Abstract
Rationale
There is no broadly accessible treatment for patients with refractory chronic cough, a disease characterized by chronic cough that persists despite treatment for other cough-related etiologies or has no identified underlying cause.
Objectives
SOOTHE (NCT04678206), a phase 2b, randomized, placebo-controlled trial, evaluated the efficacy and safety of P2X3 antagonist camlipixant in adults with refractory chronic cough (cough duration, ⩾1 yr; baseline awake cough frequency, ⩾25 coughs/h).
Methods
After a single-blind, 16-day placebo run-in, patients were randomized (1:1:1:1) to receive camlipixant 12.5, 50, or 200 mg twice daily or placebo for 4 weeks. The primary endpoint was change from baseline to Day 28 in objective 24-hour cough frequency. Secondary endpoints included cough severity and cough-related quality of life.
Measurements and Main Results
Overall, 310 patients were randomized. A statistically significant reduction in placebo-adjusted 24-hour cough frequency was seen in the 50 mg (−34.4%; 95% confidence interval, −50.5 to −13.3; P = 0.0033) and 200 mg (−34.2%; 95% confidence interval, −50.7 to −12.2; P = 0.0047) camlipixant arms. All camlipixant arms showed a trend for greater improvement in cough severity visual analog scale and Leicester Cough Questionnaire scores over placebo. Camlipixant was well tolerated with no serious treatment-emergent adverse events reported. Taste alteration occurred in 4.8–6.5% of patients in camlipixant arms (vs. 0% with placebo); these were usually mild–moderate.
Conclusions
Camlipixant treatment reduced cough frequency and improved patient-reported outcomes in patients with refractory chronic cough, with an acceptable safety profile.
Clinical trial registered with www.clinicaltrials.gov (NCT04678206).
Keywords: chronic cough, P2X3 antagonists, refractory chronic cough, therapeutics
At a Glance Commentary
Scientific Knowledge on the Subject
There is no broadly accessible treatment for patients with refractory chronic cough, a disease characterized by chronic cough that persists despite treatment for other cough-related etiologies or has no identified underlying cause.
What This Study Adds to the Field
Camlipixant, a P2X3 antagonist, significantly reduced 24-hour cough frequency versus placebo in patients with refractory chronic cough (including unexplained chronic cough) enrolled in the SOOTHE phase 2b trial. The stratification of patients by baseline cough frequency demonstrated the feasibility of selecting patients with awake cough frequency of ⩾25 coughs/h to accurately assess treatment response. The favorable findings of the SOOTHE trial suggest that further clinical investigation of camlipixant for the treatment of refractory chronic cough is warranted.
In adults, chronic cough is defined as a cough lasting for >8 weeks (1). Estimates of the global prevalence of chronic cough vary between 4% and 10% and may differ by region, ranging from 2% to 18% (2–6). Chronic cough can impose considerable physical and psychosocial burdens on patients, including interference with social interactions, sleep disruption, fatigue, urinary incontinence, and anxious and depressive symptoms (7–11). Other serious physical outcomes associated with chronic cough include hernias, rib fractures, and cough syncope (9, 10). After considering critical conditions in patients presenting with chronic cough, current guidelines suggest carrying out investigations such as full blood counts, chest radiography, and spirometry (12), and a sequential trial of different therapies is recommended (13, 14).
A substantial proportion of patients (between 38% and 64%) presenting with chronic cough are estimated to have refractory chronic cough (RCC; including unexplained chronic cough) (15–18). However, the exact prevalence of RCC in patients with chronic cough is unknown (15–18). RCC is a disease believed to arise from a primary disorder of the neuronal pathways controlling cough (19, 20) and manifests as a long-term cough that persists for >8 weeks despite treatment of other possible underlying cough-related etiologies or has no diagnosable cause (i.e., unexplained chronic cough) (12). Patients with RCC have a clinical profile similar to that of other patients presenting with chronic cough, with an average age of onset of over 40 years old and a high proportion of women being affected (21–23).
Because of the lack of broad access to a safe and effective approved treatment for RCC (24), nonspecific, off-label, centrally acting drugs are recommended in clinical guidelines to suppress chronic cough, including gabapentin, pregabalin, and low-dose slow-release morphine (12, 14, 25, 26). Drugs with neuromodulatory effects have limited evidence for efficacy in patients with RCC, and their use is restricted by concerns about dependence and misuse; they may also be associated with significant adverse events (AEs) (12, 27–34).
Therapies for RCC that target receptors in the peripheral nervous system may reduce the adverse effects associated with centrally acting therapies (26). P2X3 receptors are ATP-gated ion channels located on primary sensory neurons in airways (35). ATP may be released by cell damage, inflammation, or infection (36); on binding extracellular ATP, P2X3 receptors can activate sensory neurons that initiate the cough reflex (36, 37). In clinical trials of patients with RCC, P2X3 antagonists have reduced objective cough frequency and severity, suggesting that a P2X3-dependent pathway is likely to be involved in disease pathophysiology (13, 38, 39). Camlipixant is a novel, peripherally acting P2X3 antagonist under investigation for the treatment of patients with RCC (24, 37).
RELIEF (A Dose Escalation Study of BLU-5937 in Unexplained or Refractory Chronic Cough; ClinicalTrials.gov identifier NCT03979638), was a phase 2a randomized dose escalation trial evaluating the efficacy and safety of camlipixant in adults with RCC. Although the RELIEF trial did not meet its primary endpoint of a statistically significant reduction in placebo-adjusted 24-hour cough frequency from baseline, a statistically significant interaction was observed between baseline cough frequency and cough frequency reduction with camlipixant, suggesting that patients with higher baseline cough frequency experienced the greatest reductions (40). The RELIEF trial was therefore critical in informing the study design of SOOTHE (Evaluation of the Efficacy and Safety of BLU-5937 in Adults with Refractory Chronic Cough; ClinicalTrials.gov identifier NCT04678206), a phase 2b dose-finding trial of camlipixant in adults with RCC and a baseline awake cough frequency of ⩾25 coughs/h (41). Here, we report the results of the SOOTHE trial. Some of the results of this study were previously reported in the form of two abstracts (41, 42).
Methods
Study Design
SOOTHE was a multicenter, phase 2b, randomized, placebo-controlled, double-blind, parallel-group dose-finding trial in patients with a persistent cough lasting ⩾1 year. A 16-day placebo run-in period was included in the trial design to ensure consistency in cough frequency between screening and baseline and to minimize any placebo effect; the 16-day duration included the anticipated steepest ascent of the placebo response. After the placebo run-in period, patients in the main population with screening and baseline awake cough frequencies of ⩾25 coughs/h were randomized (1:1:1:1) to receive camlipixant 12.5, 50, or 200 mg orally twice daily or placebo for 4 weeks (Figure 1). At randomization, patients were stratified by post-placebo run-in awake cough frequency of <45 coughs/h and ⩾45 coughs/h to ensure that patients with the highest baseline awake cough frequencies were evenly distributed between treatment arms.
Figure 1.
SOOTHE study design. BID = twice daily.
