Relative Bioavailability of 2 Oral Formulations of Nintedanib

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02572752
• Collaborator: (none)
• Enrollment: 70
• Location: 1
• Arms: 3
• Duration (Months): 3
• Patients Per Site Per Month: 23.2

Study Details

Study Description

Brief Summary

To establish the bioequivalence of 1 soft gelatine capsule containing 200 mg nintedanib compared to 2 soft gelatine capsules containing 100 mg nintedanib

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 70 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Bioequivalence of 1 Soft Gelatine Capsule Containing 200 mg Nintedanib Compared to 2 Soft Gelatine Capsules Containing 100 mg Nintedanib Following Oral Administration in Healthy Male Subjects
• Study Start Date: Aug 1, 2015
• Actual Primary Completion Date: Nov 1, 2015
• Actual Study Completion Date: Nov 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment T (Test) Nintedanib, 1 capsule, oral with 240 mL of water	Drug: Nintedanib; 1 soft gelatine capsule, single dose, oral
Experimental: Treatment R - 1 (Reference) Nintedanib, 2 capsules, oral with 240 mL of water	Drug: Nintedanib; Nintedanib, 2 soft gelatine capsules, single dose, oral
Experimental: Treatment R - 2 (Reference) Nintedanib, 2 capsules, oral with 240 mL of water	Drug: Nintedanib; Other Names: Nintedanib, 2 soft gelatine capsules, single dose, oral

Outcome Measures

Primary Outcome Measures

1. AUC0-tz [-1:00 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 3:30h, 4:00h, 4:30h, 5:00h, 5:30h, 6:00h, 7:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h and 72:00h after drug administration.]

   Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz). The unadjusted geometric mean (gMean) and geometric coefficient variation (gCV) was calculated for Test treatment (T), Reference treatment 1 (R1) and Reference treatment 2 (R2) separately.

2. Cmax [-1:00 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 3:30h, 4:00h, 4:30h, 5:00h, 5:30h, 6:00h, 7:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h and 72:00h after drug administration.]

   Maximum measured concentration of the analyte in plasma (Cmax). The unadjusted geometric mean (gMean) and geometric coefficient variation (gCV) was calculated for Test treatment (T), Reference 1 treatment (R1) and Reference 2 treatment (R2) separately.

Secondary Outcome Measures

1. AUC0-inf [-1:00 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 3:30h, 4:00h, 4:30h, 5:00h, 5:30h, 6:00h, 7:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h and 72:00h after drug administration.]

   Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity (AUC0-inf). The unadjusted geometric mean (gMean) and geometric coefficient variation (gCV) was calculated for Test treatment (T), Reference 1 treatment (R1) and Reference 2 treatment (R2) separately.

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 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.

2. Age of 18 to 50 years (incl.)

3. Body weight of at least 70 kg

4. BMI of 21 to 31 kg/m2 (incl.)

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

6. Male subjects, who are willing to use a medically acceptable method of contraception during the first 3 months after administration of nintedanib. Acceptable methods of contraception for use by male volunteers include sexual abstinence, a vasectomy performed at least 1 year prior to dosing and barrier contraception (condom). Subjects, who are not vasectomised or sexually abstinent have to ensure that an additional acceptable method of contraception will be used by his female partner such as IUD (intrauterine device), surgical sterilisation (including hysterectomy), hormonal contraception (e.g. implants, injectables, combined oral or vaginal contraceptives) that started at least 2 months prior to first nintedanib administration, or barrier method (e.g. diaphragm with spermicide).

Exclusion criteria:

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

2. 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 45 to 90 bpm

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

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

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

6. Cholecystectomy and/or surgery of the gastrointestinal tract that could interfere with the pharmacokinetics of the trial medication (except appendectomy and simple hernia repair)

7. Diseases of the central nervous system (including but not limited to any kind of seizures or stroke), and other relevant neurological or psychiatric disorders

8. History of relevant orthostatic hypotension, fainting spells, or blackouts

9. Chronic or relevant acute infections

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

11. 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

12. Within 10 days prior to administration of trial medication, use of drugs that might reasonably influence the results of the trial

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

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

15. Inability to refrain from smoking on specified trial days

16. Alcohol abuse (consumption of more than 30 g per day for males)

17. Drug abuse or positive drug screening

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

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

20. Inability to comply with dietary regimen of trial site

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
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: NCT02572752
• Other Study ID Numbers: 1199.237; 2015-001348-12
• First Posted: Oct 9, 2015
• Last Update Posted: Jan 5, 2017
• Last Verified: Oct 1, 2016

• Additional relevant MeSH terms: Nintedanib

Study Results

Participant Flow

Pre-assignment Detail	The trial was randomised and open-label with a 3-way crossover design (2 administrations of reference treatment and 1 administration of test treatment in all subjects). In this study 70 subjects were entered and treated.

