The Therapeutic Landscape in Chronic Cough.

In recent years, there has been a substantial increase in the development of antitussive therapies and the first new therapy, gefapixant has been licenced in Europe. This review describes current unlicenced treatments for chronic cough and details treatments currently in development for refractory chronic cough and cough in idiopathic pulmonary fibrosis, as well as compounds previously explored.

Efficacy and safety of gefapixant, a P2X3 receptor antagonist, in refractory chronic cough and unexplained chronic cough (COUGH-1 and COUGH-2): results from two double-blind, randomised, parallel-group, placebo-controlled, phase 3 trials.

BACKGROUND: Gefapixant is an oral P2X3 receptor antagonist that has previously shown efficacy and safety in refractory chronic cough and unexplained chronic cough. We therefore aim to confirm the efficacy and safety of gefapixant in participants with refractory chronic cough and unexplained chronic cough. METHODS: COUGH-1 and COUGH-2 were both double-blind, randomised, parallel-group, placebo-controlled, phase 3 trials. COUGH-1 was done in 156 sites in 17 countries and COUGH-2 in 175 sites in 20 countries. We enrolled participants who were 18 years or older with a diagnosis of refractory chronic cough or unexplained chronic cough of 1 year duration or more. Participants were also required to have a cough severity visual analogue scale score of 40 mm or more at screening and baseline. Eligible participants were randomly allocated (1:1:1), using a computer-generated allocation schedule, to one of three treatment groups: placebo, gefapixant 15 mg twice per day, or gefapixant 45 mg twice per day. All study treatments were given orally. Participants were treated over a 12-week main study period in COUGH-1 and a 24-week main study period in COUGH-2; followed by extension periods for a total of up to 52 weeks of treatment in both trials. The primary outcome was placebo-adjusted mean change in 24-h cough frequency at 12 weeks in COUGH-1 and 24 weeks in COUGH-2. Both studies were registered with ClinicalTrials.gov, NCT03449134 (COUGH-1) and NCT03449147 (COUGH-2). FINDINGS: From March 14, 2018, (first participant screened) to July 26, 2019, (last participant screened) 732 patients were recruited in COUGH-1 and 1317 in COUGH-2. COUGH-1 randomly assigned and treated 730 participants (243 [33×3%] with placebo, 244 [33×4%] with gefapixant 15 mg twice per day, and 243 [33×3%] with gefapixant 45 mg twice per day); COUGH-2 randomly assigned and treated 1314 participants (435 [33×1%] with placebo, 440 [33×5%] with gefapixant 15 mg twice per day, and 439 [33×4%] with gefapixant 45 mg twice per day). Participants were mostly female (542 [74×2%] of 730 in COUGH-1 and 984 [74×9%] of 1314 in COUGH-2). The mean age was 59×0 years (SD 12×6) in COUGH-1 and 58×1 years (12×1) in COUGH-2, and the mean cough duration was 11·6 years (SD 9·5) in COUGH-1 and 11·2 years (9·8) in COUGH-2. Gefapixant 45 mg twice per day showed significant reductions in 24-h cough frequency compared with placebo at week 12 in COUGH-1 (18·5% [95% CI 32·9-0·9]; p=0·041) and at week 24 in COUGH-2 (14·6% [26·1-1·4]; p=0·031). Gefapixant 15 mg twice per day did not show a significant reduction in cough frequency versus placebo in both studies. The most common adverse events were related to taste disturbance: ageusia (36 [4·9%] of 730 in COUGH-1 and 86 [6·5%] of 1314 in COUGH-2), dysgeusia (118 [16·2%] in COUGH-1 and 277 [21·1%] in COUGH-2), hypergeusia (3 [0·4%] in COUGH-1 and 6 [0×5%] in COUGH-2), hypogeusia (19 [2·6%] in COUGH-1 and 80 [6·1%] in COUGH-2), and taste disorder (28 [3·8%] in COUGH-1 and 46 [3·5%] in COUGH-2). INTERPRETATION: Gefapixant 45 mg twice per day is the first treatment to show efficacy with an acceptable safety profile in phase 3 clinical trials for refractory chronic cough or unexplained chronic cough. FUNDING: Merck Sharp & Dohme.

