Investigation of Drug-drug Interaction of Nintedanib and Ketoconazole in Healthy Male Volunteers

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01679613
• Collaborator: (none)
• Enrollment: 34
• Location: 1
• Arms: 4
• Duration (Months): 2
• Patients Per Site Per Month: 17

Study Details

Study Description

Brief Summary

The objective of the current study is to investigate the relative bioavailability of a single dose of nintedanib low or high dose with and without coadministration of ketoconazole at steady state

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: Nintedanib; Drug: Nintedanib; Drug: Ketoconazole; Drug: Nintedanib; Drug: Nintedanib; Drug: Ketoconazole	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 34 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Relative Bioavailability of Nintedanib Given Alone and in Combination With Ketoconazole at Steady State in Healthy Male Volunteers (an Open-label, Randomised, Two-way Cross-over Clinical Phase I Study)
• Study Start Date: Sep 1, 2012
• Actual Primary Completion Date: Nov 1, 2012
• Actual Study Completion Date: Nov 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 Nintedanib (Reference) single dose, oral with 240 ml water	Drug: Nintedanib; low dose oral administration
Experimental: 2 Nintedanib + Ketoconazole (Test) Nintedanib single dose, Ketoconazole steady state, oral with 240 ml water	Drug: Ketoconazole; oral administration; Drug: Nintedanib; low dose oral administration
Experimental: 3 Nintedanib (Reference) single dose, oral with 240 ml water	Drug: Nintedanib; low or medium dose depending on pilot part
Experimental: 4 Nintedanib + Ketoconazole (Test) Nintedanib single dose, Ketoconazole steady state, oral with 240 ml water	Drug: Nintedanib; low or medium dose depending on pilot part; Drug: Ketoconazole; oral administration

Outcome Measures

Primary Outcome Measures

1. Area Under the Curve From 0 Extrapolated to Infinity (AUC0-∞) [1 hour (h) before drug administration and 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 6h, 8h, 10h, 12h, 15h, 24h, 36h, 48h and 72h after the drug administration]

   AUC0-∞ represents the Area under the concentration-time curve of nintedanib in plasma over the time interval from 0 extrapolated to infinity For this endpoint, the "measured values" show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities

2. Maximum Measured Concentration (Cmax) [1 hour (h) before drug administration and 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 6h, 8h, 10h, 12h, 15h, 24h, 36h, 48h and 72h after the drug administration]

   Cmax represents the maximum concentration of nintedanib in plasma For this endpoint, the "measured values" show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities

Secondary Outcome Measures

1. Area Under the Curve From 0 to the Last Quantifiable Concentration (AUC0-tz) [1 hour (h) before drug administration and 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 6h, 8h, 10h, 12h, 15h, 24h, 36h, 48h and 72h after the drug administration]

   AUC0-tz represents the area under the plasma concentration-time curve of nintedanib from time 0 to the last quantifiable nintedanib plasma concentration. For this endpoint, the "measured values" show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 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	1199.161.1 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: NCT01679613
• Other Study ID Numbers: 1199.161; 2012-001009-26
• First Posted: Sep 6, 2012
• Last Update Posted: Nov 27, 2014
• Last Verified: Nov 1, 2014

• Additional relevant MeSH terms: Ketoconazole; Nintedanib

Study Results

Participant Flow

Pre-assignment Detail	This was a randomised, open-label trial with a 2-way cross-over Pilot part, followed by a 2-way cross-over Main part. Subjects participated either in the Pilot part with 2 treatment sequences (A_B and B_A) or in the Main part with treatment sequences (C_D and D_C) with wash-out period of at least 14 days between each sequence.

Arm/Group Title	Nintedanib (Pilot Part)/ Nintedanib+Ketoconazole (Pilot Part)	Nintedanib+Ketoconazole (Pilot Part)/ Nintedanib (Pilot Part)	Nintedanib (Main Part)/ Nintedanib+Ketoconazole (Main Part)	Nintedanib+Ketoconazole (Main Part)/ Nintedanib (Main Part)
Arm/Group Description	Nintedanib 50mg was given as a single dose (Treatment A). Following a wash out period of at least 14 days, ketoconazole 400mg was given once daily for three days and nintedanib 50 mg was given as a single dose 1 hour (h) after the ketoconazole administration with ketoconazole under steady-state conditions (Treatment B)	Ketoconazole 400mg was given once daily for three days and nintedanib 50 mg was given as a single dose 1 hour (h) after the ketoconazole administration with ketoconazole under steady-state conditions (Treatment B). Following a wash out period of at least 14 days, nintedanib 50mg was given as a single dose (Treatment A).	Based on the results from the Pilot part, nintedanib 50mg was given as a single dose (Treatment C). Following a wash out period of at least 14 days, ketoconazole 400mg was given once daily for 3 days followed by administration of nintedanib 50mg as a single dose 1h after administration of ketoconazole, based on the results from the Pilot part. Nintedanib administration was done under steady state ketoconazole (Treatment D)	Ketoconazole 400mg was given once daily for 3 days followed by administration of nintedanib 50mg as a single dose 1h after administration of ketoconazole, based on the results from the Pilot part. Nintedanib administration was done under steady state ketoconazole (Treatment D). Following a wash out period of at least 14 days, nintedanib 50mg was given as a single dose, based on the results from the Pilot part (Treatment C).
Period Title: Overall Study
STARTED	4	4	13	13
Received Nintedanib (Pilot)	4	3	0	0
Received Nintedanib+Ketoconazole (Pilot)	4	4	0	0
Received Nintedanib (Main)	0	0	13	11
Received Nintedanib+Ketoconazole (Main)	0	0	13	13
COMPLETED	4	3	11	11
NOT COMPLETED	0	1	2	2

Baseline Characteristics

Arm/Group Title	Overall Study
Arm/Group Description	This was a randomised, open-label trial in healthy male subjects with a 2-way cross-over Pilot part, followed by a 2-way cross-over Main part. Subjects participated either in the Pilot part with 2 treatments (A and B) given in 1 of the 2 treatment sequences (A_B and B_A) or in the Main part with also 2 treatments (C and D) given in 1 of the 2 treatment sequences (C_D and D_C). Nintedanib administrations of the 2 respective treatments (A and B or C and D) were to be separated by a wash-out period of at least 14 days. The Pilot part was separated from the Main part by at least 3 weeks to allow for interim analysis
Overall Participants	34
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	35.9 (10.7)
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	34 100%

Outcome Measures

1. Primary Outcome

Title	Area Under the Curve From 0 Extrapolated to Infinity (AUC0-∞)
Description	AUC0-∞ represents the Area under the concentration-time curve of nintedanib in plasma over the time interval from 0 extrapolated to infinity For this endpoint, the "measured values" show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities
Time Frame	1 hour (h) before drug administration and 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 6h, 8h, 10h, 12h, 15h, 24h, 36h, 48h and 72h after the drug administration

Outcome Measure Data

Analysis Population Description

The treated set (TS) includes all subjects who were dispensed study medication and were documented to have taken at least one dose of study medication (nintedanib or ketoconazole).

Arm/Group Title	Nintedanib	Nintedanib + Ketoconazole
Arm/Group Description	In both parts (Pilot and Main) 50 mg of nintedanib were given as a single dose on Day 1. In the Main part, alternatively, a single dose of 100mg could have been given. The chosen dosing scheme depended on the increase in nintedanib exposure due to ketoconazole co-administration observed in the Pilot part.	In both parts (Pilot and Main) of the study 400 mg ketoconazole were given once daily for 3 days starting on Day -2 and 50 mg nintedanib were given as a single dose 1 h after the ketoconazole administration on Day 1, with ketoconazole under steady-state conditions. In the Main part, alternatively, a single dose of 100mg could have been given 1 h after the ketoconazole administration or 4 h before the ketoconazole administration on Day 1. The chosen dosing scheme depended on the increase in nintedanib exposure due to ketoconazole co-administration observed in the Pilot part.
Measure Participants	31	29
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	38.6 (42.5)	61.3 (40.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nintedanib, Nintedanib + Ketoconazole
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.0000
	Comments	p-value for ratio outside interval 0.8 - 1.25
	Method	ANOVA
	Comments	The model includes fixed effects for sequence, period, and treatment. Subjects within sequences is included as random effect.
Method of Estimation	Estimation Parameter	Geometric Mean Ratio in percentage
	Estimated Value	160.48
	Confidence Interval	(2-Sided) 90%; 148.245 to 173.736
	Parameter Dispersion	Type: Standard Deviation; Value: 17.9
	Estimation Comments	Ratio calculated as nintedanib+ketoconazole divided by nintedanib (in %). The standard deviation is actually the geometric coefficient of variation (gCV).

2. Primary Outcome

Title	Maximum Measured Concentration (Cmax)
Description	Cmax represents the maximum concentration of nintedanib in plasma For this endpoint, the "measured values" show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities
Time Frame	1 hour (h) before drug administration and 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 6h, 8h, 10h, 12h, 15h, 24h, 36h, 48h and 72h after the drug administration

Outcome Measure Data

Analysis Population Description

TS

Arm/Group Title	Nintedanib	Nintedanib + Ketoconazole
Arm/Group Description	In both parts (Pilot and Main) 50 mg of nintedanib were given as a single dose on Day 1. In the Main part, alternatively, a single dose of 100mg could have been given. The chosen dosing scheme depended on the increase in nintedanib exposure due to ketoconazole co-administration observed in the Pilot part.	In both parts (Pilot and Main) of the study 400 mg ketoconazole were given once daily for 3 days starting on Day -2 and 50 mg nintedanib were given as a single dose 1 h after the ketoconazole administration on Day 1, with ketoconazole under steady-state conditions. In the Main part, alternatively, a single dose of 100mg could have been given 1 h after the ketoconazole administration or 4 h before the ketoconazole administration on Day 1. The chosen dosing scheme depended on the increase in nintedanib exposure due to ketoconazole co-administration observed in the Pilot part.
Measure Participants	31	29
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	4.19 (71.0)	7.13 (44.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nintedanib, Nintedanib + Ketoconazole
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.0000
	Comments	p-value for ratio outside interval 0.8 - 1.25
	Method	ANOVA
	Comments	The model includes fixed effects for sequence, period, and treatment. Subjects within sequences is included as random effect.
Method of Estimation	Estimation Parameter	Geometric Mean Ratio in percentage
	Estimated Value	179.62
	Confidence Interval	(2-Sided) 90%; 157.557 to 204.779
	Parameter Dispersion	Type: Standard Deviation; Value: 29.9
	Estimation Comments	The standard deviation is actually the gCV (in %). Ratio calculated as nintedanib+ketoconazole divided by nintedanib

3. Secondary Outcome

Title	Area Under the Curve From 0 to the Last Quantifiable Concentration (AUC0-tz)
Description	AUC0-tz represents the area under the plasma concentration-time curve of nintedanib from time 0 to the last quantifiable nintedanib plasma concentration. For this endpoint, the "measured values" show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities
Time Frame	1 hour (h) before drug administration and 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 6h, 8h, 10h, 12h, 15h, 24h, 36h, 48h and 72h after the drug administration

Outcome Measure Data

Analysis Population Description

TS

Arm/Group Title	Nintedanib	Nintedanib + Ketoconazole
Arm/Group Description	In both parts (Pilot and Main) 50 mg of nintedanib were given as a single dose on Day 1. In the Main part, alternatively, a single dose of 100mg could have been given. The chosen dosing scheme depended on the increase in nintedanib exposure due to ketoconazole co-administration observed in the Pilot part.	In both parts (Pilot and Main) of the study 400 mg ketoconazole were given once daily for 3 days starting on Day -2 and 50 mg nintedanib were given as a single dose 1 h after the ketoconazole administration on Day 1, with ketoconazole under steady-state conditions. In the Main part, alternatively, a single dose of 100mg could have been given 1 h after the ketoconazole administration or 4 h before the ketoconazole administration on Day 1. The chosen dosing scheme depended on the increase in nintedanib exposure due to ketoconazole co-administration observed in the Pilot part.
Measure Participants	31	29
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	35.7 (47.8)	59.4 (40.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nintedanib, Nintedanib + Ketoconazole
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments	p-value for ratio outside interval 0.8 to 1.25
	Method	ANOVA
	Comments	The model includes fixed effects for sequence, period, and treatment. Subjects within sequences is included as random effect.
Method of Estimation	Estimation Parameter	Geometric Mean Ratio in percentage
	Estimated Value	168.09
	Confidence Interval	(2-Sided) 90%; 155.252 to 181.981
	Parameter Dispersion	Type: Standard Deviation; Value: 17.9
	Estimation Comments	The standard deviation is actually the gCV. Ratio calculated as nintedanib+ketoconazole divided by nintedanib (in %).

Adverse Events

Time Frame	From the first trial drug administration until 18 days after the last trial drug administration, up to 32 days.
Arm/Group Title	Ketoconazole		Nintedanib		Nintedanib + Ketoconazole
Arm/Group Description	In both parts (Pilot and Main) of the study 400 mg ketoconazole were given once daily for 3 days starting on Day -2		In both parts (Pilot and Main) 50 mg of nintedanib were given as a single dose on Day 1. In the Main part, alternatively, a single dose of 100mg could have been given. The chosen dosing scheme depended on the increase in nintedanib exposure due to ketoconazole co-administration observed in the Pilot part.		In both parts (Pilot and Main) of the study 400 mg ketoconazole were given once daily for 3 days starting on Day -2 and 50 mg nintedanib were given as a single dose 1 h after the ketoconazole administration on Day 1, with ketoconazole under steady-state conditions. In the Main part, alternatively, a single dose of 100mg could have been given 1 h after the ketoconazole administration or 4 h before the ketoconazole administration on Day 1. The chosen dosing scheme depended on the increase in nintedanib exposure due to ketoconazole co-administration observed in the Pilot part.
All Cause Mortality
	Ketoconazole		Nintedanib		Nintedanib + Ketoconazole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Ketoconazole		Nintedanib		Nintedanib + Ketoconazole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/34 (0%)		0/31 (0%)		0/29 (0%)
Other (Not Including Serious) Adverse Events
	Ketoconazole		Nintedanib		Nintedanib + Ketoconazole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/34 (5.9%)		6/31 (19.4%)		6/29 (20.7%)
Infections and infestations
Nasopharyngitis	0/34 (0%)		2/31 (6.5%)		1/29 (3.4%)
Musculoskeletal and connective tissue disorders
Back pain	0/34 (0%)		0/31 (0%)		2/29 (6.9%)
Nervous system disorders
Headache	2/34 (5.9%)		5/31 (16.1%)		5/29 (17.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights