A Study of Mirikizumab (LY3074828) in Participants With Moderate to Severe Ulcerative Colitis

Study Overview
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Brief Summary
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The main purpose of this study is to test the hypothesis that treatment with mirikizumab is superior to placebo in providing clinical benefit to participants with moderate to severe ulcerative colitis (UC). This study will also investigate how the body processes the drug.

Official Title
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A Phase 2, Multicenter, Randomized, Double-Blind, Parallel, Placebo-Controlled Study of LY3074828 in Subjects With Moderate to Severe Ulcerative Colitis

Conditions
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Ulcerative Colitis

Intervention / Treatment
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* Drug: Mirikizumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have moderate to severe active UC as defined by a Mayo score of 6 to 12 with an endoscopic subscore ≥2 within 14 days before the first dose of study treatment (note: a partial Mayo score of at least 4 and other eligibility criteria must have been met before endoscopy is performed as a study procedure) Have evidence of UC extending proximal to the rectum (≥15 centimeters [cm] of involved colon) Up-to-date colorectal cancer surveillance (performed according to local standard), for subjects with family history of colorectal cancer, personal history of increased colorectal cancer risk, age >50 years, or other known risk factor Participants must either: be naive to biologic therapy (eg, tumor necrosis factor [TNF] antagonists or vedolizumab) and have at least 1 of the following: inadequate response or failure to tolerate current treatment with oral or intravenous corticosteroids or immunomodulators (6-mercaptopurine or azathioprine) or history of corticosteroid dependence (an inability to successfully taper corticosteroids without return of UC) OR have received treatment with 1 or more biologic agents (eg, TNF antagonists or vedolizumab) at doses approved for the treatment of UC with documented history of failure to respond to or tolerate such treatment Exclusion Criteria: Have been diagnosed with indeterminate colitis, proctitis (distal disease involving the rectum only; less than 15 cm from the anal verge) or Crohn's Disease Have had surgery for treatment of UC or are likely to require surgery for UC during the study Have received any of the following for treatment of UC: cyclosporine or thalidomide within 30 days of screening, corticosteroid enemas, corticosteroid suppositories, or topical treatment with 5-aminosalicyclic acid within 30 days of screening

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 50 mg Mirikizumab IV Q4W (Induction)<br>50 mg mirikizumab administered every 4 weeks (Q4W) intravenously (IV) during the induction period. Participants who do not have a clinical response may choose to participate in the unblinded study extension period. | Drug: Mirikizumab<br> <br> * Other names: LY3074828;|
| Experimental: 200 mg Mirikizumab IV Q4W (induction)<br>200 mg mirikizumab administered every 4 weeks (Q4W) intravenously (IV) during the induction period. Participants who do not have a clinical response may choose to participate in the unblinded study extension period. | Drug: Mirikizumab<br> <br> * Other names: LY3074828;|
| Experimental: 600 mg Mirikizumab IV Q4W (Induction)<br>600 mg mirikizumab administered every 4 weeks (Q4W) intravenously (IV) during the induction period. Participants who do not have a clinical response may choose to participate in the unblinded study extension period. | Drug: Mirikizumab<br> <br> * Other names: LY3074828;|
| Placebo Comparator: Placebo IV Q4W (Induction)<br>Placebo administered every 4 weeks (Q4W) intravenously (IV) during the induction period. | Drug: Placebo<br> <br> |
| Experimental: 200 mg Mirikizumab SC Q4W (Maintenance)<br>Induction mirikizumab responders were re-randomized: 200 mg mirikizumab administered subcutaneously (SC) Q4W during the maintenance period. | Drug: Mirikizumab<br> <br> * Other names: LY3074828;|
| Experimental: 200 mg Mirikizumab SC Q12W (Maintenance)<br>Induction mirikizumab responders were re-randomized: 200 mg mirikizumab administered subcutaneously (SC) once every 12 weeks (Q12W) during the maintenance period. | Drug: Mirikizumab<br> <br> * Other names: LY3074828;|
| Placebo Comparator: Placebo SC Q4W (Maintenance)<br>Induction placebo responders: Placebo administered subcutaneously (SC) Q4W during the maintenance period. | Drug: Placebo<br> <br> |
| Experimental: 600mg Mirikizumab IV Q4W Extension Open-Label<br>Induction non-responders: 600 mg mirikizumab administered intravenously (IV) once every 4 weeks (Q4W) during the Extension Open-Label. | Drug: Mirikizumab<br> <br> * Other names: LY3074828;|
| Experimental: 1000mg Mirikizumab IV Q4W Extension Open-Label<br>Induction non-responders: 1000 mg mirikizumab administered intravenously (IV) once every 4 weeks (Q4W) during the Extension Open-Label. | Drug: Mirikizumab<br> <br> * Other names: LY3074828;|
| Experimental: 200mg Mirikizumab SC Q4W Extension Open-Label<br>Extension Induction responders: 200 mg mirikizumab administered subcutaneously (SC) once every 4 weeks (Q4W) during the Extension Open-Label | Drug: Mirikizumab<br> <br> * Other names: LY3074828;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Induction Period: Percentage of Participants With Clinical Remission at Week 12 | Clinical remission at week 12 is a defined as achieving a 9-pt Mayo subscore for rectal bleeding=0, stool frequency=0 or 1 with ≥ 1 point decrease from baseline, and endoscopy=0 or 1, excluding Physician's Global Assessment (PGA). Stool Frequency Subscore, based on the participant's diary and scored from 0 (normal number of stools) to 3 (5 or more stools than normal); Rectal Bleeding Subscore, based on the participant's diary and scored from 0 (no blood) to 3 (blood only passed); Endoscopy Subscore, based on colonoscopy or sigmoidoscopy and scored from 0 (normal or inactive disease) to 3 (severe disease, spontaneous bleeding, ulceration); Physician's Global Assessment subscore, based on the physician's overall assessment, and scored from 0 (normal) to 3 (severe disease). The total score ranges from 0 to 9 points, with higher scores representing more severe disease. | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Induction Period: Percentage of Participants With Clinical Response at Week 12 | Clinical response at week 12 is defined as a decrease in the 9-point Mayo subscores (rectal bleeding, stool frequency and the endoscopic findings) inclusive of >= 2 points and >=35% from baseline with either a decrease of rectal bleeding subscore of >=1 or rectal bleeding subscore of 0 or 1. The Mayo score is a composite score of ulcerative colitis disease activity calculated as the sum of four subscores: Stool Frequency Subscore, based on the participant's diary and scored from 0 (normal number of stools) to 3 (5 or more stools than normal); Rectal Bleeding Subscore, based on the participant's diary and scored from 0 (no blood) to 3 (blood only passed); Endoscopy Subscore, based on colonoscopy or sigmoidoscopy and scored from 0 (normal or inactive disease) to 3 (severe disease, spontaneous bleeding, ulceration). The total score ranges from 0 to 9 points, with higher scores representing more severe disease. | Week 12 | 
| Induction Period: Percentage of Participants With Endoscopic Remission at Week 12 | Endoscopic remission at week 12 is defined as achieving a Mayo endoscopic score of 0 at Week 12. Endoscopy Subscore is based on colonoscopy or sigmoidoscopy and scored from 0 (normal or inactive disease) to 3 (severe disease, spontaneous bleeding, ulceration); The total score ranges from 0 to 3 points, with higher scores representing more severe disease. | Week 12 | 
| Maintenance Period: Percentage of Participants With Endoscopic Remission at Week 52 | Endoscopic remission at week 52 is defined as achieving a Mayo endoscopic subscore of 0 at Week 52. Endoscopy Subscore is based on colonoscopy or sigmoidoscopy and scored from 0 (normal or inactive disease) to 3 (severe disease, spontaneous bleeding, ulceration); The total score ranges from 0 to 3 points, with higher scores representing more severe disease. | Week 52 | 
| Induction Period: Change From Baseline to Week 12 in Inflammatory Bowel Disease Questionnaire (IBDQ) Total Score | The IBDQ is a 32-item subject-completed questionnaire that measures 4 aspects of subjects' lives: symptoms directly related to the primary bowel disturbance, systemic symptoms, emotional function, and social function (Guyatt et al. 1989). Responses are graded on a 7-point. Likert scale in which 7 denotes not a problem at all and 1 denotes a very severe problem. Scores range from 32 to 224; a higher score indicates a better quality of life. LS Mean was calculated using MMRM model for post-baseline measures: Variable = Baseline + Geographical Region + Prior Biologic Therapy Group (N) + Treatment + Time + Treatment*Time (Type III sum of squares). | Baseline, Week 12 | 
| Induction Period: Change From Baseline to Week 12 in 36-Item Short Form Health Survey (SF-36) | SF-36 Health Status Survey is a generic, health-related scale assessing participant's quality of life on 8 domains: physical functioning, social functioning, bodily pain, vitality, mental health, role-physical, role-emotional and general health. Domain scores: general health (range: 5-25); physical functioning (range: 10-30); role-physical (range: 4-8); role-emotional (range: 3-15); social functioning (range: 2-10); bodily pain (range: 2-12); vitality (range: 4-20); mental health (range: 5-25). Each raw scale score was converted to a scale score ranging from 0-100 points, with higher values representing a better outcome [(Raw score) - min{raw score}] / (max {raw score} - min{raw score}) x 100]. LS Mean was calculated using Mixed effect Model Repeat Measurement (MMRM) model for post-baseline measures: Variable = Baseline + Geographical Region + Prior Biologic Therapy Group (N) + Treatment + Time + Treatment*Time (Type III sum of squares). | Baseline, Week 12 | 
| Induction Period: Change From Baseline to Week 12 in Patient's Global Impressions of Severity (PGI-S) Score | PGI-S is a 1-item subject-rated questionnaire designed to assess the subject's impression of their disease symptoms at baseline (Guy 1976; Yalcin and Bump 2003). Responses are graded on a 7-point scale in which a score of 1 indicates that the subject's symptom(s) are normal, a score of 2 indicates that the subject feels borderline ill, a score of 3 indicates that the subject feels mildly ill, a score of 4 indicates that the subject(s) feel moderately ill, and scores of 5, 6, and 7 indicate that the subject feels markedly ill, severely ill, and extremely ill, respectively. LS Mean was calculated using MMRM model for post-baseline measures: Variable = Baseline + Geographical Region + Prior Biologic Therapy Group (N) + Treatment + Time + Treatment*Time (Type III sum of squares). | Baseline, Week 12 | 
| Induction Period: Patient's Global Impressions of Improvement (PGI-I) Score at Week 12 | PGI-I scale is a subject-rated instrument designed to assess the subject's impression of change in their symptom(s) (Guy 1976; Yalcin and Bump 2003). Responses are graded on a 7-point Likert scale in which a score of 1 indicates that the subject's symptom(s) is very much better, a score of 4 indicates that the subject's symptom(s) has experienced no change, and a score of 7 indicates that the subject's symptom(s) is very much worse. | Week 12 | 
| Pharmacokinetics (PK): Area Under the Concentration-Time Curve During Dosing Interval at Steady State (AUCss, Tau) of Mirikizumab | Pharmacokinetics (PK): Area Under the Concentration-Time Curve During Dosing Interval at Steady State (AUCss, tau) of Mirikizumab | Induction Period: Day (D) 1, D15 ± 2d, D29 ± 2d, D43 ± 2d, D57 ± 2d, D78-85; Maintenance Period: D85-92,D113± 7d,D141± 7d,D169± 7d,D225 ±7d,D281 ±7d,D337 ±7d,D393± 7d,D448± 7d,D504± 7d,D560± 7d,D616± 7d,D672± 7d,D728± 7d,D784± 7d,D840± 7d | 
| Induction Period: Percentage of Participants With Symptomatic Remission at Week 12 | Symptomatic remission is defined as a stool frequency score of 0 or 1 and a rectal bleeding score of 0. Stool Frequency Subscore is based on the participant's diary and scored from 0 (normal number of stools) to 3 (5 or more stools than normal). Rectal Bleeding Subscore is based on the participant's diary and scored from 0 (no blood) to 3 (blood only passed). The total score ranges from 0 to 1 points, with higher scores representing more severe disease. The percentage of response is calculated by dividing number of participants in the specified category by number of participants with non-missing values multiplied by 100. | Week 12 | 
| Maintenance Period: Percentage of Participants With Symptomatic Remission at Week 52 | Symptomatic remission is defined as a stool frequency score of 0 or 1 and a rectal bleeding score of 0. Stool Frequency Subscore , based on the participant's diary and scored from 0 (normal number of stools) to 3 (5 or more stools than normal); Rectal Bleeding Subscore , based on the participant's diary and scored from 0 (no blood) to 3 (blood only passed); Endoscopy Subscore , based on colonoscopy or sigmoidoscopy and scored from 0 (normal or inactive disease) to 3 (severe disease, spontaneous bleeding, ulceration); Physician's Global Assessment subscore, based on the physician's overall assessment, and scored from zero (normal) to 3 (severe disease). The total score ranges from 0 to 1 points, with higher scores representing more severe disease. The percentage of response is calculated by dividing number of participants in the specified category by number of participants with non-missing values multiplied by 100. | Week 52 | 
| Induction Period: Percentage of Participants With Endoscopic Improvement at Week 12 | Endoscopic Improvement defined as achieving an endoscopic findings subscore of 0 or 1. Endoscopy Subscore is based on colonoscopy or sigmoidoscopy and scored from 0 (normal or inactive disease) to 3 (severe disease, spontaneous bleeding, ulceration). The percentage of response is calculated by dividing number of participants in the specified category by number of participants with non-missing values multiplied by 100. | Week 12 | 
| Maintenance Period: Percentage of Participants With Endoscopic Improvement at Week 52 | Endoscopic Improvement defined as achieving an endoscopic findings subscore of 0 or 1. Endoscopy Subscore is based on colonoscopy or sigmoidoscopy and scored from 0 (normal or inactive disease) to 3 (severe disease, spontaneous bleeding, ulceration). The percentage of response is calculated by dividing number of participants in the specified category by number of participants with non-missing values multiplied by 100. | Week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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IL-23 antibody