SELECT-BEYOND: A Study to Compare Upadacitinib (ABT-494) to Placebo in Adults With Rheumatoid Arthritis on Stable Dose of Conventional Synthetic Disease-Modifying Antirheumatic Drugs (csDMARDs) With an Inadequate Response or Intolerance to Biologic DMARDs

• Sponsor: AbbVie (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02706847
• Collaborator: (none)
• Enrollment: 499
• Locations: 188
• Arms: 4
• Actual Duration (Months): 70.8
• Patients Per Site: 2.7
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The study objective of Period 1 (Day 1 to Week 24) is to compare the safety and efficacy of 30 mg once daily (QD) and 15 mg QD upadacitinib versus placebo for the treatment of signs and symptoms of participants with moderately to severely active RA who were on a stable dose of csDMARDs and had an inadequate response to or intolerance to at least 1 bDMARD.

The study objective of Period 2 (Week 24 to Week 260) is to evaluate the long-term safety, tolerability, and efficacy of upadacitinib 15 mg QD and 30 mg QD in participants with RA who completed Period 1.

Condition or Disease	Intervention/Treatment	Phase
Rheumatoid Arthritis	Drug: Upadacitinib; Drug: Placebo	Phase 3

Detailed Description

This study includes a 35-day screening period; a 24-week randomized, double-blind, parallel-group, placebo controlled treatment period (Period 1); a 236-week blinded long-term extension period (Period 2); and a 30-day follow-up period (call or visit).

Period 1 consists of a 12-week double-blind, placebo-controlled treatment phase plus a 12-week double-blind phase where all participants were to receive upadacitinib; at Week 12 participants assigned to placebo will be switched to upadacitinib according to their randomization assignment.

Participants who meet eligibility criteria will be randomized in a 2:2:1:1 ratio to one of four treatment groups:

• Group 1: Upadacitinib 30 mg QD (Day 1 to Week 12) → upadacitinib 30 mg QD (Week 12 and thereafter)

• Group 2: Upadacitinib 15 mg QD (Day 1 to Week 12) → upadacitinib 15 mg QD (Week 12 and thereafter)

• Group 3: Placebo (Day 1 to Week 12) → upadacitinib 30 mg QD (Week 12 and thereafter)

• Group 4: Placebo (Day 1 to Week 12) → upadacitinib 15 mg QD (Week 12 and thereafter)

Participants will continue stable dose of csDMARD therapy for the first 24 weeks of the study.

Participants who complete the Week 24 visit (end of Period 1) will enter the blinded long-term extension portion of the study, Period 2 and continue to receive the same dose of upadacitinib per original randomization assignment in a blinded manner. Starting at Week 24, at least 20% improvement in both swollen joint count (SJC) and tender joint count (TJC) compared to Baseline is required to remain on study drug. Starting at Week 24, initiation of or change in corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen, or adding or increasing doses in up to 2 csDMARDs (concomitant use of up to 2 csDMARDs except the combination of methotrexate and leflunomide) is allowed as per local label.

With the implementation of Protocol Amendment 4, all participants in the extension period will receive open-label upadacitinib 15 mg QD, including those currently on upadacitinib 30 mg QD.

Study Design

• Study Type: Interventional
• Actual Enrollment: 499 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Randomized, Double-Blind Study Comparing Upadacitinib (ABT-494) to Placebo on Stable Conventional Synthetic Disease-Modifying Anti-Rheumatic Drugs (csDMARDs) in Subjects With Moderately to Severely Active Rheumatoid Arthritis With Inadequate Response or Intolerance to Biologic DMARDs (bDMARDs)
• Actual Study Start Date: Mar 15, 2016
• Actual Primary Completion Date: Apr 3, 2017
• Actual Study Completion Date: Feb 8, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Upadacitinib 15 mg Period 1: Participants receive upadacitinib 15 mg once daily for 24 weeks. Period 2: Participants will continue on upadacitinib 15 mg once daily from Week 24 to Week 260.	Drug: Upadacitinib; Tablet; Oral; Other Names: ABT-494 Rinvoq
Experimental: Upadacitinib 30 mg Period 1: Participants receive upadacitinib 30 mg once daily for 24 weeks. Period 2: Participants continue on upadacitinib 30 mg once daily until implementation of Protocol Amendment 4, then participants begin to receive upadacitinib 15 mg once daily up to Week 260.	Drug: Upadacitinib; Tablet; Oral; Other Names: ABT-494 Rinvoq
Placebo Comparator: Placebo / Upadacitnib 15 mg Period 1: Participants receive placebo once daily for 12 weeks followed by upadacitinib 15 mg once daily for 12 weeks. Period 2: Participants will continue on upadacitinib 15 mg once daily from Week 24 to Week 260.	Drug: Upadacitinib; Tablet; Oral; Other Names: ABT-494 Rinvoq ; Drug: Placebo; Tablet; Oral
Placebo Comparator: Placebo / Upadacitnib 30 mg Period 1: Participants receive placebo once daily for 12 weeks followed by upadacitinib 30 mg once daily for 12 weeks. Period 2: Participants continue on upadacitinib 30 mg once daily until implementation of Protocol Amendment 4, then participants begin to receive upadacitinib 15 mg once daily up to Week 260.	Drug: Upadacitinib; Tablet; Oral; Other Names: ABT-494 Rinvoq ; Drug: Placebo; Tablet; Oral

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response at Week 12 [Baseline and Week 12]

   The primary endpoint for United States (US)/Food and Drug Administration (FDA) regulatory purposes was ACR 20% response (ACR20) at Week 12. Participants who met the following 3 conditions for improvement from baseline were classified as meeting the ACR20 response criteria: ≥ 20% improvement in 68-tender joint count; ≥ 20% improvement in 66-swollen joint count; and ≥ 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 Questionnaire - Disability Index (HAQ-DI) High-sensitivity C-reactive protein (hsCRP).

2. Percentage of Participants Achieving Low Disease Activity (LDA) Based on DAS28(CRP) at Week 12 [Week 12]

   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 12. 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 or equal to 3.2 indicates low disease activity.

Secondary Outcome Measures

1. Change From Baseline in in Disease Activity Score 28 (CRP) at Week 12 [Baseline and Week 12]

   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.

2. Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12 [Baseline and Week 12]

   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 Baseline in the overall score indicates improvement.

3. Change From Baseline in Short-Form 36 (SF-36) Physical Component Score (PCS) at Week 12 [Baseline and Week 12]

   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 the standard deviation equals 10. Higher scores are associated with better functioning/quality of life; a positive change from baseline score indicates an improvement.

4. Percentage of Participants With an American College of Rheumatology 50% (ACR50) Response at Week 12 [Baseline and Week 12]

   Participants who met the following 3 conditions for improvement from baseline were classified as meeting the ACR50 response criteria: ≥ 50% improvement in 68-tender joint count; ≥ 50% improvement in 66-swollen joint count; and ≥ 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).

5. Percentage of Participants With an American College of Rheumatology 70% (ACR70) Response at Week 12 [Baseline and Week 12]

   Participants who met the following 3 conditions for improvement from baseline were classified as meeting the ACR70 response criteria: ≥ 70% improvement in 68-tender joint count; ≥ 70% improvement in 66-swollen joint count; and ≥ 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).

6. Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response at Week 1 [Baseline and week 1]

   Participants who met the following 3 conditions for improvement from baseline were classified as meeting the ACR20 response criteria: ≥ 20% improvement in 68-tender joint count; ≥ 20% improvement in 66-swollen joint count; and ≥ 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 Questionnaire - Disability Index (HAQ-DI) High-sensitivity C-reactive protein (hsCRP).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 99 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Diagnosis of rheumatoid arthritis (RA) for≥ 3 months.

