Interaction of BI 691751 With Itraconazole

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02044393
• Collaborator: (none)
• Enrollment: 20
• Location: 1
• Arms: 2
• Duration (Months): 3.9
• Patients Per Site Per Month: 5.1

Study Details

Study Description

Brief Summary

Investigation of the relative bioavailability of a single dose of BI 691751 when given alone and together with itraconazole; safety and tolerability

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: itraconazole; Drug: BI 691751; Drug: BI 691751	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 a Single Oral Dose of BI 691751 When Administered Alone or in Combination With Multiple Oral Doses of Itraconazole in Healthy Male Subjects (an Open-label, Randomised, Two-period, Two-sequence Crossover Study)
• Study Start Date: Jan 1, 2014
• Actual Primary Completion Date: May 1, 2014
• Actual Study Completion Date: May 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Reference single dose BI 691751	Drug: BI 691751; single dose BI 691751 given as tablet
Experimental: Test multiple doses of itraconazole + single dose BI 691751	Drug: itraconazole; multiple doses of itraconazole given as capsules; Drug: BI 691751; single dose BI 691751 given as tablet

Outcome Measures

Primary Outcome Measures

1. AUC0-tz (Area Under the Concentration-time Curve of BI 691751 in Plasma and Whole Blood Over the Time Interval From 0 up to the Last Quantifiable Concentration) [from day 1 to 31 days postdose relative to BI 691751 administration (h:min): -2:00, 0:10, 0:20, 0:40, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 24:00, 34:00, 47:00, 71:00, 95:00, 119:00, 143:00, 215:00, 287:00, 383:00, 551:00, 719:00h.]

   AUC0-tz: area under the concentration-time curve of BI 691751 in plasma and whole blood over the time interval from 0 up to the last quantifiable concentration.

2. Cmax (Maximum Measured Concentration of BI 691751 in Plasma and Whole Blood) [From day 1 to 31 days postdose relative to BI 691751 administration (h:min): -2:00, 0:10, 0:20, 0:40, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 24:00, 34:00, 47:00, 71:00, 95:00, 119:00, 143:00, 215:00, 287:00, 383:00, 551:00, 719:00h.]

   Cmax (maximum measured concentration of BI 691751 in plasma and whole blood).

Secondary Outcome Measures

1. AUC0-infinity (Area Under the Concentration-time Curve of BI 691751 in Plasma and Whole Blood Over the Time Interval From 0 Extrapolated to Infinity) [from day 1 to 31 days postdose relative to BI 691751 administration time: -2:00, 0:10, 0:20, 0:40, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 24:00, 34:00, 47:00, 71:00, 95:00, 119:00, 143:00, 215:00, 287:00, 383:00, 551:00, 719:00h.]

   AUC0-infinity (area under the concentration-time curve of BI 691751 in plasma and whole blood over the time interval from 0 extrapolated to infinity).

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

2. body mass index (BMI) of 18.5 to 29.9 kg/m2

3. Subjects must be able to understand and comply with study requirements

Exclusion criteria:

1. Any finding in the medical examination (including blood pressure (BP), pulse rate (PR), or electrocardiogram (ECG)) deviating from normal and judged clinically relevant by the investigator.

2. Pulse rate outside 45 to 100 bpm or repeated measurements of systolic BP outside 90 to 140 mmHg or diastolic BP outside 50 to 90 mmHg.

3. Any laboratory value outside the reference range that the investigator considers to be of clinical relevance

4. Any alanine transaminase (ALT/GPT), aspartate transaminase (AST/GOT), or gammaglutamyltransferase (GGT) value outside the reference range at the screening examination

5. Any evidence of a concomitant disease judged clinically relevant by the investigator

6. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological, or hormonal disorders

7. Any history of relevant liver diseases such as disturbance of liver function, jaundice, drug induced liver injury, Dubin-Johnson syndrome, Rotor syndrome, or liver tumors

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	1334.10.1 Boehringer Ingelheim Investigational Site	Biberach		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: NCT02044393
• Other Study ID Numbers: 1334.10; 2013-003814-42
• First Posted: Jan 24, 2014
• Last Update Posted: Dec 16, 2015
• Last Verified: Nov 1, 2015

• Additional relevant MeSH terms: Itraconazole

Study Results

Participant Flow

Arm/Group Title	Itraconazole (IT) +BI 691751 / BI 691751	BI 691751 / IT+BI 691751
Arm/Group Description	Subjects in treatment sequence of tested drug treatment in period 1, then reference drug treatment in period 2 (T/R): two capsules of 100 mg itraconazole were given twice daily on Day -3 (loading dose) and once daily on Day -2 to Day 7 (10 days of itraconazol treatment in total). In addition, 1 tablet of 10 mg BI 691751 was given as a single dose on Day 1 (corresponding to the fourth day of the 10-day itraconazole treatment) in period 1. One tablet of 10 mg BI 691751 was given as a single dose on Day 1 in period 2. The BI 691751 single dose administrations in the 2 treatment periods were separated by a washout period of at least 7 weeks. Oral administration with 240 mL water after intake of a standardised meal.	Subjects in treatment sequence of reference drug treatment in period 1, then tested drug treatment in period 2 (R/T): One tablet of 10 mg BI 691751 was given as a single dose on Day 1 in period 1. Two capsules of 100 mg itraconazole were given twice daily on Day -3 (loading dose) and once daily on Day -2 to Day 7 (10 days of itraconazol treatment in total), and, 1 tablet of 10 mg BI 691751 was given as a single dose on Day 1 (corresponding to the fourth day of the 10-day itraconazole treatment) in period 2. Oral administration with 240 mL water after intake of a standaridsed meal.
Period Title: Period 1
STARTED	10	10
COMPLETED	10	10
NOT COMPLETED	0	0
Period Title: Period 1
STARTED	10	10
COMPLETED	10	10
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Itraconazole (IT) +BI 691751 / BI 691751	BI 691751 / IT+BI 691751	Total
Arm/Group Description	Subjects in treatment sequence of tested drug treatment in period 1, then reference drug treatment in period 2 (T/R): two capsules of 100 mg itraconazole were given twice daily on Day -3 (loading dose) and once daily on Day -2 to Day 7 (10 days of itraconazol treatment in total). In addition, 1 tablet of 10 mg BI 691751 was given as a single dose on Day 1 (corresponding to the fourth day of the 10-day itraconazole treatment) in period 1. One tablet of 10 mg BI 691751 was given as a single dose on Day 1 in period 2. The BI 691751 single dose administrations in the 2 treatment periods were separated by a washout period of at least 7 weeks. Oral administration with 240 mL water after intake of a standardised meal.	Subjects in treatment sequence of reference drug treatment in period 1, then tested drug treatment in period 2 (R/T): One tablet of 10 mg BI 691751 was given as a single dose on Day 1 in period 1. Two capsules of 100 mg itraconazole were given twice daily on Day -3 (loading dose) and once daily on Day -2 to Day 7 (10 days of itraconazol treatment in total), and, 1 tablet of 10 mg BI 691751 was given as a single dose on Day 1 (corresponding to the fourth day of the 10-day itraconazole treatment) in period 2. Oral administration with 240 mL water after intake of a standaridsed meal.	Total of all reporting groups
Overall Participants	10	10	20
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	35.1 (9.9)	37.4 (6.6)	36.3 (8.3)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	10 100%	10 100%	20 100%

Outcome Measures

1. Primary Outcome

Title	AUC0-tz (Area Under the Concentration-time Curve of BI 691751 in Plasma and Whole Blood Over the Time Interval From 0 up to the Last Quantifiable Concentration)
Description	AUC0-tz: area under the concentration-time curve of BI 691751 in plasma and whole blood over the time interval from 0 up to the last quantifiable concentration.
Time Frame	from day 1 to 31 days postdose relative to BI 691751 administration (h:min): -2:00, 0:10, 0:20, 0:40, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 24:00, 34:00, 47:00, 71:00, 95:00, 119:00, 143:00, 215:00, 287:00, 383:00, 551:00, 719:00h.

