Despite the intuitive attractiveness of bringing research to participants rather thanmaking them come to central study sites, widespread decentralized enrollment has not been common in clinical trials. The need for clinical research in the context of the COVID-19 pandemic, along with innovations in technology, led us to use a decentralized trial approach in our Phase 2 COVID-19 trial. We used real-time acquisition and transmission of health-related data using home-based monitoring devices and mobile applications to assess outcomes. This approach not only avoids spreading COVID-19but it also can support inclusion of participants in more diverse socioeconomic circumstances and in rural settings. Our team developed and deployed a decentralized trial platform to support patient engagement and adverse event reporting. Clinicians, engineers, and informaticians on our research team developed a Clinical-Trial-in-a-Box tool to optimally collect and analyze data from multiple decentralized platforms. Applying the decentralized model in Long COVID, using digital health technology and personal devices integrated with our telehealth platform, we share the lessons learned from our work, along with challenges and future possibilities.