Arm/Group Title	Nin 2x100 mg(R1) / Nin 2x100 mg(R2) / Nin 1x200 mg(T)	Nin 2x100 mg(R1) / Nin 1x200 mg(T) / Nin 2x100 mg(R2)	Nin 1x200 mg(T) / Nin 2x100 mg(R1) / Nin 2x100 mg(R2)
Arm/Group Description	Subjects were treated with single oral dose, started in Period 1 (Reference treatment (R1)) and Period 2 (Reference treatment (R2)) with nintedanib (nin) soft gelatine capsule, 200 mg (2x100 mg) with about 240 mL of water, followed in Period 3 (Test treatment (T)) with nintedanib soft gelatine capsule, 200 mg (1x200mg) with about 240 mL of water. Treatment periods were separated by a wash-out phase of at least 12 days.	Subjects were treated with single oral dose, started in Period 1 (Reference treatment (R1)) with nintedanib soft gelatine capsule, 200 mg (2x100mg) with about 240 mL of water, followed in Period 2 (Test treatment (T)) with nintedanib soft gelatine capsule, 200 mg (1x200mg) with about 240 mL of water and in Period 3 (Reference treatment (R2)) with nintedanib soft gelatine capsule, 200 mg (2x100mg) with about 240 mL of water. Treatment periods were separated by a wash-out phase of at least 12 days.	Subjects were treated with single oral dose, started in Period 1 (Test treatment (T)) with nintedanib soft gelatine capsule, 200 mg (1x200mg) with about 240 mL of water, followed in Period 2 (Reference treatment (R1)) and Period 3 (Reference treatment (R2)) with nintedanib soft gelatine capsule, 200 mg (2x100 mg) with about 240 mL of water. Treatment periods were separated by a wash-out phase of at least 12 days.
Period Title: Period 1 Including Washout
STARTED	23	23	24
COMPLETED	23	23	24
NOT COMPLETED	0	0	0
Period Title: Period 1 Including Washout
STARTED	23	23	24
COMPLETED	23	23	24
NOT COMPLETED	0	0	0
Period Title: Period 1 Including Washout
STARTED	23	23	24
COMPLETED	23	23	24
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Nin 2x100 mg(R1) / Nin 2x100 mg(R2) / Nin 1x200 mg(T)	Nin 2x100 mg(R1) / Nin 1x200 mg(T) / Nin 2x100 mg(R2)	Nin 1x200 mg(T) / Nin 2x100 mg(R1) / Nin 2x100 mg(R2)	Total
Arm/Group Description	Subjects were treated with single oral dose, started in Period 1 (Reference treatment (R1)) and Period 2 (Reference treatment (R2)) with nintedanib (nin) soft gelatine capsule, 200 mg (2x100 mg) with about 240 mL of water, followed in Period 3 (Test treatment (T)) with nintedanib soft gelatine capsule, 200 mg (1x200mg) with about 240 mL of water. Treatment periods were separated by a wash-out phase of at least 12 days.	Subjects were treated with single oral dose, started in Period 1 (Reference treatment (R1)) with nintedanib soft gelatine capsule, 200 mg (2x100mg) with about 240 mL of water, followed in Period 2 (Test treatment (T)) with nintedanib soft gelatine capsule, 200 mg (1x200mg) with about 240 mL of water and in Period 3 (Reference treatment (R2)) with nintedanib soft gelatine capsule, 200 mg (2x100mg) with about 240 mL of water. Treatment periods were separated by a wash-out phase of at least 12 days.	Subjects were treated with single oral dose, started in Period 1 (Test treatment (T)) with nintedanib soft gelatine capsule, 200 mg (1x200mg) with about 240 mL of water, followed in Period 2 (Reference treatment (R1)) and Period 3 (Reference treatment (R2)) with nintedanib soft gelatine capsule, 200 mg (2x100 mg) with about 240 mL of water. Treatment periods were separated by a wash-out phase of at least 12 days.	Total of all reporting groups
Overall Participants	23	23	24	70
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	34.0 (10.3)	36.6 (9.5)	31.6 (7.2)	34.0 (9.2)
Gender (Count of Participants)
Female	0 0%	0 0%	0 0%	0 0%
Male	23 100%	23 100%	24 100%	70 100%

