Introduction Les patients souffrant de toux chronique réfractaire sont souvent traités pour des maladies sous-jacentes connues pour être fréquemment associées à de la toux. L’objectif est d’évaluer dans la toux chronique réfractaire (TOCRI) les traitements utilisés au cours du temps pour ces causes suspectées de la toux. Méthodes L’étude SOOTHE (NCT04678206) est une étude clinique de phase 2b, randomisée, multicentrique, en double aveugle, contrôlée par placebo, en 2 groupes parallèles permettant de déterminer la dose thérapeutique de camlipixant dans le traitement de la TOCRI. Cette étude post-hoc évalue les traitements antérieurs et concomitants rapportés par les patients (pts) et notés par les investigateurs. Résultats Parmi les 310 pts analysés avec TOCRI, 73,2 %, 75,5 % et 69,4 % rapportaient un traitement antérieur et 31,6 %, 36,5 % et 28,4 % un traitement concomitant au moment du screening pour respectivement l’asthme, le reflux gastro-œsophagien (RGO) et le syndrome de toux d’origine des voies aériennes supérieures (STOVAS). La plupart des pts déclarant avoir reçu antérieurement un traitement pour l’asthme, le RGO ou le STOVAS, ont déclaré l’absence d’amélioration de leurs symptômes, aussi bien les hommes que les femmes. Au screening, plus d’hommes que de femmes ont déclaré un traitement concomitant pour l’asthme. La proportion de pts qui rapportaient un traitement préalable ou concomitant de l’asthme ou du STOVAS était similaire chez les<65 ans et≥65 ans mais plus de patients≥65 ans avaient reçu ou recevaient un traitement du RGO. Davantage de pts<65 ans ont déclaré l’absence d’amélioration avec un traitement préalable par antileucotriène par rapport aux≥65 ans (Fig. 1). Conclusion Malgré l’utilisation de traitements pour des causes potentielles classiques de toux chronique, les patients inclus n’avaient pas un contrôle correct de leur toux indépendamment de leur âge ou de leur genre.

IntroductionIn two phase 3, randomized, double-blind trials of the P2X3-receptor antagonist gefapixant (COUGH-1 and COUGH-2), participants with refractory or unexplained chronic cough (RCC and UCC) demonstrated significant reductions in 24-hour cough frequency with gefapixant 45 mg twice daily (BID) following 12 (COUGH-1) and 24 (COUGH-2) weeks of treatment. Herein, we present a pooled analysis of patient-reported outcomes (PROs) and safety data from an extension of COUGH-1 and COUGH-2 through 52 weeks of treatment.MethodsCOUGH-1 and COUGH-2 enrolled participants aged ≥18 years with chronic cough lasting ≥1 year, a diagnosis of RCC or UCC, and a baseline cough severity visual analog scale (VAS) score ≥40 mm on a 100-mm scale. Participants were randomized to receive placebo, gefapixant 15 mg BID, or gefapixant 45 mg BID for 52 weeks. The PROs used to evaluate efficacy included the Leicester Cough Questionnaire (LCQ), cough severity VAS, and Cough Severity Diary (CSD). Logistic-regression models evaluated change from baseline to week 52, where participants were classified as responders as follows: ≥1.3-point increase in LCQ total score, ≥30-mm reduction in mean weekly cough severity VAS, and ≥1.3- and ≥2.7-point reductions in mean weekly CSD total score. Adverse events (AEs) were monitored. Because efficacy was only demonstrated with gefapixant 45 mg BID, only the placebo and gefapixant 45 mg BID cohorts are presented in this report.ResultsThere were 2044 participants included in the pooled data set. Across all PROs and time points, gefapixant 45 mg BID was consistently favored over placebo (figure 1). Frequently reported AEs were taste related. Discontinuations due to taste-related AEs were 14% vs <1% in the gefapixant 45 mg BID vs placebo cohorts, respectively. Serious AEs occurred in 6% of participants in each cohort.ConclusionsTreatment for 52 weeks with gefapixant 45 mg BID resulted in clinically meaningful patient-reported efficacy relative to placebo across all PROs. Taste-related AEs led to discontinuations in a small proportion of participants who received gefapixant, and the occurrence of serious AEs with gefapixant was similar to that of placebo. These data support the long-term, patient-relevant efficacy of gefapixant 45 mg BID for treatment of RCC or UCC.

Introduction Previous studies characterizing patients with chronic cough (CC) have typically included patients with CC without a specific focus on patients with guidelines-diagnosed refractory CC (RCC) or unexplained CC (UCC). This analysis assessed the medical history, cough severity, and cough-related quality of life (QOL) at baseline in participants with RCC and UCC enrolled in two global phase 3 trials. Methods Pooled data from participants enrolled in two phase 3, randomized, placebo-controlled clinical trials of the P2X3-receptor antagonist gefapixant (COUGH-1, NCT03449134; COUGH-2, NCT03449147) were used in this analysis. Participants were adults with cough lasting ≥1 year, a diagnosis of RCC or UCC according to guidelines from the American College of Chest Physicians, and a baseline cough severity score ≥40 mm on a 100-mm visual analog scale. Comorbidities and prior medications were identified from participant medical records. Baseline cough metrics included the Cough Severity Diary (CSD) and Leicester Cough Questionnaire (LCQ). The CSD measures cough severity across 3 domains (frequency, intensity, and disruption), with items measured on an 11-point scale (higher scores indicate greater severity). The LCQ assesses health-related QOL, including physical, psychological, and social domains, with a total score ranging from 3 to 21 (lower scores indicate a more impaired QOL). Results Of 2044 participants randomized and treated in COUGH-1 or COUGH-2, 41%, 41%, and 29% had prior diagnoses of asthma, gastroesophageal reflux disease, and rhinitis/upper-airway cough syndrome, respectively; 8% had prior diagnoses of all 3 conditions. Prior medications were consistent with treatments indicated for these comorbidities or cough and included drugs for obstructive airway diseases (70%), acid-related disorders (55%), rhinitis preparations (nasal preparations, 53%; systemic antihistamines, 35%), and cough/cold preparations (34%). Baseline mean total CSD score (N=2038) was 6.0 and baseline mean total LCQ score (N=1949) was 10.4 (table 1). Conclusions Participants in COUGH-1 and COUGH-2 with RCC or UCC had medical histories consistent with diagnostic and treatment workup of CC according to published guidelines. Participants also reported severe cough with significant cough-related QOL impairment. These data help characterize the profile of patients with RCC or UCC and highlight unmet needs for treatments that can relieve their cough burden. Please refer to page A191 for declarations of interest related to this abstract.

IntroductionChronic cough (CC) is a relatively common condition often associated with comorbidities such as asthma, gastroesophageal reflux disease, or upper-airway cough syndrome. A subset of patients experience CC that does not resolve after treatment of cough-associated conditions (refractory CC [RCC]) or for which there is no known cause of CC despite clinical evaluation according to published guidelines (unexplained CC [UCC]). However, no treatments are currently approved for RCC or UCC. In two large phase 3 trials (COUGH-1, NCT03449134; COUGH-2, NCT03449147), the P2X3-receptor antagonist gefapixant demonstrated significant reductions in the primary endpoint (24-hour cough frequency) in participants with RCC or UCC at a dosage of 45 mg twice daily (BID) vs placebo.1 The current analysis assessed objective cough frequency in the pooled population of COUGH-1 and COUGH-2.MethodsAdults aged ≥18 years with CC lasting ≥1 year, a diagnosis of RCC or UCC according to CHEST guidelines, and a baseline cough severity visual analog scale score ≥40 mm were eligible for COUGH-1 and COUGH-2. Participants were randomized to placebo, gefapixant 15 mg BID, or gefapixant 45 mg BID. Objective cough frequency was measured using the VitaloJAK™ (Vitalograph; Buckinghamshire, England) recording device. Cough frequency endpoints included 24-hour and awake cough frequency assessed through Weeks 12 and 24 (COUGH-1 and COUGH-2, respectively). Data were pooled across trials and analyzed at Week 12 using longitudinal analysis of covariance based on log-transformed data.ResultsThe pooled population from COUGH-1 and COUGH-2 included 2044 total participants. Baseline 24-hour and awake cough frequency were similar across treatment groups (table 1). Relative reductions in 24-hour and awake cough frequency for gefapixant 45 mg BID vs placebo were 18.6% (95% CI: 9.2, 27.1) and 17.4% (95% CI: 7.5, 26.2), respectively. No differences in serious adverse events (AEs) were observed across treatment groups. The most common AEs with gefapixant were taste related.ConclusionsCOUGH-1 and COUGH-2 are the largest clinical trials investigating treatment of CC. In this pooled analysis, gefapixant 45 mg BID demonstrated significant reductions in 24-hour and awake cough frequency vs placebo, with no increase in serious AEs.ReferenceMcGarvey, et al. Eur Respir J. 2020;56(suppl 64):3800. Please refer to page A192 for declarations of interest related to this abstract.

