Relative Bioavailability of a Single Dose of Nintedanib Given Alone and in Combination With Multiple Doses of Rifampicin

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01770392
• Collaborator: (none)
• Enrollment: 26
• Location: 1
• Arms: 2
• Duration (Months): 1.9
• Patients Per Site Per Month: 13.4

Study Details

Study Description

Brief Summary

To investigate the effect of the P-gp inducer rifampicin on the pharmacokinetic parameters of nintedanib

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 26 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Relative Bioavailability of a Single Oral Dose of Nintedanib Given Alone and in Combination With Multiple Oral Doses of Rifampicin in Healthy Male Volunteers (an Open-label, Two-period, Fixed Sequence Phase I Trial)
• Study Start Date: Jan 1, 2013
• Actual Primary Completion Date: Mar 1, 2013
• Actual Study Completion Date: Mar 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Test multiple doses of Rifampicin + single dose of Nintedanib	Drug: Rifampicin; single dose once daily for 7 days; Drug: Nintedanib; single dose administration
Experimental: Reference single dose of Nintedanib	Drug: Nintedanib; single dose administration

Outcome Measures

Primary Outcome Measures

1. Area Under the Curve From 0 Extrapolated to Infinity (AUC0-∞) [1.5 hour (h) before the first drug administration and 0.5h, 1h, 2h, 2.5h, 3h, 3.5h, 4h, 5h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after administration of nintedanib]

   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) [1.5 hour (h) before the first drug administration and 0.5h, 1h, 2h, 2.5h, 3h, 3.5h, 4h, 5h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after administration of nintedanib]

   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) [1.5 hour (h) before the first drug administration and 0.5h, 1h, 2h, 2.5h, 3h, 3.5h, 4h, 5h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after administration of nintedanib]

   AUC0-tz represents the area under the plasma concentration-time curve of nintedanib from 0 to the last quantifiable analyte 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	1199.162.1 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: NCT01770392
• Other Study ID Numbers: 1199.162; 2012-002507-18
• First Posted: Jan 17, 2013
• Last Update Posted: Nov 27, 2014
• Last Verified: Nov 1, 2014

• Additional relevant MeSH terms: Rifampin; Nintedanib

Study Results

Participant Flow

Arm/Group Title	Overall Study
Arm/Group Description	This was an open-label, two-period, fixed-sequence trial. During the first period 150 mg of nintedanib was administered orally in form of a soft gelatine capsule. In the second period, a single dose of 600 mg of rifampicin was administered orally via film-coated tablet every day for a week, then a single dose of nintedanib was administered. The administrations of nintedanib were separated by a washout period of at least 14 days.
Period Title: Nintedanib
STARTED	26
COMPLETED	26
NOT COMPLETED	0
Period Title: Nintedanib
STARTED	26
COMPLETED	25
NOT COMPLETED	1
Period Title: Nintedanib
STARTED	25
COMPLETED	25
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Overall Study
Arm/Group Description	This was an open-label, two-period, fixed-sequence trial. During the first period 150 mg of nintedanib was administered orally in form of a soft gelatine capsule. In the second period, a single dose of 600 mg of rifampicin was administered orally via film-coated tablet every day for a week, then a single dose of nintedanib was administered. The administrations of nintedanib were separated by a washout period of at least 14 days.
Overall Participants	26
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	37.3 (8.7)
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	26 100%

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	1.5 hour (h) before the first drug administration and 0.5h, 1h, 2h, 2.5h, 3h, 3.5h, 4h, 5h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after administration of nintedanib

Outcome Measure Data

Analysis Population Description

TS

Arm/Group Title	Nintedanib	Nintedanib + Rifampicin
Arm/Group Description	150 mg of nintedanib was given as a single dose on Day 1.	600 mg rifampicin was given every evening from Day -7 to Day -1, followed by a single dose of 150 mg nintedanib in the morning of Day 1.
Measure Participants	26	25
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	183 (36.1)	89.4 (36.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nintedanib, Nintedanib + Rifampicin
	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 effect for treatment and effect "subjects" was considered as random
Method of Estimation	Estimation Parameter	Geometric Mean Ratio in percentage
	Estimated Value	50.12
	Confidence Interval	(2-Sided) 90%; 47.155 to 53.275
	Parameter Dispersion	Type: Standard Deviation; Value: 12.7
	Estimation Comments	The standard deviation is actually the geometric coefficient of variation (in %). The ratio has been calculated as (nintedanib+ rifampicin) divided by nintedanib (in %)

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	1.5 hour (h) before the first drug administration and 0.5h, 1h, 2h, 2.5h, 3h, 3.5h, 4h, 5h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after administration of nintedanib

Outcome Measure Data

Analysis Population Description

TS

Arm/Group Title	Nintedanib	Nintedanib + Rifampicin
Arm/Group Description	150 mg of Nintedanib was given as a single dose on Day 1.	600 mg Rifampicin was given every evening from Day -7 to Day -1, followed by a single dose of 150 mg nintedanib in the morning of Day 1.
Measure Participants	26	25
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	22.1 (51.8)	12.8 (43.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nintedanib, Nintedanib + Rifampicin
	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 effect for treatment and effect "subjects" was considered as random
Method of Estimation	Estimation Parameter	Geometric Mean Ratio in percentage
	Estimated Value	59.76
	Confidence Interval	(2-Sided) 90%; 53.829 to 66.348
	Parameter Dispersion	Type: Standard Deviation; Value: 21.9
	Estimation Comments	The standard deviation is actually the geometric coefficient of variation (in %). The ratio has been calculated as (nintedanib+ rifampicin) divided by nintedanib (in %).

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 0 to the last quantifiable analyte plasma concentration. For this endpoint, the "measured values" show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.
Time Frame	1.5 hour (h) before the first drug administration and 0.5h, 1h, 2h, 2.5h, 3h, 3.5h, 4h, 5h, 6h, 8h, 10h, 12h, 24h, 36h, 48h and 72h after administration of nintedanib

Outcome Measure Data

Analysis Population Description

TS

Arm/Group Title	Nintedanib	Nintedanib + Rifampicin
Arm/Group Description	150 mg of nintedanib was given as a single dose on Day 1.	600 mg rifampicin was given every evening from Day -7 to Day -1, followed by a single dose of 150 mg nintedanib in the morning of Day 1.
Measure Participants	26	25
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	173 (36.9)	84.1 (38.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nintedanib, Nintedanib + Rifampicin
	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 effect for treatment and effect "subjects" was considered as random
Method of Estimation	Estimation Parameter	Geometric Mean Ratio in percentage
	Estimated Value	49.98
	Confidence Interval	(2-Sided) 90%; 46.886 to 53.286
	Parameter Dispersion	Type: Standard Deviation; Value: 13.3
	Estimation Comments	The standard deviation is actually the geometric coefficient of variation (in %). The ratio has been calculated as (nintedanib+ rifampicin) divided by nintedanib (in %).

Adverse Events

Time Frame	From the first trial drug administration until up to 14 days after last trial drug administration, up to 28 days
Arm/Group Title	Nintedanib		Washout Period		Rifampicin		Nintedanib + Rifampicin
Arm/Group Description	150 mg of nintedanib was given as a single dose on Day 1.		washout period of at least 14 days between the administrations of nintedanib. During this period no trial drug was administered		600 mg rifampicin was given every evening from Day -7 to Day -1		600 mg rifampicin was given every evening from Day -7 to Day -1, followed by a single dose of 150 mg nintedanib in the morning of Day 1.
All Cause Mortality
	Nintedanib		Washout Period		Rifampicin		Nintedanib + Rifampicin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Nintedanib		Washout Period		Rifampicin		Nintedanib + Rifampicin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/26 (0%)		0/26 (0%)		0/25 (0%)		0/25 (0%)
Other (Not Including Serious) Adverse Events
	Nintedanib		Washout Period		Rifampicin		Nintedanib + Rifampicin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/26 (19.2%)		2/26 (7.7%)		25/25 (100%)		4/25 (16%)
Gastrointestinal disorders
Diarrhoea	5/26 (19.2%)		0/26 (0%)		1/25 (4%)		3/25 (12%)
Faeces discoloured	0/26 (0%)		0/26 (0%)		3/25 (12%)		0/25 (0%)
Flatulence	0/26 (0%)		0/26 (0%)		2/25 (8%)		0/25 (0%)
General disorders
Fatigue	0/26 (0%)		0/26 (0%)		2/25 (8%)		0/25 (0%)
Nervous system disorders
Dizziness	0/26 (0%)		0/26 (0%)		2/25 (8%)		0/25 (0%)
Headache	1/26 (3.8%)		2/26 (7.7%)		5/25 (20%)		2/25 (8%)
Renal and urinary disorders
Chromaturia	0/26 (0%)		0/26 (0%)		25/25 (100%)		0/25 (0%)

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