BACKGROUND: Baricitinib is an oral, reversible, selective Janus kinase 1 and 2 inhibitor.
METHODS: In this phase III, double-blind 24-week study, 684 biologic disease-modifying antirheumatic drug (DMARD)-naïve patients with rheumatoid arthritis and inadequate response or intolerance to ≥1 conventional synthetic DMARDs were randomly assigned 1:1:1 to placebo or baricitinib (2 or 4 mg) once daily, stratified by region and the presence of joint erosions. Endpoint measures included American College of Rheumatology 20% response (ACR20, primary endpoint), Disease Activity Score (DAS28) and Simplified Disease Activity Index (SDAI) score ≤3.3.
RESULTS: More patients achieved ACR20 response at week 12 with baricitinib 4 mg than with placebo (62% vs 39%, p≤0.001). Compared with placebo, statistically significant improvements in DAS28, SDAI remission, Health Assessment Questionnaire-Disability Index, morning joint stiffness, worst joint pain and worst tiredness were observed. In a supportive analysis, radiographic progression of structural joint damage at week 24 was reduced with baricitinib versus placebo. Rates of adverse events during the treatment period and serious adverse events (SAEs), including serious infections, were similar among groups (SAEs: 5% for baricitinib 4 mg and placebo). One patient had an adverse event of tuberculosis (baricitinib 4 mg); one patient had an adverse event of non-melanoma skin cancer (baricitinib 4 mg). Two deaths and three major adverse cardiovascular events occurred (placebo). Baricitinib was associated with a decrease in neutrophils and increases in low-density and high-density lipoprotein.
CONCLUSIONS: In patients with rheumatoid arthritis and an inadequate response or intolerance to conventional synthetic DMARDs, baricitinib was associated with clinical improvement and inhibition of progression of radiographic joint damage.
TRIAL REGISTRATION NUMBER: NCT01721057; Results.
OBJECTIVE: To evaluate effects of tofacitinib or adalimumab on patient-reported outcomes (PROs) in patients with moderate to severe RA and inadequate responses to MTX.
METHODS: In this 12-month, phase 3, randomized controlled trial (ORAL Standard), patients (n = 717) receiving background MTX were randomized to tofacitinib 5 or 10 mg twice daily (BID), adalimumab 40 mg once every 2 weeks or placebo. PROs included HAQ-Disability Index, Patient Global Assessment of Arthritis, Patient Assessment of Arthritis Pain, health-related quality of life (Short Form-36 [SF-36]), fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue) and sleep (Medical Outcomes Study-Sleep).
RESULTS: At month 3, tofacitinib 10 mg BID treatment resulted in significant changes from baseline vs placebo across all PROs, sustained to month 12, with the highest number of patients reporting improvements ⩾minimum clinically important differences vs placebo (P < 0.05). Changes from baseline at month 3 with tofacitinib 5 mg BID and adalimumab were similar and statistically significant vs placebo across most PROs, excluding SF-36 Mental Component Score and Social Functioning, Role Emotional, and Mental Health domains, with significantly more patients reporting improvements ⩾minimum clinically important differences. Numbers Needed to Treat were lowest for tofacitinib 10 mg BID and similar between tofacitinib 5 mg BID and adalimumab.
CONCLUSION: Patients with moderate to severe RA and inadequate responses to MTX reported improvements across a broad range of PROs with tofacitinib 5 and 10 mg BID and adalimumab that were significantly superior to placebo.
BACKGROUND: In phase 2 studies, baricitinib, an oral Janus kinase 1 and 2 inhibitor, reduced disease activity in patients with rheumatoid arthritis who had not previously received treatment with biologic disease-modifying antirheumatic drugs (DMARDs).
METHODS: In this phase 3 study involving 527 patients with an inadequate response to or unacceptable side effects associated with one or more tumor necrosis factor inhibitors, other biologic DMARDs, or both, we randomly assigned the patients in a 1:1:1 ratio to baricitinib at a dose of 2 or 4 mg daily or placebo for 24 weeks. End points, tested hierarchically at week 12 to control type 1 error, were the American College of Rheumatology 20% (ACR20) response (primary end point), the Health Assessment Questionnaire-Disability Index (HAQ-DI) score, the 28-joint Disease Activity Score based on C-reactive protein level (DAS28-CRP), and a Simplified Disease Activity Index (SDAI) score of 3.3 or less (on a scale of 0.1 to 86.0, with a score of 3.3 or less indicating remission). Comparisons with placebo were made first with the 4-mg dose of baricitinib and then with the 2-mg dose.
RESULTS: Significantly more patients receiving baricitinib at the 4-mg dose than those receiving placebo had an ACR20 response at week 12 (55% vs. 27%, P<0.001). Differences between the higher-dose baricitinib group and the placebo group were also significant for the HAQ-DI score and the DAS28-CRP but not for an SDAI score of 3.3 or less. Adverse-event rates through 24 weeks were higher for patients receiving the 2-mg dose of baricitinib and those receiving the 4-mg dose than for patients receiving placebo (71% and 77%, respectively, vs. 64%), including infections (44% and 40%, vs. 31%). The rates of serious adverse events were 4%, 10%, and 7% in the three groups, respectively. Two nonmelanoma skin cancers and two major adverse cardiovascular events, including a fatal stroke, occurred in the higher-dose group. Baricitinib was associated with a small reduction in neutrophil levels and increases in serum creatinine and low-density lipoprotein cholesterol levels.
CONCLUSIONS: In patients with rheumatoid arthritis and an inadequate response to biologic DMARDs, baricitinib at a daily dose of 4 mg was associated with clinical improvement at 12 weeks. (Funded by Eli Lilly and Incyte; ClinicalTrials.gov number, NCT01721044.).
OBJECTIVES: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Here we investigated the effects of tofacitinib on patient-reported outcomes (PRO) in patients with active RA.
METHODS: Two, 6-month, double-blind, placebo-controlled Phase 2b studies were performed. The combination study evaluated patients with inadequate response to methotrexate who received tofacitinib 1-15 mg twice daily (BID), 20 mg once daily or placebo, on background methotrexate. In the monotherapy study, patients with inadequate response to disease-modifying anti-rheumatic drugs received tofacitinib 1-15 mg BID, adalimumab 40 mg once every other week or placebo. PROs measured were: Patient's Assessment of Arthritis Pain (PAAP), Patient's Assessment of Disease Activity, HAQ-DI, FACIT-F and SF-36.
RESULTS: In the combination study (n=507), significant improvements (p<0.05) versus placebo were observed at Week 12 in PAAP (visual analogue scale) and HAQ-DI for all tofacitinib groups. In the monotherapy study (n=384), significant improvements in PAAP were observed at Week 12 for tofacitinib 5, 10 and 15 mg BID, and in HAQ-DI for tofacitinib 3, 5, 10 and 15 mg BID. Significant improvements versus placebo were seen at Week 2 in PAAP (both studies) and HAQ‑DI (monotherapy study) with tofacitinib, and were maintained throughout each study. In both studies, improvements in several domains of the SF-36 in the tofacitinib groups were observed at Weeks 12 and 24.
CONCLUSIONS: In patients with active RA, tofacitinib, either in combination with methotrexate or as monotherapy, demonstrated rapid and sustained improvement in pain, physical functioning and health-related quality of life.
OBJECTIVE: To evaluate efficacy and safety, baricitinib [Janus kinase (JAK) 1/JAK2 inhibitor] was compared with placebo in Japanese patients with active rheumatoid arthritis (RA) despite background treatment with methotrexate (MTX).
METHODS: This was a phase IIB, double-blind, randomized, placebo-controlled study (clinicaltrials.gov: NCT01469013). Patients had moderate to severe active adult-onset RA despite stable treatment with MTX. Patients (n = 145) were randomized in a 2:1:1:1:1 ratio to placebo or 1 mg, 2 mg, 4 mg, or 8 mg oral baricitinib daily for 12 weeks. The primary analysis compared the combined 4/8-mg dose groups with placebo for the American College of Rheumatology (ACR) 20 response rate at 12 weeks. Other outcomes included additional measures of disease activity, physical function, laboratory abnormalities, and adverse events.
