Clinical trial NCT03759288: An Active and Placebo-Controlled Study of Brazikumab in Participants With Moderately to Severely Active Crohn's Disease
Official title: 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 (INTREPID Lead-In)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
PHASE3
Conditions: Crohn's Disease
IBD
Keywords: Crohn's Disease
Inflammatory bowel disease
Brazikumab
IL23 receptor
IBD
CD
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2018-11-29
Enrollment: 89
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study seeks to evaluate the safety and efficacy of brazikumab versus placebo (Stage I) and versus an active comparator (Stage 2) in participants with moderately to severely active CD and will include assessments of clinical response as demonstrated by improvement of symptoms and colonic mucosal appearance as observed on endoscopy


Eligibility criteria: Inclusion and Exclusion Criteria are the same for both Stage 1 and Stage 2; however, participants enrolled in Stage 1 will not be permitted to enroll in Stage 2.

Inclusion Criteria:

1. At the time of signing the informed consent, the participant must be 18 to 80 years of age, inclusive.
2. A diagnosis of ileal, ileocolonic, or colonic CD with an onset of symptoms for a minimum of 3 months prior to Screening as determined by the investigator based on clinical history, exclusion of other etiologies including infectious causes, and characteristic endoscopic and/or histologic findings.
3. Moderately to severely active CD defined by a CDAI score of 220 to 450 AND; CDAI LSF score ≥ 5 OR CDAI AP score ≥ 2; AND SES-CD of at least 6
4. Participant 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.
5. Participants taking 5-aminosalicylates, Oral prednisone (or equivalent), Budesonide, Immunomodulators, Oral antibiotics, Immunomodulators, Probiotics must be at a stable dose.
6. Participant must have the QFT-TB test performed and meet the following TB criteria.

A TB worksheet must also be completed:

1. Participant has no known history of active TB.
2. Participant has no known history of latent TB without completion of an appropriate course of intervention.
3. Meets 1 of the following acceptable TB test results:

i. Negative QFT-TB obtained from central laboratory during Screening, OR ii. For a positive QFT-TB test obtained during Screening from the central laboratory, active TB must be ruled out or treated and negative QFT-TB confirmed by central laboratory OR iii. Indeterminate QFT-TB test obtained during the Screening Period from the central laboratory with ongoing QFT-TB testing as outlined in Appendix G. Participants with an indeterminate QFT-TB test can continue with Screening if they have all of the following:

1. no symptoms/risk factors per TB worksheet provided by the sponsor
2. no known recent exposure to a case of active TB
3. no evidence of active TB on chest x-ray within 8 weeks prior to Screening or during Screening
4. confirmed QFT-TB negative by central laboratory

7 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.

8 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.

9 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.

10 Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in the protocol.

11 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.

12 Provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of samples for optional genetic research that supports Genomic Initiative.

Complete inclusion criteria are in the study protocol

Exclusion Criteria:

1. Participant is unable or unwilling to have endoscopic procedures performed during the study.
2. History or current diagnosis of ulcerative colitis, indeterminate colitis, microscopic colitis, ischemic colitis, colonic mucosal dysplasia, primary sclerosing cholangitis, or untreated bile acid malabsorption.
3. History of toxic megacolon within 3 months prior to Randomization.
4. 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 irrespective of the time from surgery.
5. 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).
6. Bowel perforation during the 6 months prior to Screening or evidence of obstruction within 3 months of Screening.
7. 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.
8. 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).
9. Ongoing nutritional dependency for total parenteral nutrition or an elemental diet at Screening.
10. 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. • Participant has clinical evidence of or suspected to have an abscess during Screening. • Diagnosis of peritonitis or receiving treatment for peritonitis within 8 weeks prior to Screening • Participant has any underlying condition that predisposes participant to infections • 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
11. 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.
12. Chronic hepatitis B or C infection.
13. Known history of primary immunodeficiency, splenectomy, or any underlying condition that predisposes the subject to infection, includingHIV infection.
14. Prior history of or current diagnosis of a demyelinating disorder.
15. Participant has received the following treatment: • Adalimumab, certolizumab pegol, infliximab, or golimumab: within 8 weeks prior to Randomization • Vedolizumab or ustekinumab within 12 weeks prior to Randomization • Other prohibited medication, biologic or small molecule treatment within 5 half-lives prior to Randomization • Fecal microbiota transplantation: within 8 weeks prior to Screening ileocolonoscopy
16. Except for ustekinumab, prior exposure to any biologic agent targeting IL-12 or IL-23.
17. Participants who received cyclosporine, mycophenolate mofetil, sirolimus (rapamycin), thalidomide, tacrolimus (FK-506), or tofacitinib within 2 weeks prior to Screening Visit 1.
18. 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.
19. Participants received more than 1 dose of IV or intramuscular steroids within 2 weeks prior to Screening Visit 1.
20. Participant received topical (rectal) aminosalicylic acid (eg, mesalamine) or topical (rectal) steroids within 2 weeks prior to Randomization.
21. 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.
22. 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 325mg per day) and/or opiates, drug, or alcohol abuse.
23. History of cancer with the following exceptions: (a) 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 (b) Carcinoma in situ of the cervix, with apparent successful curative therapy, greater than 12 months prior to Screening.
24. 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.
25. 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).
26. Clinically significant kidney disease
27. Abnormal laboratory results at Screening
28. 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.
29. 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)
30. Transfusion of blood, plasma, or platelets within the 30 days prior to Screening.
31. 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.
32. Employees of the clinical study site or any other individuals involved with the conduct of the study, or immediate family members of such individuals.
33. Previous randomization in the present study. . Complete exclusion criteria are in the study protocol