How often do healthy people cough?

Objective cough frequency has been reported in several respiratory conditions but the amount that healthy individuals cough daily is unclear. Seventy-nine healthy volunteers (38 males, median [IQR] age 41y [IQR 30-53]) completed 24-hour ambulatory cough monitoring (VitaloJAK™). The audio recording was filtered using a custom written algorithm to remove non-cough sounds and then all individual explosive cough sounds in the filtered file were tagged electronically by trained cough counters. Most coughing occurred during the day and cough numbers over 24 h were generally low (geometric mean of 4.6 coughs) but there was large variability; ranging from 0 to 136 coughs overall. Cough frequency was independent of participant characteristics apart from sex with males coughing significantly, 4-5 fold, more than females during the day and over 24 h (median [IQR] 16.1 [3.8-33.4] vs. 4.1 [1.0-15.0] total coughs; p = 0.015). This is the first report to describe cough frequency in a balanced group of healthy adults using an accurate cough monitoring system. The data reveal a further example of sexual dimorphism in cough, which warrants additional investigation.

Demographic, clinical, and patient-reported outcome data from 2 global, phase 3 trials of chronic cough.

BACKGROUND: The current characterization of patients with refractory or unexplained chronic cough (RCC and UCC, respectively) primarily stems from relatively small clinical studies. OBJECTIVE: To report the baseline medical history and clinical characteristics of individuals with RCC or UCC who were enrolled in COUGH-1 and COUGH-2, 2 large, global, phase 3 trials of gefapixant, a P2 × 3-receptor antagonist. METHODS: Adults with a chronic cough lasting for more than 1 year, diagnosis of RCC or UCC, and score greater than 40 mm on a 100-mm cough severity visual analog scale at both screening and baseline were eligible for enrollment. Demographics, medical history, and cough characteristics were collected at baseline. Cough-related measures included objective cough frequency, cough severity visual analog scale, Leicester Cough Questionnaire, and Hull Airway Reflux Questionnaire. The data were summarized using descriptive statistics. RESULTS: Of 2044 participants, 75% were women; mean age was 58 years, and mean cough duration was approximately 11 years. Among all participants, 73% were previously diagnosed with asthma, gastroesophageal reflux disease, or upper airway cough syndrome. The mean Leicester Cough Questionnaire total score was 10.4, with domain scores reflecting impaired cough-specific quality of life across physical, psychological, and social domains. The mean Hull Airway Reflux Questionnaire score was 39.6, with some of the most burdensome reported items being consistent with features of cough-reflex hypersensitivity. Participant characteristics and cough burden were comparable across geographic regions. CONCLUSION: Participants with RCC or UCC had characteristics consistent with published demographics associated with chronic cough. These data reflect a global population with burdensome cough of long duration and substantial impairment to quality of life. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: COUGH-1, NCT03449134 (https://www. CLINICALTRIALS: gov/ct2/show/NCT03449134); COUGH-2, NCT03449147 (https://clinicaltrials.gov/ct2/show/NCT03449147).

Efficacy and Safety of Eliapixant in Refractory Chronic Cough: The Randomized, Placebo-Controlled Phase 2b PAGANINI Study.

INTRODUCTION: The PAGANINI study evaluated the efficacy and safety of the selective P2X3 antagonist eliapixant in patients with refractory chronic cough (RCC). METHODS: PAGANINI was a randomized, double-blind, parallel-group, placebo-controlled, multicenter, dose-finding, phase 2b study. Adults with RCC lasting ≥ 12 months and cough severity ≥ 40 mm on a visual analog scale at screening were enrolled. Participants were randomized 1:1:1:1 to twice-daily 25 mg, 75 mg, or 150 mg oral eliapixant or placebo for 12 weeks. The primary endpoint was change from baseline in 24-h cough count after 12 weeks of intervention. RESULTS: Overall, 310 participants were randomized to twice-daily eliapixant 25 mg (n = 75), 75 mg (n = 78), 150 mg (n = 80), or placebo (n = 77). A statistically significant dose-response signal with eliapixant was detected for the primary endpoint (all dose-response models, adjusted p < 0.1; one-sided). Adverse events (AEs) were reported in 39 (51%) participants with placebo and 43-51 (57-65%) participants receiving eliapixant. The most common AE was dysgeusia, occurring in 1% (n = 1) of the placebo group and 1-16% (n = 1-13) of the eliapixant groups in a dose-related manner. One case of a moderate drug-induced liver injury occurred in a participant receiving 150 mg twice-daily eliapixant. CONCLUSION: Eliapixant demonstrated efficacy and a favorable taste tolerability profile in RCC. However, a drug-induced liver injury contributed to intensified liver monitoring in clinical trials with eliapixant and discontinuation of the entire development program in all indications by Bayer AG. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04562155; registered September 18, 2020.

A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Phase 2b Trial of P2X3 Receptor Antagonist Sivopixant for Refractory or Unexplained Chronic Cough.

INTRODUCTION: To determine the optimal dose of sivopixant, a highly selective P2X3 receptor antagonist, for refractory or unexplained chronic cough (RCC/UCC). METHODS: In this phase 2b, randomized, double-blind, placebo-controlled, parallel-group, multicenter trial, patients received sivopixant 50, 150, or 300 mg or placebo once daily for 4 weeks. The primary endpoint was a change from baseline in 24-h cough frequency (coughs/h) with sivopixant vs placebo. RESULTS: Overall, 390/406 randomized patients completed the study. Placebo-adjusted changes in hourly cough count over 24 h were 13.17% (P = 0.3532), - 1.77% (P = 0.8935), and - 12.47% (P = 0.3241) and in cough severity (visual analog scale) were 1.75 mm (P = 0.5854), - 1.21 mm (P = 0.7056), and - 6.55 mm (P = 0.0433) with sivopixant 50, 150, and 300 mg, respectively. Placebo-adjusted changes from baseline in Leicester Cough Questionnaire total scores were - 0.37 (P = 0.4207), - 0.07 (P = 0.8806), and 0.69 (P = 0.1473) with sivopixant 50, 150, and 300 mg, respectively. Additionally, 61.3%, 78.3%, 86.8%, and 71.4% of patients receiving sivopixant 50, 150, and 300 mg and placebo, respectively, reported any improvements in Patient Global Impression of Change. The incidence of treatment-emergent adverse events (TEAEs) was 25.7%, 32.0%, 49.0%, and 20.6% in sivopixant 50, 150, and 300 mg and placebo groups, respectively; all TEAEs in the sivopixant group were mild-to-moderate. CONCLUSION: Sivopixant did not demonstrate a statistically significant difference vs placebo in change from baseline in 24-h cough frequency. The dose of 300 mg has potential for RCC/UCC, showing the greatest improvements in cough frequency and patient-reported outcomes and dose-related mild to moderate reversible taste disturbance, although further trials are needed. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04110054; registered September 26, 2019.

Longitudinal assessment of lung clearance index to monitor disease progression in children and adults with cystic fibrosis.

