This is a Phase 2b, outpatient, randomized, double-blinded (with a single-blind extension), placebo-controlled, dose-ranging, parallel-group study of baricitinib (LY3009104) in Japanese participants with active rheumatoid arthritis (RA) on background methotrexate (MTX) therapy. Baricitinib will be orally administered once a day with background methotrexate \[6 to 16 milligrams (mg)/week\] therapy for 12 weeks in the double-blind treatment period (1, 2, 4 or 8 mg/day, or placebo), and for 52 weeks in the single-blind extension period (4 or 8 mg/day).
Background Baricitinib, a novel, oral inhibitor of JAK1/JAK2 in the JAK-STAT signaling pathway, was evaluated in a blinded Phase 2b study in Japanese patients (pts) with rheumatoid arthritis (RA) with an inadequate response to methotrexate (MTX). Objectives The primary objective was to evaluate the efficacy of baricitinib as determined by the combined proportion of pts in the 4- and 8-mg dose groups who achieved an ACR20 response compared to placebo at Week 12. Methods Pts were randomized 2:1:1:1:1 to receive placebo (PBO) or 1 of 4 once-daily baricitinib doses (1, 2, 4, or 8 mg, respectively) for 12 weeks. Results Of the 145 pts randomized, 77% of the combined 4- and 8-mg (67% of the 4-mg and 88% of the 8-mg dose) groups achieved ACR20 responses compared with 31% of PBO-treated pts (p≤0.001) at Week 12. Significant differences versus PBO (p<0.05) were observed in the proportion of patients achieving ACR50 in a dose-dependent manner at Week 12 (Table). Greater benefit was also seen in the 4- and 8-mg groups compared to PBO using additional measures of efficacy including DAS28-CRP and HAQ-DI (Table). The rates of treatment-emergent adverse events (AEs) were similar in the PBO and combined baricitinib groups through 12 weeks (53% vs 55%, respectively). Most AEs were mild. Serious AEs were reported in 2 pts. There were no opportunistic infections and no deaths. Hemoglobin changes (median, in mmol/L) from baseline at 12 weeks were -0.13, 0.13, -0.10, 0.0, and -0.19 for PBO, 1-, 2-, 4-, and 8-mg groups, respectively. Neutrophil count changes (median, in109/L) from baseline at 12 weeks were -0.25, -0.32, -0.60, -1.12, and -0.48 for PBO, 1-, 2-, 4-, and 8-mg groups, respectively. Dose-related increases from baseline (median) in serum creatinine and both HDL- and LDL-cholesterol were observed at 12 weeks, with the largest changes observed for the 8-mg group. Dose-dependent changes in several bone metabolic markers were also observed. Conclusions Clinical efficacy was demonstrated in this Phase 2b study of baricitinib in combination with background MTX in Japanese RA pts through 12 weeks. Safety signals observed through 12 weeks were consistent with a previous study of baricitinib in non-Japanese pts with RA.1 (Table Presented).
<b>OBJECTIVE: </b>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).<b>METHODS: </b>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.<b>RESULTS: </b>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.<b>CONCLUSION: </b>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: Baricitinib (bari), a selective, transient and reversible inhibitor of Janus kinase (JAK)1 and JAK2, improved signs and symptoms of active rheumatoid arthritis (RA) in multiple phase 3 studies. Since erythropoietin (EPO) stimulates erythrocyte production via the JAK2 signaling pathway, haemoglobin (Hgb) and other haematologic parameters were thoroughly evaluated in the bari RA clinical development program. Objectives: To evaluate baseline and subsequent changes in Hgb and related laboratory parameters in RA patients (pts) treated with bari (2 or 4 mg once daily), placebo (PBO), or active comparator (methotrexate [MTX] or adalimumab [ADA]). Methods: Blood samples were analyzed at baseline and at each study visit for complete blood count, with more extensive phlebotomy at baseline (Wk 0) and Wks 12, 24, and 52 (Figure 1). Data were aggregated from completed Phase 2 and 3 RA studies and one ongoing long-term extension study. EPO and reticulocyte (RET) data were collected from a Phase 2 RA study in Japan. Results: Hgb levels below the gender-adjusted lower limit of normal (LLN) were often observed at baseline (25%). Small declines in Hgb were observed at Wk 2 and again at Wk 14 in bari (2 and 4 mg) and PBO-treated RA pts consistent with the volume and frequency of phlebotomy (Figure 1). Initial decreases in Hgb were accompanied by declines in RET counts in bari-treated RA pts. Subsequent increases in Hgb were associated with increases in RET after Wk 8 and statistically significant dose-dependent increases vs. PBO in total iron (Fe), total iron binding capacity (TIBC) and EPO. Treatment-emergent (TE) shifts in Hgb from normal to <LLN were very common in all groups without differences across groups except for ADA, which was associated with a lower incidence of TE low Hgb. TE Common Terminology Criteria for Adverse Events (CTCAE) shifts in Hgb from <grade 3 to ≥grade 3 (<4.9 and ≥4.0 mmol/L; <8.0g/dL and ≥6.5g/dL) were uncommon and occurred in similar proportions of RA pts across groups (Table 1). Permanent discontinuation of study drug due to CTCAE ≥grade 3 Hgb shifts was uncommon (0.2%). Conclusions: The proportions of RA pts with TE abnormally low Hgb did not differ significantly between bari and PBO. Reductions in Hgb, including to ≥grade 3, were generally not associated with adverse outcomes. Despite concerns about the impact of JAK2 inhibition on EPO signaling, following initial declines incident to phlebotomy, dose-dependent increases in EPO, Fe, and TIBC with return to baseline in RET and Hgb were observed with bari. This suggests that homeostatic mechanisms counterbalance the pharmacologic effect of JAK inhibition on EPO signaling and that bari treatment enhances iron utilisation markers associated with anaemia of chronic disease.
In Table 1, Phase II, NCT01469013 is mentioned twice. The second occurrence is unnecessary. In the Results section, page 9, last paragraph, the first sentence should read as follows: The herpes zoster IR was significantly higher for 4 mg compared to placebo (4.3 vs 1.0) and was numerically higher for 4 mg compared to 2 mg in 2 mg‐4 mg.extended. Bold face indicates words added for clarity. Table 4. Adverse events (AE) detail. • Three AE (EAIR ≥ 0.2) and their data have been added under the category Temporary interruption because of AE ≥ 0.2 EAIR for 4 mg.treated patients in placebo‐4 mg, n (EAIR). See below. • Under the category Permanent discontinuation because of AE ≥ 0.2 EAIR for 4 mg.treated patients in placebo‐4 mg, n (EAIR) in the row for infections and infestations, under the 2mg‐4mg‐extended set, for baricitinib 4 mg, the p value is < 0.05, indicating significance. Table 5. The corrected table is below. Changes are indicated in bold face. • HDL numbers have been corrected. • Units for hemoglobin were corrected to g/dl. • Hemoglobin < 10 g/dl: the corrected values for baricitinib 2 mg and baricitinib 4 mg under the Placebo‐2 mg.4 mg set are 33/462 (7.1) and 35/467 (7.5), respectively. • In the Placebo‐4 mg set, under Baricitinib 4 mg, the corrected values for ALT > 3x ULN are 15/987 (1.5), and for ALT ≥ 5x ULN, 7/988 (0.7) (Table Presented).
This is a Phase 2b, outpatient, randomized, double-blinded (with a single-blind extension), placebo-controlled, dose-ranging, parallel-group study of baricitinib (LY3009104) in Japanese participants with active rheumatoid arthritis (RA) on background methotrexate (MTX) therapy. Baricitinib will be orally administered once a day with background methotrexate \[6 to 16 milligrams (mg)/week\] therapy for 12 weeks in the double-blind treatment period (1, 2, 4 or 8 mg/day, or placebo), and for 52 weeks in the single-blind extension period (4 or 8 mg/day).
