P2X3 receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2 study

Abdulqawi, Rayid; Dockry, Rachel; Holt, Kimberley; Layton, Gary; McCarthy, Bruce G.; Ford, Anthony; Smith, Jaclyn A.

doi:10.1016/s0140-6736(14)61255-1

Cited by 423 publications

(386 citation statements)

References 32 publications

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“…There was significant risk of bias identified in two studies [86,91]. Randomization and concealment of allocation were determined to be of high risk in the Jeyakumar et al [86] study, specifically patients were randomized by chart numbers (not computer-generated randomization) and there was a predictable allocation sequence (patients with even chart numbers were placed on amitriptyline, odd numbers were placed on codeine/guaifenesin).…”

Section: Resultsmentioning

confidence: 99%

“…Randomization and concealment of allocation were determined to be of high risk in the Jeyakumar et al [86] study, specifically patients were randomized by chart numbers (not computer-generated randomization) and there was a predictable allocation sequence (patients with even chart numbers were placed on amitriptyline, odd numbers were placed on codeine/guaifenesin). Blinding of the intervention and incomplete data were determined to be of high risk in the Abdulqawi et al [91] study. This was due to the notable taste disturbances of AF-219 that led to 25% of patients withdrawing before the end of the trial.…”

Section: Resultsmentioning

confidence: 99%

“…Most common AE was headache reported in 3 patients (14%) during placebo treatment and 2 patients (10%) during SB-705498 treatment.1-sided statistical test to detect a 2.5% difference between SB-705498 and placebo was used. A two-sided test would have resulted in larger p -values for this study.Abdulqawi et al, 2015 [91]Randomized, double-blind, placebo-controlled two-period, crossover (phase II) study24Patients received AF-219 (P2X3 Antagonist) , 600 mg or placebo twice a day. After a 2 week washout, patients were then assigned to receive the other treatment.Primary outcome: Daytime cough frequency at baseline and after 2 weeks of treatment using 24 h ambulatory cough recordings.…”

Section: Resultsmentioning

confidence: 99%

“…Abdulqawi et al [91] investigated the efficacy of AF-219 on 24 patients with refractory CC (six [25%] patients had a productive cough) (Table 5). Patients taking ACE inhibitors, opioids, neuromodulators or any other treatment that might modulate cough were excluded.…”

Section: Resultsmentioning

confidence: 99%

“…We also compared the placebo RCT P2X3 receptor antagonist trials that had used the same cough outcome measure, that is, cough frequency with an automated cough monitor in coughs/h from Abdulqawi et al (AF-219) study [91] and the Smith et al (MK-7264) study [92]. …”

Section: Methodsmentioning

confidence: 99%

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An update and systematic review on drug therapies for the treatment of refractory chronic cough

Ryan

Vertigan

Birring

2018

Expert Opinion on Pharmacotherapy

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Introduction: Chronic Cough (CC) is common and often associated with significant comorbidity and decreased quality of life. In up to 50% of cases, the cough is refractory despite extensive investigation and treatment trials. It is likely that the key abnormality in refractory CC is dysfunctional, hypersensitive sensory nerves, similar to conditions such as laryngeal hypersensitivity and neuropathic pain.Areas covered: The aim of this systematic review is to assess drug therapies for refractory CC. The authors review the current management of CC and provide discussion of the similarities between neuropathic pain and refractory CC. They review repurposed and new pharmacological treatments. Several meta-analyses were performed to compare the efficacy of treatments where possible.Expert opinion: Repurposed pain medications such as gabapentin and pregabalin reduce the frequency of cough and improve quality of life. Along with speech pathology, they are important and alternate treatments for refractory CC. However, more treatments are needed and the P2X3 ion channel receptor antagonists show the most promise. With a better understanding of neuronal activation and sensitisation and their signal processing in the brain, improved animal models of cough, and the use of validated cough measurement tools, more effective treatments will develop.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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An update and systematic review on drug therapies for the treatment of refractory chronic cough

Ryan

Vertigan

Birring

2018

Expert Opinion on Pharmacotherapy

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Efficacy and Tolerability of Gefapixant for Treatment of Refractory or Unexplained Chronic Cough

Kum,

Patel,

Diab

et al. 2023

JAMA

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ImportanceGefapixant represents an emerging therapy for patients with refractory or unexplained chronic cough.ObjectiveTo evaluate the efficacy and tolerability of gefapixant for the treatment of adults with refractory or unexplained chronic cough.Data SourcesMEDLINE, Embase, Cochrane Central Register of Controlled Trials, and Web of Science from November 2014 to July 2023.Study SelectionTwo reviewers independently screened for parallel and crossover randomized clinical trials (RCTs) that compared, in patients with refractory or unexplained chronic cough, either gefapixant with placebo, or 2 or more doses of gefapixant with or without placebo.Data Extraction and SynthesisTwo reviewers independently extracted data. A frequentist random-effects dose-response meta-analysis or pairwise meta-analysis was used for each outcome. The GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach was used to rate the certainty in whether patients would perceive the effects as important (greater than the minimal important difference [MID]) or small (less than the MID).Main Outcomes and MeasuresCough frequency (measured using the VitaloJAK cough monitor; MID, 20%), cough severity (measured using the 100-mm visual analog scale [VAS]; higher score is worse; MID, 30 mm), cough-specific quality of life (measured using the Leicester Cough Questionnaire [LCQ]; score range, 3 [maximal impairment] to 21 [no impairment]; MID, 1.3 points), treatment-related adverse events, adverse events leading to discontinuation, and taste-related adverse events.ResultsNine RCTs including 2980 patients were included in the primary analysis. Compared with placebo, gefapixant (45 mg twice daily) had small effects on awake cough frequency (17.6% reduction [95% CI, 10.6%-24.0%], moderate certainty), cough severity on the 100-mm VAS (mean difference, −6.2 mm [95% CI, −4.1 to −8.4]; high certainty), and cough-specific quality of life on the LCQ (mean difference, 1.0 points [95% CI, 0.7-1.4]; moderate certainty). Compared with placebo, gefapixant (45 mg twice daily) probably caused an important increase in treatment-related adverse events (32 more per 100 patients [95% CI, 13-64 more], moderate certainty) and taste-related adverse events (32 more per 100 patients [95% CI, 22-46 more], high certainty). High-certainty evidence suggests that gefapixant (15 mg twice daily) had small effects on taste-related adverse events (6 more per 100 patients [95% CI, 5-8 more]).Conclusions and RelevanceCompared with placebo, gefapixant (45 mg orally twice daily) led to modest improvements in cough frequency, cough severity, and cough-specific quality of life but increased taste-related adverse events.

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Speech and language therapy for management of chronic cough

Slinger

Mehdi

Milan

et al. 2018

Cochrane Database of Systematic Reviews

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P2X3 receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2 study

Cited by 423 publications

References 32 publications

An update and systematic review on drug therapies for the treatment of refractory chronic cough

An update and systematic review on drug therapies for the treatment of refractory chronic cough

Efficacy and Tolerability of Gefapixant for Treatment of Refractory or Unexplained Chronic Cough

Speech and language therapy for management of chronic cough

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