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

2.Taste effects

• 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.