Clinical phase II and phase III trial results assessing effects of P2X3 receptor antagonists versus placebo on awake cough frequency in patients with refractory chronic cough (RCC)
| Drug | Dose regimen (n); design, duration | Cough frequency time period | Baseline coughs per hour, mean±sd | End of treatment coughs per hour, mean±sd | Mean % change in cough frequency versus placebo, (95% CI) | Taste AEs, % (dysgeusia, hypogeusia) | |||
| Placebo | Active | Placebo | Active | Placebo | Active | ||||
| Gefapixant, (phase II) [42] | 600 mg twice daily (n=24); 2 weeks | Awake | 65.5±163.4 (n=21) | 37.1±32.2 (n=19) | 43.6±51.4 (n=21) | 11.0±8.3 (n=19) | −75 (−88, −50), p=0.0003 | 0, 0 | 88, 54 |
| 24 h | 44.7±105.2 (n=20) | 26.6±22.6 (n=18) | 28.9±31.2 (n=20) | 7.7±6.0 (n=18) | −74 (−87, −46), p=0.001 | ||||
| Gefapixant dose escalation, (phase II) [43] | Part 1: 50–200 mg twice daily (n=29); crossover, 16 days Part 2: 7.5–50 mg twice daily (n=30); crossover, 16 days | Awake | Part 1: 52.8±40.4 Part 2: 46.1±39.8 | Part 1: 54.5±41.1 Part 2: 49.6±44.0 | Part 1: 54.0±39.3 Part 2: 50.6±34.4 | Part 1: 28.0±23.8 Part 2: 27.0±27.4 | Part 1: −41 (−59, −15), p<0.05 to −57 (−73, −31), p<0.05 Part 2: −15 (−35, 13) to −56 (−72, −31), p<0.05 | 0, 0 | Part 1: 46–85, 7–15 Part 2: 7–53, NA |
| 24 h | Part 1: 37.9±27.5 Part 2: 32.2±28.0 | Part 1: 39.7±28.4 Part 2: 36.3±32.3 | Part 1: 40.6±28.4 Part 2: 37.3±25.9 | Part 1: 21.3±18.0 Part 2: 20.8±20.5 | NA, p<0.05 NA, p<0.05 | ||||
| Gefapixant, (phase IIb) [126] | 7.5–50 mg twice daily (n=253); 12 weeks | Awake | 27.6±2.3# | 24.1±3.0# to 28.8±2.2# | 18.2±3.1# | 11.3±2.8# to 14.5±3.7# | −22 (−42, −5), p=0.097 to −37 (−53, −15), p=0.0027 | 5, 2 | 10–48, 0–24 |
| 24 h | 20.5±2.2# | 17.6±3.0# to 21.9±2.2# | 13.7±2.9# | 8.5±2.8# to 10.8±3.6# | −21 (−40, 5), p=0.10 to −38 (−53, −17), p=0.0014 | ||||
| Gefapixant (phase III) [138] | 15 mg twice daily; 45 mg twice daily COUGH-1 (n=730): 12 weeks COUGH-2 (n=1314): 24 weeks | 24 h | COUGH-1: 22.8¶ COUGH-2: 19.5¶ | COUGH-1: 19.9¶; 18.2¶ COUGH-2: 19.4¶; 18.6¶ | COUGH-1: 10.3¶ COUGH-2: 8.3¶ | COUGH-1: 9.7¶; 7.1¶ COUGH-2: 8.1¶; 6.8¶ | COUGH-1: 2 (−16, 23), ns −18 (−33, −1), p=0.041 COUGH-2: −1 (−14, −14), ns −15 (−26, −1), p=0.031 | COUGH- 1: 3 COUGH-2: 8 | COUGH-1: 11, 58 COUGH-2: 20, 69 |
| Eliapixant (phase IIa) [128] | 10–750 mg twice daily (n=40); crossover, 3 weeks | Awake | 33.3±2.5# | 35.4±2.5# (n=39) | 30.5±2.5# | 10 mg: 30.0±2.7 (n=39) 50 mg: 25.6±2.8 (n=39) 200 mg: 22.9±2.7 (n=39) 750 mg: 22.6±2.4 (n=38) | 10 mg: 5 (−11, 24)+, ns 50 mg: –16 (−29, 0.3)+, p<0.05 200 mg: −24 (−36, −11)+, p=0.002 750 mg: −26 (−38, −13)+, p=0.002 | 3, 0 | 0–10, 0–3 |
| 24 h | 25.5±2.5# | 26.6±2.5# | 22.6±2.5 | 10 mg: 22.8±2.6 (n=39) 50 mg: 18.8±2.8 (n=39) 200 mg: 17.1±2.6 (n=39) 750 mg: 16.6±2.4 (n=38) | 10 mg: 10 (−7, 29)+, ns 50 mg: −15 (−28, 0.4)+, ns 200 mg: −23 (−34, −9)+, p=0.004 750 mg: −25 (−37, −12)+, p=0.002 | ||||
| Filapixant (phase IIa) [129] | 20–250 mg twice daily (n=23); crossover, ascending-dose, 4 days per dose | 24 h | NA | NA | NA | NA | 20 mg: NA, ns 80 mg: −17, p=0.015 150 mg: −28, p<0.001 250 mg: −37, p<0.001 | 12 | 4−57 |
| Sivopixant (phase IIa) [131] | 150 mg every day (n=31); crossover, 2 weeks | Awake | NA | NA | NA | NA | −32 (−54, 1), p=0.055 | NA | 3, 3 |
| 24 h | NA | NA | NA | −31, (p=0.0386) | |||||
Data are arithmetic mean±sd unless otherwise stated. #: Geometric mean±geometric sd. ¶: Geometric mean. +: 90% credible limits. AE: adverse event; CI: confidence interval; NA: not available; ns: non-significant; RCC: refractory chronic cough.