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

Moderate to Severe Ulcerative Colitis Clinical Trial

Official title:

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04700449
• Other study ID #: CBP-307CN002
• Status: Completed
• Phase: Phase 2
• Start date: February 27, 2019
• Est. completion date: November 10, 2022

Study information

• Verified date: April 2024
• Source: Suzhou Connect Biopharmaceuticals, Ltd.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 145
• Est. completion date: November 10, 2022
• Est. primary completion date: February 23, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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:

1. 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;

2. 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.

Related Conditions & MeSH terms

• Colitis
• Colitis, Ulcerative
• Moderate to Severe Ulcerative Colitis
• Ulcer

Intervention

Drug:
• Double-Blind 0.2mg CBP-307
0.2 mg capsule oral administration
• Double-Blind Placebo
Placebo capsule oral administration
• Open-label CBP-307
0.2 mg capsule oral administration
• Double-Blind 0.1mg CBP-307
0.1 mg capsule oral administration

Locations

Country	Name	City	State
China	Connect Investigative Site 2001	Beijing	Beijing
China	Connect Investigative Site 2008	Beijing	Beijing
China	Connect Investigative Site 2013	Chengdu	Sichuan
China	Connect Investigative Site 2043	Chongqing	Sichuan
China	Connect Investigative Site 2025	Dalian	Liaoning
China	Connect Investigative Site 2006	Fuzhou	Fujian
China	Connect Investigative Site 2003	Guangzhou	Guangdong
China	Connect Investigative Site 2009	Guangzhou	Guangdong
China	Connect Investigative Site 2034	Haikou	Hainan
China	Connect Investigative Site 2032	Hangzhou	Zhejiang
China	Connect Investigative Site 2047	Hangzhou	Zhejiang
China	Connect Investigative Site 2004	Hefei	Anhui
China	Connect Investigative Site 2018	Hefei	Anhui
China	Connect Investigative Site 2015	Jilin	Changchun
China	Connect Investigative Site 2028	Jinan	Shandong
China	Connect Investigative Site 2044	Jinan	Shandong
China	Connect Investigative Site 2046	Nanchang	Jiangxi
China	Connect Investigative Site 2023	Nanjing	Jiangsu
China	Connect Investigative Site 2027	Nanjing	Jiangsu
China	Connect Investigative Site 2031	Nanjing	Jiangsu
China	Connect Investigative Site 2030	Nanning	Guangxi
China	Connect Investigative Site 2024	Qingdao	Shandong
China	Connect Investigative Site 2007	Shanghai	Shanghai
China	Connect Investigative Site 2011	Shanghai	Shanghai
China	Connect Investigative Site 2019	Shanghai	Shanghai
China	Connect Investigative Site 2035	Shanghai	Shanghai
China	Connect Investigative Site 2038	Shanghai	Shanghai
China	Connect Investigative Site 2040	Shenyang	Liaoning
China	Connect Investigative Site 2017	Shenzhen	Guangdong
China	Connect Investigative Site 2021	Shenzhen	Guangdong
China	Connect Investigative Site 2026	Shijiazhuang	Hebei
China	Connect Investigative Site 2041	Shijiazhuang	Hebei
China	Connect Investigative Site 2033	Suzhou	Jiangsu
China	Connect Investigative Site 2020	Taiyuan	Shanxi
China	Connect Investigative Site 2045	Wenzhou	Zhejiang
China	Connect Investigative Site 2005	Wuhan	Hubei
China	Connect Investigative Site 2016	Wuhan	Hubei
China	Connect Investigative Site 2012	Xiamen	Fujian
China	Connect Investigative Site 2022	Zhengzhou	Henan
Pakistan	Connect Investigative Site 2151	Karachi	Sindh Province
Pakistan	Connect Investigative Site 2152	Karachi	Sindh Province
Ukraine	Connect Investigative Site 2211	Dnipro
Ukraine	Connect Investigative Site 2217	Ivano-Frankivsk
Ukraine	Connect Investigative Site 2202	Kharkiv
Ukraine	Connect Investigative Site 2208	Kharkiv
Ukraine	Connect Investigative Site 2205	Kyiv
Ukraine	Connect Investigative Site 2220	Kyiv
Ukraine	Connect Investigative Site 2215	Lviv
Ukraine	Connect Investigative Site 2216	Lviv
Ukraine	Connect Investigative Site 2218	Uzhhorod
Ukraine	Connect Investigative Site 2209	Vinnytsia
Ukraine	Connect Investigative Site 2214	Zaporizhzhia
United States	Connect Investigative Site 2307	Atlanta	Georgia
United States	Connect Investigative Site 2315	Cincinnati	Ohio
United States	Connect Investigative Site 2311	Cypress	Texas
United States	Connect Investigative Site 2314	Hialeah	Florida
United States	Connect Investigative Site 2309	Homestead	Florida
United States	Connect Investigative Site 2320	Kissimmee	Florida
United States	Connect Investigative Site 2318	Miami	Florida
United States	Connect Investigative Site 2308	Mission Hills	California
United States	Connect Investigative Site 2321	Oklahoma City	Oklahoma
United States	Connect Investigative Site 2302	Orlando	Florida
United States	Connect Investigative Site 2304	Orlando	Florida
United States	Connect Investigative Site 2306	Orlando	Florida
United States	Connect Investigative Site 2316	Phoenix	Arizona
United States	Connect Investigative Site 2319	San Antonio	Texas

Sponsors (1)

Lead Sponsor	Collaborator
Suzhou Connect Biopharmaceuticals, Ltd.

Countries where clinical trial is conducted

United States,  China,  Pakistan,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Mucosal Healing Rate	Mucosal healing rate at week 12 after treatment (mucosal healing is defined as Mayo endoscopic subscore = 1)	at Week 12
Secondary	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
Secondary	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
Secondary	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
Secondary	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