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)

• Sponsor: AbbVie (Industry)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02706951
• Collaborator: (none)
• Enrollment: 648
• Locations: 153
• Arms: 4
• Anticipated Duration (Months): 76.5
• Patients Per Site: 4.2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

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.

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

Detailed Description

The study includes a 35-day screening period; a 14-week randomized, double-blind, parallel-group, controlled treatment period (Period 1); a 246-week blinded extension period (Period 2); and a 30-day follow-up visit.

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

• Group 1: upadacitinib 30 mg QD (Period 1) → upadacitinib 30 mg QD (Period 2)

• Group 2: upadacitinib 15 mg QD (Period 1) → upadacitinib 15 mg QD (Period 2)

• Group 3: MTX (Period 1) → upadacitinib 30 mg QD (Period 2)

• Group 4: MTX (Period 1) → upadacitinib 15 mg QD (Period 2)

Starting with implementation of Protocol Amendment 5, 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: 648 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) Monotherapy to Methotrexate (MTX) in Adults With Moderately to Severely Active Rheumatoid Arthritis With Inadequate Response to MTX
• Actual Study Start Date: Mar 23, 2016
• Actual Primary Completion Date: Oct 2, 2017
• Anticipated Study Completion Date: Aug 8, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Upadacitinib 30 mg Period 1: Participants receive upadacitnib 30 mg once daily and placebo to methotrexate once weekly for 14 weeks. Period 2: Participants receive upadacitinib 30 mg once daily until implementation of Protocol Amendment 5 when participants begin to receive upadacitinib 15 mg once daily up to Week 260.	Drug: Upadacitinib; Tablet; Oral; Other Names: ABT-494 Rinvoq ; Drug: Placebo Methotrexate; Capsule; Oral
Experimental: Upadacitinib 15 mg Period 1: Participants receive upadacitnib 15 mg once daily and placebo to methotrexate once weekly for 14 weeks. Period 2: Participants receive upadacitinib 15 mg once daily up to Week 260.	Drug: Upadacitinib; Tablet; Oral; Other Names: ABT-494 Rinvoq ; Drug: Placebo Methotrexate; Capsule; Oral
Experimental: Methotrexate / Upadacitinib 30 mg Period 1: Participants receive methotrexate once weekly and placebo to upadacitinib once daily for 14 weeks. Period 2: Participants receive upadacitinib 30 mg once daily until implementation of Protocol Amendment 5 when participants begin to receive upadacitinib 15 mg once daily up to Week 260.	Drug: Methotrexate; Capsule; Oral; Drug: Upadacitinib; Tablet; Oral; Other Names: ABT-494 Rinvoq ; Drug: Placebo Upadacitinib; Tablet; Oral; Drug: Placebo Methotrexate; Capsule; Oral
Experimental: Methotrexate / Upadacitinib 15 mg Period 1: Participants receive methotrexate once weekly and placebo to upadacitinib for 14 weeks. Period 2: Participants receive upadacitinib 15 mg once daily up to Week 260.	Drug: Methotrexate; Capsule; Oral; Drug: Upadacitinib; Tablet; Oral; Other Names: ABT-494 Rinvoq ; Drug: Placebo Upadacitinib; Tablet; Oral; Drug: Placebo Methotrexate; Capsule; Oral

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response at Week 14 [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: ≥ 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 14 [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 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 14 [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.

2. Change From Baseline in Heath Assessment Questionnaire and Disability Index (HAQ-DI) at Week 14 [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 Baseline in the overall score indicates improvement.

3. Change From Baseline in Short-Form 36 (SF-36) Physical Component Score (PCS) at Week 14 [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 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 Achieving Clinical Remission (CR) Based on DAS28(CRP) at Week 14 [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.

5. Change From Baseline in Duration of Morning Stiffness at Week 14 [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.

6. Percentage of Participants With an American College of Rheumatology 50% (ACR50) Response at Week 14 [Baseline and week 14]

   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).

7. Percentage of Participants With an American College of Rheumatology 70% (ACR70) Response at Week 14 [Baseline and week 14]

   Participants who met the following 3 conditions for improvement from baseline were classified as meeting the ACR50 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).

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 RA for >= 3 months.

• Subjects must have been on oral or parenteral MTX therapy >= 3 months and on a stable dose for >= 4 weeks prior to first dose of study drug.

• Must have discontinued all conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) (other than MTX) >= 4 weeks prior to first dose of study drug.

• Meets the following minimum disease activity criteria: >= 6 swollen joints (based on 66 joint counts) and >= 6 tender joints (based on 68 joint counts) at Screening and Baseline Visits.

Exclusion Criteria:

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

• Prior exposure to any biological disease-modifying anti-rheumatic drugs (bDMARDs).

