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

Phase 2

Completed

Conditions: Ulcerative Colitis

Interventions: Biological: Abrilumab
Drug: Placebo

Registration Number: NCT01694485

Lead Sponsor: Amgen

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 359

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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Abrilumab 7 mg Q4W/Abrilumab 210 mg Q3M	Abrilumab	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.
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.
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.
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 thereafter until week 24. During the open-label period, participants received abrilumab 210 mg once every 3 months (Q3M) for 108 weeks.
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.

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants With Response at Week 8	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 Sustained Remission at Week 8 and Week 24	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).
Percentage of Participants With Mucosal Healing at Week 8	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).