difficulty of inclusion

Comparison of trough level-based spacing and clinical-based spacing of infliximab infusions in patients with inflammatory bowel disease in deep remission A prospective, multicenter, open-label, randomized, controlled Study

Infliximab (IFX) is common treatment for refractory inflammatory bowel disease (IBD) (5 mg/kg/8 weeks in maintenance). A large majority of IBD patients treated with IFX are currently in long-term clinical remission under maintenance IFX monotherapy or cotherapy with azathioprine or methotrexate. There is no recommendation on optimal duration of anti-TNF therapy once it is started. A key question is to know if the treatment could be stopped/decreased without clinical relapse. Anti-TNF therapy is also a major burden in health care costs in France. Identifying an optimal duration of anti-TNF therapy and criteria for stopping/decreasing could help in lowering these therapies cost without altering disease control. Prospective studies have investigated the withdrawal of IFX in IBD patients showing 50% of clinical relapse at 1 year in patient in clinical remission, 30% in patients in deep remission.

Another alternative to deescalate anti-TNF treatment would be to increase the infusion interval without stopping the drug. Indeed, this infusion interval spacing is strongly requested by patients who seek an improvement in their quality of life. This empirical spacing corresponded to an increase of the infusion interval to 10 weeks then to 12 weeks maximum in patients with persistent clinical remission. In France and in Europe, even if there is no recommendation about infliximab de-escalation and increase of the infusion interval, many physicians have already performed empirically an infliximab infusion interval spacing in IBD patients in longstanding remission while on infliximab maintenance therapy. This empirical infusion interval increase in patients in clinical remission leads to a clinical relapse in 30% of these patients with a median delay of 12.6 months (IQR: 10.4- 18.4) (Dufour et al. UEGW 2017).

Since the last ten years, it was demonstrated that the serum level of infliximab measured just before the last infliximab infusion (defined as a trough level) is correlated to the clinical activity of the disease1. A serum IFX trough level between 3 and 7 ug/ml has been identified as therapeutic with more clinical relapse in patients with IFX < 3 ug/ml and safe dose reduction in patients with IFX trough level > 7 ug/ml.

Thus, we hypothesized that using the determination of serum infliximab trough level could decrease the risk of clinical relapse observed in IBD patients who underwent an empirical infliximab infusion interval spacing (approximatively 30% of the cases). Indeed, in an infliximab trough level-based spacing strategy, only patients with a supratherapeutic (>7ug/ml) infliximab trough level would have a spacing of infliximab infusion.

The aim of our study is to compare an IFX infusion interval spacing strategy based on IFX trough level with an IFX infusion interval spacing strategy based on clinical evaluation for maintaining clinical and biological remission in IBD patients in deep remission.

Inclusion Criteria:

• Age greater than 18 years

  • Patients with a diagnosis of Crohn's disease or ulcerative colitis according to clinical, biological, morphological and endoscopic criteria defined by the ECCO guidelines22, 23

  • Patients in deep remission since at least 6 months17:

    • CDAI < 150 for CD, Partial Mayo score < 3 for UC
    • CRP (C reactive protein) < 10 mg/l
    • CDEIS < 6 (<3 in each segment) for CD, Mayo endoscopic subscore of 0 or 1 for UC
    • For CD patients with small bowel disease: No ulceration on MRI, only asymptomatic fibrotic stenosis without inflammation and retro dilatation. No ulceration on wireless capsule endoscopy if feasible
    • For patients with perianal disease: No active draining fistula, or perianal abscess on clinical exam and MRI

  • Treatment with infliximab at stable dose (5mg/kg) with a stable interval for at least 4 months

  • Infliximab trough level > 3 ug/ml

  • No change in other IBD therapies in the past 4 months

  • Signed informed consent form

  • Subjects must be able to attend all scheduled visits and to comply with all trial procedures

  • Subjects must be covered by public health insurance

Exclusion Criteria:

• Subject unable to read or/and write

  • Planned longer stay outside the region that prevents compliance with the visit plan
  • Subject who are in a dependency or employment with the sponsor or the investigator
  • Participation in another clinical trial or administration of an unapproved drug within the last 4 weeks before the screening date
  • Previous withdrawal or spacing over 8 weeks of infliximab therapy
  • Infliximab therapy at 10 mg/kg
  • Patients who have presented a severe acute or delayed reaction to infliximab.
  • 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
  • Steroid use ≤3 months prior to screening