A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of ABT-494 for the Induction of Symptomatic and Endoscopic Remission in Subjects With Moderately to Severely Active Crohn's Disease Who Have Inadequately Responded to or Are Intolerant to Immunomodulators or Anti-TNF Therapy

• ClinicalTrials.gov Identifier: NCT02365649
• Recruitment Status: Completed
• First Posted: February 19, 2015
• Last Update Posted: August 3, 2021
• Sponsor: AbbVie
• Information provided by (Responsible Party): AbbVie

Tracking Information

• First Submitted Date: February 16, 2015
• First Posted Date: February 19, 2015
• Last Update Posted Date: August 3, 2021
• Actual Study Start Date: March 17, 2015
• Actual Primary Completion Date: November 25, 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 30, 2021)

• Percentage of Participants Who Achieve Endoscopic Remission at Week 12/16 [ Time Frame: Up to Week 16. (At Baseline, subjects were allocated by randomization 1:1 to have their end of induction colonoscopy done at either Week 12 or Week 16; this endpoint combines the two time points.) ]
  Endoscopic remission was determined using Simplified Endoscopic Score for Crohn's Disease (SES-CD). SES-CD subscores assess the following: presence and size of ulcers in 5 visualized bowel segments; extent of ulcerated surface in 5 visualized bowel segments; extent of affected surface in 5 visualized bowel segments; presence and type of narrowings in 5 visualized bowel segments. Subscores range from 0 to 15, and are summed for a total SES-CD score ranging from 0 to 56; higher scores indicate greater severity of mucosal inflammation. Endoscopic remission: SES-CD ≤ 4 and at least 2-point reduction versus Baseline and no subscore > 1 in any individual variable. Modified intention to Treat (mITT) Population: all randomized subjects who took at least 1 dose of study drug in the Induction Period. Non-responder imputation.
• Percentage of Participants Who Achieve Clinical Remission at Week 16 [ Time Frame: Week 16 ]
  Clinical remission: average daily stool frequency ≤ 1.5 and not worse than Baseline AND average daily abdominal pain ≤ 1.0 and not worse than Baseline. The very soft/liquid stool frequency and abdominal pain scores at a visit were the average of the daily values reported during the 7 usable days preceding the scheduled assessment visit. Abdominal Pain was rated on a 4-point scale from 0 (none) to 3 (severe). mITT Population: all randomized subjects who took at least 1 dose of study drug in the Induction Period. Non-responder imputation.

Original Primary Outcome Measures (submitted: February 16, 2015)

• Proportion of subjects who achieve endoscopic remission [ Time Frame: Up to Week 16 ]
  Endoscopic remission will be determined using Simplified Endoscopic Score for Crohn's Disease (SES-CD).
• Proportion of subjects who achieve clinical remission [ Time Frame: Week 16 ]
  Clinical remission to be determined at Week16

Current Secondary Outcome Measures (submitted: July 30, 2021)

