| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Acute mild to moderate ulcerative colitis. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Acute mild to moderate ulcerative colitis. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10066678 |
| E.1.2 | Term | Acute ulcerative colitis |
| E.1.2 | System Organ Class | 100000004856 |
|
| 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 |
This is a proof of concept placebo-controlled study to determine the efficacy and safety of 3 dose groups of K(D)PT in patients with acute mild to moderate ulcerative colitis.
The primary objective is to determine the time to response to K(D)PT, defined as the time from Day 0 to the earliest treatment visit at which a sustained improvement in CAI of ≥50% is determined (CAI scored according to Rachmilewitz, 1989). |
|
| E.2.2 | Secondary objectives of the trial |
To determine:
• remission at Weeks 4, 8 and 12, defined as CAI ≤3
• response at Weeks 4, 8 and 12, defined as an improvement in CAI of ≥50% from Day 0
• improvement in CAI during the (total) treatment period defined as the area under the curve of CAI values from Day 1 until Week 8.
• response at Week 8, defined as a decrease from baseline in Disease Activity Index (DAI) of 30% or more
• response at Week 8, defined as a change from baseline in endoscopy index (EI) of >1.5
• endoscopic remission, defined as flexible proctosigmoidoscopy score of 0 to 1 at Week 8.
• the improvement in faecal calprotectin concentration from baseline to Weeks 4, 8, and 12.
• the improvement in C-reactive protein (CRP) from baseline to Weeks 4, 8, and 12.
• the improvement in the score for Inflammatory Bowel Disease Questionnaire (IBDQ) from baseline to Weeks 8 and 12.
• the incidence of adverse events (AEs) throughout the study. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Provide written informed consent, i.e. they must be willing and able to comply with the study procedures.
2. Adult males or females, aged 18 to 70 years (inclusive).
3. Females of childbearing potential must have a negative urine pregnancy test at screening and must agree to use adequate contraception (e.g. oral, depot or implanted hormonal contraception, intrauterine device, surgical sterilisation, partner vasectomy, or double-barrier method) from screening visit until at least 4 weeks after last dose of study medication (Week 12). A double
barrier method means condom and occlusive cap (diaphragm or cervical/vault caps) with
spermicidal foam, gel, film, cream, or suppository. A female condom and a male condom should
not be used together as friction between the two can result in either product failing.
4. Females of non-child bearing potential should be postmenopausal for >1 year or permanently sterilised (e.g. tubal occlusion, hysterectomy, bilateral salpingectomy).
5. Male patients must agree to use adequate contraception (e.g. vasectomy or adequate partner contraception).
6. Body mass index (BMI) ≥19 and ≤30 kg/m2.
7. Mild to moderately active UC proven by endoscopy and criteria according to European Crohn's and Colitis Organisation (ECCO) guidelines and defined as a CAI of 6 to 12.
8. Pre-treatment of active ulcerative colitis with any of the following:
- a stable dose of oral mesalazine, sulphasalazine or olsalazine for >4 weeks (oral), and/or
- a stable dose of azathioprine or 6-mercaptopurin for >3 months, and/or
- a stable dose of oral corticosteroids of ≤20 mg oral prednisolone or equivalent for >2 weeks before baseline (Visit 2).
|
|
| E.4 | Principal exclusion criteria |
1. Pregnant, planning to become pregnant during the study, or breast feeding females.
2. Previous participation in any clinical study with K(D)PT.
3. Crohn’s disease.
4. Treatment-naive.
5. Infectious diarrhoea within the screening period (up to 14 days prior to randomisation [Visit 2]),
after randomisation or during the treatment period.
6. Indeterminate colitis.
7. Significantly impaired liver, renal, pulmonary or cardiovascular function.
8. Use of systemic or topical gastrointestinal antibiotics within 4 weeks before or during the treatment period (Day 1).
9.Use of E. coli Nissle within 4 weeks before or during the treatment period.
10. Previous use of cyclosporine, anti-TNF therapy (e.g. infliximab) or tacrolimus at any time.
11. Any rectal therapy four weeks before or during the treatment period.
12. Use of corticosteroids >20 mg oral prednisolone or equivalent.
13. Use of methotrexate within 3 months before or during the treatment period.
14. Use of anti-diarrhoeal drugs within 2 weeks before or during the treatment period.
15. Effective anti-coagulation therapy (e.g. Marcumar) or severe grade coagulation defects.
16. Any clinically relevant abnormal findings at screening, vital signs or ECG which, in the opinion of the investigator, may put the patient at risk because of his or her participation in the study. Patients must have undergone colonoscopy for dysplasia screening according to local guidelines
before randomisation.
17. History of any clinically significant disease or disorder which, in the opinion of the investigator, may either put the patient at risk because of participation in the study, or could influence the results, or the patient’s ability to participate in the study.
18. History of or current alcohol or drug abuse, as judged by the investigator.
19. Participation in another investigational drug study within 3 months before first administration of study medication.
20. Donation of blood within 3 months, or donation of plasma within 2 weeks, before the first administration of study medication. Planned donation of blood, plasma or sperm at any time
during the study (from the start of screening until the follow-up visit).
21. Proctitis (≤5 cm).
22. QTcF >450 ms or <350 ms or QT >500 ms or other relevant ECG abnormality as judged by the investigator.
23. History of major pathological skin condition or melanoma within the previous 5 years.
24. Known intolerance to methylparaben or propylparaben.
25. Known intolerance to any other excipient of the investigational medicinal product (IMP).
26. Positive history of hepatitis B and/or C and/or history of human immunodeficiency virus (HIV).
27. Planned surgery or hospitalisation during the study.
28. Patients who, in the opinion of the investigator, should not participate in the study.
29. Patients unable to understand informed consent. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is the time to sustained response to study medication, where response is defined as an improvement in CAI of ≥50% from Day 0 (CAI scored according to Rachmilewitz, 1989). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Week 2, week 4, week 6, week 8 and week 12 |
|
| E.5.2 | Secondary end point(s) |
• Frequency of remission, defined as CAI ≤3 (CAI scored according to Rachmilewitz, 1989), at Weeks 4, 8 and 12.
• Response to study medication at Weeks 4, 8 and 12, where response is defined as an improvement in CAI of ≥50% (CAI scored according to Rachmilewitz, 1989).
• Area under the curve for the change from baseline in CAI scores during the (total) treatment period from Day 1 until Week 8
• Frequency of response rates at Week 8 with response defined as decrease from baseline in DAI of 30% or more
• Frequency of response rates at Week 8 with response defined as change from baseline in EI of >1.5
• Frequency of patients with endoscopic remission
• Change from baseline to Weeks 4, 8, and 12 in faecal calprotectin concentrations.
• Change from baseline to Weeks 4, 8, and 12 in CRP concentrations.
• Change from baseline to Week 8 and 12 in IBDQ scores. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Varies between day 1 to week 12. |
|
| 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 | No |
| 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 | Yes |
| 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 | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 40 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| 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 | |
| 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 | 6 |
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