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

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

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.

Study Overview

• Status: Completed
• Conditions: Ulcerative Colitis
• Intervention / Treatment: Biological: Abrilumab; Drug: Placebo

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
• Enrollment (Actual): 359
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Bankstown, New South Wales, Australia, 2200
      • Research Site
    • Concord, New South Wales, Australia, 2139
      • Research Site
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Research Site
  • Victoria
    • Box Hill, Victoria, Australia, 3128
      • Research Site
• Austria
  • Innsbruck, Austria, 6020
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  • St Veit an der Glan, Austria, 9300
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  • Wien, Austria, 1090
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• Belgium
  • Bonheiden, Belgium, 2820
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  • Brussels, Belgium, 1200
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  • Bruxelles, Belgium, 1000
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  • Gent, Belgium, 9000
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  • Leuven, Belgium, 3000
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  • Liège, Belgium, 4000
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• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N1
      • Research Site
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 1M9
      • Research Site
    • Vancouver, British Columbia, Canada, V6Z 2K5
      • Research Site
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3A 1R9
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  • Ontario
    • Kingston, Ontario, Canada, K7L 5G2
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    • London, Ontario, Canada, N6A 5A5
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    • Toronto, Ontario, Canada, M5G 1X5
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• Czechia
  • Hradec Kralove, Czechia, 500 12
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  • Praha 4, Czechia, 140 59
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  • Praha 7, Czechia, 170 04
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  • Usti nad Labem, Czechia, 401 13
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• Denmark
  • Aalborg, Denmark, 9000
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  • Herlev, Denmark, 2730
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  • Hvidovre, Denmark, 2650
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  • Køge, Denmark, 4600
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  • Odense C, Denmark, 5000
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  • Århus C, Denmark, 8000
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• Estonia
  • Tallinn, Estonia, 10117
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  • Tallinn, Estonia, 10138
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  • Tartu, Estonia, 51014
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• France
  • Amiens, France, 80054
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  • Caen, France, 14000
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  • Lille, France, 59037
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  • Nice Cedex 3, France, 06202
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  • Paris cedex 12, France, 75571
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  • Pessac Cedex, France, 33604
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  • Toulouse Cedex 9, France, 31059
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  • Vandoeuvre les Nancy, France, 54511
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• Germany
  • Berlin, Germany, 14050
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  • Berlin, Germany, 13353
    • Research Site
  • Frankfurt am Main, Germany, 60431
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  • Halle (Saale), Germany, 06120
    • Research Site
  • Heidelberg, Germany, 69120
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  • Kiel, Germany, 24105
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• Greece
  • Athens, Greece, 10676
    • Research Site
  • Haidari, Greece, 12462
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  • Heraklion, Greece, 71110
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  • Larissa, Greece, 41110
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  • Piraeus, Greece, 18454
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• Hungary
  • Bekescsaba, Hungary, 5600
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  • Budapest, Hungary, 1125
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  • Budapest, Hungary, 1088
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  • Debrecen, Hungary, 4032
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  • Miskolc, Hungary, 3529
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  • Miskolc, Hungary, 3526
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  • Pecs, Hungary, 7624
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  • Szeged, Hungary, 6725
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  • Szekszard, Hungary, 7100
    • Research Site
• Italy
  • Bologna, Italy, 40138
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  • Firenze, Italy, 50134
    • Research Site
  • Milano, Italy, 20157
    • Research Site
  • Padova, Italy, 35128
    • Research Site
  • Roma, Italy, 00152
    • Research Site
  • Rozzano MI, Italy, 20089
    • Research Site
• Latvia
  • Riga, Latvia, 1002
    • Research Site
  • Riga, Latvia, LV-1005
    • Research Site
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Research Site
  • Breda, Netherlands, 4818 CK
    • Research Site
  • Leiden, Netherlands, 2333 ZA
    • Research Site
  • Maastricht, Netherlands, 6229 HX
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  • Rotterdam, Netherlands, 3015 CE
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• Norway
  • Oslo, Norway, 0450
    • Research Site
  • Tromsø, Norway, 9038
    • Research Site
• Poland
  • Bialystok, Poland, 15-950
    • Research Site
  • Bydgoszcz, Poland, 85-079
    • Research Site
  • Lodz, Poland, 90-153
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  • Lodz, Poland, 90-302
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  • Lodz, Poland, 90-242
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  • Warszawa, Poland, 03-580
    • Research Site
• Russian Federation
  • Moscow, Russian Federation, 123423
    • Research Site
  • Nizhny Novgorod, Russian Federation, 603126
    • Research Site
  • Samara, Russian Federation, 443063
    • Research Site
  • St. Petersburg, Russian Federation, 191015
    • Research Site
  • St.-Petrsburg, Russian Federation, 196247
    • Research Site
  • Stavropol, Russian Federation, 355017
    • Research Site
• Switzerland
  • Basel, Switzerland, 4031
    • Research Site
  • Bern, Switzerland, 3010
    • Research Site
  • Zurich, Switzerland, 8091
    • Research Site
• United Kingdom
  • Birmingham, United Kingdom, B15 2TH
    • Research Site
  • Blackpool, United Kingdom, FY3 8NR
    • Research Site
  • Coventry, United Kingdom, CV2 2DX
    • Research Site
  • Derby, United Kingdom, DE22 3NE
    • Research Site
  • London, United Kingdom, NW3 2QG
    • Research Site
  • Manchester, United Kingdom, M13 9WL
    • Research Site
  • Norwich, United Kingdom, NR4 7UY
    • Research Site
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35216
      • Research Site
    • Dothan, Alabama, United States, 36305
      • Research Site
    • Mobile, Alabama, United States, 36608
      • Research Site
  • Arizona
    • Scottsdale, Arizona, United States, 85260
      • Research Site
  • California
    • La Jolla, California, United States, 92093
      • Research Site
    • Torrance, California, United States, 90505
      • Research Site
  • Colorado
    • Lone Tree, Colorado, United States, 80124
      • Research Site
  • Florida
    • Jacksonville, Florida, United States, 32256
      • Research Site
    • Miami, Florida, United States, 33136
      • Research Site
    • Naples, Florida, United States, 34102
      • Research Site
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Research Site
  • Illinois
    • Arlington Heights, Illinois, United States, 60005
      • Research Site
    • Urbana, Illinois, United States, 61801
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  • Louisiana
    • Hammond, Louisiana, United States, 70403
      • Research Site
  • Michigan
    • Chesterfield, Michigan, United States, 48047
      • Research Site
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Research Site
  • New York
    • Great Neck, New York, United States, 11021
      • Research Site
    • New York, New York, United States, 10029
      • Research Site
  • North Carolina
    • Charlotte, North Carolina, United States, 28210
      • Research Site
    • Greenville, North Carolina, United States, 27834
      • Research Site
  • Ohio
    • Mentor, Ohio, United States, 44060
      • Research Site
  • Tennessee
    • Germantown, Tennessee, United States, 38138
      • Research Site
  • Texas
    • San Antonio, Texas, United States, 78229
      • Research Site
  • Washington
    • Seattle, Washington, United States, 98101
      • Research Site
    • Seattle, Washington, United States, 98185
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.	Biological: Abrilumab; Administered by subcutaneous injection.; Other Names: AMG 181; Drug: Placebo; Placebo matching to abrilumab administered by subcutaneous injection
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.	Biological: Abrilumab; Administered by subcutaneous injection.; Other Names: AMG 181
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.	Biological: Abrilumab; Administered by subcutaneous injection.; Other Names: AMG 181
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.	Biological: Abrilumab; Administered by subcutaneous injection.; Other Names: AMG 181
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.	Biological: Abrilumab; Administered by subcutaneous injection.; Other Names: AMG 181; Drug: Placebo; Placebo matching to abrilumab administered by subcutaneous injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Remission at 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).	Week 8

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Response at 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).	Baseline and week 8
Percentage of Participants With Mucosal Healing at 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).	Week 8
Percentage of Participants With Sustained Remission at 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).	Week 8 and week 24

Collaborators and Investigators

• Sponsor: Amgen

Publications and helpful links

General 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.

Helpful Links

• AmgenTrials clinical trials website

Study record dates

Study Major Dates

• Study Start (Actual): November 16, 2012
• Primary Completion (Actual): July 13, 2015
• Study Completion (Actual): April 10, 2018

Study Registration Dates

• First Submitted: September 24, 2012
• First Submitted That Met QC Criteria: September 26, 2012
• First Posted (Estimate): September 27, 2012

Study Record Updates

• Last Update Posted (Actual): June 27, 2019
• Last Update Submitted That Met QC Criteria: May 24, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Keywords: Ulcerative Colitis, IBD
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Gastrointestinal Diseases; Gastroenteritis; Colonic Diseases; Intestinal Diseases; Inflammatory Bowel Diseases; Ulcer; Colitis; Colitis, Ulcerative
• Other Study ID Numbers: 20110166; 2011-005251-13 (EudraCT Number)