Abrilumab (AMG 181) in Adults With Moderate to Severe Ulcerative Colitis

• ClinicalTrials.gov Identifier: NCT01694485
• Recruitment Status: Completed
• First Posted: September 27, 2012
• Results First Posted: June 27, 2019
• Last Update Posted: June 27, 2019
• Sponsor: Amgen
• Information provided by (Responsible Party): Amgen

Tracking Information

• First Submitted Date: September 24, 2012
• First Posted Date: September 27, 2012
• Results First Submitted Date: April 8, 2019
• Results First Posted Date: June 27, 2019
• Last Update Posted Date: June 27, 2019
• Actual Study Start Date: November 16, 2012
• Actual Primary Completion Date: July 13, 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 24, 2019)

Percentage of Participants With Remission at Week 8 [ Time Frame: Week 8 ]

Remission was defined as a total Mayo Score ≤ 2 points, with no individual subscore > 1 point. The Mayo Score is a composite index of four items (stool frequency, rectal bleeding, rectosigmoidoscopy findings, and physician's global assessment) with each item graded semi-quantitatively on a score of 0 to 3 where 0 represents normal and higher score represents more severe disease status. The total Mayo Score is the sum of the four item scores, with a result ranging from 0 to 12 points. Higher scores represent more severe disease. The remission rate (percentage of participants with remission) was calculated based on observed data (unadjusted remission rate) and also after applying a logistic regression model including the factors of treatment group, stratification factors (prior anti-TNF use and pre- versus post-Protocol Amendment 3) and baseline total Mayo Score (adjusted remission rate).

Original Primary Outcome Measures (submitted: September 26, 2012)

Remission at week 8 [ Time Frame: Week 8 ]

To evaluate the effect of AMG 181 on induction of remission in subjects at week 8 as assessed by the total Mayo Score

Current Secondary Outcome Measures (submitted: May 24, 2019)

• Percentage of Participants With Response at Week 8 [ Time Frame: Baseline and week 8 ]
  Response was defined by a decrease from baseline in the total Mayo Score of ≥ 3 points and ≥ 30%, with an accompanying decrease in the rectal bleeding subscore ≥ 1 point or an absolute rectal bleeding subscore = 0 or 1. The Mayo Score is a composite index of four items (stool frequency, rectal bleeding, rectosigmoidoscopy findings, and physician's global assessment), each graded semi-quantitatively on a scale of 0 to 3 where 0 represents normal and higher score represents more severe disease status. The total Mayo Score is the sum of the four item scores, ranging from 0 to 12 points. Higher scores represent more severe disease. The response rate (percentage of participants with response) was calculated based on observed data (unadjusted response rate) and also after applying a logistic regression model including the factors of treatment group, stratification factors (prior anti-TNF use and pre- versus post-Protocol Amendment 3) and baseline total Mayo Score (adjusted response rate).
• Percentage of Participants With Mucosal Healing at Week 8 [ Time Frame: Week 8 ]
  Mucosal healing was defined using the rectosigmoidoscopy subscore of Mayo assessment as absolute subscore for rectosigmoidoscopy of 0 or 1. Flexible rectosigmoidoscopy was performed as part of the Mayo assessment, graded semi-quantitatively on a scale of 0 to 3 where 0 represents normal and higher score represents more severe disease status. The healing rate (percentage of participants with mucosal healing) was calculated based on observed data (unadjusted healing rate) and also after applying a logistic regression model including the factors of treatment group, stratification factors (prior anti-TNF use and pre- versus post-Protocol Amendment 3) and baseline rectosigmoidoscopy score (adjusted healing rate).
• Percentage of Participants With Sustained Remission at Week 8 and Week 24 [ Time Frame: Week 8 and week 24 ]
  Remission was defined as a total Mayo Score ≤ 2 points, with no individual subscore > 1 point. Sustained remission was defined as achieving the criteria for remission at both week 8 and week 24. The Mayo Score is a composite index of four items (stool frequency, rectal bleeding, rectosigmoidoscopy findings, and physician's global assessment), each graded semi-quantitatively on a scale of 0 to 3 where 0 represents normal and higher scores represent more severe disease status. The total Mayo Score is the sum of the four item scores, with a and ranges from 0 to 12 points. Higher scores represent more severe disease. The remission rate (percentage of participants with sustained remission) was calculated based on observed data (unadjusted remission rate) and also after applying a logistic regression model including the factors of treatment group, stratification factors (prior anti-TNF use and pre- versus post-Protocol Amendment 3) and baseline total Mayo Score (adjusted remission rate).

