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

Abstract

Importance: Proactive therapeutic drug monitoring (TDM), defined as individualized drug dosing based on scheduled monitoring of serum drug levels, has been proposed as an alternative to standard therapy to maximize efficacy and safety of infliximab and other biological drugs. However, whether proactive TDM improves clinical outcomes when implemented at the time of drug initiation, compared with standard therapy, remains unclear.

Objective: To assess whether TDM during initiation of infliximab therapy improves treatment efficacy compared with standard infliximab therapy without TDM.

Design, setting, and participants: Randomized, parallel-group, open-label clinical trial of 411 adults with rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, ulcerative colitis, Crohn disease, or psoriasis initiating infliximab therapy in 21 hospitals in Norway. Patients were recruited from March 1, 2017, to January 10, 2019. Final follow-up occurred on November 5, 2019.

Interventions: Patients were randomized 1:1 to receive proactive TDM with dose and interval adjustments based on scheduled monitoring of serum drug levels and antidrug antibodies (TDM group; n = 207) or standard infliximab therapy without drug and antibody level monitoring (standard therapy group; n = 204).

Main outcomes and measures: The primary end point was clinical remission at week 30.

Results: Among 411 randomized patients (mean age, 44.7 [SD, 14.9] years; 209 women [51%]), 398 (198 in the TDM group and 200 in the standard therapy group) received their randomized intervention and were included in the full analysis set. Clinical remission at week 30 was achieved in 100 (50.5%) of 198 and 106 (53.0%) of 200 patients in the TDM and standard therapy groups, respectively (adjusted difference, 1.5%; 95% CI, -8.2% to 11.1%; P = .78). Adverse events were reported in 135 patients (68%) and 139 patients (70%) in the TDM and standard therapy groups, respectively.

Conclusions and relevance: Among patients with immune-mediated inflammatory diseases initiating treatment with infliximab, proactive therapeutic drug monitoring, compared with standard therapy, did not significantly improve clinical remission rates over 30 weeks. These findings do not support routine use of therapeutic drug monitoring during infliximab induction for improving disease remission rates.

Trial registration: ClinicalTrials.gov Identifier: NCT03074656.

Figure 1.. Flow of Participants Through the Norwegian Drug Monitoring Trial Part A

^aChronic immune-mediated inflammatory disease included rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, ulcerative colitis, Crohn disease, and psoriasis. ^bRandomization was stratified by diagnosis. ^cPatient had a colostomy, which was one of the defined exclusion criteria (outcome measure includes stool frequency). ^dMajor protocol violations were prespecified in the statistical analysis plan as follows: deviations to inclusion and/or exclusion criteria or delay in scheduled infusion with an infusion interval of more than 12 weeks, or investigator nonadherence to study algorithm, defined as discrepancies between recommended and actual dose/interval at more than 1 visit. ^ePatients for various reasons were not able to adhere to the study routine (eg, did not arrive for scheduled infusions).

Figure 2.. Clinical Remission at 30 Weeks (Primary Outcome)

Adjusted difference in clinical remission rate at 30 weeks overall (the primary end point) and by disease subgroup. The adjusted difference in remission rate was assessed by mixed-effects logistic regression using data from all patients exposed to the randomized intervention (patients having received the second infusion with a recorded treatment decision for the third infusion). Size of data markers is proportional to the number of patients in the group. Clinical remission was defined by disease-specific composite scores: a Disease Activity Score in 28 Joints lower than 2.6 in patients with rheumatoid arthritis and psoriatic arthritis, an Ankylosing Spondylitis Disease Activity Score lower than 1.3 in patients with spondyloarthritis, a Partial Mayo Score of 2 or lower with no subscores greater than 1 in patients with ulcerative colitis, a Harvey-Bradshaw Index of 4 or lower in patients with Crohn disease, and a Psoriasis Area and Severity Index of 4 or lower in patients with psoriasis. See the Box and eTable 3 in Supplement 1 for detailed descriptions of the Disease Activity Score in 28 Joints, Ankylosing Spondylitis Disease Activity Score, Partial Mayo Score, Harvey-Bradshaw Index, and Psoriasis Area and Severity Index.

Figure 3.. Disease Activity by Disease Subgroup

Orange indicates therapeutic drug monitoring; blue, standard therapy. Box tops and bottoms indicate interquartile range; horizontal bars inside boxes, median; whiskers, highest and lowest values within 1.5 × the interquartile range. Dots indicate individual patient outliers. See the Box and eTable 3 in Supplement 1 for detailed descriptions of the Disease Activity Score in 28 Joints, Ankylosing Spondylitis Disease Activity Score, Partial Mayo Score, Harvey-Bradshaw Index, and Psoriasis Area and Severity Index.