oRIoN: An investigation into whether the methodology used in hypotonic saline cough challenge can be refined

INTERVENTION: This study is split into two phases. Phase A: Assessing changes to the challenge protocol 60 participants with refractory chronic cough and 30 healthy volunteers will be recruited from a single UK centre and undergo inhalational cough challenges at 2‐7 day intervals with hypo‐osmolar saline and isotonic saline in a randomised order. Each of the hypo‐osmolar challenges will have a slightly different methodology. Participants will be randomised to a sequence group defining the order in which cough challenges are to be performed, according to a computer‐generated schedule. Participants will be blinded to the nature of each challenge agent but the investigator performing the challenges will not due to the nature of the challenges. Phase B: Assessing the challenge using different nebuliser devices 12 participants with refractory chronic cough and 12 healthy volunteers will be recruited from a single UK centre and undergo inhalational cough challenges at 2‐14 day intervals with hypo‐osmolar saline. Participants will be randomised to a sequence group defining the order in which nebuliser devices are to used for each challenge, according to a computer‐generated schedule. Patients will be blinded to which challenge is using the "original" nebuliser device and which is using the new "alternate" nebuliser device. The investigator performing the challenge will not be blinded due to the nature of the devices. CONDITION: Chronic cough ; Respiratory PRIMARY OUTCOME: Phase A: Agreement between the original challenge and other challenge protocols in classification of disease status measured using by the cough response at to each cough challenge Phase B: Agreement in the classification of disease status using the original nebuliser device and the alternative device measured using by the cough response at to each cough challenge SECONDARY OUTCOME: Cough responses in all subjects measured using Ema Xand ED50 at each challenge visit Evidence of any systematic differences in disease classification (RUCC vs HV) between the challenge using the original device versus the alternative device (Phase B) measured using based on the cough response at to each challenge Evidence of any systematic differences in disease classification (RUCC vs HV) between the original challenge protocol and other challenge protocols measured using based on the cough response at to each challenge Participant‐reported acceptability of the cough challenge measured using set questions at the end of each challenge Patient reported cough quality of life measured using the Leicester Cough Questionnaire (LCQ) at baseline (Phase A and Phase B) and at the last visit (Phase B) Patient reported cough triggers and sensations measured using the TOPIC questionnaire at baseline Patient‐reported sensations measured using visual analogue scale at before and after each inhalational challenge Repeatability of evoked cough responses to hypotonic saline challenge using an alternative device measured using Ema Xand ED50 at least 2 weeks apart INCLUSION CRITERIA: All participants: 1. Males and females aged =18 years 2. Non‐smokers, or ex‐smokers with =20 pack years smoking history and =6 months abstinence 3. Spirometry within normal limits (defined as forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) predicted values =70% and FEV1/FVC ratio of =70%) 4. Has capacity to consent 5. Able to attend all the scheduled visits at the clinical research facility (CRF) within the protocol timeline Healthy volunteers: 1. No clinically relevant medical conditions (self‐reported), which, in the opinion of the investigator may affect participation or study results 2. No history of or current respiratory disease Chronic cough patients: 1. Have a physician diagnosis of refractory and/or unexplained chronic cough as defined by British Thoracic Society (BTS)/European Respiratory Society (ERS) guidelines 2. No evidence of asthma during clinical evaluation of chronic cough e.g. e