FormalPara Key Summary Points

Why carry out this study?

For most patients, rheumatoid arthritis (RA) is a life-long disease, and multiple successive therapies are required throughout life. Faster onset of action, which is one of the important factors in patient preference, could improve the probability of treatment adherence and therefore enable optimal clinical outcomes.

Baricitinib is an oral, selective inhibitor of Janus kinase which demonstrates clinical efficacy in patients with RA and inadequate response to one or more disease-modifying antirheumatic drugs.

This post hoc analysis evaluates the onset time of baricitinib 4 mg in Chinese patients with moderately to severely active RA who had an inadequate response to methotrexate.

What was learned from the study?

Baricitinib 4 mg demonstrated rapid and durable improvements in a variety of clinical measures for the treatment of Chinese patients with moderately to severely active RA.

Digital Features

This article is published with digital features, including a summary slide to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13214090.

Introduction

Rheumatoid arthritis (RA) is a systemic inflammatory autoimmune disease, affecting patients’ physical function and quality of life [1, 2]. According to 2019 European League Against Rheumatism guidelines, RA is a life-long disease that cannot currently be cured for most patients with RA, and multiple successive therapies are required throughout life [3]. Standard treatments for RA are disease-modifying antirheumatic drugs (DMARDs) including conventional synthetic DMARDS (csDMARDs), biologic DMARDs (bDMARDs), and targeted synthetic DMARDs (tsDMARDs). The ongoing development of new therapies has been improving the management of RA substantially in recent years [4, 5].

RA affects about 0.28–0.45% of the population in mainland China [6, 7]. On the basis of results of a large-scale cross-sectional observational study in China, 84.63% of patients with RA were prescribed at least one of the csDMARDs and 6.68% of patients received bDMARDs, but only 5.04% of patients achieved the remission status based on Simplified Disease Activity Index (SDAI) [7], indicating an unmet need for more therapeutic options superior to current treatments for patients with RA.

Baricitinib is an oral, selective inhibitor of the Janus kinase (JAK) family of protein tyrosine kinases with high potency and selectivity for JAK1 and JAK2. Baricitinib has been approved in many countries for treatment of moderately to severely active RA in patients with inadequate response to one or more DMARDs. Rapid onset of action was noted in baricitinib-treated patients with RA from different phase 3 studies where statistically significant improvements were seen in many efficacy measures as early as 1–4 weeks of treatment [8,9,10,11,12,13]. According to an observational, descriptive, exploratory, and cross-sectional study based on a discrete choice experiment, time to onset of action is one of the top three decision-making drivers for both rheumatologists and patients [14]. However, specific analyses to evaluate the onset time of efficacy in RA treatments were rarely performed and reported [13]. The current analysis evaluated onset time of baricitinib in Chinese patients who had moderately to severely active RA with inadequate response to methotrexate (MTX-IR), based on results of a phase 3 study RA-BALANCE [12, 15].

Methods

Study Design

RA-BALANCE was a randomized, double-blind, placebo-controlled, multicenter, phase 3 study that evaluated the efficacy and safety of baricitinib compared to placebo in patients with moderately to severely active RA. After screening [12], patients enrolled in RA-BALANCE were randomized 1:1 to receive orally baricitinib 4 mg once daily or placebo for 24 weeks (24-week, double-blind, placebo-controlled period) and patients receiving placebo were switched to baricitinib from the end of week 24 though week 52 (28-week, open-label period). Rescue treatment (open-label baricitinib 4 mg) was available from week 16 at the discretion of the investigator. Patients who completed the trial were eligible to enter a long-term extension study or a 28-day post-treatment follow-up period. More details about study design of RA-BALANCE have been reported previously [12]. This post hoc analysis evaluated the onset of action by comparing baricitinib 4 mg versus placebo during the 24-week, double-blind, placebo-controlled period on American College of Rheumatology 20% (ACR20) response, ACR core set values, disease activity, and patient-reported outcome (PRO) improvements in a Chinese subpopulation of RA-BALANCE.

This study complied with the 1964 Declaration of Helsinki and its later amendments, and ethics committee approval was obtained from each study center. Each enrolled patient provided written informed consent.

Outcome Parameters

Efficacy measures evaluated in this analysis included ACR20 response rate, high-sensitivity C-reactive protein (hsCRP), Health Assessment Questionnaire-Disability Index (HAQ-DI), patient’s assessment of pain, Physician’s Global Assessment (PGA) of Disease Activity, Patient’s Global Assessment (PtGA) of Disease Activity, swollen joint count based on 66 joints and tender joint count based on 68 joints, Disease Activity Score modified to include the 28 diarthrodial joint count (DAS28)-hsCRP, DAS28-erythrocyte sedimentation rate (ESR), SDAI, Clinical Disease Activity Index (CDAI), DAS28-hsCRP ≤ 3.2 response rate (low disease activity), and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) score. All efficacy measures were recorded at weeks 1, 2, 4, 8, 12, 14, 16, 20, and 24 except for FACIT-F recorded every 4 weeks from week 4 to week 24.

Statistical Analysis

For analysis of all categorical efficacy measures, patients who were rescued or discontinued study treatment, or with missing values, were thereafter defined as nonresponders (nonresponder imputation). Treatment comparisons of categorical efficacy variables were made using a logistic regression analysis. Fisher’s exact test was used in case the sample size requirements for the logistic regression model were not met. For continuous efficacy measures, modified last observation carried forward was used for the imputation of values at time points post rescue or discontinuation, or missing measures. Treatment comparisons of continuous efficacy and health outcomes variables were made using analysis of covariance with treatment group. All statistical tests of treatment effects were performed at two-sided significance levels of 0.05. All statistical analyses were performed using SAS® version 9.4.

Results

A total of 231 Chinese patients were randomized to receive placebo (n = 115) or baricitinib 4 mg once daily (n = 116). Patients were well balanced with respect to demographic characteristics and disease activity (Table 1). A detailed patient disposition has been reported previously [15].

Table 1 Demographic and baseline characteristics of study patients
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More patients achieved ACR20 response as early as week 1 (17.2% vs 8.7%, p = 0.048) in the baricitinib-treated group compared with placebo (Fig. 1). Statistically significant (p ≤ 0.05) improvements (change from baseline) in ACR core set values including hsCRP, HAQ-DI, patient’s assessment of pain, PGA of Disease Activity, PtGA of Disease Activity, swollen joint count, and tender joint count were observed in baricitinib-treated patients compared with placebo by 1–4 weeks of treatment (Fig. 1). For disease activity measures including DAS28-hsCRP, DAS28-ESR, SDAI, and CDAI, statistically significant (p ≤ 0.05) improvements were observed in baricitinib-treated patients compared to placebo as early as week 1 (Fig. 2). More patients (p ≤ 0.001) achieved DAS28-hsCRP ≤ 3.2 (low disease activity) in the baricitinib-treated group compared with placebo by 4 weeks of treatment. From week 4 (the first measure point after baseline), statistically significant (p ≤ 0.05) improvements in FACIT-F were observed in the baricitinib-treated group compared with placebo (Fig. 3). Furthermore, significant improvements in all efficacy measures were sustained through 24 weeks.

Fig. 1
figure 1

Improvements in ACR20 response rate and ACR core set values comparing baricitinib 4 mg with placebo through 24 weeks of treatment: a percentage of patients achieving ACR20; b–h LSM change in hsCRP, HAQ-DI, patient’s assessment of pain, PGA of Disease Activity, PtGA of Disease Activity, tender joint count based on 68 joints, and swollen joint count based on 66 joints. *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001 vs placebo; p values are based on logistic regression model in a and analysis of covariance model in b–h. Data presented in a are percentage of patients using NRI on modified intent-to-treat population. Data presented b–h in are LSM of change from baseline using modified last observation carried forward in the modified intent-to-treat population. ACR20 20% improvement in American College of Rheumatology criteria, HAQ-DI Health Assessment Questionnaire–Disability Index, hsCRP high-sensitivity C-reactive protein, LSM least squares mean, NRI nonresponder imputation, PGA Physician’s Global Assessment, PtGA Patient’s Global Assessment