• Current diagnosis of inflammatory joint disease other than RA. 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# 146009	Huntsville	Alabama	United States	35801
2	Alabama Medical Group, PC /ID# 153941	Mobile	Alabama	United States	36608-1787
3	ArthroCare Arthritis Care & Re /ID# 143751	Gilbert	Arizona	United States	85234
4	Elite Clinical Studies, LLC /ID# 143760	Phoenix	Arizona	United States	85018
5	University of Arizona Cancer Center - North Campus /ID# 147175	Tucson	Arizona	United States	85719-1478
6	NEA Baptist Womens Clinic /ID# 148904	Jonesboro	Arkansas	United States	72401
7	C.V. Mehta MD, Med Corporation /ID# 143762	Hemet	California	United States	92543
8	Arthritis Assoc & Osteo Ctr /ID# 147176	Colorado Springs	Colorado	United States	80920
9	Ctr Rheum, Immuno, Arthritis /ID# 143766	Fort Lauderdale	Florida	United States	33309
10	South Florida Research Ph I-IV /ID# 151983	Miami Springs	Florida	United States	33166-7225
11	Advent Clinical Research /ID# 143767	Pinellas Park	Florida	United States	33781
12	Sarasota Arthritis Center /ID# 146011	Sarasota	Florida	United States	34239
13	W. Broward Rheum Assoc Inc. /ID# 146010	Tamarac	Florida	United States	33321
14	Clinical Research West FL /ID# 148726	Tampa	Florida	United States	33603
15	SW FL Clin Res Ctr, Tampa, FL /ID# 143763	Tampa	Florida	United States	33609
16	University of South Florida /ID# 146004	Tampa	Florida	United States	33612
17	BayCare Medical Group, Inc. /ID# 151985	Tampa	Florida	United States	33614-7101
18	BayCare Medical Group, Inc. /ID# 163595	Tampa	Florida	United States	33614-7101
19	Jefrey D. Lieberman, MD, P.C. /ID# 151816	Decatur	Georgia	United States	30033
20	Great Lakes Clinical Trials /ID# 150935	Chicago	Illinois	United States	60640
21	PRN Professional Research Network of Kansas, LLC /ID# 143761	Wichita	Kansas	United States	67205
22	Ochsner Clinic Foundation /ID# 153573	Baton Rouge	Louisiana	United States	70836-6455
23	The Arthritis & Diabetes Clinic, Inc. /ID# 160809	Monroe	Louisiana	United States	71203
24	Vanguard Medical Research, LLC /ID# 153124	Shreveport	Louisiana	United States	71011
25	Mansfield Health Center /ID# 161627	Mansfield	Massachusetts	United States	02048
26	Quality Clinical Research Inc. /ID# 156415	Omaha	Nebraska	United States	68114
27	Dartmouth-Hitchcock Medical Center /ID# 146008	Lebanon	New Hampshire	United States	03756
28	Albuquerque Clinical Trials, Inc /ID# 147618	Albuquerque	New Mexico	United States	87102
29	Arthritis and Osteo Assoc /ID# 147177	Las Cruces	New Mexico	United States	88011
30	Coastal Carolina Health Care /ID# 149275	New Bern	North Carolina	United States	28562
31	STAT Research, Inc. /ID# 143770	Vandalia	Ohio	United States	45377-9464
32	Health Research Oklahoma /ID# 159550	Oklahoma City	Oklahoma	United States	73103-2400
33	Healthcare Research Consultant /ID# 147632	Tulsa	Oklahoma	United States	74135
34	Innovative Clinical Research /ID# 143757	Greenville	South Carolina	United States	29601
35	Nashville Arthritis and Rheumatology /ID# 162641	Nashville	Tennessee	United States	37203
36	Tekton Research, Inc. /ID# 159554	Austin	Texas	United States	78745
37	Diagnostic Group Integrated He /ID# 148725	Beaumont	Texas	United States	77701
38	Trinity Universal Res Assoc /ID# 150138	Carrollton	Texas	United States	75007
39	Arth and Osteo Clin Brazo Valley /ID# 160810	College Station	Texas	United States	77845
40	Adriana Pop-Moody MD Clinic PA /ID# 147627	Corpus Christi	Texas	United States	78404
41	Accurate Clinical Management /ID# 143768	Houston	Texas	United States	77004
42	Accurate Clinical Research /ID# 143769	Houston	Texas	United States	77089
43	Pioneer Research Solutions, Inc. /ID# 143765	Houston	Texas	United States	77098-5294
44	P&I Clinical Research /ID# 151358	Lufkin	Texas	United States	75904-3132
45	SW Rheumatology Res. LLC /ID# 147620	Mesquite	Texas	United States	75150
46	Sun Research Institute /ID# 159553	San Antonio	Texas	United States	78215
47	Arthritis Clinic of Central TX /ID# 149266	San Marcos	Texas	United States	78666
48	Adv Rheumatology of Houston /ID# 162609	The Woodlands	Texas	United States	77382
49	DM Clinical Research /ID# 151359	Tomball	Texas	United States	77375
50	Arthritis & Osteoporosis Clinic /ID# 143752	Waco	Texas	United States	76710
51	Ctr for Arth and Rheum Disease /ID# 143759	Chesapeake	Virginia	United States	23320
52	Aurora Rheumatology and Immunotherapy Center /ID# 160811	Franklin	Wisconsin	United States	53132
53	Mautalen Salud e Investigacion /ID# 145980	Buenos Aires		Argentina	1128
54	Ctr Privado Med Familiar /ID# 149183	Buenos Aires		Argentina	1417
55	Consultorio Reumatologic Pampa /ID# 145979	Buenos Aires		Argentina	1428
56	Centro de Educación Médica e Investigaciones Clínicas "Norberto Quimo" - CEMIC /ID# 149176	Buenos Aires		Argentina	1431
57	Cordis S.A. /Id# 152621	Salta		Argentina	4400
58	Centro de Enfermedades /ID# 153543	Santa Fe		Argentina	2000
59	Royal Prince Alfred Hospital /ID# 146028	Camperdown	New South Wales	Australia	2050
60	Rheuma-Zentrum Wien-Oberlaa /ID# 144728	Wien		Austria	1100
61	Algemeen Stedelijk Ziekenhuis /ID# 148720	Aalst	Oost-Vlaanderen	Belgium	9300
62	ReumaClinic Genk /ID# 146030	Genk		Belgium	3600
63	Diag Consult Ctr 17 Sofia EOOD /ID# 144730	Sofia		Bulgaria	1505
64	UMHAT Sv. Ivan Rilski /ID# 147351	Sofia		Bulgaria	1612
65	Reg. Clinical Hosptial Concepcion /ID# 151267	Concepcion		Chile	4070038
66	Quantum Research LTDA. /ID# 145984	Puerto Varas		Chile	5550170
67	Quantum Research Stgo. /ID# 145983	Santiago		Chile	7500588
68	CTCenter MaVe, s.r.o. /ID# 144823	Olomouc	Olomoucky Kraj	Czechia	779 00
69	Nuselská poliklinika, Revmatologie /ID# 145986	Prague 4	Praha 4	Czechia	140 00
70	Thomayerova nemocnice /ID# 144736	Prague 4	Praha 4	Czechia	140 00
71	RHEUMA s.r.o. /ID# 144737	Breclav		Czechia	690 02
72	Medical Plus, s.r.o. /ID# 144821	Uherské Hradište		Czechia	686 01
73	MediTrials /ID# 159745	Tartu	Tartumaa	Estonia	50406
74	North Estonian Medical Centre /ID# 145455	Tallinn		Estonia	13419
75	General Hospital of Athens "Ippokratio" /ID# 144739	Athens		Greece	11527
76	Vital Medical Center Orvosi es /ID# 144740	Veszprém	Veszprem	Hungary	8200
77	Magyar Honvedseg Egeszsegugyi Kozpont /ID# 144743	Budapest		Hungary	1134
78	Pest Megyei Flor Ferenc Korhaz /ID# 144742	Kistarcsa		Hungary	2143
79	Fejer Megyei Szent Gyorgy Korh /ID# 144741	Szekesfehervar		Hungary	8000
80	Barzilai Medical Center /ID# 144744	Ashkelon		Israel	78278
81	Bnai Zion Medical Center /ID# 144745	Haifa		Israel	3339419
82	The Lady Davis Carmel MC /ID# 147174	Haifa		Israel	3436212
83	Sheba Medical Center /ID# 144824	Ramat Gan		Israel	5262100
84	Universita di Catanzaro Magna Graecia /ID# 144747	Catanzaro	Calabria	Italy	88100
85	A.O.U.I. di Verona Policlinico /ID# 144746	Verona		Italy	37134
86	Kondo Clinic for Rheum & Ortho /ID# 148268	Fukuoka-shi	Fukuoka	Japan	810-0001
87	NHO Kyushu Medical Center /ID# 148279	Fukuoka-shi	Fukuoka	Japan	810-8563
88	NHO Kyushu Medical Center /ID# 148280	Fukuoka-shi	Fukuoka	Japan	810-8563
89	Aso Iizuka Hospital /ID# 148272	Iizuka-shi	Fukuoka	Japan	820-8505
90	Inoue Hospital /ID# 148069	Takasaki	Gunma	Japan	3700053
91	Bay Side Misato Medical Center /ID# 148281	Kochi-shi	Kochi	Japan	781-0112
92	Center for Arthritis and Clinical Rheumatology Matsubara Clinic /ID# 148269	Kumamoto-shi	Kumamoto	Japan	862-0920
93	Kumamoto Shinto General Hospital /ID# 148286	Kumamoto-shi	Kumamoto	Japan	8628655
94	Nagasaki University Hospital /ID# 149859	Nagasaki-shi	Nagasaki	Japan	852-8501
95	Sasebo Chuo Hospital /ID# 148275	Sasebo-city	Nagasaki	Japan	857-1195
96	Osaka Red Cross Hospital /ID# 148267	Osaka-shi	Osaka	Japan	543-8555
97	Seirei Hamamatsu General Hosp /ID# 148270	Hamamatsu		Japan	430-8558
98	Ohira Orthopaedic Hospital /ID# 157944	Hyuga		Japan	883-0043
99	Shirahama Hamayu Hospital /ID# 148277	Nishimura		Japan	649-2211
100	Sanuki Municipal Hospital /ID# 158080	Sanuki		Japan	769-2321
101	Hokkaido University Hospital /ID# 148285	Sapporo		Japan	060-8648
102	Hokkaido Medical Center for Rheumatic Diseases /ID# 148274	Sapporo		Japan	063-0811
103	Miyasato Clinic /ID# 148271	Shunan		Japan	745-0824
104	Takaoka Rheumatic Orthopedic Clinic /ID# 148068	Takaoka		Japan	933-0874
105	Matsuta Clinic /ID# 148278	Tokyo		Japan	155-0032
106	National Hospital Organization Shimoshizu National Hospital /ID# 148273	Yotsukaido		Japan	284-0003
107	Desarrollos Biomedicos y Biotc /ID# 147379	Monterrey	Nuevo LEON	Mexico	64060
108	Cryptex Investigación Clínica S.A de C.V /ID# 147095	Mexico City		Mexico	06100
109	WroMedica I. Bielicka, A. Strzalkowska s.c. /ID# 157622	Wrocław	Dolnoslaskie	Poland	51-685
110	REUMED Sp.z o.o. Filia nr 1 /ID# 144752	Lublin	Lubelskie	Poland	20-607
111	Centralny Szpital Kliniczny MSWiA w Warszawie /ID# 149521	Warszawa	Mazowieckie	Poland	02-507
112	Osteo-Medic spolka cywilna /ID# 144753	Białystok	Podlaskie	Poland	15-351
113	Centrum Badań Klinicznych Pi-House /ID# 149520	Gdansk	Pomorskie	Poland	80-546
114	NZOZ Centrum Reumatologiczne /ID# 144749	Elblag	Warminsko-mazurskie	Poland	82-300
115	Medyczne Centrum Hetmanska /ID# 144751	Poznań	Wielkopolskie	Poland	60-218
116	Instituto Portugues De Reumatologia /ID# 149281	Lisbon	Lisboa	Portugal	1050-034
117	Centro Hospitalar De Vila Nova /ID# 146036	Vila Nova De Gaia	Porto	Portugal	4434-502
118	Centro Hospitalar Lisboa Norte, EPE /ID# 146035	Lisboa		Portugal	1649-035
119	Centro Hospitalar Baixo Vouga /ID# 152916	Porto		Portugal	4050-111
120	Dr. Ramon L. Ortega-Colon, MD /ID# 145989	Carolina		Puerto Rico	00983
121	Ponce School of Medicine /ID# 145990	Ponce		Puerto Rico	00716
122	Spitalul Municipal Ploiesti /ID# 144756	Ploiesti		Romania	100337
123	Clinical Hospital No.1 n.a. N.I.Pirogov /ID# 147255	Moscow	Moskva	Russian Federation	119049
124	LLC Medical Center /ID# 144758	Novosibirsk	Novosibirskaya Oblast	Russian Federation	630099
125	Perm Clinical Center of FMBA /ID# 145993	Perm	Permskiy Kray	Russian Federation	614109
126	Tver Regional Clinical Hosp. /ID# 147254	Tver	Tverskaya Oblast	Russian Federation	170036
127	Сity Clinical Hospital 4 /ID# 145994	Ivanovo		Russian Federation	153005
128	City Clinical Hospital Botkina /ID# 145995	Moscow		Russian Federation	125284
129	City Clinical Hospital #5 /ID# 149832	Nizhnij Novgorod		Russian Federation	603005
130	Orenburg State Medical Academy /ID# 145992	Orenburg		Russian Federation	460000
131	Republican Clin Hos n.a. Baran /ID# 147251	Petrozavodsk		Russian Federation	185019
132	Samara Regional Clinical Hosp /ID# 150934	Samara		Russian Federation	443095
133	Reg Clin Hosp n.a. Kuvatova G. /ID# 144757	UFA		Russian Federation	450005
134	Yaroslavi State Medical Univer /ID# 147253	Yaroslavl		Russian Federation	150000
135	Institute for Rheumatology /ID# 144759	Belgrade	Beograd	Serbia	11000
136	Institute for Rheumatology /ID# 144761	Belgrade	Beograd	Serbia	11000
137	Institute for Rheumatology /ID# 144762	Belgrade	Beograd	Serbia	11000
138	Special Hospital for Rheuma /ID# 144760	Novi Sad	Vojvodina	Serbia	21000
139	Wits Clinical Research Site /ID# 149835	Johannesburg	Gauteng	South Africa	2193
140	University of Pretoria /ID# 148740	Pretoria	Gauteng	South Africa	0001
141	Synexus Helderberg Clinical Tr /ID# 148724	Cape Town	Western Cape	South Africa	7130
142	Tiervlei Trial Centre /ID# 153086	Cape Town	Western Cape	South Africa	7530
143	Hospital Plató /ID# 145999	Barcelona		Spain	08006
144	Hospital Univ Germans Trias I /ID# 146037	Barcelona		Spain	08916
145	Hospital Infanta Luisa /ID# 144771	Sevilla		Spain	41010
146	Hospital Universitario de Valm /ID# 144770	Sevilla		Spain	41014
147	Hospital Universitario La Fe /ID# 158013	Valencia		Spain	46026
148	Uludağ Üniversitesi Atatürk Rehabilitasyon Uygulama ve Araştırma Merkezi /ID# 144772	Osmangazi	Bursa	Turkey	16080
149	Lviv Regional Clinical Hospita /ID# 154448	Lviv	Lvivska Oblast	Ukraine	79013
150	Vinnytsia Regional Clinical Hospital n.a. M.I.Pyrogov /ID# 146002	Vinnytsia	Vinnytska Oblast	Ukraine	21018
151	Regional Clinical Hospital /ID# 152007	Ivano-frankivsk		Ukraine	76018
152	NSC-Strazhesko Ist Cardiology /ID# 152004	Kiev		Ukraine	03680
153	Zaporizhzhia Regional Clinical /ID# 146000	Zaporizhia		Ukraine	69600

Sponsors and Collaborators

• AbbVie

Investigators

• Study Director: AbbVie Inc., AbbVie

Study Documents (Full-Text)

• Study Protocol - Oct 25, 2017
• Statistical Analysis Plan - Nov 29, 2017

More Information

Additional Information:

• Related Info.

Publications

• Smolen JS, Pangan AL, Emery P, Rigby W, Tanaka Y, Vargas JI, Zhang Y, Damjanov N, Friedman A, Othman AA, Camp HS, Cohen S. 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. Lancet. 2019 Jun 8;393(10188):2303-2311. doi: 10.1016/S0140-6736(19)30419-2. Epub 2019 May 23. Erratum in: Lancet. 2019 Jun 29;393(10191):2590.

• Responsible Party: AbbVie
• ClinicalTrials.gov Identifier: NCT02706951
• Other Study ID Numbers: M15-555; 2015-003376-75
• First Posted: Mar 11, 2016
• Last Update Posted: Aug 1, 2022
• Last Verified: Jul 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; Upadacitinib; ABT-494
• Additional relevant MeSH terms: Arthritis; Arthritis, Rheumatoid; Methotrexate; Upadacitinib

Study Results

Participant Flow

Recruitment Details	A total of 648 participants with rheumatoid arthritis (RA) on a stable dose of methotrexate (MTX) were randomized at 138 study sites located in 24 countries. The study is currently ongoing; results are reported up to the end of Period 1 (Week 14).
Pre-assignment Detail	Participants were randomized in a 2:2:1:1 ratio to 1 of 4 groups: Upadacitinib 30 mg (Periods 1 and 2) Upadacitinib 15 mg (Periods 1 and 2) MTX (Period 1) → upadacitinib 30 mg (Period 2) MTX (Period 1) → upadacitinib 15 mg (Period 2) Randomization was stratified by geographic region. The MTX groups were pooled for Week 14 analyses.

Arm/Group Title	Methotrexate	Upadacitinib 15 mg	Upadacitinib 30 mg
Arm/Group Description	Participants randomized to receive up to 25 mg methotrexate once a week and placebo to upadacitinib once daily (QD) for 14 weeks in Period 1.	Participants randomized to receive upadacitinib 15 mg once daily and placebo to methotrexate once a week for 14 weeks in Period 1.	Participants randomized to receive upadacitinib 30 mg once daily and placebo to methotrexate once a week for 14 weeks in Period 1.
Period Title: Overall Study
STARTED	216	217	215
COMPLETED	202	201	205
NOT COMPLETED	14	16	10

Baseline Characteristics

Arm/Group Title	Methotrexate	Upadacitinib 15 mg	Upadacitinib 30 mg	Total
Arm/Group Description	Participants randomized to receive up to 25 mg methotrexate once a week and placebo to upadacitinib once daily for 14 weeks in Period 1.	Participants randomized to receive upadacitinib 15 mg once daily and placebo to methotrexate once a week for 14 weeks in Period 1.	Participants randomized to receive upadacitinib 30 mg once daily and placebo to methotrexate once a week for 14 weeks in Period 1.	Total of all reporting groups
Overall Participants	216	217	215	648
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55.3 (11.12)	54.5 (12.20)	53.1 (12.72)	54.3 (12.05)
Age, Customized (Count of Participants)
< 40 years	23 10.6%	28 12.9%	31 14.4%	82 12.7%
40 - 64 years	148 68.5%	147 67.7%	141 65.6%	436 67.3%
≥ 65 years	45 20.8%	42 19.4%	43 20%	130 20.1%
Sex: Female, Male (Count of Participants)
Female	179 82.9%	174 80.2%	170 79.1%	523 80.7%
Male	37 17.1%	43 19.8%	45 20.9%	125 19.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	50 23.1%	52 24%	54 25.1%	156 24.1%
Not Hispanic or Latino	166 76.9%	165 76%	161 74.9%	492 75.9%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
White	176 81.5%	173 79.7%	180 83.7%	529 81.6%
Black or African American	11 5.1%	15 6.9%	9 4.2%	35 5.4%
American Indian/Alaska Native	3 1.4%	4 1.8%	3 1.4%	10 1.5%
Asian	24 11.1%	24 11.1%	21 9.8%	69 10.6%
Multiple	2 0.9%	1 0.5%	2 0.9%	5 0.8%
Geographic Region (Count of Participants)
North America	64 29.6%	64 29.5%	64 29.8%	192 29.6%
South/Central America	31 14.4%	30 13.8%	30 14%	91 14%
Western Europe	8 3.7%	8 3.7%	8 3.7%	24 3.7%
Eastern Europe	79 36.6%	80 36.9%	80 37.2%	239 36.9%
Asia - Japan	22 10.2%	22 10.1%	21 9.8%	65 10%
Other	12 5.6%	13 6%	12 5.6%	37 5.7%
Duration of RA Diagnosis (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	5.8 (6.63)	7.5 (8.88)	6.5 (6.98)	6.6 (7.58)
Tender Joint Count (joints) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [joints]	25.2 (15.99)	24.5 (15.10)	24.8 (15.19)	24.8 (15.41)
Swollen Joint Count (joints) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [joints]	16.9 (11.52)	16.4 (10.94)	16.9 (10.23)	16.7 (10.90)
Patient's Assessment of Pain (mm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mm]	62.5 (21.26)	62.3 (22.53)	61.9 (22.12)	62.3 (21.94)
Patient's Global Assessment of Disease Activity (mm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mm]	59.6 (21.78)	62.2 (22.29)	59.4 (22.79)	60.4 (22.29)
Physician's Global Assessment of Disease Activity (mm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mm]	62.1 (17.47)	65.7 (18.49)	62.6 (17.81)	63.5 (17.98)
Health Assessment Questionnaire - Disability Index (HAQ-DI) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	1.5 (0.66)	1.5 (0.66)	1.5 (0.65)	1.5 (0.66)
High-sensitivity C-reactive Protein (hsCRP) (mg/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/L]	14.5 (17.33)	14.0 (16.49)	16.3 (20.77)	14.9 (18.28)
Disease Activity Score 28 Based on CRP (DAS28[CRP]) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	5.6 (1.04)	5.6 (0.92)	5.6 (1.06)	5.6 (1.01)

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response at Week 14
Description	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: ≥ 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 14

Outcome Measure Data

Analysis Population Description

Full analysis set; participants who prematurely discontinued from study drug prior to Week 14 or for whom ACR data were missing at Week 14 were considered non-responders.

Arm/Group Title	Methotrexate	Upadacitinib 15 mg	Upadacitinib 30 mg
Arm/Group Description	Participants randomized to receive up to 25 mg methotrexate once a week and placebo to upadacitinib once daily for 14 weeks in Period 1.	Participants randomized to receive upadacitinib 15 mg once daily and placebo to methotrexate once a week for 14 weeks in Period 1.	Participants randomized to receive upadacitinib 30 mg once daily and placebo to methotrexate once a week for 14 weeks in Period 1.
Measure Participants	216	217	215
Number (95% Confidence Interval) [percentage of participants]	41.2 19.1%	67.7 31.2%	71.2 33.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Methotrexate, Upadacitinib 15 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	The overall type I error prevalence of the primary and ranked key secondary endpoints for the two doses of upadacitinib were strongly controlled by means of a graphic 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 stratification factor geographic region.
Method of Estimation	Estimation Parameter	Response Rate Difference
	Estimated Value	26.5
	Confidence Interval	(2-Sided) 95%; 17.5 to 35.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Response Rate Difference = Upadacitinib - Methotrexate

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Methotrexate, Upadacitinib 30 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	The overall type I error prevalence of the primary and ranked key secondary endpoints for the two doses of upadacitinib were strongly controlled by means of a graphic 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 stratification factor geographic region.
Method of Estimation	Estimation Parameter	Response Rate Difference
	Estimated Value	30.0
	Confidence Interval	(2-Sided) 95%; 21.0 to 38.9
	Parameter Dispersion	Type: Value:
	Estimation Comments	Response Rate Difference = Upadacitinib - Methotrexate

2. Primary Outcome

Title	Percentage of Participants Achieving Low Disease Activity (LDA) Based on DAS28(CRP) at Week 14
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 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 or equal to 3.2 indicates low disease activity.
Time Frame	Week 14

Outcome Measure Data

Analysis Population Description

Full analysis set; participants who prematurely discontinued from study drug prior to Week 14 or for whom DAS28 data were missing at Week 14 were considered non-responders.

