Table 2.

Ongoing and recently completed clinical trials investigating targeted therapies for RCC/UCC (data not yet presented or published) ^a

Drug	Trial identifier	Study design	Key eligibility criteria	Outcome measures	Estimated completion a
Oral capsaicin (TRPV1 agonist)	NCT04125563	Phase II, crossover, double‐blind, placebo‐controlled RCT in pts with chronic idiopathic cough 4 weeks of treatment with pure capsaicin (oral capsules, 0.4 mg) or placebo separated by 2‐week washout period in randomized sequence Estimated enrollment: 60	Diagnosed chronic idiopathic cough (per specialized physician) Troublesome coughing and easily evoked cough reflex for ≥ 2 months HARQ‐S total score ≥ 13 points Positive capsaicin inhalation cough test Present nonsmoker	Primary: capsaicin cough sensitivity (LogC2, LogC5) Secondary: objective cough count, symptom VAS	Primary: June 2020 Study: December 2020
AX‐8 (TRPM8 agonist)	EudraCT identifier, 2017‐003108‐27	Phase II, open‐label pilot study in pts with RCC/UCC Single dose of AX‐8 (5 mg) Estimated enrollment: 10–15	Diagnosis of RCC/UCC for ≥ 1 year per BTS guidelines Upper‐airway symptoms (throat/laryngeal irritation, tickling, dryness, or discomfort) for ≥ 8 weeks Chest radiograph or CT thorax within past 5 years not demonstrating abnormalities that may contribute significantly to cough Baseline cough severity VAS ≥ 40 mm Excludes recent (< 12 months) smokers or history > 20 pack‐years	Primary: ACF Secondary: 24‐hour cough frequency, cough severity VAS, irritation and urge‐to‐cough VAS, sensation of throat cooling VAS, safety and tolerability	Completed (data posted online in EudraCT.gov but not yet presented or published)
Gefapixant (P2X3 antagonist)	NCT03449134 (COUGH‐1)	Phase III, double‐blind, parallel‐group, placebo‐controlled RCT in pts with RCC/UCC 3 groups: gefapixant 45 mg b.i.d., gefapixant 15 mg b.i.d., or placebo 12‐week main study period followed by 40‐week extension period (52‐week total study duration) Estimated enrollment: 720	RCC/UCC for ≥ 1 year Chest radiograph or CT thorax within 5 years not demonstrating any abnormalities that may contribute significantly to cough Excludes current or recent (< 12 months) smokers No current or recent (< 3 months) treatment with ACEI	Primary: 24‐hour cough frequency (12 weeks), incidence of AEs (54 weeks), discontinuations due to AEs (52 weeks) Secondary: ACF, ≥ 30% reduction in 24‐hour cough frequency, ≥ 1.3 and ≥ 2.7 reduction in weekly CSD, ≥ 30 mm reduction in cough severity VAS, ≥ 1.3 increase in LCQ total score (all at 12 weeks)	Completed (data yet to be presented or published)
	NCT03449147 (COUGH‐2)	Phase III, double‐blind, parallel‐group, placebo‐controlled RCT in pts with RCC/UCC 3 groups: gefapixant 45 mg b.i.d., gefapixant 15 mg b.i.d., or placebo 24‐week main study period followed by 28‐week extension period (52‐week total study duration) Estimated enrollment: 1290	RCC/UCC for ≥ 1 year Chest radiograph or CT thorax within 5 years not demonstrating any abnormalities that may contribute significantly to cough Excludes current or recent (< 12 months) smokers or history > 20 pack‐years No current or recent (< 3 months) treatment with ACEI	Primary: 24‐hour cough frequency (24 weeks), incidence of AEs (54 weeks), discontinuations due to AEs (52 weeks) Secondary: ACF, ≥ 30% reduction in 24‐hour cough frequency, ≥ 1.3 and ≥ 2.7 reduction in weekly CSD, ≥ 30 mm reduction in cough severity VAS, ≥ 1.3 increase in LCQ total score (all at 12 weeks)	Completed (data yet to be presented or published)
BLU‐5937 (P2X3 antagonist)	NCT03979638 (RELIEF)	Phase II, double‐blind, placebo‐controlled, crossover, dose‐escalation RCT in pts with RCC/UCC Crossover design of 4 doses of BLU‐5937 (25, 50, 100, and 200 mg b.i.d.) or matching placebo Estimated enrollment: 65	RCC/UCC for ≥ 1 year Chest radiograph or CT thorax within 1 year not demonstrating any abnormality that may contribute significantly to cough Screening cough frequency ≥ 10 coughs/hour Cough severity VAS ≥ 40 mm Excludes current or recent (< 6 months) smokers or history > 20 pack‐years	Primary: ACF (at days 4, 8, 12, 16, 34, 38, 42, and 46) Secondary: 24‐hour cough frequency, incidence of AEs	Terminated early (data yet to be presented or published)
BAY1902607 (P2X3 antagonist)	NCT03535168	Phase I/II, double‐blind, placebo‐controlled, parallel‐group RCT in healthy male volunteers (part 1) and pts with RCC/UCC (part 2) Part 1: ascending multiple doses of BAY1902607 or placebo in healthy male volunteers, including PK impact on subtherapeutic dose of midazolam Part 2: ascending doses of BAY1902607 or placebo in two‐way crossover in pts with RCC/UCC Estimated enrollment: 59	Male volunteers who are nonsmokers for at least past 6 months and history ≤ 5 pack‐years (part 1) Males or females with RCC for ≥ 1 year, cough severity VAS ≥ 40 mm, current or recent (< 6 months) smokers or smokers with history > 20 pack‐years excluded (part 2)	Primary: safety through 5 weeks, PK (part 1); safety through 12 weeks, 24‐hour cough count (part 2)	Completed (data yet to be published)
S‐600918 (P2X3 antagonist)	NCT04110054	Phase IIb, double‐blind, placebo‐controlled, parallel‐group, dose‐selection RCT in pts with RCC/UCC S‐600918 50, 150, or 300 mg q.d. or placebo for 28 days Estimated enrollment: 372	RCC/UCC for ≥ 1 year Excludes current or recent (< 1 year) smoker or user of potentially irritating inhalational agents or history > 20 pack‐years Excludes those with clinically significant finding on chest x‐ray or chest CT in last year	Primary: 24‐hour cough frequency (week 4) Secondary: ≥ 30%, ≥ 50%, and ≥ 70% reduction in 24‐hour cough frequency and ACF; asleep cough frequency; cough severity VAS; mean LCQ and LCQ increase ≥ 1.3; ICIQ‐SF and SF‐36 (baseline and week 4); PGIC (week 4); cough severity VAS (week 1)	Primary: May 2021 Secondary: May 2021
Orvepitant (NK‐1 antagonist)	NCT02993822 (VOLCANO‐2)	Phase II, double‐blind, placebo‐controlled, parallel‐group RCT in pts with RCC/UCC Orvepitant 10, 20, or 30 mg q.d. or placebo for 12 weeks Actual enrollment: 315	RCC/UCC for ≥ 1 year per ACCP/BTS guidelines Screening ACF ≥ 10 coughs/hour Excludes current or recent (< 6 months) smokers or history > 10 pack‐years No treatment with ACEI within 3 months of screening	Primary: ACF (week 12)	Completed (data yet to be published)
Bradanicline (ATA‐101)	NCT03622216	Phase II, double‐blind, crossover, placebo‐controlled, dose‐escalation RCT in pts with RCC/UCC Crossover of three different doses of bradanicline tablets (q.d.) or matching placebo Actual enrollment: 46	RCC/UCC for ≥ 1 year Chest radiograph or CT thorax within 1 year not demonstrating any abnormality that may contribute significantly to cough Current or recent (< 1 year) smokers (including e‐cigarettes) excluded No current or recent (< 12 weeks) treatment with ACEI	Primary: ACF (7, 14, 21, 43, 50, and 57 days) Secondary: 24‐hour cough frequency (7, 14, 21, 43, 50, and 57 days), incidence of AEs (57 days)	Completed (data yet to be published)
Indomethacin	NCT03662269	Phase III, double‐blind, placebo‐controlled, parallel‐group RCT Indomethacin 75 mg b.i.d. or placebo + omeprazole 25 mg q.d. for 14 days Estimated enrollment: 84	RCC/UCC Cough severity VAS ≥ 30 mm Excludes current and recent (< 6 month) smokers or smokers with > 20 pack‐year history No ACEI	Primary: cough severity VAS, LCQ Secondary: cough frequency, laryngeal dysfunction score, cough reflex sensitivity (capsaicin cough challenge)	Primary: August 2020 Secondary: December 2020

ACCP, American College of Chest Physicians; ACEI, angiotensin‐converting enzyme inhibitor; ACF, awake cough frequency; AE, adverse event; b.i.d., twice daily; BTS, British Thoracic Society; CSD, cough severity diary; CT, computed tomography; EUDRA‐CT, European Union Drug Regulating Authorities Clinical Trials Database; HARQ‐S, Hull Airway Reflex Questionnaire–Swedish version; ICIQ‐SF, International Consultation on Incontinence Questionnaire Short Form; LCQ, Leicester Cough Questionnaire; LogCn, logarithmic values of inhaled capsaicin threshold concentration needed to reach n coughs; P2X3, ATP‐gated (purine) cation channel subtype 3; PGIC, patient global impression of change; PK, pharmacokinetic; pts, patients; q.d., once daily; RCC, refractory chronic cough; RCT, randomized controlled trial; SF‐36, Short Form (36) Health Survey; TRPM, transient receptor potential melastatin; TRPV, TRP vanilloid; UCC, unexplained chronic cough; VAS, visual analog scale.

^aIncludes trial information available in clinical trial registries (e.g., ClinicalTrials.gov).