| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Ulcerative Colitis is a type of inflammatory bowel disease that causes the lining of the large intestine (colon) to become inflamed (irritated and swollen) which may cause ulcers and bleeding. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10045365 |
| E.1.2 | Term | Ulcerative colitis |
| E.1.2 | System Organ Class | 100000004856 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| -To compare the efficacy of brazikumab with that of placebo to achieve clinical remission at week 10 |
|
| E.2.2 | Secondary objectives of the trial |
-To compare the efficacy of brazikumab with that of placebo to achieve sustained clinical remission
-To compare the efficacy of brazikumab with that of placebo to achieve corticosteroid-free (CS-free) clinical remission
-To compare the efficacy of brazikumab with that of placebo to achieve clinical response
-To compare the efficacy of brazikumab with that of placebo to achieve endoscopic improvement
-To evaluate the pharmacokinetics (PK) and immunogenicity of brazikumab
-To characterize the exposure-response relationships of brazikumab
-To evaluate the safety and tolerability of brazikumab |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Ability to provide informed consent prior to any study procedures and willing and able to attend all study visits.
2.Aged 18 to 80 years of age at the time of signing the informed consent.
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 (5a and 5b must be met):
(a) Stool Frequency and Rectal Bleeding subscores obtained during Screening on an eDiary.
i. Average daily mMS Stool Frequency subscore ≥ 1 AND
ii. Average daily mMS Rectal Bleeding subscore ≥ 1
(b) Modified Mayo endoscopic subscore of ≥ 2 based on a full colonoscopy within 14 days prior to initial IRT randomization.
6.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 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.Where applicable, participants taking any of the following medications must be at a stable dose or discontinued:
(a) Oral 5-aminosalicylates must be at a stable dose for 2 weeks prior to the Screening colonoscopy.
(b) Oral prednisone up to 25 mg/day or equivalent, must be at a stable dose for 2 weeks prior to the Screening colonoscopy and kept stable until the Week 10 assessment.
(c) Oral budesonide up to 9 mg/day, must be at a stable dose for 2 weeks prior to the Screening colonoscopy and kept stable until the Week 10 assessment.
(d) Topical (rectal) aminosalicylic acid (eg, mesalamine) or topical (rectal) steroids should be discontinued within 2 weeks prior to Screening colonoscopy. Rectal therapies should not be restarted after the Screening colonoscopy.
(e) An immunomodulator: participants must have been on treatment for a minimum of 8 weeks and must be kept at stable doses as below:
i. Azathioprine, must be at a stable dose for 4 weeks prior to Screening, OR
ii. 6-mercaptopurine, must be at a stable dose for 4 weeks prior to Screening, OR
iii. Methotrexate, must be at a stable dose for 4 weeks prior to Screening.
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 (confirmed by the investigator) from randomization throughout the study duration and for at least 18 weeks after 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. |
|
| E.4 | Principal 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:
(a) Infliximab: within 8 weeks prior to randomization.
(b) Adalimumab, certolizumab pegol, or golimumab: within 8 weeks prior to randomization.
(c) Vedolizumab or ustekinumab within 12 weeks of randomization.
(d) Other prohibited medication, biologic or small molecule treatment within 5 half-lives prior to randomization.
(e) Fecal microbiota transplantation: within 8 weeks prior to randomization.
5.Removed as part of Amd.5.
6.Except for ustekinumab, prior exposure to any biologic agent targeting IL-12 or IL-23 (risankizumab, brazikumab, mirikizumab, guselkumab, tildrakizumab).
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:
(a) Evidence of a recent systemic fungal infection, requiring inpatient hospitalization, and/or antifungal treatment.
(b) Any infection requiring hospitalization or treatment with IV anti-infectives within 4 weeks of Screening.
(c) Cytomegalovirus or Epstein-Barr virus infection that has not resolved within 8 weeks prior to Screening.
(d) Clinically significant chronic infection that has not resolved within 8 weeks of Screening.
(e) Nonserious infection requiring oral anti-infectives within 2 weeks prior to randomization must be further discussed with study medical monitor.
(f) Clinical evidence of or suspected to have an abscess during Screening.
(g) Any underlying condition that predisposes the participant to infections.
(h) Participant had previous allogenic bone marrow transplant or history of organ or cell-based transplantation.
(i) Clinically significant active infection or signs/symptoms of infection that has the potential to worsen with immunosuppressive therapy.
(j) 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 including but not limited to:
(a) Acute kidney injury within 6 weeks of Screening.
(b) Chronic kidney disease with an estimated glomerular filtration rate of less than 30 mL/min.
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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Clinical remission:
- 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 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1-Sustained clinical remission:
-mMS at both Week10 and Week54:
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.
2- CS-free clinical remission:
-mMS at Week 54 for participants who are CS-free for at least the last 12 weeks before the assessment at Week 54:
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.
3-Clinical response:
-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 at Week10
4-Endoscopic improvement:
-Endoscopy subscore ≤ 1 at Week10
5-Population PK model of serum concentrations of brazikumab and analysis for serum anti-brazikumab antibodies.
6-Exposure-response model linking primary endpoints to metrics of model-predicted individual brazikumab exposures.
7-AEs, clinical laboratory values, vital signs, physical exams, ECGs |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
Blood and stool samples will be collected and analyzed to evaluate protein, nucleic acid, and
cellular biomarkers, optional blood sample for genetic research |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 56 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| India |
| Israel |
| Japan |
| Korea, Republic of |
| South Africa |
| Taiwan |
| United States |
| Austria |
| France |
| Poland |
| Spain |
| Czechia |
| Germany |
| Italy |
| Hungary |
| Russian Federation |
| Slovakia |
| Ukraine |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 27 |
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