Efficacy and Safety of varying dosage of Gefapixant in Patients with chronic cough. A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Efficacy and Safety of varying dosage of Gefapixant in Patients with chronic cough. 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A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Muhammad Hudaib, Nabira Tabassum, Hurais Malik, Umer Bin Tariq, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5779351/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background A cough that remains unresolved for longer than 8 weeks is referred to as chronic cough, and it is estimated that 10% of the adult population of the world suffers from chronic cough. Gefapixant is a purinergic receptor P2x3 receptor antagonist. P2x3 receptors are ATP-gated ion channels on the peripheral sensory C fibers in the airways. Objective We conducted a systematic review and meta-analysis of RCTs to investigate whether the chronic cough patients would benefit from gefapixant administration or not when compared to placebo. Methods We selected only those double-arm randomized controlled trials (RCTs) which included participants presenting with a chronic cough in patients 18 years or older. We excluded all the articles published in languages other than English Language. Furthermore, all the studies other than RCTs were also omitted. Articles yielded from the electronic search were exported to EndNote Reference Library software to remove any duplicates. Analyses were done using the Review Manager 5.4 tool. Mean values and standard deviations were retrieved for the continuous outcomes given as raw data. Results 8 RCTs selected for the statistical analysis consisted of 2024 participants (1011 in the intervention group and 1013 in the placebo group). The outcomes resulted to be significant with 24-hour cough frequency, the mean difference [MD] = -5.26, 95% confidence interval [CI] -7.18 to -3.33; p = 0.00001; n = 3518, awake cough frequency (c/h) [MD] = -6.78, 95% confidence interval [CI] -9.46 to -4.09; p = 0.00001; n = 3472 patients., night cough frequency (c/h) [MD] = -4.07, 95% confidence interval [CI] -5.49 to -2.65; p = 0.00001; n = 479, patients cough severity VAS (mm) [MD] = -14.84, 95% confidence interval [-19.92, -9.76], p = 0.00001, n= 1297, cough severity diary difference [MD] = -0.85; 95% confidence interval [CI]: -1.14, -0.56; p-value = 0.00001; n = 1219, Total LCQ score MD=2.04, 95% CI = 1.09 to 2.98, p<0.0001, n =869. Conclusion To conclude, the lowest efficacious dose was 50 mg twice daily and helped reduce 24-hour cough frequency, awake cough frequency, night cough frequency, and cough severity using VAS in a dose-dependent manner. Gefapixant showed a significant risk of adverse events which include dysgeusia, hypogeusia, nausea, any adverse event, taste-related and drug-related adverse events, and serious AEs Pulmonology Chronic cough P2x3 receptors Gefapixant 24-hour cough frequency cough severity diary Visual Analog Scale Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Highlights There are about six studies that investigate gefapixant’s effects on patients with chronic cough Although gefapixant has improved impact on chronic cough by reducing symptoms however this meta-analysis illicit that there is a significant risk of adverse effects. Gefapixant helped reduce 24-hour cough frequency, awake cough frequency, night cough frequency, and cough severity using VAS in a dose-dependent manner. Gefapixant showed a significant risk of adverse events which include dysgeusia, hypogeusia, nausea, any adverse event, taste-related and drug-related adverse events, and serious adverse events. Introduction Cough, often regarded as a seemingly innocuous reflex, is the most frequently reported symptom in medical practice.[ 1 ] However, when this reflex becomes persistent and endures for more than eight weeks, it takes on a more ominous character known as chronic cough. Chronic cough is a global health concern, impacting millions worldwide and presenting a significant therapeutic challenge. Its implications extend beyond the physical, profoundly affecting patients' quality of life. It is estimated that approximately 10% of the world's adult population grapples with this vexing condition.[ 2 ] The etiology of chronic cough is multifaceted, with both pulmonary and extrapulmonary origins. Pulmonary causes encompass a spectrum of conditions, including asthma, chronic obstructive pulmonary disease, bronchiectasis, pulmonary fibrosis, and rhinosinusitis. Extrapulmonary culprits extend to gastroesophageal reflux disease, cardiac cough, and somatic cough.[ 3 ] In cases where the cough defies resolution even after addressing the underlying cause, it assumes the unenviable label of refractory chronic cough. Astonishingly, in 42% of chronic cough cases, an underlying cause remains elusive.[ 4 ] The impact of chronic cough extends far beyond its intrinsic discomfort. It exerts a substantial adverse effect on patients' quality of life, leading to increased healthcare utilization and economic burden.[ 5 ] Patients suffering from chronic cough are not only more likely to experience urinary stress incontinence but also endure cough syncope, depression, anxiety, and a myriad of other distressing consequences. Emerging evidence has begun to unveil the role of hypersensitive neuronal pathways in perpetuating this recalcitrant condition.[ 6 ] Consequently, drugs capable of modifying these neuronal pathways, such as Gabapentin, morphine, and amitriptyline, have emerged as promising therapeutic options.[ 7 – 9 ] Gefapixant, a purinergic receptor P2X3 antagonist, offers new hope in the quest to conquer refractory chronic cough. These P2X3 receptors are ATP-gated ion channels found on peripheral sensory C fibers in the airways[^10^]. By targeting these receptors, gefapixant acts to normalize the afferent sensitivity innervating the airways. Clinical studies have demonstrated its effectiveness in reducing cough frequency, with doses ranging from 7.5 mg to 600 mg twice daily.[ 11 – 13 ] However, it's worth noting that high doses of gefapixant have been associated with altered taste sensation, possibly attributed to its effects on gustatory innervation. Despite encouraging results from individual randomized controlled trials, a comprehensive evaluation of gefapixant's efficacy and safety across multiple studies is conspicuously absent. This meta-analysis aims to bridge this gap by systematically reviewing eight randomized controlled trials. The objective is to compare gefapixant's effectiveness in reducing both day and night cough frequency, as well as cough severity, across these trials. Furthermore, we will scrutinize the safety profile of gefapixant by examining reported side effects in participants receiving the drug, as compared to those receiving a placebo or alternative control interventions. By synthesizing data from multiple trials, this meta-analysis promises to provide a robust assessment of gefapixant's potential as a therapeutic option for chronic cough. The findings will not only enhance our comprehension of gefapixant's efficacy and safety but also equip clinicians with evidence-based insights to inform their clinical decisions, thereby advancing the management of this debilitating condition. Methods Study Design This systematic review and meta-analysis meticulously adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.[ 14 ] Data Sources and Search Strategy A systematic and thorough literature search was carried out across three major online databases: PubMed, Google Scholar, and Embase. The search strategy aimed to encompass all relevant studies up to May 10, 2023, and utilized an array of keywords and Medical Subject Heading (MeSH) terms, including specific drug names such as "MK 7264," "cough," "Gefapixant," and "AF 219." The detailed search syntax is available in Supplementary Table 1. Eligibility Criteria The inclusion of studies was contingent upon predefined eligibility criteria. Only double-arm randomized controlled trials (RCTs) were considered for inclusion in this systematic review and meta-analysis. The target population comprised individuals aged 18 years or older diagnosed with chronic cough. The intervention of interest was the administration of the antitussive agent, gefapixant, in comparison to a placebo. Primary outcomes were designed to assess the efficacy of gefapixant, specifically focusing on reductions in both daytime and nighttime cough frequency, as well as cough severity. Exclusion criteria encompassed studies with non-RCT designs, studies published in languages other than English, trials employing active agents instead of placebos, studies involving participants with acute cough, individuals younger than 18 years of age, and animal experiments. Data Extraction and Quality Assessment Upon conducting the comprehensive database search, EndNote Reference Library software was employed to facilitate the removal of duplicate studies. Subsequently, two authors (M.H. and H.M.) meticulously screened titles and abstracts, excluding irrelevant articles. This was followed by an in-depth full-text review to assess eligibility. Discrepancies in the study selection process were resolved through consultation with a third author (A.R.S.S). Data extracted from eligible studies was systematically recorded in an online Microsoft Excel Spreadsheet. This information included crucial study characteristics, such as the first author's name, publication year, study design, and the number of enrolled patients. (Table 1 ). Table 1 Baseline Characteristics of Included RCTs. Study Subgroups Study design No. of patients Age in Years (Mean ± SD) Males (%) BMI (kg/m2) (Mean ± SD) Cough duration (years) (Mean ± SD) Cough severity VAS (mm) (Mean ± SD) Cough severity diary (CSD) (Mean ± SD) Total LCQ Score (Mean ± SD) Abdulqawi 2014 [12] RCT 24 49.5 ± 36.2 6 (25) 26.9 ± 11.8 N/A N/A N/A N/A Morice 2019 [18] Healthy volunteers RCT 12 37.8 ± 8.6 1 (8.3) N/A N/A N/A N/A N/A Chronic cough patients 24 61.1 ± 8.6 3 (12.5) N/A 14.6 ± 9.8 68.6 ± 17.45 N/A N/A Smith 1 2020 [19] Gefapixant RCT 29 63.2 ± 7.3 4 (13.7) 26.6 ± 4.8 N/A 58.4 ± 18.7 4.2 ± 1.9 12.3 ± 3.1 Placebo 52.2 ± 19.2 3.7 ± 1.6 13.1 ± 3.4 Smith 2 2020 [19] Gefapixant RCT 30 60.2 ± 11.0 6 (20) 26.5 ± 4.8 N/A 54.5 ± 24.3 4.5 ± 2.0 12.6 ± 4.0 Placebo 57.2 ± 23.7 4.5 ± 1.9 13.3 ± 3.8 Smith 3 2020 [20] 7.5 mg RCT 64 59·9 ± 10·5 48 (75) 27·9 ± 4·5 13·5 ± 10·0 56·7 ± 20·7 4·1 ± 1·7 12·1 ± 2·7 20 mg 63 61·8 ± 9·1 48 (76) 28·0 ± 4·6 14·9 ± 13·9 58·3 ± 25·1 4·2 ± 2·1 12·0 ± 3·3 50 mg 63 59·3 ± 9·2 50 (79) 27·2 ± 5·0 12·3 ± 8·2 57·9 ± 19·7 4·3 ± 1·8 11·4 ± 2·8 Placebo 63 60·0 ± 10·9 47 (75) 27·6 ± 4·8 17·1 ± 13·3 57·4 ± 23·1 4·1 ± 1·8 12·2 ± 2·8 McGarvey 1 2022 [21] 15 mg RCT 244 59·6 ± 11·7 63 (25.8) N/A 11·8 ± 9·1 68·2 ± 15·0 6·1 ± 1·7 10·5 ± 2·9 45 mg 243 59·4 ± 13·1 63 (25.9) N/A 11·2 ± 9·4 67·9 ± 12·8 6·1 ± 1·5 10·5 ± 2·7 Placebo 243 57·9 ± 13·1 62 (25.5) N/A 11·7 ± 9·9 69·1 ± 13·9 6·2 ± 1·5 10·0 ± 3·1 McGarvey 2 2022 [21] 15 mg RCT 440 58·6 ± 11·4 111 (25.2) N/A 11·9 ± 10·7 67·4 ± 14·8 5·9 ± 1·8 10·4 ± 3·0 45 mg 439 57·8 ± 12·4 110 (25) N/A 10·9 ± 9·9 67·7 ± 13·9 6·0 ± 1·6 10·4 ± 3·0 Placebo 435 58·0 ± 12·6 109 (25) N/A 10·7 ± 8·8 68·5 ± 14·3 6·0 ± 1·6 10·3 ± 3·0 McGarvey 3 2023 [22] 45 mg RCT 206 52.5 ± 13.8 