The findings from this study confirm our hypothesis that, compared to placebo, gefapixant significantly improves cough-related quality of life in patients with ROCC, consistent with previous Phase 3 data from COUGH-1 and COUGH-2 in RCC and UCC participants who had chronic cough of longer duration1. The demographics of participants randomized in this study were broadly similar to those of COUGH-1 and COUGH-2 and consistent with previous chronic cough clinical trials as well as data reported from observational studies in the general population [1, 6]. In this trial, the mean age of participants was approximately 7 years younger and duration of chronic cough was considerably shorter, as expected, compared with COUGH-1 and COUGH-2 (i.e., mean of ~7 months vs. ~11 years) [1].

Our results suggest that treatment with gefapixant 45 mg BID improves cough-specific health status to a greater extent than placebo in patients with RCC or UCC who are younger and have had chronic cough for a shorter period of time than previously studied. The majority of the PROs improved by 6 weeks, when the first measurements were collected, and benefits continued to improve over the 12-week study.

While a statistically significant improvement in the in LCQ total score was observed with gefapixant compared to placebo, it should be acknowledged that the estimated between-group difference was numerically small (0.75), due primarily to the large improvement in LCQ observed for both the gefapixant and placebo groups. However, results from the post hoc analysis to determine the proportion of participants reporting a clinically meaningful improvement in LCQ total score (i.e., a > 1.3-point improvement in total LCQ score) showed that a greater proportion of participants randomized to gefapixant 45 mg BID were LCQ responders compared to those in the placebo group. This finding that treatment with gefapixant conferred a greater likelihood of improvement than placebo is consistent with the findings in COUGH-2 [1].

The results of the additional PROs assessed in this study, the change in mean cough severity VAS score, and mean weekly CSD total score were consistent with the primary endpoint and supportive of our hypothesis that gefapixant is superior to placebo in the treatment of RCC and UCC in patients with ROCC. The results from the PGIC, which provides an impression of how patients generally feel regarding treatment of their cough, demonstrated improvement in a higher proportion of patients receiving gefapixant compared to placebo with greatest differences between treatments noted in the category of those feeling “much better.” Results from the WPAI suggested improvement in work productivity and less activity impairment for gefapixant compared to placebo.

We did not identify any single baseline characteristic to be more associated with mean change in LCQ from baseline, which is consistent with an analysis of baseline characteristics in relation to 24-h cough frequency in the COUGH-1 and COUGH-2 trials. Similar to the results presented here for ROCC, no baseline characteristics were found to be associated with reduced or greater efficacy in COUGH-1 or COUGH-2 in participants with RCC or UCC of longer baseline duration [1].

Results from this trial are consistent with previous research with gefapixant in that the most commonly reported AEs were taste related [1, 5, 7]. However, serious AEs occurred in a similar proportion among both the gefapixant- and placebo-treated participants.

The large placebo response observed in the current study is consistent with other gefapixant trials [1, 5] and studies of chronic cough [8, 9]. As with gefapixant, improvement in health status with placebo was evident at the first study time point (6 weeks) and continued to the end of study at 12 weeks. It is not clear whether such improvements would be maintained over longer periods of time in the ROCC group of patients with RCC or UCC. There is likely a multifactorial cause for the placebo responses that have been observed consistently in trials of treatments for chronic cough. One factor may be anticipation of a treatment that has shown positive results in a condition that has no approved treatment. However, it is unlikely to be the sole contributor based on the magnitude of the response observed. Such dramatic improvements in health status among patients with chronic cough have not been reported in other settings in the absence of an active treatment. Another contributor to the observed phenomenon is that cough is a reflex that can be under voluntary control with higher brain involvement [9, 10]. Higher brain involvement has been suggested as a factor for placebo responses in other respiratory conditions [11,12,13,14] and has been observed as a factor in cough challenge studies [15]. Nonetheless, although a large placebo response was observed in this trial, participants in this trial experienced important improvements in cough-specific health status with gefapixant vs. placebo.

There were limitations in this study that should be acknowledged. There was no objective cough measure to compare with the primary endpoints of Phase 2b and Phase 3 studies. There was also no pre-specified analysis plan to reliably determine the timing of onset of efficacy. Additionally, while we demonstrated that intervention with gefapixant earlier in the natural history of RCC or UCC was successful in terms of improvements in cough-related health status, longer-term benefits of earlier treatment have yet to be evaluated. Nevertheless, results from this study demonstrate favorable effects on multiple PROs that are consistent with results observed in the larger, Phase 3 studies [1].

In summary, treatment with gefapixant 45 mg BID provided significantly greater improvements in cough-specific health status than placebo in patients with ROCC. Patients treated with gefapixant were also more likely to report clinically meaningful improvements in cough-specific health status and larger reductions in patient-reported measures of cough severity compared to placebo. The most common AEs were related to taste, consistent with previous studies of gefapixant.[1, 5]. Serious AEs with gefapixant 45 mg BID were uncommon and occurred in a similar proportion of participants as those on placebo. These data indicate a favorable benefit/risk profile for gefapixant in the treatment of individuals with RCC or UCC with a diagnosis of chronic cough for less than a year.