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

Phase 2

Completed

Conditions: Crohn's Disease

Interventions: Drug: Abrilumab
Drug: Placebo

Registration Number: NCT01696396

Lead Sponsor: Amgen

Brief Summary: 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.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 254

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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Abrilumab 70 mg Q4W/Abrilumab 210 mg Q3M	Abrilumab	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.
Abrilumab 210 mg/Abrilumab 210 mg Q3M	Abrilumab	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.
Abrilumab 210 mg/Abrilumab 210 mg Q3M	Placebo	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.
Placebo Q4W/Abrilumab 210 mg Q3M	Placebo	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.
Placebo Q4W/Abrilumab 210 mg Q3M	Abrilumab	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.
Abrilumab 21 mg Q4W/Abrilumab 210 mg Q3M	Abrilumab	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.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With Remission at Week 8	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).

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants With Response at Week 12	Baseline and 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).
Percentage of Participants With Response at Week 8	Baseline and 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).
Percentage of Participants With Remission at Week 12	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).
Percentage of Participants With Sustained Remission at Both Week 12 and Week 24	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).
Percentage of Participants With Sustained Remission at Both Week 8 and Week 24	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).
Change From Baseline in CDAI Score at Week 12	Baseline and 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.
Change From Baseline in CDAI Score at Week 8	Baseline and 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.