72 (34.9) N/A N/A 67.2 ± 14.9 N/A 10.8 ± 3.0 Placebo 209 52.5 ± 13.8 75 (35.8) N/A N/A 66.2 ± 14.9 N/A 11.3 ± 2.8 Primary outcomes included the efficacy of gefapixant, as measured by awake cough frequency (coughs per hour), night cough frequency (coughs per hour), 24-hour cough frequency (coughs per hour), cough severity assessed by the 100 mm Visual Analog Scale (VAS), cough severity diary data, and total Leicester Cough Questionnaire (LCQ) scores for assessing the quality of life. Secondary outcomes encompassed the safety profile of gefapixant, incorporating adverse events such as ageusia, dysgeusia, hypotension, parenthesis, hypoaesthesia, cough, headache, nausea, nasopharyngitis, upper respiratory tract infections, urological/renal events, taste-related adverse effects, drug-related adverse effects, serious adverse effects, and discontinuation due to adverse effects. (Table 2 ) Table 2 Secondary outcomes Outcomes Effect size RR 95% CI p-value Ageusia 5.71 2.57–12.69 0.06 Dysgeusia 6.78 4.30-10.69 0.0002 Hypogeusia 9.31 5.39–16.08 0.6 Paraesthesia 1.32 0.74–2.37 0.79 Hypoaesthesia 1.72 0.83–3.56 0.85 Cough 1.9 0.80–4.49 0.98 Headache 1.08 0.91–1.28 0.51 Nausea 2.44 0.94–6.29 0.002 Nasopharyngitis 1.14 0.96–1.36 0.28 Upper respiratory tract infection 1.43 0.98–2.07 0.13 Renal/Urological events 0.56 0.29–1.08 0.96 Any adverse events 1.18 0.95–1.47 0.00001 Taste-related AE 4.12 1.80–9.42 0.00001 Drug-related AEs 2.5 1.86–3.37 0.00001 Serious AEs 0.52 0.24–1.11 0.0003 Discontinued due to AEs 1.64 0.70–3.85 0.14 The efficacy of Gefapixant on chronic cough has been reported in the outcome table as mean difference and standard deviation while the safety profile as frequency and percentage.To calculate the missing Standard deviation (SD) of some of the follow-up variables, the mean of follow-up variables was divided by the mean of baseline standard deviations.Change in mean was calculated by subtracting baseline mean from follow-up mean and change in standard deviation was calculated using the following formula: SD change= \(\:\sqrt{SD{\left(baseline\right)}^{2}+SD{\left(final\right)}^{2}-2\times\:r\times\:SD\left(baseline\right)\times\:SD\left(final\right)}\) [ 15 ] Where “r” is the correlation coefficient for the correlation between the baseline and final value. Statistical Analysis Continuous outcomes were reported as mean differences (MD) along with 95% confidence intervals (CIs), while dichotomous variables were presented as relative risks (RR) with their respective 95% CIs. The analysis was conducted utilizing a random-effect model, and forest plots were generated using the Generic-inverse variance method. Statistical significance was determined at a threshold of P < 0.05. Heterogeneity among the included studies was assessed using Higgins I^2 statistic, with results categorized as low (I^2 < 50%), moderate (50% ≤ I^2 < 75%), or high (I^2 ≥ 75%) heterogeneity.[ 16 ] In cases of high heterogeneity, individual study impact on pooled results was explored using sensitivity analysis or meta-regression. The comprehensive statistical analysis was conducted using the Cochrane Collaboration's Review Manager (RevMan, Version 5.4). Quality Assessment The risk of bias within the included studies was meticulously assessed by two independent authors (H.M. and U.T.) using the revised Cochrane Risk of Bias Tool for Randomized Controlled Trials (RoB2.0).[ 17 ] Each study's quality was categorized as low risk, high risk, or some concerns of bias. In instances of disagreement regarding risk of bias assessment, resolution was achieved through discussion between the two assessors, with a third author (A.R.S.S.) acting as an arbiter when necessary (Supplementary Fig. 1). Publication Bias Assessment Funnel plots were generated for all outcomes using a random-effect model to assess the potential presence of publication bias (Supplementary Fig. 2–7). Results Study Selection A comprehensive search across four databases yielded a total of 493 initial results. After the meticulous application of study eligibility criteria, 168 articles were excluded based on the evaluation of titles and abstracts. Subsequently, a thorough full-text review was conducted, resulting in the inclusion of 8 randomized controlled trials (RCTs) for the systematic review and meta-analysis. A visual representation of the study selection process is presented in Fig. 1 . Patients' Demographics (Table 1 ) The analysis encompasses a total of 8 trials, comprising 1011 participants in the intervention group and 1013 in the placebo group, all of which employed RCT designs. Notably, the included studies exhibited considerable variability in the dosage of gefapixant administered, spanning from 7.5 to 600 mg twice daily. Participants in these studies displayed a mean or median age ranging from 37.8 to 63.2 years. Furthermore, all eight trials exhibited a lower proportion of male participants. The mean duration of cough among the study populations ranged from 10.7 to 17.1 years, with a notable presence of overweight participants. All the studies were dedicated to investigating the efficacy of gefapixant in patients afflicted with chronic cough. Detailed information regarding treatment duration and follow-up can be found in Supplementary Table 2. Primary Outcomes 24‑h Cough Frequency (c/h) (Fig. 2 ) Eight studies were included in this updated meta-analysis[ 12 , 18 – 22 ], with seven of them reporting data on 24-hour cough frequency (c/h). The pooled analysis demonstrated a significant reduction in 24-hour cough frequency in patients treated with gefapixant compared to those receiving a placebo (MD = -5.26, 95% CI -7.18 to -3.33; p = 0.00001; I^2 = 97%; n = 3518 patients). To address the high heterogeneity observed, a subgroup analysis focusing on the 7.5mg dose of gefapixant demonstrated homogeneity (p = 0.25; I^2 = 26%), revealing a trend towards lower 24-hour cough frequency in the treatment group compared to the placebo (MD = -2.43, 95% CI -3.13 to -1.73; p = 0.00001). Awake Cough Frequency (c/h) (Fig. 3 ) Six studies were included in this analysis, which explored the correlation between gefapixant treatment and awake cough frequency among chronic cough patients[ 12 , 19 – 21 ]. The pooled results demonstrated a significant difference in awake cough frequency, favoring the gefapixant treatment group (MD = -6.78, 95% CI -9.46 to -4.09; p = 0.00001; I^2 = 98%; n = 3472 patients). Subgroup analysis at the 7.5mg dose level showed homogeneity (p = 0.4, I^2 = 0%), further favoring gefapixant (MD = -3.52, 95% CI -4.25 to -2.78; p = 0.00001). Night Cough Frequency (c/h) (Fig. 4 ) Night cough frequency was assessed by three studies[ 12 , 19 , 20 ], and quantitative analysis demonstrated a significant difference (MD = -4.07, 95% CI -5.49 to -2.65; p = 0.00001; I^2 = 0%; n = 479 patients) in favor of gefapixant treatment. Cough Severity Using Visual Analog Scale (mm) (Fig. 5 ) A total of six out of eight studies were included in the analysis, revealing a significant dose-dependent difference in cough severity between the gefapixant and placebo groups (MD = -14.84, 95% CI [-19.92, -9.76], p = 0.00001, n = 1297). However, significant heterogeneity was detected among the included studies (p = 0.00001, I^2 = 81%). Subgroup analysis based on gefapixant dosage showed no significant heterogeneity at doses of 7.5 mg (p = 0.57, I^2 = 0%), 50 mg (p = 0.64, I^2 = 0%), and 100 mg (p = 0.93, I^2 = 0%). Cough Severity Diary (Fig. 6 ) Four out of eight studies reported a cough severity diary as an outcome measure[ 19 , 20 , 22 ]. The meta-analysis demonstrated a statistically significant difference in cough severity diary scores, favoring gefapixant treatment (MD = -0.85; 95% CI: -1.14, -0.56; p-value = 0.00001; I^2 = 63%; n = 1219). A subgroup analysis highlighted the effectiveness of the 7.5 mg dose of gefapixant in reducing cough severity (MD = -0.50; 95% CI -0.88, -0.12; p < 0.009; I^2 = 0%), while the 50 mg dose showed a non-significant trend toward reducing cough severity (MD = -0.46; 95% CI -0.96, 0.03; p < 0.07; I^2 = 55%). Total Leicester Cough Questionnaire Score (Fig. 7 ) The analysis of cough-related quality of life, as assessed by the LCQ score in four studies[ 19 , 20 , 22 ], indicated that the placebo group had significantly higher Total LCQ Scores compared to the gefapixant group (MD = 2.04, 95% CI = 1.09 to 2.98, p < 0.0001, I^2 = 84%; 869 participants). Heterogeneity was observed, and subgroup analysis based on the 50 mg dosage of gefapixant demonstrated moderate heterogeneity (MD = 2.80, 95% CI: 1.64 to 3.96, p = 0.00001, I^2 = 58%). Secondary Outcomes (Table 2 ) A comprehensive assessment of secondary outcomes, including ageusia, dysgeusia, hypogeusia, paraesthesia, hypoesthesia, cough, headache, nausea, nasopharyngitis, upper respiratory tract infection, renal/urological events, any adverse events, taste-related adverse effects, drug-related adverse effects, serious adverse effects, and discontinuation due to adverse effects, revealed that gefapixant was associated with several significant adverse effects. Specifically, gefapixant demonstrated significant associations with dysgeusia, nausea, any adverse events, taste-related adverse effects, drug-related adverse effects, and serious adverse effects. Quality Assessment The Cochrane risk of bias tool assessed the included randomized controlled trials (RCTs), indicating a low risk of bias in selection, performance, and reporting domains. However, McGarvey1 showed attrition bias, suggesting potential impact from participant loss or incomplete data. [ 21 ] Smith S1 exhibited detection bias, indicating systematic outcome assessment differences between intervention and control groups.[ 19 ] (Fig. 1 ) Publication Bias (Supplementary Fig. 1) Funnel plots were made to evaluate the presence of publication bias. The funnel plots visually displayed the distribution of studies for each outcome, with the vertical axis representing the effect size and the horizontal axis representing the precision of the estimates. In general, the funnel plots exhibited an equal and symmetrical distribution of studies on both sides of the vertical axis, indicating no significant publication bias for most outcomes. However, it is worth noting that two outcomes, cough severity dairy and cough severity VAS, displayed an asymmetric distribution of studies, with an apparent lack of smaller studies reporting more extreme effect sizes. This observation suggests a potential publication bias in these specific outcomes. Discussion Our systematic review and meta-analysis aimed at determining the efficacy of gefapixant as a novel antitussive agent in patients with chronic cough included six studies with eight randomized control trials consisting of 2024 individuals. Our findings show that administering gefapixant to participants with a chronic cough had no practical impact on quality of life (LCQ score) nevertheless, gefapixant is shown to have a positive effect on mitigating serious adverse events. It reveals the effectiveness of gefapixant in reducing cough frequency (24-hour, awake and night/asleep) in a dose-dependent pattern. Furthermore, a trend favoring gefapixant was seen in the severity of cough (VAS and diary). Additionally, there was a rise in the risk of all-type adverse events, drug-related adverse events, including those related to taste (ageusia, hypogeusia, dysgeusia), and nausea in a dose-dependent manner. However, the risk of hypogeusia did not increase proportionally with the dose. There were no significant differences in hypoesthesia, paraesthesia, cough, headache, nasopharyngitis, upper respiratory tract infections, and renal/urological adverse events so discontinuation of the treatment was rare. In both primary and specialty care, chronic cough (CC) is frequently experienced and is referred to as a cough that lasts for more than eight weeks, negatively affecting the quality of life with a prevalence of 5–10%. [ 23 , 24 – 27 ] Majority of adult patients who seek medical assistance due to CC primarily share a common clinical presentation.[ 28 , 29 ] These patients frequently report heightened sensitivity to environmental irritants such as perfumes, bleaches, frigid air, citric acid, or capsaicin.[ 6 ] Inhalation of such stimuli, inflammation, or mechanical stress/injury can result in a sensation of tickling or irritation in the throat and an urge to cough, indicating increased sensitivity of the neuronal pathways that regulate cough.[ 27 , 31 ] We know that continuous stimulation of the P2X3 receptor found on sensory nerve fibers (vagal afferent), predominantly C fibers in the larynx can lead to prolonged hypersensitivity. This can be achieved by TRPV4, a nociceptor present throughout the airway epithelium when activated by hypo-osmotic stimuli.[ 32 , 33 ] The authors demonstrate that TRPV4 activation leads to ATP release through pannexin channels, and the subsequent ATP activation of neurons can be inhibited by a P2X3 antagonist.[ 34 ] The term "cough hypersensitivity syndrome" (CHS) was introduced to describe the clinical condition characterized by an increased cough reflex, which may or may not encompass specific phenotypes such as cough-variant asthma or eosinophilic bronchitis, which is characterized by eosinophilic inflammation. On the other hand, patients with predominately heartburn symptoms may have a phenotype that reflects gastroesophageal reflux disease (GERD) and cough.[ 6 , 35 , 36 ] A previous study hypothesized about the molecular makeup to understand the mode of action of gefapixant (formerly known as AF-219). The crystal structure of P2X3 complexed with AF-219 and the differences in the amino acid sequences contributing to the selectivity of AF-219 for P2X3 over the other P2X subtypes.[ 37 ] However further investigation is needed to solidify this statement. Another study confirms the efficacy of MK-7264 (Gefapixant) in rat models thereby supporting its clinical investigation for chronic sensitization conditions.[ 38 ] Gefapixant has been evaluated in patients with CC at doses ranging from 7.5 mg to 600 mg twice daily. Firstly, we found a significant reduction in 24-hour and awake cough frequency by gefapixant through a dose-escalation pattern in both participants who had chronic coughs either for a longer or shorter duration. It is to be noted that doses of ⩾30 mg produce maximal reductions in objective cough frequency and patient-reported outcomes such as cough severity as acknowledged by our results. Secondly, the improvement in night-time cough frequency is observed only at higher dosages of the medication. This can be attributed to the fact that a higher dosage of the medication may be more effective in reducing cough symptoms during sleep and give a maximal therapeutic effect. Raj AA et.al [ 39 ] established the minimal important difference (MID) of the LCQ for patients with chronic cough as ⩾1.3 to be considered significant. Of note, our finding on the lag in improvement in quality of life (LCQ score) is consistence with a cross-sectional survey by Chamberlain SA et al [ 23 ] who concluded that gefapixant brings a negative impact on quality of life. Ultimately, understanding why the LCQ score did not favor gefapixant requires a close examination of the study design, patient population, and other factors that may have influenced the results. Despite the large placebo response observed in the trial, patients who were treated with gefapixant experienced significant improvements in their cough-specific health status compared to those who received the placebo. These findings suggest that gefapixant may be a promising treatment option for patients with chronic cough who have not responded to other therapies. For A.Es, we observed a particularly large placebo response for nausea in relation to previous studies in which placebo responses have been observed. There are a few explanations for why this could be, one of which involves stimulation of higher regions within the central nervous system (such as the cerebral cortex) by vagal afferents, inducing nausea.[ 40 ] Additionally, through a statistical point of view, the least risk ratio was seen in the case of renal/urological events [ 41 ] and severe adverse events indicating a trend towards gefapixant while a large effect size of hypogeusia (diminished sense of taste) and dysgeusia (altered perception of taste) was drawn from subgroup analysis indicating a trend favoring placebo.[ 41 ] Concurring with these outcomes, results were consistent with RCT conducted by Nussbaum J 41, especially for the prevalence of taste-related adverse events, often resolved while on treatment or soon after discontinuation. Based on the patterns of P2X3 receptor expression in vagal C fibers, the effectiveness of cough treatment relies more on the P2X3 homomeric receptor. [ 42 ] Whereas contingent on animal studies (double knock-out mice), it is believed that the heterotrimeric P2X2/3 receptor plays a role in facilitating communication between taste buds and gustatory sensory nerves.[ 41 ] Further data utilizing both selective and non-selective compounds could provide valuable insights into the comparison of P2X3 homotrimers and P2X2/3 heterotrimers in terms of efficacy and taste-related adverse events. This additional information would help in understanding the relative contributions of these receptor types and their potential impact on treatment outcomes and the occurrence of taste-related side effects. There are several new P2X3 receptors antagonists like BLU-5937, eliapixant (BAY1817080), filapixant (BAY1902607), and sivopixant (S-600918), [ 44 – 46 ] that have been developed recently and are currently being studied. [ 44 – 46 ] These newer agents offer a higher P2X3 selectivity over P2X2/3 receptors, which may help reduce taste-related adverse effects compared to gefapixant. However, this potential benefit needs to be validated in larger-scale and comparative trials in the future. Limitations While our study provides a comprehensive analysis of Gefapixant's effectiveness, it comes with several limitations. Firstly, no previous study has considered the collective impact of all published randomized controlled trials on Gefapixant, making our meta-analysis pioneering. Secondly, we exclusively included randomized, double-blinded, and placebo-controlled trials, potentially excluding valuable data from other study types. Our focus was on adults with unexplained chronic coughs, leaving the medication's efficacy in other patient populations unexplored. Furthermore, we excluded active smokers, ex-smokers, and patients with recent respiratory tract infections, limiting our understanding of Gefapixant's effectiveness in these groups. Some trials measured responses subjectively, introducing potential bias, and our follow-up periods were relatively short, not fully capturing long-term effects. Lastly, we identified publication bias in some outcomes, requiring cautious interpretation. Conclusions In conclusion, Gefapixant represents a promising development in the treatment of chronic cough and could potentially be a 'game-changer' for individuals suffering from this condition. Our analysis revealed that Gefapixant exhibited efficacy across multiple domains, with the lowest efficacious dose identified as 50 mg twice daily. It effectively reduced 24-hour cough frequency, awake cough frequency, night cough frequency, and cough severity, as assessed by the Visual Analog Scale (VAS), in a dose-dependent manner. However, it's important to note that Gefapixant was associated with a significant risk of adverse events, including dysgeusia, hypogeusia, nausea, and various other adverse events, both drug-related and not. Serious adverse events were also observed. Notably, there was no significant association with ageusia, paraesthesia, hypoesthesia, cough, headache, nasopharyngitis, respiratory and urinary tract infections, or discontinuation due to adverse events. Declarations Funding : No funding was received to assist with the preparation of this manuscript. Conflicts of interest Financial interests : The authors declare they have no financial interests Non-financial interests : none The authors declare that they have no financial or non-financial interests to disclose The corresponding author makes this declaration on behalf of all the authors involved in this publication. References Schappert SM (1993) National Ambulatory Medical Care Survey: 1991 summary. 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Int J Mol Sci 22(11):5797 Published 2021 May 28. 10.3390/ijms22115797 Nussbaum J, Hussain A, Ford A et al (2022) A Randomized, Placebo-Controlled Study to Investigate the Safety, Tolerability, and Pharmacokinetics of 3 Weeks of Orally Administered Gefapixant in Healthy Younger and Older Adults. Lung 200(3):315–323. 10.1007/s00408-022-00543-0 Ford AP (2012) In pursuit of P2X3 antagonists: novel therapeutics for chronic pain and afferent sensitization. Purinergic Signal 8(Suppl 1):3–26. 10.1007/s11302-011-9271-6 Finger TE, Danilova V, Barrows J et al (2005) ATP signaling is crucial for communication from taste buds to gustatory nerves. Science 310(5753):1495–1499. 10.1126/science.1118435 Friedrich C, Francke K, Birring SS et al (2023) The P2X3 receptor antagonist filapixant in patients with refractory chronic cough: a randomized controlled trial. Respir Res. ;24(1):109. Published 2023 Apr 11. 10.1186/s12931-023-02384-8 Niimi A, Saito J, Kamei T et al (2022) Randomised trial of the P2X3 receptor antagonist sivopixant for refractory chronic cough. Eur Respir J 59(6):2100725 Published 2022 Jun 2. 10.1183/13993003.00725-2021 Zhang M, Wang S, Yu L, Xu X, Qiu Z (2020) The role of ATP in cough hypersensitivity syndrome: new targets for treatment. J Thorac Dis 12(5):2781–2790. 10.21037/jtd-20-cough-001 Morice A, Smith JA, McGarvey L et al (2021) Eliapixant (BAY 1817080), a P2X3 receptor antagonist, in refractory chronic cough: a randomised, placebo-controlled, crossover phase 2a study. Eur Respir J 58(5):2004240 Published 2021 Nov 18. 10.1183/13993003.04240-2020 Additional Declarations The authors declare no competing interests. 