Clinical trial NCT02706951: A Study Comparing Upadacitinib (ABT-494) Monotherapy to Methotrexate (MTX) Monotherapy in Adults With Rheumatoid Arthritis (RA) Who Have an Inadequate Response to MTX (SELECT-MONOTHERAPY)
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Rheumatoid Arthritis
Keywords: Musculoskeletal Disease
Arthritis
Joint Disease
Anti-inflammatory agents
Antirheumatic agents
Upadacitinib
ABT-494
Lead sponsor: AbbVie
Sponsor class: INDUSTRY
First posted: 2016-03-11
Enrollment: 648
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response at Week 14
timeFrame: Baseline and week 14
measure: Percentage of Participants Achieving Low Disease Activity (LDA) Based on DAS28(CRP) at Week 14
timeFrame: Week 14
Secondary outcomes:
measure: Change From Baseline in in Disease Activity Score 28 (CRP) at Week 14
timeFrame: Baseline to week 14
measure: Change From Baseline in Heath Assessment Questionnaire and Disability Index (HAQ-DI) at Week 14
timeFrame: Baseline to week 14
measure: Change From Baseline in Short-Form 36 (SF-36) Physical Component Score (PCS) at Week 14
timeFrame: Baseline to week 14
measure: Percentage of Participants Achieving Clinical Remission (CR) Based on DAS28(CRP) at Week 14
timeFrame: Week 14
measure: Change From Baseline in Duration of Morning Stiffness at Week 14
timeFrame: Baseline to week 14
measure: Percentage of Participants With an American College of Rheumatology 50% (ACR50) Response at Week 14
timeFrame: Baseline and week 14
measure: Percentage of Participants With an American College of Rheumatology 70% (ACR70) Response at Week 14
timeFrame: Baseline and week 14
Other outcomes:
Locations:
city: Huntsville
country: United States
facility: Rheum Assoc of North Alabama /ID# 146009
state: Alabama
city: Mobile
country: United States
facility: Alabama Medical Group, PC /ID# 153941
state: Alabama
city: Gilbert
country: United States
facility: ArthroCare Arthritis Care & Re /ID# 143751
state: Arizona
city: Phoenix
country: United States
facility: Elite Clinical Studies, LLC /ID# 143760
state: Arizona
city: Tucson
country: United States
facility: University of Arizona Cancer Center - North Campus /ID# 147175
state: Arizona
city: Jonesboro
country: United States
facility: NEA Baptist Womens Clinic /ID# 148904
state: Arkansas
city: Hemet
country: United States
facility: C.V. Mehta MD, Med Corporation /ID# 143762
state: California
city: Colorado Springs
country: United States
facility: Arthritis Assoc & Osteo Ctr /ID# 147176
state: Colorado
city: Fort Lauderdale
country: United States
facility: Ctr Rheum, Immuno, Arthritis /ID# 143766
state: Florida
city: Miami Springs
country: United States
facility: South Florida Research Ph I-IV /ID# 151983
state: Florida
city: Pinellas Park
country: United States
facility: Advent Clinical Research /ID# 143767
state: Florida
city: Sarasota
country: United States
facility: Sarasota Arthritis Center /ID# 146011
state: Florida
city: Tamarac
country: United States
facility: W. Broward Rheum Assoc Inc. /ID# 146010
state: Florida
city: Tampa
country: United States
facility: Clinical Research West FL /ID# 148726
state: Florida
city: Tampa
country: United States
facility: SW FL Clin Res Ctr, Tampa, FL /ID# 143763
state: Florida
city: Tampa
country: United States
facility: University of South Florida /ID# 146004
state: Florida
city: Tampa
country: United States
facility: BayCare Medical Group, Inc. /ID# 151985
state: Florida
city: Tampa
country: United States
facility: BayCare Medical Group, Inc. /ID# 163595
state: Florida
city: Decatur
country: United States
facility: Jefrey D. Lieberman, MD, P.C. /ID# 151816
state: Georgia
city: Chicago
country: United States
facility: Great Lakes Clinical Trials /ID# 150935
state: Illinois
city: Wichita
country: United States
facility: PRN Professional Research Network of Kansas, LLC /ID# 143761
state: Kansas
city: Baton Rouge
country: United States
facility: Ochsner Clinic Foundation /ID# 153573
state: Louisiana
city: Monroe
country: United States
facility: The Arthritis & Diabetes Clinic, Inc. /ID# 160809
state: Louisiana
city: Shreveport
country: United States
facility: Vanguard Medical Research, LLC /ID# 153124
state: Louisiana
city: Mansfield
country: United States
facility: Mansfield Health Center /ID# 161627
state: Massachusetts
city: Omaha
country: United States
facility: Quality Clinical Research Inc. /ID# 156415
state: Nebraska
city: Lebanon
country: United States
facility: Dartmouth-Hitchcock Medical Center /ID# 146008
state: New Hampshire
city: Albuquerque
country: United States
facility: Albuquerque Clinical Trials, Inc /ID# 147618
state: New Mexico
city: Las Cruces
country: United States
facility: Arthritis and Osteo Assoc /ID# 147177
state: New Mexico
city: New Bern
country: United States
facility: Coastal Carolina Health Care /ID# 149275
state: North Carolina
city: Vandalia
country: United States
facility: STAT Research, Inc. /ID# 143770
state: Ohio
city: Oklahoma City
country: United States
facility: Health Research Oklahoma /ID# 159550
state: Oklahoma
city: Tulsa
country: United States
facility: Healthcare Research Consultant /ID# 147632
state: Oklahoma
city: Greenville
country: United States
facility: Innovative Clinical Research /ID# 143757
state: South Carolina
city: Nashville
country: United States
facility: Nashville Arthritis and Rheumatology /ID# 162641
state: Tennessee
city: Austin
country: United States
facility: Tekton Research, Inc. /ID# 159554
state: Texas
city: Beaumont
country: United States
facility: Diagnostic Group Integrated He /ID# 148725
state: Texas
city: Carrollton
country: United States
facility: Trinity Universal Res Assoc /ID# 150138
state: Texas
city: College Station
country: United States
facility: Arth and Osteo Clin Brazo Valley /ID# 160810
state: Texas
city: Corpus Christi
country: United States
facility: Adriana Pop-Moody MD Clinic PA /ID# 147627
state: Texas
city: Houston
country: United States
facility: Accurate Clinical Management /ID# 143768
state: Texas
city: Houston
country: United States
facility: Accurate Clinical Research /ID# 143769
state: Texas
city: Houston
country: United States
facility: Pioneer Research Solutions, Inc. /ID# 143765
state: Texas
city: Lufkin
country: United States
facility: P&I Clinical Research /ID# 151358
state: Texas
city: Mesquite
country: United States
facility: SW Rheumatology Res. LLC /ID# 147620
state: Texas
city: San Antonio
country: United States
facility: Sun Research Institute /ID# 159553
state: Texas
city: San Marcos
country: United States
facility: Arthritis Clinic of Central TX /ID# 149266
state: Texas
city: The Woodlands
country: United States
facility: Adv Rheumatology of Houston /ID# 162609
state: Texas
city: Tomball
country: United States
facility: DM Clinical Research /ID# 151359
state: Texas
city: Waco
country: United States
facility: Arthritis & Osteoporosis Clinic /ID# 143752
state: Texas
city: Chesapeake
country: United States
facility: Ctr for Arth and Rheum Disease /ID# 143759
state: Virginia
city: Franklin
country: United States
facility: Aurora Rheumatology and Immunotherapy Center /ID# 160811
state: Wisconsin
city: Buenos Aires
country: Argentina
facility: Mautalen Salud e Investigacion /ID# 145980
city: Buenos Aires
country: Argentina
facility: Ctr Privado Med Familiar /ID# 149183
city: Buenos Aires
country: Argentina
facility: Consultorio Reumatologic Pampa /ID# 145979
city: Buenos Aires
country: Argentina
facility: Centro de Educación Médica e Investigaciones Clínicas "Norberto Quimo" - CEMIC /ID# 149176
city: Salta
country: Argentina
facility: Cordis S.A. /Id# 152621
city: Santa Fe
country: Argentina
facility: Centro de Enfermedades /ID# 153543
city: Camperdown
country: Australia
facility: Royal Prince Alfred Hospital /ID# 146028
state: New South Wales
city: Wien
country: Austria
facility: Rheuma-Zentrum Wien-Oberlaa /ID# 144728
city: Aalst
country: Belgium
facility: Algemeen Stedelijk Ziekenhuis /ID# 148720
state: Oost-Vlaanderen
city: Genk
country: Belgium
facility: ReumaClinic Genk /ID# 146030
city: Sofia
country: Bulgaria
facility: Diag Consult Ctr 17 Sofia EOOD /ID# 144730
city: Sofia
country: Bulgaria
facility: UMHAT Sv. Ivan Rilski /ID# 147351
city: Concepcion
country: Chile
facility: Reg. Clinical Hosptial Concepcion /ID# 151267
city: Puerto Varas
country: Chile
facility: Quantum Research LTDA. /ID# 145984
city: Santiago
country: Chile
facility: Quantum Research Stgo. /ID# 145983
city: Olomouc
country: Czechia
facility: CTCenter MaVe, s.r.o. /ID# 144823
state: Olomoucky Kraj
city: Prague 4
country: Czechia
facility: Nuselská poliklinika, Revmatologie /ID# 145986
state: Praha 4
city: Prague 4
country: Czechia
facility: Thomayerova nemocnice /ID# 144736
state: Praha 4
city: Breclav
country: Czechia
facility: RHEUMA s.r.o. /ID# 144737
city: Uherské Hradište
country: Czechia
facility: Medical Plus, s.r.o. /ID# 144821
city: Tartu
country: Estonia
facility: MediTrials /ID# 159745
state: Tartumaa
city: Tallinn
country: Estonia
facility: North Estonian Medical Centre /ID# 145455
city: Athens
country: Greece
facility: General Hospital of Athens "Ippokratio" /ID# 144739
city: Veszprém
country: Hungary
facility: Vital Medical Center Orvosi es /ID# 144740
state: Veszprem
city: Budapest
country: Hungary
facility: Magyar Honvedseg Egeszsegugyi Kozpont /ID# 144743
city: Kistarcsa
country: Hungary
facility: Pest Megyei Flor Ferenc Korhaz /ID# 144742
city: Szekesfehervar
country: Hungary
facility: Fejer Megyei Szent Gyorgy Korh /ID# 144741
city: Ashkelon
country: Israel
facility: Barzilai Medical Center /ID# 144744
city: Haifa
country: Israel
facility: Bnai Zion Medical Center /ID# 144745
city: Haifa
country: Israel
facility: The Lady Davis Carmel MC /ID# 147174
city: Ramat Gan
country: Israel
facility: Sheba Medical Center /ID# 144824
city: Catanzaro
country: Italy
facility: Universita di Catanzaro Magna Graecia /ID# 144747
state: Calabria
city: Verona
country: Italy
facility: A.O.U.I. di Verona Policlinico /ID# 144746
city: Fukuoka-shi
country: Japan
facility: Kondo Clinic for Rheum & Ortho /ID# 148268
state: Fukuoka
city: Fukuoka-shi
country: Japan
facility: NHO Kyushu Medical Center /ID# 148279
state: Fukuoka
city: Fukuoka-shi
country: Japan
facility: NHO Kyushu Medical Center /ID# 148280
state: Fukuoka
city: Iizuka-shi
country: Japan
facility: Aso Iizuka Hospital /ID# 148272
state: Fukuoka
city: Takasaki
country: Japan
facility: Inoue Hospital /ID# 148069
state: Gunma
city: Kochi-shi
country: Japan
facility: Bay Side Misato Medical Center /ID# 148281
state: Kochi
city: Kumamoto-shi
country: Japan
facility: Center for Arthritis and Clinical Rheumatology Matsubara Clinic /ID# 148269
state: Kumamoto
city: Kumamoto-shi
country: Japan
facility: Kumamoto Shinto General Hospital /ID# 148286
state: Kumamoto
city: Nagasaki-shi
country: Japan
facility: Nagasaki University Hospital /ID# 149859
state: Nagasaki
city: Sasebo-city
country: Japan
facility: Sasebo Chuo Hospital /ID# 148275
state: Nagasaki
city: Osaka-shi
country: Japan
facility: Osaka Red Cross Hospital /ID# 148267
state: Osaka
city: Hamamatsu
country: Japan
facility: Seirei Hamamatsu General Hosp /ID# 148270
city: Hyuga
country: Japan
facility: Ohira Orthopaedic Hospital /ID# 157944
city: Nishimura
country: Japan
facility: Shirahama Hamayu Hospital /ID# 148277
city: Sanuki
country: Japan
facility: Sanuki Municipal Hospital /ID# 158080
city: Sapporo
country: Japan
facility: Hokkaido University Hospital /ID# 148285
city: Sapporo
country: Japan
facility: Hokkaido Medical Center for Rheumatic Diseases /ID# 148274
city: Shunan
country: Japan
facility: Miyasato Clinic /ID# 148271
city: Takaoka
country: Japan
facility: Takaoka Rheumatic Orthopedic Clinic /ID# 148068
city: Tokyo
country: Japan
facility: Matsuta Clinic /ID# 148278
city: Yotsukaido
country: Japan
facility: National Hospital Organization Shimoshizu National Hospital /ID# 148273
city: Monterrey
country: Mexico
facility: Desarrollos Biomedicos y Biotc /ID# 147379
state: Nuevo LEON
city: Mexico City
country: Mexico
facility: Cryptex Investigación Clínica S.A de C.V /ID# 147095
city: Wrocław
country: Poland
facility: WroMedica I. Bielicka, A. Strzalkowska s.c. /ID# 157622
state: Dolnoslaskie
city: Lublin
country: Poland
facility: REUMED Sp.z o.o. Filia nr 1 /ID# 144752
state: Lubelskie
city: Warszawa
country: Poland
facility: Centralny Szpital Kliniczny MSWiA w Warszawie /ID# 149521
state: Mazowieckie
city: Białystok
country: Poland
facility: Osteo-Medic spolka cywilna /ID# 144753
state: Podlaskie
city: Gdansk
country: Poland
facility: Centrum Badań Klinicznych Pi-House /ID# 149520
state: Pomorskie
city: Elblag
country: Poland
facility: NZOZ Centrum Reumatologiczne /ID# 144749
state: Warminsko-mazurskie
city: Poznań
country: Poland
facility: Medyczne Centrum Hetmanska /ID# 144751
state: Wielkopolskie
city: Lisbon
country: Portugal
facility: Instituto Portugues De Reumatologia /ID# 149281
state: Lisboa
city: Vila Nova De Gaia
country: Portugal
facility: Centro Hospitalar De Vila Nova /ID# 146036
state: Porto
city: Lisboa
country: Portugal
facility: Centro Hospitalar Lisboa Norte, EPE /ID# 146035
city: Porto
country: Portugal
facility: Centro Hospitalar Baixo Vouga /ID# 152916
city: Carolina
country: Puerto Rico
facility: Dr. Ramon L. Ortega-Colon, MD /ID# 145989
city: Ponce
country: Puerto Rico
facility: Ponce School of Medicine /ID# 145990
city: Ploiesti
country: Romania
facility: Spitalul Municipal Ploiesti /ID# 144756
city: Moscow
country: Russian Federation
facility: Clinical Hospital No.1 n.a. N.I.Pirogov /ID# 147255
state: Moskva
city: Novosibirsk
country: Russian Federation
facility: LLC Medical Center /ID# 144758
state: Novosibirskaya Oblast
city: Perm
country: Russian Federation
facility: Perm Clinical Center of FMBA /ID# 145993
state: Permskiy Kray
city: Tver
country: Russian Federation
facility: Tver Regional Clinical Hosp. /ID# 147254
state: Tverskaya Oblast
city: Ivanovo
country: Russian Federation
facility: Сity Clinical Hospital 4 /ID# 145994
city: Moscow
country: Russian Federation
facility: City Clinical Hospital Botkina /ID# 145995
city: Nizhnij Novgorod
country: Russian Federation
facility: City Clinical Hospital #5 /ID# 149832
city: Orenburg
country: Russian Federation
facility: Orenburg State Medical Academy /ID# 145992
city: Petrozavodsk
country: Russian Federation
facility: Republican Clin Hos n.a. Baran /ID# 147251
city: Samara
country: Russian Federation
facility: Samara Regional Clinical Hosp /ID# 150934
city: UFA
country: Russian Federation
facility: Reg Clin Hosp n.a. Kuvatova G. /ID# 144757
city: Yaroslavl
country: Russian Federation
facility: Yaroslavi State Medical Univer /ID# 147253
city: Belgrade
country: Serbia
facility: Institute for Rheumatology /ID# 144759
state: Beograd
city: Belgrade
country: Serbia
facility: Institute for Rheumatology /ID# 144761
state: Beograd
city: Belgrade
country: Serbia
facility: Institute for Rheumatology /ID# 144762
state: Beograd
city: Novi Sad
country: Serbia
facility: Special Hospital for Rheuma /ID# 144760
state: Vojvodina
city: Johannesburg
country: South Africa
facility: Wits Clinical Research Site /ID# 149835
state: Gauteng
city: Pretoria
country: South Africa
facility: University of Pretoria /ID# 148740
state: Gauteng
city: Cape Town
country: South Africa
facility: Synexus Helderberg Clinical Tr /ID# 148724
state: Western Cape
city: Cape Town
country: South Africa
facility: Tiervlei Trial Centre /ID# 153086
state: Western Cape
city: Barcelona
country: Spain
facility: Hospital Plató /ID# 145999
city: Barcelona
country: Spain
facility: Hospital Univ Germans Trias I /ID# 146037
city: Sevilla
country: Spain
facility: Hospital Infanta Luisa /ID# 144771
city: Sevilla
country: Spain
facility: Hospital Universitario de Valm /ID# 144770
city: Valencia
country: Spain
facility: Hospital Universitario La Fe /ID# 158013
city: Osmangazi
country: Turkey
facility: Uludağ Üniversitesi Atatürk Rehabilitasyon Uygulama ve Araştırma Merkezi /ID# 144772
state: Bursa
city: Lviv
country: Ukraine
facility: Lviv Regional Clinical Hospita /ID# 154448
state: Lvivska Oblast
city: Vinnytsia
country: Ukraine
facility: Vinnytsia Regional Clinical Hospital n.a. M.I.Pyrogov /ID# 146002
state: Vinnytska Oblast
city: Ivano-frankivsk
country: Ukraine
facility: Regional Clinical Hospital /ID# 152007
city: Kiev
country: Ukraine
facility: NSC-Strazhesko Ist Cardiology /ID# 152004
city: Zaporizhia
country: Ukraine
facility: Zaporizhzhia Regional Clinical /ID# 146000
Study officials:
affiliation: AbbVie
name: AbbVie Inc.
role: STUDY_DIRECTOR
References:
citation: 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.
citation: Bergman M, Buch MH, Tanaka Y, Citera G, Bahlas S, Wong E, Song Y, Zueger P, Ali M, Strand V. Routine Assessment of Patient Index Data 3 (RAPID3) in Patients with Rheumatoid Arthritis Treated with Long-Term Upadacitinib Therapy in Five Randomized Controlled Trials. Rheumatol Ther. 2022 Dec;9(6):1517-1529. doi: 10.1007/s40744-022-00483-4. Epub 2022 Sep 20.
citation: Bergman M, Tundia N, Yang M, Orvis E, Clewell J, Bensimon A. Economic Benefit from Improvements in Quality of Life with Upadacitinib: Comparisons with Tofacitinib and Methotrexate in Patients with Rheumatoid Arthritis. Adv Ther. 2021 Dec;38(12):5649-5661. doi: 10.1007/s12325-021-01930-4. Epub 2021 Oct 12.
citation: Yamaoka K, Tanaka Y, Kameda H, Khan N, Sasaki N, Harigai M, Song Y, Zhang Y, Takeuchi T. The Safety Profile of Upadacitinib in Patients with Rheumatoid Arthritis in Japan. Drug Saf. 2021 Jun;44(6):711-722. doi: 10.1007/s40264-021-01067-x. Epub 2021 May 27.
citation: Strand V, Tundia N, Wells A, Buch MH, Radominski SC, Camp HS, Friedman A, Suboticki JL, Dunlap K, Goldschmidt D, Bergman M. Upadacitinib monotherapy improves patient-reported outcomes in rheumatoid arthritis: results from SELECT-EARLY and SELECT-MONOTHERAPY. Rheumatology (Oxford). 2021 Jul 1;60(7):3209-3221. doi: 10.1093/rheumatology/keaa770.
citation: Cohen SB, van Vollenhoven RF, Winthrop KL, Zerbini CAF, Tanaka Y, Bessette L, Zhang Y, Khan N, Hendrickson B, Enejosa JV, Burmester GR. Safety profile of upadacitinib in rheumatoid arthritis: integrated analysis from the SELECT phase III clinical programme. Ann Rheum Dis. 2021 Mar;80(3):304-311. doi: 10.1136/annrheumdis-2020-218510. Epub 2020 Oct 28.
citation: Nader A, Mohamed MF, Winzenborg I, Doelger E, Noertersheuser P, Pangan AL, Othman AA. Exposure-Response Analyses of Upadacitinib Efficacy and Safety in Phase II and III Studies to Support Benefit-Risk Assessment in Rheumatoid Arthritis. Clin Pharmacol Ther. 2020 Apr;107(4):994-1003. doi: 10.1002/cpt.1671. Epub 2019 Nov 30.