Prospective randomised controlled trial of adults with perianal fistulising Crohn’s disease and optimised therapeutic infliximab levels: PROACTIVE trial study protocol

Abstract

IntroductionPerianal fistulising Crohn’s disease (pfCD) can be somewhat treatment refractory. Higher infliximab trough levels (TLIs) may improve fistula healing rates; however, it remains unclear whether escalating infliximab therapy to meet higher TLI targets using proactive, or routine, therapeutic drug monitoring (TDM) improves outcomes. This randomised controlled trial aimed to assess whether infliximab therapy targeting higher TLIs guided by proactive TDM improves outcomes compared with standard therapy.Methods and analysisPatients with active pfCD will be randomised 1:1 to either the proactive TDM arm or standard dosing arm and followed up for 54 weeks. Patients in the proactive TDM arm will have infliximab dosing optimised to target higher TLIs. The targets will be TLI ≥ 25 µg/mL at week 2, ≥ 20 µg/mL at week 6 and ≥ 10 µg/mL during maintenance therapy. The primary objective will be fistula healing at week 32. Secondary objectives will include fistula healing, fistula closure, radiological fistula healing, patient-reported outcomes and economic costs up to 54 weeks. Patients in the standard dosing arm will receive conventional infliximab dosing not guided by TLIs (5 mg/kg at weeks 0, 2 and 6, and 5 mg/kg 8 weekly thereafter). Patients aged 18–80 years with pfCD with single or multiple externally draining complex perianal fistulas who are relatively naïve to infliximab treatment will be included. Patients with diverting ileostomies or colostomies and pregnant or breast feeding will be excluded. Fifty-eight patients per arm will be required to detect a 25% difference in the primary outcome measure, with 138 patients needed to account for an estimated 6.1% primary non-response rate and 10% dropout rate.Ethics and disseminationResults will be presented in peer-reviewed journals and international conferences. Ethics approval has been granted by the South Western Sydney Local Health District Human Research Ethics Committee in Australia.Trial registration numberAustralian New Zealand Clinical Trials Registry (ACTRN12621000023853); Pre-results.

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“…Prospective data on TDM for perianal fistulizing CD are awaited. The results of the PROACTIVE (Prospective Randomised Controlled Trial of Adults with Perianal Fistulising Crohn’s Disease and Optimised Therapeutic Infliximab Levels) RCT regarding adults with perianal fistulizing CD and proactively optimized infliximab concentrations) [ 52 ] is expected to shed more light regarding the role of proactive TDM in this situation.…”

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“…One ongoing interventional randomized controlled study by Gu et al may offer a better insight on how TDM could effectively be used in PFCD [ 43 ]. The PROACTIVE trial (Prospective randomized controlled trial of adults with perianal fistulizing Crohn’s disease and optimized therapeutic IFX levels) is enrolling patients with active PFCD randomized to either a proactive TDM group or standard dosing group with a 54 week follow up period.…”

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“…53 The Prospective Randomized Controlled Trial of Adults With Perianal Fistulizing CD And Optimized Therapeutic Infliximab Levels (PROACTIVE; ACTRN12621000023853) is investigating the role of proactive TDM in patients with perianal fistulizing CD compared with standard dosing. 54 Patients With Genetic Susceptibility for Accelerated Clearance Specific variant alleles significantly impact infliximab pharmacokinetics (PK) and treatment outcomes. For instance, the presence of the HLA-DQA105 allele is linked to an increased risk of immunogenicity and LOR.…”

“…53 The Prospective Randomized Controlled Trial of Adults With Perianal Fistulizing CD And Optimized Therapeutic Infliximab Levels (PROACTIVE; ACTRN12621000023853) is investigating the role of proactive TDM in patients with perianal fistulizing CD compared with standard dosing. 54…”