1.Real world experience observational studies of gefapixant use in patients with RCC/UCC
• Descriptive analysis of gefapixant patients in general: Frequency, severity, daytime/nighttime cough, cough bouts, tolerance for triggering factors, other
• Onset of action of improvements in cough frequency and severity
• Long term durability of treatment effects with treatment continuation or discontinuation and follow up beyond 1 year
• Effects of RCC/UCC treatment with gefapixant on co-morbidities potentially caused by CC (see example list below)
• Impact of cough frequency reduction and/or severity on patient-relevant outcomes (see example list below)
Examples of cough outcomes:
• Cough-specific QoL (e.g., LCQ)
• Patients/clinician global impression of change
• Patients’ overall satisfaction with treatment
• Quantified impact on daily activities, including work
• Sustainability of cough improvement after stopping gefapixant and effectiveness of restarting
• Spouse/family impact
• Evaluation of “short and simple” validated PRO cough management/scoring tools in treatment of RCC and UCC
Examples of co-morbidity outcomes:
• Sleep quality improvement
• Depression, anxiety, other mood disorders
• Musculo-skeletal pain
• Management of taste effects, e.g.: timing of dosing (before/after meals/nighttime), timing of food intake, other …
• Assessment by patients of both cough improvement, tolerability of taste effects and overall treatment satisfaction
3.Studies in human (tissues) to evaluate pathophysiological mechanisms of RCC and UCC
• Characterization of ATP release and c-fiber stimulation in patients
- Is RCC/UCC associated with/caused by increased ATP production by airway epithelial cells or increased ATP sensitivity of P2X3 and P2X2/3 receptors, or both?
• Is local reduction of ATP metabolism in patients with RCC/UCC a possible alternative mechanism?
• Characterization of neurologic pathways and mechanisms involved in RCC and UCC, including neuroplasticity.
- Understanding of centrally mediated circuitry/control of the hypersensitized reflex arc that characterizes RCC/UCC
- Does reduced ability to suppress cough play a role in modulating RCC/UCC and the responsiveness, or lack thereof, to peripheral P2X3 inhibition?
4.Pre-clinical mechanistic studies to investigate
• ATP release and its role in cough (i.e. cells that release ATP, factors that result in release, effects upstream from ATP release, other functions/effects of ATP release in airways).
• Potential mechanisms to further understand excessive ATP release vs hyper-response of ATP receptors.
• The role of the P2X3, P2X2 and P2X2/3 receptor activation and inhibition in animal models of cough and taste.