Colitis, Ulcerative
Conditions
Keywords
Colitis, Ulcerative, Gastrointestinal Diseases, Inflammatory Bowel Diseases, Immunomodulatory Therapy, Glucocorticoids, Anti-Inflammatory Agents, Therapeutic uses
Brief summary
The purpose of this study is to determine if cobitolimod (former called Kappaproct®) is effective in the treatment of chronic active ulcerative colitis patients not responding to available therapy.
Detailed description
The study is a placebo-controlled, double-blind, randomised study to assess the efficacy and safety of cobitolimod as an add-on to current practice in treatment refractory ulcerative colitis patients. The study population will be chronic active ulcerative colitis patients who are no longer responding adequately to standard therapies and who are potential candidates for colectomy. Cobitolimod/placebo will be add-on treatment allowing all included patients to be on concomitant medication, as well as mandatory steroids at inclusion, throughout the study. Cobitolimod (DIMS0150) is a modified single strand DNA-based synthetic oligodeoxyribonucleotide of 19 bases in length. The drug functions as an immunomodulatory agent by targeting the Toll-like receptor 9 (TLR9) present in immune cells (i.e., B-cells and pDCs) residing in high abundance on mucosal surfaces, such as colonic and nasal mucosa. The mucosa of the colon and rectum of patients with ulcerative colitis contains active immune cells, which produce damage to the tissue. The activation of these cells by cobitolimod results in the systemic release of specific cytokines (e.g., IL-10 and type I interferons) and chemokines which are believed to be important factors for the clinical effect cobitolimod of cobitolimod. 131 eligible patients was randomly assigned in a 2:1 allocation to receive two single rectal doses of cobitolimod at 30 mg each, or placebo, at week 0 and 4. The primary endpoint is the induction of clinical remission at week 12 and patients will be continuously followed for efficacy and safety until 12 months after the first dose. Secondary endpoints include the induction of symptomatic remission (number of stools and blood in stools), induction of registration remission (clinical and endoscopic remission) and rate of colectomy.
Interventions
DRUGCobitolimod
30 mg rectal dose at week 0 and 4
DRUGPlacebo
Rectal dose at week 0 and 4
Sponsors
InDex Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female ≥ 18 years of age. 2. Well established diagnosis of moderate to moderately severe chronic active UC with a CAI score ≥9, an endoscopic score ≥2, not responding adequately to currently available therapies and potential candidates for colectomy. Previously tried therapies should include: * At least one treatment course with mesalazine; at least 2.4 g/day for at least 4 weeks, or at least one treatment course with similar drugs in this class. * At least one full dose treatment course of corticosteroids (which can be the treatment of a recent relapse), with up to 0.75 mg/kg as a starting dose or highest dose according to local clinical practice. * At least one treatment course of azathioprine or mercaptopurine of at least 3 months duration and/or at least one adequate treatment course of an anti-TNF alpha. * Any unsuccessful combination treatment of the above. * May have tried treatment with cyclosporine and/or tacrolimus or any other immunosuppressant/immunomodulating agent. * Intolerance to any of the above medications is judged as inadequate response. 3. Patients shall at study enrolment be on an accumulated stable tolerable GCS dose equivalent to at least 140 mg of prednisolone/prednisone (by any route of administration) for the last two weeks. Patients may also be on concomitant therapies such as, but not restricted to, 5-ASA, azathioprine and sulphasalazine. 4. Ability to understand the treatment, willingness to comply with all study requirements, and ability to provide informed consent.
Exclusion criteria
1. Patients with suspicion of Crohn's enterocolitis, ischaemic colitis, radiation colitis, diverticular disease associated colitis, as well as microscopic colitis should be excluded. Patients with disease limited to the rectum (ulcerative proctitis) should also be excluded. 2. History or presence of a clinically significant cardiovascular, hepatic, renal, haematological, endocrine, neurological, psychiatric disease, or immune compromised state as judged relevant by the investigator. 3. Patients with acute fulminant UC and/or signs of systemic toxicity to an extent that requires immediate surgical action. 4. History or presence of any colonic malignancy and/or dysplasia. 5. Concomitant treatment with cyclosporine, tacrolimus, anti-TNFs or similar immunosuppressants/immunomodulators is not allowed and should have been discontinued 4 weeks before enrolment. Patients who fail the wash-out criteria can undergo wash-out and be re-screened at a later time point. Ongoing treatment of anti-TNFs, tacrolimus or similar immunomodulators/immunosuppressant drugs should only be stopped in case of documented lack of efficacy or in case of intolerable side effects. 6. Treatment with antibiotics or Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) within two weeks before enrolment. 7. An active ongoing infection. 8. History of latent or active tuberculosis, evidence of prior or currently active tuberculosis by chest x-ray, patient with or having had frequent close contact with person with active tuberculosis, patients who previously have tested positive for a tuberculin skin test, or Mantoux (PPD) test, except in the case of previous vaccination or positive interferon gamma release test during screening or within 12 weeks prior to randomisation. 9. Known history of HIV infection based on documented history with positive serology or HIV positive serology. 10. Previously documented positive hepatitis B surface antigen determination, determination of total antibodies to the hepatitis B capsid antigen and/or hepatitis C antibody (HCVAb) with confirmation using the ribonucleic acid of hepatitis B virus. 11. Positive Clostridium difficile stool assay. 12. Currently receiving parenteral nutrition or blood transfusions. 13. Pregnancy or breast-feeding. 14. Women of childbearing potential not using reliable contraceptive methods (reliable methods are barrier protection, hormonal contraception, intra-uterine device or abstinence) throughout the duration of the study (52 weeks). 15. Concurrent participation in another clinical study with investigational therapy or previous use of investigational therapy within 30 days before enrolment. Patients who fail the wash-out criteria can undergo wash-out and be re-screened at a later time point.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Induction of Clinical Remission | Week 12 | The induction of clinical remission at week 12, defined as a CAI score of ≤4.(Full Analysis Set) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Rate of Colectomy | at 12 months | Percentage of participants undergoing colectomy at 12 months after 1st dose. |
| Steroid Free Remission at 12 Months | at 12 months | Percentage of participants with steroid free remission at 12 months after 1st dose. |
| The Time to Colectomy | Within 12 months | Median time to colectomy after 1st dose. |
| The Induction of Symptomatic Remission | Week 4, 12 | Percentage of participants with induction of symptomatic remission, defined as subscores of blood in stool and number of stools weekly not exceeding 0 and 0 or 1, respectively, at week 4 and 12. |
| The Induction of Registration Remission | Week 4 and 12 | Percentage of participants with induction of registration remission, defined as a CAI score of ≤4 and an endoscopic score of 0 or 1, at week 4 and 12. |
| The Induction of Mucosal Healing | Week 4 and 12 | Percentage of participants with induction of mucosal healing, defined as an endoscopic score of 0 or 1, at week 4 and 12. |
Countries
Czechia, France, Germany, Hungary, Italy, Poland, United Kingdom
Participant flow
Recruitment details
There were 162 subjects screened. Whereof 31 did not meet the criteria
Pre-assignment details
There were131 patients randomly assigned in a 2:1 allocation to receive 2 rectal doses of cobitolimod at 30 mg, or placebo, respectively.
Participants by arm
| Arm | Count |
|---|---|
| Cobitolimod 2 doses 4 weeks apart
Cobitolimod: 30 mg rectal dose at week 0 and 4 | 81 |
| Placebo 2 doses 4 weeks apart
Placebo: Rectal dose at week 0 and 4 | 43 |
| Total | 124 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Lack of Efficacy | 15 | 9 |
| Overall Study | Non-specified | 4 | 4 |
| Overall Study | Protocol Violation | 3 | 0 |
| Overall Study | Withdrawal by Subject | 10 | 4 |
Baseline characteristics
| Characteristic | Cobitolimod | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 5 Participants | 3 Participants | 8 Participants |
| Age, Categorical Between 18 and 65 years | 76 Participants | 40 Participants | 116 Participants |
| Age, Continuous | 41.1 years STANDARD_DEVIATION 13.88 | 43.1 years STANDARD_DEVIATION 12.31 | 41.8 years STANDARD_DEVIATION 13.34 |
| Region of Enrollment Czech Republic | 13 participants | 6 participants | 19 participants |
| Region of Enrollment Germany | 20 participants | 11 participants | 31 participants |
| Region of Enrollment Hungary | 13 participants | 6 participants | 19 participants |
| Region of Enrollment Italy | 2 participants | 3 participants | 5 participants |
| Region of Enrollment Poland | 25 participants | 14 participants | 39 participants |
| Region of Enrollment United Kingdom | 8 participants | 3 participants | 11 participants |
| Sex: Female, Male Female | 33 Participants | 11 Participants | 44 Participants |
| Sex: Female, Male Male | 48 Participants | 32 Participants | 80 Participants |
| Summary of CAI score at baseline by treatment group | 11.1 units on a scale STANDARD_DEVIATION 2.2 | 10.8 units on a scale STANDARD_DEVIATION 2.1 | 11.0 units on a scale STANDARD_DEVIATION 2.1 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 31 / 87 | 6 / 43 |
| serious Total, serious adverse events | 10 / 87 | 8 / 43 |
Outcome results
Primary
Induction of Clinical Remission
The induction of clinical remission at week 12, defined as a CAI score of ≤4.(Full Analysis Set)
Time frame: Week 12
Population: The FAS consited of all randomized patients who met the inclusion criteria (as assessed by the investigator on the inclusion/exclusion criteria form), and received at least 1 dose of study drug (active or placebo), and who had at least 1 post randomization eligible value of the primary efficacy endpoint
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cobitolimod | Induction of Clinical Remission | 44.4 Percentage of participants |
| Placebo | Induction of Clinical Remission | 46.5 Percentage of participants |
Secondary
Steroid Free Remission at 12 Months
Percentage of participants with steroid free remission at 12 months after 1st dose.
Time frame: at 12 months
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cobitolimod | Steroid Free Remission at 12 Months | 32.1 Percentage of Subjects |
| Placebo | Steroid Free Remission at 12 Months | 30.2 Percentage of Subjects |
Secondary
The Induction of Mucosal Healing
Percentage of participants with induction of mucosal healing, defined as an endoscopic score of 0 or 1, at week 4 and 12.
Time frame: Week 4 and 12
Population: FAS
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cobitolimod | The Induction of Mucosal Healing | Week 4 | 34.6 Percentage of Subjects |
| Cobitolimod | The Induction of Mucosal Healing | Week 12 | 42.0 Percentage of Subjects |
| Placebo | The Induction of Mucosal Healing | Week 4 | 18.6 Percentage of Subjects |
| Placebo | The Induction of Mucosal Healing | Week 12 | 41.9 Percentage of Subjects |
Secondary
The Induction of Registration Remission
Percentage of participants with induction of registration remission, defined as a CAI score of ≤4 and an endoscopic score of 0 or 1, at week 4 and 12.
Time frame: Week 4 and 12
Population: FAS
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cobitolimod | The Induction of Registration Remission | Week 4 | 21.0 Percentage of Subjects |
| Cobitolimod | The Induction of Registration Remission | Week 12 | 30.9 Percentage of Subjects |
| Placebo | The Induction of Registration Remission | Week 4 | 4.7 Percentage of Subjects |
| Placebo | The Induction of Registration Remission | Week 12 | 30.2 Percentage of Subjects |
Secondary
The Induction of Symptomatic Remission
Percentage of participants with induction of symptomatic remission, defined as subscores of blood in stool and number of stools weekly not exceeding 0 and 0 or 1, respectively, at week 4 and 12.
Time frame: Week 4, 12
Population: FAS
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cobitolimod | The Induction of Symptomatic Remission | Week 4 | 32.1 Percentage of Subjects |
| Cobitolimod | The Induction of Symptomatic Remission | Week 12 | 43.2 Percentage of Subjects |
| Placebo | The Induction of Symptomatic Remission | Week 4 | 14.0 Percentage of Subjects |
| Placebo | The Induction of Symptomatic Remission | Week 12 | 32.6 Percentage of Subjects |
Secondary
The Rate of Colectomy
Percentage of participants undergoing colectomy at 12 months after 1st dose.
Time frame: at 12 months
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cobitolimod | The Rate of Colectomy | 4.9 Percentage of Subjects |
| Placebo | The Rate of Colectomy | 11.6 Percentage of Subjects |
Secondary
The Time to Colectomy
Median time to colectomy after 1st dose.
Time frame: Within 12 months
Population: FAS
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cobitolimod | The Time to Colectomy | NA Time |
| Placebo | The Time to Colectomy | NA Time |