RESULTS: A significantly higher proportion of patients in the combined 4/8-mg baricitinib group (37/48, 77%) compared with the placebo group (15/49, 31%) had at least an ACR20 response after 12 weeks of treatment (p < 0.001). Significant improvements in disease activity, remission, and physical function were observed as early as Week 2 of treatment with baricitinib, particularly with daily doses of ≥ 4 mg. Only 1 patient receiving baricitinib discontinued because of an adverse event. Adverse event rates with baricitinib doses ≤ 4 mg daily were similar to placebo, but there was a higher incidence of adverse events and laboratory abnormalities in the 8-mg group.
CONCLUSION: In this phase II study, baricitinib was well tolerated and rapidly improved the signs, symptoms, and physical function of Japanese patients with active RA, supporting continued development of baricitinib (clinicaltrials.gov NCT01469013).
Background: In ph 2 studies, baricitinib (bari) improved disease activity with an acceptable safety profile in pts with active RA naïve to biologic DMARDs (bDMARDs).1,2 Objectives: To report patient-reported outcomes (PRO) from a ph 3 study of bari in pts with active RA on 1 or 2 conventional DMARDs (cDMARDs) and an inadequate response or intolerance to ≥1 TNF inhibitors. Methods: Pts were randomized 1:1:1 to placebo (PBO) or bari (2 or 4 mg) QD for 24 wks. PROs are listed in the table. Analyses included ANCOVA, logistic regression, and nonparametric methods and compared bari 2 or 4 mg vs. PBO. Results: 527 pts were randomized. Assessment of PROs at baseline revealed severe impairment of physical function (HAQ-DI: 1.7-1.8) and QoL. Bari 2 and 4 mg resulted in statistically significant improvements from baseline vs. PBO in most PROs at 24 wks (Table). Conclusions: In this ph 3 study of pts with active RA on cDMARDs and an inadequate response to bDMARDs, bari was associated with significant improvement in most PROs through 24 wks compared to PBO. (Table Presented).
INTRODUCTION: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis.
METHOD: In this 6-month, phase 3, randomized, placebo-controlled trial, 611 patients with inadequate response to disease-modifying anti-rheumatic drugs (DMARD-IR) were randomized 4:4:1:1 to receive: tofacitinib 5 mg BID or tofacitinib 10 mg BID for the duration of the study, or placebo for 3 months followed by tofacitinib 5 mg BID or tofacitinib 10 mg BID. Patient-reported outcomes (PROs) included: Patient Global Assessment of Disease Activity (PtGA); Patient Assessment of Pain (Pain); Health Assessment Questionnaire-Disability Index (HAQ-DI); Medical Outcomes Survey (MOS) Short Form-36 (SF-36); Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F); and MOS Sleep Scale. Time-to-event data (PtGA and Pain) were collected using an interactive voice response system daily diary (baseline through day 14).
RESULTS: At month 3, tofacitinib 5 and 10 mg BID demonstrated statistically significant improvements versus placebo in PtGA (both p < 0.0001), Pain (both p < 0.0001), HAQ-DI (both p < 0.0001), SF-36 Physical (p < 0.0001) and Mental (p < 0.05 [5 mg BID] and p < 0.0001 [10 mg BID]), Component Summary scores and all domain scores (p < 0.05-p < 0.0001) and FACIT-F (both p < 0.0001). Statistically significant changes from baseline in MOS Sleep Scale were reported for 10 mg BID (p < 0.05). Benefits of tofacitinib treatment were rapid in onset and significant improvements were reported at week 2 for PtGA, Pain and HAQ-DI, and differentiation from baseline was seen as early as 3 days after treatment initiation for interactive voice response system (IVRS) PtGA and IVRS Pain. The numbers needed to treat for patients to report changes greater than or equal to the minimum clinically important difference in PtGA, Pain, HAQ-DI, SF-36 Physical Component Summary score and FACIT-F ranged between 4.0-6.1 (5 mg BID) and 3.2-5.0 (10 mg BID).
CONCLUSION: Tofacitinib monotherapy in DMARD-IR patients resulted in statistically significant and clinically meaningful improvements in multiple PROs versus placebo at month 3, with sustained improvements over 6 months.
TRIAL REGISTRATION: Clinicaltrials.gov registration NCT00814307 , registered 22 December 2008.
