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

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

Detailed Description
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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. Study Stage 1 After screening, subjects entered the randomized, double-blind, placebo-controlled induction therapy for 12 weeks. Subjects were screened at 1 to 21 days prior to the baseline visit. The eligible subjects were enrolled and randomized at the baseline visit. As per study protocol (version 5.0 or earlier), subjects received CBP 307 0.1 mg, CBP-307 0.2 mg, and placebo at a ratio of 1:1:1. The subjects enrolled under protocol (version 6.0) were randomized to CBP-307 0.2 mg and placebo at a ratio of 1:1 into the 2 groups (approximately 52 subjects in each group) and stratified according to whether the subject failed a previous tumor necrosis factor (TNF)-α antagonist therapy. Subjects assigned were blinded to their treatment assignment (CBP-307 or placebo) in the 12-week double-blinded placebo-controlled treatment period. Subjects randomized to CBP-307 group underwent dose titration for 1 week, while those in placebo group underwent simulated titration. Both CBP-307 and placebo were administered through the oral route. For subjects in the CBP-307 0.1 mg QD group, a daily dose of 0.05 mg CBP-307 was given from Day 1 to Day 4; then a daily dose of 0.1 mg CBP-307 was given for 3 days from Day 5 to Day 7; from Day 8, a daily target dose of 0.1 mg was administered. For subjects in the group of CBP-307 0.2 mg QD, a daily dose of 0.05 mg CBP-307 was given from Day 1 to Day 4; then, a dose of 0.1 mg CBP-307 was given daily for 3 days from Day 5 to Day 7; from Day 8, a daily target dose of 0.2 mg was administered. For the subjects already enrolled as per study protocol version 5.0 or earlier, they continued the treatment in the Stage 1 according to the previous planned schedule. Eligible subjects completing 12 weeks of induction therapy in Stage 1 were permitted to enter Stage 2 to be evaluated for the long-term maintenance administration of CBP-307. Subjects who withdrew early from the study or completed the Stage 1, but did not enter Stage 2, entered a 4-week safety follow-up period. Study stage 2 All subjects who completed 12 weeks of induction therapy in the study Stage 1 and completed all examinations (including colonoscopy) at Week 12 (visit 11) could choose to enter the study Stage 2 of a total length of 40 weeks, including 36 weeks of continuous treatment and 4 weeks of safety follow up after the last dose. Subjects who chose to enter the Stage 2 signed an updated informed consent form (ICF) and screened for eligibility. The study Stage 2 contained sub-study 1 and sub-study 2. Subjects entered 1 of sub-studies based on their results of efficacy evaluation in the study Stage 1. Sub-study 1 (subjects who achieved clinical response by adapted Mayo score): Subjects who achieved clinical response at Week 12 in the study Stage 1 and met the eligibility criteria for Stage 2 entered sub study 1 of the study Stage 2 to receive double-blind maintenance treatment for 36 weeks (Week 13 to 48), i.e., the therapeutic regimen for them in Stage 1 was continually maintained. Safety follow-up was completed at 4 weeks after the last dose. Subjects who presented with recurrent UC during maintenance treatment were terminated from the treatment and withdrew from the study. For the subjects already enrolled as per study protocol version 5.0 or earlier, they followed the previous planned treatment in the sub-study 1 of Stage 2 study. Sub-study 2 (subjects who did not achieve clinical response by adapted Mayo score): Subjects who did not achieve clinical response at Week 12 in study Stage 1 and met the eligibility criteria for Stage 2 entered open-label treatment with CBP-307 0.2 mg. Subjects received CBP-307 QD at an oral dose of 0.2 mg in sub study 2 regardless of whether they received CBP-307 or placebo in the study Stage 1. For subjects who entered sub-study 2 of study Stage 2, 1-week dose titration was performed at Week 13. Dose titration involved administration of CBP 0.05 mg for 4 consecutive days from Titration Day 1 to Day 4, followed by administration of CBP-307 0.1 mg for 3 days from Titration Day 5 to Day 7, and administration of CBP-307 at a target dose of 0.2 mg initiated on Titration Day 8. After dose titration was completed, subjects received oral treatment with CBP-307 0.2 mg QD, for 36 weeks. Safety follow-up was completed at 4 weeks after the last dose. If the subjects did not achieve clinical response by the efficacy evaluation including colonoscopy at Week 24, the treatment was to be discontinued and the subjects were to withdraw from the study.

Official Title
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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)

Conditions
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Moderate to Severe Ulcerative Colitis

Intervention / Treatment
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* Drug: Double-Blind 0.2mg CBP-307
* Drug: Double-Blind Placebo
* Drug: Open-label CBP-307
* Drug: Double-Blind 0.1mg CBP-307


