The Efficacy and Safety of Cobitolimod in Participants With Moderate to Severe Active Left-Sided Ulcerative Colitis

Study Overview
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Brief Summary
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The purpose of the study is to evaluate the efficacy of cobitolimod treatment compared to placebo in inducing clinical remission, in participants with moderate to severe active left-sided UC and to evaluate the efficacy of cobitolimod maintenance treatment compared to placebo in inducing or maintaining clinical remission at week 52, in participants with clinical response at week 6 after induction treatment with cobitolimod.

Detailed Description
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This phase III study protocol includes an induction study for 6 weeks and a maintenance study for an additional 45 weeks. In the induction study there will be an initial phase to explore the best dose, between cobitolimod 250 mg and cobitolimod 500 mg using adaptive design.

Official Title
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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

Conditions
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Ulcerative Colitis

Intervention / Treatment
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* Drug: Cobitolimod 250 mg
* Drug: Cobitolimod 500 mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Induction: Male or female ≥ 18 years of age. Established diagnosis of UC. Moderate to severe active left-sided UC assessed by central reading. Have inadequate response, loss of response or be intolerant of at least one of the following treatments: Oral GCS, AZA/6-MP, Biologics, JAK-inhibitors, or other approved advanced therapies for UC. Allowed to receive a therapeutic dose of the following UC drugs during the study: Oral GCS therapy (≤20 mg prednisone or equivalent/day) , Oral 5-ASA/SP compounds, AZA/6-MP. Ability to understand the treatment, willingness to comply with all study requirements, and ability to provide informed consent. Exclusion Criteria Induction: Suspicion of differential diagnosis. Acute fulminant UC and/or signs of systemic toxicity. UC limited to the rectum or extending beyond the splenic flexure. Have failed treatment with more than three advanced therapies of two different therapeutic classes. Have had surgery for treatment of UC. History of malignancy, unless treated with no relapse of the disease and ≥ 5 years since last treatment (cured). History or presence of any clinically significant disorder. Concomitant treatment with cyclosporine, methotrexate, tacrolimus, or advanced therapies or similar immunosuppressants and immunomodulators. Treatment with rectal GCS, 5-ASA/SP or tacrolimus. Long-term treatment (>14 days) with antibiotics or NSAIDs . Serious known active infection including history of latent or active tuberculosis. Gastrointestinal infections including positive Clostridium difficile stool assay. Females who are lactating or have a positive serum pregnancy test. Women of childbearing potential not using highly effective contraceptive methods. Concurrent participation in another clinical study. Previous exposure to cobitolimod. Inclusion Criteria Maintenance: Participants are eligible to be included in the maintenance study if they have achieved clinical response at week 6 and have adhered to the protocol procedures of the induction study. Exclusion Criteria Maintenance: Participants will not be eligible for the maintenance study if they are not willing to comply with all further study requirements.

Ages Eligible for Study
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Minimum Age: 18 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: Cobitolimod 250 mg<br>Dose of 250 mg cobitolimod 2 treatments during induction study and subsequently every third week | Drug: Cobitolimod 250 mg<br>* Rectal administration<br>* Other names: Kappaproct;|
| Experimental: Cobitolimod 500 mg<br>Dose of 500 mg cobitolimod 2 treatments during induction study and subsequently every third week | Drug: Cobitolimod 500 mg<br>* Rectal administration<br>* Other names: Kappaproct;|
| Placebo Comparator: Placebo<br>Dose of Placebo 2 treatments during induction study and subsequently every third week | Drug: Placebo<br>* Rectal administration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Induction - Proportion of participants with clinical remission. | Clinical remission defined by the 3-component Mayo score. | Week 6 | 
| Maintenance - Proportion of participants with clinical remission. | Clinical remission defined by the 3-component Mayo score. | Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Induction - Proportion of participants with endoscopic improvement. | Endoscopic improvement defined by the Mayo Endoscopic score. | Week 6 | 
| Induction - Proportion of participants with symptomatic remission. | Symptomatic remission defined by the 2-component Mayo score. | Week 6 | 
| Induction - Proportion of participants with clinical response. | Clinical remission defined by the 3-component Mayo score. | Week 6 | 
| Induction - Proportion of participants with normalisation of stool frequency. | Stool frequency defined by the Mayo score for Stool Frequency. | Week 6 | 
| Induction - Proportion of participants with absence of rectal bleeding. | Rectal bleeding defined by the Mayo score for Rectal Bleeding. | Week 6 | 
| Induction - Mean stool frequency. | Mean stool frequency defined by the Mayo score for Stool Frequency. | Week 6 | 
| Induction - Proportion of participants with histologic improvement. | Defined by the Robarts Histologic Index. | Week 6 | 
| Induction - Proportion of participants with histologic remission. | Histologic remission defined by the Robarts Histologic Index. | Week 6 | 
| Induction - Proportion of participants with mucosal healing. | Mucosal healing defined by the Mayo Endoscopic score and Robarts Histologic Index. | Week 6 | 
| Induction - Mean ln-transformed faecal calprotectin. | Mean ln-transformed faecal calprotectin defined by faecal calprotectin values. | Week 6 | 
| Induction - Mean 3-component and 4-component Mayo scores. | Defined by 3-component and 4-component Mayo scores. | Week 6 | 
| Induction - Mean IBDQ total score. | Defined by the Inflammatory Bowel Disease Questionnaire (IBDQ). | Week 6 | 
| Induction - Proportion of participants with an improvement in IBDQ total score. | Defined by the IBDQ. | Week 6 | 
| Maintenance - Proportion of participants with endoscopic improvement. | Endoscopic improvement defined by the Mayo Endoscopic score. | Week 52 | 
| Maintenance - Proportion of participants with clinical remission and steroid-free. | Defined by the 3-component Mayo score and use of glucocorticosteroids. | Week 52 | 
| Maintenance - Proportion of participants with clinical remission among those who achieved clinical remission | Defined by the 3-component Mayo score. | Week 52 | 
| Maintenance - Proportion of participants with symptomatic remission. | Symptomatic remission defined by the 2-component Mayo score. | Week 52 | 
| Maintenance - Proportion of participants with histologic improvement. | Histologic improvement defined by the Robarts Histologic Index. | Week 52 | 
| Maintenance - Proportion of participants with histologic remission. | Histologic remission defined by the Robarts Histologic Index. | Week 52 | 
| Maintenance - Proportion of participants with mucosal healing. | Mucosal healing defined by the Mayo Endoscopic score and Robarts Histologic Index. | Week 52 | 
| Maintenance - Proportion of participants with clinical response. | Clinical response defined by the 3-component Mayo score. | Week 52 | 
| Maintenance - Proportion of participants with absence of rectal bleeding. | Rectal bleeding defined by the Mayo score for Rectal Bleeding. | Week 52 | 
| Maintenance - Proportion of participants with normalisation of stool frequency. | Stool frequency defined by the Mayo score for Stool Frequency. | Week 52 | 
| Maintenance - Mean stool frequency. | Mean stool frequency defined by the Mayo score for Stool Frequency. | Week 52 | 
| Maintenance - Mean ln-transformed faecal calprotectin. | Mean ln-transformed faecal calprotectin. | Week 52 | 
| Maintenance - Mean 3-component and 4-component Mayo scores. | Defined by 3-component and 4-component Mayo scores. | Week 52 | 
| Maintenance - Mean IBDQ total score. | Defined by the use of the Inflammatory Bowel Disease Questionnaire (IBDQ). | Week 52 | 
| Maintenance - Proportion of participants with an improvement in IBDQ total score. | Defined by the IBDQ. | Week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TLR9 agonist, Colitis, Ulcerative, Gastrointestinal Disease, Inflammatory Bowel Diseases, Glucocorticosteroids, Anti-Inflammatory Agents, Therapeutic uses, Cobitolimod, Toll like receptor 9 agonist, Kappaproct, IDX0150, DIMS0150