Clinical trial NCT01493960: The Efficacy and Safety of Cobitolimod (Kappaproct®) in Chronic Active Treatment Refractory Ulcerative Colitis Patients
Official title: A Placebo-controlled, Double-blind, Randomised Study to Assess the Efficacy and Safety of Cobitolimod as an add-on to Current Practice in Chronic Active Treatment Refractory Ulcerative Colitis Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Colitis, Ulcerative
Keywords: Colitis, Ulcerative
Gastrointestinal Diseases
Inflammatory Bowel Diseases
Immunomodulatory Therapy
Glucocorticoids
Anti-Inflammatory Agents
Therapeutic uses
Lead sponsor: InDex Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2011-12-16
Enrollment: 131
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Induction of Clinical Remission
timeFrame: Week 12
Secondary outcomes:
measure: The Time to Colectomy
timeFrame: Within 12 months
measure: The Rate of Colectomy
timeFrame: at 12 months
measure: Steroid Free Remission at 12 Months
timeFrame: at 12 months
measure: The Induction of Mucosal Healing
timeFrame: Week 4 and 12
measure: The Induction of Symptomatic Remission
timeFrame: Week 4, 12
measure: The Induction of Registration Remission
timeFrame: Week 4 and 12
Other outcomes:
Locations:
city: Hradec Kralove
country: Czechia
facility: Site 402
city: Hradec Kralove
country: Czechia
facility: Site 404
city: Ostrava
country: Czechia
facility: Site 406
city: Ostrava
country: Czechia
facility: Site 407
city: Prague
country: Czechia
facility: Site 405
city: Prague
country: Czechia
facility: Site 409
city: Slaný
country: Czechia
facility: Site 403
city: Pierre Bénite
country: France
facility: Site 702
city: Berlin
country: Germany
facility: Site 501
city: Bottrop
country: Germany
facility: Site 508
city: Erlangen
country: Germany
facility: Site 514
city: Frankfurt
country: Germany
facility: Site 510
city: Freiburg
country: Germany
facility: Site 509
city: Hannover
country: Germany
facility: Site 504
city: Herne
country: Germany
facility: Site 511
city: Jena
country: Germany
facility: Site 503
city: Regensburg
country: Germany
facility: Site 507
city: Stade
country: Germany
facility: Site 502
city: Stuttgart
country: Germany
facility: Site 513
city: Budapest
country: Hungary
facility: Site 204
city: Budapest
country: Hungary
facility: Site 207
city: Békéscsaba
country: Hungary
facility: Site 205
city: Kaposvar
country: Hungary
facility: Site 203
city: Szekszard
country: Hungary
facility: Site 202
city: Rome
country: Italy
facility: Site 302
city: Rome
country: Italy
facility: Site 304
city: Krakow
country: Poland
facility: Site 604
city: Lodz
country: Poland
facility: Site 605
city: Lodz
country: Poland
facility: Site 607
city: Rzeszów
country: Poland
facility: Site 606
city: Warszawa
country: Poland
facility: Site 601
city: Warszawa
country: Poland
facility: Site 602
city: Warszawa
country: Poland
facility: Site 603
city: Edinburgh
country: United Kingdom
facility: Site 104
city: London
country: United Kingdom
facility: Site 102
city: Norwich
country: United Kingdom
facility: Site 103
city: Nottingham
country: United Kingdom
facility: Site 101
Study officials:
affiliation: Nottingham Digestive Diseases Centre, Queens Campus University Hospitals, Nottingham, UK
name: Christopher Hawkey, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Atreya R, Reinisch W, Peyrin-Biroulet L, Scaldaferri F, Admyre C, Knittel T, Kowalski J, Neurath MF, Hawkey C. Clinical efficacy of the Toll-like receptor 9 agonist cobitolimod using patient-reported-outcomes defined clinical endpoints in patients with ulcerative colitis. Dig Liver Dis. 2018 Oct;50(10):1019-1029. doi: 10.1016/j.dld.2018.06.010. Epub 2018 Jun 22.