Arm/Group Title	Methotrexate	Upadacitinib 15 mg	Upadacitinib 30 mg
Arm/Group Description	Participants randomized to receive up to 25 mg methotrexate once a week and placebo to upadacitinib once daily for 14 weeks in Period 1.	Participants randomized to receive upadacitinib 15 mg once daily and placebo to methotrexate once a week for 14 weeks in Period 1.	Participants randomized to receive upadacitinib 30 mg once daily and placebo to methotrexate once a week for 14 weeks in Period 1.
Measure Participants	216	217	215
Number (95% Confidence Interval) [percentage of participants]	19.4 9%	44.7 20.6%	53.0 24.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Methotrexate, Upadacitinib 15 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	The overall type I error prevalence of the primary and ranked key secondary endpoints for the two doses of upadacitinib were strongly controlled by means of a graphic 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 stratification factor geographic region.
Method of Estimation	Estimation Parameter	Response Rate Difference
	Estimated Value	25.3
	Confidence Interval	(2-Sided) 95%; 16.8 to 33.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	Response Rate Difference = Upadacitinib - Methotrexate

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Methotrexate, Upadacitinib 30 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	The overall type I error prevalence of the primary and ranked key secondary endpoints for the two doses of upadacitinib were strongly controlled by means of a graphic 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 stratification factor geographic region.
Method of Estimation	Estimation Parameter	Response Rate Difference
	Estimated Value	33.6
	Confidence Interval	(2-Sided) 95%; 25.1 to 42.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	Response Rate Difference = Upadacitinib - Methotrexate

3. Secondary Outcome

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

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	Methotrexate	Upadacitinib 15 mg	Upadacitinib 30 mg
Arm/Group Description	Participants randomized to receive up to 25 mg methotrexate once a week and placebo to upadacitinib once daily for 14 weeks in Period 1.	Participants randomized to receive upadacitinib 15 mg once daily and placebo to methotrexate once a week for 14 weeks in Period 1.	Participants randomized to receive upadacitinib 30 mg once daily and placebo to methotrexate once a week for 14 weeks in Period 1.
Measure Participants	215	215	213
Least Squares Mean (95% Confidence Interval) [scores on a scale]	-1.20	-2.29	-2.61

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Methotrexate, Upadacitinib 15 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	The overall type I error prevalence of the primary and ranked key secondary endpoints for the two doses of upadacitinib were strongly controlled by means of a graphic 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 as the fixed factor, and baseline value and geographic region as the covariates.
Method of Estimation	Estimation Parameter	Least Squares (LS) Mean Difference
	Estimated Value	-1.08
	Confidence Interval	(2-Sided) 95%; -1.32 to -0.85
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference = Upadacitinib - Methotrexate

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Methotrexate, Upadacitinib 30 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	The overall type I error prevalence of the primary and ranked key secondary endpoints for the two doses of upadacitinib were strongly controlled by means of a graphic 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 as the fixed factor, and baseline value and the stratification factor geographic region as the covariates.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-1.40
	Confidence Interval	(2-Sided) 95%; -1.64 to -1.17
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference = Upadacitinib - Methotrexate

4. Secondary Outcome

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

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	Methotrexate	Upadacitinib 15 mg	Upadacitinib 30 mg
Arm/Group Description	Participants randomized to receive up to 25 mg methotrexate once a week and placebo to upadacitinib once daily for 14 weeks in Period 1.	Participants randomized to receive upadacitinib 15 mg once daily and placebo to methotrexate once a week for 14 weeks in Period 1.	Participants randomized to receive upadacitinib 30 mg once daily and placebo to methotrexate once a week for 14 weeks in Period 1.
Measure Participants	216	216	215
Least Squares Mean (95% Confidence Interval) [scores on a scale]	-0.32	-0.65	-0.73

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Methotrexate, Upadacitinib 15 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	The overall type I error prevalence of the primary and ranked key secondary endpoints for the two doses of upadacitinib were strongly controlled by means of a graphic 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 as the fixed factor, and baseline value and the stratification factor geographic region as the covariates.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.33
	Confidence Interval	(2-Sided) 95%; -0.43 to -0.22
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference = Upadacitinib - Methotrexate

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Methotrexate, Upadacitinib 30 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	The overall type I error prevalence of the primary and ranked key secondary endpoints for the two doses of upadacitinib were strongly controlled by means of a graphic 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 as the fixed factor, and baseline value and the stratification factor geographic region as the covariates.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.41
	Confidence Interval	(2-Sided) 95%; -0.51 to -0.30
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference = Upadacitinib - Methotrexate

5. Secondary Outcome

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

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 14 was used.

Arm/Group Title	Methotrexate	Upadacitinib 15 mg	Upadacitinib 30 mg
Arm/Group Description	Participants randomized to receive up to 25 mg methotrexate once a week and placebo to upadacitinib once daily for 14 weeks in Period 1.	Participants randomized to receive upadacitinib 15 mg once daily and placebo to methotrexate once a week for 14 weeks in Period 1.	Participants randomized to receive upadacitinib 30 mg once daily and placebo to methotrexate once a week for 14 weeks in Period 1.
Measure Participants	195	200	201
Least Squares Mean (95% Confidence Interval) [scores on a scale]	4.32	8.28	10.19

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Methotrexate, Upadacitinib 15 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	The overall type I error prevalence of the primary and ranked key secondary endpoints for the two doses of upadacitinib were strongly controlled by means of a graphic 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, treatment-by-visit interaction, and geographic region, and the baseline value as covariate.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	3.97
	Confidence Interval	(2-Sided) 95%; 2.52 to 5.42
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference = Upadacitinib - Methotrexate

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Methotrexate, Upadacitinib 30 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	The overall type I error prevalence of the primary and ranked key secondary endpoints for the two doses of upadacitinib were strongly controlled by means of a graphic 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, treatment-by-visit interaction, and geographic region, and the baseline value as covariate.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	5.87
	Confidence Interval	(2-Sided) 95%; 4.42 to 7.32
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference = Upadacitinib - Methotrexate

6. Secondary Outcome

Title	Percentage of Participants Achieving Clinical Remission (CR) Based on DAS28(CRP) at Week 14
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 DAS28 score less than 2.6 indicates clinical remission.
Time Frame	Week 14

Outcome Measure Data

Analysis Population Description

Full analysis set; participants who prematurely discontinued from study drug prior to Week 14 or for whom DAS28 data were missing at Week 14 were considered non-responders

Arm/Group Title	Methotrexate	Upadacitinib 15 mg	Upadacitinib 30 mg
Arm/Group Description	Participants randomized to receive up to 25 mg methotrexate once a week and placebo to upadacitinib once daily for 14 weeks in Period 1.	Participants randomized to receive upadacitinib 15 mg once daily and placebo to methotrexate once a week for 14 weeks in Period 1.	Participants randomized to receive upadacitinib 30 mg once daily and placebo to methotrexate once a week for 14 weeks in Period 1.
Measure Participants	216	217	215
Number (95% Confidence Interval) [percentage of participants]	8.3 3.8%	28.1 12.9%	40.5 18.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Methotrexate, Upadacitinib 15 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	The overall type I error prevalence of the primary and ranked key secondary endpoints for the two doses of upadacitinib were strongly controlled by means of a graphic 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 stratification factor geographic region.
Method of Estimation	Estimation Parameter	Response Rate Difference
	Estimated Value	19.8
	Confidence Interval	(2-Sided) 95%; 12.8 to 26.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Response Rate Difference = Upadacitinib - Methotrexate

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Methotrexate, Upadacitinib 30 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	The overall type I error prevalence of the primary and ranked key secondary endpoints for the two doses of upadacitinib were strongly controlled by means of a graphic 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 stratification factor geographic region.
Method of Estimation	Estimation Parameter	Response Rate Difference
	Estimated Value	32.1
	Confidence Interval	(2-Sided) 95%; 24.6 to 39.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	Response Rate Difference = Upadacitinib - Methotrexate

7. Secondary Outcome

Title	Change From Baseline in Duration of Morning Stiffness at Week 14
Description	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.
Time Frame	Baseline to week 14

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 14 was used.

Arm/Group Title	Methotrexate	Upadacitinib 15 mg	Upadacitinib 30 mg
Arm/Group Description	Participants randomized to receive up to 25 mg methotrexate once a week and placebo to upadacitinib once daily for 14 weeks in Period 1.	Participants randomized to receive upadacitinib 15 mg once daily and placebo to methotrexate once a week for 14 weeks in Period 1.	Participants randomized to receive upadacitinib 30 mg once daily and placebo to methotrexate once a week for 14 weeks in Period 1.
Measure Participants	196	199	202
Least Squares Mean (95% Confidence Interval) [minutes]	-53.03	-94.56	-102.34

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Methotrexate, Upadacitinib 15 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	The overall type I error prevalence of the primary and ranked key secondary endpoints for the two doses of upadacitinib were strongly controlled by means of a graphic 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, treatment-by-visit interaction, and geographic region, and the baseline value as covariate.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-41.53
	Confidence Interval	(2-Sided) 95%; -66.56 to -16.50
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference = Upadacitinib - Methotrexate

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Methotrexate, Upadacitinib 30 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	The overall type I error prevalence of the primary and ranked key secondary endpoints for the two doses of upadacitinib were strongly controlled by means of a graphic 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, treatment-by-visit interaction, and geographic region, and the baseline value as covariate.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-49.31
	Confidence Interval	(2-Sided) 95%; -74.23 to -24.40
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference = Upadacitinib - Methotrexate

8. Secondary Outcome

Title	Percentage of Participants With an American College of Rheumatology 50% (ACR50) Response at Week 14
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 14

Outcome Measure Data

Analysis Population Description

Full analysis set; participants who prematurely discontinued from study drug prior to Week 14 or for whom ACR data were missing at Week 14 were considered non-responders.

Arm/Group Title	Methotrexate	Upadacitinib 15 mg	Upadacitinib 30 mg
Arm/Group Description	Participants randomized to receive up to 25 mg methotrexate once a week and placebo to upadacitinib once daily for 14 weeks in Period 1.	Participants randomized to receive upadacitinib 15 mg once daily and placebo to methotrexate once a week for 14 weeks in Period 1.	Participants randomized to receive upadacitinib 30 mg once daily and placebo to methotrexate once a week for 14 weeks in Period 1.
Measure Participants	216	217	215
Number (95% Confidence Interval) [percentage of participants]	15.3 7.1%	41.9 19.3%	52.1 24.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Methotrexate, Upadacitinib 15 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	This comparison was not part of the pre-specified multiplicity testing sequence; the nominal p-value is reported.
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusted for stratification factor geographic region.
Method of Estimation	Estimation Parameter	Response Rate Difference
	Estimated Value	26.7
	Confidence Interval	(2-Sided) 95%; 18.5 to 34.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Response Rate Difference = Upadacitinib - Methotrexate

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Methotrexate, Upadacitinib 30 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	This comparison was not part of the pre-specified multiplicity testing sequence; the nominal p-value is reported.
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusted for stratification factor geographic region.
Method of Estimation	Estimation Parameter	Response Rate Difference
	Estimated Value	36.8
	Confidence Interval	(2-Sided) 95%; 28.6 to 45.0
	Parameter Dispersion	Type: Value:
	Estimation Comments	Response Rate Difference = Upadacitinib - Methotrexate

9. Secondary Outcome

Title	Percentage of Participants With an American College of Rheumatology 70% (ACR70) Response at Week 14
Description	Participants who met the following 3 conditions for improvement from baseline were classified as meeting the ACR50 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 14

Outcome Measure Data

Analysis Population Description

Full analysis set; participants who prematurely discontinued from study drug prior to Week 14 or for whom ACR data were missing at Week 14 were considered non-responders.

Arm/Group Title	Methotrexate	Upadacitinib 15 mg	Upadacitinib 30 mg
Arm/Group Description	Participants randomized to receive up to 25 mg methotrexate once a week and placebo to upadacitinib once daily for 14 weeks in Period 1.	Participants randomized to receive upadacitinib 15 mg once daily and placebo to methotrexate once a week for 14 weeks in Period 1.	Participants randomized to receive upadacitinib 30 mg once daily and placebo to methotrexate once a week for 14 weeks in Period 1.
Measure Participants	216	217	215
Number (95% Confidence Interval) [percentage of participants]	2.8 1.3%	22.6 10.4%	33.0 15.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Methotrexate, Upadacitinib 15 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	This comparison was not part of the pre-specified multiplicity testing sequence; the nominal p-value is reported.
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusted for stratification factor geographic region.
Method of Estimation	Estimation Parameter	Response Rate Difference
	Estimated Value	19.8
	Confidence Interval	(2-Sided) 95%; 13.8 to 25.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Response Rate Difference = Upadacitinib - Methotrexate

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Methotrexate, Upadacitinib 30 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	This comparison was not part of the pre-specified multiplicity testing sequence; the nominal p-value is reported.
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test adjusted for stratification factor geographic region.
Method of Estimation	Estimation Parameter	Response Rate Difference
	Estimated Value	30.2
	Confidence Interval	(2-Sided) 95%; 23.6 to 36.9
	Parameter Dispersion	Type: Value:
	Estimation Comments	Response Rate Difference = Upadacitinib - Methotrexate

Adverse Events

Time Frame	14 weeks
Arm/Group Title	Methotrexate		Upadacitinib 15 mg		Upadacitinib 30 mg
Arm/Group Description	Participants received up to 25 mg methotrexate once a week and placebo to upadacitinib once daily for 14 weeks in Period 1		Participants received upadacitinib 15 mg once daily and placebo to methotrexate once a week for 14 weeks in Period 1.		Participants received upadacitinib 30 mg once daily and placebo to methotrexate once a week for 14 weeks in Period 1.
All Cause Mortality
	Methotrexate		Upadacitinib 15 mg		Upadacitinib 30 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/216 (0%)		1/217 (0.5%)		0/215 (0%)
Serious Adverse Events
	Methotrexate		Upadacitinib 15 mg		Upadacitinib 30 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/216 (2.8%)		11/217 (5.1%)		6/215 (2.8%)
Cardiac disorders
ATRIAL FIBRILLATION	1/216 (0.5%)	1	1/217 (0.5%)	1	0/215 (0%)	0
MYOCARDIAL INFARCTION	0/216 (0%)	0	0/217 (0%)	0	1/215 (0.5%)	1
SINUS TACHYCARDIA	0/216 (0%)	0	1/217 (0.5%)	1	0/215 (0%)	0
General disorders
CHEST PAIN	0/216 (0%)	0	1/217 (0.5%)	1	0/215 (0%)	0
PYREXIA	0/216 (0%)	0	1/217 (0.5%)	1	0/215 (0%)	0
Hepatobiliary disorders
CHOLECYSTITIS ACUTE	2/216 (0.9%)	2	0/217 (0%)	0	0/215 (0%)	0
CHOLELITHIASIS	0/216 (0%)	0	0/217 (0%)	0	2/215 (0.9%)	2
Infections and infestations
ABSCESS LIMB	0/216 (0%)	0	1/217 (0.5%)	1	0/215 (0%)	0
UROSEPSIS	1/216 (0.5%)	1	0/217 (0%)	0	0/215 (0%)	0
Injury, poisoning and procedural complications
HUMERUS FRACTURE	0/216 (0%)	0	0/217 (0%)	0	1/215 (0.5%)	1
JOINT DISLOCATION	0/216 (0%)	0	0/217 (0%)	0	1/215 (0.5%)	1
Musculoskeletal and connective tissue disorders
MUSCULOSKELETAL CHEST PAIN	1/216 (0.5%)	1	0/217 (0%)	0	0/215 (0%)	0
RHEUMATOID ARTHRITIS	0/216 (0%)	0	1/217 (0.5%)	1	1/215 (0.5%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
BREAST CANCER	0/216 (0%)	0	1/217 (0.5%)	1	0/215 (0%)	0
NON-HODGKIN'S LYMPHOMA	0/216 (0%)	0	1/217 (0.5%)	1	0/215 (0%)	0
Nervous system disorders
HAEMORRHAGIC STROKE	0/216 (0%)	0	1/217 (0.5%)	1	0/215 (0%)	0
ISCHAEMIC STROKE	0/216 (0%)	0	0/217 (0%)	0	1/215 (0.5%)	1
Renal and urinary disorders
NEPHROLITHIASIS	1/216 (0.5%)	1	0/217 (0%)	0	0/215 (0%)	0
Respiratory, thoracic and mediastinal disorders
CHRONIC OBSTRUCTIVE PULMONARY DISEASE	0/216 (0%)	0	1/217 (0.5%)	1	0/215 (0%)	0
PULMONARY EMBOLISM	0/216 (0%)	0	1/217 (0.5%)	1	0/215 (0%)	0
Vascular disorders
HYPERTENSION	0/216 (0%)	0	1/217 (0.5%)	1	0/215 (0%)	0
Other (Not Including Serious) Adverse Events
	Methotrexate		Upadacitinib 15 mg		Upadacitinib 30 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/216 (6%)		9/217 (4.1%)		6/215 (2.8%)
Infections and infestations
UPPER RESPIRATORY TRACT INFECTION	13/216 (6%)	16	9/217 (4.1%)	9	6/215 (2.8%)	6

Limitations/Caveats

[Not Specified]

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Principal Investigators are NOT employed by the organization sponsoring the study.

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