Evaluation of Efficacy and Safety of Brazikumab (MEDI2070) in Participants With Active, Moderate to Severe Crohn's Disease

Study Overview
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Brief Summary
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A Phase 2b study to evaluate the efficacy and safety of brazikumab (MEDI2070) in participants with moderate to severe Crohn's disease who have failed or are intolerant to anti-tumor necrosis factor-alpha (anti-TNFα) therapy.

Detailed Description
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This is a four-part Phase 2b study comprised of a 16-week, double-blind, placebo-controlled, Induction Period, a 12-week double-blind, placebo-controlled, Maintenance Period, a 24-week, Open-label Period and a post-treatment 28 week observational safety follow-up period designed to evaluate the short-term efficacy and the short- and long term safety of brazikumab in participants with moderate to severe, active Crohn's disease (CD) who have failed or are intolerant to anti-TNFα therapy as determined by the Investigator.

Official Title
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A Phase 2b Double-Blind, Multi-Dose, Placebo-Controlled Study to Evaluate the Efficacy and Safety of MEDI2070 in Subjects With Moderate to Severe Crohn's Disease Who Have Failed or Are Intolerant to Anti-tumor Necrosis Factor-alpha Therapy

Conditions
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Crohn's Disease

Intervention / Treatment
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* Drug: Brazikumab IV Infusion
* Drug: Brazikumab SC Injection
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of ileal, ileo-colonic, or colonic Crohn's Disease (CD) for > 3 months prior to screening Men or women age 18 - 80 years at the time of screening Moderate to severely active CD, as defined by Crohn's Disease Activity Index (CDAI) and endoscopic demonstration of inflammation Stable dose of medications for Crohn's disease therapy Prior treatment failure or intolerance with at least one Anti-Tumor Necrosis Factor-Alpha Therapy (anti-TNF α) agent Effective contraception from screening, and for 36 weeks after the last dose of investigational product No known history of active tuberculosis (TB) & negative assessment for TB/latent TB Exclusion Criteria: Severe underlying immunosuppression Severe gastrointestinal complications; e.g., short bowel syndromes, obstructing strictures, recent or planned bowel surgery, Ileostomy and/or colostomy, recent bowel perforation Significant infections at screening; Infected abscess, positive for Clostridium difficile, recent infectious hospitalization Recent treatment with approved or investigational biologic therapy for Crohn's disease Recent or planned live attenuated vaccine History of cancer, except for basal cell carcinoma or carcinoma in situ (CIS) of the cervix with apparent cure ≥ 12 months before screening Pregnancy/breast feeding Drug abuse

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo-matching brazikumab intravenous (IV) infusion and subcutaneous (SC) injection at Weeks 0 and 4 followed by placebo-matching brazikumab SC injection at Weeks 8 and 12 in the induction phase and at Weeks 16, 20 and 24 in the maintenance phase. Participants received brazikumab 210 mg, SC injection every 4 weeks up to Week 48 in the open-label period. | Drug: Brazikumab IV Infusion<br>* Brazikumab IV infusion as per protocol specified dosing schedule.<br>* Other names: MEDI2070;Drug: Brazikumab SC Injection<br>* Brazikumab IV infusion as per protocol specified dosing schedule.<br>* Other names: MEDI2070;Drug: Placebo<br>* Placebo-matching Brazikumab IV infusion as per protocol specified dosing schedule.<br>|
| Experimental: Brazikumab High Dose<br>Brazikumab 700 mg, IV infusion and placebo-matching brazikumab, SC injection at Weeks 0 and 4 followed by brazikumab 210 mg, SC injection at Weeks 8 and 12 in the induction phase. Participants received brazikumab 210 mg, SC injection every 4 weeks in the maintenance phase and open-label period up to Week 48. | Drug: Brazikumab IV Infusion<br>* Brazikumab IV infusion as per protocol specified dosing schedule.<br>* Other names: MEDI2070;Drug: Brazikumab SC Injection<br>* Brazikumab IV infusion as per protocol specified dosing schedule.<br>* Other names: MEDI2070;Drug: Placebo<br>* Placebo-matching Brazikumab IV infusion as per protocol specified dosing schedule.<br>|
| Experimental: Brazikumab High-Medium Dose<br>Brazikumab 280 mg, IV infusion and placebo-matching brazikumab, SC injection at Week 0 followed by brazikumab 210 mg, SC injection and placebo-matching brazikumab, IV infusion at Week 4, followed by brazikumab 210 mg, SC injection at Weeks 8 and 12 in the induction phase. Participants received brazikumab 210 mg, SC injection every 4 weeks in the maintenance phase and open-label period up to Week 48. | Drug: Brazikumab IV Infusion<br>* Brazikumab IV infusion as per protocol specified dosing schedule.<br>* Other names: MEDI2070;Drug: Brazikumab SC Injection<br>* Brazikumab IV infusion as per protocol specified dosing schedule.<br>* Other names: MEDI2070;Drug: Placebo<br>* Placebo-matching Brazikumab IV infusion as per protocol specified dosing schedule.<br>|
| Experimental: Brazikumab Low-Medium Dose<br>Brazikumab 210 mg, SC injection and placebo-matching brazikumab, IV infusion at Week 0 followed by brazikumab 105 mg, SC injection and placebo-matching brazikumab, IV infusion at Week 4, followed by brazikumab 105 mg, SC injection at Weeks 8 and 12 in the induction phase. Participants received brazikumab 105 mg, SC injection every 4 weeks up to Week 24 in the maintenance phase. Participants received brazikumab 210 mg, SC injection, every 4 weeks up to Week 48 in the open-label period. | Drug: Brazikumab IV Infusion<br>* Brazikumab IV infusion as per protocol specified dosing schedule.<br>* Other names: MEDI2070;Drug: Brazikumab SC Injection<br>* Brazikumab IV infusion as per protocol specified dosing schedule.<br>* Other names: MEDI2070;Drug: Placebo<br>* Placebo-matching Brazikumab IV infusion as per protocol specified dosing schedule.<br>|
| Experimental: Brazikumab Low Dose<br>Brazikumab 70 mg, SC injection and placebo-matching brazikumab, IV infusion at Week 0 followed by brazikumab 35 mg, SC injection and placebo-matching brazikumab, IV infusion at Week 4, followed by brazikumab 35 mg, SC injection at Weeks 8 and 12 in the induction phase. Participants received brazikumab 35 mg, SC injection every 4 weeks up to Week 24 in the maintenance phase. Participants received brazikumab 210 mg, SC injection, every 4 weeks up to Week 48 in the open-label period. | Drug: Brazikumab IV Infusion<br>* Brazikumab IV infusion as per protocol specified dosing schedule.<br>* Other names: MEDI2070;Drug: Brazikumab SC Injection<br>* Brazikumab IV infusion as per protocol specified dosing schedule.<br>* Other names: MEDI2070;Drug: Placebo<br>* Placebo-matching Brazikumab IV infusion as per protocol specified dosing schedule.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Crohn's Disease Activity Index (CDAI) Remission at Week 8 | CDAI remission was defined as a CDAI score of <150 at Week 8. CDAI score was calculated by summing weighted scores for subjective items [number of liquid or very soft stools, abdominal pain (on a scale of 0=none to 3=severe) and general well-being (on a scale of 1=generally well to 4=terrible)] recorded by a diary during a 1-week period, and objective items [associated symptoms, taking antidiarrheal agents such as loperamide/opiates, abdominal mass, hematocrit, daily morning temperature, and body weight]. CDAI scores range from 0 to approximately 600 points, higher score indicates higher disease activity. | Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Loose/Liquid Stool Frequency Response | Loose/liquid stool frequency response is the stools identified as Type 6 or 7 on Bristol Stool Form Scale, ≥ 30% reduction in weekly loose/liquid stool count compared to baseline. The participant recorded their stool consistency each day in a daily patient diary using the Bristol Stool Form Scale. It is a scale between 1-7, it measured the shape of the stool, where 1 correlates with the firmest stool and 7 correlates with entirely liquid stool. | Baseline, Weeks 8, 16 and 28 | 
| Percentage of Participants With Crohn's Disease Activity Index (CDAI) Response | CDAI response was defined as a decrease from baseline in the CDAI score of ≥100. CDAI score was calculated by summing weighted scores for subjective items [number of liquid or very soft stools, abdominal pain (on a scale of 0=none to 3=severe) and general well-being (on a scale of 1=generally well to 4=terrible)] recorded by a diary during a 1-week period, and objective items [associated symptoms, taking antidiarrheal agents such as loperamide/opiates, abdominal mass, hematocrit, daily morning temperature, and body weight]. CDAI scores range from 0 to approximately 600 points, higher score indicates higher disease activity. | Baseline, Weeks 8, 16 and 28 | 
| Percentage of Participants With CDAI Clinical Remission | CDAI clinical remission was defined as a CDAI score of <150. CDAI score was calculated by summing weighted scores for subjective items [number of liquid or very soft stools, abdominal pain (on a scale of 0=none to 3=severe) and general well-being (on a scale of 1=generally well to 4=terrible)] recorded by a diary during a 1-week period, and objective items [associated symptoms, taking antidiarrheal agents such as loperamide/opiates, abdominal mass, hematocrit, daily morning temperature, and body weight]. CDAI scores range from 0 to approximately 600 points, higher score indicates higher disease activity. | Weeks 16 and 28 | 
| Percentage of Participants With Simple Endoscopic Score for Crohn's Disease (SES-CD) Response | SES-CD response was defined as a decrease from baseline in SES-CD score of ≥ 50%. The SES-CD evaluates 4 endoscopic variables [ulcer size, proportion of the surface area that is ulcerated, proportion of the surface area affected, and stenosis] each rated from 0 (best) to 3 (worst) in 5 segments evaluated during ileocolonoscopy [ileum, right colon, transverse colon, left colon, and rectum]. The score for each endoscopic variable is the sum of values obtained for each segment. The SES-CD total is the sum of the 4 endoscopic variable scores from 0 to 60, where higher scores indicates more severe disease. | Baseline, Weeks 16 and 28 | 
| Percentage of Participants With Loose/Liquid Stool Frequency Remission | Loose/liquid stool frequency response is the stools identified as Type 6 or 7 on Bristol Stool Form Scale, ≥ 30% reduction in weekly loose/liquid stool count compared to baseline. The participant recorded their stool consistency each day in a daily patient diary using the Bristol Stool Form Scale. It is a scale between 1-7, it measured the shape of the stool, where 1 correlates with the firmest stool and 7 correlates with entirely liquid stool. | Baseline, Weeks 8, 16 and 28 | 
| Percentage of Participants With Simple Endoscopic Score for Crohn's Disease (SES-CD) Remission | SES-CD remission was defined as a Total SES-CD score of ≤4 and no subscore >2. The SES-CD evaluates 4 endoscopic variables [ulcer size, proportion of the surface area that is ulcerated, proportion of the surface area affected, and stenosis] each rated from 0 (best) to 3 (worst) in 5 segments evaluated during ileocolonoscopy [ileum, right colon, transverse colon, left colon, and rectum]. The score for each endoscopic variable is the sum of values obtained for each segment. The SES-CD total is the sum of the 4 endoscopic variable scores from 0 to 60, where higher scores indicates more severe disease. | Weeks 16 and 28 | 
| Percentage of Participants With Patient Response Outcome-2 (PRO2) Remission | PRO2 evaluated 2 patient-reported symptoms: the frequency of liquid or soft stools and abdominal pain (on an 11-point scale where 0=no pain to 10=worst imaginable pain). A weekly score was calculated for the liquid or soft stool frequency and a separate weekly score was calculated for abdominal pain, in each case based on daily symptom reporting. PRO2-remission was defined as PRO2 less than 8 points. PRO2 is a composite index consisting of weighted scoring of both variables. PRO2 scores ranges from 0 to approximately 45, higher score indicates higher disease activity. | Weeks 8, 16 and 28 | 
| Percentage of Participants With PRO2 Response | PRO2 evaluated 2 patient-reported symptoms: the frequency of liquid or soft stools and abdominal pain. PRO2 response was defined as remission or response in one symptom (either abdominal pain or stool frequency) plus response in the other: a) abdominal pain remission: On an 11-point (0 to 10) pain scale: During 1 week, no daily score > 2, b) abdominal pain response: On an 11-point (0 to 10) pain scale: ≥ 30% reduction in weekly pain score from baseline, c) loose/liquid stool frequency remission: Counting stools identified as Type 6 or 7 on Bristol Stool Form Scale (BSFS), (The BSFS is a scale between 1-7, where 1 correlates with the firmest stool and 7 correlates with entirely liquid stool), during 1 week, each daily loose/liquid stool count ≤ 3, d) loose/liquid stool frequency response: Counting stools identified as Type 6 or 7 on BSFS, ≥ 30% reduction in weekly loose/liquid stool count compared to baseline. | Baseline, Weeks 8, 16 and 28 | 
| Serum Interleukin (IL)-22 and Serum Lipocalin 2 (LCN2) Concentration as a Biomarker of Brazikumab's Efficacy |  | Weeks 16 and 28 | 
| Percentage of Participants With CDAI Modified Sustained Clinical Remission at Both Weeks 8 and 28 | CDAI modified sustained clinical remission was defined as a CDAI score of <150 at both Weeks 8 and 28. CDAI score was calculated by summing weighted scores for subjective items [number of liquid or very soft stools, abdominal pain (on a scale of 0=mild to 3=severe) and general well-being (on a scale of 1=generally well to 4=terrible)] recorded by a diary during a 1-week period, and objective items [associated symptoms, taking antidiarrheal agents such as loperamide/opiates, abdominal mass, hematocrit, daily morning temperature and body weight]. CDAI scores range from 0 to approximately 600 points, higher score indicates higher disease activity. | Weeks 8 and 28 | 
| Serum Brazikumab Concentration |  | Predose at Weeks 0, 1, 4, 8, 12, 16, 28; Postdose at Weeks 0 and 4 | 
| Number of Participants With Serum Anti-drug Antibodies for Brazikumab |  | Predose at Weeks 0, 4, 12, 16, 28, 40 and 52 | 
| Number of Participants With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (TESAEs), TEAEs of Special Interest and TEAEs Leading to Discontinuation | An AE is any untoward medical occurrence in a patient/clinical investigation participant administered a pharmaceutical product and which does not necessarily have a causal relationship with treatment. An adverse event can therefore be any unfavorable and unintended sign (including abnormal laboratory finding), symptom, or disease temporally associated with the use of investigational product, whether or not related to the investigational product. A TEAE is any new AE or worsening of an existing condition after initiation of treatment. An SAE is an AE that resulted in death, inpatient hospitalization/prolongation of existing hospitalization, persistent or significant disability or incapacity, life threatening, a congenital anomaly/birth defect, or an important medical event. AE of special interest were infusion/injection-site reactions, hypersensitivity reactions, malignancies, cardiac events like myocardial infarction, stroke/cardiovascular death, ocular AE including cataracts. | From first dose of study drug up to 28 weeks post last dose (approximately up to Week 80) | 
| Number of Participants With Clinically Significant Laboratory Values | Laboratory parameters included tests for hematology, serum chemistry and urinalysis. Laboratory values that were outside the reference range, considered clinically significant were reported. | From first dose of study drug up to 28 weeks post last dose (approximately up to Week 80) | 
| Percentage of Participants With Abdominal Pain Response | Abdominal pain response is defined as a ≥ 30% reduction in weekly pain score from baseline on an 11-point (0 to 10) pain scale, where 0 = no pain and 10 = worst imaginable pain. | Baseline; Weeks 8, 16 and 28 | 
| Percentage of Participants With Abdominal Pain Remission | Abdominal pain remission is defined as no daily score > 2 on an 11-point (0 to 10) pain scale during 1 week, where 0 = no pain and 10 = worst imaginable pain. | Weeks 8, 16 and 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MEDI2070, inflammatory bowel disease, moderate to severe Crohn's Disease, IL-23