Effect of Therapeutic Drug Monitoring vs Standard Therapy During Maintenance Infliximab Therapy on Disease Control in Patients With Immune-Mediated Inflammatory Diseases: A Randomized Clinical Trial

Abstract

Importance: Proactive therapeutic drug monitoring (TDM), consisting of individualized treatment based on scheduled assessments of serum drug levels, has been proposed as an alternative to standard therapy to optimize efficacy and safety of infliximab and other biologic drugs. However, it remains unclear whether proactive TDM improves clinical outcomes during maintenance therapy.

Objective: To assess whether proactive TDM during maintenance therapy with infliximab improves treatment efficacy by preventing disease worsening compared with standard infliximab therapy without TDM.

Design, setting, and participants: Randomized, parallel-group, open-label clinical trial including 458 adults with rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, ulcerative colitis, Crohn disease, or psoriasis undergoing maintenance therapy with infliximab in 20 Norwegian hospitals. Patients were recruited from June 7, 2017, to December 12, 2019. Final follow-up took place on December 14, 2020.

Interventions: Patients were randomized 1:1 to proactive TDM with dose and interval adjustments based on scheduled monitoring of serum drug levels and antidrug antibodies (TDM group; n = 228) or to standard infliximab therapy without drug and antibody level monitoring (standard therapy group; n = 230).

Main outcome and measures: The primary outcome was sustained disease control without disease worsening, defined by disease-specific composite scores or consensus about disease worsening between patient and physician leading to a major change in treatment (switching to another biologic drug, adding an immunosuppressive drug including glucocorticoids, or increasing the infliximab dose), during the 52-week study period.

Results: Among 458 randomized patients (mean age, 44.8 [SD, 14.3] years; 216 women [49.8%]), 454 received their randomly allocated intervention and were included in the full analysis set. The primary outcome of sustained disease control without disease worsening was observed in 167 patients (73.6%) in the TDM group and 127 patients (55.9%) in the standard therapy group. The estimated adjusted difference was 17.6% (95% CI, 9.0%-26.2%; P < .001) favoring TDM. Adverse events were reported in 137 patients (60%) and 142 patients (63%) in the TDM and standard therapy groups, respectively.

Conclusions and relevance: Among patients with immune-mediated inflammatory diseases undergoing maintenance therapy with infliximab, proactive TDM was more effective than treatment without TDM in sustaining disease control without disease worsening. Further research is needed to compare proactive TDM with reactive TDM, to assess the effects on long-term disease complications, and to evaluate the cost-effectiveness of this approach.

Trial registration: ClinicalTrials.gov Identifier: NCT03074656.

Figure 1.. Participant Flow in the NOR-DRUM B Trial

^aChronic immune-mediated inflammatory disease included spondyloarthritis, ulcerative colitis, rheumatoid arthritis, Crohn disease, psoriatic arthritis, and psoriasis. ^bRandomization was stratified by diagnosis and prior therapeutic drug monitoring. ^cPatient had discontinued infliximab prior to randomization. ^dMajor protocol violations were prespecified in the statistical analysis plan as follows: deviations from inclusion and/or exclusion criteria, delay in scheduled infusion with an interval between infusions longer than 12 weeks, or investigator nonadherence to study algorithm, defined as discrepancies between recommended and actual dose or interval at more than 1 visit. ^eOne patient had both a withdrawal from study prior to week 52 and a prolonged infusion interval. ^fPatients for various reasons were not able to adhere to the study routine (eg, did not arrive for scheduled infusions). ^gPatients included in the sensitivity analysis had high adherence to the protocol (ie, those who did not withdraw from the study prior to week 52 and had no major protocol violations).

Figure 2.. Sustained Disease Control With No Disease Worsening (Primary Outcome)

Adjusted difference in the rate of sustained disease control without disease worsening during 52 weeks of follow-up overall (the primary outcome) and by disease subgroup. Size of data markers is proportional to the number of patients in the group. Disease worsening was defined by disease-specific composite scores or a consensus about disease worsening between patient and physician leading to a major change in treatment. Disease worsening according to disease-specific composite measures was defined as follows: for rheumatoid arthritis and psoriatic arthritis, an increase from baseline of 1.2 points or more with a minimum score of 3.2 in the Disease Activity Score in 28 Joints; for spondyloarthritis, an increase from baseline of 1.1 points or more with a minimum score of 2.1 in the Ankylosing Spondylitis Disease Activity Score; for ulcerative colitis, an increase from baseline of more than 3 points with a score of 5 or greater in the Partial Mayo Score; for Crohn disease, an increase from baseline of 4 points or more and a score of 7 or greater in the Harvey-Bradshaw Index; and for psoriasis, an increase from baseline of 3 points or more and a score of 5 or greater in the Psoriasis Area and Severity Index. See Table 1 footnotes for detailed descriptions of the scales and eTable 1 in Supplement 2 for more information.

Figure 3.. Time to Disease Worsening

Disease worsening was defined by disease-specific composite scores or a consensus about disease worsening between patient and physician leading to a major change in treatment as defined in the legend of Figure 2. Events that occurred after day 365 (but within the 4-week window of the week 52 visit) were set as having occurred at day 365.