (3) 5 (8) 3 (9) 5 (6) 6 (13) 0 Grade 2: ≥ 1000 to < 1500 cells/mm3 3 (6) 5 (10) 9 (18) 1 (1) 1 (2) 3 (5) 3 (9) 2 (3) 1 (2) 1 (6) Grade 3: ≥ 500 to < 1000 cells/mm3 1 (2) 0 1 (2) 1 (1) 0 0 0 0 0 0 Decreased lymphocytes Grade 1: ≥ 800 cells/mm3 to < LLN 6 (12) 8 (15) 10 (20) 15 (14) 4 (7) 5 (8) 4 (13) 7 (9) 5 (11) 3 (17) Grade 2: ≥ 500 to < 800 cells/mm3 2 (4) 6 (12) 10 (20) 5 (5) 0 5 (8) 4 (13) 9 (11) 4 (9) 3 (17) Grade 3: ≥ 200 to < 500 cells/mm3 0 0 0 0 0 1 (2) 1 (3) 0 0 0 Elevated platelets Platelet count > 600,000 cells/µla 0 2 (4) 0 2 (2) 0 1 (2) 1 (3) 1 (1) 0 0 Decreased hemoglobin Grade 1: ≥ 10.0 g/dl to < LLN 10 (19) 11 (21) 18 (36) 22 (20) 5 (8) 12 (20) 5 (16) 14 (18) 4 (9) 1 (6) Grade 2: ≥ 8.0 to < 10.0 g/dl 4 (8) 4 (8) 6 (12) 1 (1) 0 3 (5) 2 (6) 1 (1) 2 (4) 2 (11) Grade 3: < 8.0 to ≥ 6.5 g/dl 0 0 0 2 (2) 0 1 (2) 1 (3) 0 0 0 Grade 4: < 6.5 g/dl 0 0 0 0 0 0 0 0 1 (2) 0 Elevated ALT Grade 1: > ULN and ≤ 2.5 × ULN 8 (15) 12 (23) 12 (24) 18 (17) 2 (3) 14 (23) 5 (16) 16 (20) 9 (19) 1 (6) Grade 2: > 2.5 × ULN and ≤ 5 × ULN 1 (2) 3 (6) 1 (2) 7 (6) 0 0 1 (3) 2 (3) 4 (9) 0 Grade 3: > 5 × ULN and ≤ 20 × ULN 0 1 (2) 1 (2) 2 (2) 0 0 0 0 0 0 Grade 4: > 20 × ULN 0 0 0 0 0 0 1 (3) 0 0 0 Elevated creatinine Grade 1: > ULN and ≤ 1.5 × ULN 3 (6) 6 (12) 2 (4) 8 (7) 1 (2) 3 (5) 1 (3) 4 (5) 0 0 Grade 2: > 1.5 × ULN and ≤ 3 × ULN 0 1 (2) 1 (2) 0 0 0 0 1 (1) 0 0 Baseline in the blinded period is Week 0, baseline in the first OLE is Week 24, and baseline in the second OLE is Week 76. Laboratory grades defined using Common Terminology Criteria for Adverse Events, version 4.0. 4/4 mg = 4 mg baricitinib through Week 128. 4:8/4 = 4 mg baricitinib through Week 28 or 32, then 8 mg through Week 76 and 4 mg for weeks 76–128. 8/4 mg = 8 mg baricitinib through Week 76 and 4 mg for weeks 76–128. Pre-rescue includes all abnormalities that occurred on or before the date of dose escalation. Post-rescue includes all abnormalities that occurred after the date of dose escalation.
↵a Incidence of protocol-defined thrombocytosis in patients with platelet counts > 600,000 cells/µl. ALT: alanine aminotransferase; LLN: lower limit of normal; OLE: open-label extension; ULN: upper limit of normal.
- Table 5.
The proportions of patients achieving selected efficacy endpoints at Week 24, Week 76, and Week 128. Values are n (%).
Week 24a Week 76b Week 128c 4 mg, n = 108 4:8 mg, n = 61 8 mg, n = 32 4 mg, n = 108 4:8 mg, n = 61 8 mg, n = 32 4/4 mg, n = 79 4:8/4 mg, n = 47 8/4 mg, n = 18 ACR20 87 (81) 38 (62) 24 (75) 77 (71) 41 (67) 19 (59) 61 (77) 27 (57) 13 (72) ACR50 53 (49) 12 (20) 18 (56) 53 (49) 25 (41) 14 (44) 46 (58) 14 (30) 8 (44) ACR70 29 (27) 5 (8) 9 (28) 31 (29) 11 (18) 8 (25) 22 (28) 8 (17) 4 (22) ACR/EULAR Boolean remission 17 (16) 1 (2) 3 (9) 21 (19) 5 (8) 3 (9) 15 (19) 3 (6) 3 (17) HAQ-DId 47 (44) 25 (41) 22 (69) 55 (51) 29 (48) 22 (69) 39 (49) 19 (40) 10 (56) DAS28-CRP ≤ 3.2 64 (59) 15 (25) 18 (56) 63 (58) 23 (38) 14 (44) 47 (59) 17 (36) 10 (56) DAS28-CRP < 2.6 43 (40) 5 (8) 13 (41) 56 (52) 13 (21) 7 (22) 37 (47) 12 (26) 7 (39) DAS28-ESR ≤ 3.2 38 (35) 5 (8) 12 (38) 45 (42) 15 (25) 9 (28) 39 (49) 12 (26) 5 (28) DAS28-ESR < 2.6 27 (25) 1 (2) 7 (22) 30 (28) 10 (16) 4 (13) 27 (34) 6 (13) 4 (22) CDAI ≤ 2.8 24 (22) 1 (2) 9 (28) 27 (25) 6 (10) 5 (16) 22 (28) 5 (11) 4 (22) SDAI ≤ 3.3 24 (22) 1 (2) 7 (22) 27 (25) 6 (10) 5 (16) 23 (29) 3 (6) 4 (22) 4/4 mg = 4 mg baricitinib for weeks 24–76 and weeks 76–128. 4:8/4 = 4 mg baricitinib through Week 28 or 32, then 8 mg through Week 76 and 4 mg for weeks 76–128. 8/4 mg = 8 mg baricitinib for weeks 24–76 and 4 mg for weeks 76–128.
↵a Observed data for patients entering OLE at Week 24 according to the treatment(s) received in the first OLE.
↵b Nonresponse imputed for discontinuing prior to Week 76, but not for dose escalation.
↵c Among patients entering additional OLE, nonresponse imputed for discontinuing prior to Week 128.
↵d Patients achieving minimum clinically important difference (≥ 0.3): improvement relative to Week 0. ACR: American College of Rheumatology; ACR20: ACR 20% improvement; ACR50: ACR 50% improvement; ACR70: ACR 70% improvement; CDAI: Clinical Disease Activity Index; DAS28-CRP: Disease Activity Score for 28 joints based on the C-reactive protein level; DAS28-ESR: DAS28 based on the erythrocyte sedimentation rate; EULAR: European League Against Rheumatism; HAQ-DI: Health Assessment Questionnaire–Disability Index; OLE: open-label extension; SDAI: Simplified Disease Activity Index.
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