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Set (PKS): included all subjects from the TS who provided at least one primary or secondary pharmacokinetic endpoint in any period that is judged as evaluable for pharmacokinetics and is not affected by protocol violations relevant to the statistical evaluation of bioavailability

Arm/Group Title	BI 691751	IT + BI 691751
Arm/Group Description	single dose BI 691751 BI 691751: 10 mg single dose oral administration with 240 mL water after intake of a standard meal.	Two capsules of 100 mg IT were given twice daily on Day -3 and once daily on Day -2 to Day 7. 1 tablet of 10 mg BI 691751 was given as a single dose on Day 1 with 240 mL water after intake of a standard meal.
Measure Participants	20	20
in plasma	2830 (34.6)	2090 (43.2)
in whole blood	25000 (25.8)	21600 (25.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BI 691751, IT + BI 691751
	Comments	gMean ratio of IT+BI 691751 to BI 69175 treatment (in plasma)
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	90% confidence interval for gMean ratio of IT+BI 691751 to BI 69175 treatment was provided. The ANOVA model included the fixed effects 'sequence', 'period' and 'treatment' and as a random effect 'subject within sequence' as source of variation.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	gMean ratio
	Estimated Value	74.07
	Confidence Interval	(2-Sided) 90%; 62.371 to 87.959
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 32.1
	Estimation Comments	ratio of IT+BI 691751 to BI 691751 treatment. Estimated value and its confidence interval (CI) are in percentage unit. The standard error of the mean actually is the geometric coefficient of variance.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BI 691751, IT + BI 691751
	Comments	gMean ratio of IT+BI 691751 to BI 691751 treatment (in whole blood)
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	90% confidence interval for gMean ratio of IT+BI 691751 to BI 69175 treatment was provided. The ANOVA model included the fixed effects 'sequence', 'period' and 'treatment' and as a random effect 'subject within sequence' as source of variation.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	gMean ratio
	Estimated Value	86.35
	Confidence Interval	(2-Sided) 90%; 78.04 to 95.56
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 18.6
	Estimation Comments	ratio of IT+BI 691751 to BI 691751 treatment. Estimated value and its confidence interval (CI) are in percentage unit. The standard error of the mean actually is the geometric coefficient of variance.

2. Primary Outcome

Title	Cmax (Maximum Measured Concentration of BI 691751 in Plasma and Whole Blood)
Description	Cmax (maximum measured concentration of BI 691751 in plasma and whole blood).
Time Frame	From day 1 to 31 days postdose relative to BI 691751 administration (h:min): -2:00, 0:10, 0:20, 0:40, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 24:00, 34:00, 47:00, 71:00, 95:00, 119:00, 143:00, 215:00, 287:00, 383:00, 551:00, 719:00h.

Outcome Measure Data

Analysis Population Description

PKS

Arm/Group Title	BI 691751	IT + BI 691751
Arm/Group Description	10 mg BI 691751 single dose oral administration with 240 mL water after intake of a standard meal.	Two capsules of 100 mg IT were given twice daily on Day -3 and once daily on Day -2 to Day 7. 1 tablet of 10 mg BI 691751 was given as a single dose on Day 1 with 240 mL water after intake of a standard meal.
Measure Participants	20	20
in plasma	157 (24.4)	150 (34.1)
in whole blood	217 (16.0)	203 (21.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BI 691751, IT + BI 691751
	Comments	gMean ratio of test to reference treatment (in plasma)
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	90% confidence interval for gMean ratio of IT+BI 691751 to BI 69175 treatment was provided. The ANOVA model included the fixed effects 'sequence', 'period' and 'treatment' and as a random effect 'subject within sequence' as source of variation.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	gMean ratio
	Estimated Value	95.59
	Confidence Interval	(2-Sided) 90%; 84.195 to 108.537
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 23.5
	Estimation Comments	ratio of test to reference treatment. The standard error of the mean actually is the geometric coefficient of variance.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BI 691751, IT + BI 691751
	Comments	gMean ratio of test to reference treatment (in whole blood)
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	90% confidence interval for gMean ratio of IT+BI 691751 to BI 69175 treatment was provided. The ANOVA model included the fixed effects 'sequence', 'period' and 'treatment' and as a random effect 'subject within sequence' as source of variation.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	gMean ratio
	Estimated Value	93.54
	Confidence Interval	(2-Sided) 90%; 86.142 to 101.570
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 15.1
	Estimation Comments	ratio of test to reference treatment. The standard error of the mean actually is the geometric coefficient of variance.

3. Secondary Outcome

Title	AUC0-infinity (Area Under the Concentration-time Curve of BI 691751 in Plasma and Whole Blood Over the Time Interval From 0 Extrapolated to Infinity)
Description	AUC0-infinity (area under the concentration-time curve of BI 691751 in plasma and whole blood over the time interval from 0 extrapolated to infinity).
Time Frame	from day 1 to 31 days postdose relative to BI 691751 administration time: -2:00, 0:10, 0:20, 0:40, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 24:00, 34:00, 47:00, 71:00, 95:00, 119:00, 143:00, 215:00, 287:00, 383:00, 551:00, 719:00h.

Outcome Measure Data

Analysis Population Description

PKS

Arm/Group Title	BI 691751	IT + BI 691751
Arm/Group Description	10 mg BI 691751 single dose oral administration with 240 mL water after intake of a standard meal.	Two capsules of 100 mg IT were given twice daily on Day -3 and once daily on Day -2 to Day 7. 1 tablet of 10 mg BI 691751 was given as a single dose on Day 1 with 240 mL water after intake of a standard meal.
Measure Participants	20	20
in plasma	3160 (34.8)	2360 (43.3)
in whole blood	27700 (29.6)	24600 (29.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BI 691751, IT + BI 691751
	Comments	gMean ratio of IT+BI 691751 to BI 691751 treatment (in plasma)
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	90% confidence interval for gMean ratio of IT+BI 691751 to BI 69175 treatment was provided. The ANOVA model included the fixed effects 'sequence', 'period' and 'treatment' and as a random effect 'subject within sequence' as source of variation.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	gMean ratio
	Estimated Value	74.86
	Confidence Interval	(2-Sided) 90%; 62.946 to 89.035
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 32.4
	Estimation Comments	ratio of IT+BI 691751 to BI 691751 treatment. The standard error of the mean actually is the geometric coefficient of variance.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BI 691751, IT + BI 691751
	Comments	gMean ratio of IT+BI 691751 to BI 691751 treatment (in whole blood)
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	90% confidence interval for gMean ratio of IT+BI 691751 to BI 69175 treatment was provided. The ANOVA model included the fixed effects 'sequence', 'period' and 'treatment' and as a random effect 'subject within sequence' as source of variation.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	gMean ratio
	Estimated Value	88.19
	Confidence Interval	(2-Sided) 90%; 78.60 to 98.95
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 20.7
	Estimation Comments	ratio of IT+BI 691751 to BI 691751 treatment. The standard error of the mean actually is the geometric coefficient of variance.

Adverse Events

Time Frame	From the 1st trial drug administration of a treatment until the 1st trial drug intake in the next treatment or until 31 days after the last administration of BI were assigned to the respective on-treatment phases (BI alone, loading IT, BI + further IT)
Adverse Event Reporting Description	More specifically, for: BI 691751 - up to 50 days, Loading IT - 3 days, BI + further IT - up to 47 days
Arm/Group Title	BI 691751		Loading Itraconazole (IT)		BI 691751 + Further IT		Total BI 691751		Total on Treatment
Arm/Group Description	10 mg single dose oral administration with 240 mL water after intake of a standard meal. (only in the reference treatment period)		200 mg of itraconazole (introductory treatment with itraconazole over three days, prior to the first administration of BI 691751 only in the test treatment period).		10 mg of BI 691751 in combination with multiple oral doses of itraconazole (only in the test treatment period after the introductory treatment with itraconazole alone over three days).		total subjects with BI 691751 treatment (either BI 691751 alone or IT+BI 691751)		combination of BI 691751, loading IT and BI 691751+ further IT.
All Cause Mortality
	BI 691751		Loading Itraconazole (IT)		BI 691751 + Further IT		Total BI 691751		Total on Treatment
	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 691751		Loading Itraconazole (IT)		BI 691751 + Further IT		Total BI 691751		Total on Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/20 (0%)		0/20 (0%)		0/20 (0%)		0/20 (0%)
Other (Not Including Serious) Adverse Events
	BI 691751		Loading Itraconazole (IT)		BI 691751 + Further IT		Total BI 691751		Total on Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/20 (0%)		0/20 (0%)		0/20 (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.