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Among patients with immune-mediated inflammatory diseases undergoing maintenance therapy with infliximab, is proactive therapeutic drug monitoring (TDM) more effective than standard therapy to sustain disease control without disease worsening?
In this randomized clinical trial that included 458 patients, the proportion of patients with sustained disease control without disease worsening during 52 weeks of follow-up was 74% in the TDM group and 56% in the standard therapy group, a statistically significant difference.
Proactive TDM compared with treatment without TDM during maintenance infliximab therapy was more likely to lead to sustained disease control over 52 weeks for patients with immune-mediated inflammatory diseases.
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.
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.
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.
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.
ClinicalTrials.gov Identifier: NCT03074656
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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.
Corresponding Author: Silje Watterdal Syversen, MD, PhD, Division of Rheumatology and Research, Diakonhjemmet Hospital, PO Box 23 Vinderen, N-0319 Oslo, Norway (email@example.com).
Accepted for Publication: November 9, 2021.
Author Contributions: Drs Syversen and Sexton had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Syversen, Jørgensen, and Goll contributed equally. Drs Jahnsen, Bolstad, and Haavardsholm contributed equally.
Concept and design: Syversen, Jørgensen, Goll, Sandanger, Sexton, Olsen, Gehin, Mørk, Kvien, Jahnsen, Bolstad, Haavardsholm.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Syversen, Jørgensen, Goll, Brun, Bjørlykke, Sexton, Gehin, Mørk, Kvien, Jahnsen, Bolstad.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Syversen, Brun, Bjørlykke, Sexton, Olsen, Haavardsholm.
Obtained funding: Syversen, Kvien, Bolstad, Haavardsholm.
Administrative, technical, or material support: Syversen, Jørgensen, Goll, Brun, Sandanger, Bjørlykke, Sexton, Gehin, Warren, Klaasen, Noraberg, Bruun, Dotterud, Ljoså, Haugen, Njålla, Zettel, Ystrøm, Bragnes, Skorpe, Thune, Seeberg, Michelsen, Blomgren, Strand, Mielnik, Torp, Mørk, Kvien, Jahnsen, Bolstad, Haavardsholm.
Supervision: Syversen, Jørgensen, Goll, Brun, Sandanger, Bjørlykke, Sexton, Gehin, Noraberg, Bruun, Dotterud, Ljoså, Haugen, Njålla, Zettel, Ystrøm, Bragnes, Skorpe, Thune, Seeberg, Michelsen, Blomgren, Strand, Mielnik, Torp, Mørk, Kvien, Jahnsen, Bolstad, Haavardsholm.
Conflict of Interest Disclosures: Dr Syversen reported receipt of personal fees from Thermo Fisher. Dr Jørgensen reported receipt of personal fees from Bristol Myers Squibb, Roche, Celltrion, and Norgine. Dr Goll reported receipt of personal fees from AbbVie, Pfizer, Sandoz, Celltrion, Lilly, UCB, and Boehringer Ingelheim. Dr Dotterud reported receipt of personal fees from LEO Pharma. Dr Michelsen reported receipt of personal fees from Novartis and grants from Novartis paid to her employer. Dr Mørk reported receipt of personal fees from Novartis Norge, LEO Pharma, ACO Hud Norge, Cellgene, AbbVie, and Galderma Nordic. Dr Kvien reported receipt of grants from AbbVie, Amgen, Bristol Myers Squibb, Novartis, Pfizer, and UCB and personal fees from Amgen, Celltrion, Egis, Evapharma, Ewopharma, Gilead, Hikma, Mylan, Oktal, Pfizer, Sandoz, Sanofi, and UCB. Dr Bolstad reported receipt of personal fees from Roche, Janssen, and Novartis. Dr Haavardsholm reported receipt of personal fees from Pfizer, AbbVie, Celgene, Novartis, Janssen, Gilead, Lilly, and UCB. No other disclosures were reported.
Funding/Support: This study was funded by grants from the Norwegian Regional Health Authorities (interregional KLINBEFORSK grants) and the South-Eastern Norway Regional Health Authorities. The sponsor of the study was Diakonhjemmet Hospital.
Role of the Funder/Sponsor: Neither the funder of the study (the Regional Health Authorities) nor the sponsor (Diakonhjemmet Hospital) had any role in design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. Neither the funder nor the sponsor had any right to veto publication or to control the decision regarding to which journal the manuscript was submitted. All drafts of the manuscript were prepared by the authors. All authors approved the final submitted version.
Additional Contributions: We acknowledge the patient representatives, Jon Hagfors (Norwegian Rheumatism Association), Bjørn Gulbrandsen (Norwegian IBD Patient Organization), and Hilde Mellum (Psoriasis and Eczema Association of Norway), for their contributions during planning and conduct of the study. We acknowledge the members of the scientific advisory board, Josef Smolen, MD, PhD (University of Vienna), Alejandro C. Balsa, MD, PhD (University Hospital La Paz, Madrid), Geert D’Haens, MD, PhD (Amsterdam Academic Medical Center), Jørn Brynskov, MD, PhD (University of Copenhagen Herlev Hospital), and Diamant Thaci, MD, PhD (University of Lubeck). No compensation was received for their contributions to the protocol. We acknowledge Cecilie Moe, Bjørn Solvang, Nina Flatner, Trond Smedsrud, and Marius Eid, Department of Research Support for Clinical Trials at Oslo University Hospital, and Anja Bye, Clinical Research Unit Central Norway, for research support and data management (received compensation for their work).
Data Sharing Statement: See Supplement 3.
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