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Fig. 2
figure 2

Improvements in disease activity results comparing baricitinib 4 mg with placebo through 24 weeks of treatment: a–d LSM change in SDAI, CDAI, DAS28-hsCRP, and DAS28-ESR; e percentage of patients achieving DAS28-hsCRP ≤ 3.2 (low disease activity). *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001 vs placebo; p values are based on analysis of covariance model in a–d and logistic regression model in e. Data presented in a–d are LSM of change from baseline using modified last observation carried forward in the modified intent-to-treat population. Data presented in e are percentage of patients using NRI on modified intent-to-treat population. CDAI Clinical Disease Activity Index, DAS28 Disease Activity Score modified to include the 28 diarthrodial joint count, ESR erythrocyte sedimentation rate, hsCRP high-sensitivity C-reactive protein, LSM least squares mean, NRI nonresponder imputation, SDAI Simplified Disease Activity Index

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Fig. 3
figure 3

Improvements in FACIT-F comparing baricitinib 4 mg with placebo through 24 weeks of treatment. *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001 vs placebo; p values are based on analysis of covariance model. Data presented are LSM of change from baseline using modified last observation carried forward in the modified intent-to-treat population. FACIT-F Functional Assessment of Chronic Illness Therapy-Fatigue, LSM least squares mean

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Discussion

Faster onset of action, which is one of the important factors in patient preference, could improve the probability of treatment adherence and therefore enable optimal clinical outcomes [14]. Actually, there is no unified definition of efficacy onset time in clinical treatment of RA. In clinical practice, the efficacy onset time was generally estimated by physicians according to the disease improvement description by patients and results of inflammatory marker tests. The onset of efficacy in this analysis was defined by the first study week at which significant (p ≤ 0.05) improvements compared to placebo were observed. According to the results, baricitinib 4 mg demonstrated rapid and durable improvements in a variety of clinical measures for Chinese patients with moderately to severely active RA.

For patients in the placebo group, 45 patients were rescued (rescue subgroup) and all during weeks 16–24; 58 patients were never rescued through week 52 but switched to baricitinib 4 mg at week 24 (switch subgroup). Change from baseline over time in DAS28-hsCRP, DAS28-ESR, SDAI, and CDAI for patients from the rescue subgroup and switch subgroup were analyzed. Although the rescue time of patients from the rescue subgroup were different (weeks 16–24), great improvements in all outcomes were observed after being rescued. Similarly, apparent improvements in all outcomes were observed for patients from the switch subgroup after week 24 when they switched to baricitinib 4 mg. Apparent improvements in DAS28-hsCRP, DAS28-ESR, SDAI, and CDAI observed in both rescue and switch subgroups after receiving baricitinib 4 mg signify the rapid onset of efficacy of baricitinib. However, improvements observed in the switch subgroup were less evident than those in the rescue subgroup, which is reasonable since patients rescued were less likely to respond to background MTX therapy and control the disease compared with patients switched.

Additionally, results of Chinese patients reported in this analysis are consistent with the results observed in the overall patient population of RA-BALANCE (Table 1 in the electronic supplementary material) [12]. In another pivotal phase 3 study of baricitinib, RA-BEAM (NCT01710358), the efficacy of baricitinib 4 mg versus placebo or adalimumab 40 mg biweekly was evaluated in the treatment of patients with RA and MTX-IR. Consistent with results in this analysis, rapid and sustained improvements were also seen for the baricitinib group compared to the placebo group in RA-BEAM [9]. Furthermore, the onset time of efficacy for baricitinib 4 mg was similar to that of the active control, adalimumab [9]. As reported for tofacitinib, an oral JAK inhibitor approved for the treatment of RA, significant (p ≤ 0.05) clinical differences were evident by 2–4 weeks of treatment with tofacitinib 5 mg twice daily compared to placebo and sustained during 6 months’ therapy for patients with RA and MTX-IR [16]. The comparable results in onset time of efficacy for these RA therapies support the rapid onset of baricitinib for RA treatment.

As to the limitations, this study has a relatively small sample size and short time frame for the placebo-controlled phase (24 weeks). In addition, the evaluation frequencies of the efficacy measures used in this analysis were on average less frequent than once a week, which led to a general range of onset time rather than a precise time point.

Conclusion

For Chinese patients who had moderately to severely active RA with MTX-IR, once-daily oral baricitinib 4 mg was associated with rapid and durable improvements compared to placebo in ACR20 response, ACR core set values, disease activity, and PROs.