| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Luminal Crohn’s disease patients with steroid free remission for at least 6 months and a combination therapy with infliximab and anti-metabolites for at least 8 months |
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| E.1.1.1 | Medical condition in easily understood language |
| Luminal Crohn’s disease patients with steroid free remission for at least 6 months and a combination therapy with infliximab and anti-metabolites for at least 8 months |
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| E.1.1.2 | Therapeutic area | Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Therapeutic techniques [E02] |
| 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 |
|
| 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 in the three groups. To assess time spent inclinical remission. To assess the rate of treatment failure in the study groups. To assess the time to treatment failure in the study groups. To assess progression of bowel damage in the groups. To assess the safety and efficacy of infliximab retreatment in the antimetabolites group.To assess safety in the study groups. To assess the health related quality of life in the study groups. To assess direct and indirect costs in the study groups. To assess evolution of blood CRP and fecal calprotectin in the study groups. To assess evolution of infliximab trough levels and ATI in the 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 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Signed informed consent
• 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 3 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.
• Use of highly effective contraception (Pearl-Index < 1) to prevent pregnancy in women of childbearing potential.
• Patients able to understand the information provided to them and to give written informed consent for the study |
|
| 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
• Steroid use ≤6 months prior to screening
• Currently receiving steroids, immunosuppressive agents (other than purine, methotrexate), biologic
treatment (other than infliximab) or thalidomide
• 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
• Steroid use ≤6 months prior to screening
• Currently receiving steroids, immunosuppressive agents (other than purine, methotrexate), biologic treatment (other than infliximab) or thalidomide
• Patients, who are institutionalized by order of a court or a government agency
• Patients, who are employees of the sponsor, the study site, or the study personnel or in any other way dependent from them
• Risk of acute or latent tuberculosis
The risk has to be assessed by the investigator in accordance with the Summary of Product Characteristics (SmPC, “Fachinformation”). The investigator has to make sure that the recommendations from the SmPC have been followed before the initiation of treatment with infliximab. Patients that cannot be enrolled include
o Patients with any clinical signs or diagnostic imaging suggestive of active tuberculosis.
o Patients with a history or diagnostic tests suggestive of latent tuberculosis
- Patients with a positive interferon-gamma release assay or Mendel-Mantoux test
- Patients with a Chest X-ray suggestive of a history of tuberculosis
- Patients with possible previous contact with tuberculosis, in whom active or untreated latent tuberculosis cannot be ruled out, or a personal history of tuberculosis
Patients with previous latent tuberculosis are not excluded if a treatment for latent tuberculosis had been started at least one month earlier and no new exposure to tuberculosis has occurred in the meantime.
• Hypersensitivity to infliximab, to other murine proteins, or to any of the excipients included in Remicade®, Remsima® or Inflectra®
• severe infections such as sepsis, abscesses, and opportunistic infections
• moderate or severe heart failure (NYHA class III/IV) |
|
| 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)
- An episode of intestinal obstruction due to Crohn’s lesions confirmed by medical imaging and requiring
hospitalisation (also considered as treatment failure, see below)
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 will be summed up within the two first years.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| 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
perianal abscess and the occurrence 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 wil be assessed according to Ring et Messmer classification (6).
- Tissue damage progression will be assessed by the Lémann Score absolute and relative change between
baseline and end of the study (2 years).
- Other secondary judgement criteria: CDEIS/SES-CD, MaRIA score, CDMRIS, 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 health scale, EQ-5D.
|
|
| 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 | 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 | 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| 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 |
| Australia |
| France |
| Germany |
| Netherlands |
| Sweden |
| United Kingdom |
|
| 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 | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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