Original Secondary Outcome Measures (submitted: September 26, 2012)

• Induction of response at week 8 [ Time Frame: Week 8 ]
  To evaluate the effects of AMG 181 on induction of response at week 8 as assessed by the total Mayo Score
• Mucosal healing at week 8 [ Time Frame: week 8 ]
  To evaluate the effects of AMG 181 on mucosal healing at week 8 as assessed by rectosigmoidoscopy

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

Descriptive Information

• Brief Title: Abrilumab (AMG 181) in Adults With Moderate to Severe Ulcerative Colitis
• Official Title: A Randomized, Double Blind, Multiple Dose Placebo Controlled Study to Evaluate the Safety, Tolerability, and Efficacy of AMG 181 in Subjects With Moderate to Severe Ulcerative Colitis
• Brief Summary: The primary objective of this study is to evaluate the effect of abrilumab on induction of remission in adults with moderate to severe ulcerative colitis after 8 weeks of treatment as assessed by a total Mayo Score ≤ 2 points, with no individual subscore > 1 point.

Detailed Description

The study consisted of a 24-week double-blind, placebo-controlled treatment period followed by an open-label period of approximately 108 weeks. Participants were eligible to enter the open-label period of the study early if they did not achieve a response at week 8 and had an inadequate response at week 12 or later or if they experienced disease worsening after achieving response and/or remission at week 8. Failure to achieve response at week 8 was defined as failure to achieve a decrease from baseline in total Mayo Score ≥ 3 points and ≥ 30% decrease from baseline. Inadequate response at week 12 or later was defined as failure to achieve a 2-point decrease and 25% improvement in partial Mayo Score compared with screening and minimum partial Mayo Score ≥ 5 points. Disease worsening was defined as an increase in partial Mayo Score ≥ 3 points from the week 8 value and minimum partial Mayo Score ≥ 5 points with recto-sigmoidoscopy sub-score ≥ 2.

Participants were planned to be randomized in a 2:1:2:2:2 ratio to placebo or abrilumab at 7 mg, 21 mg, 70 mg (on day 1, week 2, week 4, and every 4 weeks thereafter until week 24), or 210 mg (on day 1 followed by placebo in weeks 2 and 4 and every 4 weeks thereafter until week 24), respectively. Due to a consistent discrepancy between the investigational product (IP) instruction manual (IPIM) description of vial positions and the actual vial positions in the IP package participants were initially randomized to 3 arms (placebo, 70 mg, and 210 mg) with a randomization ratio of 4:3:2. The study was temporarily paused while this issue was investigated. Once the discrepancy was corrected, Protocol Amendment 3 implemented, and affected participants completed their double-blind treatment period, the study resumed enrollment and randomization per protocol. Neither the randomization nor study blind was compromised and therefore the intent-to-treat principle was maintained.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
• Condition: Ulcerative Colitis

Intervention

• Biological: Abrilumab
  Administered by subcutaneous injection.
  Other Name: AMG 181
• Drug: Placebo
  Placebo matching to abrilumab administered by subcutaneous injection

Study Arms

• Placebo Comparator: Placebo Q4W/Abrilumab 210 mg Q3M

  Participants received placebo by subcutaneous injection on day 1, week 2, week 4, and every 4 weeks thereafter until week 24.

  During the open-label period, participants received abrilumab 210 mg once every 3 months (Q3M) for 108 weeks.

  Interventions:

  • Biological: Abrilumab
  • Drug: Placebo
• Experimental: Abrilumab 7 mg Q4W/Abrilumab 210 mg Q3M

  Participants received 7 mg abrilumab by subcutaneous injection on day 1, week 2, week 4, and every 4 weeks (Q4W) thereafter until week 24.

  During the open-label period, participants received abrilumab 210 mg once every 3 months (Q3M) for 108 weeks.

  Intervention: Biological: Abrilumab
• Experimental: Abrilumab 21 mg Q4W/Abrilumab 210 mg Q3M

  Participants received 21 mg abrilumab by subcutaneous injection on day 1, week 2, week 4, and every 4 weeks thereafter until week 24.

  During the open-label period, participants received abrilumab 210 mg once every 3 months (Q3M) for 108 weeks.

  Intervention: Biological: Abrilumab
• Experimental: Abrilumab 70 mg Q4W/Abrilumab 210 mg Q3M

  Participants received 70 mg abrilumab by subcutaneous injection on day 1, week 2, week 4, and every 4 weeks thereafter until week 24.

  During the open-label period, participants received abrilumab 210 mg once every 3 months (Q3M) for 108 weeks.

  Intervention: Biological: Abrilumab
• Experimental: Abrilumab 210 mg/Abrilumab 210 mg Q3M

  Participants received a single dose of 210 mg abrilumab by subcutaneous injection on day 1, followed by placebo at week 2, week 4, and every 4 weeks thereafter until week 24.

