E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Crohn´s disease
Ulcerative colitis |
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E.1.1.1 | Medical condition in easily understood language |
Crohn´s disease
Ulcerative colitis |
Crohns sjukdom
Ulcerös kolit |
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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 |
The aim is to identify clinical and biological markers that offer guidance as to which patients successfully may discontinue maintenance anti-TNF treatment, and which patients on the contrary need to continue treatment over an extended period of time in order to remain in remission. |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
For patients with ulcerative colitis:
• Diagnosis: Ulcerative colitis
• Age 18-80 years.
• Male or female.
• IFX or ADA treatment since >12 months; last 3 doses at the same dose and interval. If the patient is on a biosimilar-infliximab the patient must have received at least 3 doses, and at the same dose and interval.
• SCCAI score of ≤3.
• Endoscopic Baron score of 0-1. The most inflamed part in the rectum/ sigmoid colon is evaluated. A minimum of 40 cm of the colon should be examined.
For patients with Crohn's disease:
• Diagnosis: Crohn's disease
• Age 18-80 years.
• Male or female.
• IFX or ADA treatment since >12 months; last 3 doses at the same dose and interval. If the patient is on a biosimilar-infliximab the patient must have received at least 3 doses, and at the same dose and interval.
• Simplified HBI (sHBI; abdominal palpation excluded) score of ≤4.
• Simplified Endoscopic Score for CD (SES-CD) of ≤4 and no ulcer ≥5 mm other than a potential anastomotic ulcer (ie apthous ulcers allowed).
• F-calprotectin <200 mg/kg (PhiCal) or <350 mg/kg (Buhlmann).
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E.4 | Principal exclusion criteria |
For patients with ulcerative colitis:
• Corticosteroid (rectal or systemic) or rectal 5-ASA treatment during the last 6 months.
• Colonic resection.
• Pregnancy.
For patients with Crohn's disease:
• Documented engagement/inflammation of the small bowel proximally of a level of 50 cm from the ileocecal valve. Any examination modality is accepted, and a current/new small intestinal examination is not required. A limited number of small (<5 mm) lesions on capsule endoscopy allowed.
• Corticosteroid (rectal or systemic) or rectal 5-ASA treatment during the last 6 months.
• Colonic surgery with removal of more than half of the transverse colon.
• Pregnancy.
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E.5 End points |
E.5.1 | Primary end point(s) |
The proportion of patients that relapses, as defined by symptomatic scoring in combination with endoscopy, at 12 and 24 months after discontinuation of anti-TNF treatment with identification of factors at study-start that correlate positively or negatively with the event of relapse. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
time-points 12 and 24 months |
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E.5.2 | Secondary end point(s) |
• Endoscopic scores at 12 and 24 months among those who relapsed compared to those who remained in remission.
• Fecal calprotectin levels at 12 and 24 months among those who relapsed compared to those who remained in remission.
• Fecal calprotectin levels at study start among ulcerative colitis patients who relapsed compared to those who remained in remission.
• The rate of relapse among ulcerative colitis patients with the following fecal calprotectin level ranges (<30 mg/kg for Calpro [C] and <60 mg/kg for Buhlmann [B]; 30-99 mg/kg C and 60-199 mg/kg B; 100-299 mg/kg C and 200-599 mg/kg B; ≥300 mg/kg C and ≥600 mg/kg B.
• The optimal fecal calprotectin level cut-off with regards to sensitivity and specificity for relapse, for ulcerative colitis and Crohn's disease patients, respectively.
• Trough concentrations of infliximab and adalimumab among those who relapsed compared to those who remained in remission.
• The rate of relapse among those with undetectable infliximab or adalimumab trough concentrations, those with 0.5-2.9 ug/ml, 3.0-7.0 ug/ml, >7.0 ug/ml for infliximab, and ≥10.0 ug/ml for adalimumab.
• The optimal trough concentration cut-off with regards to sensitivity and specificity for relapse, for infliximab and adalimumab, respectively.
• Area under the infliximab or adalimumab concentration curve during the last therapy cycle among those who relapsed compared to those who remained in remission.
• Presence of anti-drug antibodies among those who relapsed compared to those who remained in remission.
• The rate of relapse among those with anti-drug antibodies versus those without.
• Time to relapse among those who relapse, comparing ADA versus IFX treated and UC versus CD.
• The level of gut microbiota dysbiosis among those who relapsed compared to those who remained in remission.
• The rate of relapse among those with a dysbiosis score of 1, 2-3, and 4-5, respectively.
• Correlation analyses of genes showing high versus low expression in mucosal biopsies and blood samples, with the event of relapse.
• Correlation analyses of gene-variants with the event of relapse.
• Additional factors that will be correlated with relapse rates: Endoscopic scores (Baron score 0 versus 1 for UC and SES-CD 0-1 versus 3-4 for Crohn's disease); corticosteroid use between 12 and 6 months before baseline; previous anti-TNF treatment; dose intensification of anti-TNF treatment; mono- versus concomitant immunomodulator-treatment; previously maximal inflammatory extent (Montreal classification); disease duration (<2 years, <5 years, <10 years, >10 years); extraintestinal manifestations; gender; smoking; hemoglobin; white blood cell count; platelet count; CRP; and histology/immunohistochemistry (basal plasmocytosis and numbers of different leukocyte and lymphocyte subpopulations).
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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 | No |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
Therapy de-escalation |
Terapiutsättning |
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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 | No |
E.8.1.1 | Randomised | No |
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 | No |
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 | 23 |
E.8.5 | The trial involves multiple Member States | No |
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 | 4 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |