Effect of Multiple Doses of Itraconazole on the Pharmacokinetics of a Single Oral Dose of BI 1026706 in Healthy Male Subjects

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02513446
• Collaborator: (none)
• Enrollment: 16
• Location: 1
• Arms: 2
• Actual Duration (Months): 1.7
• Patients Per Site Per Month: 9.4

Study Details

Study Description

Brief Summary

The primary objective of this trial is to investigate the effect of multiple doses of itraconazole on the pharmacokinetics of BI 1026706 given as single dose. The assessment of safety and tolerability of BI 1026706 is an additional objective of this trial. Furthermore, the pharmacokinetics of the metabolite BI 1072668 will be explored.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: BI 1026706; Drug: Itraconazole	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 16 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Effect of Multiple Doses of Itraconazole on the Pharmacokinetics of a Single Oral Dose of BI 1026706 in Healthy Male Subjects (an Open-label, Randomised, Two-period, Two-sequence Crossover Study)
• Actual Study Start Date: Sep 29, 2015
• Actual Primary Completion Date: Nov 14, 2015
• Actual Study Completion Date: Nov 20, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: BI 1026706 Single dose	Drug: BI 1026706; Single dose of BI 1026706 on Day 1
Experimental: BI 1026706 + Itraconazole 7 days of itraconazole treatment combined with a single dose of 1026706 on day 4	Drug: BI 1026706; Single dose of BI 1026706 on Day 1; Drug: Itraconazole; 7 days of itraconazole treatment combined with a single dose of BI 1026706 on the fourth day

Outcome Measures

Primary Outcome Measures

1. Area Under the Curve of BI 1026706 From 0 to the Last Quantifiable Data Point (AUC0-tz) [-3 hours (h) before drug administration and 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 47h, 71h and 95h after drug administration]

   Area under the concentration-time curve of BI 1026706 in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz)

2. Maximum Concentration of BI 1026706 (Cmax) [0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 47h, 71h and 95h after drug administration]

   Maximum measured concentration of BI 1026706 in plasma (Cmax)

Secondary Outcome Measures

1. Area Under the Curve of BI 1026706 From 0 Extrapolated to Infinity (AUC0-inf) [-3 hours (h) before drug administration and 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 47h, 71h and 95h after drug administration]

   Area under the concentration-time curve of BI 1026706 in plasma over the time interval from 0 extrapolated to infinity (AUC0-inf)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: Yes

Inclusion criteria:

• Healthy male subjects according to the investigators assessment, based on a complete medical history including a physical examination, vital signs (BP, PR), 12-lead ECG, and clinical laboratory tests

• Age of 18 to 55 years (incl.)

• BMI of 18.5 to 29.9 kg/m2 (incl.)

• Signed and dated written informed consent prior to admission to the study in accordance with GCP and local legislation

Exclusion criteria:

• Any finding in the medical examination (including BP, PR or ECG) is deviating from normal and judged as clinically relevant by the investigator

• Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the range of 50 to 90 bpm

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

• Any evidence of a concomitant disease judged as clinically relevant by the investigator

• Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders

• Surgery of the gastrointestinal tract that could interfere with the pharmacokinetics of the trial medication (except appendectomy and simple hernia repair)

• Diseases of the central nervous system (such as epilepsy), other relevant neurological or psychiatric disorders

• History of relevant orthostatic hypotension, fainting spells, or blackouts

• Chronic or relevant acute infections

• History of relevant allergy or hypersensitivity (including allergy to the trial medication or its excipients)

• Intake of drugs with a long half-life (more than 24 h) within 30 days or less than 10 half-lives of the respective drug prior to administration of trial medication

• Within 10 days prior to administration of trial medication, use of drugs that might reasonably influence the results of the trial or that might prolong the QT/QTc interval

• Participation in another trial where an investigational drug has been administered within 60 days prior to planned administration of trial medication

• Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)

• Inability to refrain from smoking during in-house confinement at trial site

• Alcohol abuse (consumption of more than 30 g per day)

• Drug abuse or positive drug screening

• Blood donation of more than 100 mL within 30 days prior to administration of trial medication or intended donation during the trial

• Intention to perform excessive physical activities within one week prior to administration of trial medication or during the trial

• Inability to comply with dietary regimen of trial site

• A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are repeatedly greater than 450 ms) or any other relevant ECG finding at screening

• A history of additional risk factors for Torsades de Pointes (such as heart failure, hypokalaemia, or family history of Long QT Syndrome)

• Subject is assessed as unsuitable for inclusion by the investigator, for instance, because the subject is considered not able to understand and comply with study requirements, or because he has a condition that would not allow safe participation in the study

In addition, the following trial-specific exclusion criteria apply:

• Liver enzyme (ALT, AST, GGT) values above upper limit of normal at the screening examination

• Galactose intolerance, lactase deficiency, or glucose/galactose malabsorption

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	1320.20.1 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: NCT02513446
• Other Study ID Numbers: 1320.20; 2015-002140-14
• First Posted: Jul 31, 2015
• Last Update Posted: Mar 29, 2019
• Last Verified: Dec 1, 2018

• Additional relevant MeSH terms: Itraconazole

Study Results

Participant Flow

Pre-assignment Detail	An open-label, randomised, two-period, two-sequence crossover study with healthy male subjects

Arm/Group Title	Sequence RT	Sequence TR
Arm/Group Description	Treatment R (BI 1026706 alone): Oral administration of a single dose of 25 mg BI 1026706 film-coated tablets was given on Day 1. Treatment T (itraconazole + BI 1026706): Itraconazole (200 mg) as capsules was given orally twice daily as a loading dose on Day -3 and once daily from Day -2 to Day 4 (7 days in total). A single dose of 25 mg BI 1026706 was given orally on the fourth day (Day 1) of the itraconazole treatment (1 h after the itraconazole administration on the respective day). The single dose administrations of BI 1026706 in treatments R and T were separated by a wash-out period of at least 10 days.	Treatment T (itraconazole + BI 1026706): Itraconazole (200 mg) as capsules was given orally twice daily as a loading dose on Day -3 and once daily from Day -2 to Day 4 (7 days in total). A single dose of 25 mg BI 1026706 was given orally on the fourth day (Day 1) of the itraconazole treatment (1 h after the itraconazole administration on the respective day). Treatment R (BI 1026706 alone): Oral administration of a single dose of 25 mg BI 1026706 film-coated tablets was given on Day 1. The single dose administrations of BI 1026706 in treatments T and R were separated by a wash-out period of at least 10 days.
Period Title: Period 1
STARTED	8	8
COMPLETED	8	8
NOT COMPLETED	0	0
Period Title: Period 1
STARTED	8	8
COMPLETED	8	8
NOT COMPLETED	0	0
Period Title: Period 1
STARTED	8	8
COMPLETED	8	8
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Sequence RT	Sequence TR	Total
Arm/Group Description	Treatment R (BI 1026706 alone): Oral administration of a single dose of 25 mg BI 1026706 film-coated tablets was given on Day 1. Treatment T (itraconazole + BI 1026706): Itraconazole (200 mg) as capsules was given orally twice daily as a loading dose on Day -3 and once daily from Day -2 to Day 4 (7 days in total). A single dose of 25 mg BI 1026706 was given orally on the fourth day (Day 1) of the itraconazole treatment (1 h after the itraconazole administration on the respective day). The single dose administrations of BI 1026706 in treatments R and T were separated by a wash-out period of at least 10 days.	Treatment T (itraconazole + BI 1026706): Itraconazole (200 mg) as capsules was given orally twice daily as a loading dose on Day -3 and once daily from Day -2 to Day 4 (7 days in total). A single dose of 25 mg BI 1026706 was given orally on the fourth day (Day 1) of the itraconazole treatment (1 h after the itraconazole administration on the respective day). Treatment R (BI 1026706 alone): Oral administration of a single dose of 25 mg BI 1026706 film-coated tablets was given on Day 1. The single dose administrations of BI 1026706 in treatments T and R were separated by a wash-out period of at least 10 days.	Total of all reporting groups
Overall Participants	8	8	16
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	37.9 (10.2)	33.0 (8.1)	35.4 (9.3)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	8 100%	8 100%	16 100%

Outcome Measures

1. Primary Outcome

Title	Area Under the Curve of BI 1026706 From 0 to the Last Quantifiable Data Point (AUC0-tz)
Description	Area under the concentration-time curve of BI 1026706 in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz)
Time Frame	-3 hours (h) before drug administration and 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 47h, 71h and 95h after drug administration

Outcome Measure Data

Analysis Population Description

Pharmacokinetic set (PKS) included all treated subjects that provided at least 1 primary or secondary pharmacokinetic parameter that was not excluded due to a protocol violation relevant to the evaluation of pharmacokinetics or due to pharmacokinetic non-evaluability..

Arm/Group Title	Treatment R (BI 1026706 Alone)	Treatment T (Itraconazole + BI 1026706)
Arm/Group Description	Oral administration of single dose of 25 mg BI 1026706 was given on Day 1.	Itraconazole (200 mg) was given orally twice daily as a loading dose on Day -3 and once daily from Day -2 to Day 4 (7 days in total). A single dose of 25 mg BI 1026706 was given orally on the fourth day (Day 1) of the itraconazole treatment (1 h after the itraconazole administration on the respective day).
Measure Participants	16	15
Geometric Mean (Geometric Coefficient of Variation) [nmol*h/L]	921 (47.8)	1580 (55.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment R (BI 1026706 Alone), Treatment T (Itraconazole + BI 1026706)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted gMean T/R ratio
	Estimated Value	176.1
	Confidence Interval	(2-Sided) 90%; 160.5 to 193.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Ratio of the treatment adjusted geometric means (gMean) of (T) versus (R).

2. Primary Outcome

Title	Maximum Concentration of BI 1026706 (Cmax)
Description	Maximum measured concentration of BI 1026706 in plasma (Cmax)
Time Frame	0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 47h, 71h and 95h after drug administration

Outcome Measure Data

Analysis Population Description

PKS

Arm/Group Title	Treatment R (BI 1026706 Alone)	Treatment T (Itraconazole + BI 1026706)
Arm/Group Description	Oral administration of single dose of 25 mg BI 1026706 was given on Day 1.	Itraconazole (200 mg) was given orally twice daily as a loading dose on Day -3 and once daily from Day -2 to Day 4 (7 days in total). A single dose of 25 mg BI 1026706 was given orally on the fourth day (Day 1) of the itraconazole treatment (1 h after the itraconazole administration on the respective day).
Measure Participants	16	15
Geometric Mean (Geometric Coefficient of Variation) [nmol/L]	206 (48.9)	279 (62.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment R (BI 1026706 Alone), Treatment T (Itraconazole + BI 1026706)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted gMean T/R ratio
	Estimated Value	136.5
	Confidence Interval	(2-Sided) 90%; 109.9 to 169.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	Ratio of the treatment adjusted geometric means (gMean) of (T) versus (R).

3. Secondary Outcome

Title	Area Under the Curve of BI 1026706 From 0 Extrapolated to Infinity (AUC0-inf)
Description	Area under the concentration-time curve of BI 1026706 in plasma over the time interval from 0 extrapolated to infinity (AUC0-inf)
Time Frame	-3 hours (h) before drug administration and 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 47h, 71h and 95h after drug administration

Outcome Measure Data

Analysis Population Description

PKS

Arm/Group Title	Treatment R (BI 1026706 Alone)	Treatment T (Itraconazole + BI 1026706)
Arm/Group Description	Oral administration of single dose of 25 mg BI 1026706 was given on Day 1.	Itraconazole (200 mg) was given orally twice daily as a loading dose on Day -3 and once daily from Day -2 to Day 4 (7 days in total). A single dose of 25 mg BI 1026706 was given orally on the fourth day (Day 1) of the itraconazole treatment (1 h after the itraconazole administration on the respective day).
Measure Participants	16	15
Geometric Mean (Geometric Coefficient of Variation) [nmol*h/L]	943 (46.9)	1600 (54.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment R (BI 1026706 Alone), Treatment T (Itraconazole + BI 1026706)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted gMean T/R ratio
	Estimated Value	174.8
	Confidence Interval	(2-Sided) 90%; 159.1 to 192.0
	Parameter Dispersion	Type: Value:
	Estimation Comments	Ratio of the treatment adjusted geometric means (gMean) of (T) versus (R).

Adverse Events

Time Frame	From first drug administration through the residual effect period (REP) until the individual subject's end-of-trial; Up to 14 days
Arm/Group Title	Treatment R (BI 1026706 Alone)		Treatment T (Itraconazole + BI 1026706)		Total
Arm/Group Description	Oral administration of single dose of 25 mg BI 1026706 was given on Day 1.		Itraconazole (200 mg) was given orally twice daily as a loading dose on Day -3 and once daily from Day -2 to Day 4 (7 days in total). A single dose of 25 mg BI 1026706 was given orally on the fourth day (Day 1) of the itraconazole treatment (1 h after the itraconazole administration on the respective day).		Total
All Cause Mortality
	Treatment R (BI 1026706 Alone)		Treatment T (Itraconazole + BI 1026706)		Total
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Treatment R (BI 1026706 Alone)		Treatment T (Itraconazole + BI 1026706)		Total
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/16 (0%)		0/16 (0%)		0/16 (0%)
Other (Not Including Serious) Adverse Events
	Treatment R (BI 1026706 Alone)		Treatment T (Itraconazole + BI 1026706)		Total
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/16 (18.8%)		4/16 (25%)		5/16 (31.3%)
Gastrointestinal disorders
Dyspepsia	0/16 (0%)		1/16 (6.3%)		1/16 (6.3%)
Nausea	1/16 (6.3%)		0/16 (0%)		1/16 (6.3%)
Infections and infestations
Nasopharyngitis	1/16 (6.3%)		1/16 (6.3%)		2/16 (12.5%)
Nervous system disorders
Headache	1/16 (6.3%)		2/16 (12.5%)		2/16 (12.5%)

Limitations/Caveats

[Not Specified]

More Information

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.