Introduction

Inflammatory bowel disease (IBD) includes ulcerative colitis (UC) and Crohn’s disease (CD), two chronic, immune-mediated gastrointestinal disorders.1 2 Infliximab, a chimeric antitumour necrosis factor (TNF) monoclonal antibody, is effective for induction and maintenance of remission in both CD3–5 and UC.6 However, secondary loss of response to infliximab is common, occurring at a rate of 10%–20% annually.7–9 Dose intensification of infliximab is an effective therapeutic manoeuvre that recaptures response in up to 85% of patients.10 11 Management decisions based on therapeutic drug monitoring (TDM) of infliximab have been shown to be cost-effective and to improve patient outcomes.12 13 There is a well-established exposure–response relationship for intravenous infliximab, with multiple studies demonstrating that higher trough drug levels are associated with improved patient outcomes.12–16 Advances in the uptake and understanding of infliximab TDM allow more informed patient selection for intravenous infliximab dose intensification.14

Accessing and maintaining the additional infliximab required for dose-intensified therapy is expensive and labour-intensive.13 17 Furthermore, both patients and clinicians may prefer subcutaneous (SC) rather than centre-based intravenous therapy.18–21 SC infliximab is superior to placebo22 23 and appears comparable to intravenous infliximab for the management of moderate-severe UC and luminal CD.24 However, the two available interventional controlled studies comparing SC to intravenous infliximab in IBD are inadequately powered to assess efficacy and safety differences between the two methods of administration.24 25 Data supporting SC infliximab in patients requiring dose-intensified infliximab therapy are also limited.

Retrospective and prospective real-world cohort studies have demonstrated that up to 95% of patients with CD and UC on dose-intensified intravenous infliximab therapy can be switched to SC therapy and maintain both objective remission and drug levels at 6 months.26–28 However, failure rates appear to be associated with the degree of dose intensification. In the largest published dose-intensified cohort, two-thirds of patients receiving high intravenous infliximab doses (10 mg/kg 4-weekly) relapsed by 6 months26 and 93% by 18 months.29 More data are required to confirm these observations and establish non-inferiority of SC infliximab to a broader range of dose-intensified intravenous infliximab regimens.

Across the majority of existing studies, ‘trough’ drug levels are higher in patients receiving SC infliximab compared with those treated with intravenous infliximab.26–28 30 However, comparing drug levels at ‘trough’ does not adequately reflect total drug exposure between the two formulations.31 The impact of higher SC infliximab ‘trough’ drug levels on disease activity, immunogenicity and treatment persistence in IBD is yet to be determined. There is also an unmet need to establish the role of SC infliximab TDM and to determine concentration thresholds associated with remission. Prospective, randomised controlled studies incorporating TDM are required to demonstrate comparable efficacy between SC infliximab and dose-intensified intravenous infliximab and to confirm that changes in drug administration and associated pharmacokinetics are comparable in this cohort.32

The primary aim of the DISCUS-IBD trial is to assess if SC infliximab is non-inferior to dose-intensified intravenous infliximab in maintaining clinical and biochemical steroid-free remission at 48 weeks. Secondary aims include comparing pharmacokinetic and objective disease response, identifying predictors of disease flare, characterising changes in infliximab TDM and assessing patient satisfaction, health-related quality of life and adverse events within and between the two arms.

Methods and analysisOverall trial design

This is an investigator-initiated, prospective, multicentre, randomised, open-label non-inferiority study comparing week 48 clinical and pharmacokinetic outcomes in patients randomised to continue dose-intensified intravenous infliximab to those who are switched to SC infliximab therapy.

Participants

Adult (18–85 years) patients receiving dose-intensified intravenous infliximab for either UC or luminal CD of any phenotype, including concomitant perianal CD, will be invited to participate. All participants must be receiving stable, maintenance intravenous infliximab regimens for at least 3 months at study enrolment. Dose intensification is defined by intravenous infliximab administration at doses greater than 5 mg/kg 8-weekly—including an increased dose (>5 mg/kg), a shorter dosing interval (<8-weekly) or both, up to a maximum of 10 mg/kg 4-weekly. Participants must be in clinical steroid-free remission for at least 6 months (Harvey Bradshaw Index (HBI)33 <5 or partial Mayo score34 <2) as well as biochemical remission at study entry, defined by both C reactive protein (CRP) <5 mg/L and faecal calprotectin (FCP) <250 µg/g. Concomitant immunomodulators (IMM; thiopurines or methotrexate) are permitted and use is recorded. Patients will be recruited from participating academic IBD centres across Australia.

