COLLECT: The Efficacy and Safety of Cobitolimod (Kappaproct®) in Chronic Active Treatment Refractory Ulcerative Colitis Patients

• Sponsor: InDex Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01493960
• Collaborator: (none)
• Enrollment: 131
• Locations: 37
• Arms: 2
• Duration (Months): 27
• Patients Per Site: 3.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Colitis, Ulcerative	Drug: Cobitolimod; Drug: Placebo	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 131 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• 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 Start Date: Dec 1, 2011
• Actual Primary Completion Date: Jun 1, 2013
• Actual Study Completion Date: Mar 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cobitolimod 2 doses 4 weeks apart	Drug: Cobitolimod; 30 mg rectal dose at week 0 and 4; Other Names: DIMS0150, Kappaproct
Placebo Comparator: Placebo 2 doses 4 weeks apart	Drug: Placebo; Rectal dose at week 0 and 4

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. The Time to Colectomy [Within 12 months]

   Median time to colectomy after 1st dose.

2. The Rate of Colectomy [at 12 months]

   Percentage of participants undergoing colectomy at 12 months after 1st dose.

3. Steroid Free Remission at 12 Months [at 12 months]

   Percentage of participants with steroid free remission at 12 months after 1st dose.

4. 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.

5. 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.

6. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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.

1. 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.

2. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Site 402	Hradec Kralove		Czechia
2	Site 404	Hradec Kralove		Czechia
3	Site 406	Ostrava		Czechia
4	Site 407	Ostrava		Czechia
5	Site 405	Prague		Czechia
6	Site 409	Prague		Czechia
7	Site 403	Slaný		Czechia
8	Site 702	Pierre Bénite		France
9	Site 501	Berlin		Germany
10	Site 508	Bottrop		Germany
11	Site 514	Erlangen		Germany
12	Site 510	Frankfurt		Germany
13	Site 509	Freiburg		Germany
14	Site 504	Hannover		Germany
15	Site 511	Herne		Germany
16	Site 503	Jena		Germany
17	Site 507	Regensburg		Germany
18	Site 502	Stade		Germany
19	Site 513	Stuttgart		Germany
20	Site 204	Budapest		Hungary
21	Site 207	Budapest		Hungary
22	Site 205	Békéscsaba		Hungary
23	Site 203	Kaposvar		Hungary
24	Site 202	Szekszard		Hungary
25	Site 302	Rome		Italy
26	Site 304	Rome		Italy
27	Site 604	Krakow		Poland
28	Site 605	Lodz		Poland
29	Site 607	Lodz		Poland
30	Site 606	Rzeszów		Poland
31	Site 601	Warszawa		Poland
32	Site 602	Warszawa		Poland
33	Site 603	Warszawa		Poland
34	Site 104	Edinburgh		United Kingdom
35	Site 102	London		United Kingdom
36	Site 103	Norwich		United Kingdom
37	Site 101	Nottingham		United Kingdom

Sponsors and Collaborators

• InDex Pharmaceuticals

Investigators

• Principal Investigator: Christopher Hawkey, MD, Nottingham Digestive Diseases Centre, Queens Campus University Hospitals, Nottingham, UK

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: InDex Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01493960
• Other Study ID Numbers: CSUC-01/10; 2011-003130-14
• First Posted: Dec 16, 2011
• Last Update Posted: Jan 24, 2018
• Last Verified: Jun 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by InDex Pharmaceuticals: Colitis, Ulcerative; Gastrointestinal Diseases; Inflammatory Bowel Diseases; Immunomodulatory Therapy; Glucocorticoids; Anti-Inflammatory Agents; Therapeutic uses
• Additional relevant MeSH terms: Colitis; Colitis, Ulcerative; Ulcer

Study Results

Participant Flow

Recruitment Details	There were 162 subjects screened. Whereof 31 did not meet the criteria
Pre-assignment Detail	There were131 patients randomly assigned in a 2:1 allocation to receive 2 rectal doses of cobitolimod at 30 mg, or placebo, respectively.

Arm/Group Title	Cobitolimod	Placebo
Arm/Group Description	2 doses 4 weeks apart Cobitolimod: 30 mg rectal dose at week 0 and 4	2 doses 4 weeks apart Placebo: Rectal dose at week 0 and 4
Period Title: Overall Study
STARTED	87	44
Received Study Drug	87	43
COMPLETED	55	26
NOT COMPLETED	32	18

Baseline Characteristics

Arm/Group Title	Cobitolimod	Placebo	Total
Arm/Group Description	2 doses 4 weeks apart Cobitolimod: 30 mg rectal dose at week 0 and 4	2 doses 4 weeks apart Placebo: Rectal dose at week 0 and 4	Total of all reporting groups
Overall Participants	81	43	124
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	76 93.8%	40 93%	116 93.5%
>=65 years	5 6.2%	3 7%	8 6.5%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	41.1 (13.88)	43.1 (12.31)	41.8 (13.34)
Sex: Female, Male (Count of Participants)
Female	33 40.7%	11 25.6%	44 35.5%
Male	48 59.3%	32 74.4%	80 64.5%
Region of Enrollment (participants) [Number]
Czech Republic	13 16%	6 14%	19 15.3%
Hungary	13 16%	6 14%	19 15.3%
Poland	25 30.9%	14 32.6%	39 31.5%
Italy	2 2.5%	3 7%	5 4%
United Kingdom	8 9.9%	3 7%	11 8.9%
Germany	20 24.7%	11 25.6%	31 25%
Summary of CAI score at baseline by treatment group (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	11.1 (2.2)	10.8 (2.1)	11.0 (2.1)

Outcome Measures

1. Primary Outcome

Title	Induction of Clinical Remission
Description	The induction of clinical remission at week 12, defined as a CAI score of ≤4.(Full Analysis Set)
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

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/Group Title	Cobitolimod	Placebo
Arm/Group Description	2 doses 4 weeks apart Cobitolimod: 30 mg rectal dose at week 0 and 4	2 doses 4 weeks apart Placebo: Rectal dose at week 0 and 4
Measure Participants	81	43
Number (95% Confidence Interval) [Percentage of participants]	44.4 54.8%	46.5 108.1%

2. Secondary Outcome

Title	The Time to Colectomy
Description	Median time to colectomy after 1st dose.
Time Frame	Within 12 months

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Cobitolimod	Placebo
Arm/Group Description	2 doses 4 weeks apart Cobitolimod: 30 mg rectal dose at week 0 and 4	2 doses 4 weeks apart Placebo: Rectal dose at week 0 and 4
Measure Participants	81	43
Median (95% Confidence Interval) [Time]	NA	NA

3. Secondary Outcome

Title	The Rate of Colectomy
Description	Percentage of participants undergoing colectomy at 12 months after 1st dose.
Time Frame	at 12 months

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Cobitolimod	Placebo
Arm/Group Description	2 doses 4 weeks apart Cobitolimod: 30 mg rectal dose at week 0 and 4	2 doses 4 weeks apart Placebo: Rectal dose at week 0 and 4
Measure Participants	81	43
Number (95% Confidence Interval) [Percentage of Subjects]	4.9	11.6

4. Secondary Outcome

Title	Steroid Free Remission at 12 Months
Description	Percentage of participants with steroid free remission at 12 months after 1st dose.
Time Frame	at 12 months

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Cobitolimod	Placebo
Arm/Group Description	2 doses 4 weeks apart Cobitolimod: 30 mg rectal dose at week 0 and 4	2 doses 4 weeks apart Placebo: Rectal dose at week 0 and 4
Measure Participants	81	43
Number (95% Confidence Interval) [Percentage of Subjects]	32.1	30.2

5. Secondary Outcome

Title	The Induction of Mucosal Healing
Description	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

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Cobitolimod	Placebo
Arm/Group Description	2 doses 4 weeks apart Cobitolimod: 30 mg rectal dose at week 0 and 4	2 doses 4 weeks apart Placebo: Rectal dose at week 0 and 4
Measure Participants	81	43
Week 4	34.6	18.6
Week 12	42.0	41.9

6. Secondary Outcome

Title	The Induction of Symptomatic Remission
Description	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

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Cobitolimod	Placebo
Arm/Group Description	2 doses 4 weeks apart Cobitolimod: 30 mg rectal dose at week 0 and 4	2 doses 4 weeks apart Placebo: Rectal dose at week 0 and 4
Measure Participants	81	43
Week 4	32.1	14.0
Week 12	43.2	32.6

7. Secondary Outcome

Title	The Induction of Registration Remission
Description	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

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Cobitolimod	Placebo
Arm/Group Description	2 doses 4 weeks apart Cobitolimod: 30 mg rectal dose at week 0 and 4	2 doses 4 weeks apart Placebo: Rectal dose at week 0 and 4
Measure Participants	81	43
Week 4	21.0	4.7
Week 12	30.9	30.2

Adverse Events

Time Frame	1 year, 2 weeks
Adverse Event Reporting Description	All patients who entered into the study and were treated with at least 1 dose of study drug are included in the safety analysis set.
Arm/Group Title	Cobitolimod		Placebo
Arm/Group Description	2 doses 4 weeks apart Cobitolimod: 30 mg rectal dose at week 0 and 4		2 doses 4 weeks apart Placebo: Rectal dose at week 0 and 4
All Cause Mortality
	Cobitolimod		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Cobitolimod		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/87 (11.5%)		8/43 (18.6%)
Blood and lymphatic system disorders
Anemia	1/87 (1.1%)		0/43 (0%)
Cardiac disorders
Acute Coronary syndrome	1/87 (1.1%)		0/43 (0%)
Myocardial Ischemia	0/87 (0%)		1/43 (2.3%)
Eye disorders
Glaucoma	1/87 (1.1%)		0/43 (0%)
Retinal Veon Thrombosis	0/87 (0%)		1/43 (2.3%)
Gastrointestinal disorders
Intestinal obstruction	0/87 (0%)		1/43 (2.3%)
Perirectal abscess	1/87 (1.1%)		0/43 (0%)
Vomiting	0/87 (0%)		1/43 (2.3%)
Infections and infestations
Herpes Zoster	0/87 (0%)		1/43 (2.3%)
Injury, poisoning and procedural complications
Overdose	2/87 (2.3%)		1/43 (2.3%)
Musculoskeletal and connective tissue disorders
Osteoarthritis	1/87 (1.1%)		0/43 (0%)
Spinal compression fracture	1/87 (1.1%)		0/43 (0%)
Nervous system disorders
Sensory Distrurbance	0/87 (0%)		1/43 (2.3%)
Movement disorder	0/87 (0%)		1/43 (2.3%)
Reproductive system and breast disorders
Clostridial infection	0/87 (0%)		1/43 (2.3%)
Benign Dysplaisa	1/87 (1.1%)		0/43 (0%)
Respiratory, thoracic and mediastinal disorders
Pneumonia	0/87 (0%)		1/43 (2.3%)
Skin and subcutaneous tissue disorders
Rash	1/87 (1.1%)		0/43 (0%)
Vascular disorders
Epistaxis	1/87 (1.1%)		0/43 (0%)
Other (Not Including Serious) Adverse Events
	Cobitolimod		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	31/87 (35.6%)		6/43 (14%)
Blood and lymphatic system disorders
Anemia	4/87 (4.6%)		1/43 (2.3%)
Endocrine disorders
Cushingoid	4/87 (4.6%)		0/43 (0%)
Gastrointestinal disorders
Abdominal Pain	3/87 (3.4%)		0/43 (0%)
Infections and infestations
Nasopharyngitis	5/87 (5.7%)		1/43 (2.3%)
Musculoskeletal and connective tissue disorders
Back Pain	3/87 (3.4%)		1/43 (2.3%)
Nervous system disorders
Headache	5/87 (5.7%)		2/43 (4.7%)
Psychiatric disorders
Depression	3/87 (3.4%)		0/43 (0%)
Skin and subcutaneous tissue disorders
Rash	4/87 (4.6%)		1/43 (2.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.