| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Crohn's disease and Ulcerative colitis |
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| E.1.1.1 | Medical condition in easily understood language |
| Crohn's disease and Ulcerative colitis |
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| 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 | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10045365 |
| E.1.2 | Term | Ulcerative colitis |
| E.1.2 | System Organ Class | 10017947 - Gastrointestinal disorders |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10013099 |
| E.1.2 | Term | Disease Crohns |
| E.1.2 | System Organ Class | 10017947 - Gastrointestinal disorders |
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| 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 assess if a top-down treatment can improve treatment outcomes in IBD patients with a high risk of poor disease course, defined by a serum protein signature at diagnosis.
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| E.2.2 | Secondary objectives of the trial |
| To assess if a top-down treatment is safe and can improve quality of life and health resource allocation in IBD patients with a high risk of poor disease course, defined by a serum protein signature at diagnosis. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
To be included in the study, the study subject must meet the following criteria:
• UC or CD diagnosed within < 4 weeks using standard endoscopic, histologic or radiological criteria (ECCO Criteria) Histology report may not be available at baseline.
• Naïve to immunomodulators, biologics and small molecules, i.e. JAK-inhibitors at the baseline visit.
• Aged 18-70 years old.
• Is considered eligible according to tuberculosis (TB) screening criteria.
• Written informed consent to participate in the study
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| E.4 | Principal exclusion criteria |
Study subjects may not be included in the study if any of the following criteria are met:
• A previous known diagnosis of Crohn’s disease, ulcerative colitis or IBD-U, since >6 weeks before baseline
• Unable to provide informed consent
• Unable to comply with protocol requirements (e.g. for reasons including alcohol and/or recreational drug abuse)
• Ongoing sepsis
• Acute obstructive symptoms AND evidence of a fixed stricture on radiology or colonoscopy, which suggest that the patient is in need of surgery over the following year. N.B. patients with modest degrees of stricturing on imaging but no obstructive symptoms may be included according to clinician judgement
• Contra-indications to trial medications including a history of hepatitis B or C, tuberculosis, Cardiac failure, NYHA III-IV or hypersensitivity. Hypersenstitivity to a thiopurine agent should alert the prescriber to probable hypersensitivity to other thiopurines.
• History of malignancy
• Pregnancy
• Other serious medical or psychiatric illness
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Co-Primary Endpoints
Proportion of subjects with corticosteroid-free clinical remission and endoscopic remission at Week 52, defined as below. Surgery because of IBD during follow-up will be defined as treatment failure.
Ulcerative colitis
Clinical remission per patient reported Mayo: A stool frequency subscore (SFS) ≤ 1, and not greater than baseline, and a rectal bleeding subscore (RBS) of 0
Endoscopic remission: An endoscopic Mayo subscore of 0 (OR in patients without endoscopy at week 52, normalization of f-Calprotecin, defined as < 250μg/g (EK-Cal, Bühlmann Laboratories, Switzerland).
Crohn’s disease
Clinical remission: An average daily Stool Frequency (SF) ≤ 2.8 and not worse than Baseline AND average daily Abdominal Pain (AP) score ≤ 1 and not worse than Baseline.
Endoscopic remission: SES-CD≤2 (OR in patients without endoscopy at week 52, normalization of f-Calprotecin, defined as < 250μg/g (EK-Cal, Bühlmann Laboratories, Switzerland).
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
1. Clinical remission at 52 weeks
2. Endoscopic remission at 52 weeks
3. Clinical response:
Ulcerative colitis: A decrease from baseline in the adapted Mayo score by ≥30% or ≥2 points, with either a decrease from baseline in the rectal bleeding subscore ≥1 or an absolute rectal bleeding subscore ≤1 (range, 0 to 9, with higher scores indicating more severe disease).
Crohn’s disease: ≥ 30% decrease in average daily SF and/or ≥ 30% decrease in average daily AP score and both not worse than Baseline.
4. Endoscopic response:
Ulcerative colitis: An endoscopic Mayo subscore of ≤1 (OR in patients without endoscopy at week 52, a reduction of f-Calprotecin by ≥50% compared to baseline (EK-Cal, Bühlmann Laboratories, Switzerland).
Crohn’s disease: decrease in SES-CD > 50% from Baseline (or for a Baseline SES-CD of 4, at least a 2 point reduction from Baseline) (OR in patients without endoscopy at week 52, a reduction of f-Calprotecin by ≥50% compared to baseline (EK-Cal, Bühlmann Laboratories, Switzerland).
5. The proportion of patients with drug-related adverse events
6. Time to occurrence of the first major adverse outcome, defined as the composite of surgery or hospital admission for IBD, or development of a serious disease related complication (the individual components of this outcome will also be assessed independently). Serious complications were the occurrence of substantially worsening disease activity defined by:
• new abscess, fistula, or stricture among Crohn’s disease patients
• progression in disease extent among ulcerative colitis patients
• extra-intestinal manifestations, among patients with Crohn’s disease or ulcerative colitis
7. The cumulative glucocorticoid (measured as prednisolone equivalents) use over time through Week 52 (see appendix X for definition of prednisolone equivalents).
8. The change from baseline in CRP concentration over time through Week 52.
9. The change from baseline in faecal calprotectin concentration over time through Week 52.
10. The change from baseline in each of the 4 dimensions of the IBDQ at 52 weeks.
11. A >20-point improvement from baseline in the IBDQ score at 52 weeks.
12. The change from baseline for each of the 8 individual subscales of the SF-36 and the PCS and MCS scores at 52 weeks.
13. The changes from baseline in the EQ-5D dimensions, EQ-5D index, and health state VAS scores at 52 weeks.
14. Maintenance of clinical remission through Week 52 among the subjects who had achieved clinical remission at week 12.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| 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 | No |
| E.6.5 | Efficacy | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| 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 | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Same medicinal products but prescribed according to standard of care, as per clinical routine |
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| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
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