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Randomized, Double-blind, Parallel Group, Phase 2b Dose-finding, Efficacy and Safety Study of 12-week Twice Daily Oral Administration of BAY 1817080 Compared to Placebo in the Treatment of Refractory and/or Unexplained Chronic Cough (RUCC) (PAGANINI)

Clinical Study to Evaluate the Efficacy and Safety of Three Different Doses of BAY1817080 Compared to Placebo in Patients With Chronic Cough (PAGANINI)

310

In the FAS, overall, 77.7% of the participants were female, 87.1% were white. The mean (SD) age was about 59 (11.8) years, ranging from 19 to 81 years. In the PPS, the baseline 24-h cough count per hour (geometric mean [geometric SD]) was 17.42 [2.81] with the highest baseline 24-h cough count in the eliapixant 75 mg BID group (19.23 coughs per hour) and the lowest in the 150 mg BID group (15.61 coughs per hour). The baseline awake cough count per hour was higher than the 24-h cough count per hour in all treatment groups (total: geometric mean of 23.70). Cough Severity VAS (mean [SD]) at baseline was 65.51 (14.64) in 25 mg BID group, 67.08 (14.89) in 75 mg BID group and 66.79 (15.86) in 150 mg BID group; in placebo group it was 61.52 (18.51). LCQ (mean [SD]) at baseline was 12.00 (2.54) in 25 mg BID group, 11.76 (2.77) in 75 mg BID group, 11.15 (2.56) in 150 mg BID group and 11.53 (3.27) in the placebo group.

Overall, 399 participants were screened, 89 of whom were screening failures. The remaining 310 participants were randomized to 4 treatment groups (75 to eliapixant 25 mg BID, 78 to eliapixant 75 mg BID, 80 to eliapixant 150 mg BID, and 77 to placebo). This distribution was in accordance with the randomization ratio of 1:1:1:1. All 310 randomized participants received at least one dose of study intervention. 34 participants (11.0%) discontinued the study intervention prematurely. Discontinuation rate was from 11.5% to 13.8% in the eliapixant groups and 5.2% in the placebo group. AE was the most common reason for discontinuation of the study intervention in the eliapixant groups (from 3.8% to 10.0%) and withdrawal by participant in the placebo group (3.9%). Safety follow-up was not completed by 16 of the 310 randomized participants (5.2%). Withdrawal by participant was the most common reason (8 participants overall, 2.6%). Number of participants in each analysis set was as follows: - Full analysis set (FAS): 310 randomized participants - Safety analysis set (SAF): 310 (identical to the FAS, i.e. all randomized participants) - Per protocol set (PPS): 283 participants (91.3% of all randomized participants)

Treatment-emergent AEs (TEAEs) were defined as AEs arising or worsening after the start of study intervention administration until 14 days after the last intake of study intervention. Safety results are presented for the SAF. Overall, TEAEs were reported for 184 participants (59.4%). Frequency of TEAEs was slightly higher in the eliapixant groups (57.3% in 25 mg BID, 65.4% in 75 mg BID, and 63.8% in 150 mg BID) compared to the placebo group (50.6%). Serious and severe TEAEs were rare: serious TEAEs were reported for 4 participants (1.3% overall) and severe TEAEs for 7 participants (2.3% overall). No deaths were reported during the study. The majority of the TEAEs were either mild (30.3% overall) or moderate (26.8% overall). The most commonly reported TEAEs were dysgeusia (7.7% of the participants), cough (6.8% of the participants), headache (6.8% of the participants), and fatigue (4.8% of the participants). There was a clear dose-dependency of study intervention-related TEAEs, with the frequency of 12.0% in the eliapixant 25 mg BID group, 19.2% in 75 mg BID, 37.5% in 150 mg BID, and 11.7% in the placebo group. These differences were driven by taste-related TEAEs. The only study intervention-related serious TEAE (liver function test abnormal), assessed as drug-induced liver injury, was observed in the highest eliapixant dose group (i.e. 150 mg BID). Taste- and/or smell-related TEAEs were reported for 12.6% of the participants overall during the study. There was a clear dose-dependency for the incidence of taste- and/or smell-related TEAEs (4.0% in the eliapixant 25 mg BID group, 15.4% in 75 mg BID, 23.8% in 150 mg BID, and 6.5% in the placebo group).

Efficacy results are presented for the PPS. Primary endpoint: The primary endpoint was the change from baseline in 24-h cough count after 12 weeks of intervention. The ratio of geometric means (SD) in 24-hour cough count at Week 12/termination visit was 0.56 (0.9191) in the eliapixant 25 mg BID group, 0.47 (0.9019) in the 75 mg BID group, 0.52 (0.8608) in the 150 mg BID group and 0.64 (0.7855) in the placebo group. The generalized MCP-Mod approach combining multiple comparison procedures (MCP) principles with modeling techniques was used for the evaluation of the dose-response. A dose-response signal was considered established if >=1 model was statistically significant (multiplicity-adjusted, one-sided p=<0.1). A dose-response signal was established in this study with all four dose-response models,0.0376 (Emax ED50=50), 0.0319 (sigmoidal Emax ED50=30; Hill coefficient=3), and 0.0603 (sigmoidal Emax ED50=60; Hill coefficient=5). Secondary endpoints: - Change from baseline in 24-hour cough count after 2, 4, and 8 weeks of intervention: The ratio of geometric means (SD) in awake cough frequency at Week 2 was 0.78 (0.6324), 0.60 (0.8295), 0.60 (0.6695) and 0.77 (0.4660) in the eliapixant 25 mg BID group, the 75 mg BID group, the 150 mg BID group and the placebo group, respectively. The same applies hereinafter, it at Week 4 was 0.67 (0.7390), 0.53 (0.8128), 0.57 (0.8983) and 0.72 (0.6637), respectively. It at Week 8 was 0.55 (0.9274), 0.47 (0.9576), 0.50 (0.9154) and 0.72 (0.6698), respectively. And it at Week 12/termination visit was 0.56 (0.9582), 0.47 (0.9051), 0.47 (1.1338) and 0.65 (0.7926), respectively. - Change from baseline in cough severity after 12 weeks of intervention (measured by VAS): The mean change (SD) in cough severity from baseline to Week 12/termination visit was -17.69 (23.87), -22.66 (22.98), -22.87 (24.54) and -17.02 (21.88) in the eliapixant 25 mg BID group, the 75 mg BID group, the 150 mg BID group and the placebo group, respectively. - Change from baseline in cough-related quality of life after 12 weeks of intervention (LCQ Total Score, ranging from 3 to 21 score units): change from baseline to Week 12/termination visit (arithmetic mean [SD]) (improvement) was 2.18 (3.44) in the 25 mg eliapixant BID group, 2.50 (3.29) in the 75 mg eliapixant BID group, 2.73 (3.53) in the 150 mg eliapixant BID group, and 2.16 (3.12) in the placebo group.

The study met its objective to detect a dose-response signal of eliapixant for the treatment of RUCC. The identified optimal dose was 75 mg BID, showing a clinically relevant effect in cough count reduction after 12 weeks of intervention and a good safety and tolerability profile. The only study intervention-related serious TEAE was observed in the 150 mg BID group and was a case of moderate drug-induced liver injury.

Oct. 20, 2022

No

https://jrct.mhlw.go.jp/latest-detail/jRCT2031200185

Myoishi Masashi

Bayer Yakuhin, Ltd.

2-4-9 Umeda, Kita-ku, Osaka, Osaka

byl_ct_contact@bayer.com

contact Dedicated

Bayer Yakuhin, Ltd.

2-4-9 Umeda, Kita-ku, Osaka, Osaka

+81-6-6133-6363

byl_ct_contact@bayer.com

Complete

Oct. 30, 2020

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

treatment purpose

-Adults >= 18 years of age at the time of signing the informed consent.
-A cough that has lasted for at least 12 months (unresponsive to treatment options) with a diagnosis of refractory chronic cough and/or idiopathic (unexplained) chronic cough.
-Persistent cough for at least the last 8 weeks before screening. -Women of childbearing potential must agree to use acceptable effective or highly effective birth control methods during the study and for at least 30 days after the last dose.
-Capable of giving signed informed consent.

-Smoking history within the last 12 months before screening (all forms of smoking, including e-cigarettes, cannabis and others), and any former smoker with more than 20 pack-years.
-Ongoing or previous exposure to inhalational toxic fumes (e.g. ammonia, chlorine, nitrogen dioxide, phosgene and sulfur dioxide) within the last 12 months before screening.
-Respiratory tract infection within 4 weeks before screening.
-History of chronic bronchitis.
-Systolic blood pressure >= 160 mmHg and/or diastolic blood pressure >= 100 mmHg at screening visit.
-Positive SARS-CoV-2 virus RNA and/or serology IgG tests at screening visit.

Both

Refractory and/or Unexplained Chronic Cough

Each participant will be randomized to receive one of three oral doses of BAY 1817080 or placebo, administered twice daily over the course of 12 weeks.

Change from baseline in 24-hour cough count (measured by cough recording digital wearable monitoring device) after 12 weeks of intervention

1. Percentage of participants with a >= 30% reduction from baseline in 24-hour cough count after 12 weeks of intervention (measured by cough recording digital wearable monitoring device)
2. Change from baseline in 24-hour cough count after 2, 4, and 8 weeks of intervention (measured by cough recording digital wearable monitoring device)
3. Change from baseline in awake cough frequency per hour after 2, 4, 8 and 12 weeks of intervention (measured by cough recording digital wearable monitoring device)
4. Change from baseline in cough related quality of life (measured by Leicester Cough Questionnaire [LCQ]) after 12 weeks of intervention
5. Change from baseline in cough severity after 12 weeks of intervention (measured by Cough Severity Visual Analogue Scale [VAS])
6. Percentage of participants with a >= 30 scale units reduction from baseline after 12 weeks of intervention (measured by cough Severity VAS)
7. Percentage of participants with a >= 1.3-point increase from baseline after 12 weeks of intervention (measured with LCQ Total Score)
8. Frequency and associated severity of treatment-emergent adverse events (TEAEs)

+81-3-5712-5050

Sept. 23, 2020

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