The care for individuals with cystic fibrosis (CF) with at least one F508del mutation will greatly change as a result of the unparalleled clinical benefits observed with the new triple combination CF transmembrane regulator (CFTR) modulator therapy elexacaftor/tezacaftor/ivacaftor (ETI). Incorporating ETI into standard of care creates new motivation and opportunity to consider reductions in overall treatment burden and evaluate whether other chronic medications can now be safely discontinued without loss of clinical benefit. SIMPLIFY is a master protocol poised to test the impact of discontinuing versus continuing two commonly used chronic therapies in people with CF who are at least 12 and older andstable on ETI therapy. The protocol is comprised of two concurrent randomized, controlled trials designed to evaluate the independent short-term effects of discontinuing hypertonic saline or dornase alfa, enabling individuals on both therapies to participate in one or both trials. The primary objective for each trial is to determine whether discontinuing treatment is non-inferior to continuing treatment after establishment of ETI, as measured by the 6-week absolute change in forced expiratory volume in one second (FEV1) % predicted. Developing this study required a balance between ideal study design principles and feasibility. SIMPLIFY will be the largest multicenter, randomized, controlled medication withdrawal study in CF. This study is uniquely positioned to provide timely evidence on whether daily treatment burden can be reduced among individuals on CFTR modulator therapy. Clinical trial registered with www.clinical trials.gov (NCT04378153).  .