• Treated for ≥ 3 months with ≥ 1 bDMARD therapy, but continue to exhibit active RA or had to discontinue due to intolerability or toxicity, irrespective of treatment duration prior to the first dose of study drug.

• Participant has 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 both of 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.

• hsCRP ≥ 3mg/L at Screening Visit.

Exclusion Criteria:

• Prior exposure to any Janus kinase (JAK) inhibitor (including but not limited to tofacitinib, baricitinib, and filgotinib).

• History of any arthritis with onset prior to age 17 years or current diagnosis of inflammatory joint disease other than RA (including but not limited to gout, systemic lupus erythematosus, psoriatic arthritis, axial spondyloarthritis including ankylosing spondylitis and non-radiographic axial spondyloarthritis, reactive arthritis, overlap connective tissue diseases, scleroderma, polymyositis, dermatomyositis, fibromyalgia [currently with active symptoms]). Current diagnosis of secondary Sjogren's Syndrome is permitted.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Rheum Assoc of North Alabama /ID# 145959	Huntsville	Alabama	United States	35801
2	AZ Arthritis and Rheum Assoc /ID# 148593	Mesa	Arizona	United States	85202
3	AZ Arthritis and Rheum Researc /ID# 142816	Phoenix	Arizona	United States	85032-9306
4	AZ Arthritis and Rheum Researc /ID# 146075	Phoenix	Arizona	United States	85032-9306
5	AZ Arthritis and Rheum Researc /ID# 148592	Phoenix	Arizona	United States	85032-9306
6	Arizona Research Center, Inc. /ID# 142741	Phoenix	Arizona	United States	85053-4061
7	AZ Arthr & Rheum Research /ID# 155256	Prescott	Arizona	United States	86305
8	AZ Arthritis & Rheum Research /ID# 156090	Sun City	Arizona	United States	85351
9	NEA Baptist Clinic /ID# 149280	Jonesboro	Arkansas	United States	72401
10	Covina Arthritis Clinic /ID# 142794	Covina	California	United States	91722
11	Rheumatology Ctr of San Diego /ID# 153576	Escondido	California	United States	92025
12	St. Joseph Heritage Healthcare /ID# 149273	Fullerton	California	United States	92835
13	TriWest Research Associates- La Mesa /ID# 142792	La Mesa	California	United States	91942
14	Arthritis & Osteo Medical Ctr /ID# 142770	La Palma	California	United States	90623-1728
15	Valerius Med Grp & Res Ctr /ID# 142799	Los Alamitos	California	United States	90720-5402
16	Pacific Arthritis Ctr Med Grp /ID# 142783	Los Angeles	California	United States	90045
17	University of California, Los Angeles /ID# 148348	Los Angeles	California	United States	90095
18	Desert Medical Advances /ID# 142765	Palm Desert	California	United States	92260
19	Stanford University School of Med /ID# 142761	Stanford	California	United States	94305-2200
20	Robin K. Dore MD, Inc /ID# 150908	Tustin	California	United States	92780
21	Inland Rheum Clin Trials Inc. /ID# 142787	Upland	California	United States	91786
22	Medvin Clinical Research /ID# 142814	Whittier	California	United States	90606
23	Arthritis Assoc & Osteo Ctr /ID# 142809	Colorado Springs	Colorado	United States	80920
24	Denver Arthritis Clinic /ID# 142771	Denver	Colorado	United States	80230
25	New England Research Associates, LLC /ID# 142763	Bridgeport	Connecticut	United States	06606-1827
26	Delaware Arthritis /ID# 142803	Lewes	Delaware	United States	19958
27	Lakes Research, LLC /ID# 142755	Miami	Florida	United States	33014
28	Medallion Clinical Research Institute, LLC /ID# 142740	Naples	Florida	United States	34102
29	Omega Research Consultants /ID# 142780	Orlando	Florida	United States	32810
30	Millennium Research /ID# 142782	Ormond Beach	Florida	United States	32174
31	Arthritis Research of Florida /ID# 142811	Palm Harbor	Florida	United States	34684-2672
32	Arthritis Center, Inc. /ID# 142822	Palm Harbor	Florida	United States	34684
33	Advent Clinical Research /ID# 142817	Pinellas Park	Florida	United States	33781
34	St. Anthony Comprehsve Res Ins /ID# 148349	Saint Petersburg	Florida	United States	33705
35	University of South Florida /ID# 145611	Tampa	Florida	United States	33612
36	BayCare Medical Group, Inc. /ID# 142747	Tampa	Florida	United States	33614-7101
37	Lovelace Scientific Resources /ID# 142779	Venice	Florida	United States	34292
38	Jefrey D. Lieberman, MD, P.C. /ID# 151713	Decatur	Georgia	United States	30033
39	Marietta Rheumatology Assoc /ID# 151347	Marietta	Georgia	United States	30060
40	St. Luke's Clinic - Rheumatolo /ID# 150923	Boise	Idaho	United States	83702
41	Institute of Arthritis Res /ID# 142810	Idaho Falls	Idaho	United States	83404
42	Advanced Clinical Research /ID# 153089	Meridian	Idaho	United States	83642
43	Great Lakes Clinical Trials /ID# 148341	Chicago	Illinois	United States	60640
44	Clinical Investigation Special /ID# 149270	Skokie	Illinois	United States	60076
45	Springfield Clinic /ID# 142818	Springfield	Illinois	United States	62702-3749
46	Deerbrook Medical Associates /ID# 151712	Vernon Hills	Illinois	United States	60061
47	The Arthritis & Diabetes Clinic, Inc. /ID# 142793	Monroe	Louisiana	United States	71203
48	Vanguard Medical Research, LLC /ID# 153123	Shreveport	Louisiana	United States	71011
49	MMP Women's Health /ID# 145612	Portland	Maine	United States	04102
50	The Center for Rheumatology & /ID# 142742	Wheaton	Maryland	United States	20902
51	Mansfield Health Center /ID# 147628	Mansfield	Massachusetts	United States	02048
52	Clinical Pharmacology Study Gr /ID# 142744	Worcester	Massachusetts	United States	01605
53	June DO, PC /ID# 142756	Lansing	Michigan	United States	48910
54	North Mississippi Med Clinics /ID# 142781	Tupelo	Mississippi	United States	38801
55	Clayton Medical Associates dba Saint Louis Rheumatology /ID# 142745	Saint Louis	Missouri	United States	63119-3845
56	Barbara Caciolo, MD /ID# 142749	Saint Louis	Missouri	United States	63139-2338
57	Westroads Clinical Research /ID# 142802	Omaha	Nebraska	United States	68114
58	Dartmouth-Hitchcock Medical Center /ID# 145958	Lebanon	New Hampshire	United States	03756
59	Atlantic Coast Research /ID# 148347	Toms River	New Jersey	United States	08755
60	Ocean Rheumatology, PA /ID# 142785	Toms River	New Jersey	United States	08755
61	The Center for Rheumatology /ID# 142784	Albany	New York	United States	12206
62	North Shore University Hospital /ID# 142772	New Hyde Park	New York	United States	11040
63	Buffalo Rheumatology /ID# 142766	Orchard Park	New York	United States	14127
64	Joint & Muscle Research Instit /ID# 142797	Charlotte	North Carolina	United States	28204
65	DJL Clinical Research, PLLC /ID# 142769	Charlotte	North Carolina	United States	28210-8508
66	Cape Fear Arthritis Care /ID# 148344	Leland	North Carolina	United States	28451
67	Coastal Carolina Health Care /ID# 148351	New Bern	North Carolina	United States	28562
68	Shanahan Rheuma & Immuno /ID# 142812	Raleigh	North Carolina	United States	27617
69	Trinity Health Med Arts Clinic /ID# 142754	Minot	North Dakota	United States	58701
70	Cincinnati Rheumatic Disease Study Group, Inc. /ID# 142791	Cincinnati	Ohio	United States	45242-4468
71	STAT Research, Inc. /ID# 142821	Vandalia	Ohio	United States	45377-9464
72	Health Research Oklahoma /ID# 142751	Oklahoma City	Oklahoma	United States	73103-2400
73	Healthcare Research Consultant /ID# 142815	Tulsa	Oklahoma	United States	74135
74	East Penn Rheumatology Assoc /ID# 142790	Bethlehem	Pennsylvania	United States	18015
75	Clinical Research Ctr Reading /ID# 151714	Wyomissing	Pennsylvania	United States	19610
76	Columbia Arthritis Center /ID# 153728	Columbia	South Carolina	United States	29204
77	West Tennessee Research Inst /ID# 142739	Jackson	Tennessee	United States	38305
78	Arthritis Associates, PLLC /ID# 142774	Kingsport	Tennessee	United States	37660
79	Arthritis Associates, PLLC /ID# 155462	Kingsport	Tennessee	United States	37660
80	Dr. Ramesh Gupta /ID# 142767	Memphis	Tennessee	United States	38119
81	Tekton Research, Inc. /ID# 142805	Austin	Texas	United States	78745
