Drug-drug Interaction Trial of BI 113608 in Combination With Ketoconazole and Voriconazole in Healthy Male Subjects

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01787032
• Collaborator: (none)
• Enrollment: 20
• Location: 1
• Arms: 3
• Duration (Months): 3
• Patients Per Site Per Month: 6.8

Study Details

Study Description

Brief Summary

The primary objective of this trial is to investigate the relative bioavailability of a single oral dose of BI 113608 without and with ketoconazole and voriconazole at steady state. The assessment of safety and tolerability of BI 113608 administered alone and upon co-administration will be an additional objective of this trial.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: BI 113608; Drug: BI 113608; Drug: BI 113608; Drug: Ketoconazole; Drug: Voriconazole	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Relative Bioavailability of Single Oral Dose of BI 113608 When Administered Alone or in Combination With Multiple Oral Doses of Ketoconazole or Voriconazole in Healthy Male Subjects (an Open-label, Randomised, Three-period Cross-over Trial)
• Study Start Date: Jan 1, 2013
• Actual Primary Completion Date: Apr 1, 2013
• Actual Study Completion Date: Apr 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Period 3: BI 113608+Voriconazole tablets with 240 ml water	Drug: BI 113608; tablet; Drug: Voriconazole; tablet
Experimental: Period 2: BI 113608+Ketoconazole tablets with 240 ml water	Drug: BI 113608; tablet; Drug: Ketoconazole; tablet
Experimental: Period 1: BI 113608 tablets with 240 ml water	Drug: BI 113608; tablet

Outcome Measures

Primary Outcome Measures

1. Area Under the Concentration-time Curve of BI 113608 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) [1 hour before drug administration and 0:25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 24, 34, 48 and 72 hours after drug administration.]

   This outcome measure presents the area under the concentration-time curve of BI 113608 in plasma over the time interval from 0 to the last quantifiable data point. The parameter dispersion type (standard deviation) is actually intra individual geometric coefficient of variation (intraindividual gCV). Statistical analysis 1: The ratio (Other) is calculated as BI+K (T1): BI (R) [%]. Statistical analysis 2: The ratio (Other) is calculated as BI + V (T2): BI (R) [%].

2. Maximum Measured Concentration of BI 113608 in Plasma (Cmax) [1 hour before drug administration and 0:25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 24, 34, 48 and 72 hours after drug administration.]

   This outcome measure presents the maximum measured concentration of BI 113608 in plasma. The parameter dispersion type (standard deviation) is actually intra individual geometric coefficient of variation (intraindividual gCV). Statistical analysis 1: The ratio (Other) is calculated as BI + K (T1): BI (R) [%]. Statistical analysis 2: The ratio (Other) is calculated as BI + V (T2): BI (R) [%].

Secondary Outcome Measures

1. Area Under the Concentration-time Curve of BI 113608 in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) [1 hour before drug administration and 0:25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 24, 34, 48 and 72 hours after drug administration.]

   This outcome measure presents area under the concentration-time curve of BI 113608 in plasma over the time interval from 0 to infinity. The parameter dispersion type (standard deviation) is actually intra individual geometric coefficient of variation (intraindividual gCV). Statistical analysis 1: The ratio (Other) is calculated as BI + K (T1): BI (R) [%]. Statistical analysis 2: The ratio (Other) is calculated as BI + V (T2): BI (R) [%].

2. Time From Dosing to Maximum Measured Concentration of BI 113608 in Plasma (Tmax) [1 hour before drug administration and 0:25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 24, 34, 48 and 72 hours after drug administration.]

   This outcome measure presents time from dosing to maximum measured concentration of BI 113608 in plasma.

3. Terminal Half-life of BI 113608 in Plasma (t1/2) [1 hour before drug administration and 0:25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 24, 34, 48 and 72 hours after drug administration.]

   This outcome measure presents terminal half-life of BI 113608 in plasma.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 50 Years
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: Yes

Inclusion criteria:

1. Healthy male subjects

Exclusion criteria:

1. Any relevant deviation from healthy conditions.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Boehringer Ingelheim Investigational Site	Ingelheim		Germany

Sponsors and Collaborators

• Boehringer Ingelheim

Investigators

• Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT01787032
• Other Study ID Numbers: 1314.7; 2012-002538-36
• First Posted: Feb 8, 2013
• Last Update Posted: Mar 15, 2017
• Last Verified: Jan 1, 2017

• Additional relevant MeSH terms: Ketoconazole; Voriconazole

Study Results

Participant Flow

Recruitment Details	The primary objective of this trial was to investigate the relative bioavailability of BI 113608 as a single treatment (BI; Treatment A; Reference (R)) and in combination with Ketoconazole (K) (BI + K; Treatment B; Test1(T1)) or Voriconazole (V) (BI + V; Treatment C; Test2 (T2)).

Arm/Group Title	BI 113608/BI 113608 + Ketoconazole/BI 113608 + Voriconazole	BI 113608/BI 113608 + Voriconazole/ BI 113608 + Ketoconazole	BI 113608 + Ketoconazole/ BI 113608/ BI 113608 + Voriconazole	BI 113608 + Ketoconazole/ BI 113608 + Voriconazole/ BI 113608	BI 113608 + Voriconazole/ BI 113608/ BI 113608 + Ketoconazole	BI 113608 + Voriconazole/ BI 113608 + Ketoconazole/ BI 113608
Arm/Group Description	The subjects received BI 113608 film-coated tablet 25 mg orally for 1 day (Day 1) orally with 240 mL of water followed by Ketokonazol film-coated tablet (200 mg bid) (Brand name: Ketokonazol Polfarmex 200 mg film tablets) for 4 days (Days -2, -1, 1, and 2) plus BI 113608 (25 mg single dose) for 1 day (Day 1) followed by Voriconazole (400 mg bid) (Brand name: Vfend® 200 mg film tablets) for 1 day on Day -2 (loading dose) Voriconazole (200 mg bid) for 3 days (Days -1, 1, and 2) plus BI 113608 (25 mg single dose) for 1 day (Day 1) orally with 240 mL of water after an overnight fast of at least 10 hours. A wash-out period of at least 6 days was respected between the administrations of BI 113608.	The subjects received BI 113608 film-coated tablet 25 mg orally for 1 day (Day 1) orally with 240 mL of water followed by Voriconazole (400 mg bid) (Brand name: Vfend® 200 mg film tablets) for 1 day on Day -2 (loading dose) Voriconazole (200 mg bid) for 3 days (Days -1, 1, and 2) plus BI 113608 (25 mg single dose) for 1 day (Day 1) followed by Ketokonazol film-coated tablet (200 mg bid) (Brand name: Ketokonazol Polfarmex 200 mg film tablets) for 4 days (Days -2, -1, 1, and 2) plus BI 113608 (25 mg single dose) for 1 day (Day 1) orally with 240 mL of water after an overnight fast of at least 10 hours. A wash-out period of at least 6 days was respected between the administrations of BI 113608.	The subjects received Ketokonazol film-coated tablet (200 mg bid) (Brand name: Ketokonazol Polfarmex 200 mg film tablets) for 4 days (Days -2, -1, 1, and 2) plus BI 113608 (25 mg single dose) for 1 day (Day 1) orally with 240 mL of water after an overnight fast of at least 10 hours followed by BI 113608 film-coated tablet 25 mg orally for 1 day (Day 1) orally with 240 mL of water followed by Voriconazole (400 mg bid) (Brand name: Vfend® 200 mg film tablets) for 1 day on Day -2 (loading dose) Voriconazole (200 mg bid) for 3 days (Days -1, 1, and 2) plus BI 113608 (25 mg single dose) for 1 day (Day 1) orally with 240 mL of water after an overnight fast of at least 10 hours. A wash-out period of at least 6 days was respected between the administrations of BI 113608.	The subjects received Ketokonazol film-coated tablet (200 mg bid) (Brand name: Ketokonazol Polfarmex 200 mg film tablets) for 4 days (Days -2, -1, 1, and 2) plus BI 113608 (25 mg single dose) for 1 day (Day 1) followed by Voriconazole (400 mg bid) (Brand name: Vfend® 200 mg film tablets) for 1 day on Day -2 (loading dose) Voriconazole (200 mg bid) for 3 days (Days -1, 1, and 2) plus BI 113608 (25 mg single dose) for 1 day (Day 1) orally with 240 mL of water after an overnight fast of at least 10 hours followed by BI 113608 film-coated tablet 25 mg orally for 1 day (Day 1) orally with 240 mL of water. A wash-out period of at least 6 days was respected between the administrations of BI 113608.	The subjects received Voriconazole (400 mg bid) (Brand name: Vfend® 200 mg film tablets) for 1 day on Day -2 (loading dose) Voriconazole (200 mg bid) for 3 days (Days -1, 1, and 2) plus BI 113608 (25 mg single dose) for 1 day (Day 1) orally with 240 mL of water after an overnight fast of at least 10 hours followed by BI 113608 film-coated tablet 25 mg orally for 1 day (Day 1) orally with 240 mL of water followed by Ketokonazol film-coated tablet (200 mg bid) (Brand name: Ketokonazol Polfarmex 200 mg film tablets) for 4 days (Days -2, -1, 1, and 2) plus BI 113608 (25 mg single dose) for 1 day (Day 1) orally with 240 mL of water after an overnight fast of at least 10 hours. A wash-out period of at least 6 days was respected between the administrations of BI 113608.	The subjects received Voriconazole (400 mg bid) (Brand name: Vfend® 200 mg film tablets) for 1 day on Day -2 (loading dose) Voriconazole (200 mg bid) for 3 days (Days -1, 1, and 2) plus BI 113608 (25 mg single dose) for 1 day (Day 1) followed by Ketokonazol film-coated tablet (200 mg bid) (Brand name: Ketokonazol Polfarmex 200 mg film tablets) for 4 days (Days -2, -1, 1, and 2) plus BI 113608 (25 mg single dose) for 1 day (Day 1) orally with 240 mL of water after an overnight fast of at least 10 hours followed by BI 113608 film-coated tablet 25 mg orally for 1 day (Day 1) orally with 240 mL of water. A wash-out period of at least 6 days was respected between the administrations of BI 113608.
Period Title: Overall Study
STARTED	3	3	3	3	4	4
Received R	3	3	3	3	4	3
Received T1	3	3	3	3	3	4
Received T2	3	3	3	3	4	4
COMPLETED	3	3	3	3	3	3
NOT COMPLETED	0	0	0	0	1	1

Baseline Characteristics

Arm/Group Title	BI 113608/BI 113608 + Ketoconazole/BI 113608 + Voriconazole	BI 113608/BI 113608 + Voriconazole/ BI 113608 + Ketoconazole	BI 113608 + Ketoconazole/ BI 113608/ BI 113608 + Voriconazole	BI 113608 + Ketoconazole/ BI 113608 + Voriconazole/ BI 113608	BI 113608 + Voriconazole/ BI 113608/ BI 113608 + Ketoconazole	BI 113608 + Voriconazole/ BI 113608 + Ketoconazole/ BI 113608	Total
Arm/Group Description	The subjects received BI 113608 film-coated tablet 25 mg orally for 1 day (Day 1) orally with 240 mL of water followed by Ketokonazol film-coated tablet (200 mg bid) (Brand name: Ketokonazol Polfarmex 200 mg film tablets) for 4 days (Days -2, -1, 1, and 2) plus BI 113608 (25 mg single dose) for 1 day (Day 1) followed by Voriconazole (400 mg bid) (Brand name: Vfend® 200 mg film tablets) for 1 day on Day -2 (loading dose) Voriconazole (200 mg bid) for 3 days (Days -1, 1, and 2) plus BI 113608 (25 mg single dose) for 1 day (Day 1) orally with 240 mL of water after an overnight fast of at least 10 hours. A wash-out period of at least 6 days was respected between the administrations of BI 113608.	The subjects received BI 113608 film-coated tablet 25 mg orally for 1 day (Day 1) orally with 240 mL of water followed by Voriconazole (400 mg bid) (Brand name: Vfend® 200 mg film tablets) for 1 day on Day -2 (loading dose) Voriconazole (200 mg bid) for 3 days (Days -1, 1, and 2) plus BI 113608 (25 mg single dose) for 1 day (Day 1) followed by Ketokonazol film-coated tablet (200 mg bid) (Brand name: Ketokonazol Polfarmex 200 mg film tablets) for 4 days (Days -2, -1, 1, and 2) plus BI 113608 (25 mg single dose) for 1 day (Day 1) orally with 240 mL of water after an overnight fast of at least 10 hours. A wash-out period of at least 6 days was respected between the administrations of BI 113608.	The subjects received Ketokonazol film-coated tablet (200 mg bid) (Brand name: Ketokonazol Polfarmex 200 mg film tablets) for 4 days (Days -2, -1, 1, and 2) plus BI 113608 (25 mg single dose) for 1 day (Day 1) orally with 240 mL of water after an overnight fast of at least 10 hours followed by BI 113608 film-coated tablet 25 mg orally for 1 day (Day 1) orally with 240 mL of water followed by Voriconazole (400 mg bid) (Brand name: Vfend® 200 mg film tablets) for 1 day on Day -2 (loading dose) Voriconazole (200 mg bid) for 3 days (Days -1, 1, and 2) plus BI 113608 (25 mg single dose) for 1 day (Day 1) orally with 240 mL of water after an overnight fast of at least 10 hours. A wash-out period of at least 6 days was respected between the administrations of BI 113608.	The subjects received Ketokonazol film-coated tablet (200 mg bid) (Brand name: Ketokonazol Polfarmex 200 mg film tablets) for 4 days (Days -2, -1, 1, and 2) plus BI 113608 (25 mg single dose) for 1 day (Day 1) followed by Voriconazole (400 mg bid) (Brand name: Vfend® 200 mg film tablets) for 1 day on Day -2 (loading dose) Voriconazole (200 mg bid) for 3 days (Days -1, 1, and 2) plus BI 113608 (25 mg single dose) for 1 day (Day 1) orally with 240 mL of water after an overnight fast of at least 10 hours followed by BI 113608 film-coated tablet 25 mg orally for 1 day (Day 1) orally with 240 mL of water. A wash-out period of at least 6 days was respected between the administrations of BI 113608.	The subjects received Voriconazole (400 mg bid) (Brand name: Vfend® 200 mg film tablets) for 1 day on Day -2 (loading dose) Voriconazole (200 mg bid) for 3 days (Days -1, 1, and 2) plus BI 113608 (25 mg single dose) for 1 day (Day 1) orally with 240 mL of water after an overnight fast of at least 10 hours followed by BI 113608 film-coated tablet 25 mg orally for 1 day (Day 1) orally with 240 mL of water followed by Ketokonazol film-coated tablet (200 mg bid) (Brand name: Ketokonazol Polfarmex 200 mg film tablets) for 4 days (Days -2, -1, 1, and 2) plus BI 113608 (25 mg single dose) for 1 day (Day 1) orally with 240 mL of water after an overnight fast of at least 10 hours. A wash-out period of at least 6 days was respected between the administrations of BI 113608.	The subjects received Voriconazole (400 mg bid) (Brand name: Vfend® 200 mg film tablets) for 1 day on Day -2 (loading dose) Voriconazole (200 mg bid) for 3 days (Days -1, 1, and 2) plus BI 113608 (25 mg single dose) for 1 day (Day 1) followed by Ketokonazol film-coated tablet (200 mg bid) (Brand name: Ketokonazol Polfarmex 200 mg film tablets) for 4 days (Days -2, -1, 1, and 2) plus BI 113608 (25 mg single dose) for 1 day (Day 1) orally with 240 mL of water after an overnight fast of at least 10 hours followed by BI 113608 film-coated tablet 25 mg orally for 1 day (Day 1) orally with 240 mL of water. A wash-out period of at least 6 days was respected between the administrations of BI 113608.	Total of all reporting groups
Overall Participants	3	3	3	3	4	4	20
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	45.0 (1.7)	33.3 (12.3)	35.0 (6.2)	35.3 (8.4)	32.8 (9.9)	37.3 (12.5)	36.3 (9.2)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Male	3 100%	3 100%	3 100%	3 100%	4 100%	4 100%	20 100%

Outcome Measures

1. Primary Outcome

Title	Area Under the Concentration-time Curve of BI 113608 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz)
Description	This outcome measure presents the area under the concentration-time curve of BI 113608 in plasma over the time interval from 0 to the last quantifiable data point. The parameter dispersion type (standard deviation) is actually intra individual geometric coefficient of variation (intraindividual gCV). Statistical analysis 1: The ratio (Other) is calculated as BI+K (T1): BI (R) [%]. Statistical analysis 2: The ratio (Other) is calculated as BI + V (T2): BI (R) [%].
Time Frame	1 hour before drug administration and 0:25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 24, 34, 48 and 72 hours after drug administration.

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Set (PKS): The 'PK set' included all subjects of the treated set who provided at least one evaluable observation for at least one primary PK endpoint in at least one treatment period without important protocol violations relevant to the evaluation of PK; PK analyses were based on the PK set.

Arm/Group Title	BI 113608	BI 113608 + Ketoconazole	BI 113608 + Voriconazole
Arm/Group Description	The subjects received BI 113608 film-coated tablet 25 mg orally for 1 day (Day 1) orally with 240 mL of water.	The subjects received Ketokonazol film-coated tablet (200 mg bid) (Brand name: Ketokonazol Polfarmex 200 mg film tablets) for 4 days (Days -2, -1, 1, and 2) plus BI 113608 (25 mg single dose) for 1 day (Day 1) orally with 240 mL of water after an overnight fast of at least 10 hours.	The subjects received Voriconazole (400 mg bid) (Brand name: Vfend® 200 mg film tablets) for 1 day on Day -2 (loading dose) Voriconazole (200 mg bid) for 3 days (Days -1, 1, and 2) plus BI 113608 (25 mg single dose) for 1 day (Day 1) orally with 240 mL of water after an overnight fast of at least 10 hours.
Measure Participants	18	18	18
Geometric Mean (Geometric Coefficient of Variation) [nanomol*hours/litre (nmol*h/L)]	494 (36.7)	1840 (36.9)	1320 (51.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BI 113608, BI 113608 + Ketoconazole
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	373.66
	Confidence Interval	(2-Sided) 90%; 346.029 to 403.507
	Parameter Dispersion	Type: Standard Deviation; Value: 13.2
	Estimation Comments	ANOVA model on the logarithmic scale: included effects accounting for following sources of variation: 'sequence', 'patients within sequence', 'period' and 'treatment'. Random effect: 'patients within sequences', others considered as fixed effects.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BI 113608, BI 113608 + Voriconazole
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	266.94
	Confidence Interval	(2-Sided) 90%; 243.267 to 292.914
	Parameter Dispersion	Type: Standard Deviation; Value: 16.0
	Estimation Comments	ANOVA model on the logarithmic scale: included effects accounting for following sources of variation: 'sequence', 'patients within sequence', 'period' and 'treatment'. Random effect: 'patients within sequences', others considered as fixed effects.

2. Primary Outcome

Title	Maximum Measured Concentration of BI 113608 in Plasma (Cmax)
Description	This outcome measure presents the maximum measured concentration of BI 113608 in plasma. The parameter dispersion type (standard deviation) is actually intra individual geometric coefficient of variation (intraindividual gCV). Statistical analysis 1: The ratio (Other) is calculated as BI + K (T1): BI (R) [%]. Statistical analysis 2: The ratio (Other) is calculated as BI + V (T2): BI (R) [%].
Time Frame	1 hour before drug administration and 0:25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 24, 34, 48 and 72 hours after drug administration.

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Set (PKS): The 'PK set' included all subjects of the treated set who provided at least one evaluable observation for at least one primary PK endpoint in at least one treatment period without important protocol violations relevant to the evaluation of PK; PK analyses were based on the PK set.

Arm/Group Title	BI 113608	BI 113608 + Ketoconazole	BI 113608 + Voriconazole
Arm/Group Description	The subjects received BI 113608 film-coated tablet 25 mg orally for 1 day (Day 1) orally with 240 mL of water.	The subjects received Ketokonazol film-coated tablet (200 mg bid) (Brand name: Ketokonazol Polfarmex 200 mg film tablets) for 4 days (Days -2, -1, 1, and 2) plus BI 113608 (25 mg single dose) for 1 day (Day 1) orally with 240 mL of water after an overnight fast of at least 10 hours.	The subjects received Voriconazole (400 mg bid) (Brand name: Vfend® 200 mg film tablets) for 1 day on Day -2 (loading dose) Voriconazole (200 mg bid) for 3 days (Days -1, 1, and 2) plus BI 113608 (25 mg single dose) for 1 day (Day 1) orally with 240 mL of water after an overnight fast of at least 10 hours.
Measure Participants	18	18	18
Geometric Mean (Geometric Coefficient of Variation) [nanomol/litre (nmol/L)]	102 (55.5)	267 (41.9)	218 (54)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BI 113608, BI 113608 + Ketoconazole
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	261.34
	Confidence Interval	(2-Sided) 90%; 211.692 to 322.633
	Parameter Dispersion	Type: Standard Deviation; Value: 37.3
	Estimation Comments	ANOVA model on the logarithmic scale: included effects accounting for following sources of variation: 'sequence', 'patients within sequence', 'period' and 'treatment'. Random effect: 'patients within sequences', others considered as fixed effects.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BI 113608, BI 113608 + Voriconazole
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	213.39
	Confidence Interval	(2-Sided) 90%; 175.783 to 259.051
	Parameter Dispersion	Type: Standard Deviation; Value: 34.1
	Estimation Comments	ANOVA model on the logarithmic scale: included effects accounting for following sources of variation: 'sequence', 'patients within sequence', 'period' and 'treatment'. Random effect: 'patients within sequences', others considered as fixed effects.

3. Secondary Outcome

Title	Area Under the Concentration-time Curve of BI 113608 in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞)
Description	This outcome measure presents area under the concentration-time curve of BI 113608 in plasma over the time interval from 0 to infinity. The parameter dispersion type (standard deviation) is actually intra individual geometric coefficient of variation (intraindividual gCV). Statistical analysis 1: The ratio (Other) is calculated as BI + K (T1): BI (R) [%]. Statistical analysis 2: The ratio (Other) is calculated as BI + V (T2): BI (R) [%].
Time Frame	1 hour before drug administration and 0:25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 24, 34, 48 and 72 hours after drug administration.

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Set (PKS): The 'PK set' included all subjects of the treated set who provided at least one evaluable observation for at least one primary PK endpoint in at least one treatment period without important protocol violations relevant to the evaluation of PK; PK analyses were based on the PK set.

Arm/Group Title	BI 113608	BI 113608 + Ketoconazole	BI 113608 + Voriconazole
Arm/Group Description	The subjects received BI 113608 film-coated tablet 25 mg orally for 1 day (Day 1) orally with 240 mL of water.	The subjects received Ketokonazol film-coated tablet (200 mg bid) (Brand name: Ketokonazol Polfarmex 200 mg film tablets) for 4 days (Days -2, -1, 1, and 2) plus BI 113608 (25 mg single dose) for 1 day (Day 1) orally with 240 mL of water after an overnight fast of at least 10 hours.	The subjects received Voriconazole (400 mg bid) (Brand name: Vfend® 200 mg film tablets) for 1 day on Day -2 (loading dose) Voriconazole (200 mg bid) for 3 days (Days -1, 1, and 2) plus BI 113608 (25 mg single dose) for 1 day (Day 1) orally with 240 mL of water after an overnight fast of at least 10 hours.
Measure Participants	18	18	18
Geometric Mean (Geometric Coefficient of Variation) [nanomol*hours/litre (nmol*h/L)]	496 (36.7)	1850 (36.9)	1320 (51.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BI 113608, BI 113608 + Ketoconazole
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	372.88
	Confidence Interval	(2-Sided) 90%; 345.456 to 402.477
	Parameter Dispersion	Type: Standard Deviation; Value: 13.1
	Estimation Comments	ANOVA model on the logarithmic scale: included effects accounting for following sources of variation: 'sequence', 'patients within sequence', 'period' and 'treatment'. Random effect: 'patients within sequences', others considered as fixed effects.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BI 113608, BI 113608 + Voriconazole
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	266.56
	Confidence Interval	(2-Sided) 90%; 242.955 to 292.456
	Parameter Dispersion	Type: Standard Deviation; Value: 16.0
	Estimation Comments	ANOVA model on the logarithmic scale: included effects accounting for following sources of variation: 'sequence', 'patients within sequence', 'period' and 'treatment'. Random effect: 'patients within sequences', others considered as fixed effects.

4. Secondary Outcome

Title	Time From Dosing to Maximum Measured Concentration of BI 113608 in Plasma (Tmax)
Description	This outcome measure presents time from dosing to maximum measured concentration of BI 113608 in plasma.
Time Frame	1 hour before drug administration and 0:25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 24, 34, 48 and 72 hours after drug administration.

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Set (PKS): The 'PK set' included all subjects of the treated set who provided at least one evaluable observation for at least one primary PK endpoint in at least one treatment period without important protocol violations relevant to the evaluation of PK; PK analyses were based on the PK set.

Arm/Group Title	BI 113608	BI 113608 + Ketoconazole	BI 113608 + Voriconazole
Arm/Group Description	The subjects received BI 113608 film-coated tablet 25 mg orally for 1 day (Day 1) orally with 240 mL of water.	The subjects received Ketokonazol film-coated tablet (200 mg bid) (Brand name: Ketokonazol Polfarmex 200 mg film tablets) for 4 days (Days -2, -1, 1, and 2) plus BI 113608 (25 mg single dose) for 1 day (Day 1) orally with 240 mL of water after an overnight fast of at least 10 hours.	The subjects received Voriconazole (400 mg bid) (Brand name: Vfend® 200 mg film tablets) for 1 day on Day -2 (loading dose) Voriconazole (200 mg bid) for 3 days (Days -1, 1, and 2) plus BI 113608 (25 mg single dose) for 1 day (Day 1) orally with 240 mL of water after an overnight fast of at least 10 hours.
Measure Participants	18	18	18
Geometric Mean (Geometric Coefficient of Variation) [hours (h)]	1.25 (74.5)	1.40 (56.9)	1.43 (63.9)

5. Secondary Outcome

Title	Terminal Half-life of BI 113608 in Plasma (t1/2)
Description	This outcome measure presents terminal half-life of BI 113608 in plasma.
Time Frame	1 hour before drug administration and 0:25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 24, 34, 48 and 72 hours after drug administration.

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Set (PKS): The 'PK set' included all subjects of the treated set who provided at least one evaluable observation for at least one primary PK endpoint in at least one treatment period without important protocol violations relevant to the evaluation of PK; PK analyses were based on the PK set.

Arm/Group Title	BI 113608	BI 113608 + Ketoconazole	BI 113608 + Voriconazole
Arm/Group Description	The subjects received BI 113608 film-coated tablet 25 mg orally for 1 day (Day 1) orally with 240 mL of water.	The subjects received Ketokonazol film-coated tablet (200 mg bid) (Brand name: Ketokonazol Polfarmex 200 mg film tablets) for 4 days (Days -2, -1, 1, and 2) plus BI 113608 (25 mg single dose) for 1 day (Day 1) orally with 240 mL of water after an overnight fast of at least 10 hours.	The subjects received Voriconazole (400 mg bid) (Brand name: Vfend® 200 mg film tablets) for 1 day on Day -2 (loading dose) Voriconazole (200 mg bid) for 3 days (Days -1, 1, and 2) plus BI 113608 (25 mg single dose) for 1 day (Day 1) orally with 240 mL of water after an overnight fast of at least 10 hours.
Measure Participants	18	18	18
Geometric Mean (Geometric Coefficient of Variation) [hours (h)]	11.0 (28.0)	9.20 (18.3)	10.6 (18.8)

Adverse Events

Time Frame	15 days of treatment (including two 6-days-wash-out periods between BI 113608 treatments) followed by up to 12 days until the end of study. After study completion there was 30 days Adverse Event (AE) follow up period. 57 days on total.
Arm/Group Title	BI 113608		BI 113608 + Ketoconazole		BI 113608 + Voriconazole		Ketoconazole		Voriconazole
Arm/Group Description	The subjects received BI 113608 film-coated tablet 25 mg orally for 1 day (Day 1) orally with 240 mL of water.		The subjects received Ketokonazol film-coated tablet (200 mg bid) (Brand name: Ketokonazol Polfarmex 200 mg film tablets) for 4 days (Days -2, -1, 1, and 2) plus BI 113608 (25 mg single dose) for 1 day (Day 1) orally with 240 mL of water after an overnight fast of at least 10 hours.		The subjects received Voriconazole (400 mg bid) (Brand name: Vfend® 200 mg film tablets) for 1 day on Day -2 (loading dose) Voriconazole (200 mg bid) for 3 days (Days -1, 1, and 2) plus BI 113608 (25 mg single dose) for 1 day (Day 1) orally with 240 mL of water after an overnight fast of at least 10 hours.		The subjects received Ketokonazol film-coated tablet (200 mg bid) (Brand name: Ketokonazol Polfarmex 200 mg film tablets) for 4 days (Days -2, -1, 1, and 2) orally with 240 mL of water after an overnight fast of at least 10 hours.		The subjects received Voriconazole (400 mg bid) (Brand name: Vfend® 200 mg film tablets) for 1 day on Day -2 (loading dose) Voriconazole (200 mg bid) for 3 days (Days -1, 1, and 2) orally with 240 mL of water after an overnight fast of at least 10 hours.
All Cause Mortality
	BI 113608		BI 113608 + Ketoconazole		BI 113608 + Voriconazole		Ketoconazole		Voriconazole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	BI 113608		BI 113608 + Ketoconazole		BI 113608 + Voriconazole		Ketoconazole		Voriconazole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/18 (0%)		0/18 (0%)		0/19 (0%)		0/19 (0%)		0/20 (0%)
Other (Not Including Serious) Adverse Events
	BI 113608		BI 113608 + Ketoconazole		BI 113608 + Voriconazole		Ketoconazole		Voriconazole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/18 (16.7%)		3/18 (16.7%)		5/19 (26.3%)		9/19 (47.4%)		12/20 (60%)
Eye disorders
Photopsia	0/18 (0%)		0/18 (0%)		1/19 (5.3%)		0/19 (0%)		11/20 (55%)
Vision blurred	0/18 (0%)		0/18 (0%)		2/19 (10.5%)		0/19 (0%)		0/20 (0%)
Gastrointestinal disorders
Abdominal pain	1/18 (5.6%)		0/18 (0%)		0/19 (0%)		1/19 (5.3%)		0/20 (0%)
General disorders
Fatigue	0/18 (0%)		1/18 (5.6%)		0/19 (0%)		0/19 (0%)		2/20 (10%)
Infections and infestations
Nasopharyngitis	0/18 (0%)		0/18 (0%)		1/19 (5.3%)		0/19 (0%)		0/20 (0%)
Rhinitis	1/18 (5.6%)		0/18 (0%)		1/19 (5.3%)		0/19 (0%)		0/20 (0%)
Sinusitis	0/18 (0%)		0/18 (0%)		0/19 (0%)		1/19 (5.3%)		0/20 (0%)
Injury, poisoning and procedural complications
Laceration	0/18 (0%)		1/18 (5.6%)		0/19 (0%)		0/19 (0%)		0/20 (0%)
Musculoskeletal and connective tissue disorders
Musculoskeletal pain	1/18 (5.6%)		0/18 (0%)		0/19 (0%)		0/19 (0%)		0/20 (0%)
Pain in extremity	0/18 (0%)		0/18 (0%)		0/19 (0%)		1/19 (5.3%)		0/20 (0%)
Nervous system disorders
Headache	1/18 (5.6%)		2/18 (11.1%)		1/19 (5.3%)		5/19 (26.3%)		3/20 (15%)
Presyncope	0/18 (0%)		0/18 (0%)		0/19 (0%)		1/19 (5.3%)		0/20 (0%)
Psychiatric disorders
Insomnia	0/18 (0%)		0/18 (0%)		0/19 (0%)		0/19 (0%)		2/20 (10%)
Respiratory, thoracic and mediastinal disorders
Nasal dryness	0/18 (0%)		1/18 (5.6%)		0/19 (0%)		0/19 (0%)		0/20 (0%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.