The exploratory population included patients with screening and baseline awake cough frequencies of ⩾10 and <25 coughs/h, randomized 1:1 to receive camlipixant 200 mg twice daily or placebo for 4 weeks. The cutoffs in baseline awake cough frequency that defined the exploratory population were prospectively selected on the basis of examination of the responses versus baseline cough frequency in the RELIEF trial (40).
Patients
Eligible patients were aged 18–80 years with persistent cough of ⩾1 year before screening, a diagnosis of RCC, an awake cough frequency of ⩾25 coughs/h (main population) at screening and at baseline (Day –6), and a score ⩾40 mm on the cough severity visual analog scale (CS-VAS) at screening and on Day 1. Key eligibility criteria are listed in Table E1 in the data supplement.
Outcomes
The primary efficacy endpoint was the change from baseline to Day 28 in objective 24-hour cough frequency (coughs/h) measured using a semiautomated ambulatory cough monitor (VitaloJAK; Vitalograph Ltd); cough frequency data were analyzed using a natural log scale (43).
Secondary efficacy endpoints included change from baseline to Day 15 in 24-hour cough frequency, change from baseline in awake cough frequency on Days 15 and 28, percentage of patients showing a ⩾30%, ⩾50%, and ⩾70% reduction in cough frequency on Days 15 and 28 (for both 24-h cough response and awake cough response), change from baseline in nighttime cough frequency on Days 15 and 28, and patient-reported outcomes such as cough severity and cough-related quality of life on Days 15 and 29, as assessed using the CS-VAS and the Leicester Cough Questionnaire (LCQ), respectively (44, 45). Key study endpoints are detailed in Table E2. Safety outcomes included AEs; treatment-emergent AEs; and abnormal findings based on physical examination, electrocardiography, vital signs, or clinical laboratory values.
Statistical Analyses
Efficacy data were analyzed according to randomized treatment in all patients who were randomized to receive treatment during the double-blind period (i.e., the intention-to-treat/main population). For the primary endpoint in the main population, it was estimated that a sample size of 240 patients was needed (60 patients in each trial arm) to provide 83% power at the one-sided 5% α-level, assuming a 25% relative reduction between camlipixant and placebo and log-scale standard deviation estimate of 0.60. For the exploratory population, it was determined that a sample size of 60 patients (30 patients in each treatment arm) would allow the relative difference between camlipixant and placebo to be estimated with a standard error between approximately −14% and 17%. The exploratory population was not powered to determine a treatment effect. All cough frequency data were natural log transformed.
All statistical analyses were performed using SAS version 9.4 (SAS Institute Inc.) (46). Because this was a phase 2b dose-finding trial, no adjustment for multiplicity was made. All P values presented are two-sided nominal P values.
Ethical Statement
Written informed consent was obtained from each patient before enrollment. The original protocol and other relevant documentation were approved by the institutional review board and an independent ethics committee. The trial was performed in accordance with the Declaration of Helsinki, the International Council for Harmonization Good Clinical Practice guidelines, and all applicable regulations (47, 48).
Results
Patient Characteristics and Disposition
Overall, 310 patients met eligibility criteria and were randomized into the trial. The main population (baseline awake cough frequency, ⩾25 coughs/h) included 249 patients; each camlipixant arm included 62 patients, and 63 patients were randomized to placebo (Figure 2). The exploratory population (baseline awake cough frequency, ⩾10 and <25 coughs/h) included 61 patients: 31 in the camlipixant 200 mg twice daily arm and 30 in the placebo arm. All patients in the trial (main and exploratory populations) received at least one dose of camlipixant or placebo; safety analyses were performed per population. At baseline, patient characteristics in the main population (Table 1) and the exploratory population (Table E3) were representative of patients with RCC and were well balanced between the treatment arms.
Figure 2.
CONSORT (Consolidated Standards of Reporting Trials) diagram. *The cough frequency cutoff resulted in exclusion of 37.7% (n = 156 of 414) of patients who did not meet eligibility criteria during the screening period. Of the 178 patients who failed the run-in, 165 patients did not meet eligibility criteria, and of these, 73.3% (n = 121 of 165) were excluded on the basis of the cough frequency cutoff. AE = adverse event.
Table 1.
Patient Characteristics and Disposition at Baseline (Main Population: Awake Cough Frequency ⩾25 Coughs/h)
| Placebo | Camlipixant (Twice Daily) |
|||
|---|---|---|---|---|
| 12.5 mg | 50 mg | 200 mg | ||
| Number of patients, n | 63 | 62 | 62 | 62 |
| Sex, n (%) | ||||
| Male | 14 (22.2) | 14 (22.6) | 10 (16.1) | 7 (11.3) |
| Female | 49 (77.8) | 48 (77.4) | 52 (83.9) | 55 (88.7) |
| Age, yr, mean (SD) | 61.4 (11.3) | 60.7 (10.1) | 61.6 (9.6) | 59.7 (11.4) |
| BMI, kg/m2, mean (SD) | 27.9 (5.6) | 28.1 (5.3) | 28.6 (7.3) | 27.9 (5.7) |
| Ethnic origin, n (%) | ||||
| Hispanic or Latinx | 3 (4.8) | 3 (4.8) | 5 (8.1) | 3 (4.8) |
| Not Hispanic or Latinx | 60 (95.2) | 59 (95.2) | 57 (91.9) | 59 (95.2) |
| Race, n (%) | ||||
| White | 62 (98.4) | 58 (93.5) | 60 (96.8) | 60 (96.8) |
| Asian | 1 (1.6) | 3 (4.8) | 0 (0.0) | 0 (0.0) |
| Black | 0 (0.0) | 0 (0.0) | 1 (1.6) | 2 (3.2) |
| American Indian/Alaska Native | 0 (0.0) | 1 (1.6) | 1 (1.6) | 0 (0.0) |
| Region, n (%) | ||||
| United States | 25 (39.7) | 29 (46.8) | 34 (54.8) | 34 (54.8) |
| Canada | 7 (11.1) | 4 (6.5) | 7 (11.3) | 2 (3.2) |
| Europe | 31 (49.2) | 29 (46.7) | 21 (33.8) | 26 (41.9) |
| Cigarette pack-years, mean (SD) | 2.2 (4.6) | 1.6 (3.9) | 1.8 (4.3) | 1.6 (4.6) |
| FEV1/FVC ratio, mean (SD)* | 0.77 (0.073) | 0.77 (0.071) | 0.76 (0.068) | 0.77 (0.082) |
| Cough duration, yr, mean (SD) | 11.1 (9.70) | 11.9 (9.12) | 13.5 (11.53) | 10.3 (9.11) |
| Baseline 24-h cough frequency, coughs/h | ||||
| Geometric mean (log scale SD) | 39.6 (0.60) | 41.3 (0.57) | 39.9 (0.47) | 35.2 (0.48) |
| Baseline awake cough frequency (coughs/h) | ||||
| Geometric mean (log scale SD) | 56.9 (0.60) | 58.3 (0.57) | 55.8 (0.48) | 49.7 (0.46) |
| CS-VAS, mm | ||||
| Mean (SD) | 73.9 (14.9) | 71.7 (14.5) | 74.0 (14.4) | 72.0 (15.6) |
| LCQ total score | ||||
| Mean (SD) | 10.4 (3.1) | 10.7 (3.0) | 10.0 (3.1) | 11.4 (3.0) |
Definitions of abbreviations: BMI = body mass index; CS-VAS = cough severity visual analog scale; FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity; LCQ = Leicester Cough Questionnaire; SD = standard deviation.
Measured at screening or within the 2 years before screening and after the onset of cough.
Change in 24-Hour Cough Frequency During the Placebo Run-In
All randomized patients (N = 310) completed the 16-day placebo run-in before randomization. Nominal reductions in 24-hour cough frequency were observed; the geometric mean cough frequency at screening and at Day −6 in the randomized population were 32.6 coughs/h (log SD, 0.68) and 30.5 coughs/h (log SD, 0.71), respectively. The percentage change in geometric mean ratio from screening to Day −6 was −6.7% in the randomized population (N = 310) versus a 7.3% increase in the population of patients who were screened (n = 912) and a −48.3% change in patients who failed the run-in period (n = 178). Full data are presented in Table E4.
Primary Efficacy Endpoint
Change from baseline to Day 28 in 24-hour cough frequency
At Day 28, significant placebo-adjusted differences from baseline in 24-hour cough frequency of −34.4% (95% confidence interval [CI], −50.5 to −13.3; P = 0.0033) and −34.2% (95% CI, −50.7 to −12.2; P = 0.0047) were observed in the 50 and 200 mg camlipixant arms, respectively (Figure 3A and Table 2). The placebo-adjusted difference from baseline seen in the 12.5 mg camlipixant arm did not reach statistical significance (−21.1%; 95% CI, −40.5 to 4.5; P = 0.0976). Changes from baseline in 24-hour mean cough frequency are reported in Figure 3B and Table 2. In the exploratory population, the placebo-adjusted change from baseline in 24-hour cough frequency at Day 28 was 13.3% (95% CI, −26.0 to 73.6) (Table E5).
Figure 3.
Change from baseline and response analyses for 24-hour cough frequency in the main population. (A) Placebo-adjusted mean change from baseline (data points manually spread to avoid overlap), (B) nominal mean change from baseline, (C) cough response, and (D) cough response odds ratio on Day 28, calculated post hoc. Day 15, 12.5 mg, n = 59; 50 mg, n = 56; 200 mg, n = 55; placebo, n = 59. Day 28, 12.5 mg, n = 58; 50 mg, n = 61; 200 mg, n = 52; placebo, n = 56. Error bars indicate 95% CI. *P < 0.005. CI = confidence interval.
Table 2.
Efficacy Results (Main Population: Awake Cough Frequency of ⩾25 Coughs/h)
| Placebo (n = 63) | Camlipixant (Twice Daily) |
|||
|---|---|---|---|---|
| 12.5 mg (n = 62) | 50 mg (n = 62) | 200 mg (n = 62) | ||
| Primary efficacy endpoint | ||||
| 24-h cough frequency (Day 28), n | 56 | 58 | 61 | 52 |
| Baseline, coughs/h, arithmetic mean (SD) | 49.7 (46.07) | 49.4 (35.98) | 45.2 (28.88) | 39.9 (23.21) |
| Day 28, coughs/h, geometric mean (log scale SD) | 28.5 (0.95) | 22.7 (0.63) | 18.6 (0.86) | 16.8 (0.83) |
| Day 28, coughs/h, arithmetic mean (SD) | 41.1 (44.55) | 27.7 (19.56) | 25.7 (21.19) | 23.4 (26.75) |
| Change in mean cough frequency from baseline, % | −28.0 | −43.2 | −52.8 | −52.6 |
| Change in mean cough frequency from placebo, % | NA | −21.1 | −34.4 | −34.2 |
| 95% CI | NA | −40.5 to 4.5 | −50.5 to −13.3 | −50.7 to −12.2 |
| P value | NA | 0.0976 | 0.0033 | 0.0047 |
| Key secondary efficacy endpoints | ||||
| 24-h cough frequency (Day 15), n | 59 | 59 | 56 | 55 |
| Baseline, coughs/h, arithmetic mean (SD) | 49.7 (46.07) | 49.4 (35.98) | 45.2 (28.88) | 39.9 (23.21) |
| Day 15, coughs/h, geometric mean (log scale SD) | 31.2 (0.79) | 26.2 (0.68) | 20.8 (0.89) | 19.0 (0.87) |
| Day 15, coughs/h, arithmetic mean (SD) | 42.1 (40.43) | 33.1 (25.88) | 28.4 (23.10) | 26.2 (23.56) |
| Change in mean cough frequency from baseline, % | −22.0 | −36.3 | −47.2 | −48.8 |
| Change in mean cough frequency from placebo, % | NA | −18.3 | −32.4 | −34.3 |
| 95% CI | NA | −37.3 to 6.3 | −48.1 to −11.8 | −49.9 to −14.0 |
| P value | NA | 0.1314 | 0.0040 | 0.0024 |
| 24-h cough frequency responders (Day 15), n | 59 | 59 | 56 | 55 |
| ⩾30%, n (%) | 19 (32.2) | 28 (47.5) | 31 (55.4) | 31 (56.4) |
| ⩾50%, n (%) | 9 (15.3) | 14 (23.7) | 18 (32.1) | 19 (34.6) |
| ⩾70%, n (%) | 4 (6.8) | 7 (11.9) | 7 (12.5) | 10 (18.2) |
| Cumulative odds ratio (95% CI) | NA | 1.83 (0.90–3.73) | 2.46 (1.22–4.99) | 2.77 (1.35–5.69) |
| P value | NA | 0.0958 | 0.0123 | 0.0056 |
| 24-h cough frequency responders (Day 28), n | 56 | 58 | 61 | 52 |
| ⩾30%, n (%) | 20 (35.7) | 30 (51.7) | 37 (60.7) | 32 (61.5) |
| ⩾50%, n (%) | 8 (14.3) | 20 (34.5) | 27 (44.3) | 25 (48.1) |
| ⩾70%, n (%) | 4 (7.1) | 11 (19.0) | 15 (24.6) | 10 (19.2) |
| Cumulative odds ratio (95% CI) | NA | 2.24 (1.09–4.60) | 3.35 (1.66–6.79) | 3.33 (1.62–6.85) |
| P value | NA | 0.0276 | 0.0008 | 0.0011 |
| Awake cough frequency (Day 15), n | 59 | 59 | 56 | 55 |
| Baseline, coughs/h, arithmetic mean (SD) | 71.5 (66.92) | 69.4 (48.52) | 63.7 (42.57) | 55.8 (32.29) |
| Day 15, coughs/h, geometric mean (log scale SD) | 42.6 (0.88) | 37.3 (0.71) | 28.5 (0.95) | 26.8 (0.89) |
| Day 15, coughs/h, arithmetic mean (SD) | 58.6 (58.77) | 47.9 (38.77) | 39.8 (33.50) | 37.1 (33.93) |
| Change in mean cough frequency from baseline, % | −25.4 | −35.7 | −48.2 | −49.2 |
| Change in mean cough frequency from placebo, % | NA | −13.9 | −30.6 | −31.9 |
| 95% CI | NA | −35.1 to 14.3 | −47.8 to −7.7 | −49.0 to − 9.0 |
| P value | NA | 0.3003 | 0.0122 | 0.0096 |
| Awake cough frequency (Day 28), n | 56 | 58 | 61 | 52 |
| Baseline, coughs/h, arithmetic mean (SD) | 71.5 (66.92) | 69.4 (48.52) | 63.7 (42.57) | 55.8 (32.29) |
| Day 28, coughs/h, geometric mean (log scale SD) | 38.7 (1.02) | 31.5 (0.65) | 25.6 (0.89) | 22.8 (0.83) |
| Day 28, coughs/h, arithmetic mean (SD) | 56.6 (61.24) | 38.8 (27.47) | 36.3 (31.42) | 31.7 (37.31) |
| Change in mean cough frequency from baseline, % | −31.1 | −44.0 | −53.8 | −54.6 |
| Change in mean cough frequency from placebo, % | NA | −18.8 | −32.9 | −34.1 |
| 95% CI | NA | −39.6 to 9.2 | −50.0 to −10.0 | −51.4 to −10.8 |
| P value | NA | 0.1672 | 0.0080 | 0.0072 |
| CS-VAS | ||||
| Day 15, n | 62 | 59 | 59 | 55 |
| LS mean change from baseline (SE) | −3.72 (2.67) | −16.08 (2.72) | −17.71 (2.73) | −20.14 (2.81) |
| LS mean difference from placebo (SE) | NA | −12.37 (3.81) | −14.00 (3.82) | −16.43 (3.87) |
| 95% CI | NA | −19.88 to −4.85 | −21.52 to −6.48 | −24.06 to −8.80 |
| P value | NA | 0.0014 | 0.0003 | <0.0001 |
| Day 29, n | 59 | 58 | 54 | 53 |
| LS mean change from baseline (SE) | −8.29 (3.06) | −24.70 (3.10) | −22.92 (3.17) | −26.46 (3.21) |
| LS mean difference from placebo (SE) | NA | −16.42 (4.36) | −14.64 (4.41) | −18.17 (4.44) |
| 95% CI | NA | −25.01 to −7.82 | −23.32 to −5.95 | −26.92 to −9.42 |
| P value | NA | 0.0002 | 0.0010 | <0.0001 |
| LCQ | ||||
| Day 15, n | 57 | 59 | 53 | 54 |
| LS mean change from baseline (SE) | 1.07 (0.35) | 1.91 (0.35) | 1.96 (0.37) | 2.33 (0.36) |
| LS mean difference from placebo (SE) | NA | 0.84 (0.49) | 0.89 (0.51) | 1.26 (0.51) |
| 95% CI | NA | −0.13 to 1.81 | −0.11 to 1.89 | 0.26 to 2.26 |
| P value | NA | 0.0893 | 0.0796 | 0.0135 |
| Day 29, n | 57 | 58 | 54 | 53 |
| LS mean change from baseline (SE) | 1.25 (0.39) | 2.58 (0.39) | 2.08 (0.41) | 3.28 (0.41) |
| LS mean difference from placebo (SE) | NA | 1.34 (0.56) | 0.83 (0.57) | 2.03 (0.57) |
| 95% CI | NA | 0.24 to 2.43 | −0.29 to 1.95 | 0.90 to 3.15 |
| P value | NA | 0.0170 | 0.1446 | 0.0005 |
Definitions of abbreviations: CI = confidence interval; CS-VAS = cough severity visual analog scale; LCQ = Leicester Cough Questionnaire; LS = least squares; NA = not applicable; SD = standard deviation; SE = standard error.
Secondary Endpoints
Change from baseline to Day 15 in 24-hour cough frequency
Nominally significant placebo-adjusted reductions from baseline in 24-hour cough frequency were also observed at Day 15 in the 50 mg and 200 mg camlipixant arms, −32.4% (95% CI, −48.1 to −11.8; P = 0.0040) and −34.3% (95% CI, −49.9 to −14.0; P = 0.0024), respectively (Figure 3A and Table 2). The placebo-adjusted change from baseline at Day 15 was −18.3% in the camlipixant 12.5 mg arm (95% CI, −37.3 to 6.3; P = 0.1314). The percentage changes from baseline in mean 24-hour cough frequency are reported in Figure 3B and Table 2. In the exploratory population, the placebo-adjusted change from baseline in 24-hour cough frequency at Day 15 was 0.1% (95% CI, −34.5 to 52.9) (Table E5).
24-hour cough responder analysis
By Day 15, a higher proportion of patients in each of the camlipixant arms had shown a ⩾30% improvement from baseline in 24-hour cough frequency versus placebo. On Day 28, 51.7%, 60.7%, and 61.5% of patients in the camlipixant 12.5, 50, and 200 mg arms, respectively, showed ⩾30% improvement from baseline (vs. 35.7% in the placebo arm). The same trends were seen on Days 15 and 28 for ⩾50% and ⩾70% improvements in 24-hour cough frequency (Figure 3C and Table 2).
On Day 28, the likelihood of a ⩾30%, ⩾50%, or ⩾70% reduction from baseline in 24-hour cough frequency was greater across all camlipixant arms versus placebo; the odds ratio for achieving each percentage reduction from baseline in 24-hour cough frequency was nominally significant in the camlipixant 50 and 200 mg arms versus placebo (Figure 3D and Table 2). The individual odds ratios for achieving each percentage reduction for responder definition were calculated post hoc. In the exploratory population, 25.8% and 26.7% of patients receiving camlipixant saw improvements of ⩾50% from baseline in 24-hour cough frequency at Day 15 and Day 28, respectively (Table E5). Exploratory analysis at the end of the follow-up period (Day 43) showed that reductions in cough frequency continued in the placebo arm, whereas cough frequency reductions in all camlipixant arms trended back toward baseline values (Table E6).
Change from baseline in awake cough frequency
At Day 15, statistically significant placebo-adjusted differences from baseline in awake cough frequency of −30.6% (95% CI, −47.8 to −7.7; P = 0.0122) and −31.9% (95% CI, −49.0 to −9.0; P = 0.0096) were observed in the 50 and 200 mg camlipixant arms, respectively (Figure E1C and Table 2). Placebo-adjusted reductions from baseline in awake cough frequency remained statistically significant at Day 28 in the camlipixant 50 and 200 mg arms (Figure E1C and Table 2).
Awake cough responder analysis
In all camlipixant arms, a greater percentage of patients showed a ⩾30%, ⩾50%, and ⩾70% reduction from baseline in awake cough frequency by Day 15 and Day 28 than in the placebo arm (Figures E1A and E1B). By Day 28, a ⩾30% reduction from baseline was seen in 55.2%, 65.6%, and 71.2% of patients in the camlipixant 12.5, 50, and 200 mg arms, respectively (vs. 39.3% with placebo).
Change from baseline in nighttime cough frequency
A reduction from baseline to Day 15 in nighttime cough frequency was seen in all camlipixant arms and was sustained to the end of the treatment period on Day 28 (Figure E2A); however, when compared with placebo, reductions did not reach statistical significance with any of the camlipixant doses (Figure E2B).
Patient-reported Outcomes
Cough severity (CS-VAS scores)
In the main population, improvements over placebo in patient-reported CS-VAS score were observed across the three camlipixant arms on Day 15 (Figure 4A). Placebo-adjusted least squares mean difference (95% CI) were −12.37 (−19.88 to −4.85) mm in the 12.5 mg, −14.00 (−21.52 to −6.48) mm in the 50 mg, and −16.43 (−24.06 to −8.80) mm in the 200 mg camlipixant arms (Table 2). These improvements were sustained to Day 29. Changes in CS-VAS in the exploratory population are reported in Table E5.
Figure 4.
Change from baseline in patient-reported outcomes in the main population. Data points are manually spread to avoid overlap. (A) Change from baseline for CS-VAS. Day 15, placebo, n = 62; 12.5 mg, n = 59; 50 mg, n = 59; 200 mg, n = 55. Day 29, placebo, n = 59; 12.5 mg, n = 58; 50 mg, n = 54; 200 mg, n = 53. (B) Change from baseline for LCQ. Day 15, placebo, n = 57; 12.5 mg, n = 59; 50 mg, n = 53; 200 mg, n = 54. Day 29, placebo, n = 57; 12.5 mg, n = 58; 50 mg, n = 54; 200 mg, n = 53. Error bars indicate SE. Asterisks relate to the significance of treatment difference versus placebo: *P < 0.05, **P < 0.005, ***P ⩽ 0.0005, and ****P < 0.0001. CS-VAS = cough severity visual analog scale; LCQ = Leicester Cough Questionnaire.
Cough-related quality of life (LCQ scores)
In the main population at Day 15, the least squares mean changes from baseline (SE) in LCQ score were 1.91 (0.35), 1.96 (0.37), and 2.33 (0.36) in the 12.5, 50, and 200 mg camlipixant arms, respectively (vs. 1.07 [0.35] with placebo) (Figure 4B and Table 2). In the 200 mg camlipixant arm, nominal significance was achieved in least squares mean difference from placebo (1.26; 95% CI, 0.26–2.26; P = 0.0135). At Day 29, further improvements were observed with camlipixant (Figure 4B and Table 2). Nominal significance was achieved in placebo-adjusted least squares mean difference from baseline in the 12.5 mg (1.34 [95% CI, 0.24–2.43; P = 0.0170] and 200 mg (2.03 [95% CI, 0.90–3.15; P = 0.0005]) camlipixant arms. Changes in LCQ scores in the exploratory population treated are reported in Table E5.
Safety and Tolerability
In the main population, the incidence of treatment-emergent AEs was similar across all camlipixant arms and placebo (Table 3). The most common treatment-emergent AEs in the main population (⩾5% patients in any camlipixant arm) were nausea and dysgeusia (taste alteration). Dysgeusia occurred in 4.8–6.5% of patients in the camlipixant arms (vs. 0% with placebo); these were mild–moderate. No treatment-emergent serious AEs were reported. There were no reports of complete or partial loss of taste, and no taste disturbance AEs were classified by patients as severely or extremely bothersome.
Table 3.
Treatment-Emergent Adverse Events (Main Population: Awake Cough Frequency ⩾25 Coughs/h)
| Placebo (n = 63) | Camlipixant (Twice Daily) |
|||
|---|---|---|---|---|
| 12.5 mg (n = 62) | 50 mg (n = 62) | 200 mg (n = 62) | ||
| Patients with ⩾1 TEAE, n (%) | 22 (34.9) | 23 (37.1) | 13 (21.0) | 19 (30.6) |
| Patients with ⩾1 TESAE, n (%) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Patients with TEAE leading to discontinuation,* n (%) | 1 (1.6) | 0 (0.0) | 0 (0.0) | 2 (3.2) |
| Patients with taste disturbance TEAE leading to discontinuation, n (%) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Most common TEAEs (⩾5% at any dose),† n (%) | ||||
| Nausea | 0 (0.0) | 0 (0.0) | 5 (8.1) | 2 (3.2) |
| Dysgeusia (taste alteration) | 0 (0.0) | 3 (4.8) | 4 (6.5) | 3 (4.8) |
| Incidence of taste disturbance TEAE,‡ n (%) | ||||
| Dysgeusia (taste alteration) | 0 (0.0) | 3 (4.8) | 4 (6.5) | 3 (4.8) |
| Hypogeusia (partial taste loss) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Ageusia (complete taste loss) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Description of taste disturbance TEAE, n (%) | ||||
| Not bothersome | 0 (0.0) | 0 (0.0) | 1 (1.6) | 0 (0.0) |
| Slightly bothersome | 0 (0.0) | 3 (4.8) | 1 (1.6) | 3 (4.8) |
| Moderately bothersome | 0 (0.0) | 0 (0.0) | 2 (3.2) | 0 (0.0) |
| Severely bothersome | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Extremely bothersome | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
Definitions of abbreviations: TEAE = treatment-emergent adverse event; TESAE = treatment-emergent serious adverse event.
TEAEs leading to treatment discontinuation included dry mouth (200 mg camlipixant, n = 1) and cough (200 mg camlipixant and placebo, n = 1 each).
No TEAEs reported with an incidence ⩾5% in the exploratory population.
No taste disturbance TEAEs reported in the exploratory population.
Three patients in the main population discontinued treatment because of treatment-emergent AEs (200 mg camlipixant, n = 2 [3.2%]; placebo, n = 1 [1.6%]); no discontinuations were related to taste disturbance AEs (Table 3). A further two patients discontinued treatment because of AEs (hyperbilirubinemia, n = 1; SARS-CoV-2 infection, n = 1). These AEs started before the first study treatment dose and were not considered to be treatment emergent. The proportion of treatment-emergent AEs reported in the exploratory population is presented in Table E7.
Discussion
In the SOOTHE phase 2b trial, treatment with camlipixant at 50 and 200 mg twice daily met the primary efficacy endpoint of a significant reduction in 24-hour cough frequency, sustained over 28 days, versus placebo in patients with RCC and a baseline awake cough frequency ⩾25 coughs/h. The favorable primary endpoint data in this population were supported by reductions in the secondary endpoint of awake cough frequency and an acceptable safety profile. Moreover, the clinical relevance of these findings was underscored by improvements in patient-reported outcomes.
Improvements from baseline in cough frequency were observed in the exploratory population (⩾10 and <25 coughs/h) treated with 200 mg twice daily camlipixant; however, the trial was not statistically powered to identify treatment effect versus placebo in this group. The main population also demonstrated nominally significant improvements in secondary endpoints such as awake cough frequency, cough reduction responder rates, CS-VAS scores, and LCQ scores. In general, efficacy results were reflective of dose, with 12.5 mg twice daily camlipixant demonstrating lower efficacy than 50 mg twice daily or 200 mg twice daily camlipixant.
The results of the SOOTHE trial support the potential use of selective P2X3 antagonists in the treatment of RCC and extend the findings of the phase 2a RELIEF trial; together, these phase 2 trial results show that further clinical evaluation of camlipixant in a larger phase 3 trial is warranted. Although comparisons between studies should be interpreted with caution, the 34% reduction in 24-hour cough frequency versus placebo at 4 weeks in the SOOTHE trial is comparable with the reductions seen with gefapixant at 12 weeks in the phase 2b (37%) and phase 3 (18.5%) trials and with eliapixant in a phase 2b trial (15.6–19.2%) (38, 39, 48). Another P2X3 inhibitor, sivopixant, resulted in placebo-adjusted changes in hourly cough counts in 24 hours of 13.2% to –12.5% at Week 4 of treatment across the dose range studied (50–300 mg); notably, these changes were not substantial relative to a 60.4% reduction in cough frequency with placebo (49). In SOOTHE, the 16-day placebo run-in period meant that patients with a more stable cough frequency were recruited to the trial, which may have contributed to greater minimization of the reduction in 24-hour cough frequency seen in the placebo arm versus that of other P2X3 antagonists described previously (38, 49, 50).
Although the earlier phase 2a RELIEF trial of camlipixant did not meet its primary endpoint of change in awake cough frequency in the intention-to-treat population, an association between baseline awake cough frequency and cough frequency reduction was demonstrated (40). Greater and nominally significant reductions in cough frequency were recorded in prespecified subgroups of patients with baseline cough frequencies ⩾20 coughs/h and ⩾32.4 coughs/h compared with those with baseline cough frequencies <20 coughs/h and <32.4 coughs/h, respectively (40). The suggestion that P2X3 antagonists have greater efficacy in patients with higher cough frequency was established by Abdulqawi and colleagues almost a decade ago (51). A similar relationship between baseline cough frequency and treatment response has been reported in studies of other P2X3 antagonists in the treatment of patients with RCC (38, 52, 53). The reasons for this finding are not entirely understood and are an area for future research. Explanations could include high cough variability and placebo effect at lower cough frequency, an association between greater activation of P2X3-dependent pathways and higher cough rates, or limitations of cough frequency endpoints that are currently used in clinical trials. On the basis of this knowledge, the SOOTHE trial prospectively stratified patients by baseline awake cough frequency (⩾25 coughs/h in the main population; ⩾10 and <25 coughs/h in the exploratory population, with fewer patients than the main population). Indeed, a larger placebo effect was observed in the exploratory population than in the main population in the SOOTHE trial. Overall, camlipixant had a manageable safety profile with no serious treatment-emergent AEs observed; the reported incidence of taste disturbance AEs was ⩽6.5% in each treatment arm and lower than the level reported in studies of other P2X3 antagonists (38, 49, 50).
Limitations
This trial had some limitations. Because this was a phase 2 trial, no formal adjustments for multiplicity were made, and there was no explicit imputation of missing data. The duration of the trial was limited; therefore, studies of longer duration in larger numbers of patients are needed to evaluate longer-term efficacy and safety of camlipixant and the relevance of this promising result in a wider population of patients with RCC.
Conclusions
In conclusion, findings from the SOOTHE phase 2b trial showed that treatment with camlipixant reduced cough frequency, improved patient-reported outcomes, and showed an acceptable safety profile in patients with RCC and a baseline awake cough frequency of ⩾25 coughs/h. Camlipixant has the potential to be a new treatment option for patients with RCC who currently have limited treatment options. The ongoing global, multicenter phase 3 CALM-1 (A 52-Week Study of the Efficacy and Safety of BLU-5937 in Adults With Refractory Chronic Cough; ClinicalTrials.gov identifier NCT05599191) and CALM-2 (A 24-Week Study of the Efficacy and Safety of BLU-5937 in Adults With Refractory Chronic Cough; ClinicalTrials.gov identifier NCT05600777) trials will provide further insights into the efficacy and safety of camlipixant in this underserved patient population.
Supplemental Materials
Acknowledgments
Acknowledgment
The authors thank all patients and investigators who participated in the SOOTHE trial and the National Institute for Health and Care Research Clinical Research Facilities who supported study delivery in the United Kingdom. Medical writing and editorial assistance for this article were provided by Emma Butterworth, Ph.D., of Excerpta Medica (Amsterdam, the Netherlands). Medical writing support, under the direction of the authors, was also provided by Carla Smith, M.Sc., of Ashfield MedComms, an Inizio company, and was funded by GSK. Support with data and statistical content was provided by Zelie Bailes of GSK. J.A.S is supported by the NIHR Manchester Biomedical Research Centre and the study delivered by the NIHR Clinical Research Facilities in the United Kingdom.
Footnotes
Supported by Bellus Health, a GSK company (Bellus Health NCT04678206).
Author Contributions: K.J.C., J.S., and C.M.B. conceived and designed the study. J.A.S., S.S.B., L.M., A.H.M., M.S., and J.S. were responsible for running individual study sites and data collection. K.J.C., M.G., R.Y., and C.M.B. analyzed the data. J.A.S., S.S.B., M.S.B., L.M., A.H.M., M.S., K.J.C., M.G., S.L., R.Y., and C.M.B. provided data interpretation. All authors critically reviewed and revised the manuscript for intellectual content and approved the final manuscript before its submission.
Anonymized patient-level data will not be shared.
A data supplement for this document is available via the Supplements tab at the top of the online article.
Artificial Intelligence Disclaimer: No artificial intelligence tools were used in writing this manuscript.
Originally Published in Press as DOI: 10.1164/rccm.202409-1752OC on March 5, 2025
Author disclosures are available with the text of this article at www.atsjournals.org.
References
- 1. Irwin RS, French CL, Chang AB, Altman KW, CHEST Expert Cough Panel Classification of cough as a symptom in adults and management algorithms: CHEST guideline and expert panel report. Chest . 2018;153:196–209. doi: 10.1016/j.chest.2017.10.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Arinze JT, de Roos EW, Karimi L, Verhamme KMC, Stricker BH, Brusselle GG. Prevalence and incidence of, and risk factors for chronic cough in the adult population: the Rotterdam Study. ERJ Open Res . 2020;6:00300-02019. doi: 10.1183/23120541.00300-2019. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Çolak Y, Nordestgaard BG, Laursen LC, Afzal S, Lange P, Dahl M. Risk factors for chronic cough among 14,669 individuals from the general population. Chest . 2017;152:563–573. doi: 10.1016/j.chest.2017.05.038. [DOI] [PubMed] [Google Scholar]
- 4. Liang H, Ye W, Wang Z, Liang J, Yi F, Jiang M, et al. Prevalence of chronic cough in China: a systematic review and meta-analysis. BMC Pulm Med . 2022;22:62. doi: 10.1186/s12890-022-01847-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Meltzer EO, Zeiger RS, Dicpinigaitis P, Bernstein JA, Oppenheimer JJ, Way NA, et al. Prevalence and burden of chronic cough in the United States. J Allergy Clin Immunol Pract . 2021;9:4037–4044.e2. doi: 10.1016/j.jaip.2021.07.022. [DOI] [PubMed] [Google Scholar]
- 6. Song WJ, Chang YS, Faruqi S, Kim JY, Kang MG, Kim S, et al. The global epidemiology of chronic cough in adults: a systematic review and meta-analysis. Eur Respir J . 2015;45:1479–1481. doi: 10.1183/09031936.00218714. [DOI] [PubMed] [Google Scholar]
- 7. French CL, Crawford SL, Bova C, Irwin RS. Change in psychological, physiological, and situational factors in adults after treatment of chronic cough. Chest . 2017;152:547–562. doi: 10.1016/j.chest.2017.06.024. [DOI] [PubMed] [Google Scholar]
- 8. French CL, Irwin RS, Curley FJ, Krikorian CJ. Impact of chronic cough on quality of life. Arch Intern Med . 1998;158:1657–1661. doi: 10.1001/archinte.158.15.1657. [DOI] [PubMed] [Google Scholar]
- 9. Hanak V, Hartman TE, Ryu JH. Cough-induced rib fractures. Mayo Clin Proc . 2005;80:879–882. doi: 10.4065/80.7.879. [DOI] [PubMed] [Google Scholar]
- 10. Irwin RS, Dudiki N, French CL, CHEST Expert Cough Panel Life-threatening and non-life-threatening complications associated with coughing: a scoping review. Chest . 2020;158:2058–2073. doi: 10.1016/j.chest.2020.06.012. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Kuzniar TJ, Morgenthaler TI, Afessa B, Lim KG. Chronic cough from the patient’s perspective. Mayo Clin Proc . 2007;82:56–60. doi: 10.4065/82.1.56. [DOI] [PubMed] [Google Scholar]
- 12. Morice AH, Millqvist E, Bieksiene K, Birring SS, Dicpinigaitis P, Domingo Ribas C, et al. ERS guidelines on the diagnosis and treatment of chronic cough in adults and children. Eur Respir J . 2020;55:1901136. doi: 10.1183/13993003.01136-2019. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Morice A, Dicpinigaitis P, McGarvey L, Birring SS. Chronic cough: new insights and future prospects. Eur Respir Rev . 2021;30:210127. doi: 10.1183/16000617.0127-2021. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Gibson P, Wang G, McGarvey L, Vertigan AE, Altman KW, Birring SS, Chest Expert Cough Panel Treatment of unexplained chronic cough: CHEST Guideline and Expert Panel Report. Chest . 2016;149:27–44. doi: 10.1378/chest.15-1496. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Haque RA, Usmani OS, Barnes PJ. Chronic idiopathic cough: a discrete clinical entity? Chest . 2005;127:1710–1713. doi: 10.1378/chest.127.5.1710. [DOI] [PubMed] [Google Scholar]
- 16. Domingo C, Fernandez M, Garin N, Milara J, Moran I, Muerza I, et al. Determining what represents value in the treatment of refractory or unexplained chronic cough from the perspective of key stakeholders in Spain using multi-criteria decision analysis. Appl Health Econ Health Policy . 2023;21:119–130. doi: 10.1007/s40258-022-00770-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Dávila I, Puente L, Quirce S, Arismendi E, Díaz-Palacios M, Pereira-Vega A, et al. Characteristics and management of patients with refractory or unexplained chronic cough in outpatient hospital clinics in Spain: a retrospective multicenter study. Lung . 2023;201:275–286. doi: 10.1007/s00408-023-00620-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Zhang M, Morice AH, Si F, Zhang L, Chen Q, Wang S, et al. New insights into refractory chronic cough and unexplained chronic cough: a 6-year ambispective cohort study. Allergy Asthma Immunol Res . 2023;15:795–811. doi: 10.4168/aair.2023.15.6.795. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Hilton E, Marsden P, Thurston A, Kennedy S, Decalmer S, Smith JA. Clinical features of the urge-to-cough in patients with chronic cough. Respir Med . 2015;109:701–707. doi: 10.1016/j.rmed.2015.03.011. [DOI] [PubMed] [Google Scholar]
- 20. Zhang M, Sykes DL, Sadofsky LR, Morice AH. ATP, an attractive target for the treatment of refractory chronic cough. Purinergic Signal . 2022;18:289–305. doi: 10.1007/s11302-022-09877-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Lätti AM, Pekkanen J, Koskela HO. Defining the risk factors for acute, subacute and chronic cough: a cross-sectional study in a Finnish adult employee population. BMJ Open . 2018;8:e022950. doi: 10.1136/bmjopen-2018-022950. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. Morice AH, Jakes AD, Faruqi S, Birring SS, McGarvey L, Canning B, et al. Chronic Cough Registry A worldwide survey of chronic cough: a manifestation of enhanced somatosensory response. Eur Respir J . 2014;44:1149–1155. doi: 10.1183/09031936.00217813. [DOI] [PubMed] [Google Scholar]
- 23. Morice AH, Smith JA, Birring SS, McGarvey L, Dicpinigaitis P, Sher M, et al. Characteristics of participants with refractory chronic cough enrolled in a phase 2b trial of BLU-5937. Eur Respir J . 2022;60:801. [Google Scholar]
- 24. Mazzone SB, McGarvey L. Mechanisms and rationale for targeted therapies in refractory and unexplained chronic cough. Clin Pharmacol Ther . 2021;109:619–636. doi: 10.1002/cpt.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25. Visca D, Beghe B, Fabbri LM, Papi A, Spanevello A. Management of chronic refractory cough in adults. Eur J Intern Med . 2020;81:15–21. doi: 10.1016/j.ejim.2020.09.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. Smith JA. The therapeutic landscape in chronic cough. Lung . 2024;202:5–16. doi: 10.1007/s00408-023-00666-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Morice AH, Menon MS, Mulrennan SA, Everett CF, Wright C, Jackson J, et al. Opiate therapy in chronic cough. Am J Respir Crit Care Med . 2007;175:312–315. doi: 10.1164/rccm.200607-892OC. [DOI] [PubMed] [Google Scholar]
- 28. Ryan MA, Cohen SM. Long-term follow-up of amitriptyline treatment for idiopathic cough. Laryngoscope . 2016;126:2758–2763. doi: 10.1002/lary.25978. [DOI] [PubMed] [Google Scholar]
- 29. Ryan NM, Birring SS, Gibson PG. Gabapentin for refractory chronic cough: a randomised, double-blind, placebo-controlled trial. Lancet . 2012;380:1583–1589. doi: 10.1016/S0140-6736(12)60776-4. [DOI] [PubMed] [Google Scholar]
- 30. Dicpinigaitis PV, Rauf K. Treatment of chronic, refractory cough with baclofen. Respiration . 1998;65:86–88. doi: 10.1159/000029232. [DOI] [PubMed] [Google Scholar]
- 31. Bowen AJ, Nowacki AS, Contrera K, Trask D, Kaltenbach J, Milstein CF, et al. Short- and long-term effects of neuromodulators for unexplained chronic cough. Otolaryngol Head Neck Surg . 2018;159:508–515. doi: 10.1177/0194599818768517. [DOI] [PubMed] [Google Scholar]
- 32. Oh JY, Kang SY, Kang N, Won HK, Jo EJ, Lee SE, et al. Korean Chronic Cough Registry Study Group Characterization of codeine treatment responders among patients with refractory or unexplained chronic cough: a prospective real-world cohort study. Lung . 2024;202:97–106. doi: 10.1007/s00408-024-00674-6. [DOI] [PubMed] [Google Scholar]
- 33. Oh JY, Kang YR, An J, Choo E, Lee JH, Kwon HS, et al. Codeine prescription pattern and treatment responses in patients with chronic cough: a routinely collected institutional database analysis. J Thorac Dis . 2023;15:2344–2354. doi: 10.21037/jtd-22-1857. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34. Xu X, Chen Q, Liang S, Lü H, Qiu Z. Successful resolution of refractory chronic cough induced by gastroesophageal reflux with treatment of baclofen. Cough . 2012;8:8. doi: 10.1186/1745-9974-8-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35. Mazzone SB, Undem BJ. Vagal afferent innervation of the airways in health and disease. Physiol Rev . 2016;96:975–1024. doi: 10.1152/physrev.00039.2015. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36. Parker SM, Smith JA, Birring SS, Chamberlain-Mitchell S, Gruffydd-Jones K, Haines J, et al. British Thoracic Society clinical statement on chronic cough in adults. Thorax . 2023;78:s3–s19. doi: 10.1136/thorax-2023-220592. [DOI] [PubMed] [Google Scholar]
- 37. Garceau D, Chauret N. BLU-5937: a selective P2X3 antagonist with potent anti-tussive effect and no taste alteration. Pulm Pharmacol Ther . 2019;56:56–62. doi: 10.1016/j.pupt.2019.03.007. [DOI] [PubMed] [Google Scholar]
- 38. McGarvey LP, Birring SS, Morice AH, Dicpinigaitis PV, Pavord ID, Schelfhout J, et al. COUGH-1 and COUGH-2 Investigators Efficacy and safety of gefapixant, a P2X3 receptor antagonist, in refractory chronic cough and unexplained chronic cough (COUGH-1 and COUGH-2): results from two double-blind, randomised, parallel-group, placebo-controlled, phase 3 trials. Lancet . 2022;399:909–923. doi: 10.1016/S0140-6736(21)02348-5. [DOI] [PubMed] [Google Scholar]
- 39. Smith JA, Kitt MM, Morice AH, Birring SS, McGarvey LP, Sher MR, et al. Protocol 012 Investigators Gefapixant, a P2X3 receptor antagonist, for the treatment of refractory or unexplained chronic cough: a randomised, double-blind, controlled, parallel-group, phase 2b trial. Lancet Respir Med . 2020;8:775–785. doi: 10.1016/S2213-2600(19)30471-0. [DOI] [PubMed] [Google Scholar]
- 40. Smith JA, Morice AH, Birring SS, Parker SM, Marsden PA, Holcomb JR, et al. Camlipixant in refractory chronic cough: a phase 2a, randomized controlled trial (RELIEF) Am J Respir Crit Care Med . 2025;211:1072–1075. doi: 10.1164/rccm.202501-0093RL. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41. Smith J, McGarvey L, Birring SS, Morice AH, Sher MR, Dicpinigaitis P, et al. Safety and efficacy of BLU-5937 in the treatment of refractory chronic cough from the phase 2b SOOTHE trial [abstract] Am J Respir Crit Care Med . 2022;205:A5778. [Google Scholar]
- 42. Morice AH, Smith J, Birring SS, McGarvey L, Hull JH, Blaiss M, et al. Responders analyses in objective 24h cough frequency in SOOTHE, a phase 2b trial of a selective P2x3 antagonist in refractory chronic cough [abstract] Am J Respir Crit Care Med . 2022;205:A5610. [Google Scholar]
- 43. Smith JA, Holt K, Dockry R, Sen S, Sheppard K, Turner P, et al. Performance of a digital signal processing algorithm for the accurate quantification of cough frequency. Eur Respir J . 2021;58:2004271. doi: 10.1183/13993003.04271-2020. [DOI] [PubMed] [Google Scholar]
- 44. Birring SS, Prudon B, Carr AJ, Singh SJ, Morgan MD, Pavord ID. Development of a symptom specific health status measure for patients with chronic cough: Leicester Cough Questionnaire (LCQ) Thorax . 2003;58:339–343. doi: 10.1136/thorax.58.4.339. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 45. Martin Nguyen A, Bacci ED, Vernon M, Birring SS, Rosa C, Muccino D, et al. Validation of a visual analog scale for assessing cough severity in patients with chronic cough. Ther Adv Respir Dis . 2021;15:17534666211049743. doi: 10.1177/17534666211049743. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46.SAS Institute Inc. 2013. https://documentation.sas.com/doc/en/pgmsascdc/9.4_3.5/procstat/procstat_freq_toc.htm
- 47. Dixon JR., Jr. The International Conference on Harmonisation Good Clinical Practice guideline. Qual Assur . 1999;6:65–74. doi: 10.1080/105294199277860. [DOI] [PubMed] [Google Scholar]
- 48. World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA . 2013;310:2191–2194. doi: 10.1001/jama.2013.281053. [DOI] [PubMed] [Google Scholar]
- 49. McGarvey L, Smith JA, Morice A, Birring SS, Chung KF, Dicpinigaitis PV, et al. A randomized, double-blind, placebo-controlled, parallel-group phase 2b trial of P2X3 receptor antagonist sivopixant for refractory or unexplained chronic cough. Lung . 2023;201:25–35. doi: 10.1007/s00408-022-00592-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 50. Dicpinigaitis PV, Morice AH, Smith JA, Sher MR, Vaezi M, Guilleminault L, et al. Paganini Investigators Efficacy and safety of eliapixant in refractory chronic cough: the randomized, placebo-controlled phase 2b PAGANINI study. Lung . 2023;201:255–266. doi: 10.1007/s00408-023-00621-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 51. Abdulqawi R, Dockry R, Holt K, Layton G, McCarthy BG, Ford AP, et al. P2X3 receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2 study. Lancet . 2015;385:1198–1205. doi: 10.1016/S0140-6736(14)61255-1. [DOI] [PubMed] [Google Scholar]
- 52. Smith JA, Kitt MM, Butera P, Smith SA, Li Y, Xu ZJ, et al. Gefapixant in two randomised dose-escalation studies in chronic cough. Eur Respir J . 2020;55:1901615. doi: 10.1183/13993003.01615-2019. [DOI] [PubMed] [Google Scholar]
- 53. Niimi A, Saito J, Kamei T, Shinkai M, Ishihara H, Machida M, et al. Randomised trial of the P2X3 receptor antagonist sivopixant for refractory chronic cough. Eur Respir J . 2022;59:2100725. doi: 10.1183/13993003.00725-2021. [DOI] [PMC free article] [PubMed] [Google Scholar]
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