Ulcerative Colitis (UC)
Conditions
Keywords
biologics, ulcerative colitis, monoclonal antibodies, TL1A
Brief summary
The aim of the study is to evaluate the efficacy, safety, pharmacokinetics, pharmacodynamics and immunogenicity of study drug (BCD-261) in comparison with placebo and to characterize the dose-response relationship in patients with moderate to severe active ulcerative colitis. The study will be conducted in a population of male and female subjects ≥18 years and ≤75 years with moderate to severe active ulcerative colitis and an inadequate response to prior treatment with glucocorticoids, immunosuppressants, or biologics/targeted immunosuppressants.
Detailed description
Subjects meeting the eligibility criteria will be randomized in 5 groups to receive one of four studied dosage regimens of BCD-261 or placebo. The study groups will differ in drug dosages of BCD-261 (low, medium, high) during the induction and maintenance periods of therapy. After the primary endpoint assessment subjects in placebo group will be switched to BCD-261 medium studied dose.
Interventions
BIOLOGICALanti-TL1A monoclonal antibody, low dose
injection
injection
BIOLOGICALanti-TL1A monoclonal antibody, high dose
injection
OTHERPlacebo
injection
Sponsors
Biocad
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1\. Diagnosis of ulcerative colitis with involvement of the colon proximal to the rectum (≥15 cm from the distal edge of the anal canal), established ≥3 months before signing the ICF and confirmed by endoscopic examination data. 2\. Moderate to severe active ulcerative colitis with a modified Mayo score (mMS) of ≥4 and ≤9 points, which includes an endoscopic component of ≥2 points (according to a central independent review) and a stool blood score of ≥1 point. 3\. Inadequate response to therapy according to the investigator's assessment, manifested by at least one of the following signs: 1. Persistent symptoms of disease activity despite treatment with at least one course of glucocorticoids including prednisolone at a dose of ≥40 mg/day or equivalent or budesonide ≥9 mg/day or equivalent for at least 2 weeks with oral administration (at least 1 week with intravenous administration at a dose equivalent to oral prednisolone ≥40 mg/day). 2. Steroid dependence manifested by an increase in disease activity after initial improvement, with a decrease in the dose of glucocorticoids below the dose equivalent to 10 mg of oral prednisolone per day, within 3 months from the beginning of treatment, or a relapse of the disease within 3 months after the end of glucocorticoid use. 3. Persistent symptoms of disease activity despite treatment with at least one course of immunosuppressants (azathioprine at a dose of ≥2.0 mg/kg and/or 6-mercaptopurine at a dose of ≥1.0 mg/kg) for ≥12 weeks, or in response to another treatment regimen with these drugs according to a regional standard of care. 4. Primary lack of response to therapy with TNFa inhibitors and/or anti-integrins, and/or IL-12/23 inhibitors, and/or Janus kinase inhibitors, and/or sphingosine-1-phosphate receptor modulators, defined as the persistence of symptoms of disease activity despite at least one course of induction of remission according to a treatment scheme approved by the regional standard. 5. Loss of response to therapy with TNFa inhibitors and/or anti-integrins, and/or IL-12/23 inhibitors, and/or Janus kinase inhibitors, and/or sphingosine-1-phosphate receptor modulators, defined as the appearance of symptoms of disease activity after initial improvement as a result of treatment with at least one course of induction of remission and at least one course of maintenance of remission according to a treatment scheme approved by the regional standard. 6. A history of intolerance to glucocorticoids and/or immunosuppressants (azathioprine, 6-mercaptopurine) and/or biological therapy/targeted immunosuppressants (TNFa inhibitors, anti-integrins, anti-IL-12/23 monoclonal antibodies, Janus kinase inhibitors, sphingosine-1-phosphate receptor modulators) established by the treating physician. 4\. Maintaining a stable dose of concomitant medications for ≥2 weeks prior to signing the ICF and in the screening period for glucocorticoids and 5-ASCs and for ≥4 weeks prior to signing the ICF and in the screening period for immunosuppressants (azathioprine, 6-mercaptopurine).
Exclusion criteria
1. A history of or current at the time of signing the ICF Crohn's disease, unspecified colitis, ischemic colitis, radiation colitis, microscopic colitis, complicated form of diverticular disease. 2. A history of primary sclerosing cholangitis. 3. A history of fulminant colitis, toxic dilation of the colon, intestinal obstruction, intestinal perforation (except for those caused by injury or appendicitis). 4. A history of dysplasia of any grade in any part of the gastrointestinal tract at the time of signing the ICF. 5. Presence of intestinal stoma or artificial rectum or the need for them. 6. Failure of ≥3 classes of biologics/targeted immunosuppressors (according to INN) with different mechanisms of action (TNFa inhibitors, anti-integrins, IL-12/23 inhibitors, Janus kinase inhibitors, sphingosine-1-phosphate receptor modulators) or ≥4 biologics/targeted immunosuppressants, regardless of the mechanism of action. 7. Use of any of the indicated therapies within the specified time frame or need for therapy with these drugs during the study period: (1) Use of Janus kinase inhibitors within 2 weeks prior to signing the ICF or during the screening period. (2) Use of TNFa inhibitors within 8 weeks prior to signing the ICF or during the screening period. (3) Using modulators of sphingosine-1-phosphate receptors within 10 weeks prior to signing the ICF or during the screening period. (4) Use of anti-integrins, IL-12/23 inhibitors within 12 weeks before signing the ICF or during the screening period. (5) Use of oral glucocorticoids at a dose equivalent to prednisone \>20 mg/day or budesonide \>9 mg/day or rectal administration of glucocorticoids at any dose within 2 weeks prior to signing the ICF or during the screening period or parenteral administration of glucocorticoids at any dose within 4 weeks prior to signing the ICF or during the screening period. (6) Rectal administration of 5-ASCs within 2 weeks prior to signing the ICF or during the screening period. (7) Use of immunosuppressants not included in the approved therapy (tacrolimus, cyclosporine, mycophenolate mofetil, rapamycin, leflunomide, penicillamine, etc.) within 4 weeks before signing the ICF or during the screening period. (8) Long-term regular use of non-steroidal anti-inflammatory drugs (≥3 times a week for ≥6 weeks) for 2 weeks prior to signing the ICF. (9) Use of any other investigational drugs in other clinical trials at the time of signing the ICF or less than 8 weeks or 5 half-lives (whichever is longer) before the date of randomization.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of subjects who achieved clinical remission | week 14 | Proportion of subjects with modified Mayo score ≤2 points (endoscopic mucosal score ≤1, stool blood score = 0, stool frequency score ≤1, assessment for each component should not exceed the baseline level) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of subjects who achieved clinical remission | week 24 | Proportion of subjects with modified Mayo score ≤2 points (endoscopic mucosal score ≤1, stool blood score = 0, stool frequency score ≤1, assessment for each component should not exceed the baseline level) |
Other
| Measure | Time frame | Description |
|---|---|---|
| Proportion of subjects who achieved an endoscopic response | weeks 14, 24, 52, 100 | Proportion of subjects with mucosal state assessment according to the Mayo endoscopic score of ≤1 without friability. Mayo Endoscopic Score (MES) is a widely used tool for assesing the stage of ulcerative colitis based solely on endoscopic examination. MES may vary from 0 to 3, where 0 corresponds to normal or inactive, 1 - to mild, 2- to moderate and 3 - to severe disease activity. |
| Proportion of subjects who achieved endoscopic remission (mucosal healing) | weeks 14, 24, 52, 100 | Proportion of subjects with a Mayo endoscopic score of 0. Mayo Endoscopic Score (MES) is a widely used tool for assesing the stage of ulcerative colitis based solely on endoscopic examination. MES may vary from 0 to 3, where 0 corresponds to normal or inactive, 1 - to mild, 2- to moderate and 3 - to severe disease activity. |
| Proportion of subjects who achieved an endoscopic and histological response | weeks 14, 24, 52, 100 | Proportion of subjects with Mayo endoscopic score of ≤1 without friability in combination with a Geboes score ≤3.1. Mayo Endoscopic Score (MES) is a widely used tool for assesing the stage of ulcerative colitis based solely on endoscopic examination. MES may vary from 0 to 3, where 0 corresponds to normal or inactive, 1 - to mild, 2- to moderate and 3 - to severe disease activity. Histologic Geboes Score is the most commonly used histological score in ulcerative colitis. Evaluation according to the histologic Geboes score is divided into 6 grades: architectural changes \[grade 0\], chronic inflammatory infiltrate \[grade 1\], lamina propria neutrophils and eosinophils \[grade 2\], neutrophils in epithelium \[grade 3\], crypt destruction \[grade 4\] and erosions or ulcerations \[grade 5\], and each grade of the score is divided in 4 subcategories. The Geboes score ranges from 0.0 to 5.4, with higher values indicating more severe inflammation. |
| Change in the Geboes score from the baseline. | weeks 14, 24, 52, 100 | Evaluation according to the histologic Geboes score is divided into 6 grades: architectural changes \[grade 0\], chronic inflammatory infiltrate \[grade 1\], lamina propria neutrophils and eosinophils \[grade 2\], neutrophils in epithelium \[grade 3\], crypt destruction \[grade 4\] and erosions or ulcerations \[grade 5\], and each grade of the score is divided in 4 subcategories. The Geboes score ranges from 0.0 to 5.4, with higher values indicating more severe inflammation. |
| Proportion of subjects who achieved a clinical response | weeks 14, 24, 52, 100 | Proportion of subjects modified Mayo score of ≥2 points and ≥30% from the baseline with a decrease in the estimated stool blood score of ≥1 point from the baseline or the estimated stool blood score of ≤1 point) |
| Proportion of subjects who achieved a clinical response of ≥50% from baseline | weeks 14, 24, 52, 100 | Clinical response measured by two-component patient reported outcomes (PRO2) scale consist of the patient-derived items from the Mayo score (rectal bleeding and stool frequency). PRO2 scale ranges from 0-6 with higher values indicating worse outcome. |
| Change in the fecal calprotectin level from the baseline | weeks 14, 24, 52, 100 | — |
| Change in the highly sensitive C-reactive protein level from the baseline | weeks 14, 24, 52, 100 | — |
| Changes in the proportion of subjects with extra-intestinal manifestations from the baseline | weeks 14, 24, 52, 100. | — |
| Change in the partial Mayo score from the baseline | weeks 14, 24, 52, 100 | The assessment of the partial Mayo score ranges from 0 to 9 points, which are derived from 3 subscores, each of which is evaluated as 0 to 3 points: * Stool frequency assessment (0 to 3 points). * Evaluation of blood presence in the stool (0 to 3 points). * Physician's global assessment (0 to 3 points). A higher score indicates greater disease activity. It is a modification of the total Mayo score, from which Mayo Endoscopic Score (MES) was excluded. |
| Proportion of subjects who achieved clinical remission | weeks 52, 100 | Proportion of subjects with modified Mayo score ≤2 points (endoscopic mucosal score ≤1, stool blood score = 0, stool frequency score ≤1, assessment for each component should not exceed the baseline level) |
Countries
Russia
Contacts
Primary ContactAnna V Gaponova
Backup ContactAleksey V Manziuk
Outcome results
None listed