Lowering infliximab dose in IBD patients in remission, based on infliximab trough levels: the study on Lowering Infliximab in IBD patients in sustained Remission, the LIR study

Inflammatory bowel disease (IBD) is characterized by chronic inflammation of
the gastrointestinal tract. It comprises two distinct entities, Crohn*s disease
(CD) and ulcerative colitis (UC), which differ in type, site and extent of
inflammation, disease history and extraintestinal manifestations. The
pathogenesis is not fully understood but involves a chronic up-regulation of
the enteric mucosal immune system, reacting to intestinal bacterial flora.
IBD is a common disease with an incidence similar to that of diabetes mellitus
type I and epilepsy. The incidence of IBD has been rising over the last few
decades, which in the context of the absence of dramatic changes in the genetic
make-up of the population further supports a non-genetic life-style-associated
influence on disease course. Notably, a marked increase in incidence has been
described in young CD patients. In The Netherlands a further 7% growth in the
prevalence of IBD is expected in the coming decade. Currently, approximately
80.000 Dutch patients have been diagnosed with IBD and thus IBD is a serious
health problem.
The management of IBD aims to induce rapid and sustained disease remission. In
current guidelines a step up approach is advised, starting with the least
effective and simultaneously least toxic medication. Currently, mesalazine is
the initial treatment for mild-to-moderate UC and CD. After failing this
regimen corticosteroids and immunosuppressives are then initiated. Finally, at
the top of the pyramid of therapeutic strategies for IBD, anti-TNFα is
currently widely established for both CD and UC patients. In our DELTA1 cohort
50% of the newly diagnosed IBD patients received anti-TNF treatment within 18
months of diagnosis. This anti-TNF treatment is associated with high costs and
we recently showed that healthcare costs are mainly driven by medication costs,
most importantly by anti-TNFα therapy2. Hospitalization and surgery accounted
only for a minor part of the healthcare costs. Furthermore infliximab is
associated with adverse events that might be a burden for patients but also
adds to healthcare costs.
To enhance an optimized cost-effectiveness use of anti-TNF there are several
needs:
1. A decision analytical model for the initiation anti-TNF, which we currently
investigate (ZonMw projectnumber: 80-83600-98-10002).
2. New strategies for cost-effective use of anti-TNF for patients in which
starting anti-TNF is indicated. We are currently investigating whether
adjusting to infliximab level is more effective compared to clinical based
adjustment in IBD patients naïve for anti-TNF (TAILORIX from the Getaid Group,
principal investigator dr D*Haens of the AMC).
3. Strategies for patients with loss of response. It is published by Steenholdt
et al3 that treatment of secondary IFX failure using an algorithm based on
combined IFX and IFX antibody measurements significantly reduces average
treatment costs per patient compared with routine IFX dose escalation and
without any apparent negative effect on clinical efficacy.
4. Strategies for IBD patients in long-term remission and on infliximab (which
at the moment is the largest group). Louis et al4 performed a prospective stop
study of 115 patients with Crohn's disease who were treated for at least 1 year
with scheduled infliximab and an antimetabolite and had been in
corticosteroid-free remission for at least 6 months. Infliximab was stopped,
the 1-year relapse rate in this study was 43.9% ± 5.0%. Risk factors for
relapse included male sex, the absence of surgical resection, leukocyte counts
>6.0 × 10(9)/L, and levels of hemoglobin <=145 g/L, C-reactive protein >=5.0
mg/L, and fecal calprotectin >=300 µg/g. Patients with no more than 2 of these
risk factors (approximately 29% of the study population) had a 15% risk of
relapse within 1 year.

Not all patients are suitable for this stopping regimen and as we experienced
in the Netherlands with the failing of the infliximab stop trial (AMC, AZORIX
trial, ZonMw grant) most patients are very reluctant to stop infliximab
treatment. Recently the results of the TAXIT study from Leuven have been
presented at the UEGW Berlin. This study did not show difference in remission
rates when IBD patients on IFX maintenance and in stable remission where dosed
based on clinical symptoms or based on IFX levels with regards to the primary
endpoint which was the rate of clinical and biological remission.

Where previous studies have found that increasing the dose (or shortening the
dosing interval) of infliximab in patients with subtherapeutic infliximab serum
levels results in clinical response to therapy, we aim to investigate the
feasibility of the opposite strategy: to reduce the infliximab dose in IBD
patients with supratherapeutic infliximab levels. A study in patients with
rheumatoid arthritis showed that it was feasible to lower infliximab with
sustained clinical effect and also showed that lowering from 5 mg/kg inflximab
to 3 mg/kg decreased the trough levels significantly to levels accepted in
rheumatology5.
As such, we propose to lower the infliximab dose from 5 mg/kg to 3 mg/kg in IBD
patients in sustained remission (>12 months) and infliximab trough levels of 7
µg/mL or higher.

In short, the objective of our study *Lowering infliximab dose in IBD patients
in remission, based on infliximab trough levels: the study on Lowering
Infliximab in IBD patients in sustained Remission, the LIR study* is to assess
the number of patients in remission, 12 months after dose adjustment of IFX
from 5mg/kg to 3 mg/kg. Secondary objectives include: number of relapses,
defined by increase of fecal calprotectin and/or CRP and clinical activity,
subsequently confirmed by endoscopy, in infliximab treated patients with and
without dose adjustments, and the number of patients in remission at 12 months.

To assess the number of patients in remission, 12 months after dose adjustment
of IFX from 5mg/kg to 3 mg/kg.
Secondary objectives include: number of relapses, defined by increase of fecal
calprotectin and/or CRP and clinical activity, subsequently confirmed by
endoscopy, in infliximab treated patients with and without dose adjustments,
and the number of patients in remission at 12 months.

Multi center, non-randomized, patient blind prospective trial, with a maximum
follow-up time of 64 weeks

Infliximab dose reduction in patients with high trough levels

Patients treated with infliximab regularly visit the hospital for their drug
infusions. No additional visits are required for this pilot, minimizing patient
burden. During these visits, additional blood samples will be taken, which
increases patient burden.
The most relevant patient benefit is reduced exposure to IFX, which is likely
to reduce the formation of a-IFX, leading to prolonged successful IFX treatment.
The most relevant risk for patients is an increased relapse rate when IFX dose
reduction occurs.