82	Diagnostic Group Integrated He /ID# 148340	Beaumont	Texas	United States	77701
83	Arth and Osteo Clin Brazo Valley /ID# 148343	College Station	Texas	United States	77845
84	Arthritis Care and Diagnostic /ID# 151344	Dallas	Texas	United States	75231
85	Metroplex Clinical Research /ID# 142758	Dallas	Texas	United States	75231
86	Rheumatic Disease Clin Res Ctr /ID# 150914	Houston	Texas	United States	77004
87	Baylor College of Medicine /ID# 142753	Houston	Texas	United States	77030-3411
88	Rheumatology Clinic of Houston /ID# 150915	Houston	Texas	United States	77065
89	Houston Institute for Clin Res /ID# 142768	Houston	Texas	United States	77074
90	Pioneer Research Solutions, Inc. /ID# 151346	Houston	Texas	United States	77098-5294
91	Arthritis & Osteoporosis Assoc /ID# 147567	Lubbock	Texas	United States	79424
92	P&I Clinical Research /ID# 151345	Lufkin	Texas	United States	75904-3132
93	SW Rheumatology Res. LLC /ID# 142813	Mesquite	Texas	United States	75150
94	Trinity Universal Research Association /ID# 149278	Plano	Texas	United States	75024-5283
95	Arthritis & Osteo Ctr of S. TX /ID# 142773	San Antonio	Texas	United States	78232
96	Arthritis Clinic of Central TX /ID# 148346	San Marcos	Texas	United States	78666
97	DM Clinical Research /ID# 151007	Tomball	Texas	United States	77375
98	Arthritis & Osteoporosis Clinic /ID# 142760	Waco	Texas	United States	76710
99	Western Washington Arthritis C /ID# 142776	Bothell	Washington	United States	98021
100	Arthritis Northwest, PLLC /ID# 150924	Spokane	Washington	United States	99204
101	The Vancouver Clinic, INC. PS /ID# 147946	Vancouver	Washington	United States	98664
102	West Virginia Research Inst /ID# 153087	South Charleston	West Virginia	United States	25309
103	Aurora Rheumatology and Immunotherapy Center /ID# 142820	Franklin	Wisconsin	United States	53132
104	The Queen Elizabeth Hospital /ID# 142419	Woodville	South Australia	Australia	5011
105	Emeritus Research /ID# 142416	Camberwell	Victoria	Australia	3124
106	Medizinische Universität Wien /ID# 142424	Vienna	Wien	Austria	1090
107	Universitaetsklinik fuer Inner /ID# 142423	Graz		Austria	8036
108	Rheuma Zentrum Favoriten GmbH /ID# 142421	Vienna		Austria	1100
109	Rheuma-Zentrum Wien-Oberlaa /ID# 142425	Wien		Austria	1100
110	Wilhelminenspital der Stadt Wien /ID# 142422	Wien		Austria	1160
111	Cliniques Universitaires Saint Luc /ID# 142426	Woluwe-Saint-Lambert	Bruxelles-Capitale	Belgium	1200
112	Rhumaconsult SPRL /ID# 151378	Charleroi	Hainaut	Belgium	6000
113	UZ Gent /ID# 142429	Gent	Oost-Vlaanderen	Belgium	9000
114	ReumaClinic Genk /ID# 142431	Genk		Belgium	3600
115	AZ Damiaan /ID# 142427	Oostende		Belgium	8400
116	Ciads /Id# 142526	Winnipeg	Manitoba	Canada	R3N 0K6
117	Revmatologie MUDr. Klara Sirova /ID# 142536	Ostrava		Czechia	702 00
118	Medical Plus, s.r.o. /ID# 148345	Uherské Hradište		Czechia	686 01
119	MediTrials /ID# 151777	Tartu	Tartumaa	Estonia	50406
120	East Tallinn Central Hospital /ID# 142543	Tallinn		Estonia	10138
121	Kiljava Medical Research /ID# 142546	Hyvinkaa		Finland	05800
122	Paijat-Hame Central Hospital /ID# 149185	Lahti		Finland	15850
123	CHR Orleans - Hopital de la Source /ID# 142557	Orleans CEDEX 2	Centre-Val De Loire	France	45067
124	Hopital Universitaire Purpan /ID# 144697	Toulouse	Haute-Garonne	France	31059
125	Hopital Saint Eloi /ID# 142552	Montpellier CEDEX 5	Herault	France	34295
126	Centre Hospitalier Le Mans /ID# 145956	Le Mans CEDEX 9	Sarthe	France	72037
127	CHU Bordeaux-Hopital Pellegrin /ID# 144700	Bordeaux		France	33076
128	Centre Hospitalier Jean Rougie /ID# 142556	Cahors		France	46005
129	Hopital Edouard Herriot /ID# 144698	Lyon		France	69437
130	Rheumazentrum Ruhrgebiet /ID# 145600	Herne	Nordrhein-Westfalen	Germany	44649
131	Uniklinik Koln /ID# 142563	Köln	Nordrhein-Westfalen	Germany	50937
132	Charité Universitätsmedizin Campus Mitte /ID# 142559	Berlin		Germany	10117
133	Rheumaforschungszentrum II /ID# 142560	Hamburg		Germany	20095
134	Schoen Klinikum Hamburg Eilbek /ID# 142566	Hamburg		Germany	22081
135	Asklepios Klinik Altona /ID# 142561	Hamburg		Germany	22763
136	LMU Klinikum der Universität München /ID# 142564	Munich		Germany	80337
137	MVZ Planegg /ID# 142565	Planegg		Germany	82152
138	Knappschaftsklinikum Saar /ID# 142562	Püttlingen		Germany	66346
139	General Hospital of Athens Laiko /ID# 142579	Athens	Attiki	Greece	115 27
140	Vital Medical Center Orvosi es /ID# 142586	Veszprém	Veszprem	Hungary	8200
141	Revita Reumatologiai Rendelo /ID# 142590	Budapest		Hungary	1027
142	Debreceni Egyetem Kenezy Gyula Egyetemi Korhaz /ID# 142587	Debrecen		Hungary	4031
143	Bekes Megyei Pandy Kalman Korh /ID# 142588	Gyula		Hungary	5700
144	St Vincent's University Hosp /ID# 142593	Dublin		Ireland	D04 T6F4
145	Tel Aviv Sourasky Medical Ctr /ID# 142597	Tel Aviv-Yafo	Tel-Aviv	Israel	6423906
146	Bnai Zion Medical Center /ID# 151945	Haifa		Israel	3339419
147	The Lady Davis Carmel MC /ID# 142599	Haifa		Israel	3436212
148	Hanyang University Seoul Hospi /ID# 150883	Seoul	Seongdong-gu	Korea, Republic of	04763
149	Inha University Hospital /ID# 150881	Incheon		Korea, Republic of	22332
150	Seoul National University Hospital /ID# 142622	Seoul		Korea, Republic of	03080
151	LTD M+M Centers /ID# 142624	Adazi		Latvia	2164
152	P. Stradins Clinical Univ Hosp /ID# 142623	Riga		Latvia	LV-1002
153	Arthritis Clinic Ltd /ID# 153560	Riga		Latvia	LV-1050
154	Timaru Medical Specialists Ltd /ID# 142657	Timaru		New Zealand	7910
155	WroMedica I. Bielicka, A. Strzalkowska s.c. /ID# 142665	Wrocław	Dolnoslaskie	Poland	51-685
156	Pratia MCM Krakow /ID# 142664	Krakow	Malopolskie	Poland	30-510
157	Centrum Medyczne Pratia Warszawa /ID# 142667	Warsaw	Mazowieckie	Poland	01-869
158	Centrum Medyczne AMED Warszawa Targowek /ID# 142663	Warszawa	Mazowieckie	Poland	03-291
159	Centrum Medyczne Pratia Gdynia /ID# 142666	Gdynia	Pomorskie	Poland	81-338
160	Centro Hospitalar De Vila Nova /ID# 142670	Vila Nova De Gaia	Porto	Portugal	4434-502
161	Centro Hospitalar Lisboa Norte, EPE /ID# 142668	Lisboa		Portugal	1649-035
162	GCM Medical Group /ID# 142671	San Juan		Puerto Rico	00909
163	Family Outpatient clinic#4,LLC /ID# 150910	Korolev	Moskva	Russian Federation	141060
164	ARTROMAC n.o. /ID# 142692	Kosice		Slovakia	040 11
165	Nemocnica Kosice Saca, a.s. /ID# 142693	Kosice		Slovakia	040 15
166	Narodny ustav reumatickych chorob Piestany /ID# 142691	Pieštany		Slovakia	921 12
167	H. Un. Marques de Valdecilla /ID# 142706	Santander	Cantabria	Spain	39008
168	Hospital Regional de Malaga /ID# 142707	Málaga	Malaga	Spain	29009
169	Comple Hosp Univ de A Coruna /ID# 142708	A Coruna		Spain	15006
170	Hospital Clin Univ San Carlos /ID# 142711	Madrid		Spain	28040
171	Clinica Gaias /ID# 142709	Santiago de Compostela		Spain	15702
172	Hospital Universitario La Fe /ID# 142716	Valencia		Spain	46026
173	Sahlgrenska University Hosp /ID# 142720	Goteborg		Sweden	413 45
174	Capio Movement Halmstad /ID# 148236	Halmstad		Sweden	302 33
175	Orebro Universitetssjukhuset /ID# 142718	Orebro		Sweden	70185
176	Vastmanlands Sjukhus /ID# 142721	Vasteras		Sweden	72189
177	Universitaetsspital Basel /ID# 145610	Basel		Switzerland	4031
178	HFR Fribourg - Hopital Canton /ID# 142723	Fribourg		Switzerland	1708
179	Hacettepe University Medical Faculty /ID# 142729	Ankara		Turkey	06100
180	Ankara Ataturk Training & Res /ID# 142727	Ankara		Turkey	06800
181	Ondokuz mayis University Facul /ID# 142728	Samsun		Turkey	55139
182	Whipps Cross Univ Hospital /ID# 145957	London	London, City Of	United Kingdom	E11 1NR
183	The Royal Free Hospital /ID# 142733	London	London, City Of	United Kingdom	NW3 2QG
184	Mid Essex Hospitals NHS Trust /ID# 148992	Chelmsford		United Kingdom	CM1 7ET
185	Western General Hospital /ID# 142732	Edinburgh		United Kingdom	EH4 2XU
186	West Suffolk Hospital /ID# 148993	Ipswich		United Kingdom	IP33 2QZ
187	Queen Alexandra Hospital /ID# 142735	Portsmouth		United Kingdom	PO6 3LY
188	Arrowe Park Hospital /ID# 148991	Wirral		United Kingdom	CH49 5PE

