Placebo-Controlled Study of Brazikumab in Participants With Moderately to Severely Active Ulcerative Colitis

Study Overview
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Brief Summary
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The present study (D5272C00001/Legacy #3151-201-008) aims to evaluate the efficacy and safety of brazikumab in patients with moderately to severely active UC and will include assessments of clinical responses as demonstrated by improvement of symptoms and of colonic mucosal appearance as observed on endoscopy

Official Title
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A 54-Week, Multicenter, Randomized, Double-blind, Placebo Controlled, Parallel-group Phase 2 Study to Assess the Efficacy and Safety of Brazikumab in Participants With Moderately to Severely Active Ulcerative Colitis (Expedition Lead-in)

Conditions
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Ulcerative Colitis, IBD

Intervention / Treatment
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* Drug: Brazikumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability to provide informed consent Aged 18 to 80 years of age Diagnosis of UC with an onset of symptoms for a minimum of 3 months prior to Screening Evidence of UC extending proximal to the rectum (≥ 15 cm of involved colon) Moderately to severely active UC as defined by: Average daily mMS Stool Frequency subscore ≥ 1 AND Average daily mMS Rectal Bleeding subscore ≥ 1 Modified Mayo endoscopic subscore of ≥ 2 based on a full colonoscopy within 14 days prior to randomization. Participant had an inadequate response or intolerance to intervention with conventional treatment or prior biological treatment or demonstrated CS dependence for the treatment of UC. For participants who have previously used biological treatment, a participant may have failed up to 3 biologics that include up to 2 different mechanisms of action. Participants taking 5-aminosalicylates, oral prednisone (or equivalent), oral budesonide, or immunomodulators must be at a stable dose or discontinued. Topical (rectal) aminosalicylic acid or topical (rectal) steroids should be discontinued. Female participants of childbearing potential must have a negative urine pregnancy test prior to administration of study intervention and must agree to use a highly effective method of birth control throughout the study and for at least 18 weeks after the last dose of study intervention. Women not of childbearing potential are defined as women who are either permanently sterilized (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or who are postmenopausal. Non sterilized males who are sexually active with a female partner of childbearing potential should use condoms during treatment and until the end of relevant systemic exposure in the male participant, plus a further 18 weeks. No known history of active TB or latent TB without completion of appropriate intervention and negative QFT-TB during Screening. Complete inclusion criteria are in the Clinical Study Protocol Exclusion Criteria: Participant has UC limited to the rectum (ie, not beyond 15 cm of the anal verge). Current diagnosis of fulminant colitis, a diagnosis of CD or indeterminate colitis, presence or history of a fistula consistent with CD, primary sclerosing cholangitis, celiac disease, or untreated bile acid malabsorption. Participants with a history of toxic megacolon within 12 months of screening are excluded. History of subtotal colectomy with ileorectostomy or colectomy with ileoanal pouch, Koch pouch, ileostomy, or other prior colonic resection, or need for surgical intervention for control of UC anticipated within 6 months. Participant has received the following treatment: Infliximab: within 8 weeks prior to randomization. Adalimumab, certolizumab pegol, or golimumab: within 8 weeks prior to randomization. Vedolizumab or ustekinumab within 12 weeks of randomization. Other prohibited medication, biologic or small molecule treatment within 5 half-lives prior to randomization. Fecal microbiota transplantation: within 8 weeks prior to randomization. Criterion deleted as part of Amendment 5 v6.0 Except for ustekinumab, prior exposure to any biologic agent targeting IL-12 or IL-23. Known history of allergy to the study intervention formulation or any of its excipients or components of the delivery device, or to any other biologic therapy. Participant received cyclosporine, mycophenolate mofetil, sirolimus (rapamycin), thalidomide, tacrolimus (FK-506), or tofacitinib within 2 weeks prior to Screening. Participants who received IV or intramuscular steroids within 2 weeks prior to Screening. Participant is currently enrolled in another investigational device or drug study, or is within 35 days or 5 half-lives, whichever is longer, since ending another investigational device or drug study(s), or receiving other investigational agent(s). Participant received a transfusion of blood, plasma, or platelets within 30 days prior to Screening. Participant received a Bacille Calmette-Guérin vaccination within 12 months of randomization or any other live vaccine less than 4 weeks prior to randomization. Participant has any of the following criteria related to infections: Evidence of a recent systemic fungal infection, requiring inpatient hospitalization, and/or antifungal treatment. Any infection requiring hospitalization or treatment with IV anti-infectives within 4 weeks of Screening. Cytomegalovirus or Epstein-Barr virus infection that has not resolved within 8 weeks prior to Screening. Clinically significant chronic infection that has not resolved within 8 weeks of Screening. Nonserious infection requiring oral anti-infectives within 2 weeks prior to randomization must be further discussed with study medical monitor. Clinical evidence of or suspected to have an abscess during Screening. Any underlying condition that predisposes the participant to infections. Participant had previous allogenic bone marrow transplant or history of organ or cell-based transplantation. Clinically significant active infection or signs/symptoms of infection that has the potential to worsen with immunosuppressive therapy. Signs or symptoms of ongoing infection due to intestinal pathogens. Participant has known or suspected history of chronic use of NSAIDs and/or opiates, drug, or alcohol abuse. History of cancer with the following exceptions: history of basal cell carcinoma and/or squamous cell carcinoma of the skin OR carcinoma in situ of the cervix; with apparent successful curative therapy, greater than 12 months prior to Screening. Clinically significant cardiovascular conditions. Prolonged QTcF interval or conditions leading to additional risk for QT prolongation. Clinically significant kidney disease Abnormal laboratory results at Screening as defined in the study protocol Participant is pregnant or breastfeeding or plans to become pregnant during the study. Participant has other known, pre-existing, clinically significant medical conditions that are not associated with UC and are uncontrolled with standard treatment. Participant has any disorder that may compromise the ability of the participant to give written informed consent and/or to comply with all required study procedures. Employees of the clinical study site or any other individuals involved with the conduct of the study, or immediate family members of such individuals. Complete exclusion criteria are in the Clinical Study Protocol

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
Interventional Model Description: Global, multicenter, randomized, double-blind, placebo-controlled, parallel-group, Phase 2 study
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Brazikumab Dose 1<br>Intravenous brazikumab on day 1, day 15, and day 43 followed by Subcutaneous brazikumab every 4 weeks beginning on day 71 through week 50 | Drug: Brazikumab<br>* Intravenous brazikumab on day 1, day 15, and day 43 followed by Subcutaneous brazikumab every 4 weeks beginning on day 71 through Week 50<br>|
| Experimental: Brazikumab Dose 2<br>Intravenous brazikumab on day 1, day 15, and day 43 followed by Subcutaneous brazikumab every 4 weeks beginning on day 71 through Week 50 | Drug: Brazikumab<br>* Intravenous brazikumab on day 1, day 15, and day 43 followed by Subcutaneous brazikumab every 4 weeks beginning on day 71 through Week 50<br>|
| Placebo Comparator: Placebo<br>Intravenous placebo on day 1, day 15, and day 43 followed by Subcutaneous every 4 weeks beginning on day 71 through Week 50. | Drug: Placebo<br>* Intravenous placebo on day 1, day 15, and day 43 followed by Subcutaneous placebo every 4 weeks beginning on Day 71 through Week 50.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of participants with clinical remission | Clinical remission defined as: Modified Mayo Score (mMS): Endoscopy subscore = 0 or 1, AND Rectal bleeding subscore = 0, AND Stool frequency subscore = 0 or 1 AND at least a 1 point decrease from baseline | at Week 10 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of participants with sustained clinical remission | Sustained clinical remission defined as Modified Mayo Score (mMS): Endoscopy subscore = 0 or 1, AND Rectal bleeding subscore = 0, AND Stool frequency subscore = 0 or 1 AND at least a 1 point decrease from baseline | at both Week 10 and Week 54 | 
| Percentage of participants with CS-free clinical remission | CS-free clinical remission defined as mMS: Endoscopy subscore = 0 or 1, AND Rectal bleeding subscore = 0, AND Stool frequency subscore = 0 or 1 AND at least a 1 point decrease from baseline | at Week 54 for patients who are CS-free for at least the last 12 weeks before the assessment at Week 54 | 
| Percentage of participants with clinical response | Clinical response is defined as Reduction in mMS ≥ 2 points from baseline AND ≥ 30% from baseline AND a decrease in the rectal bleeding score ≥ 1 point from baseline or a score of 0 or 1 | at Week 10 | 
| Percentage of participants with endoscopic improvement | Endoscopic improvement is defined as Endoscopy subscore ≤ 1 | at Week 10 | 
| Serum concentration of brazikumab | Pharmacokinetics: concentration of brazikumab in serum | through Week 68 | 
| For each dose level: LS mean of Mayo score and brazikumab pre-dose blood concentration | Exposure-response | at 12 weeks after dosing | 
| Incidence of anti-drug antibodies | Immunogenicity: incidence of brazikumab anti-drug antibodies in serum | through week 68 | 
| Number and percentage of participants with adverse events | Number and percentage of patients with reported adverse events. | through Week 68 | 
| Percentage of participants with potentially clinically significant changes in laboratory values | Percentage of patients with potentially clinically significant changes in hematology, clinical chemistry, urinalysis. | through Week 68 | 
| Percentage of participants with potentially clinically significant changes in vital signs | Percentage of patients with potentially clinically significant changes in systolic and diastolic blood pressure, and pulse rate. | through Week 68 | 
| Clinically relevant abnormal findings at physical exam | New or aggregated clinical relevant abnormal medical finding are reported as AE unless related to the disease under study | through Week 68 | 
| Percentage of participants with potentially clinically significant changes in ECGs | Percentage of patients with potentially clinically significant changes in 12-lead ECG recordings | through Week 68 |