Outcome Measures

1. Primary Outcome

Title	AUC0-tz
Description	Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz). The unadjusted geometric mean (gMean) and geometric coefficient variation (gCV) was calculated for Test treatment (T), Reference treatment 1 (R1) and Reference treatment 2 (R2) separately.
Time Frame	-1:00 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 3:30h, 4:00h, 4:30h, 5:00h, 5:30h, 6:00h, 7:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h and 72:00h after drug administration.

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Set (PKS) : This analysis set included all treated subjects who provided at least 1 observation for at least 1 primary endpoint, and who had no important protocol violations impacting statistical evaluation of PK endpoints.

Arm/Group Title	Nintedanib, Test Treatment (T)	Nintedanib, Reference Treatment (R1)	Nintedanib, Reference Treatment (R2)
Arm/Group Description	Subjects were treated with single oral dose, started in Period 1 (Test treatment (T)) with nintedanib soft gelatine capsule, 200 mg (1x200mg) with about 240 mL of water.	Subjects were treated with single oral dose, started in Period 1 (Reference treatment (R1)) with nintedanib soft gelatine capsule, 200 mg (2x100mg) with about 240 mL of water.	Subjects were treated with single oral dose, started in Period 1 (Reference treatment (R2)) with nintedanib soft gelatine capsule, 200 mg (2x100mg) with about 240 mL of water.
Measure Participants	70	70	70
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	300 (38.8)	310 (37.6)	306 (36.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nintedanib, Test Treatment (T), Nintedanib, Reference Treatment (R1), Nintedanib, Reference Treatment (R2)
	Comments	An Analysis of variance (ANOVA) model was used on the logarithmic scale in order to compare the Test treatment vs. the Reference treatment (without differentiation between R1 and R2). This model included effects for 'sequence', 'subjects within sequences', 'period' and 'treatment'. For the two 1-sided t-test procedure, the effect 'subjects within sequences' was considered to be random, whereas the other effects were considered to be fixed
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	gMean Ratio
	Estimated Value	97.478
	Confidence Interval	(2-Sided) 90%; 94.545 to 100.502
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 11.57
	Estimation Comments	Relative bioavailability was estimated by the ratios of the gMean of nin Test treatment (T) divided by nin Reference treatment (R1 & R2). Standard Error of the mean is actually the intra individual geometric coefficient variation (gCV).

2. Primary Outcome

Title	Cmax
Description	Maximum measured concentration of the analyte in plasma (Cmax). The unadjusted geometric mean (gMean) and geometric coefficient variation (gCV) was calculated for Test treatment (T), Reference 1 treatment (R1) and Reference 2 treatment (R2) separately.
Time Frame	-1:00 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 3:30h, 4:00h, 4:30h, 5:00h, 5:30h, 6:00h, 7:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h and 72:00h after drug administration.

Outcome Measure Data

Analysis Population Description

PKS

Arm/Group Title	Nintedanib, Test Treatment (T)	Nintedanib, Reference Treatment (R1)	Nintedanib, Reference Treatment (R2)
Arm/Group Description	Subjects were treated with single oral dose, started in Period 1 (Test treatment (T)) with nintedanib soft gelatine capsule, 200 mg (1x200mg) with about 240 mL of water.	Subjects were treated with single oral dose, started in Period 1 (Reference treatment (R1)) with nintedanib soft gelatine capsule, 200 mg (2x100mg) with about 240 mL of water.	Subjects were treated with single oral dose, started in Period 1 (Reference treatment (R2)) with nintedanib soft gelatine capsule, 200 mg (2x100mg) with about 240 mL of water.
Measure Participants	70	70	70
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	39.3 (56.0)	41.1 (43.4)	39.8 (46.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nintedanib, Test Treatment (T), Nintedanib, Reference Treatment (R1), Nintedanib, Reference Treatment (R2)
	Comments	An ANOVA model was used on the logarithmic scale in order to compare the Test treatment vs. the Reference treatment (without differentiation between R1 and R2). This model included effects for 'sequence', 'subjects within sequences', 'period' and 'treatment'. For the two 1-sided t-test procedure, the effect 'subjects within sequences' was considered to be random, whereas the other effects were considered to be fixed.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	gMean Ratio
	Estimated Value	97.004
	Confidence Interval	(2-Sided) 90%; 90.948 to 103.463
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 20.77
	Estimation Comments	Relative bioavailability was estimated by the ratios of the gMean of nin Test treatment (T) divided by nin Reference treatment (R1 & R2). Standard Error of the mean is actually the intra individual geometric coefficient variation (gCV).

3. Secondary Outcome

Title	AUC0-inf
Description	Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity (AUC0-inf). The unadjusted geometric mean (gMean) and geometric coefficient variation (gCV) was calculated for Test treatment (T), Reference 1 treatment (R1) and Reference 2 treatment (R2) separately.
Time Frame	-1:00 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 3:30h, 4:00h, 4:30h, 5:00h, 5:30h, 6:00h, 7:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h and 72:00h after drug administration.

Outcome Measure Data

Analysis Population Description

PKS

Arm/Group Title	Nintedanib, Test Treatment (T)	Nintedanib, Reference Treatment (R1)	Nintedanib, Reference Treatment (R2)
Arm/Group Description	Subjects were treated with single oral dose, started in Period 1 (Test treatment (T)) with nintedanib soft gelatine capsule, 200 mg (1x200mg) with about 240 mL of water.	Subjects were treated with single oral dose, started in Period 1 (Reference treatment (R1)) with nintedanib soft gelatine capsule, 200 mg (2x100mg) with about 240 mL of water.	Subjects were treated with single oral dose, started in Period 1 (Reference treatment (R2)) with nintedanib soft gelatine capsule, 200 mg (2x100mg) with about 240 mL of water.
Measure Participants	70	70	70
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	311 (38.8)	322 (37.7)	319 (36.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nintedanib, Test Treatment (T), Nintedanib, Reference Treatment (R1), Nintedanib, Reference Treatment (R2)
	Comments	An ANOVA model was used on the logarithmic scale in order to compare the Test treatment vs. the Reference treatment (without differentiation between R1 and R2). This model included effects for 'sequence', 'subjects within sequences', 'period' and 'treatment'. For the two 1-sided t-test procedure, the effect 'subjects within sequences' was considered to be random, whereas the other effects were considered to be fixed
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	gMean Ratio
	Estimated Value	97.149
	Confidence Interval	(2-Sided) 90%; 94.223 to 100.166
	Parameter Dispersion	Type: Standard Deviation; Value: 11.40
	Estimation Comments	Relative bioavailability was estimated by the ratios of the gMean of nin Test treatment (T) divided by nin Reference treatment (R1 & R2). Standard Error of the mean is actually the intra individual geometric coefficient variation (gCV).

Adverse Events

Time Frame	From first drug administration until 12 days after the last drug administration of nintedanib, ie., upto 16 days.
Arm/Group Title	Nintedanib, Test Treatment (T)		Nintedanib, Reference Treatment (R1 & R2)
Arm/Group Description	Subjects were treated with single oral dose of nintedanib soft gelatine capsule (Test treatment (T)) , 200 mg (1x200mg) with about 240 mL of water.		Subjects were treated twice with single oral dose of nintedanib soft gelatine capsule (Reference treatment (R1 & R2)), 200 mg (2x100mg) with about 240 mL of water.
All Cause Mortality
	Nintedanib, Test Treatment (T)		Nintedanib, Reference Treatment (R1 & R2)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Nintedanib, Test Treatment (T)		Nintedanib, Reference Treatment (R1 & R2)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/70 (0%)		0/70 (0%)
Other (Not Including Serious) Adverse Events
	Nintedanib, Test Treatment (T)		Nintedanib, Reference Treatment (R1 & R2)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	24/70 (34.3%)		29/70 (41.4%)
Gastrointestinal disorders
Diarrhoea	16/70 (22.9%)		20/70 (28.6%)
Nausea	4/70 (5.7%)		6/70 (8.6%)
Infections and infestations
Nasopharyngitis	2/70 (2.9%)		4/70 (5.7%)
Nervous system disorders
Headache	7/70 (10%)		7/70 (10%)

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.