A Study of the Efficacy and Safety of Upadacitinib (ABT-494) in Participants With Moderately to Severely Active Ulcerative Colitis (U-Accomplish)

• ClinicalTrials.gov Identifier: NCT03653026
• Recruitment Status: Completed
• First Posted: August 31, 2018
• Results First Posted: November 26, 2021
• Last Update Posted: March 2, 2022
• Sponsor: AbbVie
• Information provided by (Responsible Party): AbbVie

Tracking Information

• First Submitted Date: August 28, 2018
• First Posted Date: August 31, 2018
• Results First Submitted Date: October 29, 2021
• Results First Posted Date: November 26, 2021
• Last Update Posted Date: March 2, 2022
• Actual Study Start Date: December 6, 2018
• Actual Primary Completion Date: January 14, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 29, 2021)

Percentage of Participants Who Achieved Clinical Remission Per Adapted Mayo Score at Week 8 [ Time Frame: Week 8 ]

The Adapted Mayo Score is a composite score of UC disease activity based on the following 3 subscores:

1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal).
2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed).
3. Endoscopic subscore, scored from 0 (normal or inactive disease) to 3 (severe disease, spontaneous bleeding, ulceration).

The overall Adapted Mayo score ranges from 0 to 9 where higher scores represent more severe disease. Clinical remission is defined as an Adapted Mayo score ≤ 2, with SFS ≤ 1 and not higher than Baseline, RBS of 0, and endoscopic subscore ≤ 1.

Original Primary Outcome Measures (submitted: August 28, 2018)

Proportion of participants who achieve clinical remission per Adapted Mayo score [ Time Frame: At Week 8 ]

It is defined as Stool Frequency Subscore (SFS) <=1 and not greater than baseline, Rectal Bleeding Subscore (RBS) of 0 and endoscopic subscore <=1.

Current Secondary Outcome Measures (submitted: October 29, 2021)

• Percentage of Participants With Endoscopic Improvement at Week 8 [ Time Frame: Week 8 ]
  Endoscopic improvement is defined as an endoscopic subscore of 0 or 1. Endoscopies were assessed by a blinded central reader and scored according to the following scale: 0 = Normal or inactive disease; 1 = Mild disease (erythema, decreased vascular pattern); 2 = Moderate disease (marked erythema, lack of vascular pattern, any friability, erosions); 3 = Severe disease (spontaneous bleeding, ulceration).
• Percentage of Participants With Endoscopic Remission at Week 8 [ Time Frame: Week 8 ]
  Endoscopic remission is defined as an endoscopic subscore of 0. Endoscopies were assessed by a blinded central reader and scored according to the following scale: 0 = Normal or inactive disease; 1 = Mild disease (erythema, decreased vascular pattern); 2 = Moderate disease (marked erythema, lack of vascular pattern, any friability, erosions); 3 = Severe disease (spontaneous bleeding, ulceration).
• Percentage of Participants Who Achieved Clinical Response Per Adapted Mayo Score at Week 8 [ Time Frame: Week 8 ]
  The Adapted Mayo Score is a composite score of UC disease activity based on the following 3 subscores:

  1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal).
  2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed).
  3. Endoscopic subscore, scored from 0 (normal or inactive disease) to 3 (severe disease with spontaneous bleeding, ulceration).

  The overall Adapted Mayo score ranges from 0 to 9 with higher scores representing more severe disease. Clinical response per the Adapted Mayo Score is defined as a decrease in Adapted Mayo score ≥ 2 points and ≥ 30% from Baseline, plus a decrease in RBS ≥ 1 or an absolute RBS ≤ 1.
• Percentage of Participants Who Achieved Clinical Response Per Partial Adapted Mayo Score at Week 2 [ Time Frame: Week 2 ]
  The Partial Adapted Mayo Score is a composite score of UC disease activity based on the following 2 subscores:

  1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal).
  2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed).

  The overall Partial Adapted Mayo score ranges from 0 to 6 with higher scores representing more severe disease. Clinical response per Partial Adapted Mayo Score is defined as a decrease in Partial Adapted Mayo score ≥ 1 point and ≥ 30% from Baseline, plus a decrease in RBS ≥ 1 or an absolute RBS ≤ 1.
• Percentage Of Participants Who Achieved Histologic-Endoscopic Mucosal Improvement at Week 8 [ Time Frame: Week 8 ]
  Histologic endoscopic mucosal improvement is defined as an endoscopic subscore of 0 or 1 and a Geboes score ≤ 3.1. The endoscopic subscore ranges from 0 (normal or inactive disease) to 3 (severe disease with spontaneous bleeding, ulceration). The Geboes histologic index includes seven histological features (architectural change, chronic inflammatory infiltrate, lamina propria neutrophils and eosinophils, neutrophils in epithelium, crypt destruction and erosion or ulcers). The Geboes score has 6 grades, each with 3-5 subgrades: Grade 0, structural change only; Grade 1, chronic inflammation; Grade 2, lamina propria neutrophils and eosinophils; Grade 3, neutrophils in epithelium; Grade 4, crypt destruction; and Grade 5, erosions or ulceration.
• Percentage of Participants Who Reported No Bowel Urgency at Week 8 [ Time Frame: Week 8 ]
  Bowel urgency was assessed by participants in a subject diary completed once a day.
• Percentage of Participants Who Reported No Abdominal Pain at Week 8 [ Time Frame: Week 8 ]
  Abdominal pain was assessed by participants in a subject diary completed once a day.
• Percentage of Participants Who Achieved Histologic Improvement at Week 8 [ Time Frame: Week 8 ]
  Histologic improvement is defined as a decrease from Baseline in Geboes score. The Geboes histologic index includes seven histological features (architectural change, chronic inflammatory infiltrate, lamina propria neutrophils and eosinophils, neutrophils in epithelium, crypt destruction and erosion or ulcers). The Geboes score has 6 grades, each with 3-5 subgrades: Grade 0, structural change only; Grade 1, chronic inflammation; Grade 2, lamina propria neutrophils and eosinophils; Grade 3, neutrophils in epithelium; Grade 4, crypt destruction; and Grade 5, erosions or ulceration.
• Change From Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) Total Score at Week 8 [ Time Frame: Baseline (Week 0) to Week 8 ]
  The Inflammatory Bowel Disease Questionnaire (IBDQ) is used to assess health-related quality of life (HRQoL) in patients with ulcerative colitis. It consists of 32 questions evaluating bowel and systemic symptoms, as well as emotional and social functions. Each question is answered on a scale from 1 (worst) to 7 (best). The total score ranges from 32 to 224 with higher scores indicating better health-related quality of life. A positive change from Baseline indicates improvement.
• Percentage of Participants Who Achieved Mucosal Healing at Week 8 [ Time Frame: Week 8 ]
  Mucosal healing is defined as an endoscopic score of 0 and Geboes score < 2.0. The endoscopic subscore ranges from 0 (normal or inactive disease) to 3 (severe disease with spontaneous bleeding, ulceration). The Geboes histologic index includes seven histological features (architectural change, chronic inflammatory infiltrate, lamina propria neutrophils and eosinophils, neutrophils in epithelium, crypt destruction and erosion or ulcers). The Geboes score has 6 grades, each with 3-5 subgrades: Grade 0, structural change only; Grade 1, chronic inflammation; Grade 2, lamina propria neutrophils and eosinophils; Grade 3, neutrophils in epithelium; Grade 4, crypt destruction; and Grade 5, erosions or ulceration.
• Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score at Week 8 [ Time Frame: Baseline (Week 0) to Week 8 ]
  The FACIT fatigue questionnaire was developed to assess fatigue associated with anemia. It consists of 13 fatigue-related questions. Each question is answered on a 5-point Likert scale: 0 (not at all); 1 (a little bit); 2 (somewhat); 3 (quite a bit); and 4 (very much). The total score ranges from 0 to 52, where higher scores represent less fatigue, and a positive change from Baseline indicates improvement.

