A 52-Week, Multicenter, Randomized, Double-blind, Placebo and Active-Controlled, Operationally Seamless Phase 2b/3, Parallel-group Study to Assess the Efficacy and Safety of Brazikumab in Participants with Moderately to Severely Active Crohn’s Disease
The primary goal of this study is to demonstrate the efficacy and safety of brazikumab in participants with moderately to severely active CD and demonstrate the clinical utility of a serum biomarker to identify participants who are most likely to benefit from treatment with brazikumab.
- 18-80 years of age
- Have a diagnosis of ileal, ileocolonic, or colonic Crohn’s Disease with an onset of symptoms for a minimum of 3 months prior to screening for the study.
- Moderately to severely active Crohn’s disease determined during screening (signs and symptoms and ileocolonoscopy findings)
- Participant has had an inadequate response or intolerance to intervention with conventional treatment (oral aminosalicylates, oral CS, azathioprine, methotrexate, or 6-mercaptopurine), or prior biological treatment, or demonstrated CS dependence for the treatment of CD. 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), budesonide, immunomodulators, oral antibiotics, or probiotics must be at a stable dose
- No known history of active TB or latent TB without completion of appropriate intervention. Acceptable TB test results from the central laboratory must be met.
- 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 (confirmed by the investigator) from randomization throughout the study duration and for at least 18 weeks after last dose of study intervention.
- Women not of childbearing potential are defined as women who are either permanently sterilized or who are postmenopausal. Women will be considered postmenopausal if they have been amenorrhoeic for 12 months prior to the planned date of randomization without an alternative medical cause.
- Nonsterilized males who are sexually active with a female partner of childbearing potential must comply with the methods of contraception during treatment and until the end of relevant systemic exposure in the male participant, plus a further 18 weeks.
- Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in the protocol.
- Willingness and ability to attend all study visits, comply with the study procedures, read and write in order to complete questionnaires, and be able to complete the study period.
- Participant is unable or unwilling to have endoscopic procedures performed during the study.
- History or current diagnosis of ulcerative colitis, indeterminate colitis, microscopic colitis, ischemic colitis, colonic mucosal dysplasia, primary sclerosing cholangitis, or untreated bile acid malabsorption.
- History of toxic megacolon within 3 months prior to Randomization.
- Any intra-abdominal surgery, bowel resection, diversion, placement of ostomy or stoma within 3 months prior to Screening. Participants with a draining stoma, ostomy, or extensive colonic resection are excluded.
- Participant has an enterocutaneous or enterovesicular fistula. Participants with other active fistulas, including perianal fistulas, may be considered for enrollment if there is no anticipation for surgery and there is no evidence of active infection (eg, abscess).
- Bowel perforation during the 6 months prior to Screening or evidence of obstruction within 3 months of Screening.
- Complications of CD including short bowel syndrome, strictures/stenoses with obstruction or pre-stenotic dilation, or conditions where surgery may be anticipated within 6 months, or other conditions that may confound efficacy evaluations for the study.
- Participant has any non-passable colonic stenosis/narrowing identified during the qualifying ileocolonoscopy (successful endoscope passage to the caecum with inability to enter the endoscope into the ileum is not covered under this exclusion criterion and does not require exclusion).
- Ongoing nutritional dependency for total parenteral nutrition or an elemental diet at Screening.
- Participant has any of the following related to infections:
- Evidence of a recent (within 6 months of Randomization) systemic fungal infection, requiring inpatient hospitalization, and/or antifungal treatment.
- Any infection requiring hospitalization or treatment with IV anti-infectives (including antiviral treatment) 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 (eg, osteomyelitis) 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 the Study Physician/designee. Crohnic suppressive antiviral treatment for herpes simplex virus in the absence of active lesions or uncomplicated urinary tract infections are not considered exclusionary
Participant has clinical evidence of or is suspected to have an abscess during Screening. Cutaneous and perianal/perirectal abscesses are not exclusionary if drained and adequately treated at least 3 weeks prior to Screening and there is no anticipation for surgery.
Diagnosis of peritonitis or receiving treatment for peritonitis within 8 weeks prior to Screening
Participant has any underlying condition that predisposes participant to infections.
Signs or symptoms of ongoing infection due to intestinal pathogens
- Previous allogenic bone marrow transplant or history of organ or cell-based transplantation (eg, islet cell transplantation or autologous stem cell transplantation) with the exception of corneal transplant.
- Chronic hepatitis B or C infection.
- Known history of primary immunodeficiency, splenectomy, or any underlying condition that predisposes the subject to infection, including HIV infection.
- Prior history of or current diagnosis of a demyelinating disorder.
- Participant has received the following treatment:
- Adalimumab, certolizumab pegol, infliximab, or golimumab: within 8 weeks prior to Randomization (Day 1)
- Vedolizumab or ustekinumab within 12 weeks prior to Randomization (Day 1
- Other prohibited medication, biologic or small molecule treatment within 5 half-lives prior to Randomization (Day 1
- Fecal microbiota transplantation: within 8 weeks prior to Screening ileocolonoscopy
- Except for ustekinumab, prior exposure to any biologic agent targeting IL 12 or IL-23 (eg, risankizumab, briakinumab, mirikizumab, guselkumab, tildrakizumab, or brazikumab).
