Dose reduction of infliximab in Crohn's disease, based on serum infliximab concentration.

Rationale: Recent observations suggest that not all Crohn’s disease (CD) patients who are in stable remission with infliximab (IFX) maintenance therapy may need the recommended dose of 5 mg/kg, as long as IFX trough levels (TLs) (e.g. serum drug level measured just before the next administration) remain therapeutic.

Objectives: To evaluate the efficacy and safety of infliximab dose reduction guided by serial trough level measurements, compared to treatment as usual (no dose reduction), in Crohn’s disease patients who are in stable remission with infliximab maintenance therapy.

Study design: Single-blind prospective controlled randomized trial.

Study population: Patients with CD older than 18 years, at least 6 months in remission defined as a Harvey Bradshaw index (HBI) ≤4, normal serum C-reactive protein (CRP) level (< 5 mg/l) and low fecal calprotectin level (< 250 ug/g) who have received IFX therapy >6 months at 5 mg/kg every 8 weeks without dose adjustments. These patients are eligible if they have an IFX TL >7 μg/ml.

Intervention (if applicable): Patients in the intervention arm will undergo stepwise dose reduction of IFX. IFX dose will be decreased by 1 mg/kg, every 16 weeks. Dose reduction ends in case of one or more of the following:

-Relapse, defined as:

- Rise of ≥3 points (compared to baseline) of total HBI score to a value of >4 (clinical relapse) in combination with CRP >5 mg/l

- AND/OR calpro >250 measured at previous infusion visit

-AND/OR IFX TL <7 prior to the latest infusion.

Patients in the control arm will receive continued IFX at 5 mg/kg at an 8 week interval.

Main study parameters/endpoints:
PRIMARY ENDPOINT: Proportion of patients with sustained clinical remission.
SECONDARY ENDPOINTS: Proportion of patients with clinical and biochemical relapse; Time to relapse; Presence of predictive factors for successful IFX dose reduction with specific focus on smoking status, body mass index and extent of disease; Laboratory tests (CRP and fecal calprotectin) at all study visits; Adverse events; Economic evaluation; Pharmaco-economic evaluation; Quality of life; Yearly total IFX dose per patient.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Participation will result in additional blood sampling, since TLs will be measured every 8 weeks. However, no additional venous punctures will be performed, since blood sampling is performed directly before IFX infusion. All other laboratory tests can be considered as routine care. No additional hospital visits are required.

Current evidence indicates that TLs >3 suffice, and dose reduction will be only performed when TLs remain >7. We expect that IFX dose reduction while maintaining adequate TLs is not associated with an increased risk of relapse. Moreover, we hypothesize that reducing IFX dose in patients with supratherapeutic TLs, will lead to less side effects.

The per patient annual infliximab dose can be lowered in Crohn’s disease patients in stable remission using dose reduction guided by serial trough level measurements.

Primary endpoint: after 24 months of treatment.

Patients in the intervention arm will undergo stepwise dose reduction of IFX. IFX dose will be decreased by 1 mg/kg per step. The dose reduction phase ends in case of relapse and/or if trough levels drop below < 3 μg/ml.

Patients in the control arm will receive continued IFX at 5 mg/kg at an 8 week interval.