Clinical trial NCT04700449: A Study Assessing the Efficacy and Safety of CBP-307 in Subjects With Moderate to Severe Ulcerative Colitis (UC)
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Moderate to Severe Ulcerative Colitis
Lead sponsor: Connect Biopharm LLC
Sponsor class: INDUSTRY
First posted: 2021-01-07
Enrollment: 145
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Change From Baseline for Adapted Mayo Score: 0.2 mg Versus Placebo
timeFrame: 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 outcomes:
measure: Change in Complete Mayo Score From Baseline
timeFrame: at Week 12
measure: Comparison of Clinical Response Rate by Adapted Mayo Score
timeFrame: at Week 12
measure: Comparison of Clinical Response Rate by Complete Mayo Score
timeFrame: at Week 12
measure: Comparison of Clinical Remission Rate by Adapted Mayo Score
timeFrame: at Week 12
measure: Comparison of Clinical Remission Rate by Complete Mayo Score
timeFrame: at Week 12
measure: Mucosal Healing Rate
timeFrame: at Week 12
measure: Incidence, Type and Severity of Treatment Emergent Adverse Event (TEAE)
timeFrame: for 12 consecutive weeks
measure: Incidence, Type and Severity of Serious Adverse Event (SAE)
timeFrame: for 12 consecutive weeks
measure: Incidence, Type and Severity of Adverse Events (AE)
timeFrame: for 12 consecutive weeks
measure: Change From Baseline in Adapted Mayo Score: 0.1 mg Versus Placebo
timeFrame: at Week 12
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Connect Investigative Site 2316
state: Arizona
city: Mission Hills
country: United States
facility: Connect Investigative Site 2308
state: California
city: Hialeah
country: United States
facility: Connect Investigative Site 2314
state: Florida
city: Homestead
country: United States
facility: Connect Investigative Site 2309
state: Florida
city: Kissimmee
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facility: Connect Investigative Site 2320
state: Florida
city: Miami
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facility: Connect Investigative Site 2318
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city: Orlando
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facility: Connect Investigative Site 2302
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city: Orlando
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facility: Connect Investigative Site 2304
state: Florida
city: Orlando
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facility: Connect Investigative Site 2306
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facility: Connect Investigative Site 2307
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city: Cincinnati
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facility: Connect Investigative Site 2315
state: Ohio
city: Oklahoma City
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facility: Connect Investigative Site 2321
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city: Cypress
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facility: Connect Investigative Site 2311
state: Texas
city: San Antonio
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facility: Connect Investigative Site 2319
state: Texas
city: Hefei
country: China
facility: Connect Investigative Site 2018
state: Anhui
city: Hefei
country: China
facility: Connect Investigative Site 2004
state: Anhui
city: Beijing
country: China
facility: Connect Investigative Site 2008
state: Beijing
city: Beijing
country: China
facility: Connect Investigative Site 2001
state: Beijing
city: Jilin
country: China
facility: Connect Investigative Site 2015
state: Changchun
city: Fuzhou
country: China
facility: Connect Investigative Site 2006
state: Fujian
city: Xiamen
country: China
facility: Connect Investigative Site 2012
state: Fujian
city: Guangzhou
country: China
facility: Connect Investigative Site 2003
state: Guangdong
city: Guangzhou
country: China
facility: Connect Investigative Site 2009
state: Guangdong
city: Shenzhen
country: China
facility: Connect Investigative Site 2017
state: Guangdong
city: Shenzhen
country: China
facility: Connect Investigative Site 2021
state: Guangdong
city: Nanning
country: China
facility: Connect Investigative Site 2030
state: Guangxi
city: Haikou
country: China
facility: Connect Investigative Site 2034
state: Hainan
city: Shijiazhuang
country: China
facility: Connect Investigative Site 2026
state: Hebei
city: Shijiazhuang
country: China
facility: Connect Investigative Site 2041
state: Hebei
city: Zhengzhou
country: China
facility: Connect Investigative Site 2022
state: Henan
city: Wuhan
country: China
facility: Connect Investigative Site 2016
state: Hubei
city: Wuhan
country: China
facility: Connect Investigative Site 2005
state: Hubei
city: Nanjing
country: China
facility: Connect Investigative Site 2027
state: Jiangsu
city: Nanjing
country: China
facility: Connect Investigative Site 2031
state: Jiangsu
city: Nanjing
country: China
facility: Connect Investigative Site 2023
state: Jiangsu
city: Suzhou
country: China
facility: Connect Investigative Site 2033
state: Jiangsu
city: Nanchang
country: China
facility: Connect Investigative Site 2046
state: Jiangxi
city: Dalian
country: China
facility: Connect Investigative Site 2025
state: Liaoning
city: Shenyang
country: China
facility: Connect Investigative Site 2040
state: Liaoning
city: Jinan
country: China
facility: Connect Investigative Site 2028
state: Shandong
city: Jinan
country: China
facility: Connect Investigative Site 2044
state: Shandong
city: Qingdao
country: China
facility: Connect Investigative Site 2024
state: Shandong
city: Shanghai
country: China
facility: Connect Investigative Site 2011
state: Shanghai
city: Shanghai
country: China
facility: Connect Investigative Site 2007
state: Shanghai
city: Shanghai
country: China
facility: Connect Investigative Site 2019
state: Shanghai
city: Shanghai
country: China
facility: Connect Investigative Site 2035
state: Shanghai
city: Shanghai
country: China
facility: Connect Investigative Site 2038
state: Shanghai
city: Taiyuan
country: China
facility: Connect Investigative Site 2020
state: Shanxi
city: Chengdu
country: China
facility: Connect Investigative Site 2013
state: Sichuan
city: Chongqing
country: China
facility: Connect Investigative Site 2043
state: Sichuan
city: Hangzhou
country: China
facility: Connect Investigative Site 2047
state: Zhejiang
city: Hangzhou
country: China
facility: Connect Investigative Site 2032
state: Zhejiang
city: Wenzhou
country: China
facility: Connect Investigative Site 2045
state: Zhejiang
city: Karachi
country: Pakistan
facility: Connect Investigative Site 2151
state: Sindh Province
city: Karachi
country: Pakistan
facility: Connect Investigative Site 2152
state: Sindh Province
city: Dnipro
country: Ukraine
facility: Connect Investigative Site 2211
city: Ivano-Frankivsk
country: Ukraine
facility: Connect Investigative Site 2217
city: Kharkiv
country: Ukraine
facility: Connect Investigative Site 2202
city: Kharkiv
country: Ukraine
facility: Connect Investigative Site 2208
city: Kyiv
country: Ukraine
facility: Connect Investigative Site 2205
city: Kyiv
country: Ukraine
facility: Connect Investigative Site 2220
city: Lviv
country: Ukraine
facility: Connect Investigative Site 2215
city: Lviv
country: Ukraine
facility: Connect Investigative Site 2216
city: Uzhhorod
country: Ukraine
facility: Connect Investigative Site 2218
city: Vinnytsia
country: Ukraine
facility: Connect Investigative Site 2209
city: Zaporizhzhia
country: Ukraine
facility: Connect Investigative Site 2214
Study officials:
affiliation: Connect Biopharm LLC
name: Suzhou Connect
role: STUDY_DIRECTOR
References: