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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 [greater than or equal to] 12 months and cough severity [greater than or equal to] 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., Author(s): Peter V. Dicpinigaitis [sup.1], Alyn H. Morice [sup.2], Jaclyn A. Smith [sup.3], Mandel R. Sher [sup.4], Michael Vaezi [sup.5], Laurent Guilleminault [sup.6] [sup.7], Akio Niimi [sup.8], Kerstin Gude [sup.9], [...]

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., Author(s): Lorcan McGarvey [sup.1], Jaclyn A. Smith [sup.2], Alyn Morice [sup.3], Surinder S. Birring [sup.4], Kian Fan Chung [sup.5], Peter V. Dicpinigaitis [sup.6], Akio Niimi [sup.7], Michael S. Benninger [sup.8], [...]

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., [greater than or equal to] 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; [greater than or equal to] 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., Author(s): Jaclyn A. Smith [sup.1], Surinder S. Birring [sup.2], Peter V. Dicpinigaitis [sup.3], Lorcan P. McGarvey [sup.4], Alyn H. Morice [sup.5], Ian D. Pavord [sup.6], Imran Satia [sup.7] [sup.8], Stuart [...]

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 [greater than or equal to] 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, Author(s): Alyn H. Morice [sup.1], Surinder S. Birring [sup.2], Jaclyn A. Smith [sup.3], Lorcan P. McGarvey [sup.4], Jonathan Schelfhout [sup.5], Allison Martin Nguyen [sup.5], Zhi Jin Xu [sup.5], Wen-Chi Wu [...]

Spatiotemporal variations of phytoplankton populations in agricultural irrigation ponds need to be accounted for in order to properly assess water quality. Phytoplankton cell and photosynthetic pigment concentrations are two common metrics used to characterize phytoplankton communities. This work evaluated depth and time of the day as factors affecting discrete sampling of phytoplankton. The abundance of chlorophytes, diatoms, cyanobacteria, flagellates, and dinoflagellates, as well as chlorophyll-a and phycocyanin pigments, were determined in samples taken at the surface and depth, in 0.5 m increments, in three to five spatial replications at 9 a.m., 12 p.m., and 3 p.m. in two ponds in Maryland, USA. Depth was a significant factor for photosynthetic pigment concentration variations in both ponds on most sampling dates and time of day was a significant factor for photosynthetic pigment concentrations in half of the sampling dates. Depth was not a significant factor in cell concentration variations for any of the phytoplankton groups observed, but time of day was a significant factor in 40% of the sampling dates. Two distinct patterns in pigment concentration daily variation were observed. The first featured a continuous increase with depth throughout the day. The second showed maximum concentrations at the surface in the morning changing to maximum concentrations at 0.5 m depth at 12 p.m. and 3 p.m.; these patterns corresponded to different morning solar irradiance levels. This indicates that sampling depth and time can be a significant factor when evaluating photosynthetic pigments and should be accounted for in monitoring programs that rely on pigments for decision-making. [ABSTRACT FROM AUTHOR]