• Percentage of Subjects Who Achieve Crohn's Disease Activity Index (CDAI) < 150 at Week 16 [ Time Frame: Week 16 ]
  CDAI is used to quantify the signs and symptoms of subjects with Crohn's disease. The score includes the frequency of stools, abdominal pain and general well-being as well as the presence of complications, use of antidiarrheals, presence of abdominal mass, hematocrit and weight. CDAI generally ranges from 0 to 600 where higher scores indicate more severe disease. A score below 150 indicates remission. mITT Population: all randomized subjects who took at least 1 dose of study drug in the Induction Period. Non-responder imputation.
• Percentage of Participants With a Decrease in CDAI ≥ 70 Points From Baseline at Week 16 [ Time Frame: Week 16 ]
  CDAI is used to quantify the signs and symptoms of subjects with Crohn's disease. The score includes the frequency of stools, abdominal pain and general well-being as well as the presence of complications, use of antidiarrheals, presence of abdominal mass, hematocrit and weight. CDAI generally ranges from 0 to 600 where higher scores indicate more severe disease. A 70-point decrease in the CDAI index refers to improvement in the disease activity from Baseline. mITT Population: all randomized subjects who took at least 1 dose of study drug in the Induction Period. Non-responder imputation.
• Percentage of Participants Who Achieve Clinical Remission at Week 12 [ Time Frame: Week 12 ]
  Clinical remission: average daily stool frequency ≤ 1.5 and not worse than Baseline AND average daily abdominal pain ≤ 1.0 and not worse than Baseline. The very soft/liquid stool frequency and abdominal pain scores at a visit were the average of the daily values reported during the 7 usable days preceding the scheduled assessment visit. Abdominal Pain was rated on a 4-point scale from 0 (none) to 3 (severe). mITT Population: all randomized subjects who took at least 1 dose of study drug in the Induction Period. Non-responder imputation.
• Percentage of Participants Who Achieve Remission at Week 16 [ Time Frame: Week 16 ]
  Remission is defined as endoscopic remission at Week 12/16 AND clinical remission at Week 16. Endoscopic remission: SES-CD ≤ 4 and at least 2-point reduction versus Baseline and no subscore > 1 in any individual variable. Clinical remission: average daily stool frequency ≤ 1.5 and not worse than Baseline AND average daily abdominal pain ≤ 1.0 and not worse than Baseline. The very soft/liquid stool frequency and abdominal pain scores at a visit were the average of the daily values reported during the 7 usable days preceding the scheduled assessment visit. Abdominal Pain was rated on a 4-point scale from 0 (none) to 3 (severe). Details of the SES-CD scale are provided in the description of the first primary endpoint. mITT Population: all randomized subjects who took at least 1 dose of study drug in the Induction Period. Non-responder imputation.
• Percentage of Participants Who Achieve Response at Week 16 [ Time Frame: Week 16 ]
  Response is defined as endoscopic response at Week 12/16 AND clinical response at Week 16. Endoscopic response: SES-CD at least 25% reduction from Baseline. Clinical response: average daily stool frequency at least 30% reduction from Baseline and average daily abdominal pain not worse than Baseline OR average daily abdominal pain at least 30% reduction from Baseline and average daily stool frequency not worse than Baseline. The very soft/liquid stool frequency and abdominal pain scores at a visit were the average of the daily values reported during the 7 usable days preceding the scheduled assessment visit. Abdominal Pain was rated on a 4-point scale from 0 (none) to 3 (severe). Details of the SES-CD scale are provided in the description of the first primary endpoint. mITT Population: all randomized subjects who took at least 1 dose of study drug in the Induction Period. Non-responder imputation.
• Percentage of Participants With Endoscopic Response at Week 12/16 [ Time Frame: Up to Week 16. (At Baseline, patients were allocated by randomization 1:1 to have their end of induction colonoscopy done at either Week 12 or Week 16; this endpoint combines the two time points.) ]
  Endoscopic response: SES-CD at least 25% reduction from Baseline. Details of the SES-CD scale are provided in the description of the first primary endpoint. mITT Population: all randomized subjects who took at least 1 dose of study drug in the Induction Period. Non-responder imputation.
• Percentage of Participants Who Achieve Clinical Response at Week 16 [ Time Frame: Week 16 ]
  Clinical response: average daily stool frequency at least 30% reduction from Baseline and average daily abdominal pain not worse than Baseline OR average daily abdominal pain at least 30% reduction from Baseline and average daily stool frequency not worse than Baseline. The very soft/liquid stool frequency and abdominal pain scores at a visit were the average of the daily values reported during the 7 usable days preceding the scheduled assessment visit. Abdominal Pain was rated on a 4-point scale from 0 (none) to 3 (severe). mITT Population: all randomized subjects who took at least 1 dose of study drug in the Induction Period. Non-responder imputation.
• Percentage of Subjects With an Average Daily Stool Frequency ≥ 2.5 AND Average Daily Abdominal Pain ≥ 2.0 at Baseline Who Achieve Clinical Remission at Week 16 [ Time Frame: Week 16 ]
  Clinical remission: average daily stool frequency ≤ 1.5 and not worse than Baseline AND average daily abdominal pain ≤ 1.0 and not worse than Baseline. The very soft/liquid stool frequency and abdominal pain scores at a visit were the average of the daily values reported during the 7 usable days preceding the scheduled assessment visit. Abdominal Pain was rated on a 4-point scale from 0 (none) to 3 (severe). mITT Population: all randomized subjects who took at least 1 dose of study drug in the Induction Period. Includes only mITT subjects with an average daily stool frequency ≥ 2.5 AND average daily abdominal pain ≥ 2.0 at Baseline. Non-responder imputation.
• Percentage of Participants Taking Corticosteroids at Baseline Who Discontinued Corticosteroid Use and Achieve CDAI < 150 at Week 16 [ Time Frame: Week 16 ]
  CDAI is used to quantify the signs and symptoms of subjects with Crohn's disease. The score includes the frequency of stools, abdominal pain and general well-being as well as the presence of complications, use of antidiarrheals, presence of abdominal mass, hematocrit and weight. CDAI generally ranges from 0 to 600 where higher scores indicate more severe disease. A score below 150 indicates remission. mITT Population: all randomized subjects who took at least 1 dose of study drug in the Induction Period. Includes only subjects taking corticosteroids at Baseline. Non-responder imputation.
• Percentage of Participants Taking Corticosteroids at Baseline Who Discontinued Corticosteroid Use and Achieve Remission at Week 12/16 and Clinical Remission at Week 16 [ Time Frame: Up to Week 16. (At Baseline, subjects were allocated by randomization 1:1 to have their end of induction colonoscopy done at either Week 12 or Week 16; this endpoint combines the two time points.) ]
  Remission is defined as endoscopic remission at Week 12/16 AND clinical remission at Week 16. Endoscopic remission: SES-CD ≤ 4 and at least 2-point reduction versus Baseline and no subscore > 1 in any individual variable. Clinical remission: average daily stool frequency ≤ 1.5 and not worse than Baseline AND average daily abdominal pain ≤ 1.0 and not worse than Baseline. The very soft/liquid stool frequency and abdominal pain scores at a visit were the average of the daily values reported during the 7 usable days preceding the scheduled assessment visit. Abdominal Pain was rated on a 4-point scale from 0 (none) to 3 (severe). Details of the SES-CD scale are provided in the description of the first primary endpoint. mITT Population: all randomized subjects who took at least 1 dose of study drug in the Induction Period. Includes only subjects taking corticosteroids at Baseline. Non-responder imputation.
• Percentage of Subjects Taking Corticosteroids at Baseline Who Discontinued Corticosteroid Use and Achieve Clinical Remission at Week 16 [ Time Frame: Week 16 ]
  Clinical remission: average daily stool frequency ≤ 1.5 and not worse than Baseline AND average daily abdominal pain ≤ 1.0 and not worse than Baseline. The very soft/liquid stool frequency and abdominal pain scores at a visit were the average of the daily values reported during the 7 usable days preceding the scheduled assessment visit. Abdominal Pain was rated on a 4-point scale from 0 (none) to 3 (severe). mITT Population: all randomized subjects who took at least 1 dose of study drug in the Induction Period. Includes only subjects taking corticosteroids at Baseline. Non-responder imputation.
• Percentage of Subjects Taking Corticosteroids at Baseline Who Discontinued Corticosteroid Use and Achieve Endoscopic Remission at Week 12/16 [ Time Frame: Up to Week 16. (At Baseline, patients were allocated by randomization 1:1 to have their end of induction colonoscopy done at either Week 12 or Week 16; this endpoint combines the two time points.) ]
  Endoscopic remission: SES-CD ≤ 4 and at least 2-point reduction versus Baseline and no subscore > 1 in any individual variable. Details of the SES-CD scale are provided in the description of the first primary endpoint. mITT Population: all randomized subjects who took at least 1 dose of study drug in the Induction Period. Includes only subjects taking corticosteroids at Baseline. Non-responder imputation.
• Change from Baseline in Fecal Calprotectin Level Over Time During the Induction Phase [ Time Frame: Baseline, Week 4, Week 16 ]
  mITT Population: all randomized subjects who took at least 1 dose of study drug in the Induction Period. Includes only subjects with an assessment at Baseline and Week 16. n=subjects with an assessment at given time point.
• Change from Baseline in High-Sensitivity C-Reactive Protein (hs-CRP) at Week 16 [ Time Frame: Baseline, Week 16 ]
  mITT Population: all randomized subjects who took at least 1 dose of study drug in the Induction Period. Includes only subjects with an assessment at Baseline and Week 16.
• Change From Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) Over Time During the Induction Phase [ Time Frame: Baseline, Week 8, Week 16 ]
  The IBDQ is a disease-specific instrument composed of 32 Likert-scaled items. The total score ranges from 32 to 224 using the 7-point response options, with higher scores indicating better health-related quality of life. The IBDQ scale contains 4 component subscales: bowel symptoms, systemic symptoms, emotional function, and social function. Each subscale can be computed with total scores ranging from 10 to 70, 5 to 35, 12 to 84, and 5 to 35, respectively. mITT Population: all randomized subjects who took at least 1 dose of study drug in the Induction Period. Includes only subjects with an assessment at Baseline and Week 16. n=number of subjects with an assessment at given time point.
• Percentage of Subjects With Isolated Ileal Crohn's Disease at Baseline Who Achieve Remission at Week 16 [ Time Frame: Week 16 ]
  Remission is defined as endoscopic remission AND clinical remission. Endoscopic remission: SES-CD ≤ 4 and at least 2-point reduction versus Baseline and no subscore > 1 in any individual variable. Clinical remission: average daily stool frequency ≤ 1.5 and not worse than Baseline AND average daily abdominal pain ≤ 1.0 and not worse than Baseline. The very soft/liquid stool frequency and abdominal pain scores at a visit were the average of the daily values reported during the 7 usable days preceding the scheduled assessment visit. Abdominal Pain was rated on a 4-point scale from 0 (none) to 3 (severe). Details of the SES-CD scale are provided in the description of the first primary endpoint. mITT Population: all randomized subjects who took at least 1 dose of study drug in the Induction Period. Only mITT subjects with isolated ileal Crohn's disease at Baseline are included. Non-responder imputation.

Original Secondary Outcome Measures (submitted: February 16, 2015)

• Proportion of subjects who achieve Crohn's Disease Activity Index (CDAI) less than 150 [ Time Frame: Week 16 ]
  Outcome to be measured by using CDAI
• Proportion of subjects with decrease in CDAI greater than or equal to 70 points [ Time Frame: Up to Week 16 ]
  Outcome to be measured by using CDAI
• Proportion of subjects who achieve remission at Week 52 [ Time Frame: Week 52 ]
  Remission to be determined at Week 52

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

Descriptive Information

• Brief Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of ABT-494 for the Induction of Symptomatic and Endoscopic Remission in Subjects With Moderately to Severely Active Crohn's Disease Who Have Inadequately Responded to or Are Intolerant to Immunomodulators or Anti-TNF Therapy
• Official Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of ABT-494 for the Induction of Symptomatic and Endoscopic Remission in Subjects With Moderately to Severely Active Crohn's Disease Who Have Inadequately Responded to or Are Intolerant to Immunomodulators or Anti-TNF Therapy
• Brief Summary: To determine the efficacy and safety of multiple doses of ABT-494 in subjects with moderately to severely active Crohn's Disease with a history of inadequate response to or intolerance to Immunomodulators or anti-Tumor Necrosis Factor (TNF) therapy.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Crohn's Disease

Intervention

• Drug: Placebo
  Oral Dosing
• Drug: ABT-494
  Oral Dosing
  Other Name: Upadacitinib

Study Arms

• Active Comparator: Induction Period ABT-494 Twice Daily Medium/High Dose
  Induction Period ABT-494 Twice Daily Medium/High Dose orally dosed twice a day
  Intervention: Drug: ABT-494
• Active Comparator: Extension Phase ABT-494 High Dose
  Extension Phase ABT-494 High Dose orally dosed twice a day
  Intervention: Drug: ABT-494
• Placebo Comparator: Induction Period Placebo
  Induction Period Placebo orally dosed twice a day
  Intervention: Drug: Placebo
• Active Comparator: Induction Period ABT-494 Low Dose
  Induction Period ABT-494 Low Dose orally dosed twice a day
  Intervention: Drug: ABT-494
• Active Comparator: Induction Period ABT-494 Once Daily Medium/High Dose
  Induction Period ABT-494 Once Daily Medium/High Dose orally dosed once a day
  Intervention: Drug: ABT-494
• Active Comparator: Extension Phase ABT-494 Low Dose
  Extension Phase ABT-494 Low Dose orally dosed twice a day
  Intervention: Drug: ABT-494
• Active Comparator: Induction Period ABT-494 High Dose
  Induction Period ABT-494 High Dose orally dosed twice a day
  Intervention: Drug: ABT-494
• Active Comparator: Induction Period ABT-494 Low/Medium Dose
  Induction Period ABT-494 Low/Medium Dose orally dosed twice a day
  Intervention: Drug: ABT-494
• Active Comparator: Extension Phase ABT-494 Medium Dose
  Extension Phase ABT-494 Medium Dose orally dosed twice a day
  Intervention: Drug: ABT-494