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(mm)\u003c/p\u003e","description":"","filename":"figure5.png","url":"https://assets-eu.researchsquare.com/files/rs-5779351/v1/3bbf86f52d197867c7b70f8f.png"},{"id":73516156,"identity":"3c252721-aa6a-4c2c-a674-d5ba5921b2db","added_by":"auto","created_at":"2025-01-10 17:46:29","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":46329,"visible":true,"origin":"","legend":"\u003cp\u003ecough severity diary\u003c/p\u003e","description":"","filename":"figure6.png","url":"https://assets-eu.researchsquare.com/files/rs-5779351/v1/2f813f48a9f414a54c62b98a.png"},{"id":73517448,"identity":"1d7777bc-3fa9-48a9-bf5d-3419789e8ebb","added_by":"auto","created_at":"2025-01-10 17:54:29","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":29446,"visible":true,"origin":"","legend":"\u003cp\u003etotal Leicester cough questionnaire score\u003c/p\u003e","description":"","filename":"figure7.png","url":"https://assets-eu.researchsquare.com/files/rs-5779351/v1/afb97f20d12ceec1939f88ab.png"},{"id":73518381,"identity":"4beb31b8-43a8-4824-83a4-dabf59897249","added_by":"auto","created_at":"2025-01-10 18:02:30","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1995586,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5779351/v1/ad491018-df35-4fda-92bd-f86fd97ceb1c.pdf"},{"id":73517447,"identity":"f921b9a5-0e64-477b-a429-c422c3c4f00f","added_by":"auto","created_at":"2025-01-10 17:54:29","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":81975,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary File\u003c/p\u003e","description":"","filename":"supplementaryfile15.docx","url":"https://assets-eu.researchsquare.com/files/rs-5779351/v1/73939a8a7da5bb1cefafca6d.docx"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eEfficacy and Safety of varying dosage of Gefapixant in Patients with chronic cough. A Systematic Review and Meta-Analysis of Randomized Controlled Trials.\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Highlights","content":"\u003cul type=\"disc\"\u003e\n \u003cli\u003eThere are about six studies that investigate gefapixant\u0026rsquo;s \u0026nbsp;effects on patients with chronic cough\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eAlthough gefapixant has improved impact on chronic cough by reducing symptoms however this meta-analysis illicit that there is a significant risk of adverse effects.\u003c/li\u003e\n \u003cli\u003eGefapixant helped reduce 24-hour cough frequency, awake cough frequency, night cough frequency, and cough severity using VAS in a dose-dependent manner.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eGefapixant showed a significant risk of adverse events which include dysgeusia, hypogeusia, nausea, any adverse event, taste-related and drug-related adverse events, and serious adverse events.\u0026nbsp;\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"Introduction","content":"\u003cp\u003eCough, often regarded as a seemingly innocuous reflex, is the most frequently reported symptom in medical practice.[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] However, when this reflex becomes persistent and endures for more than eight weeks, it takes on a more ominous character known as chronic cough. Chronic cough is a global health concern, impacting millions worldwide and presenting a significant therapeutic challenge. Its implications extend beyond the physical, profoundly affecting patients' quality of life. It is estimated that approximately 10% of the world's adult population grapples with this vexing condition.[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eThe etiology of chronic cough is multifaceted, with both pulmonary and extrapulmonary origins. Pulmonary causes encompass a spectrum of conditions, including asthma, chronic obstructive pulmonary disease, bronchiectasis, pulmonary fibrosis, and rhinosinusitis. Extrapulmonary culprits extend to gastroesophageal reflux disease, cardiac cough, and somatic cough.[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] In cases where the cough defies resolution even after addressing the underlying cause, it assumes the unenviable label of refractory chronic cough. Astonishingly, in 42% of chronic cough cases, an underlying cause remains elusive.[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eThe impact of chronic cough extends far beyond its intrinsic discomfort. It exerts a substantial adverse effect on patients' quality of life, leading to increased healthcare utilization and economic burden.[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] Patients suffering from chronic cough are not only more likely to experience urinary stress incontinence but also endure cough syncope, depression, anxiety, and a myriad of other distressing consequences. Emerging evidence has begun to unveil the role of hypersensitive neuronal pathways in perpetuating this recalcitrant condition.[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] Consequently, drugs capable of modifying these neuronal pathways, such as Gabapentin, morphine, and amitriptyline, have emerged as promising therapeutic options.[\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eGefapixant, a purinergic receptor P2X3 antagonist, offers new hope in the quest to conquer refractory chronic cough. These P2X3 receptors are ATP-gated ion channels found on peripheral sensory C fibers in the airways[^10^]. By targeting these receptors, gefapixant acts to normalize the afferent sensitivity innervating the airways. Clinical studies have demonstrated its effectiveness in reducing cough frequency, with doses ranging from 7.5 mg to 600 mg twice daily.[\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] However, it's worth noting that high doses of gefapixant have been associated with altered taste sensation, possibly attributed to its effects on gustatory innervation.\u003c/p\u003e \u003cp\u003eDespite encouraging results from individual randomized controlled trials, a comprehensive evaluation of gefapixant's efficacy and safety across multiple studies is conspicuously absent. This meta-analysis aims to bridge this gap by systematically reviewing eight randomized controlled trials. The objective is to compare gefapixant's effectiveness in reducing both day and night cough frequency, as well as cough severity, across these trials. Furthermore, we will scrutinize the safety profile of gefapixant by examining reported side effects in participants receiving the drug, as compared to those receiving a placebo or alternative control interventions.\u003c/p\u003e \u003cp\u003eBy synthesizing data from multiple trials, this meta-analysis promises to provide a robust assessment of gefapixant's potential as a therapeutic option for chronic cough. The findings will not only enhance our comprehension of gefapixant's efficacy and safety but also equip clinicians with evidence-based insights to inform their clinical decisions, thereby advancing the management of this debilitating condition.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design\u003c/h2\u003e \u003cp\u003e This systematic review and meta-analysis meticulously adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eData Sources and Search Strategy\u003c/h3\u003e\n\u003cp\u003eA systematic and thorough literature search was carried out across three major online databases: PubMed, Google Scholar, and Embase. The search strategy aimed to encompass all relevant studies up to May 10, 2023, and utilized an array of keywords and Medical Subject Heading (MeSH) terms, including specific drug names such as \"MK 7264,\" \"cough,\" \"Gefapixant,\" and \"AF 219.\" The detailed search syntax is available in Supplementary Table\u0026nbsp;1.\u003c/p\u003e\n\u003ch3\u003eEligibility Criteria\u003c/h3\u003e\n\u003cp\u003eThe inclusion of studies was contingent upon predefined eligibility criteria. Only double-arm randomized controlled trials (RCTs) were considered for inclusion in this systematic review and meta-analysis. The target population comprised individuals aged 18 years or older diagnosed with chronic cough. The intervention of interest was the administration of the antitussive agent, gefapixant, in comparison to a placebo. Primary outcomes were designed to assess the efficacy of gefapixant, specifically focusing on reductions in both daytime and nighttime cough frequency, as well as cough severity.\u003c/p\u003e \u003cp\u003eExclusion criteria encompassed studies with non-RCT designs, studies published in languages other than English, trials employing active agents instead of placebos, studies involving participants with acute cough, individuals younger than 18 years of age, and animal experiments.\u003c/p\u003e\n\u003ch3\u003eData Extraction and Quality Assessment\u003c/h3\u003e\n\u003cp\u003eUpon conducting the comprehensive database search, EndNote Reference Library software was employed to facilitate the removal of duplicate studies. Subsequently, two authors (M.H. and H.M.) meticulously screened titles and abstracts, excluding irrelevant articles. This was followed by an in-depth full-text review to assess eligibility. Discrepancies in the study selection process were resolved through consultation with a third author (A.R.S.S).\u003c/p\u003e \u003cp\u003eData extracted from eligible studies was systematically recorded in an online Microsoft Excel Spreadsheet. This information included crucial study characteristics, such as the first author's name, publication year, study design, and the number of enrolled patients. (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline Characteristics of Included RCTs.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"11\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStudy\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSubgroups\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eStudy design\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo. of patients\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAge in Years (Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMales\u003c/p\u003e \u003cp\u003e(%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eBMI (kg/m2)\u003c/p\u003e \u003cp\u003e(Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eCough duration (years)\u003c/p\u003e \u003cp\u003e(Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eCough severity VAS (mm)\u003c/p\u003e \u003cp\u003e(Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eCough severity diary\u003c/p\u003e \u003cp\u003e(CSD)\u003c/p\u003e \u003cp\u003e(Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c11\"\u003e \u003cp\u003eTotal LCQ Score\u003c/p\u003e \u003cp\u003e(Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbdulqawi\u003c/p\u003e \u003cp\u003e2014 \u003csup\u003e[12]\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e49.5\u0026thinsp;\u0026plusmn;\u0026thinsp;36.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6 (25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e26.9\u0026thinsp;\u0026plusmn;\u0026thinsp;11.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eMorice\u003c/p\u003e \u003cp\u003e2019 \u003csup\u003e[18]\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHealthy volunteers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eRCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e37.8\u0026thinsp;\u0026plusmn;\u0026thinsp;8.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1 (8.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eChronic cough patients\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e61.1\u0026thinsp;\u0026plusmn;\u0026thinsp;8.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3 (12.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e14.6\u0026thinsp;\u0026plusmn;\u0026thinsp;9.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e68.6\u0026thinsp;\u0026plusmn;\u0026thinsp;17.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eSmith 1\u003c/p\u003e \u003cp\u003e2020 \u003csup\u003e[19]\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGefapixant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eRCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e63.2\u0026thinsp;\u0026plusmn;\u0026thinsp;7.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e4 (13.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e26.6\u0026thinsp;\u0026plusmn;\u0026thinsp;4.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e58.4\u0026thinsp;\u0026plusmn;\u0026thinsp;18.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e4.2\u0026thinsp;\u0026plusmn;\u0026thinsp;1.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e12.3\u0026thinsp;\u0026plusmn;\u0026thinsp;3.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePlacebo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e52.2\u0026thinsp;\u0026plusmn;\u0026thinsp;19.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e3.7\u0026thinsp;\u0026plusmn;\u0026thinsp;1.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e13.1\u0026thinsp;\u0026plusmn;\u0026thinsp;3.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eSmith 2\u003c/p\u003e \u003cp\u003e2020 \u003csup\u003e[19]\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGefapixant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eRCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e60.2\u0026thinsp;\u0026plusmn;\u0026thinsp;11.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e6 (20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e26.5\u0026thinsp;\u0026plusmn;\u0026thinsp;4.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e54.5\u0026thinsp;\u0026plusmn;\u0026thinsp;24.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e4.5\u0026thinsp;\u0026plusmn;\u0026thinsp;2.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e12.6\u0026thinsp;\u0026plusmn;\u0026thinsp;4.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePlacebo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e57.2\u0026thinsp;\u0026plusmn;\u0026thinsp;23.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e4.5\u0026thinsp;\u0026plusmn;\u0026thinsp;1.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e13.3\u0026thinsp;\u0026plusmn;\u0026thinsp;3.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003eSmith 3\u003c/p\u003e \u003cp\u003e2020 \u003csup\u003e[20]\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.5 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003eRCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e59\u0026middot;9\u0026thinsp;\u0026plusmn;\u0026thinsp;10\u0026middot;5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e48 (75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e27\u0026middot;9\u0026thinsp;\u0026plusmn;\u0026thinsp;4\u0026middot;5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e13\u0026middot;5\u0026thinsp;\u0026plusmn;\u0026thinsp;10\u0026middot;0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e56\u0026middot;7\u0026thinsp;\u0026plusmn;\u0026thinsp;20\u0026middot;7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e4\u0026middot;1\u0026thinsp;\u0026plusmn;\u0026thinsp;1\u0026middot;7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e12\u0026middot;1\u0026thinsp;\u0026plusmn;\u0026thinsp;2\u0026middot;7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e61\u0026middot;8\u0026thinsp;\u0026plusmn;\u0026thinsp;9\u0026middot;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e48 (76)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e28\u0026middot;0\u0026thinsp;\u0026plusmn;\u0026thinsp;4\u0026middot;6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e14\u0026middot;9\u0026thinsp;\u0026plusmn;\u0026thinsp;13\u0026middot;9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e58\u0026middot;3\u0026thinsp;\u0026plusmn;\u0026thinsp;25\u0026middot;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e4\u0026middot;2\u0026thinsp;\u0026plusmn;\u0026thinsp;2\u0026middot;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e12\u0026middot;0\u0026thinsp;\u0026plusmn;\u0026thinsp;3\u0026middot;3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e59\u0026middot;3\u0026thinsp;\u0026plusmn;\u0026thinsp;9\u0026middot;2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e50 (79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e27\u0026middot;2\u0026thinsp;\u0026plusmn;\u0026thinsp;5\u0026middot;0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e12\u0026middot;3\u0026thinsp;\u0026plusmn;\u0026thinsp;8\u0026middot;2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e57\u0026middot;9\u0026thinsp;\u0026plusmn;\u0026thinsp;19\u0026middot;7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e4\u0026middot;3\u0026thinsp;\u0026plusmn;\u0026thinsp;1\u0026middot;8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e11\u0026middot;4\u0026thinsp;\u0026plusmn;\u0026thinsp;2\u0026middot;8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePlacebo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e60\u0026middot;0\u0026thinsp;\u0026plusmn;\u0026thinsp;10\u0026middot;9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e47 (75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e27\u0026middot;6\u0026thinsp;\u0026plusmn;\u0026thinsp;4\u0026middot;8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e17\u0026middot;1\u0026thinsp;\u0026plusmn;\u0026thinsp;13\u0026middot;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e57\u0026middot;4\u0026thinsp;\u0026plusmn;\u0026thinsp;23\u0026middot;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e4\u0026middot;1\u0026thinsp;\u0026plusmn;\u0026thinsp;1\u0026middot;8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e12\u0026middot;2\u0026thinsp;\u0026plusmn;\u0026thinsp;2\u0026middot;8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eMcGarvey 1\u003c/p\u003e \u003cp\u003e2022 \u003csup\u003e[21]\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eRCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e244\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e59\u0026middot;6\u0026thinsp;\u0026plusmn;\u0026thinsp;11\u0026middot;7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e63 (25.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e11\u0026middot;8\u0026thinsp;\u0026plusmn;\u0026thinsp;9\u0026middot;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e68\u0026middot;2\u0026thinsp;\u0026plusmn;\u0026thinsp;15\u0026middot;0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e6\u0026middot;1\u0026thinsp;\u0026plusmn;\u0026thinsp;1\u0026middot;7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e10\u0026middot;5\u0026thinsp;\u0026plusmn;\u0026thinsp;2\u0026middot;9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e243\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e59\u0026middot;4\u0026thinsp;\u0026plusmn;\u0026thinsp;13\u0026middot;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e63 (25.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e11\u0026middot;2\u0026thinsp;\u0026plusmn;\u0026thinsp;9\u0026middot;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e67\u0026middot;9\u0026thinsp;\u0026plusmn;\u0026thinsp;12\u0026middot;8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e6\u0026middot;1\u0026thinsp;\u0026plusmn;\u0026thinsp;1\u0026middot;5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e10\u0026middot;5\u0026thinsp;\u0026plusmn;\u0026thinsp;2\u0026middot;7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePlacebo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e243\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e57\u0026middot;9\u0026thinsp;\u0026plusmn;\u0026thinsp;13\u0026middot;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e62 (25.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e11\u0026middot;7\u0026thinsp;\u0026plusmn;\u0026thinsp;9\u0026middot;9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e69\u0026middot;1\u0026thinsp;\u0026plusmn;\u0026thinsp;13\u0026middot;9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e6\u0026middot;2\u0026thinsp;\u0026plusmn;\u0026thinsp;1\u0026middot;5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e10\u0026middot;0\u0026thinsp;\u0026plusmn;\u0026thinsp;3\u0026middot;1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eMcGarvey 2\u003c/p\u003e \u003cp\u003e2022 \u003csup\u003e[21]\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eRCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e440\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e58\u0026middot;6\u0026thinsp;\u0026plusmn;\u0026thinsp;11\u0026middot;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e111 (25.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e11\u0026middot;9\u0026thinsp;\u0026plusmn;\u0026thinsp;10\u0026middot;7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e67\u0026middot;4\u0026thinsp;\u0026plusmn;\u0026thinsp;14\u0026middot;8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e5\u0026middot;9\u0026thinsp;\u0026plusmn;\u0026thinsp;1\u0026middot;8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e10\u0026middot;4\u0026thinsp;\u0026plusmn;\u0026thinsp;3\u0026middot;0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e439\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e57\u0026middot;8\u0026thinsp;\u0026plusmn;\u0026thinsp;12\u0026middot;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e110 (25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e10\u0026middot;9\u0026thinsp;\u0026plusmn;\u0026thinsp;9\u0026middot;9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e67\u0026middot;7\u0026thinsp;\u0026plusmn;\u0026thinsp;13\u0026middot;9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e6\u0026middot;0\u0026thinsp;\u0026plusmn;\u0026thinsp;1\u0026middot;6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e10\u0026middot;4\u0026thinsp;\u0026plusmn;\u0026thinsp;3\u0026middot;0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePlacebo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e435\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e58\u0026middot;0\u0026thinsp;\u0026plusmn;\u0026thinsp;12\u0026middot;6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e109 (25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e10\u0026middot;7\u0026thinsp;\u0026plusmn;\u0026thinsp;8\u0026middot;8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e68\u0026middot;5\u0026thinsp;\u0026plusmn;\u0026thinsp;14\u0026middot;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e6\u0026middot;0\u0026thinsp;\u0026plusmn;\u0026thinsp;1\u0026middot;6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e10\u0026middot;3\u0026thinsp;\u0026plusmn;\u0026thinsp;3\u0026middot;0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eMcGarvey 3\u003c/p\u003e \u003cp\u003e2023 \u003csup\u003e[22]\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eRCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e206\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e52.5\u0026thinsp;\u0026plusmn;\u0026thinsp;13.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e72 (34.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e67.2\u0026thinsp;\u0026plusmn;\u0026thinsp;14.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e10.8\u0026thinsp;\u0026plusmn;\u0026thinsp;3.