A Study to Evaluate the Safety and Efficacy of Upadacitinib (ABT-494) for Induction and Maintenance Therapy in Participants With Moderately to Severely Active Ulcerative Colitis (UC)
Condition: Ulcerative Colitis (UC)
MeSH terms: Colitis; Colitis, Ulcerative; Ulcer
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Placebo; Upadacitinib
Intervention type(s): Drug; Drug
Intervention description(s): Film-coated tablet for oral administration; Film-coated tablet for oral administration
Other intervention name(s): ABT-494; RINVOQ
Intervention MeSH terms: Upadacitinib
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Upadacitinib (ABT-494); Moderately to Severely Active UC; RINVOQ