NCT02706951

A Study Comparing Upadacitinib (ABT-494) Monotherapy to Methotrexate (MTX) Monotherapy in Adults With Rheumatoid Arthritis (RA) Who Have an Inadequate Response to MTX (SELECT-MONOTHERAPY)

Completed Phase 3 Results posted Last updated 30 January 2024

What this trial tests

Phase 3 trial testing Methotrexate in Rheumatoid Arthritis in 648 participants. Completed in 10 August 2022.

Timeline

23 March 2016

Primary endpoint
2 October 2017

10 August 2022

Quick facts

Lead sponsor	AbbVie
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	quadruple
Primary purpose	treatment
Enrollment	648
Start date	23 March 2016
Primary completion	2 October 2017
Estimated completion	10 August 2022
Sites	153 locations across Italy, Japan, Poland, Russia, Belgium, Estonia, Mexico, Bulgaria

Drugs / interventions tested

• Methotrexate — full drug profile →
• Upadacitinib — full drug profile →
• Placebo Upadacitinib — full drug profile →
• Placebo Methotrexate

Conditions studied

• Rheumatoid Arthritis — all drugs for Rheumatoid Arthritis →

Sponsor

AbbVie — full company profile →

Who can join

Adults 18 to 99, any sex, with Rheumatoid Arthritis. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response at Week 14 Primary · Baseline and week 14

The primary endpoint for United States (US)/Food and Drug Administration (FDA) regulatory purposes was ACR 20% response (ACR20) at Week 14. Participants who met the following 3 conditions for improvement from baseline were classified as meeting the ACR20 response criteria: 1. ≥ 20% improvement in 68-tender joint count; 2. ≥ 20% improvement in 66-swollen joint count; and 3. ≥ 20% improvement in at least 3 of the 5 following parameters: * Physician global assessment of disease activity * Patient global assessment of disease activity * Patient assessment of pain * Health Assessment

Group	Value	95% CI
Methotrexate	41.2	34.6 – 47.8
Upadacitinib 15 mg	67.7	61.5 – 74.0
Upadacitinib 30 mg	71.2	65.1 – 77.2

Percentage of Participants Achieving Low Disease Activity (LDA) Based on DAS28(CRP) at Week 14 Primary · Week 14

The primary endpoint for European Union (EU)/European Medicines Agency (EMA) regulatory purposes was low disease activity, based on a Disease Activity Score 28 (DAS28)-CRP score of ≤ 3.2 at Week 14. The DAS28 is a composite index used to assess rheumatoid arthritis disease activity, calculated based on the tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), Patient's Global Assessment of Disease Activity (0-100 mm), and hsCRP (in mg/L). Scores on the DAS28 range from 0 to approximately 10, where higher scores indicate more disease activity. A DA

Group	Value	95% CI
Methotrexate	19.4	14.2 – 24.7
Upadacitinib 15 mg	44.7	38.1 – 51.3
Upadacitinib 30 mg	53.0	46.4 – 59.7

Change From Baseline in in Disease Activity Score 28 (CRP) at Week 14 Secondary · Baseline to week 14

The DAS28 is a composite index used to assess rheumatoid arthritis disease activity, calculated based on the tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), Patient's Global Assessment of Disease Activity (0-100 mm), and hsCRP (in mg/L). Scores on the DAS28 range from 0 to approximately 10, where higher scores indicate more disease activity. A negative change from baseline in DAS28 (CRP) indicates improvement in disease activity.

Group	Value	95% CI
Methotrexate	-1.20	-1.39 – -1.01
Upadacitinib 15 mg	-2.29	-2.48 – -2.10
Upadacitinib 30 mg	-2.61	-2.80 – -2.41

Change From Baseline in Heath Assessment Questionnaire and Disability Index (HAQ-DI) at Week 14 Secondary · Baseline to week 14

The Health Assessment Questionnaire - Disability Index is a patient-reported questionnaire that measures the degree of difficulty a person has in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and errands and chores) over the past week. Participants assessed their ability to do each task on a scale from 0 (without any difficulty) to 3 (unable to do). Scores were averaged to provide an overall score ranging from 0 to 3, where 0 represents no disability and 3 represents very severe, high-dependency disability. A negative change from Ba

Group	Value	95% CI
Methotrexate	-0.32	-0.41 – -0.23
Upadacitinib 15 mg	-0.65	-0.73 – -0.56
Upadacitinib 30 mg	-0.73	-0.82 – -0.64

Change From Baseline in Short-Form 36 (SF-36) Physical Component Score (PCS) at Week 14 Secondary · Baseline to week 14

The Short Form 36-Item Health Survey (SF-36) Version 2 is a self-administered questionnaire that measures the impact of disease on overall quality of life during the past 4 weeks. The SF-36 consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The physical component score is a weighted combination of the 8 subscales with positive weighting for physical functioning, role-physical, bodily pain, and general health. The PCS was calculated using norm-based scoring so that 50 is the average score and

Group	Value	95% CI
Methotrexate	4.32	3.19 – 5.44
Upadacitinib 15 mg	8.28	7.17 – 9.40
Upadacitinib 30 mg	10.19	9.07 – 11.30

Percentage of Participants Achieving Clinical Remission (CR) Based on DAS28(CRP) at Week 14 Secondary · Week 14

The DAS28 is a composite index used to assess rheumatoid arthritis disease activity, calculated based on the tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), Patient's Global Assessment of Disease Activity (0-100 mm), and hsCRP (in mg/L). Scores on the DAS28 range from 0 to approximately 10, where higher scores indicate more disease activity. A DAS28 score less than 2.6 indicates clinical remission.

