Discussion
throat, cough, weight gain, dizziness, RCC
DISEASE, EVENT, RECRUITMENT, ADVERSE EFFECT, RCC
The purpose of this study was to gather additional preliminary data on a novel treatment called cough desensitization treatment (CDT), whereby patients with RCC are presented with progressive concentrations of aerosolized capsaicin while suppressing cough. While the results of our first CDT pilot RCT (pilot 1) showed a significantly greater improvement with CDT over sham (sub-threshold capsaicin) on one outcome measure, the data suggested participants would have had a greater improvement with additional treatment sessions. In pilot 2, we used a similar design but doubled the number of treatment sessions, chose aerosolized physiologic saline as the sham treatment, accepted participants who had not yet received BCST, and eliminated the component of suppressing cough outside of treatment sessions.As hypothesized, a greater number of CDT sessions resulted in a greater improvement—6.35 vs. 3.20 change in total LCQ. The sham group also achieved a greater improvement in pilot 2—2.73 vs. 1.75. The result in the sham group is interesting given that change in total LCQ with a sham or placebo treatment in prior RCC randomized control trials has not been more than 1.2 (range − 0.8 to 1.2) in pharmaceutical studies [The therapeutic outcome of 12 sessions of CDT, as measured by the LCQ, surpasses pharmaceutical RCC treatments in the literature. As can be seen in Table Vertigan et al. (2016) found combining BCST with pregabalin resulted in a mean change in total LCQ of 6.6 points, which was significantly greater than BCST plus placebo. However, two weeks after discontinuing pregabalin, LCQ change dropped in the BCST + pregabalin group and was no longer different than those treated with BCST + placebo. Additionally, patients taking pregabalin reported cognitive changes (30%), dizziness (45%), and weight gain (25%). In contrast, only one adverse effect (temporary throat irritation) was reported with CDT.
Mean change in total LCQ score across RCC clinical trialsSuperscript number indicates citation reference numberGiven CDT was designed to reduce cough-reflex sensitivity, we expected to find stronger evidence of a between-group difference in capsaicin cough challenge testing (CCT). The strength of the evidence may have been limited due to reduced sensitivity of CCT procedures, which were validated and tested for reliability on healthy individuals rather than patients with RCC, a concern also pointed out by Hilton et al. [CCT reliability studies were conducted on healthy individuals, which may not accurately translate to disease populations. Patients with RCC commonly cough without a specific triggering event, making it quite feasible that a patient with RCC will exhibit a cough at some point during CCT that has nothing to do with capsaicin exposure. If this happens within 15 s following a capsaicin exposure during CCT, it could easily result in a false positive test. We would not expect to see this pattern in healthy individuals who are not likely to experience unexpected cough triggering.Hilton et al. also questioned current ERS CCT guidelines [Although this study was not designed to look specifically at changes in peripheral and/or central nervous system mechanisms of the cough reflex, the results do provide clues towards understanding how both CDT and BCST may work. We found the biggest difference between CDT and sham groups when measuring UTC during CCT. From this we can tentatively infer that CDT may have resulted in a change in interoceptive processing of vagal afferent information, or that overtly attending to UTC (i.e., strengthening interoception), while attempting to change the desired motor output response (i.e., avoid coughing), increased activation of the inhibitory motor network that has been shown by Ando and colleagues to be decreased in patients with RCC [In addition to the limitation related to objective cough sensory testing, as described above, there are several other limitations that warrant discussion. The first and foremost is the small sample size, which certainly reduces the power of the study. While we had hoped to obtain a larger sample size, the study was funded by a one-year grant (P20GM103474) and additional funding was not available to the authors to continue the study. Rather than waiting for additional funding to resume the study, it seemed prudent to look at the data to determine if sufficient preliminary data had been obtained to justify a large-scale, multiple-site and multiple-year clinical trial. We are confident our data does provide such justification.Additional limitations include interpolation of midpoint test scores as PT1 and PT2 scores in three sham participants who did not show progress at midpoint. It is unknown if these participants would have shown progress with another six sessions. To minimize participant burden and maximize recruitment, we felt it important to provide a reasonable stopping point for all participants if they were not improving. There were zero CDT participants who showed no progress at midpoint, which suggests it was an appropriate time to assess for progress.