Abrilumab (AMG 181) in Adults With Moderate to Severe Crohn's Disease

A Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety, Tolerability, and Efficacy of AMG 181 in Subjects With Moderate to Severe Crohn's Disease

The primary objective of this study is to evaluate the efficacy of abrilumab as measured by the proportion of participants achieving Crohn's Disease Activity Index (CDAI) remission (CDAI < 150) after treatment for 8 weeks.

Study Overview

• Status: Completed
• Conditions: Crohn's Disease
• Intervention / Treatment: Drug: Placebo; Drug: Abrilumab

Detailed Description

The study consisted of a 24-week double-blind treatment period, a 108-week open-label treatment period, and a 2-year safety follow-up period.

Participants who did not reach minimal improvement, or experienced disease worsening after initial response, had the option to receive open-label abrilumab 210 mg every 3 months (Q3M) beginning at double-blind period week 12 or after. Not reaching minimal improvement was defined as not having an improvement in CDAI score of ≥ 70 points from baseline on 2 consecutive visits (at or after week 8) at least 2 weeks apart. Disease worsening after week 8 (or week 12) response was defined as having an increase in CDAI score of ≥ 70 points from the week 8 (or week 12) CDAI score on 2 consecutive visits at least 2 weeks apart, and a CDAI score of > 150.

Participants were planned to be randomized in a 2:1:2:1 ratio to SC placebo or abrilumab at 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 3:2:1. 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): 254
• Phase: Phase 2

Contacts and Locations

Study Locations

• Austria
  • Innsbruck, Austria, 6020
    • Research Site
  • St Veit an der Glan, Austria, 9300
    • Research Site
  • Wien, Austria, 1090
    • Research Site
  • Wien, Austria, 1050
    • Research Site
• Belgium
  • Bonheiden, Belgium, 2820
    • Research Site
  • Brussels, Belgium, 1200
    • Research Site
  • Gent, Belgium, 9000
    • Research Site
  • Leuven, Belgium, 3000
    • Research Site
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2X8
      • Research Site
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 1M9
      • Research Site
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3A 1R9
      • Research Site
  • Ontario
    • London, Ontario, Canada, N6A 5A5
      • Research Site
    • Sudbury, Ontario, Canada, P3E 1H5
      • Research Site
    • Toronto, Ontario, Canada, M5G 1X5
      • Research Site
  • Saskatchewan
    • Saskatoon, Saskatchewan, Canada, S7N 0W8
      • Research Site
• Czechia
  • Hradec Kralove, Czechia, 500 12
    • Research Site
  • Praha 4, Czechia, 140 21
    • Research Site
  • Praha 4, Czechia, 140 59
    • Research Site
  • Praha 5, Czechia, 150 06
    • Research Site
  • Praha 7, Czechia, 170 04
    • Research Site
  • Usti nad Labem, Czechia, 401 13
    • Research Site
• Denmark
  • Aalborg, Denmark, 9000
    • Research Site
  • Herlev, Denmark, 2730
    • Research Site
  • Hvidovre, Denmark, 2650
    • Research Site
  • Køge, Denmark, 4600
    • Research Site
  • Odense C, Denmark, 5000
    • Research Site
  • Århus C, Denmark, 8000
    • Research Site
• France
  • Amiens Cedex 1, France, 80054
    • Research Site
  • Caen Cedex 9, France, 14033
    • Research Site
  • Clichy, France, 92110
    • Research Site
  • Lille, France, 59037
    • Research Site
  • Nice Cedex 3, France, 06202
    • Research Site
  • Paris Cedex 10, France, 75475
    • Research Site
  • Paris cedex 12, France, 75571
    • Research Site
  • Pessac Cedex, France, 33604
    • Research Site
  • Vandoeuvre les Nancy, France, 54511
    • Research Site
• Germany
  • Hamburg, Germany, 20148
    • Research Site
  • Leipzig, Germany, 04105
    • Research Site
  • Minden, Germany, 32423
    • Research Site
  • Stuttgart, Germany, 70376
    • Research Site
• Hungary
  • Bekescsaba, Hungary, 5600
    • Research Site
  • Budapest, Hungary, 1125
    • Research Site
  • Budapest, Hungary, 1088
    • Research Site
  • Debrecen, Hungary, 4032
    • Research Site
  • Miskolc, Hungary, 3526
    • Research Site
  • Szekszard, Hungary, 7100
    • 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
    • Research Site
  • Rotterdam, Netherlands, 3015 CE
    • Research Site
• Switzerland
  • Basel, Switzerland, 4031
    • Research Site
  • Bern, Switzerland, 3010
    • Research Site
  • Zurich, Switzerland, 8091
    • Research Site
• United Kingdom
  • Birmingham, United Kingdom, B18 7QH
    • Research Site
  • Coventry, United Kingdom, CV2 2DX
    • Research Site
  • London, United Kingdom, NW1 2BU
    • Research Site
  • Manchester, United Kingdom, M8 5RB
    • Research Site
  • Norwich, United Kingdom, NR4 7UY
    • Research Site
  • Torquay, United Kingdom, TQ2 7AA
    • 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
    • Goodyear, Arizona, United States, 85395
      • Research Site
    • Phoenix, Arizona, United States, 85012
      • Research Site
  • California
    • La Jolla, California, United States, 92093
      • Research Site
  • Florida
    • Jacksonville, Florida, United States, 32256
      • Research Site
    • Sanford, Florida, United States, 32771
      • Research Site
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Research Site
  • Illinois
    • Arlington Heights, Illinois, United States, 60005
      • Research Site
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Research Site
    • Chesterfield, Michigan, United States, 48047
      • Research Site
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Research Site
  • Missouri
    • Mexico, Missouri, United States, 65265
      • Research Site
  • New York
    • Great Neck, New York, United States, 11021
      • Research Site
    • New York, New York, United States, 10029
      • Research Site
    • New York, New York, United States, 10029
      • Hospital
  • 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
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73103
      • Research Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Research Site
  • Tennessee
    • Germantown, Tennessee, United States, 38138
      • Research Site
  • Washington
    • Seattle, Washington, United States, 98101
      • 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:

• Diagnosed with ileal, ileo-colonic, or colonic Crohn's disease for a minimum of 6 months prior to baseline
• Moderately to severely active Crohn's disease defined by a CDAI score ≥ 220 and ≤ 450 at baseline
• Evidence of active inflammation within 12 weeks prior to baseline
• Demonstrated an inadequate response to, loss of response to, or intolerance to at least one of the following agents: Immunomodulators and/or anti-tumor necrosis factor (TNF) agents or to 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
• Subject has no known history of active tuberculosis and has a negative test for tuberculosis during screening

Exclusion Criteria:

• Short bowel syndrome
• Stricture with obstructive symptoms within 3 months
• Bowel surgery within 12 weeks prior baseline, or has planned bowel surgery within 24 weeks from baseline
• Ileostomy and/or colostomy
• Any gastric or intestinal pouch
• Evidence of an infected abscess
• Bowel perforation or evidence of non-inflammatory obstruction during the 6 months prior to baseline
• Stool positive for C. difficile toxin at screening
• Any uncontrolled or clinically significant systemic disease
• Known to have tested positive for hepatitis B virus surface antigen, hepatitis C virus antibody, or human immunodeficiency virus (HIV)
• Any underlying condition that predisposes subject to infections
• Subject has malignancy (other than resected cutaneous basal or cutaneous squamous cell carcinoma, or treated in situ cervical cancer considered cured) within 5 years of baseline
• Received an anti-TNF agent, cyclosporine, mycophenolate mofetil, sirolimus (rapamycin), thalidomide, tacrolimus, topical (rectal) aminosalicylic acid (eg, mesalamine) or topical (rectal) steroids, intravenous or intramuscular corticosteroids within protocol-specified time periods.
• Any prior exposure to antagonists of integrins or integrin ligands (eg, natalizumab, efalizumab, or vedolizumab), rituximab, or TNF kinoid immunotherapies, AMG 181, or any form of cell-based transplantation
• Received treatment of infection with intravenous (within 30 days of baseline) or oral (within 14 days prior to baseline) antibiotics, antivirals, or antifungals
• Significant laboratory abnormalities
• Pregnant or breast feeding

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

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.	Drug: Placebo; Placebo matching to abrilumab administered by subcutaneous injection; Drug: 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.	Drug: 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 (Q4W) thereafter until week 24. During the open-label period, participants received abrilumab 210 mg once every 3 months (Q3M) for 108 weeks.	Drug: 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.	Drug: Placebo; Placebo matching to abrilumab administered by subcutaneous injection; Drug: Abrilumab; Administered by subcutaneous injection.; Other Names: AMG 181

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 Crohn's Disease Activity Index (CDAI) score < 150 at week 8. The CDAI is a weighted, composite index of 8 disease variables (stool frequency, severity of abdominal pain, degree of general well-being, presence or absence of extra-intestinal manifestations or fistula, use or non-use of antidiarrheal agents, presence or absence of an abdominal mass, hematocrit, and body weight). Scores range from approximately 0 to 600, with a higher score indicating more-severe disease activity. 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 CDAI Score (adjusted remission rate).	Week 8

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Remission at Week 12	Remission was defined as a Crohn's Disease Activity Index (CDAI) score < 150. The CDAI is a weighted, composite index of 8 disease variables (stool frequency, severity of abdominal pain, degree of general well-being, presence or absence of extra-intestinal manifestations or fistula, use or non-use of antidiarrheal agents, presence or absence of an abdominal mass, hematocrit, and body weight). Scores range from approximately 0 to 600, with a higher score indicating more-severe disease activity. 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 CDAI Score (adjusted remission rate).	Week 12
Percentage of Participants With Response at Week 12	Response was defined as either remission (a CDAI score < 150) or a decrease from baseline in the CDAI score of ≥ 100 points. The CDAI is a weighted, composite index of 8 disease variables (stool frequency, severity of abdominal pain, degree of general well-being, presence or absence of extra-intestinal manifestations or fistula, use or non-use of antidiarrheal agents, presence or absence of an abdominal mass, hematocrit, and body weight). Scores range from approximately 0 to 600, with a higher score indicating more-severe disease activity. 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 CDAI score (adjusted response rate).	Baseline and week 12
Percentage of Participants With Response at Week 8	Response was defined as either remission (a CDAI score < 150) or a decrease from baseline in the CDAI score of ≥ 100 points. The CDAI is a weighted, composite index of 8 disease variables (stool frequency, severity of abdominal pain, degree of general well-being, presence or absence of extra-intestinal manifestations or fistula, use or non-use of antidiarrheal agents, presence or absence of an abdominal mass, hematocrit, and body weight). Scores range from approximately 0 to 600, with a higher score indicating more-severe disease activity. 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 CDAI score (adjusted response rate).	Baseline and week 8
Percentage of Participants With Sustained Remission at Both Week 12 and Week 24	Remission was defined as a Crohn's Disease Activity Index (CDAI) score < 150. Sustained remission was defined as achieving the criteria for remission at both week 12 and week 24. The CDAI is a weighted, composite index of 8 disease variables (stool frequency, severity of abdominal pain, degree of general well-being, presence or absence of extra-intestinal manifestations or fistula, use or non-use of antidiarrheal agents, presence or absence of an abdominal mass, hematocrit, and body weight). Scores range from approximately 0 to 600, with a higher score indicating more-severe disease activity. 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 CDAI Score (adjusted remission rate).	Week 12 and week 24
Percentage of Participants With Sustained Remission at Both Week 8 and Week 24	Remission was defined as a Crohn's Disease Activity Index (CDAI) score < 150. Sustained remission was defined as achieving the criteria for remission at both week 8 and week 24. The CDAI is a weighted, composite index of 8 disease variables (stool frequency, severity of abdominal pain, degree of general well-being, presence or absence of extra-intestinal manifestations or fistula, use or non-use of antidiarrheal agents, presence or absence of an abdominal mass, hematocrit, and body weight). Scores range from approximately 0 to 600, with a higher score indicating more-severe disease activity. 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 CDAI Score (adjusted remission rate).	Week 8 and week 24
Change From Baseline in CDAI Score at Week 12	The CDAI is a weighted, composite index of 8 disease variables (stool frequency, severity of abdominal pain, degree of general well-being, presence or absence of extra-intestinal manifestations or fistula, use or non-use of antidiarrheal agents, presence or absence of an abdominal mass, hematocrit, and body weight). Scores range from approximately 0 to 600, with a higher score indicating more-severe disease activity.	Baseline and week 12
Change From Baseline in CDAI Score at Week 8	The CDAI is a weighted, composite index of 8 disease variables (stool frequency, severity of abdominal pain, degree of general well-being, presence or absence of extra-intestinal manifestations or fistula, use or non-use of antidiarrheal agents, presence or absence of an abdominal mass, hematocrit, and body weight). Scores range from approximately 0 to 600, with a higher score indicating more-severe disease activity.	Baseline and week 8

Collaborators and Investigators

• Sponsor: Amgen

Publications and helpful links

General Publications

• Dummer R, Hoeller C, Gruter IP, Michielin O. Combining talimogene laherparepvec with immunotherapies in melanoma and other solid tumors. Cancer Immunol Immunother. 2017 Jun;66(6):683-695. doi: 10.1007/s00262-017-1967-1. Epub 2017 Feb 25.

Helpful Links

• AmgenTrials clinical trials website

Study record dates

Study Major Dates

• Study Start (Actual): December 4, 2012
• Primary Completion (Actual): December 26, 2014
• Study Completion (Actual): April 10, 2018

Study Registration Dates

• First Submitted: September 27, 2012
• First Submitted That Met QC Criteria: September 28, 2012
• First Posted (Estimate): October 1, 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: IBD, Crohn's Disease
• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Intestinal Diseases; Inflammatory Bowel Diseases; Crohn Disease
• Other Study ID Numbers: 20110232; 2012-000529-31 (EudraCT Number)