Sponsors and Collaborators

• AbbVie

Investigators

• Study Director: AbbVie Inc., AbbVie

Study Documents (Full-Text)

• Study Protocol - Oct 26, 2017
• Statistical Analysis Plan - Jun 29, 2017

More Information

Additional Information:

• Related Info.

Publications

• Genovese MC, Fleischmann R, Combe B, Hall S, Rubbert-Roth A, Zhang Y, Zhou Y, Mohamed MF, Meerwein S, Pangan AL. Safety and efficacy of upadacitinib in patients with active rheumatoid arthritis refractory to biologic disease-modifying anti-rheumatic drugs (SELECT-BEYOND): a double-blind, randomised controlled phase 3 trial. Lancet. 2018 Jun 23;391(10139):2513-2524. doi: 10.1016/S0140-6736(18)31116-4. Epub 2018 Jun 18.

• Responsible Party: AbbVie
• ClinicalTrials.gov Identifier: NCT02706847
• Other Study ID Numbers: M13-542; 2015-003335-35
• First Posted: Mar 11, 2016
• Last Update Posted: Feb 25, 2022
• Last Verified: Feb 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by AbbVie: Musculoskeletal Disease; Arthritis; Joint Disease; Anti-inflammatory agents; Antirheumatic agents; ABT-494; upadacitinib
• Additional relevant MeSH terms: Arthritis; Arthritis, Rheumatoid; Upadacitinib

Study Results

Participant Flow

Recruitment Details	Participants were enrolled at 152 sites located in 26 countries from March 2016 to January 2017. Eligible participants had active rheumatoid arthritis (RA) and previous inadequate response or intolerance to biologic disease-modifying anti-rheumatic drugs (bDMARDs), and were receiving concomitant background conventional synthetic DMARDS (csDMARDs).
Pre-assignment Detail	Participants were randomized in a 1:1:2:2 ratio to one of the 4 treatment groups below. Randomization was stratified by the number of previous bDMARDs used and geographic region. The study is ongoing and data up to Week 24 are reported here.

Arm/Group Title	Placebo / Upadacitinib 15 mg	Placebo / Upadacitinib 30 mg	Upadacitinib 15 mg	Upadacitinib 30 mg
Arm/Group Description	Participants randomized to receive placebo once daily for 12 weeks followed by upadacitinib 15 mg once daily from Week 12 to Week 260.	Participants randomized to receive placebo once daily for 12 weeks followed by upadacitinib 30 mg once daily from Week 12 to Week 260.	Participants randomized to receive upadacitinib 15 mg once daily for 12 weeks followed by upadacitinib 15 mg once daily from Week 12 to Week 260.	Participants randomized to receive upadacitinib 30 mg once daily for 12 weeks followed by upadacitinib 30 mg once daily from Week 12 to Week 260.
Period Title: Day 1 to Week 12
STARTED	85	84	165	165
Received Study Treatment	85	84	164	165
COMPLETED	75	76	157	149
NOT COMPLETED	10	8	8	16
Period Title: Day 1 to Week 12
STARTED	75	76	157	149
Received Study Treatment	72	75	156	148
COMPLETED	72	74	153	135
NOT COMPLETED	3	2	4	14

Baseline Characteristics

Arm/Group Title	Placebo	Upadacitinib 15 mg	Upadacitinib 30 mg	Total
Arm/Group Description	Participants received placebo once daily for 12 weeks.	Participants received upadacitinib 15 mg once daily for 12 weeks.	Participants received upadacitinib 30 mg once daily for 12 weeks.	Total of all reporting groups
Overall Participants	169	164	165	498
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57.6 (11.39)	56.3 (11.34)	57.3 (11.55)	57.1 (11.42)
Age, Customized (Count of Participants)
< 40 years	14 8.3%	11 6.7%	14 8.5%	39 7.8%
40 - 64 years	106 62.7%	115 70.1%	103 62.4%	324 65.1%
≥ 65 years	49 29%	38 23.2%	48 29.1%	135 27.1%
Sex: Female, Male (Count of Participants)
Female	143 84.6%	137 83.5%	138 83.6%	418 83.9%
Male	26 15.4%	27 16.5%	27 16.4%	80 16.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	24 14.2%	34 20.7%	28 17%	86 17.3%
Not Hispanic or Latino	145 85.8%	130 79.3%	137 83%	412 82.7%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
White	143 84.6%	142 86.6%	148 89.7%	433 86.9%
Black or African American	21 12.4%	17 10.4%	10 6.1%	48 9.6%
American Indian/Alaska Native	0 0%	3 1.8%	4 2.4%	7 1.4%
Native Hawaiian or other Pacific Islander	0 0%	0 0%	1 0.6%	1 0.2%
Asian	5 3%	2 1.2%	2 1.2%	9 1.8%
Geographic Region (Count of Participants)
North America	110 65.1%	109 66.5%	109 66.1%	328 65.9%
Western Europe	33 19.5%	32 19.5%	32 19.4%	97 19.5%
Eastern Europe	23 13.6%	22 13.4%	22 13.3%	67 13.5%
Asia	0 0%	0 0%	1 0.6%	1 0.2%
Other	3 1.8%	1 0.6%	1 0.6%	5 1%
Prior Failed Biological Disease-modifying Anti-rheumatic Drugs (bDMARDs) (Count of Participants)
Stratum 1	117 69.2%	116 70.7%	111 67.3%	344 69.1%
Stratum 2	52 30.8%	48 29.3%	54 32.7%	154 30.9%
Duration of RA Diagnosis (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	14.5 (9.22)	12.4 (9.38)	12.7 (9.65)	13.2 (9.45)
Concomitant Conventional Synthetic DMARD Use at Baseline (Count of Participants)
Methotrexate alone	122 72.2%	118 72%	124 75.2%	364 73.1%
Methotrexate and other csDMARD	17 10.1%	19 11.6%	11 6.7%	47 9.4%
csDMARD other than methotrexate	29 17.2%	24 14.6%	29 17.6%	82 16.5%
Missing	1 0.6%	3 1.8%	1 0.6%	5 1%
Tender Joint Count (tender joints) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [tender joints]	28.5 (15.27)	27.8 (16.31)	27.3 (15.23)	27.9 (15.58)
Swollen Joint Count (swollen joints) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [swollen joints]	16.3 (9.58)	17.0 (10.75)	17.2 (11.37)	16.8 (10.57)
Patient's Assessment of Pain (mm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mm]	68.9 (21.03)	68.2 (19.77)	65.3 (20.67)	67.5 (20.52)
Patient's Global Assessment of Disease Activity (mm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mm]	66.3 (22.72)	67.2 (19.60)	64.7 (21.05)	66.1 (21.15)
Physician's Global Assessment of Disease Activity (mm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mm]	66.9 (16.92)	68.7 (16.59)	66.4 (15.63)	67.3 (16.39)
Health Assessment Questionnaire - Disability Index (HAQ-DI) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	1.6 (0.60)	1.7 (0.64)	1.6 (0.59)	1.6 (0.61)
High-sensitivity C-reactive Protein (hsCRP) (mg/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/L]	16.3 (21.10)	16.2 (18.62)	16.0 (21.23)	16.2 (20.32)
Disease Activity Score 28 Based on CRP (DAS28[CRP]) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	5.8 (1.00)	5.9 (0.95)	5.8 (0.89)	5.8 (0.95)

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response at Week 12
Description	The primary endpoint for United States (US)/Food and Drug Administration (FDA) regulatory purposes was ACR 20% response (ACR20) at Week 12. Participants who met the following 3 conditions for improvement from baseline were classified as meeting the ACR20 response criteria: ≥ 20% improvement in 68-tender joint count; ≥ 20% improvement in 66-swollen joint count; and ≥ 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 Questionnaire - Disability Index (HAQ-DI) High-sensitivity C-reactive protein (hsCRP).
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Full analysis set; participants who prematurely discontinued from study drug prior to Week 12 or for whom ACR data were missing at Week 12 were considered non-responders.

Arm/Group Title	Placebo	Upadacitinib 15 mg	Upadacitinib 30 mg
Arm/Group Description	Participants received placebo once daily for 12 weeks.	Participants received upadacitinib 15 mg once daily for 12 weeks.	Participants received upadacitinib 30 mg once daily for 12 weeks.
Measure Participants	169	164	165
Number (95% Confidence Interval) [percentage of participants]	28.4 16.8%	64.6 39.4%	56.4 34.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 15 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure.
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	The adjusted p-value under multiplicity control is reported, with significance achieved if the adjusted p-value is less than 0.05.
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusted for the stratification factor of prior biological DMARD use (stratum 1 vs stratum 2).
Method of Estimation	Estimation Parameter	Response Rate Difference
	Estimated Value	36.2
	Confidence Interval	(2-Sided) 95%; 26.2 to 46.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 30 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure.
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	The adjusted p-value under multiplicity control is reported, with significance achieved if the adjusted p-value is less than 0.05.
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusted for the stratification factor of prior biological DMARD use (stratum 1 vs stratum 2).
Method of Estimation	Estimation Parameter	Response Rate Difference
	Estimated Value	28.0
	Confidence Interval	(2-Sided) 95%; 17.8 to 38.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

2. Primary Outcome

Title	Percentage of Participants Achieving Low Disease Activity (LDA) Based on DAS28(CRP) at Week 12
Description	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 12. 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 or equal to 3.2 indicates low disease activity.
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

Full analysis set; participants who prematurely discontinued from study drug prior to Week 12 or for whom DAS28 data were missing at Week 12 were considered non-responders.

Arm/Group Title	Placebo	Upadacitinib 15 mg	Upadacitinib 30 mg
Arm/Group Description	Participants received placebo once daily for 12 weeks.	Participants received upadacitinib 15 mg once daily for 12 weeks.	Participants received upadacitinib 30 mg once daily for 12 weeks.
Measure Participants	169	164	165
Number (95% Confidence Interval) [percentage of participants]	14.2 8.4%	43.3 26.4%	42.4 25.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 15 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure.
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	The adjusted p-value under multiplicity control is reported, with significance achieved if the adjusted p-value is less than 0.05.
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusted for the stratification factor of prior biological DMARD use (stratum 1 vs stratum 2).
Method of Estimation	Estimation Parameter	Response Rate Difference
	Estimated Value	29.1
	Confidence Interval	(2-Sided) 95%; 19.9 to 38.3
	Parameter Dispersion	Type: Value:
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 30 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure.
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	The adjusted p-value under multiplicity control is reported, with significance achieved if the adjusted p-value is less than 0.05.
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusted for the stratification factor of prior biological DMARD use (stratum 1 vs stratum 2).
Method of Estimation	Estimation Parameter	Response Rate Difference
	Estimated Value	28.2
	Confidence Interval	(2-Sided) 95%; 19.0 to 37.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

3. Secondary Outcome

Title	Change From Baseline in in Disease Activity Score 28 (CRP) at Week 12
Description	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.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Full analysis set participants with available data at baseline; multiple imputation was used for missing post-baseline data.

Arm/Group Title	Placebo	Upadacitinib 15 mg	Upadacitinib 30 mg
Arm/Group Description	Participants received placebo once daily for 12 weeks.	Participants received upadacitinib 15 mg once daily for 12 weeks.	Participants received upadacitinib 30 mg once daily for 12 weeks.
Measure Participants	165	163	161
Least Squares Mean (95% Confidence Interval) [units on a scale]	-1.02	-2.31	-2.29

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 15 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure.
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	The adjusted p-value under multiplicity control is reported, with significance achieved if the adjusted p-value is less than 0.05.
	Method	ANCOVA
	Comments	Analysis of covariance (ANCOVA) model with treatment, prior biological DMARD use (stratum 1 vs stratum 2) and baseline value as covariates.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-1.29
	Confidence Interval	(2-Sided) 95%; -1.57 to -1.01
	Parameter Dispersion	Type: Value:
	Estimation Comments	Treatment Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 30 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure.
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	The adjusted p-value under multiplicity control is reported, with significance achieved if the adjusted p-value is less than 0.05.
	Method	ANCOVA
	Comments	ANCOVA model with treatment, prior biological DMARD use (stratum 1 vs stratum 2) and baseline value as covariates.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-1.28
	Confidence Interval	(2-Sided) 95%; -1.56 to -0.99
	Parameter Dispersion	Type: Value:
	Estimation Comments	Treatment Difference = Upadacitinib - Placebo

4. Secondary Outcome

Title	Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12
Description	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 Baseline in the overall score indicates improvement.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Full analysis set participants with available data at baseline; multiple imputation was used for missing data.

Arm/Group Title	Placebo	Upadacitinib 15 mg	Upadacitinib 30 mg
Arm/Group Description	Participants received placebo once daily for 12 weeks.	Participants received upadacitinib 15 mg once daily for 12 weeks.	Participants received upadacitinib 30 mg once daily for 12 weeks.
Measure Participants	165	163	160
Least Squares Mean (95% Confidence Interval) [units on a scale]	-0.17	-0.39	-0.42

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 15 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure.
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	The adjusted p-value under multiplicity control is reported, with significance achieved if the adjusted p-value is less than 0.05.
	Method	ANCOVA
	Comments	ANCOVA model with treatment, prior biological DMARD use (stratum 1 vs stratum 2) and baseline value as covariates.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.22
	Confidence Interval	(2-Sided) 95%; -0.34 to -0.10
	Parameter Dispersion	Type: Value:
	Estimation Comments	Treatment Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 30 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure.
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	The adjusted p-value under multiplicity control is reported, with significance achieved if the adjusted p-value is less than 0.05.
	Method	ANCOVA
	Comments	ANCOVA model with treatment, prior biological DMARD use (stratum 1 vs stratum 2) and baseline value as covariates.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.25
	Confidence Interval	(2-Sided) 95%; -0.38 to -0.13
	Parameter Dispersion	Type: Value:
	Estimation Comments	Treatment Difference = Upadacitinib - Placebo

5. Secondary Outcome

Title	Change From Baseline in Short-Form 36 (SF-36) Physical Component Score (PCS) at Week 12
Description	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 the standard deviation equals 10. Higher scores are associated with better functioning/quality of life; a positive change from baseline score indicates an improvement.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Full analysis set participants with available data; a mixed effect model repeat measurement (MMRM) analysis with data from observed cases to Week 12 was used.

Arm/Group Title	Placebo	Upadacitinib 15 mg	Upadacitinib 30 mg
Arm/Group Description	Participants received placebo once daily for 12 weeks.	Participants received upadacitinib 15 mg once daily for 12 weeks.	Participants received upadacitinib 30 mg once daily for 12 weeks.
Measure Participants	145	156	147
Least Squares Mean (95% Confidence Interval) [units on a scale]	2.39	5.83	7.02

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 15 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure.
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	The adjusted p-value under multiplicity control is reported, with significance achieved if the adjusted p-value is less than 0.05.
	Method	Mixed Effect Model Repeat Measurement
	Comments	MMRM model with fixed effects of treatment, visit, and treatment-by-visit interaction, previous bDMARD use, and baseline value as covariate.
Method of Estimation	Estimation Parameter	LS Mean DIfference
	Estimated Value	3.44
	Confidence Interval	(2-Sided) 95%; 1.72 to 5.15
	Parameter Dispersion	Type: Value:
	Estimation Comments	Treatment Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 30 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure.
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	The adjusted p-value under multiplicity control is reported, with significance achieved if the adjusted p-value is less than 0.05.
	Method	Mixed Effect Model Repeat Measurement
	Comments	MMRM model with fixed effects of treatment, visit, and treatment-by-visit interaction, previous bDMARD use, and baseline value as covariate.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	4.63
	Confidence Interval	(2-Sided) 95%; 2.89 to 6.36
	Parameter Dispersion	Type: Value:
	Estimation Comments	Treatment Difference = Upadacitinib - Placebo

6. Secondary Outcome

Title	Percentage of Participants With an American College of Rheumatology 50% (ACR50) Response at Week 12
Description	Participants who met the following 3 conditions for improvement from baseline were classified as meeting the ACR50 response criteria: ≥ 50% improvement in 68-tender joint count; ≥ 50% improvement in 66-swollen joint count; and ≥ 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).
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Full analysis set; participants who prematurely discontinued from study drug prior to Week 12 or for whom ACR data were missing at Week 12 were considered non-responders.

Arm/Group Title	Placebo	Upadacitinib 15 mg	Upadacitinib 30 mg
Arm/Group Description	Participants received placebo once daily for 12 weeks.	Participants received upadacitinib 15 mg once daily for 12 weeks.	Participants received upadacitinib 30 mg once daily for 12 weeks.
Measure Participants	169	164	165
Number (95% Confidence Interval) [percentage of participants]	11.8 7%	34.1 20.8%	35.8 21.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 15 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	The nominal p-value is reported
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusted for the stratification factor of prior biological DMARD use (stratum 1 vs stratum 2).
Method of Estimation	Estimation Parameter	Response Rate Difference
	Estimated Value	22.3
	Confidence Interval	(2-Sided) 95%; 13.6 to 31.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 30 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	The nominal p-value is reported
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusted for the stratification factor of prior biological DMARD use (stratum 1 vs stratum 2).
Method of Estimation	Estimation Parameter	Response Rate Difference
	Estimated Value	23.9
	Confidence Interval	(2-Sided) 95%; 15.1 to 32.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

7. Secondary Outcome

Title	Percentage of Participants With an American College of Rheumatology 70% (ACR70) Response at Week 12
Description	Participants who met the following 3 conditions for improvement from baseline were classified as meeting the ACR70 response criteria: ≥ 70% improvement in 68-tender joint count; ≥ 70% improvement in 66-swollen joint count; and ≥ 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).
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Full analysis set; participants who prematurely discontinued from study drug prior to Week 12 or for whom ACR data were missing at Week 12 were considered non-responders.

Arm/Group Title	Placebo	Upadacitinib 15 mg	Upadacitinib 30 mg
Arm/Group Description	Participants received placebo once daily for 12 weeks.	Participants received upadacitinib 15 mg once daily for 12 weeks.	Participants received upadacitinib 30 mg once daily for 12 weeks.
Measure Participants	169	164	165
Number (95% Confidence Interval) [percentage of participants]	6.5 3.8%	11.6 7.1%	23.0 13.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 15 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.110
	Comments	The nominal p-value is reported
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusted for the stratification factor of prior biological DMARD use (stratum 1 vs stratum 2).
Method of Estimation	Estimation Parameter	Response Rate Difference
	Estimated Value	5.1
	Confidence Interval	(2-Sided) 95%; -1.1 to 11.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 30 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	The nominal p-value is reported
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusted for the stratification factor of prior biological DMARD use (stratum 1 vs stratum 2).
Method of Estimation	Estimation Parameter	Response Rate Difference
	Estimated Value	16.5
	Confidence Interval	(2-Sided) 95%; 9.1 to 23.9
	Parameter Dispersion	Type: Value:
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

8. Secondary Outcome

Title	Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response at Week 1
Description	Participants who met the following 3 conditions for improvement from baseline were classified as meeting the ACR20 response criteria: ≥ 20% improvement in 68-tender joint count; ≥ 20% improvement in 66-swollen joint count; and ≥ 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 Questionnaire - Disability Index (HAQ-DI) High-sensitivity C-reactive protein (hsCRP).
Time Frame	Baseline and week 1

Outcome Measure Data

Analysis Population Description

Full analysis set; participants who prematurely discontinued from study drug prior to Week 1 or for whom ACR data were missing at Week 1 were considered non-responders.

Arm/Group Title	Placebo	Upadacitinib 15 mg	Upadacitinib 30 mg
Arm/Group Description	Participants received placebo once daily for 12 weeks.	Participants received upadacitinib 15 mg once daily for 12 weeks.	Participants received upadacitinib 30 mg once daily for 12 weeks.
Measure Participants	169	164	165
Number (95% Confidence Interval) [percentage of participants]	10.7 6.3%	27.4 16.7%	24.8 15%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 15 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	The nominal p-value is reported
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusted for the stratification factor of prior biological DMARD use (stratum 1 vs stratum 2).
Method of Estimation	Estimation Parameter	Response Rate Difference
	Estimated Value	16.8
	Confidence Interval	(2-Sided) 95%; 8.5 to 25.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Upadacitinib 30 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	The nominal p-value is reported
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusted for the stratification factor of prior biological DMARD use (stratum 1 vs stratum 2).
Method of Estimation	Estimation Parameter	Response Rate Difference
	Estimated Value	14.2
	Confidence Interval	(2-Sided) 95%; 6.1 to 22.3
	Parameter Dispersion	Type: Value:
	Estimation Comments	Response Rate Difference = Upadacitinib - Placebo

Adverse Events

Time Frame	Adverse events are reported for Weeks 1 to 12 and Weeks 1 to 24 for participants who received upadacitinib.
Arm/Group Title	Placebo: Weeks 1-12		Upadacitinib 15 mg: Weeks 1-12		Upadacitinib 30 mg: Weeks 1-12		Upadacitinib 15 mg: Weeks 1-24		Upadacitinib 30 mg: Weeks 1-24
Arm/Group Description	Participants received placebo once daily for 12 weeks.		Participants received upadacitinib 15 mg once daily for 12 weeks.		Participants received upadacitinib 30 mg once daily for 12 weeks.		Participants originally randomized to upadacitinib 15 mg received upadacitinib 15 mg for 24 weeks and participants originally randomized to placebo who switched to upadacitinib 15 mg at Week 12 and received upadacitinib 15 mg for 12 weeks.		Participants originally randomized to upadacitinib 30 mg received upadacitinib 30 mg for 24 weeks and participants originally randomized to placebo who switched to upadacitinib 30 mg at Week 12 and received upadacitinib 30 mg for 12 weeks.
All Cause Mortality
	Placebo: Weeks 1-12		Upadacitinib 15 mg: Weeks 1-12		Upadacitinib 30 mg: Weeks 1-12		Upadacitinib 15 mg: Weeks 1-24		Upadacitinib 30 mg: Weeks 1-24
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/169 (0%)		0/164 (0%)		1/165 (0.6%)		1/236 (0.4%)		1/240 (0.4%)
Serious Adverse Events
	Placebo: Weeks 1-12		Upadacitinib 15 mg: Weeks 1-12		Upadacitinib 30 mg: Weeks 1-12		Upadacitinib 15 mg: Weeks 1-24		Upadacitinib 30 mg: Weeks 1-24
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/169 (0%)		8/164 (4.9%)		12/165 (7.3%)		18/236 (7.6%)		22/240 (9.2%)
Cardiac disorders
ACUTE MYOCARDIAL INFARCTION	0/169 (0%)	0	0/164 (0%)	0	0/165 (0%)	0	0/236 (0%)	0	1/240 (0.4%)	1
CARDIAC ARREST	0/169 (0%)	0	0/164 (0%)	0	0/165 (0%)	0	1/236 (0.4%)	1	0/240 (0%)	0
CARDIAC FAILURE	0/169 (0%)	0	0/164 (0%)	0	1/165 (0.6%)	1	0/236 (0%)	0	1/240 (0.4%)	1
PERICARDIAL EFFUSION	0/169 (0%)	0	0/164 (0%)	0	1/165 (0.6%)	1	0/236 (0%)	0	1/240 (0.4%)	1
VENTRICULAR TACHYCARDIA	0/169 (0%)	0	0/164 (0%)	0	0/165 (0%)	0	0/236 (0%)	0	1/240 (0.4%)	1
Gastrointestinal disorders
ENTERITIS	0/169 (0%)	0	0/164 (0%)	0	1/165 (0.6%)	1	0/236 (0%)	0	1/240 (0.4%)	1
LARGE INTESTINE PERFORATION	0/169 (0%)	0	0/164 (0%)	0	0/165 (0%)	0	0/236 (0%)	0	1/240 (0.4%)	1
PANCREATITIS	0/169 (0%)	0	0/164 (0%)	0	0/165 (0%)	0	1/236 (0.4%)	1	0/240 (0%)	0
General disorders
CHEST PAIN	0/169 (0%)	0	1/164 (0.6%)	1	0/165 (0%)	0	1/236 (0.4%)	1	0/240 (0%)	0
FATIGUE	0/169 (0%)	0	0/164 (0%)	0	1/165 (0.6%)	1	0/236 (0%)	0	1/240 (0.4%)	1
PYREXIA	0/169 (0%)	0	0/164 (0%)	0	1/165 (0.6%)	1	1/236 (0.4%)	1	1/240 (0.4%)	1
SYSTEMIC INFLAMMATORY RESPONSE SYNDROME	0/169 (0%)	0	0/164 (0%)	0	1/165 (0.6%)	1	0/236 (0%)	0	1/240 (0.4%)	1
Hepatobiliary disorders
CHOLECYSTITIS	0/169 (0%)	0	0/164 (0%)	0	0/165 (0%)	0	1/236 (0.4%)	1	0/240 (0%)	0
CHOLELITHIASIS	0/169 (0%)	0	0/164 (0%)	0	0/165 (0%)	0	1/236 (0.4%)	1	0/240 (0%)	0
Infections and infestations
HERPES ZOSTER	0/169 (0%)	0	0/164 (0%)	0	1/165 (0.6%)	1	0/236 (0%)	0	1/240 (0.4%)	1
INFLUENZA	0/169 (0%)	0	0/164 (0%)	0	0/165 (0%)	0	0/236 (0%)	0	1/240 (0.4%)	1
OPHTHALMIC HERPES ZOSTER	0/169 (0%)	0	0/164 (0%)	0	1/165 (0.6%)	1	0/236 (0%)	0	1/240 (0.4%)	1
PNEUMONIA	0/169 (0%)	0	0/164 (0%)	0	2/165 (1.2%)	2	0/236 (0%)	0	3/240 (1.3%)	3
RESPIRATORY TRACT INFECTION	0/169 (0%)	0	0/164 (0%)	0	0/165 (0%)	0	1/236 (0.4%)	1	0/240 (0%)	0
RESPIRATORY TRACT INFECTION VIRAL	0/169 (0%)	0	0/164 (0%)	0	0/165 (0%)	0	1/236 (0.4%)	1	0/240 (0%)	0
SEPSIS	0/169 (0%)	0	0/164 (0%)	0	0/165 (0%)	0	0/236 (0%)	0	1/240 (0.4%)	1
URINARY TRACT INFECTION	0/169 (0%)	0	0/164 (0%)	0	0/165 (0%)	0	1/236 (0.4%)	1	0/240 (0%)	0
VIRAL INFECTION	0/169 (0%)	0	1/164 (0.6%)	1	0/165 (0%)	0	1/236 (0.4%)	1	0/240 (0%)	0
Injury, poisoning and procedural complications
FOREARM FRACTURE	0/169 (0%)	0	0/164 (0%)	0	1/165 (0.6%)	1	0/236 (0%)	0	1/240 (0.4%)	1
HIP FRACTURE	0/169 (0%)	0	0/164 (0%)	0	0/165 (0%)	0	0/236 (0%)	0	1/240 (0.4%)	1
HUMERUS FRACTURE	0/169 (0%)	0	0/164 (0%)	0	0/165 (0%)	0	0/236 (0%)	0	1/240 (0.4%)	1
TRAUMATIC FRACTURE	0/169 (0%)	0	0/164 (0%)	0	1/165 (0.6%)	1	0/236 (0%)	0	1/240 (0.4%)	1
Investigations
ALANINE AMINOTRANSFERASE INCREASED	0/169 (0%)	0	0/164 (0%)	0	0/165 (0%)	0	0/236 (0%)	0	1/240 (0.4%)	1
Musculoskeletal and connective tissue disorders
MUSCULAR WEAKNESS	0/169 (0%)	0	0/164 (0%)	0	0/165 (0%)	0	0/236 (0%)	0	1/240 (0.4%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
BLADDER CANCER	0/169 (0%)	0	0/164 (0%)	0	0/165 (0%)	0	1/236 (0.4%)	1	0/240 (0%)	0
MALIGNANT MELANOMA IN SITU	0/169 (0%)	0	1/164 (0.6%)	1	0/165 (0%)	0	1/236 (0.4%)	1	0/240 (0%)	0
PROSTATE CANCER	0/169 (0%)	0	0/164 (0%)	0	2/165 (1.2%)	2	0/236 (0%)	0	2/240 (0.8%)	2
Nervous system disorders
CEREBROVASCULAR ACCIDENT	0/169 (0%)	0	1/164 (0.6%)	1	0/165 (0%)	0	1/236 (0.4%)	1	0/240 (0%)	0
CERVICAL MYELOPATHY	0/169 (0%)	0	0/164 (0%)	0	0/165 (0%)	0	0/236 (0%)	0	1/240 (0.4%)	1
FACIAL PARALYSIS	0/169 (0%)	0	1/164 (0.6%)	1	0/165 (0%)	0	1/236 (0.4%)	1	0/240 (0%)	0
Psychiatric disorders
ACUTE PSYCHOSIS	0/169 (0%)	0	0/164 (0%)	0	0/165 (0%)	0	1/236 (0.4%)	1	0/240 (0%)	0
Renal and urinary disorders
ACUTE KIDNEY INJURY	0/169 (0%)	0	0/164 (0%)	0	0/165 (0%)	0	0/236 (0%)	0	1/240 (0.4%)	1
Reproductive system and breast disorders
VAGINAL HAEMORRHAGE	0/169 (0%)	0	1/164 (0.6%)	1	0/165 (0%)	0	1/236 (0.4%)	1	0/240 (0%)	0
Respiratory, thoracic and mediastinal disorders
ASTHMA	0/169 (0%)	0	1/164 (0.6%)	1	0/165 (0%)	0	1/236 (0.4%)	1	0/240 (0%)	0
CHRONIC OBSTRUCTIVE PULMONARY DISEASE	0/169 (0%)	0	1/164 (0.6%)	1	0/165 (0%)	0	2/236 (0.8%)	2	0/240 (0%)	0
PNEUMONITIS	0/169 (0%)	0	0/164 (0%)	0	1/165 (0.6%)	1	0/236 (0%)	0	1/240 (0.4%)	1
PULMONARY EMBOLISM	0/169 (0%)	0	1/164 (0.6%)	1	1/165 (0.6%)	1	4/236 (1.7%)	4	2/240 (0.8%)	2
RESPIRATORY FAILURE	0/169 (0%)	0	0/164 (0%)	0	0/165 (0%)	0	1/236 (0.4%)	1	0/240 (0%)	0
Vascular disorders
DEEP VEIN THROMBOSIS	0/169 (0%)	0	0/164 (0%)	0	0/165 (0%)	0	1/236 (0.4%)	1	0/240 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo: Weeks 1-12		Upadacitinib 15 mg: Weeks 1-12		Upadacitinib 30 mg: Weeks 1-12		Upadacitinib 15 mg: Weeks 1-24		Upadacitinib 30 mg: Weeks 1-24
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	43/169 (25.4%)		34/164 (20.7%)		32/165 (19.4%)		70/236 (29.7%)		75/240 (31.3%)
Infections and infestations
BRONCHITIS	4/169 (2.4%)	4	0/164 (0%)	0	0/165 (0%)	0	12/236 (5.1%)	12	14/240 (5.8%)	14
NASOPHARYNGITIS	11/169 (6.5%)	11	7/164 (4.3%)	8	9/165 (5.5%)	9	12/236 (5.1%)	17	18/240 (7.5%)	20
UPPER RESPIRATORY TRACT INFECTION	13/169 (7.7%)	13	13/164 (7.9%)	14	10/165 (6.1%)	10	31/236 (13.1%)	37	28/240 (11.7%)	30
URINARY TRACT INFECTION	10/169 (5.9%)	11	15/164 (9.1%)	19	9/165 (5.5%)	10	19/236 (8.1%)	27	18/240 (7.5%)	22
Musculoskeletal and connective tissue disorders
RHEUMATOID ARTHRITIS	10/169 (5.9%)	10	4/164 (2.4%)	5	6/165 (3.6%)	6	8/236 (3.4%)	9	8/240 (3.3%)	9

Limitations/Caveats

[Not Specified]

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