| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderate to Severe left-sided Active Ulcerative Colitis |
|
| E.1.1.1 | Medical condition in easily understood language |
| Moderate to Severe left-sided Active Ulcerative Colitis |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the efficacy of cobitolimod treatment at different dose levels and frequencies compared to placebo with regard to clinical remission 6 weeks after first treatment, in patients with moderate to severe active ulcerative colitis (UC). |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the safety and tolerability of cobitolimod.
• To evaluate the efficacy of cobitolimod treatment compared to placebo in clinical remission, clinical response and clinical symptoms.
• To evaluate the efficacy of cobitolimod treatment compared to placebo in endoscopic and histological remission and response.
• To evaluate the effect of cobitolimod on quality of life (QOL).
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female ≥ 18 years of age
2. Established diagnosis of UC, with minimum time from diagnosis of ≥3 months
3. Moderately to severely active left sided UC (disease should extend 15 cm or more above the anal verge and not beyond the splenic flexure) determined by a Modified Mayo score (excluding the friability at grade 1 for the endoscopic sub score) of 6 to 12 with an endoscopic sub score ≥2 assessed by central reading of endoscopy performed at screening visit 1b, and no other individual sub score <1
4. Current oral 5-ASA/SP use or a history of oral 5-ASA/SP use
5. Current GCS use or history of GCS dependency, refractory, or intolerance, including no GCS treatment due to earlier side-effects (only one of the GCS criteria have to be fulfilled, see definition in European Crohn´s and Colitis organisation (ECCO) guidelines)
6. Demonstrated an inadequate response, loss of response, or intolerance to at least one of the following agents:
• Immunomodulators, e.g. cyclosporine, methotrexate, AZA/6-MP, tacrolimus
o For example,signs and symptoms of persistently active disease despite previous treatment with at least one 8 week regimen of oral AZA (≥1.5 mg/kg) or 6-MP (≥0.75 mg/kg) or lower doses prompted by intolerance or thiopurine methyltransferase (TPMT) deficiency or
o For example, previous intolerance (including, but not limited to, nausea/vomiting, abdominal pain, pancreatitis, liver function test (LFT) abnormalities, lymphopenia, TPMT genetic mutation, infection) to at least one immunomodulator
• TNF-α inhibitors and anti-integrins:
o Signs and symptoms of persistently active disease despite previous treatment with at least one induction regimen with 2 doses at least 2 weeks apart (or doses as recommended according to the current labels) of for e.g.:
Infliximab 5 mg/kg (intravenous (IV)) or
Golimumab 200/100 mg (subcutaneous (SC)) or
Adalimumab 160/80 mg (SC) or
Vedolizumab 300 mg (IV) or
o History of intolerance (including but not limited to infusion-related reaction, demyelination, congestive heart failure, infection)
Recurrence of symptoms during maintenance dosing with any of the above medications following prior clinical benefit, (secondary failure) [discontinuation despite clinical benefit does not qualify].
7. Allowed to receive a therapeutic dose of following UC drugs during the study:
a) Oral GCS therapy (≤20 mg prednisone or equivalent/daily) providing that the dose has been stable for 2 weeks prior to visit 1a
b) Oral MMX Budesonide therapy (9mg/daily) initiated at least 8 weeks before visit 1 a.
c) Oral 5-ASA/SP compounds, providing that the dose has been stable for 2 weeks prior to visit 1a and initiated at least 8 weeks before visit 1a
d) AZA/6-MP providing that the dose has been stable for 8 weeks prior to visit 1b and been initiated at least 3 months before visit 1a
8. Ability to understand the treatment, willingness to comply with all study requirements and ability to provide informed consent |
|
| E.4 | Principal exclusion criteria |
1. Suspicion of differential diagnosis such as; Crohn’s enterocolitis, ischaemic colitis, radiation colitis, indeterminate colitis, infectious colitis, diverticular disease, associated colitis, microscopic colitis, massive pseudopolyposis or non-passable stenosis
2. Acute fulminant UC and/or signs of systemic toxicity
3. UC limited to the rectum (disease which extend <15 cm above the anal verge)
4. History of malignancy, except for:
• Treated (cured) basal cell or squamous cell in situ carcinoma
• Treated (cured) cervical intraepithelial neoplasia or carcinoma in situ of the cervix with no evidence of recurrence within the previous 5 years prior to the screening visit 1a
5. History or presence of any clinically significant disorder that, in opinion of the investigator, could impact on patient’s possibility to adhere to the protocol and protocol procedures or would confound the study result or compromise patient safety
6. Concomitant treatment with cyclosporine, methotrexate, tacrolimus TNF-α inhibitors, anti-integrins or similar immunosuppressants and immunomodulators at enrolment. Any prior treatment with such drugs must have been discontinued at least 8 weeks prior to visit 1a or have non-measurable serum concentration levels
7. Treatment with rectal GCS, 5-ASA/SP or tacrolimus within 2 Weeks before visit 1b
8. Long term treatment with antibiotics or non-steroidal anti-inflammatory drugs (NSAIDs) within two weeks prior to visit 1a (one short treatment regime for antibiotics and occasional use of NSAIDS are allowed)
9. Serious active infection
10. Gastrointestinal infections including positive Clostridium difficile stool assay
11. Currently receiving parenteral nutrition or blood transfusions
12. Females who are lactating or have a positive serum pregnancy test during the screening period
13. 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
14. Concurrent participation in another clinical study with investigational therapy or previous use of investigational therapy within 5 half-lives and within at least 30 days after last treatment of the experimental product prior to enrolment.
15. Previous exposure to cobitolimod |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of patients with clinical remission at Week 6, defined by Modified Mayo sub scores; i) rectal bleeding of 0, ii) stool frequency of 0 or 1 (with at least one point decrease from Baseline, Week 0), and iii) endoscopy score of 0 or 1 (excluding friability). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• Proportion of patients with symptomatic remission at Week 6, defined by the Mayo sub scores, i) rectal bleeding of 0, ii) stool frequency of 0 or 1 (with at least one point decrease from Baseline, Week 0), (patient reported outcome) [PRO2]
• Proportion of patients with absence of rectal bleeding at Week 6, defined by the Mayo sub score rectal bleeding of 0
• Proportion of patients with normal or enhanced stool frequency at Week 6, defined by the Mayo sub score stool frequency of 0 or 1 (with at least one point decrease from Baseline, Week 0)
• Proportion of patients with endoscopic remission at Week 6, defined by the Modified Mayo endoscopic sub score of 0 or 1 (excluding friability)
• Proportion of patients with histological remission at Week 6, defined by the Nancy histological index of grade 0 or 1
• Proportion of patients with complete histological remission at Week 6, defined by the Nancy histological index grade of 0
• Proportion of patients with histological response at Week 6, defined by the Nancy histological index score of ≤2 (if 2 then with at least one point decrease from Baseline,
Week 0)
• Proportion of patients with endoscopic and histological remission at Week 6
• Proportion of patients with symptomatic remission at Week 4, defined by the Mayo sub scores, i) rectal bleeding of 0, ii) stool frequency of 0 or 1 (with at least one point decrease from Baseline, Week 0), (patient reported outcome) [PRO2]
• Proportion of patients with absence of rectal bleeding at Week 4, defined by the Mayo sub score rectal bleeding of 0
• Proportion of patients with normal or enhanced stool frequency at Week 4, defined by the Mayo sub score stool frequency of 0 or 1 (with at least one point decrease from Baseline, Week 0)
• Proportion of patients with modified clinical remission at Week 6, defined by the Modified Mayo score ≤ 2 and sub scores, i) rectal bleeding of 0, ii) stool frequency of 0 or 1 (with at least one point decrease from Baseline, Week 0), iii) endoscopy score of 0 or 1 (excluding friability ) and iiii) physician´s global assessment (PGA) of 0 or 1
• Proportion of patients with durable symptomatic remission, defined by the Mayo sub scores, i) rectal bleeding of 0, ii) stool frequency of 0 or 1 (with at least one point decrease from Baseline, Week 0) [PRO2] at both Week 6 and Week 10
• Proportion of patients with clinical response at Week 6, defined as clinical remission or a three point and ≥30 % decrease from Baseline, Week 0 in the sum of the Modified Mayo score, i) rectal bleeding, ii) stool frequency and iii) endoscopy score (excluding friability), iiii) physicians global assessment (PGA)
• Proportion of patients with a defecation urgency score of 0 or a decrease of at least one point in defecation urgency at Week 6 compared to Baseline, Week 0
• Mean change in faecal calprotectin at Week 1, 2, 3, and 6 compared to Baseline,
Week 0
• Mean change in steroid dosage for patients in remission at Week 6 to Week 10
• Mean change in each of the inflammatory bowel disease questionnaire (IBDQ) sub domains at Week 6 compared to Baseline, Week 0 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 68 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Czech Republic |
| France |
| Germany |
| Hungary |
| Italy |
| Poland |
| Romania |
| Russian Federation |
| Serbia |
| Spain |
| Sweden |
| Ukraine |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 8 |
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