| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
| Crohn´s disease |
| Crohns sjukdom |
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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 |
| To assess the effect of two withdrawal strategies over two years in patients with stable remission for more than 6 months on combination therapy with infliximab and antimetabolites, and demonstrate that continued combination of infliximab and antimetabolites or continued monotherapy with infliximab are both superior to antimetabolites alone for maintaining sustained steroid-free clinical remission, while antimetabolites alone are non inferior with regards to the mean time spent in remission |
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| E.2.2 | Secondary objectives of the trial |
-To identify baseline predictive factors of relapse in the three study groups.
-To assess the ability of blood CRP and fecal calprotectin to predict short term relapse .
-To assess time spent in clinical remission.
-To assess endoscopic remission at baseline and end of study in the three groups
-To assess the rate of treatment failure.
-To assess the time to treatment failure.
-To assess progression of bowel damage.
-To assess the safety and efficacy of infliximab retreatment in the antimetabolites group.
-To assess safety.
-To assess the health related quality of life.
-To assess direct and indirect costs.
-To assess evolution of blood CRP and fecal calprotectin.
-To assess evolution of infliximab trough levels and ATI in the two infliximab scheduled maintenance groups.
-To assess genetic association with the various clinical and biological outcomes.
-To assess the impact of 6TGN levels on the various clinical and biological outcomes in the purine treated patients
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Diagnosis of Crohn’s disease.
Male or female, age > 18 years.
Currently treated with a combination therapy with infliximab and anti-metabolites for luminal Crohn’s disease.
Combined therapy with scheduled infliximab and anti-metabolites for at least 8 months.
Scheduled administration of infliximab 5 mg/Kg every 8 weeks over the last 4 months.
Antimetabolites administered at a stable dosage for the last 3 months: at least 1 mg/Kg or 2 mg/Kg for mercaptopurine and azathioprine, respectively, or the highest tolerated dosage if intolerance to standard dose (lower dose than standard dose is also allowed if 6 TGN > 235 pmol); at least 15 mg/week subcutaneously for methotrexate.
Patients in steroid free clinical remission for at least 6 months according to retrospective assessment of the patients’ files.
CDAI < 150 at baseline.
A contraceptive during the whole study
Patients able to understand the information provided to them and to give written informed consent for the study
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| E.4 | Principal exclusion criteria |
Patients who have presented a severe acute or delayed reaction to infliximab.
Perianal fistulae as the main indication for infliximab treatment
Active perianal/abdominal fistulae at time of inclusion, defined by active drainage
Patients with ostomy or ileoanal pouch
Pregnancy or planned pregnancy during the study
Inability to follow study procedures as judged by the investigator
Non-compliant subjects.
Participation in another therapeutic study
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| E.5 End points |
| E.5.1 | Primary end point(s) |
There will be two co-primary efficacy end points
Relapse rate at 2 years, relapse being defined by either one of the following events:
-A CDAI>250 at any visit or between 150 and 250 with an increase of at least 70 points, over two consecutive visits one week apart associated with a CRP > 5 mg/l or a fecal calprotectin > 250 microg/g
-A new opening fistula, perianal or entero-cutaneous.
-An intra-abdominal abcess (size of at least 3 cm) or perianal abcess (size of at least 2 cm) (also considered as treatment failure, see below)
-An episode of intestinal obstruction due to Crohn’s lesions confirmed by medical imaging and requiring hospitalisation (also considered as treatment failure, see below)
and
Mean restricted time spent in remission
This time will be computed in all patients, from baseline (CDAI <150 and with absence of fistula drainage) until relapse, as defined above, within the 2 first years. First and subsequent remissions (under the predefined treatment strategy according to randomization) will be summed up within the two first years.
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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) |
-Time to relapse in each arm.
-Factors associated with time to relapse.
-Time to relapse according to CRP and calprotectin value measured every 2 months over the follow up.
-Sustained clinical remission defined by CDAI<150 without steroids over two years.
-Treatment failure rate. Treatment failure is defined by not achieving remission after treatment adaptation following a relapse according to protocol (CDAI<150 or, in case of relapse defined by the occurrence of a new fistula, the absence of fistula closure, defined clinically by the persistence of an opened fistulous track and/or drainage upon gentle pressure). Treatment failure will also be defined by a major treatment side-effect leading to treatment cessation. The occurrence of an intra-abdominal or peri-anal abcess and the occurence of an intestinal obstruction due to Crohn’s lesions and requiring a surgical resection or an endoscopic dilatation are also directly considered as treatment failure and will not be managed by treatment adaptation according to protocol.
-Time to treatment failure.
-Incidence and severity of acute or delayed infliximab infusion reaction. Severity of the acute infusion reaction will be assessed according to Ring et al (6).
-Tissue damage progression will be assessed by the Lémann Score absolute and relative change between baseline and en of the study (2 years).
-Other secondary judgement criteria: CDEIS/SES-CD, disability index, adverse events and SAE, events related to re-infusions, trough levels of infliximab, ATI , hsCRP, fecal calprotectin, direct medical costs, work productivity and activity index, short IBDQ, SWE HRQoL, EQ-5D.
-Endoscopic remission at end of study. |
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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 | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| combination infliximab + azathioprine |
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| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 70 |
| 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 | 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
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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 | 5 |
| 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 | 5 |
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