Chronic cough (CC) is not well-understood outside of cough clinics. This analysis aimed to describe variations in patient reported triggers of CC.

TYPE: Abstract Publication TOPIC: Allergy and Airway PURPOSE: Phase 3 clinical trials of gefapixant, a P2X3 receptor antagonist, have completed enrollment with refractory chronic cough (RCC) or unexplained chronic cough (UCC) patients; preliminary baseline characteristics are presented here. METHODS: COUGH-2 (NCT03449147) is a Phase 3, randomized, placebo-controlled, double-blind, parallel-group trial to evaluate subjects ≥ 18 years of age, diagnosed with RCC or UCC (≥1 year), and with ≥40 mm on the Cough Severity Visual Analog Scale (VAS). The primary efficacy study period is 24 weeks with a 28-week extension period. Interventions include placebo, gefapixant 15 mg, or gefapixant 45 mg (1:1:1 ratio). Objective and subjective measures will be assessed; the primary endpoint is 24-hour cough frequency (average frequency over 24 hours at Week 24). The primary hypothesis is that at least 1 gefapixant dose level is superior to placebo in reducing 24-hour cough frequency by Week 24. RESULTS: In COUGH-2, 1314 patients were randomized and treated. Baseline demographics are in the Table. Regional distribution is Europe (56%), N. America (22%), Asia Pacific (6.2%), and Other (17%). The demographics were balanced among regions except for longer duration of cough among N. American patients (mean 14 years) vs. other regions (mean 6 to 12 years). CONCLUSIONS: Preliminary baseline characteristics of patients randomized in COUGH-2 are consistent with the demographics observed in other clinical studies of RCC/UCC. CLINICAL IMPLICATIONS: This global study will inform the efficacy and safety profile of gefapixant in the treatment of patients with RCC and UCC. DISCLOSURE: DRM, CL, EU, CA are employees of Merck & Co., Inc., Kenilworth, NJ, USA. AHM, SSB, LM, PVD, IDP, and JAS have received research grants from Merck & Co., Inc., Kenilworth, NJ, USA. This study is being funded by Merck Sharp & Dohme, a subsidiary of Merck & KEYWORDS: chronic cough, antitussive, P2X3

Introduction and objectives Airway sensory nerves involved in the cough reflex may be mediated by adenosine triphosphate (ATP) agonism of P2X purinoceptor 3 (P2X3) receptors. Transient receptor potential vanilloid 4 (TRPV4) activation causes ATP release from airway macrophages and epithelial cells and it is hypothesised that a TRPV4-ATP-P2X3 axis contributes to chronic cough. The aim of this study was to evaluate, using an adaptive design, whether blockade of TRPV4 channels, using the selective TRPV4 channel blocker GSK2798745, is effective in reducing cough. Methods A placebo-controlled, double blind, randomised, two-period crossover study was designed with interim analyses for futility and to allow possible sample size adjustment during the study. Refractory chronic cough patients were recruited from four specialist clinics. Participants received either GSK2798745 or matching placebo once daily for 7 days with a 14–21 day wash out between treatments. Dose of GSK2798745 orally administered was predicted to give ∼65–72% TRPV4 inhibition over 24-hour period. Blood samples were collected for pharmacokinetic assessment. 24-hour cough count (VitaloJAK) was recorded before and after each treatment period. The primary endpoint was total cough counts during day-time hours following 7 days of dosing. Results Interim analysis was performed after 12 participants had completed both treatment periods and showed a 32% increase in cough counts on Day 7 for GSK2798745 compared to placebo. The negative criteria for the study were met and the study was subsequently stopped. At this point 17 participants had been enrolled (Mean 61yrs; 88% female), and 15 completed the study. Final study results for posterior median cough counts are shown in table 1. Conclusion There was no evidence of an anti-tussive effect of GSK2798745, despite cough frequency being highly reproducible within patients and expected drug exposure. Leicester Cough Questionnaire and severity and urge to cough VAS were consistent with this lack of change in cough counts. The design of the study allowed the decision on lack of efficacy to be made with minimal participant exposure to the molecule.

This abstract is funded by: National Institute for Health Research Health Technology Assessment Presented at mini symposium: B14. LATE BREAKING CLINICAL TRIALS AND FIRST REPORTS IN ASTHMA AND COPD Monday 21st May 2018

Abstract Cough is frequently self-limiting, but may persist longer in certain individuals. Most of previous studies on the epidemiology of chronic cough have only measured period prevalence, and thus have afforded limited information on the burden and natural course. We aimed to investigate the epidemiology of chronic cough by using a point prevalence measure in a large-scale general population. We analyzed cross-sectional data collected from 18,071 adults who participated in the Korean National Health and Nutrition Examination Survey 2010–2012. Presence and duration of current cough was ascertained by structured questionnaires, and cough was classified into acute (<3 weeks), subacute (3–8 weeks), or chronic cough (≥8 weeks). Demographic and clinical parameters were examined in relation to chronic cough. The point prevalences of acute, subacute, and chronic cough were 2.5 ± 0.2%, 0.8 ± 0.1% and 2.6 ± 0.2%, respectively. The proportion of current cough showed a steep decrease after 1 week of duration. However, 2 peaks in the prevalence of current cough were revealed; cough durations of less than 1 week and longer than 1 year were most common (31.1% and 27.7% of current cough, respectively). Subacute and chronic cough were more prevalent in the elderly (≥65 years); the positive associations with older age were independent of other confounders, including current smoking and comorbidities. This is the first report on the epidemiology of cough using a point prevalence measure in a nationally representative population sample. Our findings indicate a high burden of chronic cough among adults with current cough in the community. The dual-peak of cough duration suggested that the pathophysiology of acute and chronic cough may differ. The preponderance of elderly people in the prevalence of chronic cough warrants further investigation. In addition, more sophistication and validation of tools to define chronic cough will help our understanding of the epidemiology.

Objectives In this study we explored the effectiveness of treatment with montelukast 10 mg as compared with prednisolone in chronic cough patients with an associated elevated FeNO (The fraction of exhaled nitric oxide in breath) – a marker of eosinophilic inflammation. Methods 50 non-asthmatic patients with chronic cough were recruited sequentially from a specialist cough clinic. 30 patients with high FeNO (≥30 ppb) were randomised to either two weeks prednisolone 20 mg or two weeks montelukast 10 mg followed by montelukast 10 mg for the subsequent two weeks in both arms. A control group of 20 patients with low FeNO (≤20 ppb) were enrolled who received four weeks montelukast. 24 hours cough counting at baseline after 2 and 4 weeks treatment was the primary endpoint. Subjective measures of cough, the Leicester Cough Questionnaire (LCQ), and Hull Airways Reflux Questionnaire (HARQ) were also administered. Results At baseline the average FeNO value in both high FeNO treatment groups was similar (around 60±30 ppb). At the end of the study there was a significant fall in FeNO of approximately 30% in both high FeNO treatment groups (p < 0.005). In the low FeNO group there was no significant change during the study (12±5 ppb). Therapy reduced the number of coughs in 24 hours by approximately 50% in both low and high FeNO groups (p<0.005). HARQ and LCQ scores also improved significantly (p<0.005) in all treatment groups. Conclusions The hypothesis that FeNO could be used as a marker of eosinophilic inflammation in chronic cough was supported by our observation at baseline in the high FeNO group of eosinophilia in both blood and sputum. However, baseline FeNO did not predict overall treatment response. Perhaps the most surprising aspect of our study is the dramatic response in the low FeNO group to montelukast. The fact that montelukast appears to be equally effective in the low FeNO group suggest the either the current markers of eosinophilic lung disease are insufficiently sensitive to pick up low levels of leukotriene activation in the low FeNO group, or that montelukast has its antitussive activity by an alternative mechanism. Abstarct S33 Figure 1 Measurements of FeNO, 24hr cough count, HARQ and LCQ in three treatment groups in three visits. Horizontal bars represent mean and SEM value.