Trial Outcomes & Findings for A Study in Healthy Men to Test Whether Bosentan Influences the Amount of BI 425809 in the Blood (NCT NCT05723874)

Last Updated: 2026-03-30

Results Overview

Area under the concentration-time curve of BI 425809 in plasma at steady state over a uniform dosing interval τ (AUCτ,ss) is reported. The dosing interval τ is 24 hours (h). Geometric least square mean (adjusted geometric mean) and adjusted geometric standard error were calculated using an analysis of variance (ANOVA) model. The ANOVA model included effects accounting for the following sources of variation: 'subjects' and 'treatment'. The effect 'subjects' was considered as random, whereas 'treatment' was considered as fixed. Time frame period 1: within 2 h before and 192 h, 216 h, 216.5 h, 217 h, 217.5 h, 218 h, 218.5 h, 219 h, 219.5 h, 220 h, 220.5 h, 222 h, 224 h, 226 h, 228 h, 240 h after BI 425809 administration on Day 1. Time frame period 2: 142 h, 311 h, 311.5 h, 312 h, 312.5 h, 313 h, 313.5 h, 314 h, 314.5 h, 315 h, 315.5 h, 317 h, 319 h, 321 h, 323 h, 335 h after BI 425809 and bosentan administration on Day 1.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

14 participants

Primary outcome timeframe

Period 1: within 2 h before and 240 h after BI 425809 administration on Day 1 (for details, see description). Period 2: within 142 h and 335 h after BI 425809 and bosentan administration on Day 1 (for details, see description).

Results posted on

2026-03-30

Participant Flow

This was a non-randomised, open-label, two-period fixed sequence trial in healthy male subjects in order to compare the test treatment (T, BI 425809 given in combination with bosentan) to the reference treatment (R, BI 425809 given alone).

All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated.

Participant milestones

Participant milestones
Measure	BI 425809 (Reference Treatment, R) Then BI 425809 + Bosentan (Test Treatment, T) Reference treatment (R): healthy male subjects administered orally once daily one film-coated tablet of 10 milligram (mg) of BI 425809 with 240 milliliter (mL) of water for 10 days (day 1 - day 10). Test treatment (T): healthy male subjects administered orally once daily one film-coated tablet of 10 mg of BI 425809 with 240 mL of water for 14 days (day 1 - day 14). In addition, subjects administered orally twice daily one film-coated tablet of 125 mg of bosentan with 240 mL of water for 14 days (day 1- day 14). Between the two periods, there was no wash-out period. Period 2 (T) immediately followed Period 1 (R).
Reference treatment (R) STARTED	14
Reference treatment (R) COMPLETED	14
Reference treatment (R) NOT COMPLETED	0
Transition period STARTED	14
Transition period COMPLETED	13
Transition period NOT COMPLETED	1
Test treatment (T) STARTED	13
Test treatment (T) COMPLETED	12
Test treatment (T) NOT COMPLETED	1

Reasons for withdrawal

Reasons for withdrawal
Measure	BI 425809 (Reference Treatment, R) Then BI 425809 + Bosentan (Test Treatment, T) Reference treatment (R): healthy male subjects administered orally once daily one film-coated tablet of 10 milligram (mg) of BI 425809 with 240 milliliter (mL) of water for 10 days (day 1 - day 10). Test treatment (T): healthy male subjects administered orally once daily one film-coated tablet of 10 mg of BI 425809 with 240 mL of water for 14 days (day 1 - day 14). In addition, subjects administered orally twice daily one film-coated tablet of 125 mg of bosentan with 240 mL of water for 14 days (day 1- day 14). Between the two periods, there was no wash-out period. Period 2 (T) immediately followed Period 1 (R).
Transition period Adverse Event	1
Test treatment (T) Adverse Event	1

Baseline Characteristics

A Study in Healthy Men to Test Whether Bosentan Influences the Amount of BI 425809 in the Blood

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	BI 425809 (Reference Treatment, R) Then BI 425809 + Bosentan (Test Treatment, T) n=14 Participants Reference treatment (R): healthy male subjects administered orally once daily one film-coated tablet of 10 milligram (mg) of BI 425809 with 240 milliliter (mL) of water for 10 days (day 1 - day 10). Test treatment (T): healthy male subjects administered orally once daily one film-coated tablet of 10 mg of BI 425809 with 240 mL of water for 14 days (day 1 - day 14). In addition, subjects administered orally twice daily one film-coated tablet of 125 mg of bosentan with 240 mL of water for 14 days (day 1- day 14). Between the two periods, there was no wash-out period. Period 2 (T) immediately followed Period 1 (R).
Age, Continuous	39.3 Years STANDARD_DEVIATION 6.8 • n=4 Participants
Sex: Female, Male Female	0 Participants n=4 Participants
Sex: Female, Male Male	14 Participants n=4 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	14 Participants n=4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=4 Participants
Race (NIH/OMB) Asian	0 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	0 Participants n=4 Participants
Race (NIH/OMB) White	13 Participants n=4 Participants
Race (NIH/OMB) More than one race	1 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=4 Participants

PRIMARY outcome

Timeframe: Period 1: within 2 h before and 240 h after BI 425809 administration on Day 1 (for details, see description). Period 2: within 142 h and 335 h after BI 425809 and bosentan administration on Day 1 (for details, see description).

Population: Pharmacokinetic parameter analysis set (PKS): this set included all subjects in the treated set who provided at least 1 pharmacokinetic (PK) endpoint that was defined as primary or secondary and was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Thus, a subject was included in the PKS, even if he contributed only 1 PK parameter value for 1 period to the statistical assessment.

Outcome measures

Outcome measures
Measure	Period 1 (Reference Treatment (R)): BI 425809 n=14 Participants Reference treatment (R): healthy male subjects administered orally once daily one film-coated tablet of 10 mg of BI 425809 with 240 mL of water for 10 days (day 1 - day 10).	Period 2 (Test Treatment (T)): Bosentan + BI 425809 n=12 Participants Test treatment (T): healthy male subjects administered orally once daily one film-coated tablet of 10 mg of BI 425809 with 240 mL of water for 14 days (day 1 - day 14). In addition, subjects administered orally twice daily one film-coated tablet of 125 mg of bosentan with 240 mL of water for 14 days (day 1- day 14).
Area Under the Concentration-time Curve of BI 425809 in Plasma at Steady State Over a Uniform Dosing Interval τ (AUCτ,ss)	4063.86 hours * nanomole/liter (h*nmol/L) Standard Error NA Adjusted geometric standard error = 1.05	1957.60 hours * nanomole/liter (h*nmol/L) Standard Error NA Adjusted geometric standard error = 1.06

PRIMARY outcome

Maximum measured concentration of BI 425809 in plasma at steady state over a uniform dosing interval τ (Cmax,ss) is reported. The dosing interval τ is 24 hours (h). Geometric least square mean (adjusted geometric mean) and adjusted geometric standard error were calculated using an analysis of variance (ANOVA) model. The ANOVA model included effects accounting for the following sources of variation: 'subjects' and 'treatment'. The effect 'subjects' was considered as random, whereas 'treatment' was considered as fixed. Time frame period 1: within 2 h before and 192 h, 216 h, 216.5 h, 217 h, 217.5 h, 218 h, 218.5 h, 219 h, 219.5 h, 220 h, 220.5 h, 222 h, 224 h, 226 h, 228 h, 240 h after BI 425809 administration on Day 1. Time frame period 2: 142 h, 311 h, 311.5 h, 312 h, 312.5 h, 313 h, 313.5 h, 314 h, 314.5 h, 315 h, 315.5 h, 317 h, 319 h, 321 h, 323 h, 335 h after BI 425809 and bosentan administration on Day 1.

Outcome measures

Outcome measures
Measure	Period 1 (Reference Treatment (R)): BI 425809 n=14 Participants Reference treatment (R): healthy male subjects administered orally once daily one film-coated tablet of 10 mg of BI 425809 with 240 mL of water for 10 days (day 1 - day 10).	Period 2 (Test Treatment (T)): Bosentan + BI 425809 n=12 Participants Test treatment (T): healthy male subjects administered orally once daily one film-coated tablet of 10 mg of BI 425809 with 240 mL of water for 14 days (day 1 - day 14). In addition, subjects administered orally twice daily one film-coated tablet of 125 mg of bosentan with 240 mL of water for 14 days (day 1- day 14).
Maximum Measured Concentration of BI 425809 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax,ss)	246.30 nanomole/liter (nmol/L) Standard Error NA Adjusted geometric standard error = 1.05	155.04 nanomole/liter (nmol/L) Standard Error NA Adjusted geometric standard error = 1.06

SECONDARY outcome

Minimum concentration of BI 425809 in plasma at steady state within a uniform dosing interval τ (Cmin,ss) is reported. The dosing interval τ is 24 hours (h). Geometric least square mean (adjusted geometric mean) and adjusted geometric standard error were calculated using an analysis of variance (ANOVA) model. The ANOVA model included effects accounting for the following sources of variation: 'subjects' and 'treatment'. The effect 'subjects' was considered as random, whereas 'treatment' was considered as fixed. Time frame period 1: within 2 h before and 192 h, 216 h, 216.5 h, 217 h, 217.5 h, 218 h, 218.5 h, 219 h, 219.5 h, 220 h, 220.5 h, 222 h, 224 h, 226 h, 228 h, 240 h after BI 425809 administration on Day 1. Time frame period 2: 142 h, 311 h, 311.5 h, 312 h, 312.5 h, 313 h, 313.5 h, 314 h, 314.5 h, 315 h, 315.5 h, 317 h, 319 h, 321 h, 323 h, 335 h after BI 425809 and bosentan administration on Day 1.

Outcome measures

Outcome measures
Measure	Period 1 (Reference Treatment (R)): BI 425809 n=14 Participants Reference treatment (R): healthy male subjects administered orally once daily one film-coated tablet of 10 mg of BI 425809 with 240 mL of water for 10 days (day 1 - day 10).	Period 2 (Test Treatment (T)): Bosentan + BI 425809 n=12 Participants Test treatment (T): healthy male subjects administered orally once daily one film-coated tablet of 10 mg of BI 425809 with 240 mL of water for 14 days (day 1 - day 14). In addition, subjects administered orally twice daily one film-coated tablet of 125 mg of bosentan with 240 mL of water for 14 days (day 1- day 14).
Minimum Concentration of BI 425809 in Plasma at Steady State Within a Uniform Dosing Interval τ (Cmin,ss)	119.47 nanomole/liter (nmol/L) Standard Error NA Adjusted geometric standard error = 1.07	43.64 nanomole/liter (nmol/L) Standard Error NA Adjusted geometric standard error = 1.07

Adverse Events

Period 1 (Reference Treatment (R)): BI 425809

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Period 2 (Test Treatment (T)): Bosentan + BI 425809

Serious events: 0 serious events

Other events: 7 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Boehringer Ingelheim, Call Center

Boehringer Ingelheim

Phone: 1-800-243-0127

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Other adverse events
Measure	Period 1 (Reference Treatment (R)): BI 425809 n=14 participants at risk Reference treatment (R): healthy male subjects administered orally once daily one film-coated tablet of 10 mg of BI 425809 with 240 mL of water for 10 days (day 1 - day 10).	Period 2 (Test Treatment (T)): Bosentan + BI 425809 n=13 participants at risk Test treatment (T): healthy male subjects administered orally once daily one film-coated tablet of 10 mg of BI 425809 with 240 mL of water for 14 days (day 1 - day 14). In addition, subjects administered orally twice daily one film-coated tablet of 125 mg of bosentan with 240 mL of water for 14 days (day 1- day 14).
Eye disorders Asthenopia	0.00% 0/14 • Period 1 (R): from first drug administration until first drug administration in period 2 (T) or, in case of treatment discontinuation, until 11 days after last treatment administration, up to 21 days. Period 2 (T): from first drug administration until 11 days after last treatment administration, or until trial termination, whatever occurs first, up to 25 days. All-cause mortality: from 1st drug intake until end of study, up to 38 days. Treated set (TS): the TS included all subjects who were treated with at least 1 dose of trial drug.	7.7% 1/13 • Period 1 (R): from first drug administration until first drug administration in period 2 (T) or, in case of treatment discontinuation, until 11 days after last treatment administration, up to 21 days. Period 2 (T): from first drug administration until 11 days after last treatment administration, or until trial termination, whatever occurs first, up to 25 days. All-cause mortality: from 1st drug intake until end of study, up to 38 days. Treated set (TS): the TS included all subjects who were treated with at least 1 dose of trial drug.
Eye disorders Dry eye	0.00% 0/14 • Period 1 (R): from first drug administration until first drug administration in period 2 (T) or, in case of treatment discontinuation, until 11 days after last treatment administration, up to 21 days. Period 2 (T): from first drug administration until 11 days after last treatment administration, or until trial termination, whatever occurs first, up to 25 days. All-cause mortality: from 1st drug intake until end of study, up to 38 days. Treated set (TS): the TS included all subjects who were treated with at least 1 dose of trial drug.	7.7% 1/13 • Period 1 (R): from first drug administration until first drug administration in period 2 (T) or, in case of treatment discontinuation, until 11 days after last treatment administration, up to 21 days. Period 2 (T): from first drug administration until 11 days after last treatment administration, or until trial termination, whatever occurs first, up to 25 days. All-cause mortality: from 1st drug intake until end of study, up to 38 days. Treated set (TS): the TS included all subjects who were treated with at least 1 dose of trial drug.
Gastrointestinal disorders Diarrhoea	0.00% 0/14 • Period 1 (R): from first drug administration until first drug administration in period 2 (T) or, in case of treatment discontinuation, until 11 days after last treatment administration, up to 21 days. Period 2 (T): from first drug administration until 11 days after last treatment administration, or until trial termination, whatever occurs first, up to 25 days. All-cause mortality: from 1st drug intake until end of study, up to 38 days. Treated set (TS): the TS included all subjects who were treated with at least 1 dose of trial drug.	7.7% 1/13 • Period 1 (R): from first drug administration until first drug administration in period 2 (T) or, in case of treatment discontinuation, until 11 days after last treatment administration, up to 21 days. Period 2 (T): from first drug administration until 11 days after last treatment administration, or until trial termination, whatever occurs first, up to 25 days. All-cause mortality: from 1st drug intake until end of study, up to 38 days. Treated set (TS): the TS included all subjects who were treated with at least 1 dose of trial drug.
Gastrointestinal disorders Dyspepsia	7.1% 1/14 • Period 1 (R): from first drug administration until first drug administration in period 2 (T) or, in case of treatment discontinuation, until 11 days after last treatment administration, up to 21 days. Period 2 (T): from first drug administration until 11 days after last treatment administration, or until trial termination, whatever occurs first, up to 25 days. All-cause mortality: from 1st drug intake until end of study, up to 38 days. Treated set (TS): the TS included all subjects who were treated with at least 1 dose of trial drug.	0.00% 0/13 • Period 1 (R): from first drug administration until first drug administration in period 2 (T) or, in case of treatment discontinuation, until 11 days after last treatment administration, up to 21 days. Period 2 (T): from first drug administration until 11 days after last treatment administration, or until trial termination, whatever occurs first, up to 25 days. All-cause mortality: from 1st drug intake until end of study, up to 38 days. Treated set (TS): the TS included all subjects who were treated with at least 1 dose of trial drug.
Gastrointestinal disorders Lip swelling	7.1% 1/14 • Period 1 (R): from first drug administration until first drug administration in period 2 (T) or, in case of treatment discontinuation, until 11 days after last treatment administration, up to 21 days. Period 2 (T): from first drug administration until 11 days after last treatment administration, or until trial termination, whatever occurs first, up to 25 days. All-cause mortality: from 1st drug intake until end of study, up to 38 days. Treated set (TS): the TS included all subjects who were treated with at least 1 dose of trial drug.	0.00% 0/13 • Period 1 (R): from first drug administration until first drug administration in period 2 (T) or, in case of treatment discontinuation, until 11 days after last treatment administration, up to 21 days. Period 2 (T): from first drug administration until 11 days after last treatment administration, or until trial termination, whatever occurs first, up to 25 days. All-cause mortality: from 1st drug intake until end of study, up to 38 days. Treated set (TS): the TS included all subjects who were treated with at least 1 dose of trial drug.
General disorders Catheter site inflammation	0.00% 0/14 • Period 1 (R): from first drug administration until first drug administration in period 2 (T) or, in case of treatment discontinuation, until 11 days after last treatment administration, up to 21 days. Period 2 (T): from first drug administration until 11 days after last treatment administration, or until trial termination, whatever occurs first, up to 25 days. All-cause mortality: from 1st drug intake until end of study, up to 38 days. Treated set (TS): the TS included all subjects who were treated with at least 1 dose of trial drug.	7.7% 1/13 • Period 1 (R): from first drug administration until first drug administration in period 2 (T) or, in case of treatment discontinuation, until 11 days after last treatment administration, up to 21 days. Period 2 (T): from first drug administration until 11 days after last treatment administration, or until trial termination, whatever occurs first, up to 25 days. All-cause mortality: from 1st drug intake until end of study, up to 38 days. Treated set (TS): the TS included all subjects who were treated with at least 1 dose of trial drug.
Infections and infestations Rhinitis	0.00% 0/14 • Period 1 (R): from first drug administration until first drug administration in period 2 (T) or, in case of treatment discontinuation, until 11 days after last treatment administration, up to 21 days. Period 2 (T): from first drug administration until 11 days after last treatment administration, or until trial termination, whatever occurs first, up to 25 days. All-cause mortality: from 1st drug intake until end of study, up to 38 days. Treated set (TS): the TS included all subjects who were treated with at least 1 dose of trial drug.	7.7% 1/13 • Period 1 (R): from first drug administration until first drug administration in period 2 (T) or, in case of treatment discontinuation, until 11 days after last treatment administration, up to 21 days. Period 2 (T): from first drug administration until 11 days after last treatment administration, or until trial termination, whatever occurs first, up to 25 days. All-cause mortality: from 1st drug intake until end of study, up to 38 days. Treated set (TS): the TS included all subjects who were treated with at least 1 dose of trial drug.
Investigations Alanine aminotransferase increased	0.00% 0/14 • Period 1 (R): from first drug administration until first drug administration in period 2 (T) or, in case of treatment discontinuation, until 11 days after last treatment administration, up to 21 days. Period 2 (T): from first drug administration until 11 days after last treatment administration, or until trial termination, whatever occurs first, up to 25 days. All-cause mortality: from 1st drug intake until end of study, up to 38 days. Treated set (TS): the TS included all subjects who were treated with at least 1 dose of trial drug.	7.7% 1/13 • Period 1 (R): from first drug administration until first drug administration in period 2 (T) or, in case of treatment discontinuation, until 11 days after last treatment administration, up to 21 days. Period 2 (T): from first drug administration until 11 days after last treatment administration, or until trial termination, whatever occurs first, up to 25 days. All-cause mortality: from 1st drug intake until end of study, up to 38 days. Treated set (TS): the TS included all subjects who were treated with at least 1 dose of trial drug.
Musculoskeletal and connective tissue disorders Arthralgia	0.00% 0/14 • Period 1 (R): from first drug administration until first drug administration in period 2 (T) or, in case of treatment discontinuation, until 11 days after last treatment administration, up to 21 days. Period 2 (T): from first drug administration until 11 days after last treatment administration, or until trial termination, whatever occurs first, up to 25 days. All-cause mortality: from 1st drug intake until end of study, up to 38 days. Treated set (TS): the TS included all subjects who were treated with at least 1 dose of trial drug.	7.7% 1/13 • Period 1 (R): from first drug administration until first drug administration in period 2 (T) or, in case of treatment discontinuation, until 11 days after last treatment administration, up to 21 days. Period 2 (T): from first drug administration until 11 days after last treatment administration, or until trial termination, whatever occurs first, up to 25 days. All-cause mortality: from 1st drug intake until end of study, up to 38 days. Treated set (TS): the TS included all subjects who were treated with at least 1 dose of trial drug.
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/14 • Period 1 (R): from first drug administration until first drug administration in period 2 (T) or, in case of treatment discontinuation, until 11 days after last treatment administration, up to 21 days. Period 2 (T): from first drug administration until 11 days after last treatment administration, or until trial termination, whatever occurs first, up to 25 days. All-cause mortality: from 1st drug intake until end of study, up to 38 days. Treated set (TS): the TS included all subjects who were treated with at least 1 dose of trial drug.	15.4% 2/13 • Period 1 (R): from first drug administration until first drug administration in period 2 (T) or, in case of treatment discontinuation, until 11 days after last treatment administration, up to 21 days. Period 2 (T): from first drug administration until 11 days after last treatment administration, or until trial termination, whatever occurs first, up to 25 days. All-cause mortality: from 1st drug intake until end of study, up to 38 days. Treated set (TS): the TS included all subjects who were treated with at least 1 dose of trial drug.
Musculoskeletal and connective tissue disorders Flank pain	0.00% 0/14 • Period 1 (R): from first drug administration until first drug administration in period 2 (T) or, in case of treatment discontinuation, until 11 days after last treatment administration, up to 21 days. Period 2 (T): from first drug administration until 11 days after last treatment administration, or until trial termination, whatever occurs first, up to 25 days. All-cause mortality: from 1st drug intake until end of study, up to 38 days. Treated set (TS): the TS included all subjects who were treated with at least 1 dose of trial drug.	7.7% 1/13 • Period 1 (R): from first drug administration until first drug administration in period 2 (T) or, in case of treatment discontinuation, until 11 days after last treatment administration, up to 21 days. Period 2 (T): from first drug administration until 11 days after last treatment administration, or until trial termination, whatever occurs first, up to 25 days. All-cause mortality: from 1st drug intake until end of study, up to 38 days. Treated set (TS): the TS included all subjects who were treated with at least 1 dose of trial drug.
Nervous system disorders Headache	7.1% 1/14 • Period 1 (R): from first drug administration until first drug administration in period 2 (T) or, in case of treatment discontinuation, until 11 days after last treatment administration, up to 21 days. Period 2 (T): from first drug administration until 11 days after last treatment administration, or until trial termination, whatever occurs first, up to 25 days. All-cause mortality: from 1st drug intake until end of study, up to 38 days. Treated set (TS): the TS included all subjects who were treated with at least 1 dose of trial drug.	15.4% 2/13 • Period 1 (R): from first drug administration until first drug administration in period 2 (T) or, in case of treatment discontinuation, until 11 days after last treatment administration, up to 21 days. Period 2 (T): from first drug administration until 11 days after last treatment administration, or until trial termination, whatever occurs first, up to 25 days. All-cause mortality: from 1st drug intake until end of study, up to 38 days. Treated set (TS): the TS included all subjects who were treated with at least 1 dose of trial drug.
Nervous system disorders Orthostatic intolerance	0.00% 0/14 • Period 1 (R): from first drug administration until first drug administration in period 2 (T) or, in case of treatment discontinuation, until 11 days after last treatment administration, up to 21 days. Period 2 (T): from first drug administration until 11 days after last treatment administration, or until trial termination, whatever occurs first, up to 25 days. All-cause mortality: from 1st drug intake until end of study, up to 38 days. Treated set (TS): the TS included all subjects who were treated with at least 1 dose of trial drug.	7.7% 1/13 • Period 1 (R): from first drug administration until first drug administration in period 2 (T) or, in case of treatment discontinuation, until 11 days after last treatment administration, up to 21 days. Period 2 (T): from first drug administration until 11 days after last treatment administration, or until trial termination, whatever occurs first, up to 25 days. All-cause mortality: from 1st drug intake until end of study, up to 38 days. Treated set (TS): the TS included all subjects who were treated with at least 1 dose of trial drug.
Nervous system disorders Paraesthesia	7.1% 1/14 • Period 1 (R): from first drug administration until first drug administration in period 2 (T) or, in case of treatment discontinuation, until 11 days after last treatment administration, up to 21 days. Period 2 (T): from first drug administration until 11 days after last treatment administration, or until trial termination, whatever occurs first, up to 25 days. All-cause mortality: from 1st drug intake until end of study, up to 38 days. Treated set (TS): the TS included all subjects who were treated with at least 1 dose of trial drug.	7.7% 1/13 • Period 1 (R): from first drug administration until first drug administration in period 2 (T) or, in case of treatment discontinuation, until 11 days after last treatment administration, up to 21 days. Period 2 (T): from first drug administration until 11 days after last treatment administration, or until trial termination, whatever occurs first, up to 25 days. All-cause mortality: from 1st drug intake until end of study, up to 38 days. Treated set (TS): the TS included all subjects who were treated with at least 1 dose of trial drug.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/14 • Period 1 (R): from first drug administration until first drug administration in period 2 (T) or, in case of treatment discontinuation, until 11 days after last treatment administration, up to 21 days. Period 2 (T): from first drug administration until 11 days after last treatment administration, or until trial termination, whatever occurs first, up to 25 days. All-cause mortality: from 1st drug intake until end of study, up to 38 days. Treated set (TS): the TS included all subjects who were treated with at least 1 dose of trial drug.	7.7% 1/13 • Period 1 (R): from first drug administration until first drug administration in period 2 (T) or, in case of treatment discontinuation, until 11 days after last treatment administration, up to 21 days. Period 2 (T): from first drug administration until 11 days after last treatment administration, or until trial termination, whatever occurs first, up to 25 days. All-cause mortality: from 1st drug intake until end of study, up to 38 days. Treated set (TS): the TS included all subjects who were treated with at least 1 dose of trial drug.
Respiratory, thoracic and mediastinal disorders Epistaxis	7.1% 1/14 • Period 1 (R): from first drug administration until first drug administration in period 2 (T) or, in case of treatment discontinuation, until 11 days after last treatment administration, up to 21 days. Period 2 (T): from first drug administration until 11 days after last treatment administration, or until trial termination, whatever occurs first, up to 25 days. All-cause mortality: from 1st drug intake until end of study, up to 38 days. Treated set (TS): the TS included all subjects who were treated with at least 1 dose of trial drug.	0.00% 0/13 • Period 1 (R): from first drug administration until first drug administration in period 2 (T) or, in case of treatment discontinuation, until 11 days after last treatment administration, up to 21 days. Period 2 (T): from first drug administration until 11 days after last treatment administration, or until trial termination, whatever occurs first, up to 25 days. All-cause mortality: from 1st drug intake until end of study, up to 38 days. Treated set (TS): the TS included all subjects who were treated with at least 1 dose of trial drug.
Respiratory, thoracic and mediastinal disorders Nasal congestion	0.00% 0/14 • Period 1 (R): from first drug administration until first drug administration in period 2 (T) or, in case of treatment discontinuation, until 11 days after last treatment administration, up to 21 days. Period 2 (T): from first drug administration until 11 days after last treatment administration, or until trial termination, whatever occurs first, up to 25 days. All-cause mortality: from 1st drug intake until end of study, up to 38 days. Treated set (TS): the TS included all subjects who were treated with at least 1 dose of trial drug.	23.1% 3/13 • Period 1 (R): from first drug administration until first drug administration in period 2 (T) or, in case of treatment discontinuation, until 11 days after last treatment administration, up to 21 days. Period 2 (T): from first drug administration until 11 days after last treatment administration, or until trial termination, whatever occurs first, up to 25 days. All-cause mortality: from 1st drug intake until end of study, up to 38 days. Treated set (TS): the TS included all subjects who were treated with at least 1 dose of trial drug.
Respiratory, thoracic and mediastinal disorders Sneezing	0.00% 0/14 • Period 1 (R): from first drug administration until first drug administration in period 2 (T) or, in case of treatment discontinuation, until 11 days after last treatment administration, up to 21 days. Period 2 (T): from first drug administration until 11 days after last treatment administration, or until trial termination, whatever occurs first, up to 25 days. All-cause mortality: from 1st drug intake until end of study, up to 38 days. Treated set (TS): the TS included all subjects who were treated with at least 1 dose of trial drug.	7.7% 1/13 • Period 1 (R): from first drug administration until first drug administration in period 2 (T) or, in case of treatment discontinuation, until 11 days after last treatment administration, up to 21 days. Period 2 (T): from first drug administration until 11 days after last treatment administration, or until trial termination, whatever occurs first, up to 25 days. All-cause mortality: from 1st drug intake until end of study, up to 38 days. Treated set (TS): the TS included all subjects who were treated with at least 1 dose of trial drug.
Skin and subcutaneous tissue disorders Rash	7.1% 1/14 • Period 1 (R): from first drug administration until first drug administration in period 2 (T) or, in case of treatment discontinuation, until 11 days after last treatment administration, up to 21 days. Period 2 (T): from first drug administration until 11 days after last treatment administration, or until trial termination, whatever occurs first, up to 25 days. All-cause mortality: from 1st drug intake until end of study, up to 38 days. Treated set (TS): the TS included all subjects who were treated with at least 1 dose of trial drug.	0.00% 0/13 • Period 1 (R): from first drug administration until first drug administration in period 2 (T) or, in case of treatment discontinuation, until 11 days after last treatment administration, up to 21 days. Period 2 (T): from first drug administration until 11 days after last treatment administration, or until trial termination, whatever occurs first, up to 25 days. All-cause mortality: from 1st drug intake until end of study, up to 38 days. Treated set (TS): the TS included all subjects who were treated with at least 1 dose of trial drug.