- Participants who received cyclosporine, mycophenolate mofetil, sirolimus (rapamycin), thalidomide, tacrolimus (FK-506), or tofacitinib within 2 weeks prior to Screening Visit 1.
- 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.
- Participants received more than 1 dose of IV or intramuscular steroids within 2 weeks prior to Screening Visit 1.
- Participant received topical (rectal) aminosalicylic acid (eg, mesalamine) or topical (rectal) steroids within 2 weeks prior to Randomization.
- Participant received a Bacille Calmette-Guérin vaccination within 12 months of Randomization or any other live vaccine less than 4 weeks prior to Randomization or is planning to receive any such vaccine over the course of the study.
- Participant has known or suspected history of chronic use of NSAIDs (defined as at least 3 times per week for more than 3 months; not applicable to daily aspirin use up to 325 mg per day) and/or opiates, drug, or alcohol abuse.
- History of cancer with the following exceptions:
- A history of basal cell carcinoma and/or squamous cell carcinoma of the skin, with apparent successful curative therapy greater than 12 months prior to Screening
- Carcinoma in situ of the cervix, with apparent successful curative therapy, greater than 12 months prior to Screening.
- Clinically significant cardiovascular conditions including recent myocardial infarction, unstable angina, stroke, transient ischemic attack, decompensated heart failure requiring hospitalization, or Class III/IV heart failure within 6 months of Screening.
- Prolonged QTcF interval (QTc >450 msec or QTC >480 for participants with bundle branch block; determined on central ECG), or conditions leading to additional risk for QT prolongation (eg, congenital long-QT syndrome).
- Clinically significant kidney disease
- Other concurrent medical conditions: Participant has known, preexisting, clinically significant endocrine, autoimmune, metabolic, neurologic, renal, gastrointestinal, hepatic, hematological, respiratory or any other system abnormalities that are not associated with CD and are uncontrolled with standard treatment.
- 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, or receiving other investigational agent(s).
- Transfusion of blood, plasma, or platelets within the 30 days prior to Screening.
- Females who are pregnant, nursing, or planning a pregnancy during the study OR females who are of childbearing potential and do not agree to use a highly effective method of contraception consistently and correctly.
- Employees of the clinical study site or any other individuals involved with the conduct of the study, or immediate family members of such individuals.
- Previous randomization in the present study.
Study description/explanation of participation:
Participants diagnosed with moderately to severely active Crohn’s Disease (CD) may be eligible to participate in a clinical study comparing brazikumab, an investigational drug (investigational means the treatment is not approved for use) to placebo, an inactive dummy treatment given in the same way as brazikumab for up to 1 ½ years. Participants who meet eligibility criteria will be randomly assigned (by chance) to brazikumab or placebo (referred to as study drug) and will not know which treatment they are taking. Participants will receive induction doses of intravenous (IV, through a vein) study drug at their first treatment visit (baseline), Week 4, and Week 8 followed by subcutaneous (SC, administered under the skin) study drug every 4 weeks until Week 48.
- Brazikumab high dose IV (Weeks 0, 4, and 8), then SC from Week 12 and every 4 weeks through Week 48.
- Brazikumab low dose IV (Weeks 0, 4, and 8), then SC from Week 12 and every 4 weeks through Week 48.
- Placebo: placebo IV (Weeks 0, 4, and 8), then SC from Week 12 and every 4 weeks through Week 48.
If you meet specific study criteria and may benefit from receiving brazikumab, you may be able to participate in a separate extension study after you finish treatment in this study.
Description of treatment or intervention (mechanism of action):
Brazikumab is a type of protein called an antibody and is designed to stick to another
protein called interleukin-23 (IL-23). IL-23 is known to play a role in causing inflammation
in patients with CD. By sticking to IL-23, it is hoped that brazikumab will stop IL-23 from
working, thereby helping to reduce the symptoms of CD.
Patient participation requirements:
- Attend all study visits
- Tell the study doctor about how you are feeling and what medications you are taking
- Follow the directions of the study doctor and research team
- Complete questionnaires on a daily electronic diary honestly and bring the diary to each study visit
- Do not participate in other research studies while you are participating in this study
Possible risks and side effects:
Brazikumab is being investigated for use in Crohn’s Disease. It is not approved in any countries and safety and efficacy have not been established. In past studies common side effects (occurring at a rate of 1 in 10 to 1 in 100 participants) included headache, nasopharyngitis (common cold), joint pain, dizziness, asthenia (lack of energy, abnormal physical weakness), skin rash, upper respiratory infections, and muscle pain.
Other potential risks associated with drugs that affect the immune response are serious infections, allergic reactions, malignancies, and infusion reactions (during the IV portion of the study).