A Phase III Study to Evaluate the Efficacy and Safety of Cobitolimod as an Induction and Maintenance Therapy in Participants with Moderate to Severe Active Left-Sided Ulcerative Colitis

• Register: EUCTR
• Last refreshed on: 8 October 2021
• Main ID: EUCTR2021-002549-13-HU
• Date of registration: 23/07/2021
• Prospective Registration: Yes
• Primary sponsor: InDex Pharmaceuticals
• Public title: A Phase III Study to Evaluate the Efficacy and Safety of Cobitolimod as an Induction and Maintenance Therapy in Participants with Moderate to Severe Active Left-Sided Ulcerative Colitis
• Scientific title: A Randomised Double-Blind Placebo-Controlled Phase III Clinical Study to Evaluate the Efficacy and Safety of Cobitolimod as an Induction and Maintenance Therapy in Participants with Moderate to Severe Active Left-Sided Ulcerative Colitis - CONCLUDE
• Date of first enrolment: 24/09/2021
• Target sample size: 440
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2021-002549-13
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 3
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Argentina, Australia, Austria, Belgium, Bosnia and Herzegovina, Brazil, Bulgaria, Canada, Colombia, Croatia, Czechia, Denmark, France, Georgia, Germany, Hungary, Israel, Italy, Korea, Democratic People's Republic of, Lithuania, Mexico, Netherlands, New Zealand, Norway, Poland, Portugal, Romania, Russian Federation, Serbia, Slovakia, South Africa, Spain, Sweden, Taiwan, Turkey, Ukraine, United Kingdom, United States

Contacts

• Name: Arnesson
• Affiliation: Karin

• Name: Arnesson
• Affiliation: Karin

Key inclusion & exclusion criteria

Inclusion criteria:
Inclusion Criteria: Induction
1. Male or female = 18 years of age.
2. Established diagnosis of UC, with minimum time from diagnosis of at least 3 months before screening visit 1b.
3. Moderate to severe active left-sided UC (disease should extend 15 cm or more above the anal verge and not beyond the splenic flexure) determined by a 3-component Mayo score of 5 to 9 with an endoscopic subscore =2 (in sigmoid or descending segments) assessed by central reading of endoscopy, and with stool frequency and rectal bleeding subscores, assessed by eDiary, each =1.
4. Have inadequate response, loss of response or be intolerant of at least one of the following treatments:
a. Oral GCS
b. AZA/6-MP
c. Biologics, JAK-inhibitors, or other approved advanced therapies for UC
5. Allowed to receive a therapeutic dose of the following UC drugs during the study:
a. Oral GCS therapy (=20 mg prednisone or equivalent/day) provided that the dose has been stable for 2 weeks prior to visit 1b, or oral Budesonide MMX® therapy (9 mg/day) initiated at least 8 weeks before visit 1b, provided that the dose has been stable for 2 weeks prior to visit 1b.
b. Oral 5-ASA/SP compounds, provided that the dose has been stable for 2 weeks prior to visit 1b and initiated at least 8 weeks before visit 1b.
c. AZA/6-MP provided that the dose has been stable for 8 weeks prior to visit 1b and initiated at least 3 months before visit 1b.
6. Ability to understand the treatment, willingness to comply with all study requirements, and ability to provide informed consent.

Inclusion Criteria: Maintenance
Participants are eligible to be included in the maintenance study if they have achieved clinical response at I-week 6 and have adhered to the protocol procedures of the induction study.
Clinical response is defined by a decrease in the 3-component Mayo score (rectal bleeding, stool frequency, and endoscopy) of at least two (2) points and at least 35% from I-week 0 with either a decrease in the rectal bleeding subscore of at least one (1) point or a rectal bleeding subscore of 0 or 1.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 330
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 110

Exclusion criteria:
Exclusion Criteria: Induction
1. Suspicion of differential diagnosis such as Crohn’s enterocolitis, ischaemic colitis, radiation colitis, indeterminate colitis, infectious colitis, diverticular disease, associated colitis, microscopic colitis, massive pseudopolyposis or non-passable stenosis.
2. Acute fulminant UC, toxic megacolon and/or signs of systemic toxicity.
3. UC limited to the rectum (disease extending <15 cm above the anal verge) or extending beyond the splenic flexure.
4. Have failed treatment with more than three advanced therapies (infliximab, adalimumab, golimumab, vedolizumab, ustekinumab or tofacitinib) of two different therapeutic classes (anti-TNF, anti-integrins, anti-IL12/23, JAKinhibitors, or other approved advanced therapies for UC).
5. Have had surgery for treatment of UC.
6. History of malignancy, unless treated with no relapse of the disease and = 5 years since last treatment (cured) or treated (cured) basal cell or squamous cell in situ carcinoma.
7. History or presence of any clinically significant disorder that, in the opinion of the investigator, could impact on the participant’s ability to adhere to the protocol and protocol procedures, or would confound the study result or compromise participant safety.
8. Concomitant treatment with cyclosporine, methotrexate, tacrolimus, or advanced therapies such as infliximab, adalimumab, golimumab, vedolizumab, ustekinumab or tofacitinib, or similar immunosuppressants and immunomodulators at enrolment.
Any prior treatment with such drugs must have been discontinued at least 8 weeks prior to visit 1b (except for ustekinumab, which must have been discontinued at least 12 weeks prior to visit 1 b) or have non-measurable serum concentration levels.
9. Treatment with rectal GCS, 5-ASA/SP or tacrolimus within 2 weeks before visit 1b.
10. Long-term treatment (>14 days) with antibiotics or NSAIDs within 2 weeks prior to visit 1b (one short treatment regimen for antibiotics, occasional use of NSAIDs and low dose NSAIDs as prophylactic therapy is allowed).
11. Serious known active infection including history of latent or active
tuberculosis, documented history of past or current tuberculosis, or living with or having frequent close contact with people with active tuberculosis or with a positive tuberculosis test according to current regulations for 12 weeks preceding randomisation. Serious infections include, but is not limited to, HIV, HBV, or HCV infections.
12. Gastrointestinal infections including positive Clostridium difficile stool assay. (Local laboratory reports must be available in accordance with normal clinic practice, to confirm that the current episode of disease exacerbation is not due to infection).
13. Females who are lactating or have a positive serum pregnancy test during the screening period.
14. Women of childbearing potential not using highly effective (failure rate < 1%) contraceptive methods throughout the duration of the study.
15. Concurrent participation in another clinical study with investigational therapy or previous use of investigational therapy within 5 half-lives and within at least 30 days after last treatment of the experimental product prior to enrolment.
16. Previous exposure to cobitolimod

Exclusion Criteria Maintenance:
Participants will not be eligible for the maintenance study if they are not willing to comply with all further study requirements.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Digestive System Diseases [C06]

Moderate to Severe left-sided Active Ulcerative Colitis
MedDRA version: 20.1 Level: LLT Classification code 10045365 Term: Ulcerative colitis System Organ Class: 100000004856

Intervention(s)

Product Name: Cobitolimod
Pharmaceutical Form: Rectal solution
INN or Proposed INN: COBITOLIMOD
CAS Number: 1527479-55-5
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 250-
Pharmaceutical form of the placebo: Rectal solution
Route of administration of the placebo: Rectal use

Product Name: Cobitolimod
Pharmaceutical Form: Rectal solution
INN or Proposed INN: COBITOLIMOD
CAS Number: 1527479-55-5
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 500-
Pharmaceutical form of the placebo: Rectal solution
Route of administration of the placebo: Rectal use

Primary Outcome(s)

Main Objective: Primary Objective: Induction
To evaluate the efficacy of cobitolimod treatment compared to placebo in inducing clinical remission, in participants with moderate to severe active left-sided UC.
Primary Objective: Maintenance
To evaluate the efficacy of cobitolimod maintenance treatment compared to placebo in inducing or maintaining clinical remission, in participants with clinical response at I-week 6 after induction treatment with cobitolimod.

