Clinical trial NCT02066389: A Study Investigating the Efficacy and Safety of Upadacitinib (ABT-494) Given With Methotrexate (MTX) in Adults With Rheumatoid Arthritis Who Have Had an Inadequate Response to MTX Alone
Official title: A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study to Investigate the Safety and Efficacy of ABT-494 With Background Methotrexate (MTX) in Subjects With Active Rheumatoid Arthritis (RA) Who Have Had an Inadequate Response to MTX Alone
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Rheumatoid Arthritis
Keywords: Musculoskeletal Disease
Arthritis
Joint Diseases
anti-inflammatory agents
antirheumatic agents
Lead sponsor: AbbVie
Sponsor class: INDUSTRY
First posted: 2014-02-19
Enrollment: 300
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The primary objective of the study was to compare the safety and efficacy of multiple doses of upadacitinib versus placebo in adults with moderately to severely active rheumatoid arthritis (RA) on stable background methotrexate therapy who had not shown an adequate response to methotrexate alone.


Eligibility criteria: Inclusion Criteria:

1. Diagnosed with RA based on either the 1987-revised American College of Rheumatology (ACR) classification criteria or the 2010 ACR/European League against Rheumatism (EULAR) criteria for ≥ 3 months.
2. Have active RA as defined by the following minimum disease activity criteria:

   * ≥ 6 swollen joints (based on 66 joint counts) at Screening and Baseline Visits.
   * ≥ 6 tender joints (based on 68 joint counts) at Screening and Baseline Visits.
   * high-sensitivity C-reactive protein (hsCRP) \> upper limit of normal (ULN) OR positive for both rheumatoid factor and anti-cyclic citrullinated peptide (CCP) at Screening.
3. Subjects must have been receiving oral or parenteral methotrexate therapy ≥ 3 months and on a stable prescription of 7.5 to 25 mg/week for at least 4 weeks prior to Baseline Visit. Subjects should also be on a stable dose of folic acid (or equivalent) for at least 4 weeks prior to Baseline Visit. Subjects should continue with their stable doses of methotrexate and folic acid throughout the study.
4. Except for MTX, subjects must have discontinued all oral disease-modifying anti-rheumatic drugs (DMARDs) prior to Baseline Visit as specified below or for at least five times the mean terminal elimination half-life of a drug, whichever is longer:

   * ≥ 4 weeks prior to Baseline Visit for minocycline, penicillamine, sulfasalazine, hydroxychloroquine, chloroquine, azathioprine, gold formulations, cyclophosphamide
   * ≥ 8 weeks prior to Baseline Visit for leflunomide if no elimination procedure was followed, or adhere to a washout procedure (i.e., 11 days washout with colestyramine, or 30 days washout with activated charcoal)
5. Subject has a negative tuberculosis (TB) Screening Assessment. If the subject has evidence of a latent TB infection, the subject must initiate and complete a minimum of 2 weeks (or per local guidelines, whichever is longer) of an ongoing TB prophylaxis or have documented completion of a full course of TB prophylaxis, prior to Baseline Visit.
6. Subjects can be taking non-steroidal anti-inflammatory drugs (NSAIDS), acetaminophen, oral corticosteroids (equivalent to prednisone ≤ 10 mg), or inhaled corticosteroids at a stable dose for at least 4 weeks prior to Baseline Visit for stable medical conditions and should be kept at a stable dose throughout the study. NSAIDs, acetaminophen, tramadol, codeine, hydrocodone and propoxyphene taken as needed are allowed but may not be taken 24 hours prior to any study visit. Oral and inhaled corticosteroids taken as needed are allowed but may not be taken 24 hours prior to any study visit.
7. Subjects must have discontinued high potency opiates including (but not limited to): oxycodone, oxymorphone, fentanyl, levorphanol, buprenorphine, methadone, hydromorphone, and morphine at least 4 weeks prior to Baseline Visit.

Exclusion Criteria:

1. Female who is pregnant or breastfeeding.
2. Prior exposure to Janus activated kinase (JAK) inhibitor (e.g., tofacitinib, baricitinib).
3. Prior exposure to any investigational or approved biologic RA therapy.
4. Receipt of any investigational drug of chemical or biologic nature within a minimum of 30 days or 5 half-lives of the drug (whichever is longer) prior to Week 0 Visit.
5. Current or expected need of other immunosuppressant medications, except methotrexate. Use of oral intake of \> 10 mg prednisone/day or equivalent corticosteroid therapy (see inclusion criterion 7).
6. Subject has been treated with intra-articular or parenteral administration of corticosteroids in the preceding 8 weeks prior to the Week 0 Visit.
7. Screening laboratory values meeting the following criteria:

   * Serum aspartate transaminase (AST) or alanine transaminase (ALT) \> 1.5 × ULN
   * Estimated glomerular filtration rate (eGRF) by simplified 4-variable Modification of Diet in Renal Disease (MDRD) formula \< 40 mL/min/1.73 m²
   * Total white blood cell count (WBC) \< 3,000/µL
   * Absolute neutrophil count (ANC) \< 1,200/µL
   * Platelet count \< 100,000/µL
   * Absolute lymphocytes count \< 750/ µL
   * Hemoglobin \< 9 gm/dL

Primary outcomes:
measure: Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response at Week 12
timeFrame: Baseline and Week 12
Secondary outcomes:
measure: Percentage of Participants With an American College of Rheumatology 50% (ACR50) Response at Week 12
timeFrame: Baseline and Week 12
measure: Percentage of Participants With an American College of Rheumatology 70% (ACR70) Response at Week 12
timeFrame: Baseline and Week 12
measure: Percentage of Participants Achieving Low Disease Activity (LDA) Based on DAS28(CRP) at Week 12
timeFrame: Week 12
measure: Secondary: Percentage of Participants Achieving Clinical Remission (CR) Based on DAS28(CRP) at Week 12
timeFrame: Week 12
measure: Percentage of Participants Achieving Low Disease Activity (LDA) Based on CDAI at Week 12
timeFrame: Week 12
measure: Percentage of Participants Achieving Clinical Remission Based on CDAI at Week 12
timeFrame: Week 12
Other outcomes:
Locations:
city: Hemet
country: United States
facility: C.V. Mehta MD, Med Corporation /ID# 126380
state: California
city: DeBary
country: United States
facility: Omega Research Consultants, LLC /ID# 125780
state: Florida
city: Venice
country: United States
facility: Lovelace Scientific Resources /ID# 127324
state: Florida
city: Lawrenceville
country: United States
facility: North Georgia Rheumatology Grp /ID# 125779
state: Georgia
city: Wichita
country: United States
facility: PRN Professional Research Network of Kansas, LLC /ID# 126148
state: Kansas
city: Wheaton
country: United States
facility: The Center for Rheumatology & /ID# 127323
state: Maryland
city: Clifton
country: United States
facility: Summit Medical Group /ID# 125776
state: New Jersey
city: Las Cruces
country: United States
facility: Arthritis and Osteo Assoc /ID# 134994
state: New Mexico
city: Duncansville
country: United States
facility: Altoona Ctr Clinical Res /ID# 125777
state: Pennsylvania
city: Wyomissing
country: United States
facility: Emkey Arthritis and Osteo Clin /ID# 134716
state: Pennsylvania
city: Houston
country: United States
facility: Accurate Clinical Research /ID# 126535
state: Texas
city: Clarksburg
country: United States
facility: Mountain State Clinical Resear /ID# 127089
state: West Virginia
city: Plovdiv
country: Bulgaria
facility: MHAT Trimontsium /ID# 127311
city: Plovdiv
country: Bulgaria
facility: UMHAT Pulmed OOD /ID# 127307
city: Plovdiv
country: Bulgaria
facility: MHAT Kaspela /ID# 127315
city: Sofia
country: Bulgaria
facility: Diagnostic Consultative Center /ID# 127313
city: Sofia
country: Bulgaria
facility: UMHAT Sv. Ivan Rilski /ID# 127314
city: Sofia
country: Bulgaria
facility: UMHAT Sv. Ivan Rilski /ID# 131608
city: Varna
country: Bulgaria
facility: Diagnostic Consultative Center /ID# 127312
city: Osorno
country: Chile
facility: Corp de Beneficencia Osorno /ID# 127337
city: Puerto Varas
country: Chile
facility: Quantum Research LTDA. /ID# 127338
city: Prague 2
country: Czechia
facility: Revmatologicky ustav Praha /ID# 127317
state: Praha 2
city: Prague 4
country: Czechia
facility: Nuselská poliklinika, Revmatologie /ID# 127318
state: Praha 4
city: Bruntál
country: Czechia
facility: Revmatologie Bruntal, s.r.o /ID# 126881
city: Ostrava
country: Czechia
facility: Artroscan s.r.o. /ID# 126845
city: Budapest III
country: Hungary
facility: Qualiclinic Kft. /ID# 127340
state: Pest
city: Veszprém
country: Hungary
facility: Veszprem Megyei Csolnoky Feren /ID# 126876
city: Ashkelon
country: Israel
facility: Barzilai Medical Center /ID# 126875
city: Haifa
country: Israel
facility: Rambam Health Care Campus /ID# 127341
city: Ramat Gan
country: Israel
facility: Sheba Medical Center /ID# 126878
city: Adazi
country: Latvia
facility: LTD M&M Centers /ID# 127346
city: Baldone
country: Latvia
facility: Arija's Ancane's Family Doctor /ID# 127342
city: Riga
country: Latvia
facility: Clinic ORTO /ID# 127345
city: Mexico City
country: Mexico
facility: Hospital de Jesús Nazareno /ID# 127352
city: Mexico City
country: Mexico
facility: Cliditer SA de CV /ID# 127347
city: Mexico City
country: Mexico
facility: Clinstile, S.A. de C.V. /ID# 127350
city: Lublin
country: Poland
facility: REUMED Sp.z o.o. Filia nr 1 /ID# 127353
state: Lubelskie
city: Krakow
country: Poland
facility: Centrum Medyczne Pratia Krakow /ID# 127358
state: Malopolskie
city: Warsaw
country: Poland
facility: NBR Polska /ID# 127359
state: Mazowieckie
city: Warsaw
country: Poland
facility: Medica Pro Familia S.A Warszawa /ID# 127361
state: Mazowieckie
city: Białystok
country: Poland
facility: Gabinet Internistyczno Reum. /ID# 127357
state: Podlaskie
city: Gdynia
country: Poland
facility: Centrum Medyczne Pratia Gdynia /ID# 127360
state: Pomorskie
city: Elbląg
country: Poland
facility: Michal Bazela Higher-Med /ID# 127355
state: Warminsko-mazurskie
city: San Juan
country: Puerto Rico
facility: GCM Medical Group /ID# 127363
city: Kazan
country: Russian Federation
facility: City Clinical Hospital #7 /ID# 127372
state: Tatarstan, Respublika
city: Tver
country: Russian Federation
facility: Tver Regional Clinical Hosp. /ID# 127375
state: Tverskaya Oblast
city: St. Petersburg
country: Russian Federation
facility: II Dzhan Research Center /ID# 127376
city: Martin
country: Slovakia
facility: MEDMAN s.r.o. /ID# 127381
city: Senica
country: Slovakia
facility: Poliklinika Senica /ID# 127396
city: Cape Town
country: South Africa
facility: Panorama Medical Centre /ID# 126846
state: Western Cape
city: Stellenbosch
country: South Africa
facility: Winelands Medical Research Ctr /ID# 126844
state: Western Cape
city: Málaga
country: Spain
facility: Hospital Regional de Malaga /ID# 127385
state: Malaga
city: Barcelona
country: Spain
facility: Hospital Plató /ID# 127384
city: Barcelona
country: Spain
facility: Hospital CIMA Sanitas /ID# 127383
city: Bilbao
country: Spain
facility: Hospital Universitario Basurto /ID# 127391
city: Madrid
country: Spain
facility: Hospital Clin Univ San Carlos /ID# 127382
city: Santiago de Compostela
country: Spain
facility: Clinica Gaias /ID# 127386
city: Sevilla
country: Spain
facility: Hospital Infanta Luisa /ID# 127389
city: Sevilla
country: Spain
facility: Hospital Universitario de Valm /ID# 127387
city: Istanbul
country: Turkey
facility: Medeniyet Univ. Goztepe Traini /ID# 132396
city: Kiev
country: Ukraine
facility: Kiev Municipal Clin Hosp 3 /ID# 127419
city: Kiev
country: Ukraine
facility: NSC-Strazhesko Ist Cardiology /ID# 127416
city: Sumy
country: Ukraine
facility: Sumy State University /ID# 127418
Study officials:
affiliation: AbbVie
name: AbbVie Inc.
role: STUDY_DIRECTOR
References:
citation: Genovese MC, Smolen JS, Weinblatt ME, Burmester GR, Meerwein S, Camp HS, Wang L, Othman AA, Khan N, Pangan AL, Jungerwirth S. Efficacy and Safety of ABT-494, a Selective JAK-1 Inhibitor, in a Phase IIb Study in Patients With Rheumatoid Arthritis and an Inadequate Response to Methotrexate. Arthritis Rheumatol. 2016 Dec;68(12):2857-2866. doi: 10.1002/art.39808.
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: 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.
citation: Mohamed MF, Klunder B, Camp HS, Othman AA. Exposure-Response Analyses of Upadacitinib Efficacy in Phase II Trials in Rheumatoid Arthritis and Basis for Phase III Dose Selection. Clin Pharmacol Ther. 2019 Dec;106(6):1319-1327. doi: 10.1002/cpt.1543. Epub 2019 Aug 23.
citation: Klunder B, Mohamed MF, Othman AA. Population Pharmacokinetics of Upadacitinib in Healthy Subjects and Subjects with Rheumatoid Arthritis: Analyses of Phase I and II Clinical Trials. Clin Pharmacokinet. 2018 Aug;57(8):977-988. doi: 10.1007/s40262-017-0605-6.