Clinical trial NCT01694485: Abrilumab (AMG 181) in Adults With Moderate to Severe Ulcerative Colitis
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Ulcerative Colitis
Keywords: Ulcerative Colitis, IBD
Lead sponsor: Amgen
Sponsor class: INDUSTRY
First posted: 2012-09-27
Enrollment: 359
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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)

Primary outcomes:
measure: Percentage of Participants With Remission at Week 8
timeFrame: Week 8
Secondary outcomes:
measure: Percentage of Participants With Response at Week 8
timeFrame: Baseline and week 8
measure: Percentage of Participants With Mucosal Healing at Week 8
timeFrame: Week 8
measure: Percentage of Participants With Sustained Remission at Week 8 and Week 24
timeFrame: Week 8 and week 24
Other outcomes:
Locations:
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country: United States
facility: Research Site
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city: Dothan
country: United States
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state: Alabama
city: Mobile
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city: Scottsdale
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state: Arizona
city: La Jolla
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country: Czechia
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country: Denmark
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country: France
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city: Nice Cedex 3
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country: Hungary
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city: Budapest
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country: Hungary
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country: Hungary
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city: Szekszard
country: Hungary
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city: Bologna
country: Italy
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country: Italy
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city: Milano
country: Italy
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city: Padova
country: Italy
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city: Roma
country: Italy
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city: Rozzano MI
country: Italy
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city: Riga
country: Latvia
facility: Research Site
city: Riga
country: Latvia
facility: Research Site
city: Amsterdam
country: Netherlands
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city: Breda
country: Netherlands
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country: Netherlands
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country: Netherlands
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city: Oslo
country: Norway
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city: Tromsø
country: Norway
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city: Bialystok
country: Poland
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city: Bydgoszcz
country: Poland
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country: Poland
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country: Poland
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country: Poland
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country: Poland
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city: Moscow
country: Russian Federation
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city: Nizhny Novgorod
country: Russian Federation
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country: Russian Federation
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city: St. Petersburg
country: Russian Federation
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city: St.-Petrsburg
country: Russian Federation
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city: Stavropol
country: Russian Federation
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city: Basel
country: Switzerland
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city: Bern
country: Switzerland
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city: Zurich
country: Switzerland
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city: Birmingham
country: United Kingdom
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city: Blackpool
country: United Kingdom
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city: Coventry
country: United Kingdom
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city: Derby
country: United Kingdom
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city: London
country: United Kingdom
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city: Manchester
country: United Kingdom
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city: Norwich
country: United Kingdom
facility: Research Site
Study officials:
affiliation: Amgen
name: MD
role: STUDY_DIRECTOR
References:
citation: 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.