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePlacebo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e209\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e \u003cp\u003e52.5\u0026thinsp;\u0026plusmn;\u0026thinsp;13.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e75 (35.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e66.2\u0026thinsp;\u0026plusmn;\u0026thinsp;14.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e11.3\u0026thinsp;\u0026plusmn;\u0026thinsp;2.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003ePrimary outcomes included the efficacy of gefapixant, as measured by awake cough frequency (coughs per hour), night cough frequency (coughs per hour), 24-hour cough frequency (coughs per hour), cough severity assessed by the 100 mm Visual Analog Scale (VAS), cough severity diary data, and total Leicester Cough Questionnaire (LCQ) scores for assessing the quality of life.\u003c/p\u003e \u003cp\u003eSecondary outcomes encompassed the safety profile of gefapixant, incorporating adverse events such as ageusia, dysgeusia, hypotension, parenthesis, hypoaesthesia, cough, headache, nausea, nasopharyngitis, upper respiratory tract infections, urological/renal events, taste-related adverse effects, drug-related adverse effects, serious adverse effects, and discontinuation due to adverse effects. (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSecondary outcomes\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOutcomes\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEffect size RR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAgeusia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5.71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.57\u0026ndash;12.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDysgeusia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4.30-10.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.0002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypogeusia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5.39\u0026ndash;16.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParaesthesia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.74\u0026ndash;2.37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.79\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypoaesthesia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.83\u0026ndash;3.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.85\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCough\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.80\u0026ndash;4.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.98\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeadache\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.91\u0026ndash;1.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.51\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNausea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.94\u0026ndash;6.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNasopharyngitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.96\u0026ndash;1.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.28\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUpper respiratory tract infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.98\u0026ndash;2.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRenal/Urological events\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.29\u0026ndash;1.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.96\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAny adverse events\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.95\u0026ndash;1.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.00001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTaste-related AE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.80\u0026ndash;9.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.00001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDrug-related AEs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.86\u0026ndash;3.37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.00001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSerious AEs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.24\u0026ndash;1.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.0003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiscontinued due to AEs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.70\u0026ndash;3.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.14\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe efficacy of Gefapixant on chronic cough has been reported in the outcome table as mean difference and standard deviation while the safety profile as frequency and percentage.To calculate the missing Standard deviation (SD) of some of the follow-up variables, the mean of follow-up variables was divided by the mean of baseline standard deviations.Change in mean was calculated by subtracting baseline mean from follow-up mean and change in standard deviation was calculated using the following formula:\u003c/p\u003e \u003cp\u003eSD change= \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:\\sqrt{SD{\\left(baseline\\right)}^{2}+SD{\\left(final\\right)}^{2}-2\\times\\:r\\times\\:SD\\left(baseline\\right)\\times\\:SD\\left(final\\right)}\\)\u003c/span\u003e\u003c/span\u003e [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eWhere \u0026ldquo;r\u0026rdquo; is the correlation coefficient for the correlation between the baseline and final value.\u003c/p\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eContinuous outcomes were reported as mean differences (MD) along with 95% confidence intervals (CIs), while dichotomous variables were presented as relative risks (RR) with their respective 95% CIs. The analysis was conducted utilizing a random-effect model, and forest plots were generated using the Generic-inverse variance method. Statistical significance was determined at a threshold of P\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003cp\u003eHeterogeneity among the included studies was assessed using Higgins I^2 statistic, with results categorized as low (I^2\u0026thinsp;\u0026lt;\u0026thinsp;50%), moderate (50% \u0026le; I^2\u0026thinsp;\u0026lt;\u0026thinsp;75%), or high (I^2\u0026thinsp;\u0026ge;\u0026thinsp;75%) heterogeneity.[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] In cases of high heterogeneity, individual study impact on pooled results was explored using sensitivity analysis or meta-regression.\u003c/p\u003e \u003cp\u003e The comprehensive statistical analysis was conducted using the Cochrane Collaboration's Review Manager (RevMan, Version 5.4).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eQuality Assessment\u003c/h2\u003e \u003cp\u003eThe risk of bias within the included studies was meticulously assessed by two independent authors (H.M. and U.T.) using the revised Cochrane Risk of Bias Tool for Randomized Controlled Trials (RoB2.0).[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] Each study's quality was categorized as low risk, high risk, or some concerns of bias. In instances of disagreement regarding risk of bias assessment, resolution was achieved through discussion between the two assessors, with a third author (A.R.S.S.) acting as an arbiter when necessary (Supplementary Fig.\u0026nbsp;1).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003ePublication Bias Assessment\u003c/h3\u003e\n\u003cp\u003eFunnel plots were generated for all outcomes using a random-effect model to assess the potential presence of publication bias (Supplementary Fig.\u0026nbsp;2\u0026ndash;7).\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eStudy Selection\u003c/h2\u003e \u003cp\u003eA comprehensive search across four databases yielded a total of 493 initial results. After the meticulous application of study eligibility criteria, 168 articles were excluded based on the evaluation of titles and abstracts. Subsequently, a thorough full-text review was conducted, resulting in the inclusion of 8 randomized controlled trials (RCTs) for the systematic review and meta-analysis. A visual representation of the study selection process is presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003ePatients' Demographics (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e)\u003c/h2\u003e \u003cp\u003eThe analysis encompasses a total of 8 trials, comprising 1011 participants in the intervention group and 1013 in the placebo group, all of which employed RCT designs. Notably, the included studies exhibited considerable variability in the dosage of gefapixant administered, spanning from 7.5 to 600 mg twice daily. Participants in these studies displayed a mean or median age ranging from 37.8 to 63.2 years. Furthermore, all eight trials exhibited a lower proportion of male participants. The mean duration of cough among the study populations ranged from 10.7 to 17.1 years, with a notable presence of overweight participants. All the studies were dedicated to investigating the efficacy of gefapixant in patients afflicted with chronic cough. Detailed information regarding treatment duration and follow-up can be found in Supplementary Table\u0026nbsp;2.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003ePrimary Outcomes\u003c/h2\u003e \u003cdiv id=\"Sec14\" class=\"Section3\"\u003e \u003ch2\u003e24‑h Cough Frequency (c/h) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e)\u003c/h2\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eEight studies were included in this updated meta-analysis[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan additionalcitationids=\"CR19 CR20 CR21\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], with seven of them reporting data on 24-hour cough frequency (c/h). The pooled analysis demonstrated a significant reduction in 24-hour cough frequency in patients treated with gefapixant compared to those receiving a placebo (MD = -5.26, 95% CI -7.18 to -3.33; p\u0026thinsp;=\u0026thinsp;0.00001; I^2\u0026thinsp;=\u0026thinsp;97%; n\u0026thinsp;=\u0026thinsp;3518 patients). To address the high heterogeneity observed, a subgroup analysis focusing on the 7.5mg dose of gefapixant demonstrated homogeneity (p\u0026thinsp;=\u0026thinsp;0.25; I^2\u0026thinsp;=\u0026thinsp;26%), revealing a trend towards lower 24-hour cough frequency in the treatment group compared to the placebo (MD = -2.43, 95% CI -3.13 to -1.73; p\u0026thinsp;=\u0026thinsp;0.00001).\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eAwake Cough Frequency (c/h) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e)\u003c/h2\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eSix studies were included in this analysis, which explored the correlation between gefapixant treatment and awake cough frequency among chronic cough patients[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. The pooled results demonstrated a significant difference in awake cough frequency, favoring the gefapixant treatment group (MD = -6.78, 95% CI -9.46 to -4.09; p\u0026thinsp;=\u0026thinsp;0.00001; I^2\u0026thinsp;=\u0026thinsp;98%; n\u0026thinsp;=\u0026thinsp;3472 patients). Subgroup analysis at the 7.5mg dose level showed homogeneity (p\u0026thinsp;=\u0026thinsp;0.4, I^2\u0026thinsp;=\u0026thinsp;0%), further favoring gefapixant (MD = -3.52, 95% CI -4.25 to -2.78; p\u0026thinsp;=\u0026thinsp;0.00001).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eNight Cough Frequency (c/h) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e)\u003c/h2\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eNight cough frequency was assessed by three studies[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], and quantitative analysis demonstrated a significant difference (MD = -4.07, 95% CI -5.49 to -2.65; p\u0026thinsp;=\u0026thinsp;0.00001; I^2\u0026thinsp;=\u0026thinsp;0%; n\u0026thinsp;=\u0026thinsp;479 patients) in favor of gefapixant treatment.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eCough Severity Using Visual Analog Scale (mm) (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e)\u003c/h2\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eA total of six out of eight studies were included in the analysis, revealing a significant dose-dependent difference in cough severity between the gefapixant and placebo groups (MD = -14.84, 95% CI [-19.92, -9.76], p\u0026thinsp;=\u0026thinsp;0.00001, n\u0026thinsp;=\u0026thinsp;1297). However, significant heterogeneity was detected among the included studies (p\u0026thinsp;=\u0026thinsp;0.00001, I^2\u0026thinsp;=\u0026thinsp;81%). Subgroup analysis based on gefapixant dosage showed no significant heterogeneity at doses of 7.5 mg (p\u0026thinsp;=\u0026thinsp;0.57, I^2\u0026thinsp;=\u0026thinsp;0%), 50 mg (p\u0026thinsp;=\u0026thinsp;0.64, I^2\u0026thinsp;=\u0026thinsp;0%), and 100 mg (p\u0026thinsp;=\u0026thinsp;0.93, I^2\u0026thinsp;=\u0026thinsp;0%).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eCough Severity Diary (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e)\u003c/h2\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eFour out of eight studies reported a cough severity diary as an outcome measure[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. The meta-analysis demonstrated a statistically significant difference in cough severity diary scores, favoring gefapixant treatment (MD = -0.85; 95% CI: -1.14, -0.56; p-value\u0026thinsp;=\u0026thinsp;0.00001; I^2\u0026thinsp;=\u0026thinsp;63%; n\u0026thinsp;=\u0026thinsp;1219). A subgroup analysis highlighted the effectiveness of the 7.5 mg dose of gefapixant in reducing cough severity (MD = -0.50; 95% CI -0.88, -0.12; p\u0026thinsp;\u0026lt;\u0026thinsp;0.009; I^2\u0026thinsp;=\u0026thinsp;0%), while the 50 mg dose showed a non-significant trend toward reducing cough severity (MD = -0.46; 95% CI -0.96, 0.03; p\u0026thinsp;\u0026lt;\u0026thinsp;0.07; I^2\u0026thinsp;=\u0026thinsp;55%).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eTotal Leicester Cough Questionnaire Score (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e)\u003c/h2\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe analysis of cough-related quality of life, as assessed by the LCQ score in four studies[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], indicated that the placebo group had significantly higher Total LCQ Scores compared to the gefapixant group (MD\u0026thinsp;=\u0026thinsp;2.04, 95% CI\u0026thinsp;=\u0026thinsp;1.09 to 2.98, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001, I^2\u0026thinsp;=\u0026thinsp;84%; 869 participants). Heterogeneity was observed, and subgroup analysis based on the 50 mg dosage of gefapixant demonstrated moderate heterogeneity (MD\u0026thinsp;=\u0026thinsp;2.80, 95% CI: 1.64 to 3.96, p\u0026thinsp;=\u0026thinsp;0.00001, I^2\u0026thinsp;=\u0026thinsp;58%).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003eSecondary Outcomes (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e)\u003c/h2\u003e \u003cp\u003eA comprehensive assessment of secondary outcomes, including ageusia, dysgeusia, hypogeusia, paraesthesia, hypoesthesia, cough, headache, nausea, nasopharyngitis, upper respiratory tract infection, renal/urological events, any adverse events, taste-related adverse effects, drug-related adverse effects, serious adverse effects, and discontinuation due to adverse effects, revealed that gefapixant was associated with several significant adverse effects. Specifically, gefapixant demonstrated significant associations with dysgeusia, nausea, any adverse events, taste-related adverse effects, drug-related adverse effects, and serious adverse effects.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003eQuality Assessment\u003c/h2\u003e \u003cp\u003eThe Cochrane risk of bias tool assessed the included randomized controlled trials (RCTs), indicating a low risk of bias in selection, performance, and reporting domains. However, McGarvey1 showed attrition bias, suggesting potential impact from participant loss or incomplete data. [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] Smith S1 exhibited detection bias, indicating systematic outcome assessment differences between intervention and control groups.[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec22\" class=\"Section2\"\u003e \u003ch2\u003ePublication Bias (Supplementary Fig.\u0026nbsp;1)\u003c/h2\u003e \u003cp\u003eFunnel plots were made to evaluate the presence of publication bias. The funnel plots visually displayed the distribution of studies for each outcome, with the vertical axis representing the effect size and the horizontal axis representing the precision of the estimates. In general, the funnel plots exhibited an equal and symmetrical distribution of studies on both sides of the vertical axis, indicating no significant publication bias for most outcomes.\u003c/p\u003e \u003cp\u003eHowever, it is worth noting that two outcomes, cough severity dairy and cough severity VAS, displayed an asymmetric distribution of studies, with an apparent lack of smaller studies reporting more extreme effect sizes. This observation suggests a potential publication bias in these specific outcomes.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur systematic review and meta-analysis aimed at determining the efficacy of gefapixant as a novel antitussive agent in patients with chronic cough included six studies with eight randomized control trials consisting of 2024 individuals.\u003c/p\u003e \u003cp\u003eOur findings show that administering gefapixant to participants with a chronic cough had no practical impact on quality of life (LCQ score) nevertheless, gefapixant is shown to have a positive effect on mitigating serious adverse events. It reveals the effectiveness of gefapixant in reducing cough frequency (24-hour, awake and night/asleep) in a dose-dependent pattern. Furthermore, a trend favoring gefapixant was seen in the severity of cough (VAS and diary). Additionally, there was a rise in the risk of all-type adverse events, drug-related adverse events, including those related to taste (ageusia, hypogeusia, dysgeusia), and nausea in a dose-dependent manner. However, the risk of hypogeusia did not increase proportionally with the dose. There were no significant differences in hypoesthesia, paraesthesia, cough, headache, nasopharyngitis, upper respiratory tract infections, and renal/urological adverse events so discontinuation of the treatment was rare.\u003c/p\u003e \u003cp\u003eIn both primary and specialty care, chronic cough (CC) is frequently experienced and is referred to as a cough that lasts for more than eight weeks, negatively affecting the quality of life with a prevalence of 5–10%. [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan additionalcitationids=\"CR25 CR26\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e–\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] Majority of adult patients who seek medical assistance due to CC primarily share a common clinical presentation.[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e] These patients frequently report heightened sensitivity to environmental irritants such as perfumes, bleaches, frigid air, citric acid, or capsaicin.[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] Inhalation of such stimuli, inflammation, or mechanical stress/injury can result in a sensation of tickling or irritation in the throat and an urge to cough, indicating increased sensitivity of the neuronal pathways that regulate cough.[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e] We know that continuous stimulation of the P2X3 receptor found on sensory nerve fibers (vagal afferent), predominantly C fibers in the larynx can lead to prolonged hypersensitivity. This can be achieved by TRPV4, a nociceptor present throughout the airway epithelium when activated by hypo-osmotic stimuli.[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e] The authors demonstrate that TRPV4 activation leads to ATP release through pannexin channels, and the subsequent ATP activation of neurons can be inhibited by a P2X3 antagonist.[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eThe term \"cough hypersensitivity syndrome\" (CHS) was introduced to describe the clinical condition characterized by an increased cough reflex, which may or may not encompass specific phenotypes such as cough-variant asthma or eosinophilic bronchitis, which is characterized by eosinophilic inflammation. On the other hand, patients with predominately heartburn symptoms may have a phenotype that reflects gastroesophageal reflux disease (GERD) and cough.[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e] A previous study hypothesized about the molecular makeup to understand the mode of action of gefapixant (formerly known as AF-219). The crystal structure of P2X3 complexed with AF-219 and the differences in the amino acid sequences contributing to the selectivity of AF-219 for P2X3 over the other P2X subtypes.[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e] However further investigation is needed to solidify this statement. Another study confirms the efficacy of MK-7264 (Gefapixant) in rat models thereby supporting its clinical investigation for chronic sensitization conditions.[\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eGefapixant has been evaluated in patients with CC at doses ranging from 7.5 mg to 600 mg twice daily. Firstly, we found a significant reduction in 24-hour and awake cough frequency by gefapixant through a dose-escalation pattern in both participants who had chronic coughs either for a longer or shorter duration. It is to be noted that doses of ⩾30 mg produce maximal reductions in objective cough frequency and patient-reported outcomes such as cough severity as acknowledged by our results. Secondly, the improvement in night-time cough frequency is observed only at higher dosages of the medication. This can be attributed to the fact that a higher dosage of the medication may be more effective in reducing cough symptoms during sleep and give a maximal therapeutic effect. Raj AA et.al [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e] established the minimal important difference (MID) of the LCQ for patients with chronic cough as ⩾1.3 to be considered significant. Of note, our finding on the lag in improvement in quality of life (LCQ score) is consistence with a cross-sectional survey by Chamberlain SA et al [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] who concluded that gefapixant brings a negative impact on quality of life. Ultimately, understanding why the LCQ score did not favor gefapixant requires a close examination of the study design, patient population, and other factors that may have influenced the results. Despite the large placebo response observed in the trial, patients who were treated with gefapixant experienced significant improvements in their cough-specific health status compared to those who received the placebo. These findings suggest that gefapixant may be a promising treatment option for patients with chronic cough who have not responded to other therapies.\u003c/p\u003e \u003cp\u003eFor A.Es, we observed a particularly large placebo response for nausea in relation to previous studies in which placebo responses have been observed. There are a few explanations for why this could be, one of which involves stimulation of higher regions within the central nervous system (such as the cerebral cortex) by vagal afferents, inducing nausea.[\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e] Additionally, through a statistical point of view, the least risk ratio was seen in the case of renal/urological events [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e] and severe adverse events indicating a trend towards gefapixant while a large effect size of hypogeusia (diminished sense of taste) and dysgeusia (altered perception of taste) was drawn from subgroup analysis indicating a trend favoring placebo.[\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e] Concurring with these outcomes, results were consistent with RCT conducted by Nussbaum J 41, especially for the prevalence of taste-related adverse events, often resolved while on treatment or soon after discontinuation. Based on the patterns of P2X3 receptor expression in vagal C fibers, the effectiveness of cough treatment relies more on the P2X3 homomeric receptor. [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e] Whereas contingent on animal studies (double knock-out mice), it is believed that the heterotrimeric P2X2/3 receptor plays a role in facilitating communication between taste buds and gustatory sensory nerves.[\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e] Further data utilizing both selective and non-selective compounds could provide valuable insights into the comparison of P2X3 homotrimers and P2X2/3 heterotrimers in terms of efficacy and taste-related adverse events. This additional information would help in understanding the relative contributions of these receptor types and their potential impact on treatment outcomes and the occurrence of taste-related side effects.\u003c/p\u003e \u003cp\u003eThere are several new P2X3 receptors antagonists like BLU-5937, eliapixant (BAY1817080), filapixant (BAY1902607), and sivopixant (S-600918), [\u003cspan additionalcitationids=\"CR45\" citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e–\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e] that have been developed recently and are currently being studied. [\u003cspan additionalcitationids=\"CR45\" citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e–\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e] These newer agents offer a higher P2X3 selectivity over P2X2/3 receptors, which may help reduce taste-related adverse effects compared to gefapixant. However, this potential benefit needs to be validated in larger-scale and comparative trials in the future.\u003c/p\u003e "},{"header":"Limitations","content":"\u003cp\u003eWhile our study provides a comprehensive analysis of Gefapixant's effectiveness, it comes with several limitations. Firstly, no previous study has considered the collective impact of all published randomized controlled trials on Gefapixant, making our meta-analysis pioneering. Secondly, we exclusively included randomized, double-blinded, and placebo-controlled trials, potentially excluding valuable data from other study types. Our focus was on adults with unexplained chronic coughs, leaving the medication's efficacy in other patient populations unexplored. Furthermore, we excluded active smokers, ex-smokers, and patients with recent respiratory tract infections, limiting our understanding of Gefapixant's effectiveness in these groups. Some trials measured responses subjectively, introducing potential bias, and our follow-up periods were relatively short, not fully capturing long-term effects. Lastly, we identified publication bias in some outcomes, requiring cautious interpretation.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn conclusion, Gefapixant represents a promising development in the treatment of chronic cough and could potentially be a 'game-changer' for individuals suffering from this condition. Our analysis revealed that Gefapixant exhibited efficacy across multiple domains, with the lowest efficacious dose identified as 50 mg twice daily. It effectively reduced 24-hour cough frequency, awake cough frequency, night cough frequency, and cough severity, as assessed by the Visual Analog Scale (VAS), in a dose-dependent manner.\u003c/p\u003e \u003cp\u003eHowever, it's important to note that Gefapixant was associated with a significant risk of adverse events, including dysgeusia, hypogeusia, nausea, and various other adverse events, both drug-related and not. Serious adverse events were also observed. Notably, there was no significant association with ageusia, paraesthesia, hypoesthesia, cough, headache, nasopharyngitis, respiratory and urinary tract infections, or discontinuation due to adverse events.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding : \u003c/strong\u003eNo funding was received to assist with the preparation of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFinancial interests : \u003c/strong\u003eThe authors declare they have no financial interests\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNon-financial interests : \u003c/strong\u003enone\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eThe authors declare that they have no financial or non-financial interests to disclose\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eThe corresponding author makes this declaration on behalf of all the authors involved in this publication.\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSchappert SM (1993) National Ambulatory Medical Care Survey: 1991 summary. 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Science 310(5753):1495\u0026ndash;1499. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1126/science.1118435\u003c/span\u003e\u003cspan address=\"10.1126/science.1118435\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFriedrich C, Francke K, Birring SS et al (2023) The P2X3 receptor antagonist filapixant in patients with refractory chronic cough: a randomized controlled trial. Respir Res. ;24(1):109. Published 2023 Apr 11. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s12931-023-02384-8\u003c/span\u003e\u003cspan address=\"10.1186/s12931-023-02384-8\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNiimi A, Saito J, Kamei T et al (2022) Randomised trial of the P2X3 receptor antagonist sivopixant for refractory chronic cough. 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J Thorac Dis 12(5):2781\u0026ndash;2790. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.21037/jtd-20-cough-001\u003c/span\u003e\u003cspan address=\"10.21037/jtd-20-cough-001\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMorice A, Smith JA, McGarvey L et al (2021) Eliapixant (BAY 1817080), a P2X3 receptor antagonist, in refractory chronic cough: a randomised, placebo-controlled, crossover phase 2a study. Eur Respir J 58(5):2004240 Published 2021 Nov 18. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1183/13993003.04240-2020\u003c/span\u003e\u003cspan address=\"10.1183/13993003.04240-2020\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Chronic cough, P2x3 receptors, Gefapixant, 24-hour cough frequency, cough severity diary, Visual Analog Scale","lastPublishedDoi":"10.21203/rs.3.rs-5779351/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5779351/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA cough that remains unresolved for longer than 8 weeks is referred to as chronic cough, and it is estimated that 10% of the adult population of the world suffers from chronic cough. Gefapixant is a purinergic receptor P2x3 receptor antagonist. P2x3 receptors are ATP-gated ion channels on the peripheral sensory C fibers in the airways.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjective\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe conducted a systematic review and meta-analysis of RCTs to investigate whether the chronic cough patients would benefit from gefapixant administration or not when compared to placebo.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe selected only those double-arm randomized controlled trials (RCTs) which included participants presenting with a chronic cough in patients 18 years or older. We excluded all the articles published in languages other than English Language. Furthermore, all the studies other than RCTs were also omitted. Articles yielded from the electronic search were exported to EndNote Reference Library software to remove any duplicates. Analyses were done using the Review Manager 5.4 tool. Mean values and standard deviations were retrieved for the continuous outcomes given as raw data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e8 RCTs selected for the statistical analysis consisted of 2024 participants (1011 in the intervention group and 1013 in the placebo group). The outcomes resulted to be significant with 24-hour cough frequency, the mean difference [MD] = -5.26, 95% confidence interval [CI] -7.18 to -3.33; p = 0.00001; n = 3518, awake cough frequency (c/h) [MD] = -6.78, 95% confidence interval [CI] -9.46 to -4.09; p = 0.00001; n = 3472 patients., night cough frequency (c/h) [MD] = -4.07, 95% confidence interval [CI] -5.49 to -2.65; p = 0.00001; n = 479, patients cough severity VAS (mm) [MD] = -14.84, 95% confidence interval [-19.92, -9.76], p = 0.00001, n= 1297, cough severity diary difference [MD] = -0.85; 95% confidence interval [CI]: -1.14, -0.56; p-value = 0.00001; n = 1219, Total LCQ score MD=2.04, 95% CI = 1.09 to 2.98, p\u0026lt;0.0001, n =869.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo conclude, the lowest efficacious dose was 50 mg twice daily and helped reduce 24-hour cough frequency, awake cough frequency, night cough frequency, and cough severity using VAS in a dose-dependent manner. Gefapixant showed a significant risk of adverse events which include dysgeusia, hypogeusia, nausea, any adverse event, taste-related and drug-related adverse events, and serious AEs\u003c/p\u003e","manuscriptTitle":"Efficacy and Safety of varying dosage of Gefapixant in Patients with chronic cough. A Systematic Review and Meta-Analysis of Randomized Controlled Trials.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-01-10 17:46:24","doi":"10.21203/rs.3.rs-5779351/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ac009e6f-e176-4d14-90f5-c2e5ef9cea08","owner":[],"postedDate":"January 10th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":42479168,"name":"Pulmonology"}],"tags":[],"updatedAt":"2025-01-10T17:46:24+00:00","versionOfRecord":[],"versionCreatedAt":"2025-01-10 17:46:24","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5779351","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5779351","identity":"rs-5779351","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}