A Study Assessing the Efficacy and Safety of CBP-307 in Subjects With Moderate to Severe Ulcerative Colitis (UC)

A Study Assessing the Efficacy and Safety of CBP-307 in Subjects With Moderate to Severe Ulcerative Colitis (UC)

A Multicenter, Randomized, Double-blind, Placebo-controlled Phase II Clinical Trial to Evaluate the Efficacy and Safety of CBP-307 in Subjects With Moderate to Severe Ulcerative Colitis (UC)

This study will evaluate the efficacy and safety of CBP-307 in subjects with moderate to severe ulcerative colitis (UC).

This is a multicenter, multicountry, randomized, double-blind, placebo-controlled phase II clinical trial to evaluate the efficacy and safety of CBP-307 in subjects with moderate to severe ulcerative colitis (UC). CBP-307 capsules are administered orally. This study includes stage 1 and stage 2. After screening, subjects will enter the randomized, double-blind, placebo-controlled induction therapy for 12 weeks, i.e., the study stage 1. All subjects who complete 12 weeks of induction therapy (with CBP-307 or placebo) in the study stage 1 and complete all examinations (including colonoscopy) at the week 12 visit can choose to enter the study stage 2 of a total of 40 weeks, including 36 weeks of continuous administration and 4 weeks of safety follow-up after the last dose.

Comparison of clinical response rate at week 12 by adapted Mayo score (defined as a decrease of ≥ 2 points and at least 30% from baseline, accompanied with a decrease of ≥ 1 point from baseline in the rectal bleeding subscore or an absolute rectal bleeding subscore of ≤ 1 point).

Comparison of clinical response rate at week 12 by complete Mayo score (defined as a decrease of ≥ 3 points and at least 30% from baseline, accompanied with a decrease of ≥ 1 point from baseline in the rectal bleeding subscore or an absolute rectal bleeding subscore of ≤ 1 point).

Comparison of clinical remission rate at week 12 by adapted Mayo score (defined as a rectal bleeding subscore = 0 and a stool frequency subscore ≤ 1, with an Endoscopy subscore ≤ 1 [excluding friability]).

Comparison of clinical remission rate at week 12 by complete Mayo score (defined as a total Mayo score of ≤ 2 points with no individual subscore > 1 point).

Mucosal healing rate at week 12 after treatment (mucosal healing is defined as Mayo endoscopic subscore ≤ 1)

The safety and tolerability will be assessed on basis of incidence, type and severity of TEAEs as well as their relations with the investigational product .

The safety and tolerability will be assessed on basis of incidence, type and severity of SAEs as well as their relations with the investigational product and SAEs that lead to discontinuation of study.

The safety and tolerability will be assessed on basis of AEs that lead to discontinuation of study, and AEs of special interest (cardiac events as well as pulmonary function tests, ophthalmologic examinations, skin examinations, and nervous system physical examinations)

Inclusion Criteria: - For the stage 1: Male or female subjects aged 18-75 years (inclusive). Female subjects of childbearing potential and male subjects who have not undergone vasectomy should use at least one highly effective methods of contraception during the entire study and 4 weeks after the last dose of investigational products after signing the informed consent form. The subject has a diagnosis of UC established at least 3 months prior to screening by clinical and endoscopic evidence corroborated by a histopathology report. Subjects are confirmed to have moderate to severe active UC within 14 days prior to the first dose of the investigational product, which is based on an adapted Mayo score of 4-9, and an endoscopic subscore of ≥ 2. Endoscopy must be performed during the screening period (day -14 to day -3, allowing centralized reading and evaluation before the first dose at week 0). The subject has evidence of UC extending to the rectum with ≥15 cm involvement on endoscopy. Subjects must be UC patients who are receiving treatment. They can be enrolled if they meet any items below. Prior to the randomization visit, subjects have received oral 5-ASA (e.g., mesalazine, sulfasalazine, olsalazine, balsalazide) for at least 4 weeks with the dose stable for at least 2 weeks. Prior to the randomization visit, subjects have received oral or IV corticosteroids e.g. prednisone (daily doses ≤ 30 mg), budesonide (daily doses ≤ 9 mg), methylprednisolone (daily doses ≤ 24 mg), or equivalent dose of corticosteroids for at least 4 weeks, with the dose stable for at least 2 weeks. If oral 5-ASA or corticosteroid for treatment of UC have been recently discontinued, they must have been stopped for at least 2 weeks prior to the screening endoscopy examination which is used for Mayo score assessment. If subjects use non-prohibited concomitant medications, a stable dosing regimen must be used, that is, within 7 days prior to first dose of investigational product or within 5 half lives of the drug (whichever is longer), there's no new concomitant medications started or changes in the dose of existing non-prohibited concomitant medications. The subject who has extensive colitis or pancolitis of >8 years duration or limited colitis of >12 years duration must have documented evidence that a surveillance colonoscopy was performed within 12 months prior to initial screening visit (can be performed during Screening if not performed in previous 12 months). For subjects' entry into the study stage 2 from the stage 1: Subjects must be those with UC who participate in the study of CBP-307CN002 and have completed 12 weeks of treatment with CBP-307 or placebo in the stage 1 and have completed all the assessments (including colonoscopy) at study visit of week 12 in study stage 1. Female subjects of childbearing potential and male subjects who have not undergone vasectomy should use at least one highly effective methods of contraception during the entire study and 4 weeks after the last dose of investigational products after signing the informed consent form. Exclusion Criteria: - UC-related exclusion criteria: At the screening visit, subjects have evidence of toxic megacolon. The subject has had, subtotal or total colectomy. The subject has an existing ileostomy, colostomy (a history of ileostomy or colostomy that has been reversed may be acceptable), or known symptomatic stenosis of the intestine. Investigator judges the subject currently requires or is anticipated to require surgical intervention for UC during the study. The subject has a history or evidence of adenomatous colonic polyps that have not been removed. Subjects were previously exposure to the following treatments: Lymphocyte-depleting therapies (e.g., alemtuzumab, anti-CD4 antibody, cladribine, rituximab, ocrelizumab, cyclophosphamide, mitoxantrone, total body irradiation, bone marrow transplantation and daclizumab). Previous treatment with D-penicillamine, leflunomide. Within 60 days prior to the screening visit, the subject has received any of the following for the treatment of UC: Intravenous immunoglobulin; Therapeutic plasma exchange (TPE). Within 30 days prior to randomization visit, the subject has received any of the following for the treatment of UC: Immunosuppressants (such as cyclosporine, tacrolimus, sirolimus or mycophenolate mofetil), thalidomide or traditional Chinese medicine; Approved non-biologic agents or traditional Chinese medicine treatment. Patients who plan to concurrently use an immunosuppressant (such as azathioprine, 6 mercaptopurine or methotrexate) after randomization. Patients treated with azathioprine, 6-mercaptopurine or methotrexate at screening are required to discontinue it prior to the first dose of the study drug. The subject has received any investigational biologic or non-biologic agent, or approved biologic agent or biosimilars within 60 days or 5 half-lives prior to screening (whichever is longer). Exclusion criteria for general conditions: History of uveitis or macular oedema. Clinically relevant cardiovascular conditions, including history or presence of any one of below: Ischemic heart disease or myocardial infarction; Unstable angina; History of angina pectoris caused by coronary artery spasm, or raynaud's phenomenon (Raynauds); Congestive heart failure (NYHA class III-IV), cardiac arrest; Stroke, transient ischemic attack; History of recurrent syncope or positive result of vasovagal syncope tilt test; Symptomatic bradycardia, sick sinus syndrome, sinoatrial block, second degree atrioventricular block (e.g., Mobitz type 2 atrioventricular block) or third degree atrioventricular block; Congenital long QT syndrome (LQTS), or prolonged QT interval corrected using Fridericia's formula (QTcF) in screening ECG (QTcF >450 ms in men, QTcF > 470 ms in women); Subjects at increased risk for QT prolongation due to hypokalemia or hypomagnesemia; or subjects who currently tacking medications to prolong QT interval (e.g., citalopram, chlorpromazine, haloperidol, methadone, and erythromycin) which result in risk for torsades de pointes; Under treatment or expected to taking treatment during the study with medications with a known impact on the cardiac conduction system (e.g., beta blockers, calcium channel blockers, Class Ia or Class III anti-arrhythmic drugs. [amiodarone, bromobenzylamine, sotalol, ibutilide, azimilide, dofetilide]); Hypertension (except well-controlled hypertension after pharmacotherapy); systolic blood pressure < 95 mm Hg or >140 mm Hg and diastolic blood pressure ≤ 50 mm Hg or ≥ 95 mm Hg at the screening visit; Resting heart rate < 55 times/min or ventricular rate < 55 times/min in 12-lead ECG at screening visit; Investigator deems that the 12-lead ECG at screening visit is clinically significant abnormal, such as, myocardial ischemia, any significant cardiac conduction abnormalities (such as the left bundle branch block), that would put the subject at risk or interfere with the study results; Any other significant heart disease that the investigator judges would put the subject at risk or interfere with the study results. Subjects have a family history of premature coronary heart disease. History of type 1 diabetes, uncontrolled type 2 diabetes (HbA1c > 7%) judged by investigator, patients with diabetes accompanied with significant complications, e.g., retinopathy or kidney disease. Pulmonary function test (including examinations of lung ventilation function and pulmonary gas exchange) at the screening visit shows one of the following abnormalities: forced expiratory volume in 1 second (FEV1) or forced vital capacity (FVC) < 70% of normal expected value. During screening period, any of the following laboratory abnormalities: HGB < 8 g/dL; WBC count < 3.5 × 10E9/L; Neutrophils count < 1.5 × 10E9/L; Lymphocyte count < 0.8 × 10E9/L; Platelet count < 100 × 10E9/L or >1200 × 10E9/L; Serum creatinine > 124 μmol/L for female or > 141 μmol/L for male; Abnormal liver function test druring the screening period, such as abonormalities in alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyltransferase (γ-GT), alkaline phosphatase (ALK) or serum total bilirubin, which suggests liver diseases or liver function impairment. If female, the subject is intending to become pregnant before, during, or within 4 weeks after participating in the study or intending to donate ova during such period. If male, the subject intends to donate sperm during the study or for 4 weeks thereafter. Exclusion criteria for infectious diseases: The subject has evidence of known active infection during the screening period. The subject has evidence of treatment for Clostridioides difficile (C. difficile) infection or other intestinal pathogen with 28 days prior to first dose of study drug. Active or latent tuberculosis (TB) evidenced. Chronic hepatitis B virus (HBV) infection* or chronic hepatitis C virus (HCV) infection**. The subject has any identified congenital or acquired immunodeficiency (e.g., common variable immunodeficiency, human immunodeficiency virus [HIV] infection, organ transplantation). The subject has received any live vaccine within 30 days prior to screening, or subjects are scheduled for immunization with any live vaccine during the study or within 1 month after the last dose of the investigational product. Positive syphilis antibody at screening. Subjects with a history of more than one episode of herpes zoster, or a history of disseminated herpes zoster or disseminated herpes simplex. For subjects' entry into the study stage 2 from the stage 1: Subjects currently have evidence of active or untreated latent tuberculosis. Subjects currently have active or chronic recurrent infections, and in the opinion of the investigator subjects are not appropriate to participate in the stage 2 of the study. History of uveitis or macular oedema. Subjects had received any of the following treatments after administration of the first dose in the stage 1 of the study: Biological product; Prednisone>30 mg/day, budesonide>9 mg/day, methylprednisolone>24 mg/day or equivalent dose of steroid treatment; Immunosuppressant (such as azathioprine and 6-mercaptopurine or methotrexate). Investigator deems that the 12-lead ECG results at the study visit of week 12 during study stage 1 is clinically significant abnormal, such as myocardial ischemia, any significant cardiac conduction abnormalities (such as the left bundle branch block), any abnormality that would put the subject at risk or interfere with the study results. Pulmonary function test (including examinations of lung ventilation function and pulmonary gas exchange) of subjects at the study visit of week 12 during the study stage 1 shows 1 of the following abnormalities: forced expiratory volume in 1 second (FEV1) or forced vital capacity (FVC) < 50% of normal predicted value. Subjects' laboratory measurements at week 12 visit during the study stage 1 meet any of the following criteria: AST or ALT> 3 ULN; Absolute lymphocyte count < 0.2×10E9/L; Serum creatinine > 124 μmol/L (in females) or > 141 μmol/L (in males) Any other reason that in the opinion of the investigator may interfere with subject compliance or evaluation of the results of the study