Group	Value	95% CI
Methotrexate	8.3	4.6 – 12.0
Upadacitinib 15 mg	28.1	22.1 – 34.1
Upadacitinib 30 mg	40.5	33.9 – 47.0

Change From Baseline in Duration of Morning Stiffness at Week 14 Secondary · Baseline to week 14

Participants were asked to indicate the time it took for them to get as limber as possible after awakening with morning stiffness over the past 7 days. A negative change from Baseline indicates improvement.

Group	Value	95% CI
Methotrexate	-53.03	-72.18 – -33.88
Upadacitinib 15 mg	-94.56	-113.57 – -75.54
Upadacitinib 30 mg	-102.34	-121.24 – -83.45

Percentage of Participants With an American College of Rheumatology 50% (ACR50) Response at Week 14 Secondary · Baseline and week 14

Participants who met the following 3 conditions for improvement from baseline were classified as meeting the ACR50 response criteria: 1. ≥ 50% improvement in 68-tender joint count; 2. ≥ 50% improvement in 66-swollen joint count; and 3. ≥ 50% improvement in at least 3 of the 5 following parameters: * Physician global assessment of disease activity * Patient global assessment of disease activity * Patient assessment of pain * Health Assessment Questionnaire - Disability Index (HAQ-DI) * High-sensitivity C-reactive protein (hsCRP).

Group	Value	95% CI
Methotrexate	15.3	10.5 – 20.1
Upadacitinib 15 mg	41.9	35.4 – 48.5
Upadacitinib 30 mg	52.1	45.4 – 58.8

Percentage of Participants With an American College of Rheumatology 70% (ACR70) Response at Week 14 Secondary · Baseline and week 14

Participants who met the following 3 conditions for improvement from baseline were classified as meeting the ACR50 response criteria: 1. ≥ 70% improvement in 68-tender joint count; 2. ≥ 70% improvement in 66-swollen joint count; and 3. ≥ 70% improvement in at least 3 of the 5 following parameters: * Physician global assessment of disease activity * Patient global assessment of disease activity * Patient assessment of pain * Health Assessment Questionnaire - Disability Index (HAQ-DI) * High-sensitivity C-reactive protein (hsCRP).

Group	Value	95% CI
Methotrexate	2.8	0.6 – 5.0
Upadacitinib 15 mg	22.6	17.0 – 28.1
Upadacitinib 30 mg	33.0	26.7 – 39.3

Adverse events — posted to ClinicalTrials.gov

Time frame: Up to 5 years. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Period 1: Methotrexate

Serious: 7/216 (3%)

Deaths: 0/216

Period 1: Upadacitinib 15 mg

Serious: 11/217 (5%)

Deaths: 0/217

Period 1: Upadacitinib 30 mg

Serious: 6/215 (3%)

Deaths: 0/215

Periods 1+2: Upadacitinib 15 mg

Serious: 95/318 (30%)

Deaths: 7/318

Periods 1+ 2: Upadacitinib 30 mg

Serious: 75/311 (24%)

Deaths: 5/311

Period 2: Upadacitinib 15 mg Switched From Upadacitinib 30 mg

Serious: 22/205 (11%)

Deaths: 4/205

Serious adverse events (177 terms)

Reaction	System	Period 1: Methotrexate	Period 1: Upadacitinib 15 mg	Period 1: Upadacitinib 30 mg	Periods 1+2: Upadacitinib …	Periods 1+ 2: Upadacitinib…	Period 2: Upadacitinib 15 …
Pneumonia	Infections and infestations	—	—	—	—	—	—
COVID-19 pneumonia	Infections and infestations	—	—	—	—	—	—
Atrial fibrillation	Cardiac disorders	—	—	—	—	—	—
Osteoarthritis	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—
Rheumatoid arthritis	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—
Myocardial infarction	Cardiac disorders	—	—	—	—	—	—
Bronchitis	Infections and infestations	—	—	—	—	—	—
Humerus fracture	Injury, poisoning and procedural complications	—	—	—	—	—	—
Coronary artery disease	Cardiac disorders	—	—	—	—	—	—
Colitis	Gastrointestinal disorders	—	—	—	—	—	—
COVID-19	Infections and infestations	—	—	—	—	—	—
Cellulitis	Infections and infestations	—	—	—	—	—	—
Herpes zoster	Infections and infestations	—	—	—	—	—	—
Urinary tract infection	Infections and infestations	—	—	—	—	—	—
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—
Angina pectoris	Cardiac disorders	—	—	—	—	—	—
Pancreatitis	Gastrointestinal disorders	—	—	—	—	—	—
Cholecystitis acute	Hepatobiliary disorders	—	—	—	—	—	—
Cholelithiasis	Hepatobiliary disorders	—	—	—	—	—	—
Arthritis bacterial	Infections and infestations	—	—	—	—	—	—
Sepsis	Infections and infestations	—	—	—	—	—	—
Road traffic accident	Injury, poisoning and procedural complications	—	—	—	—	—	—
Hyponatraemia	Metabolism and nutrition disorders	—	—	—	—	—	—
Osteonecrosis	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—
Adenocarcinoma of colon	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—	—	—	—

