Background: Implementation of an adaptive study design and leveraging historical data have the potential to significantly reduce the number of patients required for a clinical study. Herein we describe the adaptive study design used in the SPYRAL HTN-OFF MED Pivotal trial. Methods: The SPYRAL HTN-OFF MED Pivotal trial is a randomized, sham-controlled trial to evaluate the safety and efficacy of renal denervation in the absence of antihypertensive medications. The powered primary efficacy endpoint is the baseline-adjusted change in 24-h systolic blood pressure at 3 months. A Bayesian adaptive study design with an informative prior was set up to allow enrollment until a sufficient sample size is achieved to have high probability of meeting the primary efficacy endpoint. In this case the informative prior is data from the 80 patients in the previously published SPYRAL HTN-OFF MED trial, and we use a novel statistical method to incorporate this historical data in the analysis. At each of 2 planned interim analyses, the probability of success or futility will be assessed. If either condition is met, enrollment is stopped, and otherwise enrollment continues. A maximum of 300 patients will be evaluated for the primary and secondary endpoints if enrollment continues after both interim analyses. Results: Interim analyses are forthcoming for the SPYRAL HTN-OFF MED Pivotal trial. If enrollment is stopped at the first or second interim analysis because of a high probability of success, results will be available sooner with fewer patients enrolled. Conclusion: A novel Bayesian adaptive study design with an informative prior was implemented in the SPYRAL HTN-OFF MED Pivotal trial to accurately assess the safety and efficacy of renal denervation in the absence of antihypertensive medications, while reducing the number of enrolled patients, exposure to a sham control, and time to presentation of results.