Objective To present retention strategies implemented in the COVID-RED trial, a decentralised trial investigating the use of a wearable device for SARS-CoV-2 detection, and to provide insights into study retention and investigate determinants of discontinuation. Patients and Methods The COVID-RED trial collected data from 17,825 participants between 22 February and 18 November 2021. Participants wore a wearable device overnight and synchronised it with a mobile application upon waking. Retention strategies included common and personalised activities. Multivariable logistic regression was used to identify participants at high risk of discontinuation after six months in the trial. Results were combined with insights from behavioural theory to target participants with additional phone calls. Results 14,326 (80.4%) participants remained in the trial after six months and 12,208 (68.5%) until the end of the trial. Multivariable logistic regression identified age, employment situation, living situation, and COVID-19 vaccination status as predictors of discontinuation. Subgroups at high risk of discontinuation were identified and behavioural assessments indicated that the subgroup of vaccinated pensioners would receive additional phone calls. Their dropout rate was 11.4% after phone calls. Conclusion This study describes how innovative and targeted data-driven retention strategies can be applied in a large decentralised clinical trial, and presents the implemented retention strategies and discontinuation rates. Results can serve as a starting point for designing retention strategies in future decentralised trials.