Other adverse events (17 terms — click to expand)

Reaction	System	Period 1: Methotrexate	Period 1: Upadacitinib 15 mg	Period 1: Upadacitinib 30 mg	Periods 1+2: Upadacitinib …	Periods 1+ 2: Upadacitinib…	Period 2: Upadacitinib 15 …
Blood creatine phosphokinase increased	Investigations	—	—	—	—	—	—
Nasopharyngitis	Infections and infestations	—	—	—	—	—	—
Urinary tract infection	Infections and infestations	—	—	—	—	—	—
Upper respiratory tract infection	Infections and infestations	—	—	—	—	—	—
Rheumatoid arthritis	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—
Bronchitis	Infections and infestations	—	—	—	—	—	—
Herpes zoster	Infections and infestations	—	—	—	—	—	—
Hypertension	Vascular disorders	—	—	—	—	—	—
Latent tuberculosis	Infections and infestations	—	—	—	—	—	—
Alanine aminotransferase increased	Investigations	—	—	—	—	—	—
COVID-19	Infections and infestations	—	—	—	—	—	—
Anaemia	Blood and lymphatic system disorders	—	—	—	—	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—
Rash	Skin and subcutaneous tissue disorders	—	—	—	—	—	—
Aspartate aminotransferase increased	Investigations	—	—	—	—	—	—
Neutropenia	Blood and lymphatic system disorders	—	—	—	—	—	—
Influenza	Infections and infestations	—	—	—	—	—	—

Most-reported serious reactions: Pneumonia, COVID-19 pneumonia, Atrial fibrillation, Osteoarthritis, Rheumatoid arthritis, Myocardial infarction, Bronchitis, Humerus fracture.

Data from ClinicalTrials.gov NCT02706951 adverse events section.

Sponsor's own description

The study objective of Period 1 of this study is to compare the safety and efficacy (signs and symptoms) of upadacitinib 30 mg once daily (QD) alone and upadacitinib 15 mg QD alone versus continuing MTX alone adults with moderately to severely active rheumatoid arthritis (RA) with an inadequate response to MTX.

The study objective of Period 2 is to evaluate the long term safety, tolerability, and efficacy of upadacitinib 30 mg QD and 15 mg QD in adults with RA who had completed Period 1.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. JAK inhibition as a therapeutic strategy for immune and inflammatory diseases.
   Schwartz DM, Kanno Y, Villarino A, Ward M, et al · · 2017 · cited 308× · PMID 29282366 · DOI 10.1038/nrd.2017.267
2. 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.
   Smolen JS, Pangan AL, Emery P, Rigby W, et al · · 2019 · cited 256× · PMID 31130260 · DOI 10.1016/s0140-6736(19)30419-2
3. Safety profile of upadacitinib in rheumatoid arthritis: integrated analysis from the SELECT phase III clinical programme.
   Cohen SB, van Vollenhoven RF, Winthrop KL, Zerbini CAF, et al · · 2021 · cited 163× · PMID 33115760 · DOI 10.1136/annrheumdis-2020-218510
4. Safety profile of upadacitinib over 15 000 patient-years across rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and atopic dermatitis.
   Burmester GR, Cohen SB, Winthrop KL, Nash P, et al · · 2023 · cited 150× · PMID 36754548 · DOI 10.1136/rmdopen-2022-002735
5. Upadacitinib: Mechanism of action, clinical, and translational science.
   Mohamed MF, Bhatnagar S, Parmentier JM, Nakasato P, et al · · 2024 · cited 85× · PMID 37984057 · DOI 10.1111/cts.13688
6. Future therapeutic targets in rheumatoid arthritis?
   Cheung TT, McInnes IB. · · 2017 · cited 77× · PMID 28451787 · DOI 10.1007/s00281-017-0623-3
7. Safety profile of upadacitinib in patients at risk of cardiovascular disease: integrated post hoc analysis of the SELECT phase III rheumatoid arthritis clinical programme.
   Fleischmann R, Curtis JR, Charles-Schoeman C, Mysler E, et al · · 2023 · cited 39× · PMID 37308218 · DOI 10.1136/ard-2023-223916
8. Janus Kinase Inhibitors Improve Disease Activity and Patient-Reported Outcomes in Rheumatoid Arthritis: A Systematic Review and Meta-Analysis of 24,135 Patients.
   Tóth L, Juhász MF, Szabó L, Abada A, et al · · 2022 · cited 35× · PMID 35163173 · DOI 10.3390/ijms23031246