Participation Criteria
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Eligibility Criteria
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Main inclusion and exclusion criteria for the study Stage 1: Subjects were eligible to be included in the study only if all the following criteria applied: Male or female subjects aged 18 to 75 years (inclusive) with a diagnosis of UC established at least 3 months prior to screening by clinical and endoscopic evidence corroborated by a histopathology report; Confirmed to have moderately to severely active UC within 14 days prior to the first dose of the investigational product, based on an adapted Mayo score of 4 to 9, and an endoscopic subscore of ≥2; Had evidence of UC extending to the rectum with ≥15 cm involvement on endoscopy; UC patients who were receiving treatment. Subjects could be enrolled if they met any items below: Prior to the randomization visit, subjects had received oral 5-aminosalicylic acid (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 had received oral or intravenous (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; Oral 5-ASA or corticosteroid for treatment of UC had been stopped for at least 2 weeks prior to the screening endoscopy examination which was used for Mayo score assessment; A stable dosing regimen had to be used if non-prohibited concomitant medications were used. Subjects who met any of the following criteria were excluded: Subjects had evidence of toxic megacolon; Had subtotal or total colectomy; An existing ileostomy, colostomy, or known symptomatic stenosis of the intestine; a history or evidence of adenomatous colonic polyps that had not been removed; a history or evidence of colonic mucosal dysplasia including low or high grade of dysplasia, as well as indeterminate for dysplasia; a suspected or confirmed diagnosis of Crohn's enterocolitis, undiagnosed types of colitis, ischemic colitis, or radiation colitis; Previous exposure to lymphocyte-depleting therapies or D-penicillamine, leflunomide; prior exposure to approved or investigational products that inhibited the lymphocyte trafficking; Received immunosuppressants within 30 days prior to randomization; 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 was longer); Known active infection during the screening period; treatment for Clostridioides difficile (C. difficile) infection or other intestinal pathogen with 28 days prior to first dose of investigational product; active or latent tuberculosis (TB); Chronic hepatitis B virus (HBV) infection or chronic hepatitis C virus (HCV) infection; any identified congenital or acquired immunodeficiency; Received any live vaccine within 30 days prior to screening. Main Inclusion and exclusion criteria for subjects' entry into the study Stage 2 from Stage 1: Subjects who met all the following criteria entered into the study Stage 2: subjects with UC who completed 12 weeks of treatment with CBP-307 or placebo in Stage 1 and completed all the assessments (including colonoscopy) at study visit of Week 12 in study Stage 1; Good compliance in Stage 1; Subjects or their legal representatives voluntarily signed the ICF for study Stage 2. Subjects who met any of the following criteria were excluded from the study Stage 2: subjects had any unstable or uncontrolled cardiovascular, pulmonary, hepatic, renal, gastrointestinal, genitourinary, hematological, coagulation, immunological, endocrine/metabolic, or other medical disorder that, in the opinion of the investigator, were to confound the study results or compromise subject safety; Allergic to CBP 307 or its excipients, experience of significant adverse events related to the study drug during Stage 1, and not appropriate to participate in Stage 2 assessed by the investigator; Active or chronic recurrent infections; A history of uveitis or macular oedema.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Double-Blind 0.2mg CBP-307<br>0.2 mg CBP-307 capsules oral administration. | Drug: Double-Blind 0.2mg CBP-307<br>* 0.2 mg capsule oral administration<br>|
| Placebo Comparator: Double-Blind Placebo<br>Placebo capsules oral administration. | Drug: Double-Blind Placebo<br>* Placebo capsule oral administration<br>|
| Experimental: Open-Label CBP-307<br>0.2 mg CBP-307 capsules oral administration. | Drug: Open-label CBP-307<br>* 0.2 mg capsule oral administration<br>|
| Experimental: Double-Blind 0.1mg CBP-307<br>0.1 mg CBP-307 capsules oral administration. | Drug: Double-Blind 0.1mg CBP-307<br>* 0.1 mg capsule oral administration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline for Adapted Mayo Score: 0.2 mg Versus Placebo | Change in adapted Mayo score from baseline at week 12 compared between CBP-307 0.2 mg and placebo in the Full Analysis Set by Multiple Imputation. Adapted Mayo scores were calculated based on data in stool frequency, rectal bleeding, and endoscopic findings. The Mayo scores range from 0 to 9 and consist of 3 subscores, each ranging from 0 to 3. The higher the score is, the more severe the disease is. | The adapted Mayo score was evaluated at screening and Week 12 (or early termination visit) during the study Stage 1 as well as at Week 24 (only for the sub-study 2) and Week 48 (or early termination visit) during the study Stage 2. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Complete Mayo Score From Baseline | Change in complete Mayo score from baseline at week 12 after treatment. Complete Mayo scores were calculated based on data in stool frequency, rectal bleeding, endoscopic findings, and physician's global assessment. The Mayo scores range from 0 to 12 and consist of 4 subscores, each ranging from 0 to 3. The higher the score is, the more severe the disease is. | at Week 12 | 
| Comparison of Clinical Response Rate by Adapted Mayo Score | 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). | at Week 12 | 
| Comparison of Clinical Response Rate by Complete Mayo Score | 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). | at Week 12 | 
| Comparison of Clinical Remission Rate by Adapted Mayo Score | 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]). | at Week 12 | 
| Comparison of Clinical Remission Rate by Complete Mayo Score | 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). | at Week 12 | 
| Mucosal Healing Rate | Mucosal healing rate at week 12 after treatment (mucosal healing is defined as Mayo endoscopic subscore ≤ 1) | at Week 12 | 
| Incidence, Type and Severity of Treatment Emergent Adverse Event (TEAE) | 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 . | for 12 consecutive weeks | 
| Incidence, Type and Severity of Serious Adverse Event (SAE) | 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. | for 12 consecutive weeks | 
| Incidence, Type and Severity of Adverse Events (AE) | 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) | for 12 consecutive weeks | 
| Change From Baseline in Adapted Mayo Score: 0.1 mg Versus Placebo | Change from baseline in adapted Mayo score at Week 12 between CBP-307 0.1 mg and placebo in the Full Analysis Set by Multiple Imputation. Adapted Mayo scores were calculated based on data in stool frequency, rectal bleeding, and endoscopic findings. The Mayo scores range from 0 to 9 and consist of 3 subscores, each ranging from 0 to 3. The higher the score is, the more severe the disease is. | at Week 12 |