An Induction Study of Mirikizumab in Participants With Moderately to Severely Active Ulcerative Colitis (LUCENT 1)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and efficacy of Mirikizumab in participants with moderately to severely active ulcerative colitis (UC) who have had an inadequate response to, loss of response, or intolerant to conventional or biologic therapy for UC.

Official Title
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A Phase 3, Multicenter, Randomized, Double-Blind, Parallel, Placebo-Controlled Induction Study of Mirikizumab in Conventional-Failed and Biologic-Failed Patients With Moderately to Severely Active Ulcerative Colitis (LUCENT 1)

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: Diagnosis of UC for at least 3 months prior to baseline. Confirmed diagnosis of moderately or severely active UC, as assessed by the modified Mayo score (MMS). Demonstrated an inadequate response to, a loss of response to, or an intolerance to conventional or to biologic therapy for UC. If female, must meet the contraception requirements. Exclusion Criteria: Participants with a current diagnosis of Crohn's disease or inflammatory bowel disease-unclassified (indeterminate colitis). Participants with a previous colectomy. Participants with current evidence of toxic megacolon. Prior exposure to anti-IL12p40 antibodies (e.g. ustekinumab) or anti-IL-23p19 antibodies (e.g. risankizumab, brazikumab, guselkumab or tildrakizumab).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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 |
| --- | --- |
| Placebo Comparator: Placebo Intravenous (IV) Every 4 Weeks (Q4W)<br>Placebo given as an IV infusion Q4W on Weeks 0, 4, 8 for 12 weeks. | Drug: Placebo<br>* Administered IV<br>|
| Experimental: 300 Milligram (mg) Mirikizumab IV Q4W<br>300 mg mirikizumab given as an IV infusion Q4W on Weeks 0, 4, 8 for 12 weeks. | Drug: Mirikizumab<br>* Administered IV<br>* Other names: LY3074828;|
| Placebo Comparator: Placebo IV Q4W Maximum Extended Enrollment (ME2)<br>Placebo given as an IV infusion Q4W on Weeks 0, 4, 8 for 12 weeks. | Drug: Placebo<br>* Administered IV<br>|
| Experimental: 300 mg Mirikizumab IV Q4W ME2<br>300 mg mirikizumab given as an IV infusion Q4W on Weeks 0, 4, 8 for 12 weeks. | Drug: Mirikizumab<br>* Administered IV<br>* Other names: LY3074828;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Clinical Remission at Week 12 | Clinical remission at week 12 is defined as achieving a modified Mayo score (MMS) subscore for rectal bleeding=0, stool frequency=0 or 1 with ≥ 1 point decrease from baseline, and endoscopy=0 or 1 (excluding friability), excluding consideration of 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 seen) to 3 (blood alone passed); Endoscopy subscore, based on colonoscopy or sigmoidoscopy and scored from 0 (normal or inactive disease) to 3 (severe disease, spontaneous bleeding, ulceration). The confidence interval of 99.875% was chosen to match the significance level. | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Clinical Response at Week 12 | Clinical response at week 12 is defined as a decrease in the 9-point modified Mayo score (MMS) [rectal bleeding, stool frequency and the endoscopic findings] inclusive of >= 2 points and >=30% from baseline with either a decrease of rectal bleeding subscore of >=1 or rectal bleeding subscore of 0 or 1.The MMS is a composite score of ulcerative colitis disease activity calculated as the sum of three 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 seen) to 3 (blood alone passed); Endoscopy subscore, based on colonoscopy or sigmoidoscopy and scored from 0 (normal or inactive disease) to 3 (severe disease, spontaneous bleeding,ulceration).The MMS ranges from 0 to 9 points,with higher scores representing more severe disease. The confidence interval of 99.875% was chosen to match the significance level. | Week 12 | 
| Percentage of Participants With Endoscopic Remission at Week 12 | Endoscopic remission at week 12 is defined as achieving a Mayo endoscopic subscore of 0 or 1 (excluding friability) 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 Mayo endoscopic score ranges from 0 to 3 points, with higher scores representing more severe disease. The confidence interval of 99.875% was chosen to match the significance level. | Week 12 | 
| Percentage of Participants With Symptomatic Remission at Week 12 | Symptomatic remission at week 12 is defined as a Mayo subscore for rectal bleeding=0, stool frequency=0 or 1 with ≥ 1 point decrease from baseline. 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 seen) to 3 (blood alone passed). The confidence interval of 99.875% was chosen to match the significance level. | Week 12 | 
| Percentage of Participants With Symptomatic Response at Week 12 | Symptomatic response at week 12 is defined as ≥30% decrease from baseline in the sum of stool frequency and rectal bleeding 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 seen) to 3 (blood alone passed). The sum of stool frequency and rectal bleeding subscores ranges from 0 to 6. | Week 12 | 
| Percentage of Participants With Histologic Remission at Week 12 | Histologic remission was assessed using the Geboes histologic scoring system developed for assessment of histologic disease activity in ulcerative colitis. Remission was defined as Geboes histological subscore of 0 for grades: 2b (lamina propria neutrophils), and 3 (neutrophils in epithelium), and 4 (crypt destruction), and 5 (erosion or ulceration). | Week 12 | 
| Percentage of Participants With Endoscopic Response at Week 12 | Endoscopic response at week 12 is defined as achieving at least a 1 point decrease from baseline in the Mayo endoscopic subscore. The Mayo endoscopic subscore ranges from 0 to 3 points, with higher scores representing more severe disease. | Week 12 | 
| Change From Baseline to Week 12 in Bowel Urgency Based on the Urgency Numeric Rating Scale (NRS) | The Urgency NRS is a single participant reported item that measures the severity for the urgency (sudden or immediate need) to have a bowel movement in the past 24 hours using an 11-point NRS ranging from 0 (no urgency) to 10 (worst possible urgency).Higher scores indicate more severe urgency. Least square (LS) Mean was calculated using mixed model repeated measures (MMRM) model for post-baseline measures: The MMRM model includes: treatment, baseline value, visit, interaction of baseline value-by-visit, interaction of treatment-by-visit, prior biologic or tofacitinib failure (yes/no), baseline corticosteroid use (yes/no), baseline disease activity (MMS: [4-6] or [7-9]), and region (North America/Europe/Other). | Baseline, Week 12 | 
| Change From Baseline to Week 12 in Health Related Quality of Life: Inflammatory Bowel Disease Questionnaire (IBDQ) Total Score | The IBDQ is a 32-item participant-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. Least square (LS) Mean was calculated using analysis of covariance (ANCOVA) model for post-baseline measures: The ANCOVA model includes: treatment, baseline value, prior biologic or tofacitinib failure (yes/no), baseline corticosteroid use (yes/no), baseline disease activity (MMS: [4-6] or [7-9]), and region (North America/Europe/Other). | Baseline, Week 12 | 
| Change From Baseline to Week 12 in Fecal Calprotectin | Fecal calprotectin is an indicator of inflammation in the colon with higher levels indicative of higher levels of inflammation. Least square (LS) Mean was calculated using mixed model repeated measures (MMRM) model for post-baseline measures: The MMRM model includes: treatment, baseline value, visit, interaction of baseline value-by-visit, interaction of treatment-by-visit, prior biologic or tofacitinib failure (yes/no), baseline corticosteroid use (yes/no), baseline disease activity (MMS: [4-6] or [7-9]), and region (North America/Europe/Other). | Baseline, Week 12 | 
| Pharmacokinetics (PK): Clearance of Mirikizumab | Clearance of mirikizumab was evaluated. Clearance is estimated based on concentration data collected in the time frame of 0-12 weeks. | Predose on week 0, week 4, week 8 and post dose on week 0, 4 and 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Interleukin-23 (IL-23) antibody, IL-23p19