PROJECT ABSTRACT Among the 20% of US adults experiencing laryngeal symptoms, 80% are diagnosed with laryngopharyngeal reflux (LPR) based on symptoms alone and empirically treated with proton pump inhibitors (PPIs). However, laryngeal symptoms respond poorly to PPIs, and patients often seek additional evaluation (on average 10 consultations & 6 diagnostic tests). Despite an arduous journey, patients rarely achieve clarity or relief. This usual care approach for laryngeal symptoms significantly impairs quality of life, leads to PPI overuse, and accounts for $50 billion in annual health care costs. The therapeutic dilemma is that varied mechanisms beyond gastric acid contribute to laryngeal symptoms and, thus, acid suppression with PPI is insufficient as a sole therapy. Through clinical trials and outcomes research, our team has identified novel mechanism targeted laryngeal recalibration therapy to address hyper-responsive laryngeal mechanical and cognitive behaviors. Another critical challenge is in the diagnosis of LPR. Our team has developed and validated an array of novel metrics with tremendous diagnostic potential including acid exposure time, a risk prediction score and salivary biomarkers (pepsin, bile acids). These cutting-edge discoveries in light of diagnostic and therapeutic gaps for LPR indicate that a trial of mechanism guided versus usual care PPI is an urgent, unmet need. We are uniquely positioned to address these critical gaps as we have assembled a multidisciplinary team with the requisite expertise in clinical trials, esophageal physiology, laryngology and laryngeal recalibration therapy to ensure successful design and high-quality execution of the MVP (Mechanism guided vs PPI) trial for LPR. This randomized controlled trial (n=160) will compare a mechanism guided strategy which will provide laryngeal recalibration therapy to all subjects as well as PPI to those with elevated esophageal acid versus the usual care empiric PPI strategy in order to address two overarching aims. Specific Aim #1 will determine efficacy of a mechanism guided strategy in patients undergoing evaluation for LPR; and, Specific Aim #2 will examine performance characteristics of esophageal acid exposure, risk prediction score, and salivary biomarkers in order to identify reliable diagnostic methods for the evaluation of LPR. The