Relative Bioavailability of of Olodaterol and Ketoconazole

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01153711
• Collaborator: (none)
• Enrollment: 32
• Location: 1
• Arms: 2

Study Details

Study Description

Brief Summary

This clinical trial is intended to investigate a possible effect of the p-gp inhibitor ketoconazole on the bioavailability of olodaterol

Condition or Disease	Intervention/Treatment	Phase
Healthy; Pulmonary Disease, Chronic Obstructive	Drug: BI 1744; Drug: BI 1744; Drug: Ketoconazole; Drug: Ketoconazole	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 32 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Relative Bioavailability of 10 mcg Olodaterol (Solution for Inhalation Administered With the Respimat) at Steady State Alone or in Combination With Multiple Doses of 400 mg q.d. Ketoconazole (Tablet) in Healthy Male and Female Volunteers (an Open Label, Fixed Sequence, Phase I Study)
• Study Start Date: May 1, 2010
• Actual Primary Completion Date: Aug 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: BI 1744 10 mcg solution for oral inhalation	Drug: BI 1744; 10 mcg solution for oral inhalation; Drug: Ketoconazole; 400 mg tablet
Experimental: Ketoconazole 400 mg tablet	Drug: BI 1744; 10 mcg solution for oral inhalation; Drug: Ketoconazole; 400 mg tablet

Outcome Measures

Primary Outcome Measures

1. Area Under Curve From 0 to 1 Hour at Steady State (AUC0-1,ss) [Day 8 of period 1 and day 14 of period 2]

   AUC0-1,ss represents the area under the concentration curve of olodaterol in plasma from 0 to time t=1 hour at steady state, where t is defined as the latest time-point where at least 2/3 of the subjects in both treatment periods reveal quantifiable plasma concentrations of olodaterol. The geometric mean is actually the adjusted geometric mean. The geometric coefficient of variation (gCV) is the intra-individual gCV.

2. Maximum Concentration at Steady State (Cmax,ss) [Day 8 of period 1 and day 14 of period 2]

   Cmax,ss represents the maximum concentration of olodaterol and olodaterol glucuronide in plasma at steady state. The geometric mean is actually the adjusted geometric mean. The geometric coefficient of variation (gCV) is the intra-individual gCV.

Secondary Outcome Measures

1. Time From Dosing to the Maximum Concentration at Steady State (Tmax,ss) [Day 8 of period 1 and day 14 of period 2]

   tmax,ss represents the time from dosing to maximum concentration of olodaterol and olodaterol glucuronide in plasma at steady state.

2. Fraction of Urine Excretion From 0 to 24 Hours at Steady State (fe0-24,ss) [Day 8 of period 1 and day 14 of period 2]

   fe0-24,ss represents the fraction of olodaterol eliminated in urine from time point 0 to 24 hours after administration at steady state.

3. Amount of the Analyte Excreted in Urine From 0 to 24 Hours at Steady State (Ae0-24,ss) [Day 8 of period 1 and day 14 of period 2]

   Ae0-24,ss represents the amount of olodaterol and olodaterol glucuronide that is eliminated in urine from the time 0 to 24h after administration at steady state. The geometric mean is actually the adjusted geometric mean. The geometric coefficient of variation (gCV) is the intra-individual gCV.

4. Area Under Curve From 0 to 8 Hours at Steady State (AUC0-8,ss) [Day 8 of period 1 and day 14 of period 2]

   AUC0-8,ss represents the area under the concentration curve of olodaterol glucuronide in plasma from 0 to time t=8 at steady state, where t is defined as the latest time-point where at least 2/3 of the subjects in both treatment periods reveal quantifiable plasma concentrations of the analyte. The geometric mean is actually the adjusted geometric mean. The geometric coefficient of variation (gCV) is the intra-individual gCV.

5. Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG [First administration of trial medication until 6 days after last administration of trial medication]

   Clinical relevant abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG. New abnormal findings or worsening of baseline conditions were reported as treatment-induced Adverse Events.

6. Assessment of Tolerability by the Investigator [End of period 1 and end of period 2]

   The investigator assessed tolerability based on adverse events and the laboratory evaluation at the end-of-trial examination. The investigator classified the overall tolerability according to the categories 'good', 'satisfactory', 'not satisfactory', and 'bad'.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years to 50 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion criteria Healthy male and female volunteers

Exclusion criteria

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	1222.47.1 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.

• ClinicalTrials.gov Identifier: NCT01153711
• Other Study ID Numbers: 1222.47; 2010-018527-25
• First Posted: Jun 30, 2010
• Last Update Posted: Apr 30, 2014
• Last Verified: Mar 1, 2014

• Additional relevant MeSH terms: Pulmonary Disease, Chronic Obstructive; Ketoconazole

Study Results

Participant Flow

Arm/Group Title	Overall Study
Arm/Group Description	Total number of patients treated in the study. This was an open-label, fixed sequence, phase I trial in healthy volunteers. 32 subjects received in period 1 Olodaterol 10 microgram delivered by Respimat inhaler once daily for 8 days and in period 2 Olodaterol 10 microgram delivered by Respimat inhaler once daily plus 1 tablet Ketoconazole 400mg once daily, both for 14 days.
Period Title: Overall Study
STARTED	32
COMPLETED	32
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Overall Study
Arm/Group Description	Total number of patients treated in the study. This was an open-label, fixed sequence, phase I trial in healthy volunteers. 32 subjects received in period 1 Olodaterol 10 microgram delivered by Respimat inhaler once daily for 8 days and in period 2 Olodaterol 10 microgram delivered by Respimat inhaler once daily plus 1 tablet Ketoconazole 400mg once daily, both for 14 days.
Overall Participants	32
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	38.5 (7.2)
Sex: Female, Male (Count of Participants)
Female	12 37.5%
Male	20 62.5%

Outcome Measures

1. Primary Outcome

Title	Area Under Curve From 0 to 1 Hour at Steady State (AUC0-1,ss)
Description	AUC0-1,ss represents the area under the concentration curve of olodaterol in plasma from 0 to time t=1 hour at steady state, where t is defined as the latest time-point where at least 2/3 of the subjects in both treatment periods reveal quantifiable plasma concentrations of olodaterol. The geometric mean is actually the adjusted geometric mean. The geometric coefficient of variation (gCV) is the intra-individual gCV.
Time Frame	Day 8 of period 1 and day 14 of period 2

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) analysis set includes all evaluable subjects in the treated set providing at least 1 observation for at least 1 PK endpoint without important protocol violations.

Arm/Group Title	Olodaterol	Olodaterol Plus Ketoconazole
Arm/Group Description	Oral inhalation of Olodaterol 10 microgram solution with Respimat A5 device once daily for 8 days.	Oral inhalation of Olodaterol 10 microgram solution with Respimat A5 device once daily for 14 days plus Ketoconazole 400mg tablet administered orally once daily for 14 days.
Measure Participants	24	31
Geometric Mean (Geometric Coefficient of Variation) [Picogram*hours/milliliter]	2.512 (16.4)	4.231 (16.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol, Olodaterol Plus Ketoconazole
	Comments	Ratio Olodaterol plus Ketoconazole and Olodaterol
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Relative bioavailability
Statistical Test of Hypothesis	p-Value	1.0000
	Comments	P-value for ratio outside interval 0.8-1.25
	Method	ANOVA
	Comments	Adjusted geometric mean ratio
Method of Estimation	Estimation Parameter	Adjusted geometric mean ratio
	Estimated Value	168.4
	Confidence Interval	(2-Sided) 90%; 155.5 to 182.4
	Parameter Dispersion	Type: Standard Deviation; Value: 16.4
	Estimation Comments	The standard deviation is actually the geometric coefficient of variation

2. Primary Outcome

Title	Maximum Concentration at Steady State (Cmax,ss)
Description	Cmax,ss represents the maximum concentration of olodaterol and olodaterol glucuronide in plasma at steady state. The geometric mean is actually the adjusted geometric mean. The geometric coefficient of variation (gCV) is the intra-individual gCV.
Time Frame	Day 8 of period 1 and day 14 of period 2

Outcome Measure Data

Analysis Population Description

PK analysis set with evaluable data for this endpoint.

Arm/Group Title	Olodaterol	Olodaterol Plus Ketoconazole
Arm/Group Description	Oral inhalation of Olodaterol 10 microgram solution with Respimat A5 device once daily for 8 days.	Oral inhalation of Olodaterol 10 microgram solution with Respimat A5 device once daily for 14 days plus Ketoconazole 400mg tablet administered orally once daily for 14 days.
Measure Participants	32	32
Olodaterol (N=26;31)	3.113 (16.8)	5.169 (16.8)
Olodaterol glucuronide (N=32;32)	5.125 (14.7)	5.465 (14.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol, Olodaterol Plus Ketoconazole
	Comments	Ratio Olodaterol plus Ketoconazole and Olodaterol for the category Olodaterol
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Relative bioavailability
Statistical Test of Hypothesis	p-Value	1.0000
	Comments	P-value for ratio outside 0.8-1.25
	Method	ANOVA
	Comments	Adjusted geometric mean ratio
Method of Estimation	Estimation Parameter	Adjusted geometric mean ratio
	Estimated Value	166.1
	Confidence Interval	(2-Sided) 90%; 153.6 to 179.6
	Parameter Dispersion	Type: Standard Deviation; Value: 16.8
	Estimation Comments	The standard deviation is actually the geometric coefficient of variation

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Olodaterol, Olodaterol Plus Ketoconazole
	Comments	Ratio Olodaterol plus Ketoconazole and Olodaterol for the category Olodaterol glucuronide
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Relative bioavailability
Statistical Test of Hypothesis	p-Value	0.0001
	Comments	P-value for ratio outside 0.8-1.25
	Method	ANOVA
	Comments	Adjusted geometric mean ratio
Method of Estimation	Estimation Parameter	Adjusted geometric mean ratio
	Estimated Value	106.63
	Confidence Interval	(2-Sided) 90%; 100.211 to 113.463
	Parameter Dispersion	Type: Standard Deviation; Value: 14.7
	Estimation Comments	The standard deviation is actually the geometric coefficient of variation

3. Secondary Outcome

Title	Time From Dosing to the Maximum Concentration at Steady State (Tmax,ss)
Description	tmax,ss represents the time from dosing to maximum concentration of olodaterol and olodaterol glucuronide in plasma at steady state.
Time Frame	Day 8 of period 1 and day 14 of period 2

Outcome Measure Data

Analysis Population Description

PK analysis set with evaluable data for this endpoint.

Arm/Group Title	Olodaterol	Olodaterol Plus Ketoconazole
Arm/Group Description	Oral inhalation of Olodaterol 10 microgram solution with Respimat A5 device once daily for 8 days.	Oral inhalation of Olodaterol 10 microgram solution with Respimat A5 device once daily for 14 days plus Ketoconazole 400mg tablet administered orally once daily for 14 days.
Measure Participants	32	32
Olodaterol (N=26;31)	0.250	0.333
Olodaterol glucuronide (N=32;32)	4.00	3.01

4. Secondary Outcome

Title	Fraction of Urine Excretion From 0 to 24 Hours at Steady State (fe0-24,ss)
Description	fe0-24,ss represents the fraction of olodaterol eliminated in urine from time point 0 to 24 hours after administration at steady state.
Time Frame	Day 8 of period 1 and day 14 of period 2

Outcome Measure Data

Analysis Population Description

PK analysis set with evaluable data for this endpoint.

Arm/Group Title	Olodaterol	Olodaterol Plus Ketoconazole
Arm/Group Description	Oral inhalation of Olodaterol 10 microgram solution with Respimat A5 device once daily for 8 days.	Oral inhalation of Olodaterol 10 microgram solution with Respimat A5 device once daily for 14 days plus Ketoconazole 400mg tablet administered orally once daily for 14 days.
Measure Participants	32	32
Geometric Mean (Geometric Coefficient of Variation) [Percentage]	4.29 (35.2)	6.19 (35.9)

5. Secondary Outcome

Title	Amount of the Analyte Excreted in Urine From 0 to 24 Hours at Steady State (Ae0-24,ss)
Description	Ae0-24,ss represents the amount of olodaterol and olodaterol glucuronide that is eliminated in urine from the time 0 to 24h after administration at steady state. The geometric mean is actually the adjusted geometric mean. The geometric coefficient of variation (gCV) is the intra-individual gCV.
Time Frame	Day 8 of period 1 and day 14 of period 2

Outcome Measure Data

Analysis Population Description

PK analysis set with evaluable data for this endpoint.

Arm/Group Title	Olodaterol	Olodaterol Plus Ketoconazole
Arm/Group Description	Oral inhalation of Olodaterol 10 microgram solution with Respimat A5 device once daily for 8 days.	Oral inhalation of Olodaterol 10 microgram solution with Respimat A5 device once daily for 14 days plus Ketoconazole 400mg tablet administered orally once daily for 14 days.
Measure Participants	32	32
Olodaterol	428.972 (17.8)	618.716 (17.8)
Olodaterol glucuronide	445.266 (18.9)	591.620 (18.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol, Olodaterol Plus Ketoconazole
	Comments	Ratio Olodaterol plus Ketoconazole and Olodaterol for the category Olodaterol
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Relative bioavailability
Statistical Test of Hypothesis	p-Value	0.9986
	Comments	P-value for ratio outside 0.8-1.25
	Method	ANOVA
	Comments	Adjusted geometric mean ratio
Method of Estimation	Estimation Parameter	Adjusted geometric mean ratio
	Estimated Value	144.23
	Confidence Interval	(2-Sided) 90%; 133.853 to 155.417
	Parameter Dispersion	Type: Standard Deviation; Value: 17.8
	Estimation Comments	The standard deviation is actually the geometric coefficient of variation

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Olodaterol, Olodaterol Plus Ketoconazole
	Comments	Ratio Olodaterol plus Ketoconazole and Olodaterol for the category Olodaterol glucuronide
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Relative bioavailability
Statistical Test of Hypothesis	p-Value	0.8991
	Comments	P-value for ratio outside 0.8-1.25
	Method	ANOVA
	Comments	Adjusted geometric mean ratio
Method of Estimation	Estimation Parameter	Adjusted geometric mean ratio
	Estimated Value	132.87
	Confidence Interval	(2-Sided) 90%; 122.732 to 143.843
	Parameter Dispersion	Type: Standard Deviation; Value: 18.9
	Estimation Comments	The standard deviation is actually the geometric coefficient of variation

6. Secondary Outcome

Title	Area Under Curve From 0 to 8 Hours at Steady State (AUC0-8,ss)
Description	AUC0-8,ss represents the area under the concentration curve of olodaterol glucuronide in plasma from 0 to time t=8 at steady state, where t is defined as the latest time-point where at least 2/3 of the subjects in both treatment periods reveal quantifiable plasma concentrations of the analyte. The geometric mean is actually the adjusted geometric mean. The geometric coefficient of variation (gCV) is the intra-individual gCV.
Time Frame	Day 8 of period 1 and day 14 of period 2

Outcome Measure Data

Analysis Population Description

PK analysis set with evaluable data for this endpoint.

Arm/Group Title	Olodaterol	Olodaterol Plus Ketoconazole
Arm/Group Description	Oral inhalation of Olodaterol 10 microgram solution with Respimat A5 device once daily for 8 days.	Oral inhalation of Olodaterol 10 microgram solution with Respimat A5 device once daily for 14 days plus Ketoconazole 400mg tablet administered orally once daily for 14 days.
Measure Participants	25	30
Geometric Mean (Geometric Coefficient of Variation) [Picogram*hours/milliliter]	27.868 (17.9)	28.076 (17.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olodaterol, Olodaterol Plus Ketoconazole
	Comments	Ratio Olodaterol plus Ketoconazole and Olodaterol
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Relative bioavailability
Statistical Test of Hypothesis	p-Value	0.0001
	Comments	P-value for ratio outside interval 0.8-1.25
	Method	ANOVA
	Comments	Adjusted geometric mean ratio
Method of Estimation	Estimation Parameter	Adjusted geometric mean ratio
	Estimated Value	100.75
	Confidence Interval	(2-Sided) 90%; 92.534 to 109.692
	Parameter Dispersion	Type: Standard Deviation; Value: 17.9
	Estimation Comments	The standard deviation is actually the geometric coefficient of variation

7. Secondary Outcome

Title	Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG
Description	Clinical relevant abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinalysis and ECG. New abnormal findings or worsening of baseline conditions were reported as treatment-induced Adverse Events.
Time Frame	First administration of trial medication until 6 days after last administration of trial medication

Outcome Measure Data

Analysis Population Description

Treated set (TS) - Treated set includes all patients who were dispensed trial medication and were documented to have taken at least 1 dose of investigational treatment.

Arm/Group Title	Olodaterol	Olodaterol Plus Ketoconazole
Arm/Group Description	Oral inhalation of Olodaterol 10 microgram solution with Respimat A5 device once daily for 8 days.	Oral inhalation of Olodaterol 10 microgram solution with Respimat A5 device once daily for 14 days plus Ketoconazole 400mg tablet administered orally once daily for 14 days.
Measure Participants	32	32
Number [participants]	0 0%	0 NaN

8. Secondary Outcome

Title	Assessment of Tolerability by the Investigator
Description	The investigator assessed tolerability based on adverse events and the laboratory evaluation at the end-of-trial examination. The investigator classified the overall tolerability according to the categories 'good', 'satisfactory', 'not satisfactory', and 'bad'.
Time Frame	End of period 1 and end of period 2

Outcome Measure Data

Analysis Population Description

TS

Arm/Group Title	Olodaterol	Olodaterol Plus Ketoconazole
Arm/Group Description	Oral inhalation of Olodaterol 10 microgram solution with Respimat A5 device once daily for 8 days.	Oral inhalation of Olodaterol 10 microgram solution with Respimat A5 device once daily for 14 days plus Ketoconazole 400mg tablet administered orally once daily for 14 days.
Measure Participants	32	32
Good	32 100%	32 NaN
Satisfactory	0 0%	0 NaN
Not satisfactory	0 0%	0 NaN
Bad	0 0%	0 NaN
Not assessable	0 0%	0 NaN

Adverse Events

Time Frame	First administration of trial medication until 6 days after last administration of trial medication
Arm/Group Title	Olodaterol		Olodaterol Plus Ketoconazole
Arm/Group Description	Oral inhalation of Olodaterol 10 microgram solution with Respimat A5 device once daily for 8 days.		Oral inhalation of Olodaterol 10 microgram solution with Respimat A5 device once daily for 14 days plus Ketoconazole 400mg tablet administered orally once daily for 14 days.
All Cause Mortality
	Olodaterol		Olodaterol Plus Ketoconazole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Olodaterol		Olodaterol Plus Ketoconazole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/32 (0%)		0/32 (0%)
Other (Not Including Serious) Adverse Events
	Olodaterol		Olodaterol Plus Ketoconazole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/32 (15.6%)		9/32 (28.1%)
Gastrointestinal disorders
Diarrhoea	0/32 (0%)		2/32 (6.3%)
Dry mouth	1/32 (3.1%)		2/32 (6.3%)
Nausea	0/32 (0%)		5/32 (15.6%)
Immune system disorders
Allergy to arthropod bite	2/32 (6.3%)		0/32 (0%)
Nervous system disorders
Headache	2/32 (6.3%)		1/32 (3.1%)
Tremor	0/32 (0%)		2/32 (6.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Any publication of the result of this trial must be consistent with the Boehringer Ingelheim publication policy. The rights of the investigator and of the sponsor with regard to publication of the results of this trial are described in the investigator contract.