IBD, Ulcerative Colitis
Conditions
Brief summary
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
Interventions
DRUGBrazikumab
Intravenous brazikumab on day 1, day 15, and day 43 followed by Subcutaneous brazikumab every 4 weeks beginning on day 71 through Week 50
DRUGPlacebo
Intravenous placebo on day 1, day 15, and day 43 followed by Subcutaneous placebo every 4 weeks beginning on Day 71 through Week 50.
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Intervention model description
Global, multicenter, randomized, double-blind, placebo-controlled, parallel-group, Phase 2 study
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Ability to provide informed consent 2. Aged 18 to 80 years of age 3. Diagnosis of UC with an onset of symptoms for a minimum of 3 months prior to Screening 4. Evidence of UC extending proximal to the rectum (≥ 15 cm of involved colon) 5. Moderately to severely active UC as defined by: 1. Average daily mMS Stool Frequency subscore ≥ 1 AND Average daily mMS Rectal Bleeding subscore ≥ 1 2. Modified Mayo endoscopic subscore of ≥ 2 based on a full colonoscopy within 14 days prior to randomization. 6. 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. 7. 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. 8. 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. 9. Women not of childbearing potential are defined as women who are either permanently sterilized (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or who are postmenopausal. 10. 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. 11. 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
1. Participant has UC limited to the rectum (ie, not beyond 15 cm of the anal verge). 2. 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. 3. 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. 4. Participant has received the following treatment: 1. Infliximab: within 8 weeks prior to randomization. 2. Adalimumab, certolizumab pegol, or golimumab: within 8 weeks prior to randomization. 3. Vedolizumab or ustekinumab within 12 weeks of randomization. 4. Other prohibited medication, biologic or small molecule treatment within 5 half-lives prior to randomization. 5. Fecal microbiota transplantation: within 8 weeks prior to randomization. 5. Criterion deleted as part of Amendment 5 v6.0 6. Except for ustekinumab, prior exposure to any biologic agent targeting IL-12 or IL-23. 7. 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. 8. Participant received cyclosporine, mycophenolate mofetil, sirolimus (rapamycin), thalidomide, tacrolimus (FK-506), or tofacitinib within 2 weeks prior to Screening. 9. Participants who received IV or intramuscular steroids within 2 weeks prior to Screening. 10. 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). 11. Participant received a transfusion of blood, plasma, or platelets within 30 days prior to Screening. 12. Participant received a Bacille Calmette-Guérin vaccination within 12 months of randomization or any other live vaccine less than 4 weeks prior to randomization. 13. Participant has any of the following criteria related to infections: 1. Evidence of a recent systemic fungal infection, requiring inpatient hospitalization, and/or antifungal treatment. 2. Any infection requiring hospitalization or treatment with IV anti-infectives within 4 weeks of Screening. 3. Cytomegalovirus or Epstein-Barr virus infection that has not resolved within 8 weeks prior to Screening. 4. Clinically significant chronic infection that has not resolved within 8 weeks of Screening. 5. Nonserious infection requiring oral anti-infectives within 2 weeks prior to randomization must be further discussed with study medical monitor. 6. Clinical evidence of or suspected to have an abscess during Screening. 7. Any underlying condition that predisposes the participant to infections. 8. Participant had previous allogenic bone marrow transplant or history of organ or cell-based transplantation. 9. Clinically significant active infection or signs/symptoms of infection that has the potential to worsen with immunosuppressive therapy. 10. Signs or symptoms of ongoing infection due to intestinal pathogens. 14. Participant has known or suspected history of chronic use of NSAIDs and/or opiates, drug, or alcohol abuse. 15. 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. 16. Clinically significant cardiovascular conditions. 17. Prolonged QTcF interval or conditions leading to additional risk for QT prolongation. 18. Clinically significant kidney disease 19. Abnormal laboratory results at Screening as defined in the study protocol 20. Participant is pregnant or breastfeeding or plans to become pregnant during the study. 21. Participant has other known, pre-existing, clinically significant medical conditions that are not associated with UC and are uncontrolled with standard treatment. 22. 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. 23. 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Remission | at Week 10 | Efficacy was assessed using the Mayo Scoring System for assessment of Ulcerative Colitis. The Mayo score assesses * stool frequency, * rectal bleeding, * endoscopic findings, and * physician's assessment of disease activity. Each of these four subscores can be scored as 0, 1, 2, or 3, where 0 is a normal finding and 3 corresponds to severe disease. The Mayo score has been modified (modified Mayo Score, mMS) to specify no friability in the endoscopy subscore of 1 (mild disease). Clinical Remission is defined by the mMS at Week 10: * 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 Further, if the patient * discontinue treatment prematurely for any reason * takes rescue treatment or meet the rescue criteria * uses prohibited medication the patient is considered as unsuccessfully treated and imputed as non-responder |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Sustained Clinical Remission | Week 10 and 54 | 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 Further, if the patient * discontinue treatment prematurely for any reason * takes rescue treatment or meet the rescue criteria * uses prohibited medication the patient is considered as unsuccessfully treated and imputed as non-responder |
| CS-free Clinical Remission | Week 54 | 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 Further, if the patient * discontinue treatment prematurely for any reason * takes rescue treatment or meet the rescue criteria * uses prohibited medication the patient is considered as unsuccessfully treated and imputed as non-responder |
| Clinical Response | Week 10 | Efficacy was assessed using the Mayo Scoring System for assessment of Ulcerative Colitis. The Mayo score assesses * stool frequency, * rectal bleeding, * endoscopic findings, and * physician's assessment of disease activity. Each of these four subscores can be scored as 0, 1, 2, or 3, where 0 is a normal finding and 3 corresponds to severe disease. The Mayo score is the sum of the four subscores. The Mayo score has been modified (modified Mayo Score, mMS) to specify no friability in the endoscopy subscore of 1 (mild disease). 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 Further, if the patient * discontinue treatment prematurely for any reason * takes rescue treatment or meet the rescue criteria * uses prohibited medication the patient is considered as unsuccessfully treated and imputed as non-responder |
| Endoscopic Improvement | Week 10 | Efficacy was assessed using the Mayo Scoring System for assessment of Ulcerative Colitis. The Mayo score assesses * stool frequency, * rectal bleeding, * endoscopic findings, and * physician's assessment of disease activity. Each of these four subscores can be scored as 0, 1, 2, or 3, where 0 is a normal finding and 3 corresponds to severe disease. Endoscopic improvement is defined as Endoscopy subscore ≤ 1. Further, if the patient * discontinue treatment prematurely for any reason * takes rescue treatment or meet the rescue criteria * uses prohibited medication the patient is considered as unsuccessfully treated and imputed as non-responder |
| Serum Concentrations of Brazikumab (Induction) | through week 10 | Pharmacokinetics: concentration of brazikumab in serum |
| Exposure-response | through week 68 | Participants with Clinical Remission by Quartile of Brazikumab concentration |
| Incidence of Anti-drug Antibodies (Induction) | through week 10 | Immunogenicity: incidence of brazikumab anti-drug antibodies in serum |
| Adverse Events | Through week 68: Induction: AE with onset on or after first IV dose up to SC dose, or early term trt date + 18 wks after last dose. Maintenance: AE with onset on or after first SC dose up to and including 18 weeks after date of last SC dose. | Number and percentage of patients with reported adverse events. |
| Laboratory Values | through week 68 | Percentage of patients with potentially clinically significant changes in hematology, clinical chemistry, urinalysis. |
| Vital Signs | through week 68 | Percentage of patients with potentially clinically significant changes in systolic and diastolic blood pressure, and pulse rate. |
| Abnormal ECG Results Through Week 68 | through week 68 | Percentage of patients with potentially clinically significant changes in 12-lead ECG recordings |
| Serum Concentrations of Brazikumab (Maintenance) | Week 30 through week 68 | Pharmacokinetics: concentration of brazikumab in serum |
| Incidence of Anti-drug Antibodies (Maintenance) | Week 30 through week 68 | Immunogenicity: incidence of brazikumab anti-drug antibodies in serum |
| mMS Total Score (Induction) | through Week 10 | mMS total score at baseline and Week 10 |
| mMS Component Score: Endoscopy (Induction) | through Week 10 | Number of participants in each score category for Endoscopy score |
| mMS Component Score: Stool Frequency (Induction) | through Week 10 | Number of participants in each score category for Stool frequency |
| mMS Component Score: Rectal Bleeding (Induction) | through Week 10 | Number of participants in each score category for Rectal bleeding |
| Total mMS (Maintenance) | Week 54 | mMS total score at baseline and Week 54 |
| mMS Component Score: Endoscopy (Maintenance) | through Week 54 | Number of participants in each score category for Endoscopy score |
| mMS Component Score: Stool Frequency (Maintenance) | through Week 54 | Number of participants in each score category for Stool frequency score |
| mMS Component Score: Rectal Bleeding (Maintenance) | through Week 54 | Number of participants in each score category for Rectal bleeding score |
Countries
Canada, Czechia, Germany, Hungary, India, Israel, Italy, Japan, Poland, Puerto Rico, Russia, Slovakia, South Africa, South Korea, Spain, Taiwan, Ukraine, United Kingdom, United States
Contacts
STUDY_DIRECTORKathy Bohannon
AstraZeneca
Participant flow
Pre-assignment details
As of 1 June 2023, AstraZeneca discontinued the development of brazikumab. All study related dosing was immediately stopped. Because of study early termination, site data cleaning engagement proved challenging and as a result databases were locked with unclean data. A patient centric approach was taken to focus data cleaning on key safety variables (adverse events). Please be aware that the data submitted needs to be considered with the data quality in mind.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 41.4 years STANDARD_DEVIATION 14.09 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 61 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 13 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 155 Participants |
| Sex: Female, Male Female | 107 Participants |
| Sex: Female, Male Male | 31 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 73 | 0 / 73 | 0 / 10 | 0 / 10 | 0 / 71 | 0 / 31 | 0 / 28 | 0 / 31 | 0 / 31 | 0 / 6 | 0 / 4 | 0 / 9 | 0 / 58 |
| other Total, other adverse events | 31 / 73 | 33 / 73 | 7 / 10 | 5 / 10 | 24 / 71 | 16 / 31 | 5 / 28 | 16 / 31 | 15 / 31 | 5 / 6 | 3 / 4 | 5 / 9 | 23 / 58 |
| serious Total, serious adverse events | 3 / 73 | 2 / 73 | 0 / 10 | 0 / 10 | 4 / 71 | 0 / 31 | 0 / 28 | 1 / 31 | 0 / 31 | 0 / 6 | 0 / 4 | 0 / 9 | 2 / 58 |
Outcome results
None listed