Discussion
cough, Taste-related TEAEs
SEPARATION, ANTITUSSIVE
This multinational, multicenter, randomized, controlled phase 2b trial assessed the impact of different doses of the P2X3 receptor antagonist sivopixant on patients with RCC/UCC over a 4-week period. No sivopixant dose showed a statistically significant difference vs placebo for 24-h cough count at the end of 4 weeks, and the primary study endpoint was not met. Nonetheless, sivopixant showed a dose-dependent effect in reducing the 24-h cough frequency. After 4 weeks of treatment, sivopixant 300 mg showed greater reductions in hourly cough counts over 24 h than placebo, with a − 12.47% placebo-adjusted change. Patient-reported outcomes (cough severity [VAS], LCQ total score, and PGIC responder analyses) suggest that sivopixant 300 mg may be effective for RCC/UCC. Along with the well-tolerated safety profile, sivopixant 300 mg shows promising potential for evaluation in further clinical trials.While a response to placebo has been seen frequently in other CC trials, improvement in the 24-h cough count (at Week 4) in the placebo group in this study was larger than that reported in other CC trials, with a − 60.38% improvement in 24-h cough count vs a − 31.4% improvement at Week 2 in the phase 2a study [The observed absolute reductions in cough frequency with sivopixant in this study are consistent with other P2X3 receptor antagonist studies [A large proportion of subjects in the study were on concomitant medications to treat conditions with a potential effect on cough (approximately 70% across all treatment arms). Better compliance with these medications might have contributed to the lack of separation between active treatment and placebo. In a post hoc analysis (data not shown), the relative change in 24-h cough count vs placebo was very small in the subgroup with concomitant medications and was numerically larger in favor of sivopixant in the subgroup without concomitant medications. However, contrary to this notion, the magnitude of the improvement on placebo was similar in both subgroups. Careful monitoring of the treatments for comorbidities affecting cough and the use of concomitant medications might be advisable for future studies in RCC/UCC.The phase 2a study identified that patients with < 10 coughs/h at baseline showed highly variable values of cough count during the trial, although the patient number was small. In this phase 2b study, the study protocol required a minimum of 10 coughs/h at the beginning of the screening period (Visit 1) but not at Visit 2, which was close to randomization and regarded as baseline. The 24-h cough count data at Visit 2 were not available by the time of randomization to exclude those with a cough frequency of < 10 coughs/h. Therefore, we conducted a post hoc analysis to exclude patients with < 10 coughs/h at Visit 2. The subgroup of patients with a 24-h cough frequency of ≥ 10 coughs/h at both screening Visits 1 and 2 had greater improvements in cough with sivopixant 300 mg at Week 4 achieving a − 22.85% placebo-adjusted change in hourly cough counts over 24 h. Based on this finding, we considered that a baseline cough count of ≥ 10 coughs/h might be necessary to detect a treatment response to sivopixant. In addition, other CC trials reported that baseline cough counts were related to efficacy [Changes in cough severity (VAS), LCQ total score, and PGIC were more likely to show improvements with sivopixant 300 mg vs placebo. A significantly higher proportion of patients receiving sivopixant 300 mg achieved the minimal clinically important difference of a ≥ 1.3-point improvement [Taste-related TEAEs are expected with P2X3 receptor antagonists [A strength of this study is the relatively large sample size of a broad population of patients with RCC/UCC from diverse geographical backgrounds, which supports data generalizability. This may mean that more patients were naïve to antitussive therapy. However, high placebo responses suggest that some patients might have had clinical courses not typical of RCC/UCC, and a high expectation bias may have played a role. Study limitations include a high placebo response and uncertainty regarding the clinical significance of the differences seen in the VAS assessment. Furthermore, objective measurement of cough frequency may not capture other features of cough such as cough intensity, which can only be assessed subjectively.