Primary end point(s): Primary Endpoint: Induction
Proportion of participants with clinical remission at I-week 6, defined by the 3-component Mayo score, i) rectal bleeding of 0, ii) stool frequency of 0 or 1 (with at least one (1) point decrease from I-week 0 if 1 at I-week 0), and iii) endoscopic score of 0 or 1

Primary Endpoints: Maintenance
Primary Efficacy
Proportion of participants with clinical remission at M-week 45, defined by the 3-component Mayo score, i) rectal bleeding of 0, ii) stool frequency of 0 or 1 (with at least one (1) point decrease from I-week 0 if 1 at I-week 0), and iii) endoscopic score of 0 or 1.

Secondary Objective: Secondary Objectives: Induction
• To evaluate the safety and tolerability of cobitolimod compared to placebo.
• To evaluate the efficacy of cobitolimod treatment compared to placebo in clinical symptoms, endoscopy and histology endpoints.
• To evaluate the efficacy of cobitolimod treatment compared to placebo in other secondary endpoints.
Secondary Objectives: Maintenance
• To evaluate the safety and tolerability of cobitolimod compared to placebo.
• To evaluate the efficacy of cobitolimod maintenance treatment compared to placebo in
clinical symptoms, endoscopy and histology endpoints.
• To evaluate the efficacy of cobitolimod maintenance treatment compared to placebo in other secondary endpoints.
• To evaluate HRQoL and health economics

Timepoint(s) of evaluation of this end point: Timepoint primary endpoint Induction:
Induction week 6
Timepoint primary endpoint Maintenance:
Maintenance week 45

Secondary Outcome(s)

Secondary end point(s): Secondary Endpoints: Induction
Safety:
• incidence of AEs
• incidence of SAEs
• vital signs
• physical examination
• laboratory findings
Key Secondary Efficacy:
• Proportion of participants with endoscopic
improvement at I-week 6.
• Proportion of participants with symptomatic
remission at I-week 6.
Other Secondary Efficacy:
• Proportion of participants with clinical response at I-week 6.
• Proportion of participants with normalisation of stool frequency at I-week 6.
• Proportion of participants with absence of rectal bleeding at I-week 6.
• Mean stool frequency at I-week 6.
• Proportion of participants with histologic improvement at I-week 6
Proportion of participants with histologic remission at I-week 6.
• Proportion of participants with mucosal healing at I-week 6
• Mean ln-transformed faecal calprotectin at I-week 6.
• Mean 3-component and 4-component Mayo scores at I-week 6
• Mean IBDQ total score at I-week 6.
• Proportion of participants with an improvement in IBDQ total score at I-week 6 compared to I-week 0.

Secondary Endpoints: Maintenance
Safety
• incidence of AEs
• incidence of SAEs
• vital signs
• physical examination
• laboratory findings
Key Secondary Efficacy:
• Proportion of participants with endoscopic improvement at M-week 45.
• Proportion of participants with clinical remission at M-week 45 and steroid-free for at least 8 weeks prior.
• Proportion of participants with clinical remission at M-week 45 among those who achieved clinical
remission at I-week 6.
• Proportion of participants with symptomatic remission at M-week 45.
Other Secondary Efficacy:
• Proportion of participants with histologic improvement at M-week 45.
• Proportion of participants with histologic remission at M-week 45.
• Proportion of participants with mucosal healing at M-week 45.
• Proportion of participants with clinical response at M-week 45
• Proportion of participants with absence of rectal bleeding at M-week 45.
• Proportion of participants with normalisation of stool frequency at M-week 45.
• Mean stool frequency at M-week 45.
• Mean ln-transformed faecal calprotectin at Mweek 45.
• Mean 3-component and 4-component Mayo scores at M-week 45.
• Mean IBDQ total score at M-week 45.
• Proportion of participants with an improvement in IBDQ total score at M-week 45 compared to I-week 0.

Timepoint(s) of evaluation of this end point: Time point secondary endpoint induction:
Key secondary efficacy Induction-week 6
Other secondary efficacy Induction-week 6
Time point secondary endpoint maintenance:
Key secondary efficacy maintenance-week 45
Other secondary efficacy Maintenance-week 45

Secondary ID(s)

CSUC-01/21

Source(s) of Monetary Support

InDex Pharmaceuticals

Ethics review

Status: Approved
Approval date: 02/09/2021
Contact: