. 2020 Aug 28;109(3):619–636. doi: 10.1002/cpt.2003

Table 1.

Data from prospective clinical studies investigating targeted therapies in RCC/UCC ^a

Drugs	Study design	Patient population	Efficacy	Safety
TRPV1‐targeting agents
SB‐705498	Phase II, double‐blind, placebo‐controlled, crossover RCT (NCT01476098) ⁴⁶ Single dose (600 mg) with 4‐week washout between treatment periods Primary end points: cough response to capsaicin at 2 hours after dose; objective cough frequency over 24 hours after dosing	21 pts with RCC (must have undergone full investigation with treatment trials for possible causes) Current smokers and ex‐smokers with history of > 5 pack‐years were excluded C5 ≤ 250 μM Mean (range) age: 53 (34–70) year 71% female	Significant reduction in capsaicin sensitivity at 2 and 24 hours after treatment No significant difference in objective hourly cough count No significant changes in PROs (cough severity or urge‐to‐cough VAS, CQLQ scores)	No serious AEs Most common AE: headache (two pts during SB‐705498) No reports of fever or significant changes in tympanic temperature
XEN‐D0501	Phase II, double‐blind, placebo‐controlled, crossover RCT (EudraCT: 2014‐000306‐36) ⁴⁵ 14‐day treatment period (4 mg b.i.d.) separated by 14‐day washout Primary end point: ACF	20 pts with RCC by BTS guidelines ACF > 1.5 coughs/h; E_max> 4 coughs Current smokers and ex‐smokers (history > 20 pack‐years) and pts receiving cough modulators excluded Mean (SD) age: 63 (9) years 75% female	Significant reduction to capsaicin sensitivity No change in objective ACF or 24‐hour or sleep cough frequency No significant improvements in PROs (15‐point GRC, CQLQ), other than small but significant reduction in ACF VAS	1 discontinuation due to a TEAE (fatigue) No serious AEs 103 TEAEs reported by 18 (95%) pts receiving XEN‐D0501 Most common AEs were related to temperature sensations or mouth‐related events
Capsaicin (desensitization)	Double‐blind, placebo‐controlled, crossover RCT ⁴⁴ 0.4 mg of pure capsaicin q.d. for 2 weeks followed by 0.4 mg b.i.d. for 2 weeks Primary end point: capsaicin sensitivity (C2_log, C5_log)	24 nonsmoking pts with UCC lasting ≥ 1 year with claimed sensitivity to environmental irritants Negative SPT to most common respiratory allergens and negative methacholine test Mean (SD) age: 52 (12) year 91% female Median (range) duration of cough: 15 (2–50) year	Significant reduction in capsaicin sensitivity (C2_log but not C5_log) Significant improvement in cough symptoms score (assessed by Hull Cough Questionnaire)	Pts generally experienced fewer symptoms during the last week of active treatment compared with the week before baseline Symptoms occurring at a greater rate than baseline and placebo included diarrhea (18%), stomach pain (46%), flatulence (50%), and reflux (29%)
TRPV4‐channel blockers
GSK2798745	Phase I/II, double‐blind, placebo‐controlled, crossover RCT (NCT03372603) ⁵² GSK2798745 or placebo q.d. for 7 day with 14‐day to 21‐day washout between treatments Primary end point: ACF	Pts with RCC from four specialist clinics 12 pts included in interim futility analysis	32% increase in awake cough count vs. placebo Study terminated because of lack of efficacy	Not reported
P2X3‐receptor antagonists
Gefapixant	Double‐blind, placebo‐controlled, crossover RCT (NCT0142730) ⁶⁵ Treatment periods: 600 mg b.i.d. or placebo for 2 weeks, in randomized sequence separated by 2‐week washout Primary end point: daytime objective cough frequency	24 pts with RCC per BTS guidelines Current and ex‐smokers (< 6‐month abstinence or > 20 pack‐year history) and pts receiving cough modulators excluded Median (IQR) age: 54 (24–70) years 75% female Median (range) duration of cough: 9 (3–25) years	Significant 75% placebo‐adjusted reduction in mean daytime cough frequency Significant reduction in 24‐hour cough frequency, numerical reduction in nighttime cough frequency Significant reductions in daytime cough severity VAS, urge to cough VAS, and CQLQ total score Nonsignificant decrease in nighttime cough severity VAS	No serious AEs; all AEs were mild or moderate 100% of pts experienced taste disturbances during treatment, which were typically reversed within 24 hours of discontinuation Most common AE: dysgeusia (88%)