Primary outcomes:
measure: Stage 1. Percentage of patients with CDAI remission
timeFrame: at Week 12
measure: Stage 2. Percentage of patients with endoscopic response
timeFrame: at Week 52
measure: Stage 2. Percentage of patients with clinical remission
timeFrame: at Week 52
Secondary outcomes:
measure: Stage 1. Percentage of patients with endoscopic response
timeFrame: at Week 12
measure: Stage 1. Percentage of patients with clinical remission
timeFrame: at Week 12
measure: Stage 1. Percentage of patients with CDAI response
timeFrame: at Week 12
measure: Stage 1. Percentage of patients with CDAI remission
timeFrame: at both Week 12 and Week 52
measure: Stage 1. Percentage of patients with CDAI response
timeFrame: at both Week 12 and Week 52
measure: Stage 1. Percentage of patients with endoscopic response
timeFrame: at both Week 12 and Week 52
measure: Stage 1. Percentage of patients with clinical remission
timeFrame: at both Week 12 and Week 52
measure: Stage 1. Percentage of patients with endoscopic remission
timeFrame: at Week 52
measure: Stage 1. Percentage of patients with clinical remission
timeFrame: at Week 52
measure: Stage 1. Percentage of patients with CDAI response
timeFrame: at Week 52
measure: Stage 1. Percentage of patients with CDAI remission
timeFrame: at Week 52
measure: Stage 1. Percentage of patients with endoscopic response
timeFrame: at Week 52
measure: Stage 1. Percentage of patients with SES-CD total score of 0-2
timeFrame: at Week 52
measure: Stage 1. Percentage of patients with endoscopic response and endoscopic remission
timeFrame: Endoscopic response at Week 12, endoscopic remission at Week 52
measure: Stage 1. Serum concentration of brazikumab
timeFrame: Through Week 68
measure: Stage 1. Incidence of anti-drug antibodies
timeFrame: Through Week 68
measure: Stage 1. Exposure-response
timeFrame: Through Week 68
measure: Stage 1. Serum IL-22 concentration clinical cutoff for Stage 2
timeFrame: at Week 12
measure: Stage 1. Number and percentage of patients with adverse events
timeFrame: Through Week 68
measure: Stage 1. Percentage of patients with potentially clinically significant changes in laboratory values
timeFrame: Through Week 68
measure: Stage 1. Percentage of patients with potentially clinically significant changes in vital signs
timeFrame: Through Week 68
measure: Stage 1. Percentage of patients with potentially clinically significant changes in physical exams
timeFrame: Through Week 68
measure: Stage 1. Percentage of patients with potentially clinically significant changes in ECGs
timeFrame: Through Week 68
measure: Stage 2. Percentage of patients with endoscopic response
timeFrame: at both Week 12 and Week 52
measure: Stage 2. Percentage of patients with clinical remission
timeFrame: at both Week 12 and Week 52
measure: Stage 2: Percentage of patients with endoscopic remission
timeFrame: at Week 52
measure: Stage 2. Percentage of patients with clinical remission
timeFrame: at Week 52
measure: Stage 2: Percentage of patients with CS-free endoscopic remission
timeFrame: at Week 52
measure: Stage 2. Percentage of patients with CS-free clinical remission
timeFrame: at Week 52
measure: Stage 2: Percentage of patients with CS-free endoscopic remission
timeFrame: at Week 52
measure: Stage 2: Percentage of patients with CS-free clinical remission
timeFrame: at Week 52
measure: Stage 2. Percentage of patients with endoscopic response
timeFrame: at Week 12
measure: Stage 2. Percentage of patients with clinical remission
timeFrame: at Week 12
measure: Stage 2. Percentage of patients with endoscopic response and endoscopic remission
timeFrame: Endoscopic response at Week 12, endoscopic remission at Week 52
measure: Stage 2. Percentage of patients with clinical remission
timeFrame: at both Week 12 and Week 52
measure: Stage 2. Percentage of patients achieving CS-free endoscopic response
timeFrame: at Week 52
measure: Stage 2. Percentage of patients with clinical remission
timeFrame: at Week 52
measure: Stage 2. Serum concentration of brazikumab
timeFrame: Through Week 68
measure: Stage 2. Incidence of anti-drug antibodies
timeFrame: Through Week 68
measure: Stage 2. Exposure-response
timeFrame: Through Week 68
measure: Stage 2. Number and percentage of patients with adverse events
timeFrame: Through Week 68
measure: Stage 2. Percentage of patients with potentially clinically significant changes in laboratory values
timeFrame: Through Week 68
measure: Stage 2. Percentage of patients with potentially clinically significant changes in vital signs
timeFrame: Through Week 68
measure: Stage 2. Percentage of patients with potentially clinically significant changes in physical exams
timeFrame: Through Week 68
measure: Stage 2. Percentage of patients with potentially clinically significant changes in ECGs
timeFrame: Through Week 68
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Research Site
state: Arizona
city: Little Rock
country: United States
facility: Research Site
state: Arkansas
city: Lancaster
country: United States
facility: Research Site
state: California
city: Lincoln
country: United States
facility: Research Site
state: California
city: Poway
country: United States
facility: Research Site
state: California
city: San Diego
country: United States
facility: Research Site
state: California
city: Colorado Springs
country: United States
facility: Research Site
state: Colorado
city: Boca Raton
country: United States
facility: Research Site
state: Florida
city: Clearwater
country: United States
facility: Research Site
state: Florida
city: Kissimmee
country: United States
facility: Research Site
state: Florida
city: Lakeland
country: United States
facility: Research Site
state: Florida
city: Miami Lakes
country: United States
facility: Research Site
state: Florida
city: Miami
country: United States
facility: Research Site
state: Florida
city: Miami
country: United States
facility: Research Site
state: Florida
city: Miami
country: United States
facility: Research Site
state: Florida
city: Naples
country: United States
facility: Research Site
state: Florida
city: Saint Petersburg
country: United States
facility: Research Site
state: Florida
city: Tampa
country: United States
facility: Research Site
state: Florida
city: Atlanta
country: United States
facility: Research Site
state: Georgia
city: Atlanta
country: United States
facility: Research Site
state: Georgia
city: Decatur
country: United States
facility: Research Site
state: Georgia
city: Oak Lawn
country: United States
facility: Research Site
state: Illinois
city: Brownsburg
country: United States
facility: Research Site
state: Indiana
city: Chesterfield
country: United States
facility: Research Site
state: Michigan
city: Las Vegas
country: United States
facility: Research Site
state: Nevada
city: Albuquerque
country: United States
facility: Research Site
state: New Mexico
city: Morehead City
country: United States
facility: Research Site
state: North Carolina
city: Beachwood
country: United States
facility: Research Site
state: Ohio
city: Oklahoma City
country: United States
facility: Research Site
state: Oklahoma
city: Uniontown
country: United States
facility: Research Site
state: Pennsylvania
city: Carrollton
country: United States
facility: Research Site
state: Texas
city: Houston
country: United States
facility: Research Site
state: Texas
city: Houston
country: United States
facility: Research Site
state: Texas
city: McAllen
country: United States
facility: Research Site
state: Texas
city: Pflugerville
country: United States
facility: Research Site
state: Texas
city: Stafford
country: United States
facility: Research Site
state: Texas
city: North Chesterfield
country: United States
facility: Research Site
state: Virginia
city: Spokane
country: United States
facility: Research Site
state: Washington
city: New Westminster
country: Canada
facility: Research Site
state: British Columbia
city: Chicoutimi
country: Canada
facility: Research Site
state: Quebec
city: Ceske Budejovice
country: Czechia
facility: Research Site
city: Horovice
country: Czechia
facility: Research Site
city: Hradec Kralove
country: Czechia
facility: Research Site
city: Olomouc
country: Czechia
facility: Research Site
city: Augsburg
country: Germany
facility: Research Site
city: Berlin
country: Germany
facility: Research Site
city: Hamburg
country: Germany
facility: Research Site
city: Kiel
country: Germany
facility: Research Site
city: Minden
country: Germany
facility: Research Site
city: Remscheid
country: Germany
facility: Research Site
city: Ulm
country: Germany
facility: Research Site
city: Budapest
country: Hungary
facility: Research Site
city: Bangalore
country: India
facility: Research Site
city: Hyderabad
country: India
facility: Research Site
city: Jaipur
country: India
facility: Research Site
city: Surat
country: India
facility: Research Site
city: HaIFA
country: Israel
facility: Research Site
city: Jerusalem
country: Israel
facility: Research Site
city: Petah Tikva
country: Israel
facility: Research Site
city: Milano
country: Italy
facility: Research Site
city: Milano
country: Italy
facility: Research Site
city: Padova
country: Italy
facility: Research Site
city: Busan
country: Korea, Republic of
facility: Research Site
city: Daegu
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Bydgoszcz
country: Poland
facility: Research Site
city: Chojnice
country: Poland
facility: Research Site
city: Kraków
country: Poland
facility: Research Site
city: Poznań
country: Poland
facility: Research Site
city: Rzeszow
country: Poland
facility: Research Site
city: Sopot
country: Poland
facility: Research Site
city: Toruń
country: Poland
facility: Research Site
city: Warszawa
country: Poland
facility: Research Site
city: Warszawa
country: Poland
facility: Research Site
city: Warszawa
country: Poland
facility: Research Site
city: Wrocław
country: Poland
facility: Research Site
city: Zamość
country: Poland
facility: Research Site
city: Aramil
country: Russian Federation
facility: Research Site
city: Moscow
country: Russian Federation
facility: Research Site
city: Perm
country: Russian Federation
facility: Research Site
city: Banska Bystrica
country: Slovakia
facility: Research Site
city: Kosice
country: Slovakia
facility: Research Site
city: Nitra
country: Slovakia
facility: Research Site
city: Cape Town
country: South Africa
facility: Research Site
city: Cape Town
country: South Africa
facility: Research Site
city: Johannesburg
country: South Africa
facility: Research Site
city: Plumstead
country: South Africa
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Pontevedra
country: Spain
facility: Research Site
city: Valencia
country: Spain
facility: Research Site
city: Kaohsiung
country: Taiwan
facility: Research Site
city: Taichung
country: Taiwan
facility: Research Site
city: Taipei City
country: Taiwan
facility: Research Site
city: Taipei
country: Taiwan
facility: Research Site
city: Kharkiv
country: Ukraine
facility: Research Site
city: Kyiv
country: Ukraine
facility: Research Site
city: Kyiv
country: Ukraine
facility: Research Site
city: Kyiv
country: Ukraine
facility: Research Site
city: Coventry
country: United Kingdom
facility: Research Site
city: West Bromwich
country: United Kingdom
facility: Research Site
Study officials:
affiliation: AstraZeneca
name: Kathy Bohannon
role: STUDY_DIRECTOR
References: