Elsevier

The Lancet

Volume 393, Issue 10188, 8–14 June 2019, Pages 2303-2311
The Lancet

Articles
Upadacitinib as monotherapy in patients with active rheumatoid arthritis and inadequate response to methotrexate (SELECT-MONOTHERAPY): a randomised, placebo-controlled, double-blind phase 3 study

https://doi.org/10.1016/S0140-6736(19)30419-2Get rights and content

Summary

Background

Upadacitinib, an oral Janus kinase (JAK)1-selective inhibitor, showed efficacy in combination with stable background conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in patients with rheumatoid arthritis who had an inadequate response to DMARDs. We aimed to evaluate the safety and efficacy of upadacitinib monotherapy after switching from methotrexate versus continuing methotrexate in patients with inadequate response to methotrexate.

Methods

SELECT-MONOTHERAPY was conducted at 138 sites in 24 countries. The study enrolled adults (≥18 years) who fulfilled the 2010 American College of Rheumatology (ACR)–European League Against Rheumatism (EULAR) classification criteria for rheumatoid arthritis. Patients with active rheumatoid arthritis despite stable methotrexate were randomly assigned 2:2:1:1 to switch to once-daily monotherapy of upadacitinib 15 mg or 30 mg or to continue methotrexate at their existing dose as blinded study drug; starting from week 14, patients assigned to continue methotrexate were switched to 15 mg or 30 mg once-daily upadacitinib per prespecified random assignment at baseline. The primary endpoints in this report are proportion of patients achieving 20% improvement in the ACR criteria (ACR20) at week 14, and proportion achieving low disease activity defined as 28-joint Disease Activity Score using C-reactive protein (DAS28[CRP]) of 3·2 or lower, both with non-responder imputation at week 14. Outcomes were assessed in patients who received at least one dose of study drug. This study is active but not recruiting and is registered with ClinicalTrials.gov, number NCT02706951.

Findings

Patients were screened between Feb 23, 2016, and May 19, 2017 and 648 were randomly assigned to treatment. 598 (92%) completed week 14. At week 14, an ACR20 response was achieved by 89 (41%) of 216 patients (95% CI 35–48) in the continued methotrexate group, 147 (68%) of 217 patients (62–74) receiving upadacitinib 15 mg, and 153 (71%) of 215 patients (65–77) receiving upadacitinib 30 mg (p<0·0001 for both doses vs continued methotrexate). DAS28(CRP) 3·2 or lower was met by 42 (19%) of 216 (95% CI 14–25) in the continued methotrexate group, 97 (45%) of 217 (38–51) receiving upadacitinib 15 mg, and 114 (53%) of 215 (46–60) receiving upadacitinib 30 mg (p<0·0001 for both doses vs continued methotrexate). Adverse events were reported in 102 patients (47%) on continued methotrexate, 103 (47%) on upadacitinib 15 mg, and 105 (49%) on upadacitinib 30 mg. Herpes zoster was reported by one (<1%) patient on continued methotrexate, three (1%) on upadacitinib 15 mg, and six (3%) on upadacitinib 30 mg. Three malignancies (one [<1%] on continued methotrexate, two [1%] on upadacitinib 15 mg), three adjudicated major adverse cardiovascular events (one [<1%] on upadacitinib 15 mg, two [<1%] on upadacitinib 30 mg), one adjudicated pulmonary embolism (<1%; upadacitinib 15 mg), and one death (<1%; upadacitinib 15 mg, haemorrhagic stroke [ruptured aneurysm]) were reported in the study.

Interpretation

Upadacitinib monotherapy showed statistically significant improvements in clinical and functional outcomes versus continuing methotrexate in this methotrexate inadequate-responder population. Safety observations were similar to those in previous upadacitinib rheumatoid arthritis studies.

Funding

AbbVie Inc, USA.

Introduction

The treatment goal for patients with rheumatoid arthritis is control of inflammation with subsequent preservation of joint structure and function. Methotrexate, a conventional synthetic disease modifying antirheumatic drug (csDMARD), is recommended as a first-line therapy.1, 2 However, one-half to two-thirds of patients receiving methotrexate monotherapy do not achieve satisfactory disease control.3, 4 In these patients, the addition of a second csDMARD, a biological DMARD (bDMARD), or a targeted synthetic DMARD (tsDMARD) is recommended.1, 2 Despite its proven effectiveness and safety, many patients are unable to tolerate methotrexate owing to its side-effects5, 6, 7 which might affect adherence and treatment outcomes.8 Moreover, monotherapy with advanced treatments is frequently used even in the case of bDMARDs, where optimal outcomes require concomitant methotrexate.9, 10 Therefore, therapies that can be used without concomitant methotrexate have an important place in the management of rheumatoid arthritis.

Research in context

Evidence before this study

We did a PubMed search using the terms “rheumatoid arthritis”, “Janus Kinase” and “clinical trial” (article type) on Nov 28, 2018, to identify reports of phase 3 efficacy and safety trials of Janus kinase (JAK) inhibitors in rheumatoid arthritis, and obtained 44 articles. Of these, one reported a phase 3 randomised controlled trial of a JAK inhibitor as monotherapy in patients with inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs; ORAL SOLO), and one, a phase 3 randomised controlled trial in patients with inadequate response to methotrexate (ORAL STRATEGY). ORAL SOLO compared 5 mg or 10 mg of tofacitinib twice daily with placebo, assessing 20% improvement in the American College of Rheumatology criteria (ACR20), health assessment questionnaire-disability index (HAQ-DI), and 28-joint disease activity score using erythrocyte sedimentation rate (DAS28[ESR]) at 3 months, showing significantly better responses on tofacitinib versus placebo for ACR20 and HAQ-DI, but not DAS28(ESR). ORAL STRATEGY assessed non-inferiority of 5 mg of tofacitinib twice-daily monotherapy to 5 mg of tofacitinib plus methotrexate or adalimumab plus methotrexate, for ACR50 at 6 months.

Added value of this study

ORAL SOLO and SELECT-MONOTHERAPY were done in similar patient populations with established disease (approximately 6–8 years of rheumatoid arthritis disease duration), and moderately-to-severely active disease as evidenced by mean DAS 28 using C-reactive protein, and swollen and tender joint counts. ORAL SOLO compared tofacitinib with placebo on discontinuation of methotrexate and other csDMARDs in all three study groups with a washout before receiving study drug or placebo, whereas in SELECT-MONOTHERAPY no washout was permitted; at baseline, patients who were assigned to receive upadacitinib monotherapy switched from their previous stable methotrexate to upadacitinib, while others continued with their previous dose of methotrexate as a blinded study drug.

The efficacy of once-daily 15 and 30 mg of upadacitinib in combination with background csDMARDs in patients with inadequate response to csDMARDs was assessed in the SELECT-NEXT study. This trial is the first study to assess upadacitinib as monotherapy. The responses with upadacitinib in both studies at 12–14 weeks were consistent, and upadacitinib monotherapy was superior to methotrexate continuation for clinical and functional improvements. In alignment with the goals of the treat-to-target strategy, the achievement of more stringent efficacy endpoints, such as remission and low disease activity by clinical disease activity index and simplified disease activity index, were assessed. Upadacitinib monotherapy resulted in 40–50% of patients with inadequate response to methotrexate achieving low disease activity, and almost 20% achieving stringent remission by week 14.

Implications of all the available evidence

The data from our trial are supportive of monotherapy with JAK inhibitors as a potential treatment option enabling disease control in patients with inadequate response to methotrexate, for whom combination treatment might be difficult for various reasons.

The Janus kinase (JAK) family of enzymes is involved in intracellular signalling of diverse cellular processes, such as cellular proliferation, apoptosis, migration, haemopoiesis, and induction of cytokines, and thus in the pathogenesis of inflammation and immune-mediated inflammatory diseases, such as rheumatoid arthritis.11, 12

Upadacitinib, an oral, reversible, JAK1-selective inhibitor has shown efficacy with rapid onset of action in patients with an inadequate response to csDMARDs or bDMARDs when given with stable background csDMARDs.13, 14 In this study, the safety and efficacy of upadacitinib monotherapy versus continuing methotrexate treatment in patients with an inadequate response to methotrexate were assessed.

Section snippets

Study design and participants

SELECT-MONOTHERAPY was done at 138 sites in 24 countries. The study enrolled patients with rheumatoid arthritis aged at least 18 years of age, who fulfilled the 2010 American College of Rheumatology (ACR)–European League Against Rheumatism (EULAR) classification criteria for rheumatoid arthritis.15 Eligible patients must have shown active disease despite treatment with methotrexate, defined as at least six swollen joints out of 66, at least six tender joints out of 68, and more than 3 mg/L

Results

Between Feb 23, 2016, and May 19, 2017, 996 patients were screened, of whom 648 were randomly assigned to treatment and received at least one dose of the study drug (figure 1). Most patients were recruited from Eastern Europe, North America, and South and Central America (table 1). Of the 648 patients enrolled, 598 (92%) completed study drug treatment through to the end of week 14 (figure 1). Patient demographics and disease activity were balanced across the treatment arms. Most patients were

Discussion

The combination of bDMARDs and tsDMARDs with csDMARDs, in particular methotrexate, is recommended for the management of rheumatoid arthritis.1, 2 However, intolerance or contraindications to methotrexate might present an obstacle to effective treatment for some patients and information from registries suggests that about 40% of patients in clinical practice have stopped methotrexate (or other csDMARDs) after receiving a new therapy.21, 22, 23 The parenteral administration of bDMARDs is another

Data sharing

AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymised, individual and trial-level data (analysis datasets), as well as other information (eg, protocols and Clinical Study Reports), provided the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications. These clinical trial data can be requested by any qualified researchers who

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