  During the open-label period, participants received abrilumab 210 mg once every 3 months (Q3M) for 108 weeks.

  Interventions:

  • Biological: Abrilumab
  • Drug: Placebo

• Publications *: Sandborn WJ, Cyrille M, Hansen MB, Feagan BG, Loftus EV Jr, Rogler G, Vermeire S, Cruz ML, Yang J, Boedigheimer MJ, Abuqayyas L, Evangelista CM, Sullivan BA, Reinisch W. Efficacy and Safety of Abrilumab in a Randomized, Placebo-Controlled Trial for Moderate-to-Severe Ulcerative Colitis. Gastroenterology. 2019 Mar;156(4):946-957.e18. doi: 10.1053/j.gastro.2018.11.035. Epub 2018 Nov 23.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 19, 2015): 359
• Original Estimated Enrollment (submitted: September 26, 2012): 315
• Actual Study Completion Date: April 10, 2018
• Actual Primary Completion Date: July 13, 2015 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Diagnosis of ulcerative colitis (UC) established ≥ 3 months before baseline by clinical and endoscopic evidence and corroborated by a histopathology report.
• Moderate to severe active UC as defined by a total Mayo score of 6 to 12 with a centrally read rectosigmoidoscopy score ≥2 prior to baseline

• Inadequate response to, loss of response to, or intolerance to at least one of the following treatments:

  • Immunomodulators
  • Anti-TNF agents
  • Corticosteroids (non-US sites only).
• Neurological exam free of clinically significant, unexplained signs or symptoms during screening and no clinically significant change prior to randomization

Exclusion Criteria:

• Disease limited to the rectum (ie, within 10 cm of the anal verge)
• Toxic megacolon
• Crohn's Disease
• History of subtotal colectomy with ileorectostomy or colectomy with ileoanal pouch, Koch pouch, or ileostomy for UC
• Planned bowel surgery within 24 weeks from baseline
• Stool positive for C. Difficile toxin at screening
• History of gastrointestinal surgery within 8 weeks of baseline
• Primary Sclerosing Cholangitis
• Any uncontrolled or clinically significant systemic disease
• Condition or disease that, in the opinion of the investigator would pose a risk to subject safety or interfere with study evaluation, procedures or completion.
• Known to have tested positive for hepatitis B virus surface antigen, hepatitis C virus antibody or human immunodeficiency virus (HIV)
• Underlying condition that predisposes subject to infections (eg, uncontrolled diabetes; history of splenectomy)
• Known history of drug or alcohol abuse within 1 year of screening
• Malignancy (other than resected cutaneous basal or cutaneous squamous cell carcinoma, or treated in situ cervical cancer considered cured) within 5 years of screening visit (if a malignancy occurred > 5 years ago, subject is eligible with documentation of disease free state since treatment)
• Immunosuppressive therapy with either cyclosporine A, tacrolimus, or mycophenolate mofetil, within 1 month prior to baseline
• Prior exposure to anti tumor necrosis factor (TNF) agents, within 2 months, or 5 times the respective elimination half life (whichever is longer) prior to baseline
• Any prior exposure to vedolizumab, rituximab, efalizumab, natalizumab
• Use of topical (rectal) aminosalicylic acid (eg, mesalamine) or topical (rectal) steroids within 2 weeks prior to baseline
• Use of intravenous or intramuscular corticosteroids within 2 weeks prior to screening and during screening
• Previously treated with AMG 181
• Received any type of live attenuated vaccine < 1 month prior to baseline or is planning to receive any such live attenuated vaccine over the course of the study
• Treatment of infection with intravenous (within 30 days of baseline) or oral (within 14 days prior to baseline) antibiotics, antivirals, or antifungals
• Abnormal laboratory results at screening
• Any other laboratory abnormality, which, in the opinion of the investigator, will prevent the subject from completing the study or will interfere with the interpretation of the study results
• Currently enrolled in another investigational device or drug study, or less than 30 days since ending another investigational device or drug study(s), or receiving other investigational agent(s)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Austria, Belgium, Canada, Czechia, Denmark, Estonia, France, Germany, Greece, Hungary, Italy, Latvia, Netherlands, Norway, Poland, Russian Federation, Switzerland, United Kingdom, United States
• Removed Location Countries: Czech Republic

Administrative Information

• NCT Number: NCT01694485
• Other Study ID Numbers: 20110166; 2011-005251-13 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Amgen
• Original Responsible Party: Same as current
• Current Study Sponsor: Amgen
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: MD; Amgen

• PRS Account: Amgen
• Verification Date: May 2019