Development and validation of a driving simulator for evaluating the residual effects of drugs on driving performance - sensitivity analysis using zopiclone as a positive control: Study Protocol Clinical Trial (SPIRIT Compliant)

Abstract

Introduction: Drugs acting on the central nervous system (CNS), especially hypnotics, can impair driving. The US Food and Drug Administration started requiring pharmaceutical companies to evaluate the residual influence of CNS agents on driving performance to review their recommended doses. Although it is important for physicians to discuss automobile driving while on medication with patients to promote traffic safety, the package inserts of most CNS agents in Japan uniformly prohibit patients from driving. Although more evidence-based information regarding the effects of drugs on driving performance is needed, the current evaluation methods for driving performance abroad cannot be applied directly to Japanese drivers because of differences in traffic environments, laws, and constitutions. Therefore, we plan to establish a new driving simulator (DS) that would enable the next-day residual effects of drugs on driving performance to be examined.

Methods: In this double-blind, randomized, placebo-controlled, crossover trial, we plan to recruit 26 healthy Japanese males aged 21 to 64 years through advertisements. During the test periods, which will take place twice every other week, the participants will undergo a DS evaluation in the hospital for 2 days/1 night after the first and last doses of the study drug following 8 days of administration. The participants in the study drug group will take zopiclone 7.5 mg at bedtime on the first and eighth days in the hospital, and placebo on the other days. The DS evaluation consists of road tracking, car following, and harsh braking tests. The primary outcome is the standard deviation of lateral position (SDLP), which is a gold standard evaluation item, in the 60-min road-tracking test. The exploratory outcomes are other evaluation items in the DS tests, in the Karolinska Sleepiness Scale sleep questionnaire, and the Profile of Mood States Second Edition rating scale. The estimated difference in the SDLP between the zopiclone and placebo groups will then be calculated.

Trial registration: This study was registered at ClinicalTrials.gov NCT04108351, on September 30, 2019. Ethics approval was obtained from the Ethics Committee at Hakata Clinic and the Nagoya University Medical School Hospital Bioethics Review Committee.

Conflict of interest statement

MI has no conflicts of interest to declare. KI has received speakers’ honoraria from, or has served as a consultant to, Dainippon Sumitomo, Janssen, Meiji Seika Pharma, Mochida, Otsuka, Taisho, Takeda, Tanabe Mitsubishi, and Pfizer. DK and NT are employees of Taisho Pharmaceutical Co., Ltd., Japan. MA has received subsidies from Eisai. NO has received research support or speakers’ honoraria from, or has served as a consultant to, Abbvie, Asahi Kasei Pharma, Astellas, Dainippon Sumitomo, Eisai, Eli Lilly, GlaxoSmithKline, Janssen, Meiji Seika Pharma, Mochida, MSD, Novartis Pharma, Ono, Otsuka, Pfizer, Shionogi, Takeda, Tanabe Mitsubishi, Sanofi, and Yoshitomi.