Exclusion criteria include a change in infliximab dosing within 3 months, isolated perianal CD (ie, in the absence of luminal involvement), pregnancy, planning pregnancy within 12 months or actively breastfeeding as well as the extremes of weight, defined as <40 kg or >120 kg.

Randomisation and dose allocation

Patients fulfilling inclusion criteria will be centrally randomised 1:1 to receive SC infliximab or to continue intravenous infliximab stratified for disease type (CD/UC), IMM use (yes/no) and weight (<80 kg/>80 kg) (figure 1). The stratified randomisation code was generated by a statistician independent of the study coordinators. The randomisation code is embedded within Research Electronic Data Capture (REDCap) software and remains concealed from all investigators.

Figure 1

Randomisation and dosing allocation for the DISCUS-IBD trial. *Participants allocated to subcutaneous infliximab who were previously receiving 10 mg/kg 4-weekly IV infliximab will receive 240 mg 2-weekly SC IFX upfront. Created with BioRender.com. CD, Crohn’s disease; IBD, inflammatory bowel disease; IFX, infliximab; IV, intravenous; UC, ulcerative colitis.

Participants allocated to intravenous infliximab will continue infliximab at the same dose-intensified regimen they were receiving at study enrolment. SC infliximab dosing will be stratified by prior intravenous infliximab dosing. Participants allocated to SC who were previously receiving intravenous infliximab at doses <10 mg/kg 4-weekly will receive 120 mg 2-weekly SC infliximab. Participants allocated to SC who were previously receiving intravenous infliximab at a dose of 10 mg/kg 4-weekly will receive 240 mg 2-weekly SC infliximab upfront (figure 1).

Participants in the SC infliximab 120 mg 2-weekly arm meeting any of the flare criteria can be intensified to a maximum of 240 mg 2-weekly. Patients in the intravenous arm meeting any of the flare criteria can undergo one further infliximab intensification up to a maximum of 10 mg/kg 4-weekly, at the discretion of the treating physician. At the time of any intravenous or SC infliximab dose escalation, the participant will be recorded as meeting the primary endpoint but will remain in the study to 48 weeks to measure the disease and drug-level response to dose intensification. Intravenous or SC infliximab patients requiring more than one dose intensification will be withdrawn. Infliximab dose de-escalation will not be permitted, and all management changes will be recorded. Participants receiving IMMs at enrolment will remain on these throughout the study. IMM dose changes are permitted at the discretion of the treating clinician and will be recorded. Patients may also be withdrawn from the study at clinician discretion based on significant disease worsening, including as identified via incidental non-trial related objective testing such as endoscopy or cross-sectional imaging.

Study timeline

The data collection schedule is illustrated in figure 2. Patients undergo a screening period to ensure fulfilment of inclusion and absence of exclusion criteria. After randomisation, patients undergo a baseline and then 12-weekly remote assessment of clinical and biochemical disease activity, drug-level ±antidrug antibodies and monitoring of adverse events and adherence. Patient satisfaction and disease-related quality of life are also assessed at baseline, week 24 and week 48. Questionnaires (table 1) as well as blood and stool collection reminders are automatically sent to participants nominated email address 1 week prior to due date. Patients are instructed and reminded to take drug levels at trough, defined as the day of or day prior to administration. All monitoring performed throughout the study is made available to the treating clinicians and occurs in addition to the patients’ regular clinic appointments and investigations. Patients, investigators and treating clinicians are not blinded to treatment allocation.

Figure 2

DISCUS-IBD trial schema. Created with BioRender.com. Ab, antibody; CRP, C reactive protein; FCP, faecal calprotectin; HBI, Harvey Bradshaw Index; IBD, inflammatory bowel disease; pMayo, partial Mayo score.

Table 1

List of questionnaires for the DISCUS-IBD trial

Study outcomes

The primary endpoint is the rate of disease flare in each group at 48 weeks, defined as any one of:

HBI ≥5 (CD) or partial Mayo score ≥2 (UC) PLUS objective activity (CRP ≥5 mg/L OR FCP ≥250 µg/g).

Need for corticosteroids, new IMM or switch in biologic therapy.

IBD-related hospitalisation or surgery.

Secondary endpoints include:

Change in infliximab drug levels at weeks 12, 24, 36 and 48 in each group.

Rates of clinical flare at 24 and 48 weeks in each group, defined as HBI ≥5 (CD) or partial Mayo score ≥2 (UC).

Rates of biochemical disease flare at weeks 24 and 48 in each group, defined as CRP ≥5 mg/L OR FCP ≥250 µg/g.

Rates of further dose intensification due to clinical and biochemical flare at week 48.

Change in FCP between baseline and weeks 12, 24, 36 and 48 in each group.

Change in CRP between baseline and weeks 12, 24, 36 and 48 in each group.

Antibodies to infliximab at weeks 12, 24, 36 and 48 in each group.

Adverse events (including infusion or injection site reaction, hypersensitivity, rash, lymphopenia, infection) at weeks 12, 24, 36 and 48 in each group.

Patient satisfaction and health-related quality of life at baseline, weeks 24 and 48 within and across groups

Adherence (number of missed or rescheduled doses) and any impact of COVID-19 on adherence at weeks 12, 24, 36 and 48 in each group.

Success of further dose intensification in each group—measured by change in drug levels and rate of recapture of clinical and biochemical response at week 48.

Data collection and instruments

Lead investigators at Alfred Health formulated the collection instruments based on a comprehensive review of the literature (table 1). A working group constructed a list of data fields for each instrument designed to assess adherence, adverse events and patient satisfaction. The patient satisfaction survey was adapted from two prior biologic switch studies.27 35 These instruments were subsequently discussed and either accepted, modified or rejected during scheduled investigator meetings throughout 2022. Patients were not involved in the development or review of questionnaires. Participant retention is promoted via remote assessments and community pathology testing. Patients who have withdrawn or are lost to follow will not have further data collected.

Biological samples

Blood and faecal samples are collected 12-weekly. All testing is performed using the same community pathology network (Healius Pathology) to ensure assay consistency. Drug-level testing is performed using an in-house drug-sensitive ELISA. All samples with an undetectable infliximab level (<0.4 µg/mL) automatically undergo reflex testing for antidrug antibodies. To ensure TDM at trough, patients receiving intravenous infliximab at 8-weekly intervals will have their week 12 and week 36 drug level taken at weeks 16 and 40, respectively. Stool samples are returned to the laboratory within 24 hours of collection. FCP is processed using an in-house chemiluminescent immunoassay.

Adverse events and monitoring

Adverse events are recorded 12-weekly. An interim analysis will be performed when 60 patients reach week 24 to ensure that there are no significant safety concerns within the two groups that would mandate trial termination and that the recruitment and randomisation processes are functioning correctly with balanced allocation. These data will be presented to a prespecified drug safety monitoring board (DSMB), independent of the study team and study sponsors. Recommendations from the DSMB will be fed back to lead investigators and disseminated to principal investigators at participating sites. Coordinating principal investigators at Alfred Health have final decision-making on trial termination. Recruitment and data collection will continue while these data are analysed. Patients also continue their usual clinic review schedule and site study coordinators will be contacted if concerns are raised.

All serious adverse events (SAEs) and serious adverse reactions will be reported to the site principal investigator and then reported to the coordinating principal investigator throughout the study, regardless of their suspected relationship to the study drug. The coordinating centre (Alfred Health) will ensure that all sites are notified of any SAE which is considered related to the study medication and has not been previously described. Safety reports related to drugs or devices will also be reported to the Therapeutic Goods Administration by the coordinating principal investigator.