	Phase IIa, double‐blind, placebo‐controlled, crossover, dose‐escalation RCT (NCT02349425) ⁶⁶ Gefapixant or placebo for 16 days with crossover to alternative treatment for 16 days after washout Cohort 1: gefapixant 50, 100, 150, and 200 mg b.i.d.; 3‐day to 7‐day washout Cohort 2: gefapixant 7.5, 15, 30, and 50 mg b.i.d.; 14‐ to 21‐day washout Primary end point: ACF	59 pts with RCC/UCC lasting ≥ 1 year and cough severity VAS ≥ 40 mm; current and ex‐smokers (< 6‐month abstinence or> 20 pack‐year history) excluded Mean (range) age: 63 (47–76) year 83% female Median (range) duration of cough: cohort 1, 15 (1–55) years; cohort 2, 13 (2–43) years	Cohort 1: significant, statistically equivalent placebo‐adjusted improvements in ACF ranging from −41% to −57% at 50 and 200 mg b.i.d., respectively Cohort 2: dose‐related, significant placebo‐adjusted reductions in ACF at 15 mg (−25%), 30 mg (−37%), and 50 mg (−56%) Dose‐related improvements in cough severity VAS and CSD Significant improvements in LCQ scores that exceeded the MCID after 16 days of gefapixant treatment in both cohorts	Four pts discontinued early because of AEs (one for taste disturbance) 93% and 63% of pts experienced drug‐related AEs in cohort 1 and 2, respectively Taste disturbances were most common AEs and were dose related; dysgeusia was most common AE and occurred in 79% and 53% of pts in cohort 1 and 2, respectively
	Phase IIb, double‐blind, placebo‐controlled, parallel‐group RCT (NCT02612610) ⁶⁷ Gefapixant (7.5, 20, or 50 mg b.i.d.) or placebo for 12 weeks Primary end point: ACF	253 pts with RCC/UCC per ACCP/BTS guidelines lasting ≥ 1 year and cough severity VAS ≥ 40 mm; current and ex‐smokers (< 6‐month abstinence) excluded Mean (SD) age: 60 (10) years 76% female Median duration of cough: 11 years	Significant 37% placebo‐adjusted reduction in ACF at 50 mg b.i.d.; nonsignificant 22% placebo‐adjusted reduction in ACF at 7.5 and 20 mg b.i.d. Significant improvements in 24‐hour objective cough frequency, cough severity VAS, CSD total score, and LCQ total score at 50 mg b.i.d.	Dysgeusia was most common AE (48% at 50 mg b.i.d.) Incidence of taste AEs correlated with dose (10%, 49%, and 81% for 7.5, 20, and 50 mg b.i.d., respectively) 10 (16%) pts treated with 50‐mg b.i.d. dose discontinued because of an AE
	Phase II, double‐blind, placebo‐controlled, crossover RCT (NCT02476890) ³¹ Two 1‐day treatment periods (gefapixant 100 mg or matching placebo) separated by ≤ 48‐hour washout Primary end points: C2 and C5 for four different challenges (ATP, capsaicin, citric acid, and distilled water)	24 pts with RCC lasting ≥ 1 year and significant cough symptoms (score > 20/70 on HARQ) and 12 healthy volunteers All participants were nonsmokers for ≥ 5 years RCC pts mean (range) age: 61 (48–73) years RCC pts: 88% female Mean (range) duration of cough: 15 (3–44) years	Gefapixant decreased sensitivity to ATP and distilled water challenges in RCC pts and, to a lesser extent, healthy volunteers No effect of gefapixant on capsaicin or citric acid challenge Gefapixant improved cough severity VAS, urge‐to‐cough VAS, and frequency in RCC pts	Dysgeusia was most common AE (67% of RCC pts, 75% of healthy volunteers) No serious AEs or AEs leading to discontinuation
BLU‐5937	Phase I, randomized, double‐blind, placebo‐controlled study (NCT03638180) ⁶⁹ Divided into SAD and MAD cohorts SAD: 50–1,200 mg q.d. MAD: 100–400 mg b.i.d. Objective: investigate safety, tolerability, and PK profile	90 healthy volunteers (60 in SAD cohort, 30 in MAD cohort)	NA	4% incidence of taste alterations at predicted therapeutic dose of 50–100 mg No complete taste loss Most taste events were mild (one very bothersome)
S‐600918	Phase IIa, double‐blind, placebo‐controlled, crossover RCT (JapiCTI‐184027) ⁷⁰ Two 2‐week treatment periods (150‐mg S‐600918 or matching placebo q.d.) separated by a 2–3–week washout Primary end point: reduction in placebo‐adjusted objective daytime cough frequency	31 pts with RCC Mean (SD) age: 50 (15) years	Nonsignificant 32% reduction in objective daytime cough frequency (primary end point) Significant 31% reduction in 24‐hours cough frequency (secondary end point)	No significant differences in overall incidence of TEAEs between active and placebo cohorts 3% incidence of taste changes and 3% incidence of taste injury during active treatment
BAY 1817080	Phase I/IIa, double‐blind, placebo‐controlled, crossover RCT (NCT03310645) ⁷¹ 10, 50, 200, or 750 mg of BAY 1817080 or matching placebo b.i.d. in 7‐day periods Primary end point: frequency/severity of AEs	40 nonsmoking pts with RCC/UCC for ≥ 1 year Median (range) age: 63 (20–76) years 78% female	Significant reduction in 24‐hour cough frequency at higher doses (23% reduction at 200 mg; 25% reduction at 750 mg) Significant improvement in cough severity VAS at doses ≥ 50 mg	AEs occurred in 41–49% of pts receiving BAY 1817080 (most mild) Taste‐related AEs: 5%, 10%, 15%, and 21% of pts at 10, 50, 200, and 750 mg, respectively
NaV1.7 blockers
GSK2339345	Phase II, three‐part, double‐blind, placebo‐controlled, crossover RCT (NCT01899768) ⁷⁶ Part A: 3 study days with pts receiving two inhaled doses of GSK2339345 (1 mg) or placebo via inhaler device Parts B and C: full dose‐response cough challenges with capsaicin (part B) and citric acid (part C) after single dose of GSK2339345 or placebo Primary end point: 8‐hour cough count	16 pts with RCC per BTS guidelines Mean (SD) age: 57 (10) years 81% female	Significant increase in 8‐hours cough count with GSK2339345 compared with placebo GSK2339345 had protussive effect in all pts No effect on 4‐hours or hourly cough count, urge‐to‐cough VAS, or cough severity VAS No difference in sensitivity to capsaicin and citric acid challenge	Low incidence of AEs with no notable difference between GSK2339345 and placebo No serious AEs or oropharyngeal anesthesia
Neuromodulators
Gabapentin, amitriptyline, or nortriptyline	Single‐center, prospective study of pts prescribed gabapentin, amitriptyline, or nortriptyline ⁸⁵ First neuromodulator treatment trial: 19 pts received gabapentin, 6 received amitriptyline, 3 received nortriptyline Second neuromodulator treatment trial: 4 pts received amitriptyline, 2 each received gabapentin or nortriptyline One pt received a third neuromodulator treatment trial (nortriptyline) Primary end point: LCQ	28 pts assessed with ACCP algorithms with history suggestive of cough hypersensitivity and refractory to empiric treatment for common causes of cough Mean (range) age: 61 (34–77) years 57% female Mean (range) duration of cough: 8 (0.2–21) years 12 pts underwent concurrent speech pathology–led cough suppression therapy	Significant improvement in LCQ after 2 and 6 months of treatment with gabapentin (median dose of 600 and 900 mg, respectively) Significant improvement in LCQ after 2 months of treatment with TCAs (median dose of 30 mg) 19 pts failed first neuromodulator trial, with most common causes for failure being tachyphylaxis (n = 7) or lack of benefit (n = 5)	Side effects led to discontinuation in four (14%) pts during the first neuromodulator trial
Pregabalin and SPT	Phase III, double‐blind, placebo‐controlled RCT (ACTRN12611001186943) ⁸² Pregabalin (≤ 300 mg per day) plus SPT vs. SPT plus placebo for 12 weeks Primary end points: cough frequency, cough severity VAS, LCQ	40 pts with RCC/UCC No SPT for cough or dysphonia within past 12 months No concomitant medical treatment for cough Mean age: 61 years (SPT + pregabalin) vs. 64 years (SPT + placebo) 70% female (SPT + pregabalin) vs. 65% female (SPT + placebo) Mean duration of cough: 94 months (SPT + pregabalin) vs. 151 months (SPT + placebo)	Subjective cough measures (LCQ, cough severity VAS) significantly improved in both groups but significantly greater improvement was observed in group receiving pregabalin Cough frequency significantly decreased in both groups, but no significant differences were observed between groups Cough reflex sensitivity significantly improved in both groups, but no significant differences observed between groups	75% incidence of AEs in each group Blurred vision, cognitive changes, dizziness, and weight gain were significantly greater in group receiving pregabalin
