A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of Upadacitinib (ABT-494) for Induction and Maintenance Therapy in Subjects With Moderately to Severely Active Ulcerative Colitis
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of Upadacitinib (ABT-494) for Induction and Maintenance Therapy in Subjects With Moderately to Severely Active Ulcerative Colitis
This study was comprised of three substudies. The objective of Substudy 1 was to characterize the dose-response, efficacy, and safety of upadacitinib compared to placebo in inducing clinical remission to identify the induction dose of upadacitinib for further evaluation in Substudy 2. The objective of Substudy 2 was to evaluate the efficacy and safety of upadacitinib compared to placebo in inducing clinical remission in participants. The objective of Substudy 3 was to evaluate the efficacy and safety of upadacitinib compared to placebo in achieving clinical remission in participants who had a response following induction with upadacitinib.
Substudy 1 was a Phase 2b dose-ranging study designed to evaluate the efficacy and safety of different oral doses of upadacitinib compared to placebo as 8-week induction therapy in participants with moderately to severely active UC. Approximately 250 participants were planned to be randomized 1:1:1:1:1 to the placebo group and 4 upadacitinib doses (7.5, 15, 30, and 45 mg). Randomization was stratified by previous biologic therapy use (yes/no), Baseline corticosteroid use (yes/no), and Baseline Adapted Mayo score (≤ 7 or > 7). The study duration included a Screening Period of up to 5 weeks and an 8-week double-blind (DB) Induction Period. After all randomized participants completed the 8-week induction, a dose-selection analysis of efficacy and safety (selected laboratory parameters) of upadacitinib versus placebo was performed. Based on this dose-selection analysis, one induction dose (upadacitinib 45 mg) was identified for further evaluation in two Phase 3 induction studies, M14-234 Substudy 2 and M14-675 (NCT03653026). During the analysis period, 132 additional participants were randomized into Groups 3 and 4 of Substudy 1 (upadacitinib 30 mg and 45 mg dose groups; approximately 66 participants per dose group). The objectives of enrolling these additional participants were to avoid interrupting the study activities during the analysis period and to support a sufficient number of participants with clinical response to be re-randomized into the maintenance portion in Substudy 3. Substudy 1 main participants are defined as those first 250 randomized 250, and additional participants are defined as those who were randomized after the main participants.
Substudy 2 was a two-part Phase 3 dose-confirming study designed to evaluate the efficacy and safety of oral administration of upadacitinib 45 mg compared to placebo as induction therapy for up to 16 weeks in participants with moderately to severely active UC. Substudy 2 included a Screening Period of up to 5 weeks, Part 1, and Part 2. Part 1 was a randomized, DB, placebo-controlled 8-week induction period. Part 2 was an open-label, 8-week extended treatment period for clinical non-responders from Part 1 of Substudy 2. Part 1 was planned to enroll 462 subjects; actual enrollment was 474 subjects. Eligible participants were randomized in a 2:1 ratio to one of the two treatment groups (DB upadacitinib 45 mg or matching placebo) for 8 weeks. The randomization was stratified by bio-IR status (Biologic inadequate responders [bio-IR] vs Non-biologic-inadequate responders [non-bio-IR], corticosteroid use (yes or no), and Adapted Mayo score (≤ 7 or > 7) at Baseline. Within bio-IR, the randomization was further stratified by number of prior biologic treatments (≤ 1 or > 1). Within non-bio-IR, the randomization was further stratified by previous biologic use (yes or no). Part 2 was an open label, 8-week Extended Treatment Period for those who did not achieve clinical response per Adapted Mayo score at Week 8 in Part 1. All participants received upadacitinib 45 mg.
Substudy 3 was a Phase 3 maintenance study designed to evaluate the efficacy and safety of upadacitinib 15 and 30 mg once daily (QD) compared to placebo in achieving clinical remission per Adapted Mayo score in participants with moderately to severely active UC who achieved clinical response per Adapted Mayo score following induction therapy from Substudy 1, Substudy 2, or Study M14-675. A total of 1,046 subjects who achieved clinical response per Adapted Mayo score after completion of induction treatment or Extended Treatment Period in Study M14-234 Substudy 1, Substudy 2, or Study M14-675 entered Substudy 3, and 1,044 were treated with a blinded treatment assignment for up to 52 weeks. Substudy 3 included 4 cohorts. Cohort 1: 847 participants who achieved clinical response in Substudy 1, Substudy 2, or Study M14-675 at either Week 8 or Week 16, and received upadacitinib 15, 30, or 45 mg QD. The treatment groups in Cohort 1 were Group 1: upadacitinib 15 mg QD; Group 2: upadacitinib 30 mg QD; and Group 3: placebo QD. Those who achieved clinical response and received upadacitinib 15 mg QD in Substudy 1 were re-randomized 1:1 to only receive upadacitinib 15 mg QD or placebo QD (treatment Group 1 or 3). Cohort 2: 104 participants who received double-blind placebo QD treatment for 8 weeks during Substudy 1, Substudy 2 Part 1, or Study M14-675 Part 1 and achieved clinical response at Week 8 continued to receive blinded placebo QD in Substudy 3. Cohort 3: 75 participants who received upadacitinib 45 mg QD in Induction Phase and did not achieve clinical response and received upadacitinib 45 mg QD in Extended Treatment in Substudy 2 Part 2 or in Study M14-675 Part 2 and achieved clinical response at Week 16 were re-randomized 1:1 and received blinded upadacitinib 30 mg QD or upadacitinib 15 mg QD in Substudy 3. Cohort 4: 20 participants who received double-blinded treatment of upadacitinib 7.5 mg QD for 8 weeks during Substudy 1 and achieved clinical response at Week 8 continued to receive blinded treatment of upadacitinib 7.5 mg QD in Substudy 3.
Inclusion Criteria:
Note: Adolescent participants who are 16 or 17 years old will be eligible to participate if approved by the country or regulatory/health authority. If approval has not been granted, only participants ≥18 years old will be enrolled. Adolescents must weigh ≥ 40 kilograms and meet the definition of Tanner Stage 5 at Screening Visit.
Note: Participants who have had inadequate response, loss of response to conventional therapy, but have not failed biologic therapy (Non-bio-IR) and have received a prior biologic for up to 1 year may be enrolled, however they must have discontinued the biologic for reasons other than inadequate response or intolerance (e.g., change of insurance, well controlled disease) and must meet criteria for inadequate response, loss of response or intolerance to aminosalicylates, corticosteroids, and/or immunosuppressants as defined above.
Exclusion Criteria:
Mesa, Arizona 85206, United States
Los Angeles, California 90067-2001, United States
Ann Arbor, Michigan 48109, United States
Wyoming, Michigan 49519, United States
Jackson, Mississippi 39216, United States
Albuquerque, New Mexico 87131, United States
Great Neck, New York 11021, United States
North Massapequa, New York 11758, United States
Charlotte, North Carolina 28207, United States
Greenville, North Carolina 27834, United States
Winston-Salem, North Carolina 27157-0001, United States
Greenville, South Carolina 29615-3593, United States
Dallas, Texas 75246, United States
Houston, Texas 77030-3411, United States
San Antonio, Texas 78212, United States
Milwaukee, Wisconsin 53215, United States
Ciudad Autonoma de Buenos Aire, Ciuadad Autonoma de Buenos Aires 1115, Argentina
Ciudad Autonoma de Buenos Aire, Ciuadad Autonoma de Buenos Aires 1128, Argentina
Ciudad Autonoma de Buenos Aire, Ciuadad Autonoma de Buenos Aires 1280, Argentina
Macquarie University, New South Wales 2109, Australia
Fitzroy Melbourne, Victoria 3065, Australia
Banja Luka, Republika Srpska 78000, Bosnia and Herzegovina
Banja Luka, Republika Srpska 78000, Bosnia and Herzegovina
Goiânia, Goiás 74535-170, Brazil
Ribeirão Preto, São Paulo 14051-140, Brazil
Hamilton, Ontario L8S 4K1, Canada
Montreal, Quebec H3G 1A4, Canada
Wuhan, Hubei 430022, China
Wuhan, Hubei 430022, China
Shanghai, Shanghai Municipality 200065, China
Shanghai, Shanghai Municipality 200127, China
Hangzhou, Zhejiang 310009, China
Hangzhou, Zhejiang 310018, China
Bogota DC, Cundinamarca 111221, Colombia
Montería, Departamento de Córdoba 230002, Colombia
Osijek, County of Osijek-Baranja 31000, Croatia
Herne, North Rhine-Westphalia 44623, Germany
Kiel, Schleswig-Holstein 24105, Germany
Athens, 10676, Greece
Elm Park, Dublin D04 T6F4, Ireland
Rome, Roma 00168, Italy
Nagakute-shi, Aichi-ken 480-1195, Japan
Toyota-shi, Aichi-ken 470-1219, Japan
Hirosaki-shi, Aomori 036-8545, Japan
Abiko-shi, Chiba 270-1168, Japan
Kashiwa-shi, Chiba 277-0871, Japan
Sakura-shi, Chiba 285-8741, Japan
Urayasu-shi, Chiba 279-0021, Japan
Kurume-shi, Fukuoka 830-0011, Japan
Ogaki-shi, Gifu 503-8502, Japan
Fukuyama-shi, Hiroshima 720-8520, Japan
Asahikawa-shi, Hokkaido 078-8510, Japan
Obihiro-shi, Hokkaido 080-0024, Japan
Nishinomiya-shi, Hyōgo 663-8501, Japan
Higashi Ibaraki-gun, Ibaraki 311-3193, Japan
Kawasaki-shi, Kanagawa 216-8511, Japan
Yokkaichi-shi, Mie-ken 510-0016, Japan
Omura-shi, Nagasaki 856-8562, Japan
Yamatotakada-shi, Nara 635-0022, Japan
Kurashiki-shi, Okayama-ken 710-0142, Japan
Toyonaka-shi, Osaka 560-0055, Japan
Kawagoe-shi, Saitama 350-8550, Japan
Saitama-shi, Saitama 336-0963, Japan
Higashi-ohmi-shi, Shiga 527-8505, Japan
Izumo-shi, Shimane 693-8501, Japan
Sunto-gun, Shizuoka 411-8611, Japan
Bunkyo-ku, Tokyo 113-8519, Japan
Chuo-ku, Tokyo 104-8560, Japan
Hachioji-shi, Tokyo 192-0032, Japan
Itabashi-ku, Tokyo 173-8606, Japan
Minato-ku, Tokyo 108-8642, Japan
Mitaka-shi, Tokyo 181-8611, Japan
Shinjuku-ku, Tokyo 162-8655, Japan
Shinjuku-ku, Tokyo 162-8666, Japan
Shunan-shi, Yamaguchi 745-8522, Japan
Takatsuki-shi, 569-0086, Japan
Kaunas, 50161, Lithuania
Kuala Lumpur, Selangor 56000, Malaysia
Guadalajara, Jalisco 44650, Mexico
Nordbyhagen, Akershus 1474, Norway
Warsaw, Masovian Voivodeship 02-507, Poland
Guimarães, Braga District 4835-044, Portugal
Santa Maria DA Feira, Porto District 4520-211, Portugal
Ponte de Lima, Viana do Castelo District 4990-041, Portugal
Lisbon, 1169-050, Portugal
Lisbon, 1649-035, Portugal
San Juan, 00935, Puerto Rico
Saint Petersburg, Leningradskaya Oblast' 191015, Russia
Perm, Permskiy Kray 614109, Russia
Banská Bystrica, 975 17, Slovakia
Johannesburg, Gauteng 2193, South Africa
CAPE TOWN Milnerton, Western Cape 7441, South Africa
Suwon, Gyeonggido 16247, South Korea
Seoul, Seoul Teugbyeolsi 03722, South Korea
Santiago de Compostela, A Coruna 15706, Spain
Istanbul, 34098, Turkey (Türkiye)
Dnipro, 49005, Ukraine
Odesa, 65025, Ukraine
Vinnytsia, 21028, Ukraine