Search

Introduction: Perianal 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 Analysis: Patients 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 Dissemination: Results 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 Number: Australian New Zealand Clinical Trials Registry (ACTRN12621000023853); Pre-results., Competing Interests: Competing interests: NVC reports grants and personal fees from Takeda, grants and personal fees from UCB, grants from R-Biopharm, personal fees from Celltrion, personal fees from Prometheus, outside the submitted work. JA reports lecture fees, grants, Boards, Consultancies for Abbott, AbbVie, Allergan, Anatara, AstraZeneca, Bayer, Celegene, Ferring, Gilead, Hospira, Immuninc, ImmunsanT, Janssen, MSD, Nestle, Progenity, Pfizer, Shire, Takeda and Vifor, grants from the Royal Adelaide Hospital Research Fund, outside the submitted work. JB reports personal fees from Abbvie, personal fees from Pfizer, personal fees from BMS, grants and personal fees from Janssen, personal fees from Takeda, personal fees from Gilead, personal fees from Microba, grants and personal fees from Ferring, outside the submitted work. ALH has served as consultant, advisory board member or speaker for AbbVie, Arena, Atlantic, Bristol-Myers Squibb, Celgene, Celltrion, Falk, Ferring, Janssen, MSD, Napp Pharmaceuticals, Pfizer, Pharmacosmos, Shire and Takeda and serves on the Global Steering Committee for Genentech, outside the submitted work. DL reports consultancy fees from AbbVie, Astellas, AstraZeneca, Bristol-Myers Squibb, Novartis, Pfizer and Sanofi, grants from AbbVie, Astellas, AstraZeneca, Bristol-Myers Squibb, CSL-Behring, Novartis, Pfizer, Sanofi and Shire, and travel expenses from AstraZeneca and Bayer; outside the submitted work. GR-S reports fees to his institute from Ferring Australia, grants and fees to his institute from Janssen, fees to his institute from Takeda, fees to his institute from Pfizer, fees to his institute from AbbVie, outside the submitted work. JR reports grants from AbbVie, personal fees from Takeda, personal fees from Gilead, grants from Genentech, personal fees from Alimentiv, personal fees from Janssen, during the conduct of the study. TS reports personal fees from Seimens Workshop, personal fees from Bayer, outside the submitted work. CT reports grants from Janssen, grants from Pfizer, grants from MSD, outside the submitted work; and is a director of laboratory that performs therapeutic drug monitoring for infliximab. A-JW reports grants and personal fees from Ferring, personal fees and non-financial support from AbbVie, personal fees from Janssen, personal fees and non-financial support from Takeda, outside the submitted work. WN received grants from Janssen and Pfizer, during the conduct of the study; grants and personal and speaker fees from AbbVie, Takeda, Grants from Ferring and Shire unrelated to the submitted work. NSD reports personal fees from AbbVie, personal fees from Pfizer, personal fees from BMS, personal fees from Janssen, outside the submitted work. SC reports grants from Janssen, grants from Pfizer, during the conduct of the study; grants and personal fees from AbbVie, educational support from Aspen/Orphan Australia, grants and personal fees from Ferring, personal fees from Gilead, grants and personal fees from Janssen, personal fees from Novartis, grants, personal fees and educational support from Pfizer, grants, personal fees and educational support from Shire/Takeda, outside the submitted work., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Therapeutic drug monitoring (TDM) of infliximab (IFX) levels in inflammatory bowel disease (IBD) patients can help to guide dose adjustments or changes to therapy for selected patients in remission or with secondary loss of response (LOR)., Aims: To determine how IFX TDM is utilised in a real-life clinical setting and to quantify the potential for TDM to reduce the unnecessary use of IFX., Methods: Data from all public IBD IFX level testing performed across Australia were prospectively collected from June 2016 to July 2017 to assess physician-reported for testing indications (induction, in remission or LOR) and associated results. The hypothetical influence of IFX TDM was based on an optimal therapeutic range of 6-10 mg/L for mucosal healing., Results: Secondary LOR (reactive TDM) was the most common indication for TDM. These patients have consistently lower median IFX levels: 3.02 mg/L (IQR 1.14-6.67 mg/L) versus 5.22 mg/L (IQR 2.70-8.12 mg/L), P = 0.0001 compared with patients in remission (proactive TDM). TDM helped to identify unnecessary use of IFX in 30.6% of the TDM tests performed in luminal Crohn disease and ulcerative colitis patients, with an associated drug cost saving of $531.38 per IFX TDM test episode. Unnecessary IFX use was identified in 38.9% (96/247) of reactive IFX TDM tests performed and in 19.3% (35/181) of proactive testing., Conclusion: Use of both reactive and proactive IFX TDM is cost-effective for IBD management as it informs the clinician where unnecessary use of IFX can be stopped., (© 2019 Royal Australasian College of Physicians.)