Proactive infliximab optimisation using a pharmacokinetic dashboard versus standard of care in patients with Crohn's disease: study protocol for a randomised, controlled, multicentre, open-label study (the OPTIMIZE trial)

Abstract

Introduction: Preliminary data indicates that proactive therapeutic drug monitoring (TDM) is associated with better outcomes compared with empiric dose escalation and/or reactive TDM, and that pharmacokinetic (PK) modelling can improve the precision of individual dosing schedules in Crohn's disease (CD). However, there are no data regarding the utility of a proactive TDM combined PK-dashboard starting early during the induction phase, when disease activity and drug clearance are greatest. The aim of this randomised, controlled, multicentre, open-label trial is to evaluate the efficacy and safety of a proactive TDM combined PK dashboard-driven infliximab dosing compared with standard of care (SOC) dosing in patients with moderately to severely active CD.

Methods and analysis: Eligible adolescent and adult (aged ≥16-80 years) patients with moderately to severely active CD will be randomised 1:1 to receive either infliximab monotherapy with proactive TDM using a PK dashboard (iDose, Projections Research) or SOC infliximab therapy, with or without a concomitant immunomodulator (IMM) (thiopurine or methotrexate) at the discretion of the investigator. The primary outcome of the study is the proportion of subjects with sustained corticosteroid-free clinical remission and no need for rescue therapy from week 14 throughout week 52. Rescue therapy is defined as any IFX dose escalation other than what is forecasted by iDose either done empirically or based on reactive TDM; addition of an IMM after week 2; reintroduction of corticosteroids after initial tapering; switch to another biologic or need for CD-related surgery. The secondary outcomes will include both efficacy and safety end points, such as endoscopic and biological remission, durability of response and CD-related surgery and hospitalisation.

Ethics and dissemination: The protocol has been approved by the Institutional Review Board Committee of the Beth Israel Deaconess Medical Center (IRB#:2021P000391). Results will be disseminated in peer-reviewed journals and presented at scientific meetings.

Trial registration number: NCT04835506.

Keywords: clinical pharmacology; immunology; inflammatory bowel disease.

Conflict of interest statement

Competing interests: ASC: reports consultancy fees from Janssen, AbbVie, Artugen, Procise, Prometheus, Arena, Grifols, Bacainn, Bristol Myers Squibb. VJ has received consulting/advisory board fees from AbbVie, Alimentiv (formerly Robarts Clinical Trials), Arena Pharmaceuticals, Asieris, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Fresenius Kabi, Galapagos, GlaxoSmithKline, Genetech, Gilead, Janssen, Merck, Mylan, Pandion, Pendopharm, Pfizer, Reistone Biopharma, Roche, Sandoz, Takeda, Teva, Topivert; speaker’s fees from, AbbVie, Ferring, Galapagos, Janssen Pfizer Shire, Takeda. CS: reports consultancy fees from AbbVie, BMS, Lilly, Janssen, Pfizer, Prometheus, Takeda, Trellus Health; speaker's fees for CME activities for AbbVie, Janssen, Pfizer, Takeda; grant support from the Crohn’s and Colitis Foundation, Leona M. and Harry B. Helmsley Charitable Trust, AbbVie, Janssen, Pfizer, Takeda; intellectual property owned by MiTest Health (Software Company) and ColonaryConcepts; equity interest and co-founder of MiTest Health and ColonaryConcepts. KP reports lecture fees from Mitsubishi Tanabe Pharma and Physicians Education Resource; consultancy fee from Prometheus Laboratories and scientific advisory board fees from ProciseDx and Scipher Medicine Corporation. JFV: reports research support from Roche/Genentech, Takeda, Applied Molecular Transport, Celgene/Bristol Myers Squibb, AbbVie, Arena Pharmaceuticals. GZ: reports consulting fees from Alimentiv. BC: reports financial support for advisory boards and consultancy from AbbVie, Celgene-Bristol Myers Squibb, Pfizer, Sublimity Therapeutics, Takeda, TARGET RWE; CME Companies: Cornerstones, Vindico; speaker's fees from AbbVie; educational grant from Pfizer. MD: reports consultancy fees from AbbVie, Arena Pharmaceuticals, Boehringer Ingelheim International, Bristol Myers Squibb, Cengene, Eli Lilly and Company, F. Hoffmann-La Roche, Genentech, Gilead, Janssen Global Services, Pfizer, Prometheus Biosciences, Takeda Pharmaceuticals USA, UCB SA; research grants from AbbVie, Janssen Global Services, Pfizer, Prometheus Biosciences; ownership interest (stocks) Trellus Health and holds licensing fee with Takeda Pharmaceuticals USA. TR: reports speaker's fees from Takeda Pharmaceuticals, Janssen, Pfizer, Bristol Myers Squibb; data adjudication committee fees from Ferring/Rebiotix; advisory boards fees from AbbVie, Arena, Boehringer Ingelheim, Bristol Myers Squibb/Celgene, Coral Genomics (and shareholder), Ferring, Genentech/Roche, Gilead, Gossamer, Intercept, Janssen, Lilly, Pfizer, Prometheus, Sanofi, Takeda. BES: discloses research grants from Takeda, Pfizer, Theravance Biopharma R&D, Janssen; consulting fees from 4D Pharma, Abivax, AbbVie, Alimentiv, Allergan, Amgen, Arena Pharmaceuticals, AstraZeneca, Bacainn Therapeutics, Boehringer-Ingelheim, Boston Pharmaceuticals, Bristol yers Squibb, Calibr, Capella Bioscience, Celgene, Celltrion Healthcare, ClostraBio, Enthera, F. Hoffmann-La Roche, Ferring, Galapagos, Gilead, GlaxoSmithKline, GossamerBio, Immunic, Index Pharmaceuticals, Innovation Pharmaceuticals, Ironwood Pharmaceuticals, Janssen, Kaleido, Kallyope, Lilly, MiroBio, Morphic Therapeutic, Oppilan Pharma, OSE Immunotherapeutics, Otsuka, Palatin Technologies, Pfizer, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, Redhill Biopharma, Rheos Medicines, Salix Pharmaceuticals, Seres Therapeutics, Shire, Sienna Biopharmaceuticals, Sun Pharma, Surrozen, Takeda, Target PharmaSolutions, Teva Branded Pharmaceutical Products R&D, Thelium, Theravance Biopharma R&D, TLL Pharma, USWM Enterprises, Ventyx Biosciences, Viela Bio, Vivante Health, Vivelix Pharmaceuticals; and stock for Vivante Health and Ventyx Biosciences. NVC: received research grants from R-Biopharm, Takeda and UCB; and personal fees from AcelaBio, Alimentiv, Celltrion, ProciseDX, Prometheus, R-Biopharm, Takeda, UCB, Ventyx and Vividion. The remaining authors declare no conflict of interest.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

OPTIMIZE trial study design. CD, Crohn’s disease; CS, corticosteroid; IMM, immunomodulator; IFX, infliximab; MTX, methotrexate; PK, pharmacokinetic; TDM, therapeutic drug monitoring; w, week.