Morphine	Single‐center, double‐blind, placebo‐controlled, crossover RCT ⁹¹ Low‐dose, slow‐release morphine (5–10 mg b.i.d.) or matching placebo for two 5–7–day treatment periods separated by 5–7–day washout Outcomes: objective cough frequency (24 hours, daytime, nighttime), daytime and nighttime cough severity VAS, and CQLQ	22 pts receiving low‐dose morphine for RCC who volunteered to withdraw from morphine therapy and enter study Mean age: 62 years 82% female Mean cough duration: 14 years	Significant reductions in daytime, nighttime, and 24‐hour objective cough frequency Significant improvement in daytime and nighttime cough severity VAS and CQLQ score	Treatment was well tolerated (one serious AE unrelated to study treatment)
NK‐1 receptor antagonists
Orvepitant	Phase II, single‐center, open‐label pilot study (EudraCT: 2014‐003947‐36) Orvepitant q.d. for 4 weeks Primary end point: objective daytime cough frequency End points were measured at week 1 and week 4 and at 4 weeks after treatment cessation (week 8)	13 pts with RCC/UCC lasting ≥ 3 months Daytime cough frequency > 3 to < 250 coughs/hour No recent history of RTI (4 weeks), ACE inhibitors (3 months), NK‐1 antagonists (4 weeks) or opioids, anticonvulsants, or TCAs (2 weeks) Current or past smokers (< 6‐month abstinence) with > 10 pack‐years history were excluded Mean (range) age: 60 (51–75) years 85% female Mean (range) duration of cough: 158 (9–312) months	Significant reductions in objective daytime cough frequency from baseline at week 1, week 4, and week 8 Other than nighttime cough frequency, all objective and subjective cough measures were significantly improved throughout 4 weeks of treatment	26 AEs in nine pts (all mild or moderate) No serious AEs or withdrawals due to AEs Most common AEs were related to tiredness: fatigue (n = 2), lethargy (n = 1), and somnolence (n = 2) 12 AEs in five pts were considered treatment related
NMDA‐receptor antagonists
Memantine	Phase IV, open‐label, dose‐escalation study (EudraCT: 2011‐005151‐13) ¹⁰¹ Escalating doses titrated weekly from 10 mg q.d. (initial dose) up to 40 mg or MTD End points: daytime cough frequency, CQLQ after up to 4 weeks of treatment	14 pts with RCC Mean age: 58 years 93% female	No significant improvement in mean daytime cough frequency CQLQ scores remained stable	MTD was lowest investigated dose (10 mg) for majority of pts (10/14; 71%) Dose‐limiting AEs included dizziness (71%), tiredness (43%), and drowsiness (36%)
Other targets
PA101 (inhaled sodium cromoglicate)	Phase II, double‐blind, placebo‐controlled RCT (NCT02412020) ¹⁰² Two 2‐week treatment periods (40 mg of PA101 or placebo t.i.d.) separated by a 2‐week washout Primary end point: daytime cough frequency	28 pts with CC not responsive to targeted therapies for possible underlying triggers Median (range) age: 62 (23–73) years 78% female Mean (SD) duration of cough: 9.9 (9.8) years	No significant difference in daytime cough frequency No significant differences in 24‐hour cough frequency, LCQ, or cough severity VAS	No severe or serious AEs Most common TEAEs: cough (12%), dry mouth (12%), oropharyngeal pain (8%), pharyngeal hypoesthesia (8%), tremor (8%) Four discontinuations due to AEs

ACCP, American College of Chest Physicians; ACE, angiotensin‐converting enzyme; ACF, awake cough frequency; AE, adverse event; ATP, adenosine triphosphate; b.i.d., twice daily; BTS, British Thoracic Society; CC, chronic cough; C_n, concentration of capsaicin inducing at least “n” coughs after capsaicin inhalation; CQLQ, Cough‐Specific Quality‐of‐Life Questionnaire; CSD, cough severity diary; E_max, maximal capsaicin cough response over four inhalations; EudraCT, European Union Drug Regulating Authorities Clinical Trials Database; GRC, global rating of change; HARQ, Hull Airway Reflux Questionnaire; IQR, interquartile range; LCQ, Leicester Cough Questionnaire; MAD, multiple‐ascending dose; MCID, minimal clinically important difference; MTD, maximum tolerated dose; NA, not applicable; NK‐1, neurokinin 1; NMDA, N‐methyl‐D‐aspartate; PK, pharmacokinetic; PRO, patient‐reported outcome; pt, patient; P2X3, ATP‐gated (purine) cation channel subtype 3; q.d., once daily; RCC, refractory chronic cough; RCT, randomized controlled trial; RTI, respiratory tract infection; SAD, single‐ascending dose; SD, standard deviation; SPT, skin‐prick test; TCA, tricyclic antidepressant; TEAE, treatment‐emergent AE; t.i.d., three times daily; TRPV, transient receptor potential vanilloid; UCC, unexplained chronic cough; VAS, visual analog scale.

^{^a}

Includes prospective studies presented or published from January 2014 to February 2020.