Project Summary/Abstract The CDC states that smoking causes 80% of lung cancers and 443,000 deaths annually and is the leading preventable cause of death in the USA. Smokers have peak cravings at predictable times, but existing NRTs are not tailored to preempt cravings. Further, NRT is often used in isolation from behavioral support despite data supporting the benefits of traditional and mobile-based interventions. Chrono Therapeutics, Inc. (CTI) has developed, patented and clinically tested in humans a smoking cessation system (SCS) for programmed and patient-individualized pulsatile nicotine replacement therapy (NRT) paired with behavioral change techniques for smoking cessation. SCS is the first system that can automatically tailor nicotine plasma throughout the day based on the consistent, daily, predictable craving patterns that smokers experience, providing sustained peak plasma levels when cravings are high and lower (maintenance) levels when cravings are low. The SCS programmable NRT delivery device is integrated with a smartphone-based smoking cessation application, Digital Coach, which provides behavioral support that is synchronized with the smoker?s NRT, craving, and smoking cycle to enable ?smart,? tailored just-in-time digital coaching support. A ?smart? patient compliance sensor that detects when a smoker is not wearing the device will trigger compliance alerts on SCS and a smartphone for real time compliance interventions designed to increase adherence and efficacy. The proposed SBIR Phase IIB project is predicated on a recently-concluded $2.23M Fast Track SBIR Grant 5R44CA171786-03, awarded by the National Cancer Institute, entitled ?SmartStop: Programmable Transdermal Nicotine Replacement Therapy,? and will provide funds for CTI to finalize the designed-for- manufacture SCS prototype, complete FDA validation, and conduct an FDA-indicated definitive double-blind fully-powered (n=200) two-arm randomized controlled trial (RCT) of smoking cessation efficacy comparing SCS (programmable NRT Device dispensing replacement nicotine + Digital Coach) with SCS Placebo (programmable NRT Device without replacement nicotine + Digital Coach). The end goal is to show SCS functionality and superior 6-month quit-rate efficacy over placebo. CTI believes that SCS?s combination of ?smart? NRT, ?smart? behavioral support, and compliance monitoring to increase adherence will more than triple the efficacy of existing NRT products. CTI has successfully raised over $34M in private funding to date in pursuit of this important public health goal.