BACKGROUND/PURPOSE: In phase 3 studies, baricitinib (bari) improved disease activity in patients (pts) with active RA and an inadequate response (IR) to conventional synthetic DMARDs1 or biologic DMARDs2. This abstract reports the 24-wk results from a 52-wk, global, phase 3, double-blind, placebo (PBO) and active-controlled study of bari in MTX-IR RA pts. METHODS: Pts with active RA (TJC≥6 & SJC≥6 & hsCRP≥6 mg/L) despite stable background MTX were randomized 3:3:2 to PBO, bari 4 mg once daily (QD), or adalimumab (ADA) 40 mg biweekly (Q2W), stratified by region and baseline joint erosion status. Non-responders were rescued from Wk 16. At Wk 24, pts on PBO switched to bari 4 mg QD. The primary endpoint was ACR20 response at Wk 12 for bari vs. PBO. Major secondary endpoints included comparisons of bari vs. ADA for ACR20 and change in DAS28-CRP at Wk 12. RESULTS: Of 1305 randomized pts, 89%, 94% and 93% completed Wk 24 in PBO, bari and ADA groups, respectively. Rescue rates were 26%, 7% and 12% for PBO, bari and ADA, respectively. ACR20 response at Wk 12 was higher for bari vs. PBO (70% vs. 40%, p≤.001 – Table 1). At Wks 12 and 24, statistically significant improvements in ACR 20/50/70 & HAQ-DI response rates, and DAS28, CDAI, and SDAI low disease activity and remission rates were seen for bari vs. PBO, many as early as Wk 1. Compared to ADA, bari was superior with respect to measures including ACR20 response and improvement in DAS28-CRP at Wk 12. Compared to PBO, daily diary measures of morning joint stiffness (MJS) duration and severity, worst tiredness, and worst joint pain were significantly improved in pts receiving bari, from as early as Wk 1. Rates of treatment-emergent adverse events (TEAEs), including infections, were higher for bari and ADA compared to PBO (Table 2). Compared to PBO, serious adverse events (SAE) rates were similar for bari and lower for ADA; serious infection rates were similar across groups. Two deaths occurred (bari), 1 pneumonia and 1 duodenal ulcer haemorrhage. Five malignancies were reported, 2 bari and 3 PBO. Three potential opportunistic infections occurred, 2 bari and 1 PBO; none were SAEs. One case of tuberculosis occurred (ADA). There were no GI perforations. Lab abnormalities were consistent with other phase 3 studies1,2; few led to discontinuation. CONCLUSION: In pts with active RA despite background MTX, once-daily oral bari was associated with significant clinical improvements compared to PBO and to ADA, with an acceptable safety and tolerability profile.
Baricitinib is an oral, reversible, selective Janus kinase 1 and 2 inhibitor.
METHODS:
In this phase III, double-blind 24-week study, 684 biologic disease-modifying antirheumatic drug (DMARD)-naïve patients with rheumatoid arthritis and inadequate response or intolerance to ≥1 conventional synthetic DMARDs were randomly assigned 1:1:1 to placebo or baricitinib (2 or 4 mg) once daily, stratified by region and the presence of joint erosions. Endpoint measures included American College of Rheumatology 20% response (ACR20, primary endpoint), Disease Activity Score (DAS28) and Simplified Disease Activity Index (SDAI) score ≤3.3.
RESULTS:
More patients achieved ACR20 response at week 12 with baricitinib 4 mg than with placebo (62% vs 39%, p≤0.001). Compared with placebo, statistically significant improvements in DAS28, SDAI remission, Health Assessment Questionnaire-Disability Index, morning joint stiffness, worst joint pain and worst tiredness were observed. In a supportive analysis, radiographic progression of structural joint damage at week 24 was reduced with baricitinib versus placebo. Rates of adverse events during the treatment period and serious adverse events (SAEs), including serious infections, were similar among groups (SAEs: 5% for baricitinib 4 mg and placebo). One patient had an adverse event of tuberculosis (baricitinib 4 mg); one patient had an adverse event of non-melanoma skin cancer (baricitinib 4 mg). Two deaths and three major adverse cardiovascular events occurred (placebo). Baricitinib was associated with a decrease in neutrophils and increases in low-density and high-density lipoprotein.
CONCLUSIONS:
In patients with rheumatoid arthritis and an inadequate response or intolerance to conventional synthetic DMARDs, baricitinib was associated with clinical improvement and inhibition of progression of radiographic joint damage.
