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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Ulcerative Colitis

Intervention / Treatment
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* Biological: Abrilumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo Q4W/Abrilumab 210 mg Q3M<br>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<br>* Administered by subcutaneous injection.<br>* Other names: AMG 181;Drug: Placebo<br>* Placebo matching to abrilumab administered by subcutaneous injection<br>|
| Experimental: Abrilumab 7 mg Q4W/Abrilumab 210 mg Q3M<br>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<br>* Administered by subcutaneous injection.<br>* Other names: AMG 181;|
| Experimental: Abrilumab 21 mg Q4W/Abrilumab 210 mg Q3M<br>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<br>* Administered by subcutaneous injection.<br>* Other names: AMG 181;|
| Experimental: Abrilumab 70 mg Q4W/Abrilumab 210 mg Q3M<br>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<br>* Administered by subcutaneous injection.<br>* Other names: AMG 181;|
| Experimental: Abrilumab 210 mg/Abrilumab 210 mg Q3M<br>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<br>* Administered by subcutaneous injection.<br>* Other names: AMG 181;Drug: Placebo<br>* Placebo matching to abrilumab administered by subcutaneous injection<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ulcerative Colitis, IBD