Original Secondary Outcome Measures (submitted: August 28, 2018)

• Proportion of participants with endoscopic improvement [ Time Frame: At Week 8 ]
  Endoscopic improvement is defined as an endoscopic subscore <= 1
• Proportion of participants with endoscopic remission [ Time Frame: At Week 8 ]
  Endoscopic remission is defined as an endoscopic subscore = 0
• Proportion of participants achieving clinical response per Adapted Mayo score [ Time Frame: At Week 8 ]
  Clinical response per Adapted Mayo is defined as a decrease from baseline in the Adapted Mayo score >= 2 points and >= 30% from baseline, PLUS a decrease in RBS >= 1 or an absolute RBS <= 1.
• Proportion of participants achieving clinical response per Partial Adapted Mayo score [ Time Frame: At Week 2 ]
  It is defined as a decrease in the partial adapted mayo score >= 1 points and >= 30% from Baseline, PLUS a decrease in RBS>=1 or an absolute RBS<=1.
• Proportion of participants who reported no bowel urgency [ Time Frame: At Week 8 ]
  Bowel urgency is monitored electronically via a handheld device.
• Proportion of participants who reported no abdominal pain [ Time Frame: At Week 8 ]
  Abdominal pain information will be collected electronically via a handheld device.
• Proportion of participants who achieved histologic improvement [ Time Frame: At Week 8 ]
  It is defined as decrease from Baseline in Geboes score
• Proportion of participants achieving response in Inflammatory Bowel Disease Questionnaire (IBDQ) Bowel Symptom domain [ Time Frame: At Week 8 ]
  It is defined as the increase of IBDQ bowel symptom domain score >=6
• Proportion of participants with mucosal healing [ Time Frame: At Week 8 ]
  It is defined as the endoscopic and histologic remission
• Proportion of participants with UC-related hospitalizations [ Time Frame: Through Week 8 ]
  Participants with an UC related event that results in admission to the hospital will be assessed.
• Proportion of participants with UC-related surgeries [ Time Frame: Through Week 8 ]
  Participants who underwent surgery related to UC will be assessed.
• Proportion of participants achieving response in IBDQ fatigue item [ Time Frame: At Week 8 ]
  It is defined as the increase of IBDQ fatigue item score >=1

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of the Efficacy and Safety of Upadacitinib (ABT-494) in Participants With Moderately to Severely Active Ulcerative Colitis
• Official Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Induction Study to Evaluate the Efficacy and Safety of Upadacitinib (ABT-494) in Subjects With Moderately to Severely Active Ulcerative Colitis
• Brief Summary: The objective of this study is to evaluate the efficacy and safety of upadacitinib compared to placebo in inducing clinical remission (per Adapted Mayo score) in participants with moderately to severely active ulcerative colitis (UC).

Detailed Description

Study M14-675 consists of 2 parts, Part 1 and Part 2. Part 1 is a randomized, double-blind, placebo-controlled 8-week induction period. Part 2 is an open-label, 8-week extended treatment period for participants who did not achieve clinical response at Week 8 in Part 1.

Eligible participants are randomized in a 2:1 ratio to one of the two treatment groups (upadacitinib 45 mg or matching placebo) for 8 weeks. The randomization is stratified by biologic inadequate responder (bio-IR) status (bio-IR vs non-bio-IR), corticosteroid use (yes or no), and Adapted Mayo score (≤ 7 or > 7) at Baseline. Within bio-IR, the randomization is further stratified by number of prior biologic treatments (≤ 1 or > 1). Within non-bio-IR, the randomization is further stratified by previous biologic use (yes or no).

Participants who achieve clinical response defined by Adapted Mayo Score at Week 8 or Week 16 and do not meet any study discontinuation criteria are eligible to enroll into Study M14-234 Substudy 3 (NCT02819635; 52-week maintenance study) or Study M14-533 Cohort 1 (NCT03006068; long-term follow-up study).

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Ulcerative Colitis (UC)

Intervention

• Drug: Placebo
  Tablet for oral administration
• Drug: Upadacitinib
  Tablet for oral administration
  Other Names:

  • ABT-494
  • RINVOQ®

Study Arms

• Experimental: Upadacitinib 45 mg
  Participants received 45 mg upadacitinib once daily (QD) for 8 weeks. Participants who did not achieve clinical response per Adapted Mayo score at Week 8 received upadacitinib 45 mg once daily for 8 additional weeks in the open-label extension period.
  Intervention: Drug: Upadacitinib
• Placebo Comparator: Placebo
  Participants received placebo matching to upadacitinib once daily for 8 weeks. Participants who did not achieve clinical response per Adapted Mayo score at Week 8 received upadacitinib 45 mg once daily for 8 weeks in the open-label extension period.
  Interventions:

  • Drug: Placebo
  • Drug: Upadacitinib

• Publications *: Danese S, Vermeire S, Zhou W, Pangan AL, Siffledeen J, Greenbloom S, Hebuterne X, D'Haens G, Nakase H, Panes J, Higgins PDR, Juillerat P, Lindsay JO, Loftus EV Jr, Sandborn WJ, Reinisch W, Chen MH, Sanchez Gonzalez Y, Huang B, Xie W, Liu J, Weinreich MA, Panaccione R. Upadacitinib as induction and maintenance therapy for moderately to severely active ulcerative colitis: results from three phase 3, multicentre, double-blind, randomised trials. Lancet. 2022 Jun 4;399(10341):2113-2128. doi: 10.1016/S0140-6736(22)00581-5. Epub 2022 May 26. Erratum In: Lancet. 2022 Sep 24;400(10357):996.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 11, 2021): 522
• Original Estimated Enrollment (submitted: August 28, 2018): 462
• Actual Study Completion Date: January 14, 2021
• Actual Primary Completion Date: January 14, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

- Male or female participants ≥ 16 and ≤ 75 years of age at Baseline Note: Adolescent participants at the age of 16 or 17 years old will be eligible to participate if approved by the country or regulatory/health authorities.

Note: Adolescent participants at the age of 16 or 17 years old must weigh ≥ 40 kilograms and meet the definition of Tanner Stage 5 at the Screening Visit.

• Diagnosis of Ulcerative Colitis (UC) for 90 days or greater prior to Baseline, confirmed by colonoscopy during the Screening Period, with exclusion of current infection, colonic dysplasia and/or malignancy. Appropriate documentation of biopsy results consistent with the diagnosis of UC, in the assessment of the Investigator, must be available.
• Active UC with an Adapted Mayo score of 5 to 9 points and endoscopic subscore of 2 to 3.
• Demonstrated an inadequate response, loss of response, or intolerance to at lease one of the following treatments including, oral aminosalicylates, corticosteroids, immunosuppressants, and/or biologic therapies.

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 as defined above.

• Female Participants of childbearing potential must have a negative serum pregnancy test at the Screening Visit and a negative urine pregnancy test at the Baseline Visit.
• If female, participant must meet the contraception recommendation criteria.

Exclusion Criteria:

• Participant with current diagnosis of Crohn's disease (CD) or diagnosis of indeterminate colitis (IC).
• Current diagnosis of fulminant colitis and/or toxic megacolon.
• Participant with disease limited to the rectum (ulcerative proctitis) during the Screening endoscopy.
• Received cyclosporine, tacrolimus, mycophenolate mofetil, or thalidomide within 30 days prior to Baseline.
• Participant who received azathioprine or 6-mercaptopurine (6-MP) within 10 days of Baseline.
• Received intravenous corticosteroids within 14 days prior to Screening or during the Screening Period.
• Participant with previous exposure to Janus Activated Kinase (JAK) inhibitor (e.g., tofacitinib, baricitinib, filgotinib, upadacitinib).
• Screening laboratory and other analyses show any prespecified abnormal hematologic results.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 16 Years to 75 Years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Austria, Belgium, Bosnia and Herzegovina, Brazil, Canada, Chile, China, Colombia, Croatia, Czechia, Estonia, Finland, France, Germany, Greece, Hungary, Ireland, Israel, Italy, Japan, Korea, Republic of, Latvia, Lithuania, Malaysia, Mexico, Netherlands, Norway, Poland, Portugal, Puerto Rico, Russian Federation, Serbia, Singapore, Slovakia, South Africa, Spain, Switzerland, Taiwan, Turkey, Ukraine, United Kingdom, United States
• Removed Location Countries: Belarus, Egypt, Romania, Sweden

Administrative Information

• NCT Number: NCT03653026
• Other Study ID Numbers: M14-675; 2016-000642-62 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• 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

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual and trial-level data (analysis data sets), as well as other information (e.g., protocols and clinical study reports), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Clinical Study Report (CSR)
• Time Frame: For details on when studies are available for sharing, please refer to the link below.
• Access Criteria: Access to this clinical trial data can be requested by any qualified researchers who engage in rigorous, independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Use Agreement (DUA). For more information on the process, or to submit a request, visit the following link.
• URL: https://vivli.org/ourmember/abbvie/

• Current Responsible Party: AbbVie
• Original Responsible Party: Same as current
• Current Study Sponsor: AbbVie
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: ABBVIE INC.; AbbVie

• PRS Account: AbbVie
• Verification Date: February 2022