Evaluation of Efficacy and Safety of Brazikumab (MEDI2070) in Participants With Active, Moderate to Severe Crohn's Disease
- Conditions
- Crohn's Disease
- Interventions
- Registration Number
- NCT02574637
- Lead Sponsor
- AstraZeneca
- Brief Summary
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
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.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 29
- 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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo Brazikumab IV Infusion 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. Placebo Brazikumab SC Injection 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. Brazikumab High Dose Brazikumab IV Infusion 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. Brazikumab High-Medium Dose Brazikumab IV Infusion 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. Brazikumab High-Medium Dose Brazikumab SC Injection 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. Brazikumab Low-Medium Dose Brazikumab IV Infusion 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. Brazikumab Low Dose Brazikumab IV Infusion 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. Brazikumab High Dose Brazikumab SC Injection 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. Placebo Placebo 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. Brazikumab High-Medium Dose Placebo 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. Brazikumab Low Dose Brazikumab SC Injection 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. Brazikumab Low Dose Placebo 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. Brazikumab High Dose Placebo 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. Brazikumab Low-Medium Dose Brazikumab SC Injection 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. Brazikumab Low-Medium Dose Placebo 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.
- Primary Outcome Measures
Name Time Method Percentage of Participants With Crohn's Disease Activity Index (CDAI) Remission at Week 8 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.
- Secondary Outcome Measures
Name Time Method Percentage of Participants With Loose/Liquid Stool Frequency Response Baseline, Weeks 8, 16 and 28 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.
Percentage of Participants With Simple Endoscopic Score for Crohn's Disease (SES-CD) Response Baseline, Weeks 16 and 28 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.
Percentage of Participants With Loose/Liquid Stool Frequency Remission Baseline, Weeks 8, 16 and 28 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.
Percentage of Participants With Simple Endoscopic Score for Crohn's Disease (SES-CD) Remission Weeks 16 and 28 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.
Percentage of Participants With PRO2 Response Baseline, Weeks 8, 16 and 28 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.
Number of Participants With Clinically Significant Laboratory Values From first dose of study drug up to 28 weeks post last dose (approximately up to Week 80) Laboratory parameters included tests for hematology, serum chemistry and urinalysis. Laboratory values that were outside the reference range, considered clinically significant were reported.
Percentage of Participants With CDAI Clinical Remission Weeks 16 and 28 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.
Number of Participants With Serum Anti-drug Antibodies for Brazikumab Predose at Weeks 0, 4, 12, 16, 28, 40 and 52 Percentage of Participants With Crohn's Disease Activity Index (CDAI) Response Baseline, Weeks 8, 16 and 28 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.
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 Abdominal Pain Response Baseline; Weeks 8, 16 and 28 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.
Percentage of Participants With Patient Response Outcome-2 (PRO2) Remission Weeks 8, 16 and 28 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.
Number of Participants With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (TESAEs), TEAEs of Special Interest and TEAEs Leading to Discontinuation From first dose of study drug up to 28 weeks post last dose (approximately up to Week 80) 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.
Percentage of Participants With CDAI Modified Sustained Clinical Remission at Both Weeks 8 and 28 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.
Serum Brazikumab Concentration Predose at Weeks 0, 1, 4, 8, 12, 16, 28; Postdose at Weeks 0 and 4 Percentage of Participants With Abdominal Pain Remission Weeks 8, 16 and 28 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.
Trial Locations
- Locations (51)
Research Site
🇪🇸L'Hospitalet de Llobregat, Spain
Ehrhardt Clinical Research, LLC
🇺🇸Belton, Missouri, United States
Premier Medical Group of the Hudson Valley, PC
🇺🇸Poughkeepsie, New York, United States
Clinical Inquest Center Ltd
🇺🇸Dayton, Ohio, United States
Hôpital de Brabois Adultes
🇫🇷Vandoeuvre les Nancy, Meurthe Et Moselle, France
Semmelweis Egyetem
🇭🇺Budapest, Hungary
Erasmus Medisch Centrum
🇳🇱Rotterdam, Netherlands
TSBIH "Territorial Clinical Hospital"
🇷🇺Krasnoyarsk, Russian Federation
Hospital Universitari de Bellvitge
🇪🇸Hospitalet de Llobregat, Barcelona, Spain
Clinical Research of West Florida - Corporate
🇺🇸Clearwater, Florida, United States
NorthShore University HealthSystem
🇺🇸Evanston, Illinois, United States
Revival Research Institute, LLC
🇺🇸Southfield, Michigan, United States
New York University Medical Center
🇺🇸Great Neck, New York, United States
Donald Guthrie Foundation
🇺🇸Sayre, Pennsylvania, United States
Erlanger Health System
🇺🇸Chattanooga, Tennessee, United States
Gastroenterology Research of America
🇺🇸Houston, Texas, United States
University of Texas Health Science Center at Houston
🇺🇸Houston, Texas, United States
Arizona Arthritis & Rheumatology Research, PLLC
🇺🇸Phoenix, Arizona, United States
Magyar Honvedseg Egeszsegugyi Kozpont
🇭🇺Budapest, Hungary
CHU Saint Etienne - Hôpital Nord
🇫🇷Saint Etienne, Loire, France
South Denver Gastroenterology, PC
🇺🇸Lone Tree, Colorado, United States
Borland-Groover Clinic
🇺🇸Jacksonville, Florida, United States
Advanced Pharma CR, LLC
🇺🇸Miami, Florida, United States
IMIC, Inc.
🇺🇸Palmetto Bay, Florida, United States
University of Chicago Medical Center
🇺🇸Chicago, Illinois, United States
Indiana University
🇺🇸Indianapolis, Indiana, United States
Cotton-O'Neil Clinical Research Center, Digestive Health
🇺🇸Topeka, Kansas, United States
Graves Gilbert Clinic
🇺🇸Bowling Green, Kentucky, United States
Clinical Trials of SW Louisiana, LLC
🇺🇸Lake Charles, Louisiana, United States
Clinical Trials Management, LLC
🇺🇸Metairie, Louisiana, United States
Mayo Clinic - Rochester
🇺🇸Rochester, Minnesota, United States
Baylor Research Institute
🇺🇸Temple, Texas, United States
Princess Alexandra Hospital
🇦🇺Woolloongabba, Queensland, Australia
Allegiance Research Specialists, LLC
🇺🇸Milwaukee, Wisconsin, United States
Imeldaziekenhuis
🇧🇪Bonheiden, Belgium
UZ Leuven
🇧🇪Leuven, Belgium
London Health Science Centre
🇨🇦London, Ontario, Canada
LHSC - Victoria Hospital
🇨🇦London, Ontario, Canada
CHU de Toulouse - Hôpital Rangueil
🇫🇷Toulouse Cedex 09, Haute Garonne, France
Royal University Hospital
🇨🇦Saskatoon, Saskatchewan, Canada
CHU Rennes - Hôpital Pontchaillou
🇫🇷Rennes cedex 09, Ille Et Vilaine, France
Medizinische Hochschule Hannover
🇩🇪Marburg, Hessen, Germany
St. Johannes Hospital
🇩🇪Dortmund, Nordrhein Westfalen, Germany
Pavlov First Saint Petersburg State Medical University
🇷🇺Saint-Petersburg, Russian Federation
Kaplan Medical Center
🇮🇱Rechovot, Israel
Szent Janos Korhaz es Eszak-budai Egyesitett Korhazak
🇭🇺Budapest, Hungary
Maastricht University Medical Center
🇳🇱Maastricht, Netherlands
Istituto Clinico Humanitas
🇮🇹Rozzano, Milano, Italy
Hospital Universitari Germans Trias i Pujol
🇪🇸Badalona, Barcelona, Spain
University of Louisville
🇺🇸Louisville, Kentucky, United States
University of Michigan Health System
🇺🇸Ann Arbor, Michigan, United States