Publications *

• Sandborn WJ, Feagan BG, Loftus EV Jr, Peyrin-Biroulet L, Van Assche G, D'Haens G, Schreiber S, Colombel JF, Lewis JD, Ghosh S, Armuzzi A, Scherl E, Herfarth H, Vitale L, Mohamed MF, Othman AA, Zhou Q, Huang B, Thakkar RB, Pangan AL, Lacerda AP, Panes J. Efficacy and Safety of Upadacitinib in a Randomized Trial of Patients With Crohn's Disease. Gastroenterology. 2020 Jun;158(8):2123-2138.e8. doi: 10.1053/j.gastro.2020.01.047. Epub 2020 Feb 8.
• Sandborn WJ, Lewis JD, Panes J, Loftus EV, D'Haens G, Yu Z, Huang B, Lacerda AP, Pangan AL, Feagan BG. Association Between Proposed Definitions of Clinical Remission/Response and Well-Being in Patients With Crohn's Disease. J Crohns Colitis. 2022 Mar 14;16(3):444-451. doi: 10.1093/ecco-jcc/jjab161.
• Aguilar D, Revilla L, Garrido-Trigo A, Panes J, Lozano JJ, Planell N, Esteller M, Lacerda AP, Guay H, Butler J, Davis JW, Salas A. Randomized Controlled Trial Substudy of Cell-specific Mechanisms of Janus Kinase 1 Inhibition With Upadacitinib in the Crohn's Disease Intestinal Mucosa: Analysis From the CELEST Study. Inflamm Bowel Dis. 2021 Nov 15;27(12):1999-2009. doi: 10.1093/ibd/izab116.
• Peyrin-Biroulet L, Louis E, Loftus EV Jr, Lacerda A, Zhou Q, Sanchez Gonzalez Y, Ghosh S. Quality of Life and Work Productivity Improvements with Upadacitinib: Phase 2b Evidence from Patients with Moderate to Severe Crohn's Disease. Adv Ther. 2021 May;38(5):2339-2352. doi: 10.1007/s12325-021-01660-7. Epub 2021 Mar 23.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 30, 2021): 220
• Original Estimated Enrollment (submitted: February 16, 2015): 210
• Actual Study Completion Date: August 3, 2017
• Actual Primary Completion Date: November 25, 2016 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Diagnosis of Crohn's disease (CD) for at least 90 days.
2. Crohn's Disease Activity Index (CDAI) greater than or equal to 220 and less than or equal to 450.
3. Subject inadequately responded to or experience intolerance to previous treatment with immunomodulators (e.g. azathioprine, 6-mercaptopurine, or methotrexate) and/or anti-TNF agent (e.g., infliximab, adalimumab, or certolizumab pegol).

Exclusion Criteria:

1. Subjects with ulcerative colitis (UC), collagenous colitis or indeterminate colitis.
2. Subject who has had surgical bowel resections in the past 6 months or is planning resection.
3. Subjects with an ostomy or ileoanal pouch.
4. Subject with symptomatic bowel stricture or abdominal or peri-anal abcess.
5. Subject who has short bowel syndrome.
6. Subject with recurring infections or active Tuberculosis (TB).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Not Provided
• Removed Location Countries: Australia, Belgium, Canada, Czech Republic, Czechia, Denmark, France, Germany, Hungary, Israel, Italy, Netherlands, New Zealand, Norway, Poland, Puerto Rico, Romania, Slovakia, Spain, Sweden, United Kingdom, United States

Administrative Information

• NCT Number: NCT02365649
• Other Study ID Numbers: M13-740; 2014-003240-12 ( 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: Undecided

• 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: July 2021