BACKGROUND: Lung clearance index (LCI) is a valuable research tool in cystic fibrosis (CF) but clinical application has been limited by technical challenges and uncertainty about how to interpret longitudinal change. In order to help inform clinical practice, this study aimed to assess feasibility, repeatability and longitudinal LCI change in children and adults with CF with predominantly mild baseline disease. METHODS: Prospective, 3-year, multicentre, observational study of repeated LCI measurement at time of clinical review in patients with CF >5 years, delivered using a rapid wash-in system. RESULTS: 112 patients completed at least one LCI assessment and 98 (90%) were still under follow-up at study end. The median (IQR) age was 14.7 (8.6-22.2) years and the mean (SD) FEV1 z-score was -1.2 (1.3). Of 81 subjects with normal FEV1 (>-2 z-scores), 63% had raised LCI (indicating worse lung function). For repeat stable measurements within 6 months, the mean (limits of agreement) change in LCI was 0.9% (-18.8% to 20.7%). A latent class growth model analysis identified four discrete clusters with high accuracy, differentiated by baseline LCI and FEV1. Baseline LCI was the strongest factor associated with longitudinal change. The median total test time was under 19 min. CONCLUSIONS: Most patients with CF with well-preserved lung function show stable LCI over time. Cluster behaviours can be identified and baseline LCI is a risk factor for future progression. These results support the use of LCI in clinical practice in identifying patients at risk of lung function decline.

The novel bronchodilator navafenterol: a phase 2a, multicentre, randomised, double-blind, placebo-controlled crossover trial in COPD.

BACKGROUND: Navafenterol (AZD8871) belongs to a new class of bronchodilator, the single-molecule muscarinic antagonist and ß-agonist, developed for the treatment of COPD. This study aimed to evaluate the efficacy, pharmacokinetics and safety of navafenterol versus placebo and an active comparator treatment for moderate-to-severe COPD. METHODS: This phase 2a, randomised, multicentre (Germany and UK), double-blind, double-dummy, three-way complete crossover study (ClinicalTrials.gov identifier: NCT03645434) compared 2 weeks' treatment of once-daily navafenterol 600 µg via inhalation with placebo and a fixed-dose combination bronchodilator (umeclidinium/vilanterol (UMEC/VI); 62.5 µg/25 µg) in participants with moderate-to-severe COPD. The primary outcome was change from baseline in trough forced expiratory volume in 1 s (FEV1) on day 15. Secondary end-points included change from baseline in peak FEV1; change from baseline in Breathlessness, Cough and Sputum Scale (BCSS); change from baseline in COPD Assessment Tool (CAT); adverse events; and pharmacokinetics. RESULTS: 73 participants were randomised. After 14 days, trough FEV1 was significantly improved with navafenterol compared with placebo (least-squares (LS) mean difference 0.202 L; p<0.0001). There was no significant difference in FEV1 between navafenterol and UMEC/VI (LS mean difference -0.046 L; p=0.075). COPD symptoms (CAT and BCSS) showed significantly greater improvements with both active treatments versus placebo (all p<0.005). Novel objective monitoring (VitaloJAK) showed that cough was reduced with both active treatments compared with placebo. Safety profiles were similar across the treatment groups and no serious adverse events were reported in the navafenterol treatment period. CONCLUSION: Once-daily navafenterol was well tolerated, improved lung function and reduced COPD-related symptoms, similar to an established once-daily fixed-dose combination bronchodilator.

Validation and Meaningful Change Thresholds for an Objective Cough Frequency Measurement in Chronic Cough.

PURPOSE: Objective cough frequency is used to assess efficacy of chronic cough (CC) treatments. The objective of this study was to explore the relationship between objective cough frequency and cough-specific patient-reported outcomes (PROs) and estimate a clinically meaningful change threshold (MCT) for objective cough frequency. METHODS: Data collected in a phase 2b study in participants with refractory or unexplained CC were used to investigate the relationship between 24-h cough frequency (measured using an ambulatory cough monitor) and cough-specific PROs (i.e., cough severity visual analog scale, cough severity diary, Leicester Cough Questionnaire). Convergent validity was assessed using Spearman ρ. An MCT for 24-h cough frequency was estimated using the patient global impression of change (PGIC) scale as an anchor. RESULTS: Correlations between 24-h cough frequency and cough-specific PROs at baseline, Week 4, and Week 12 were significant (P < 0.0001) but low to moderate in strength (ρ = 0.30-0.58). Participants categorized as very much improved/much improved (i.e., PGIC of 1 or 2) or minimally improved (i.e., PGIC of 3) had mean 24-h cough frequency reductions of 55% and 30%, respectively. Receiver operating characteristic curve analysis suggested that a 24-h cough frequency reduction of 38% optimizes sensitivity and specificity for predicting a PGIC score of 1-3. CONCLUSION: Objective 24-h cough frequency is significantly associated with cough-specific PROs, but cough frequency and PROs most likely capture distinct aspects of CC. A ≥ 30% reduction in 24-h cough frequency is a reasonable MCT to define treatment response in CC clinical trials.

Improvements in Objective and Subjective Measures of Chronic Cough with Gefapixant: A Pooled Phase 3 Efficacy Analysis of Predefined Subgroups.

INTRODUCTION: In phase 3 trials (COUGH-1/COUGH-2), gefapixant 45 mg twice daily significantly reduced 24-h cough frequency vs placebo in refractory or unexplained chronic cough (RCC or UCC). METHODS: Here, the efficacy of gefapixant 45 mg vs placebo was evaluated across COUGH-1/COUGH-2 in predefined subgroups based on sex, region, age, cough duration, cough severity, cough frequency, and diagnosis (RCC, UCC). Awake cough frequency reductions at Week 12 and LCQ response rates (i.e., ≥ 1.3-point improvement) at Week 24 were assessed. RESULTS: Among 1360 participants analyzed, gefapixant 45 mg resulted in consistent awake cough frequency reductions overall and across predefined subgroups at Week 12. Gefapixant also resulted in improved LCQ scores across subgroups at Week 24; ≥ 70% of participants in each subgroup treated with gefapixant 45 mg had an LCQ response. CONCLUSION: These data suggest gefapixant 45 mg provides consistent objective and subjective efficacy across subgroups of individuals with RCC or UCC.

Aprepitant for Cough in Lung Cancer. A Randomized Placebo-controlled Trial and Mechanistic Insights.

Rationale: Effective cough treatments are a significant unmet need in patients with lung cancer. Aprepitant is a licensed treatment for nausea and vomiting, which blocks substance P activation of NK-1 (neurokinin 1) receptors, a mechanism also implicated in cough.Objectives: To assess aprepitant in patients with lung cancer with cough and evaluate mechanisms in vagal nerve tissue.Methods: Randomized double-blind crossover trial of patients with lung cancer and bothersome cough. They received 3 days of aprepitant or matched placebo; after a 3-day washout, patients crossed to the alternative treatment. The primary endpoint was awake cough frequency measured at screening and Day 3 of each treatment; secondary endpoints included patient-reported outcomes. In vitro, the depolarization of isolated guinea pig and human vagus nerve sections in grease-gap recording chambers, indicative of sensory nerve activation, was measured to evaluate the mechanism.Measurements and Main Results: Twenty patients with lung cancer enrolled, with a mean age 66 years (±7.7); 60% were female and 80% had non-small cell cancer, 50% had advanced stage, and 55% had World Health Organization performance status 1. Cough frequency improved with aprepitant, reducing by 22.2% (95% confidence interval [CI], 2.8-37.7%) over placebo while awake (P = 0.03), 30.3% (95% CI, 12.7-44.3) over 24 hours (P = 0.002), and 59.8% (95% CI, 15.1-86.0) during sleep (P = 0.081). Patient-reported outcomes all significantly improved. Substance P depolarized both guinea pig and human vagus nerve. Aprepitant significantly inhibited substance P-induced depolarization by 78% in guinea pig (P = 0.0145) and 94% in human vagus (P = 0.0145).Conclusions: Substance P activation of NK-1 receptors appears to be an important mechanism driving cough in lung cancer, and NK-1 antagonists show promise as antitussive therapies.

Eliapixant (BAY 1817080), a P2X3 receptor antagonist, in refractory chronic cough: a randomised, placebo-controlled, crossover phase 2a study.

BACKGROUND: ATP acting via P2X3 receptors is an important mediator of refractory chronic cough (RCC). This phase 2a double-blinded crossover study assessed the safety, tolerability and efficacy of eliapixant (BAY 1817080), a selective P2X3 receptor antagonist, in adults with RCC attending specialist centres. METHODS: In period A, patients received placebo for 2 weeks then eliapixant 10 mg for 1 week. In period B, patients received eliapixant 50, 200 and 750 mg twice daily for 1 week per dose level. Patients were randomised 1:1 to period A-B (n=20) or B-A (n=20). The primary efficacy end-point was change in cough frequency assessed over 24 h. The primary safety end-point was frequency and severity of adverse events (AEs). RESULTS: 37 patients completed randomised therapy. Mean cough frequency fell by 17.4% versus baseline with placebo. Eliapixant reduced cough frequency at doses ≥50 mg (reduction versus placebo at 750 mg: 25% (90% CI 11.5-36.5%); p=0.002). Doses ≥50 mg also significantly reduced cough severity. AEs, mostly mild or moderate, were reported in 65% of patients with placebo and 41-49% receiving eliapixant. Cumulative rates of taste-related AEs were 3% with placebo and 5-21% with eliapixant; all were mild. CONCLUSIONS: Selective P2X3 antagonism with eliapixant significantly reduced cough frequency and severity, confirming this as a viable therapeutic pathway for RCC. Taste-related side-effects were lower at therapeutic doses than with the less selective P2X3 antagonist gefapixant. Selective P2X3 antagonism appears to be a novel therapeutic approach for RCC.

Characterization of Patients With Refractory or Unexplained Chronic Cough Participating in a Phase 2 Clinical Trial of the P2X3-Receptor Antagonist Gefapixant.

PURPOSE: This analysis assesses clinical characteristics of patients with refractory chronic cough (RCC) or unexplained chronic cough (UCC) enrolled in a phase 2 study to better understand this patient population. METHODS: Patients with RCC/UCC lasting for ≥ 1 year and cough severity visual analog scale (VAS) score of > 40 mm at screening were eligible. Demographics, clinical characteristics, and medical history were collected at baseline. Cough-related measures included cough severity VAS, Cough Severity Diary (CSD), Leicester Cough Questionnaire (LCQ), and a structured cough-trigger questionnaire. Medication history included all medications 30 days before screening and chronic cough treatments within 1 year before screening. Data were summarized using descriptive statistics. RESULTS: Patients (N = 253; female, 76%; mean age, 60 years) had severe (mean cough severity VAS, 57.5 mm) and long-lasting (median duration, 11 years) cough. The most burdensome self-reported aspects included psychological and social factors (LCQ) and cough frequency and intensity (CSD). Patient-reported triggers were consistent with cough hypersensitivity (e.g., 95% to 96% reported irritation or tickle in throat). Common reported comorbidities included gastroesophageal reflux disease (GERD; 56%), allergic rhinitis (47%), and asthma (30%); 12% of patients had been diagnosed with all 3 conditions. The most common prior medications included inhaled or oral steroids (21%), antihistamines (15%), and antacids (15%). CONCLUSION: Patients with RCC/UCC had severe, long-lasting, and burdensome cough with clinical features of cough hypersensitivity. Many patients had been diagnosed with GERD, allergic rhinitis, and asthma but had a persistent cough despite treatment of these conditions. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02612610; registered November 20, 2015.

The Effect of Pain Conditioning on Experimentally Evoked Cough: Evidence of Impaired Endogenous Inhibitory Control Mechanisms in Refractory Chronic Cough.

The pathophysiology of refractory chronic cough (RCC) is unclear. We hypothesised that endogenous inhibitory control mechanisms, such as those activated by noxiousstimuli inducing pain (conditioned pain modulation (CPM)), may be capable of inhibiting coughing and urge to cough evoked by inhaled capsaicin. Furthermore, these mechanisms may be impaired in patients with RCC.The objective was to investigate the effects of pain on cough and urge to cough (UTC) in healthy volunteers (HV) and RCC. HV and RCC patients underwent a randomised, controlled, 4-way cross-over study comparing the effect of 4 interventions on capsaicin evoked coughing and UTC. The interventions comprised immersing a hand in i) noxious cold-water, ii) warm water, iii) warm water but instructed to voluntarily supress coughing and iv) no intervention. The co-primary outcomes were numbers of evoked coughs and UTC scores.Twenty HV (mean age 50.1(±SD14.2), M:F 10:10) and 20 RCC (age 60.1(±7.9), M:F 9:11) participated. Overall, noxious cold water reduced capsaicin evoked UTC scores and cough numbers compared with warm water (1.6 (95% C.I. 1.3-2.0) versus 2.2 (1.8-2.6) p<0.001; 4.8 coughs (3.7-6.2) versus 7.9 coughs (6.7-9.5) p<0.001, respectively). HV and RCC demonstrated similar reductions in the UTC during noxious cold-water immersion, but noxious cold water and voluntary suppression interventions were less effective in RCC than HV in reducing capsaicin evoked cough (p=0.041).Endogenous inhibitory control mechanisms, specifically those activated by pain, can reduce both coughing and the UTC. Impairment of endogenous inhibitory control mechanisms may contribute to excessive coughing in RCC.

Gefapixant in two randomised dose-escalation studies in chronic cough.

BACKGROUND AND OBJECTIVES: Gefapixant has previously demonstrated efficacy in the treatment of refractory chronic cough at a high daily dose. The current investigations explore efficacy and tolerability of gefapixant, a P2X3 receptor antagonist, for the treatment of chronic cough using a dose-escalation approach. MATERIALS AND METHODS: Two randomised, double-blind, placebo-controlled, crossover, dose-escalation studies recruited participants with refractory chronic cough. Patients were assigned to receive ascending doses of gefapixant (study 1: 50-200 mg, study 2: 7.5-50 mg) or placebo for 16 days, then crossed-over after washout. The primary end-point was awake cough frequency assessed using a 24-h ambulatory cough monitor at baseline and on day 4 of each dose. Patient-reported outcomes included a cough severity visual analogue scale and the cough severity diary. RESULTS: In clinical studies, gefapixant doses ≥30 mg produced maximal improvements in cough frequency compared with placebo (p<0.05); reported cough severity measures improved at similar doses. Taste disturbance exhibited a different relationship with dose, apparently maximal at doses ≥150 mg. CONCLUSIONS: P2X3 antagonism with gefapixant demonstrates anti-tussive efficacy and improved tolerability at lower doses than previously investigated. Studies of longer duration are warranted.

Allergen challenge increases capsaicin-evoked cough responses in patients with allergic asthma.

BACKGROUND: Cough is a common and troublesome symptom in asthmatic patients, but little is known about the neuronal pathways that trigger cough. The mechanisms by which airway inflammation, airway hyperresponsiveness, and variable airflow obstruction cause cough are unclear. OBJECTIVE: We sought to investigate the effects of allergen exposure on cough reflex sensitivity. METHODS: We performed a 9-visit, randomized, single-blind, placebo-controlled, 2-way crossover study comparing cough responses to inhaled capsaicin in patients with mild atopic asthma after allergen challenge compared with diluent control. Full-dose capsaicin challenge was performed at screening to determine the capsaicin dose inducing a half-maximal response, which was subsequently administered at 30 minutes and 24 hours after inhaled allergen/diluent challenge. Spontaneous coughing was measured for 24 hours after allergen/diluent. Methacholine challenge and sputum induction were performed before and after allergen/diluent challenge. RESULTS: Twelve steroid-naive subjects completed the study (6 female subjects; mean age, 34.8 years). Allergen inhalation caused both an early (mean ± SD, 38.2% ± 13.0%) and late (mean ± SD, 23.7% ± 13.2%) decrease in FEV1 and an increase in sputum eosinophil counts 24 hours later (after diluent: median, 1.9% [interquartile range, 0.8% to 5.8%]; after allergen: median, 14.9% [interquartile range, 8.9% to 37.3%]; P = .005). There was also an increase in capsaicin-evoked coughs after allergen exposure compared with diluent at both 30 minutes (geometric mean coughs, 21.9 [95% CI, 16.5-29.20] vs 12.1 [95% CI, 8.3-17.7]; P < .001) and 24 hours (geometric mean coughs, 16.1 [95% CI, 11.3-23.0] vs 9.8 [95% CI, 6.1-15.8]; P = .001). Allergen exposure was also associated with an increase in spontaneous coughs over 24 hours. CONCLUSION: Allergen-induced bronchoconstriction and airway eosinophilia result in increased cough reflex sensitivity to capsaicin associated with an increase in 24-hour spontaneous coughing.

Randomised, double-blind, placebo-controlled pilot trial of omeprazole in idiopathic pulmonary fibrosis.

BACKGROUND: Cough is a common, disabling symptom of idiopathic pulmonary fibrosis (IPF), which may be exacerbated by acid reflux. Inhibiting gastric acid secretion could potentially reduce cough. This study aimed to determine the feasibility of a larger, multicentre trial of omeprazole for cough in IPF, to assess safety and to quantify cough. METHODS: Single-centre, double-blind, randomised, placebo-controlled pilot trial of the proton pump inhibitor (PPI) omeprazole (20 mg twice daily for 3 months) in patients with IPF. Primary objectives were to assess feasibility and acceptability of trial procedures. The primary clinical outcome was cough frequency. RESULTS: Forty-five participants were randomised (23 to omeprazole, 22 to placebo), with 40 (20 in each group) having cough monitoring before and after treatment. 280 patients were screened to yield these numbers, with barriers to discontinuing antacids the single biggest reason for non-recruitment. Recruitment averaged 1.5 participants per month. Geometric mean cough frequency at the end of treatment, adjusted for baseline, was 39.1% lower (95% CI 66.0% lower to 9.3% higher) in the omeprazole group compared with placebo. Omeprazole was well tolerated and adverse event profiles were similar in both groups, although there was a small excess of lower respiratory tract infection and a small fall in forced expiratory volume and forced vital capacity associated with omeprazole. CONCLUSIONS: A large randomised controlled trial of PPIs for cough in IPF appears feasible and justified but should address barriers to randomisation and incorporate safety assessments in relation to respiratory infection and changes in lung function.

Emerging targets for cough therapies; NK1 receptor antagonists.

Cough is mediated by vagal afferent fibres innervating the larynx and proximal airways. Pre-clinical studies suggest that vagal C fibres produce Substance P, one of the tachykinin family of neuropeptides, which has been shown to enhance cough via the neurokinin-1 (NK-1) receptor and studies in animal models have also shown that NK-1 antagonists are effective at blocking induced cough. In the past, tachykinin receptor antagonists have yielded disappointing results in treating asthma and cough, however most of the activity of the agents tested was restricted to the peripheral nervous system and also the outcomes measures evaluating cough not optimal. More recently a small proof of concept study has suggest that aprepitant, an NK-1 antagonist licensed for the prevention of chemotherapy induced nausea and vomiting, might have beneficial effects on cough frequency in patients with lung cancer. In this review we investigate the current evidence for the anti-tussive effect of these therapies and the clinical trials in progress.