A Phase 3 Study to Compare Upadacitinib to Abatacept in Subjects With Rheumatoid Arthritis on Stable Dose of Conventional Synthetic Disease- Modifying Antirheumatic Drugs (csDMARDs) Who Have an Inadequate Response or Intolerance to Biologic DMARDs

Conditions

Rheumatoid Arthritis (RA)

Keywords

Musculoskeletal Disease, Arthritis, Joint Disease, Anti-inflammatory agents, Antirheumatic agents

Brief summary

The study objective of Period 1 was to compare the safety and efficacy of upadacitinib 15 mg once daily (QD) to abatacept on a background of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) for the treatment of signs and symptoms of rheumatoid arthritis (RA) in biologic disease-modifying antirheumatic drug (bDMARD)-inadequate response or bDMARD-intolerant participants with moderately to severely active RA. The study objective of Period 2 is to evaluate the long-term safety, tolerability, and efficacy of upadacitinib 15 mg QD in participants with RA who had completed Period 1.

Detailed description

This is a Phase 3 multicenter study with 2 periods. Period 1 was a 24-week, randomized, double-blind, parallel-group, active-controlled period designed to compare the safety and efficacy of upadacitinib 15 mg and abatacept for the treatment of signs and symptoms of participants with moderately to severely active RA who had an inadequate response to or intolerance to bDMARD therapy and were currently on a stable dose of csDMARD(s) and had never received abatacept. Period 2 is an open-label, long-term extension study to evaluate the long-term safety, tolerability, and efficacy of upadacitinib 15 mg once a day (QD) in participants with RA who had completed Period 1.

Burmester GR, Deodhar A, Irvine AD, Panaccione R, Winthrop KL, Vleugels RA, Levy G, Suravaram S, Palac H, Wegrzyn L, Ford S, Meerwein S, Guttman-Yassky E.

2025-08-282 citations

10.1007/s12325-025-03328-y

Safety and Efficacy of Upadacitinib in Patients with Rheumatoid Arthritis Refractory to Biologic DMARDs: Results Through Week 216 from the SELECT-CHOICE Study

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10.1007/s40744-024-00694-x

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Rheumatology and Therapy2023-11-2020 citations

10.1007/s40744-023-00621-6

MACE and VTE across upadacitinib clinical trial programmes in rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis

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10.1136/rmdopen-2023-003392

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, Yamaoka K, Richez C, Palac H, Dilley D, Liu J, Strengholt S, Burmester G.

2023-06-1238 citations

10.1136/ard-2023-223916

Safety profile of upadacitinib over 15 000 patient-years across rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and atopic dermatitis

Gerd R Burmester, Stanley Cohen, Kevin Winthrop, Peter Nash, Alan D. Irvine et al. (14 authors)

RMD Open2023-02-01180 citations

10.1136/rmdopen-2022-002735

Safety of upadacitinib in Latin American patients with rheumatoid arthritis: an integrated safety analysis of the SELECT phase 3 clinical program.

Kakehasi AM, Radominski SC, Baravalle MD, Palazuelos FCI, Garcia-Garcia C, Arruda MS, Curi M, Liu J, Qiao M, Velez-Sanchez P, Vargas JI.

2023-01-303 citations

10.1007/s10067-023-06513-y

Patient-reported outcomes of upadacitinib versus abatacept in patients with rheumatoid arthritis and an inadequate response to biologic disease-modifying antirheumatic drugs: 12- and 24-week results of a phase 3 trial

Martin Bergman, Namita Tundia, Naomi Martin, J. Suboticki, Jayeshkumar Patel et al. (8 authors)

Arthritis Research & Therapy2022-06-2414 citations

10.1186/s13075-022-02813-x

Trial of Upadacitinib or Abatacept in Rheumatoid Arthritis

Andrea Rubbert‐Roth, Jeffrey Enejosa, Aileen L. Pangan, Boulos Haraoui, Maureen Rischmueller et al. (9 authors)

New England Journal of Medicine2020-10-14281 citations

10.1056/nejmoa2008250

Population Pharmacokinetics of Upadacitinib in Healthy Subjects and Subjects with Rheumatoid Arthritis: Analyses of Phase I and II Clinical Trials.

Klünder B, Mohamed MF, Othman AA, Othman AA.

2018-08-0161 citations

10.1007/s40262-017-0605-6

Interventions

DRUGAbatacept

IV infusion

DRUGPlacebo for abatacept (0.9% Sodium Chloride Injection or Solution for Infusion)

IV infusion

DRUGUpadacitinib

15 mg extended release tablet

DRUGPlacebo for upadacitinib

Film-coated tablet

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

No

Inclusion criteria

Main Inclusion Criteria: * Diagnosis of rheumatoid arthritis (RA) for ≥ 3 months who also fulfill the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for RA * Participants have been treated for ≥ 3 months prior to the screening visit with ≥ 1 bDMARD therapy, but continue to exhibit active RA or had to discontinue due to intolerability or toxicity, irrespective of treatment duration and have never received abatacept prior to the first dose of study drug * Participants have been receiving csDMARD therapy ≥ 3 months and on a stable dose for ≥ 4 weeks prior to the first dose of study drug. The following csDMARDs are allowed: methotrexate (MTX), sulfasalazine, hydroxychloroquine, chloroquine, and leflunomide. A combination of up to two background csDMARDs is allowed except the combination of MTX and leflunomide * Meets the following criteria: ≥ 6 swollen joints (based on 66 joint counts) and ≥ 6 tender joints (based on 68 joint counts) at Screening and Baseline Visits and high-sensitivity C-reactive protein (hsCRP) ≥ 3 mg/L at Screening Main

Exclusion criteria

* Prior exposure to any Janus kinase (JAK) inhibitor (including but not limited to upadacitinib, tofacitinib, baricitinib and filgotinib) * Prior exposure to abatacept * History of any arthritis with onset prior to age 17 years or current diagnosis of inflammatory joint disease other than RA. Current diagnosis of secondary Sjogren's Syndrome is permitted * Laboratory values meeting the following criteria within the Screening period prior to the first dose of study drug: serum aspartate transaminase \> 2 × upper limit of normal (ULN); serum alanine transaminase \> 2 × ULN; estimated glomerular filtration rate by simplified 4-variable Modification of Diet in Renal Disease formula \< 40 mL/minute/1.73 meter (m)\^2; total white blood cell count \< 2,500/ μL; absolute neutrophil count \< 1,500/μL; platelet count \< 100,000/μL; absolute lymphocyte count \< 800/μL; and hemoglobin \< 10 g/dL

Design outcomes

Primary

Measure	Time frame	Description
Change From Baseline in Disease Activity Score (DAS) 28 C-Reactive Protein (CRP) at Week 12 (Non-inferiority)	Baseline and Week 12	The Disease Activity Score (DAS) 28 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 high-sensitivity C-reactive protein (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 indicates improvement in disease activity.

Secondary

Measure	Time frame	Description
Change From Baseline in Disease Activity Score (DAS) 28 C-Reactive Protein (CRP) at Week 12 (Superiority)	Baseline and Week 12	The Disease Activity Score (DAS) 28 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 high-sensitivity C-reactive protein (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 indicates improvement in disease activity.
Percentage of Participants Achieving Clinical Remission (CR) Based on Disease Activity Score (DAS) 28 C-Reactive Protein (CRP) at Week 12 (Superiority)	At Week 12	The Disease Activity Score (DAS) 28 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 high-sensitivity C-reactive protein (hsCRP; in mg/L). Scores on the DAS28 range from 0 to approximately 10, where higher scores indicate more disease activity. A DAS 28 score less than 2.6 indicates clinical remission.

Countries

Argentina, Australia, Belgium, Brazil, Bulgaria, Canada, Czechia, Germany, Greece, Hungary, Ireland, Israel, Italy, Latvia, Mexico, Netherlands, New Zealand, Poland, Portugal, Puerto Rico, Romania, Russia, Slovakia, South Korea, Spain, Sweden, Switzerland, Turkey (Türkiye), United Kingdom, United States

Participant flow

Recruitment details

The study had a 24-week, randomized, double-blind, parallel-group, active-controlled period (Period 1) and an open-label long-term extension study (Period 2). Primary Cohort: Participants enrolled under Amendment 4 or 3.01, randomized to upadacitinib 15 mg once daily (QD) or abatacept intravenous (IV)/upadacitinib 15 mg QD.

Pre-assignment details

30 mg Cohort: Participants enrolled under Amendment 3, randomized to upadacitinib 30 mg QD or abatacept IV/upadacitinib 30 mg QD. Starting with Amendment 5, all participants received open-label upadacitinib 15 mg QD, including those currently on upadacitinib 30 mg QD. One participant who was a screen failure was randomized in error and did not receive study drug (and is not included in any data table).

Participants by arm

Arm	Count
Primary Cohort: Upadacitinib 15 mg QD Period 1: One 15 mg upadacitinib oral tablet QD for 24 weeks.	303
Primary Cohort: Abatacept Period 1: 500 mg (for body weight \<60 kg); 750 mg (for body weight 60-100 kg); and 1000 mg (for body weight \>100 kg) IV infusion at Baseline, Week 2, Week 4, Week 8, Week 12, Week 16 and Week 20.	309
30 mg Cohort: Upadacitinib 30 mg QD Period 1: One upadacitinib 30 mg oral tablet QD for 24 weeks.	21
30 mg Cohort: Abatacept Period 1: 500 mg (for body weight \<60 kg); 750 mg (for body weight 60-100 kg); and 1000 mg (for body weight \>100 kg) IV infusion at Baseline, Week 2, Week 4, Week 8, Week 12, Week 16 and Week 20.	23
Total	656

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003
Period 1	Adverse Event	7	7	0	1
Period 1	Lost to Follow-up	1	3	1	0
Period 1	Missing	1	0	0	0
Period 1	Other, Not Specified	10	12	2	1
Period 1	Withdrawal by Subject	6	10	0	0
Period 2	Adverse Event	20	11	1	2
Period 2	COVID-19 Infection	5	0	0	0
Period 2	COVID-19 Logistical Restrictions	1	0	0	0
Period 2	Lost to Follow-up	6	11	1	0
Period 2	Other, Not Specified	23	22	2	4
Period 2	Withdrawal by Subject	15	25	2	2

Baseline characteristics

Characteristic	Total	Primary Cohort: Upadacitinib 15 mg QD	Primary Cohort: Abatacept	30 mg Cohort: Upadacitinib 30 mg QD	30 mg Cohort: Abatacept
Age, Customized 40 - 64 years	443 Participants	209 Participants	207 Participants	10 Participants	17 Participants
Age, Customized < 40 years	68 Participants	30 Participants	31 Participants	5 Participants	2 Participants
Age, Customized ≥ 65 years	145 Participants	64 Participants	71 Participants	6 Participants	4 Participants
Disease Activity Score Based on C-reactive protein (CRP; DAS28 [CRP]) Score ≤ 5.1	153 Participants	79 Participants	67 Participants	4 Participants	3 Participants
Disease Activity Score Based on C-reactive protein (CRP; DAS28 [CRP]) Score > 5.1	499 Participants	224 Participants	241 Participants	15 Participants	19 Participants
Disease Activity Score Based on C-reactive protein (CRP; DAS28 [CRP]) Score Missing	4 Participants	0 Participants	1 Participants	2 Participants	1 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	238 Participants	112 Participants	117 Participants	4 Participants	5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	418 Participants	191 Participants	192 Participants	17 Participants	18 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Geographic Region Asia	8 Participants	4 Participants	4 Participants	0 Participants	0 Participants
Geographic Region Eastern Europe	166 Participants	77 Participants	77 Participants	6 Participants	6 Participants
Geographic Region North America	175 Participants	72 Participants	73 Participants	14 Participants	16 Participants
Geographic Region Other	20 Participants	9 Participants	11 Participants	0 Participants	0 Participants
Geographic Region South/Central America	197 Participants	98 Participants	99 Participants	0 Participants	0 Participants
Geographic Region Western Europe	90 Participants	43 Participants	45 Participants	1 Participants	1 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	3 Participants	1 Participants	2 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized Asian	11 Participants	5 Participants	6 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized Black or African American	26 Participants	7 Participants	14 Participants	2 Participants	3 Participants
Race/Ethnicity, Customized Multiple	4 Participants	2 Participants	2 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized Other	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized White	612 Participants	288 Participants	285 Participants	19 Participants	20 Participants
Sex: Female, Male Female	538 Participants	249 Participants	253 Participants	16 Participants	20 Participants
Sex: Female, Male Male	118 Participants	54 Participants	56 Participants	5 Participants	3 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk	EG005 affected / at risk	EG006 affected / at risk	EG007 affected / at risk	EG008 affected / at risk
deaths Total, all-cause mortality	1 / 332	2 / 303	0 / 21	7 / 276	16 / 271	0 / 19	0 / 17	1 / 12	0 / 12
other Total, other adverse events	149 / 332	174 / 303	13 / 21	221 / 276	221 / 271	17 / 19	15 / 17	9 / 12	7 / 12
serious Total, serious adverse events	7 / 332	12 / 303	4 / 21	68 / 276	64 / 271	4 / 19	6 / 17	3 / 12	2 / 12

Outcome results

Primary

Change From Baseline in Disease Activity Score (DAS) 28 C-Reactive Protein (CRP) at Week 12 (Non-inferiority)

The Disease Activity Score (DAS) 28 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 high-sensitivity C-reactive protein (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 indicates improvement in disease activity.

Time frame: Baseline and Week 12

Population: Full Analysis Set: all randomized participants who received at least one dose of study drug; multiple imputation was used for missing data. (The Statistical Analysis Plan (SAP) excluded the the 30 mg Cohorts from these efficacy analyses.)

Arm	Measure	Value (LEAST_SQUARES_MEAN)
Upadacitinib 15 mg	Change From Baseline in Disease Activity Score (DAS) 28 C-Reactive Protein (CRP) at Week 12 (Non-inferiority)	-2.52 units on a scale
Abatacept	Change From Baseline in Disease Activity Score (DAS) 28 C-Reactive Protein (CRP) at Week 12 (Non-inferiority)	-2.00 units on a scale

Comparison: In order to preserve Type I error, a step-down approach was used to test the primary and ranked secondary endpoints in a pre-specified order where statistical significance at the 0.05 level could be claimed for a lower ranked endpoint only if the previous endpoint in the sequence met the requirements of significance.p-value: <0.00195% CI: [-0.69, -0.35]ANCOVA

Secondary

Change From Baseline in Disease Activity Score (DAS) 28 C-Reactive Protein (CRP) at Week 12 (Superiority)

The Disease Activity Score (DAS) 28 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 high-sensitivity C-reactive protein (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 indicates improvement in disease activity.

Time frame: Baseline and Week 12

Population: Full Analysis Set: all randomized participants who received at least one dose of study drug; multiple imputation was used for missing data. (The Statistical Analysis Plan (SAP) excluded the the 30 mg Cohorts from these efficacy analyses.)

Arm	Measure	Value (LEAST_SQUARES_MEAN)
Upadacitinib 15 mg	Change From Baseline in Disease Activity Score (DAS) 28 C-Reactive Protein (CRP) at Week 12 (Superiority)	-2.52 units on a scale
Abatacept	Change From Baseline in Disease Activity Score (DAS) 28 C-Reactive Protein (CRP) at Week 12 (Superiority)	-2.00 units on a scale

Comparison: In order to preserve Type I error, a step-down approach was used to test the primary and ranked secondary endpoints in a pre specified order where statistical significance at the 0.05 level could be claimed for a lower ranked endpoint only if the previous endpoint in the sequence met the requirements of significance.p-value: <0.00195% CI: [-0.69, -0.35]ANCOVA

Secondary

Percentage of Participants Achieving Clinical Remission (CR) Based on Disease Activity Score (DAS) 28 C-Reactive Protein (CRP) at Week 12 (Superiority)

The Disease Activity Score (DAS) 28 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 high-sensitivity C-reactive protein (hsCRP; in mg/L). Scores on the DAS28 range from 0 to approximately 10, where higher scores indicate more disease activity. A DAS 28 score less than 2.6 indicates clinical remission.

Time frame: At Week 12

Population: Full Analysis Set: all randomized participants who received at least one dose of study drug; participants who prematurely discontinued study drug were considered non-responders after discontinuation. (The Statistical Analysis Plan (SAP) excluded the the 30 mg Cohorts from these efficacy analyses.)

Arm	Measure	Value (NUMBER)
Upadacitinib 15 mg	Percentage of Participants Achieving Clinical Remission (CR) Based on Disease Activity Score (DAS) 28 C-Reactive Protein (CRP) at Week 12 (Superiority)	30.0 percentage of participants
Abatacept	Percentage of Participants Achieving Clinical Remission (CR) Based on Disease Activity Score (DAS) 28 C-Reactive Protein (CRP) at Week 12 (Superiority)	13.3 percentage of participants

Comparison: In order to preserve Type I error, a step-down approach was used to test the primary and ranked secondary endpoints in a pre-specified order where statistical significance at the 0.05 level could be claimed for a lower ranked endpoint only if the previous endpoint in the sequence met the requirements of significance.p-value: <0.00195% CI: [10.4, 23.2]Cochran-Mantel-Haenszel

A Phase 3 Study to Compare Upadacitinib to Abatacept in Subjects With Rheumatoid Arthritis on Stable Dose of Conventional Synthetic Disease- Modifying Antirheumatic Drugs (csDMARDs) Who Have an Inadequate Response or Intolerance to Biologic DMARDs

Conditions

Keywords

Brief summary

Detailed description

Related papers

Interventions

Sponsors

Study design

Eligibility

Inclusion criteria

Exclusion criteria

Design outcomes

Primary

Secondary

Countries

Participant flow

Recruitment details

Pre-assignment details

Participants by arm

Withdrawals & dropouts

Baseline characteristics

Adverse events

Outcome results

Change From Baseline in Disease Activity Score (DAS) 28 C-Reactive Protein (CRP) at Week 12 (Non-inferiority)

Change From Baseline in Disease Activity Score (DAS) 28 C-Reactive Protein (CRP) at Week 12 (Superiority)

Percentage of Participants Achieving Clinical Remission (CR) Based on Disease Activity Score (DAS) 28 C-Reactive Protein (CRP) at Week 12 (Superiority)