Table 6.

Other medications for refractory chronic cough.

Study author/s	Type of study	N	Drug treatment dose and duration	Efficacy outcome	Study results and conclusion/s	Adverse/side effects	Methodological weaknesses
Yousaf et al., 2010 [93]	Randomized, double-blind, placebo-controlled parallel trial	30	Erythromycin stearate capsules (250 mg daily), n = 15 or matching placebo capsules (one/day), n = 15 for 12 weeks.	Primary outcome was a change in log 24 h cough frequency from baseline to 12 weeks. Secondary endpoints were changes in induced sputum neutrophils differential cell count, sputum bacterial colonies, log C2, C5, cough VAS, and LCQ.	Twenty-eight patients completed the study (erythromycin n = 13, placebo n = 15); two withdraw due to personal reasons. After adjusting for baseline differences there was no difference in the change in cough frequency between erythromycin and placebo groups at 12 weeks (mean difference in fold change 1.1; 95% CI 0.7 to 1.5; p = 0.585). There was a statistically significant between-treatment difference in the change n sputum neutrophils at 12 weeks (mean difference 16.8%; 95% CI 1.6 to 32.1%; p = 0.03). There was no difference in the change in LCQ, cough VAS, log C2, or log C5 between treatments. Log bacterial colony forming units was unchanged with active and placebo treatment. IL-8 was measured in six active treatment patients and 10 placebo treatment patients resulting in a mean difference in fold change 2.9; 95% CI 0.9 to 9.5; p = 0.08).	Two patients in the placebo group reported abdominal discomfort at the 6 week visit, which had resolved by the 12 week visit. One patient in the erythromycin group reported dizziness at the 6 week visit, which resolved within a week.
Hodgson et al., 2016 [94]	Randomized, double-blind, placebo-controlled parallel trial	44	Azithromycin capsules, 500 mg daily for 3 days followed by 250 mg three times a week for 8 weeks, n = 21. The control intervention was lactose-containing placebo capsules n = 21, taken according to the same dosing schedule.	Primary outcome measure was change in LCQ score from baseline to end of treatment at week 8. Secondary outcome measures were cough severity score by VAS and FENO by (NIOX).	There was a clinically important improvement in LCQ score with azithromycin (mean change, 2.4; 95% CI, 0.5 to 4.2) but not placebo (mean change, 0.7; 95% CI, -0.6 to 1.9), but the between-group difference was not statistically significant (p = 0.12). 11 of 21 (52%) subjects in the azithromycin group had a clinically significant improvement in their LCQ score. There was a large and significant improvement in LCQ score in patients with chronic cough and a concurrent diagnosis of asthma who were treated with azithromycin (mean change, 6.19; 95% CI, 4.06 to 8.32). Treatment with low-dose azithromycin for 8 weeks did not significantly improve LCQ score compared with placebo. The use of macrolides for treatment-resistant cough cannot be recommended from this study, but they may have a place in the treatment of chronic cough associated with asthma with a large and significant improvement in LCQ.	Side effects occurred in both groups including GI effects such as diarrhea with azithromycin [4] and placebo [2]; heartburn [1], [1]; abdominal pain [2], [1]; and nausea [1], [1] respectively. Less common effects such as musculoskeletal occurred in the placebo group only.	Patients with other comorbidities such as asthma, rhinitis, or reflux were not excluded as for other refractory CC studies. The study was not designed to detect subgroup effects, so significant improvement in LCQ for the CC with asthma subgroup maybe a chance finding rather than a true treatment effect. No objective cough measurement used.
Birring et al., 2017 [125]	Multicenter, double-blind, randomized placebo-controlled, 2-period cross-over trial (Phase IIa study) in patients with IPF and chronic cough and a parallel study of similar design in patients with refractory CC.	27	PA101 cromolyn sodium formulation (40 mg) or matching placebo three times a day via oral inhalation for 2 weeks, followed by a 2 week washout, and then crossed over to the other arm.	Primary efficacy outcome was change from baseline in objective daytime cough frequency (from 24 h acoustic recording, Leicester Cough Monitor) to posttreatment. Secondary cough outcomes included the LCQ, and cough severity (VAS).	In patients with IPF, PA101 significantly reduced daytime cough frequency by 31.1% at day 14 compared with placebo (ratio of least-squares [LS] means 0.67, 95% CI 0.48–0.94, p = 0.0241). In the refractory CC cohort the daytime average cough count decreased by 12 coughs/h at Day 14 with PA101 treatment and by 9 coughs/h at Day 14 for placebo treatment, p = 0.319. The subjective endpoints of LCQ and VAS were also comparable between the two groups. Inhaled PA101 was therefore no better than placebo in the treatment of patients with refractory CC. However, PA101 was effective in the treatment of IPF patients with CC suggesting that the mechanism of cough in IPF might be disease specific. This is an important finding.	Adverse effects were comparable to placebo. Four patients (two placebo and two PA101) discontinued the study due to relatively mild side effects such as headache and cough. There were no serious AE’s reported.	Small number of patients investigated and the study was underpowered to assess subjective measures. Duration of treatment was brief. Industry sponsored trial. The sponsor participated in the study design, study oversight, medical monitoring, data management, analysis, and reporting of the data. However, an independent statistician analyzed the data.