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TRAFIC: statistical design and analysis plan for a pragmatic early phase 1/2 Bayesian adaptive dose escalation trial in rheumatoid arthritis

Lookup NU author(s): Mike Cole, Professor Fai Ng, Dr Stefan Siebert, Dr Arthur Pratt, Professor John Isaacs, Dr Deborah Stocken

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2021, The Author(s).Background: Adaptive model-based dose-finding designs have demonstrated advantages over traditional rule-based designs but have increased statistical complexity but uptake has been slow especially outside of cancer trials. TRAFIC is a multi-centre, early phase trial in rheumatoid arthritis incorporating a model-based design. Methods: A Bayesian adaptive dose-finding phase I trial rolling into a single-arm, single-stage phase II trial. Model parameters for phase I were chosen via Monte Carlo simulation evaluating objective performance measures under clinically relevant scenarios and incorporated stopping rules for early termination. Potential designs were further calibrated utilising dose transition pathways. Discussion: TRAFIC is an MRC-funded trial of a re-purposed treatment demonstrating that it is possible to design, fund and implement a model-based phase I trial in a non-cancer population within conventional research funding tracks and regulatory constraints. The phase I design allows borrowing of information from previous trials, all accumulated data to be utilised in decision-making, verification of operating characteristics through simulation, improved understanding for management and oversight teams through dose transition pathways. The rolling phase II design brings efficiencies in trial conduct including site and monitoring activities and cost. TRAFIC is the first funded model-based dose-finding trial in inflammatory disease demonstrating that small phase I/II trials can have an underlying statistical basis for decision-making and interpretation. Trial registration: Trials Registration: ISRCTN, ISRCTN36667085. Registered on September 26, 2014.


Publication metadata

Author(s): Cole M, Yap C, Buckley C, Ng WF, McInnes I, Filer A, Siebert S, Pratt A, Isaacs JD, Stocken DD

Publication type: Article

Publication status: Published

Journal: Trials

Year: 2021

Volume: 22

Issue: 1

Print publication date: 01/12/2021

Online publication date: 06/07/2021

Acceptance date: 17/06/2021

Date deposited: 21/07/2021

ISSN (electronic): 1745-6215

Publisher: BioMed Central Ltd

URL: https://doi.org/10.1186/s13063-021-05384-5

DOI: 10.1186/s13063-021-05384-5


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