Data management

Study data will be collected and managed using REDCap surveys hosted by Helix (Monash University).36 37 REDCap is a secure, web-based software platform designed to support data capture for research studies. A site-specific DISCUS-IBD REDCap database can be accessed by authorised investigators at each study site. REDCap database setup and maintenance were performed by study coordinators with support from Helix REDCap technicians (Monash University). Authorised staff members are tasked with adding data to the electronic database, maximising data quality and completeness and keeping the database current to reflect participant status during the study period. Only the lead investigators (RDL, MGW and MPS) will have access to the final trial dataset. Technical appendix, full protocol, statistical code and dataset will be made available from authors on reasonable request. No endpoint adjudication committee is required due to predefined and objective endpoints.

Statistical analysis

DISCUS-IBD is a non-inferiority study designed to achieve a statistical power of 90% at a significance of p<0.05. The prespecified non-inferiority margin is 15%. Assumptions for rates of flare were 16% in the intravenous group (group A), based on existing systematic reviews and meta-analyses,10 11 and 24% in the SC group (group B), extrapolated from 6 month data from postswitch observational studies.26 27 On this basis, a sample size of 52 patients per group was calculated,38 39 with collaboration from a statistician independent of the investigators. Allowing for >10% drop-out rate, the planned sample size is 120 patients, similar to the pivotal SC infliximab trial in IBD.24

Normally distributed continuous data will be presented as mean and SD and compared using the Student’s t-test or analysis of variance with Tukey correction for longitudinal data. Non-normally distributed continuous data will be presented as median and IQR and compared using the Mann-Whitney U test and either the Wilcoxon signed rank-sum test or Friedman test with Dunn’s correction for longitudinal data, as appropriate. Categorical data will be presented as number and %, with comparison using χ2 or Fisher’s exact test, as appropriate. Multivariate analysis for predictors of disease flare will be undertaken using logistic regression. Multilevel linear modelling will also be performed to evaluate patient and disease characteristics that predict change in serial drug-level data both between and within participants in both groups. Kaplan-Meier survival curves with log-rank tests of difference will compare the rate of flares between the two groups and a Cox proportional-hazards model will be used to identify the association of baseline independent variables with failure rate over the study period. The primary comparisons will be performed using an intention-to-treat analysis. Per-protocol analyses will be used as a supporting sensitivity analysis.40 No planned imputation will be performed to address missing data. Statistical analyses will be performed using IBM SPSS Statistics and graphs generated using GraphPad Prism software. The statistician will remain blinded to treatment groups during analyses. Statistical significance will be determined as a p<0.05.

Ethics and dissemination plan

DISCUS-IBD was prospectively registered with the Australian and New Zealand Clinical Trials Registry (ANZCTR) on 17 November 2022 prior to commencing recruitment (ANZCTR registration number: ACTRN12622001458729; https://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12622001458729).

Multisite ethics approval was obtained from the Health District Human Research Ethics Committee (HREC) at The Alfred Hospital under a National Mutual Acceptance (NMA) agreement on 13 February 2023 (HREC/90559/Alfred-2022; Local Reference: Project 618/22, protocol version 1.6). NMA is a national system for mutual acceptance of scientific and ethical review of multisite human research projects conducted in publicly funded health services across all states and territories in Australia. Recruitment commenced 6 March 2023 and is expected to conclude June 30 2025. To reach the target sample size, 13 academic centres across Australia have agreed to participate in the DISCUS-IBD trial. Six of these sites are openly recruiting, reaching a total of 51 patients at the time of writing. Analyses and publication of results are expected to conclude by 31 July 2026 and 31 September 2026, respectively. Protocol modifications and an accurate list of actively recruiting study sites will be available from the ANZCTR listing (https://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12622001458729).

Written voluntary informed consent is obtained from all participants by approved site principal investigators after a thorough explanation and provision of the patient information consent form. Procedures are taken to ensure the confidentiality of individuals participating in this study. No identifying information is recorded in the metadata exports, and all participants are assigned a unique anonymised study ID. Personal information will not be made public at any point. Individual participant results will not be made available. Participants may withdraw consent for participating in the research at any time point. Key study findings will be published in peer-reviewed journals as well as presented at national and international conferences. We will communicate published findings directly back to our study population through emailed newsletters.