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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 N

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 N

Background: Therapeutic drug monitoring (TDM) in inflammatory bowel disease (IBD) patients receiving anti-tumour necrosis factor (TNF) agents can help optimise outcomes. Consensus statements based on current evidence will help the development of treatment guidelines. Aim: To develop evidence-based consensus statements for TDM-guided anti-TNF therapy in IBD. Methods: A committee of 25 Australian and international experts was assembled. The initial draft statements were produced following a systematic literature search. A modified Delphi technique was used with 3 iterations. Statements were modified according to anonymous voting and feedback at each iteration. Statements with 80% agreement without or with minor reservation were accepted. Results: 22/24 statements met criteria for consensus. For anti-TNF agents, TDM should be performed upon treatment failure, following successful induction, when contemplating a drug holiday and periodically in clinical remission only when results would change management. To achieve clinical remission in luminal IBD, infliximab and adalimumab trough concentrations in the range of 3-8 and 5-12 μg/mL, respectively, were deemed appropriate. The range may differ for different disease phenotypes or treatment endpoints—such as fistulising disease or to achieve mucosal healing. In treatment failure, TDM may identify mechanisms to guide subsequent decision-making. In stable clinical response, TDM-guided dosing may avoid future relapse. Data indicate drug-tolerant anti-drug antibody assays do not offer an advantage over drug-sensitive assays. Further data are required prior to recommending TDM for non-anti-TNF biological agents. Conclusion: Consensus statements support the role of TDM in optimising anti-TNF agents to treat IBD, especially in situations of treatment failure.

Introduction: Therapeutic drug monitoring (TDM)-guided biological drug therapy in inflammatory bowel disease (IBD) may improve clinical outcomes and reduce treatment cost, beyond fixed or clinically guided dosing. TDM of biological drugs involves measurement of drug levels and antidrug antibodies, and data are most comprehensive for TDM of anti-tumor necrosis factor (TNF) agents. Reactive TDM is performed during treatment failure to elicit mechanisms of failure and guide appropriate treatment changes (dose escalation versus changing to another agent), while proactive TDM is performed routinely in patients who maintain response in order to optimize drug levels and prevent future disease flares and loss of response. We produced consensus statements based on current evidence to aid implementation of TDM-guided therapy of biological drugs in IBD. Method(s): Consensus statements were produced via a modified Delphi method. A steering committee invited Australian and international experts in IBD and TDM of biological drugs. A literature search aided the steering committee in producing an initial draft of the consensus statements. Two rounds of online voting were undertaken, with modification of statements following each round based on voting results and feedback. On a final face-to-face voting round, each statement was presented, modified, and voted on. Panelists voted on their level of agreement with individual statements as follows: A) agree without reservation; B) agree with minor reservation; C) agree with major reservation; D) disagree with some reservation; E) disagree without reservation; or F) reserved. Statements with >= 80% agreement with no or only minor reservation met criteria for consensus. Level of evidence and grade of recommendation for each statement was agreed upon based on National Health and Medical Research Council (NHMRC) recommendations. Result(s): Of 26 panel nominees, 25 accepted to participate in this project, including the following: 18 Australi

Introduction: Therapeutic drug monitoring (TDM)-guided biological drug therapy in inflammatory bowel disease (IBD) may improve clinical outcomes and reduce treatment cost, beyond fixed or clinically guided dosing. TDM of biological drugs involves measurement of drug levels and antidrug antibodies, and data are most comprehensive for TDM of anti-tumor necrosis factor (TNF) agents. Reactive TDM is performed during treatment failure to elicit mechanisms of failure and guide appropriate treatment changes (dose escalation versus changing to another agent), while proactive TDM is performed routinely in patients who maintain response in order to optimize drug levels and prevent future disease flares and loss of response. We produced consensus statements based on current evidence to aid implementation of TDM-guided therapy of biological drugs in IBD. Method(s): Consensus statements were produced via a modified Delphi method. A steering committee invited Australian and international experts in IBD and TDM of biological drugs. A literature search aided the steering committee in producing an initial draft of the consensus statements. Two rounds of online voting were undertaken, with modification of statements following each round based on voting results and feedback. On a final face-to-face voting round, each statement was presented, modified, and voted on. Panelists voted on their level of agreement with individual statements as follows: A) agree without reservation; B) agree with minor reservation; C) agree with major reservation; D) disagree with some reservation; E) disagree without reservation; or F) reserved. Statements with >= 80% agreement with no or only minor reservation met criteria for consensus. Level of evidence and grade of recommendation for each statement was agreed upon based on National Health and Medical Research Council (NHMRC) recommendations. Result(s): Of 26 panel nominees, 25 accepted to participate in this project, including the following: 18 Australi