Nintedanib in Volunteers With Hepatic Impairment Compared With Healthy Volunteers

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02191865
• Collaborator: (none)
• Enrollment: 33
• Location: 1
• Arms: 3
• Duration (Months): 6
• Patients Per Site Per Month: 5.5

Study Details

Study Description

Brief Summary

The primary objective of this study is to investigate the effect of mild (Child-Pugh A, score 5-6) and moderate (Child-Pugh B, score 7-9) hepatic impairment on the pharmacokinetics, safety and tolerability of nintedanib, in comparison with a control group with normal hepatic function following oral administration of nintedanib as single dose.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 33 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Pharmacokinetics, Safety and Tolerability of Nintedanib Single Oral Dose in Male and Female Patients With Different Degrees of Hepatic Impairment (Child-Pugh Classification A and B) as Compared With Nintedanib Administration to Male and Female Healthy Subjects (a Non-blinded, Parallel Group Study of Phase I)
• Study Start Date: Jul 1, 2014
• Actual Primary Completion Date: Dec 1, 2014
• Actual Study Completion Date: Jan 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Mild liver impairment Patients with mild hepatic impaired function (Child-Pugh A)	Drug: Nintedanib; Soft gelatine capsule
Experimental: Moderate liver impairment Patients with moderate hepatic impaired function (Child-Pugh B)	Drug: Nintedanib; Soft gelatine capsule
Experimental: Healthy volunteers Healthy control subjects	Drug: Nintedanib; Soft gelatine capsule

Outcome Measures

Primary Outcome Measures

1. AUC (0-inf) of Nintedanib [Pre-dose and 1 hour (h), 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 72h, 96h, 120h, 144h and 168h after drug administration]

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

2. Cmax of Nintedanib [Pre-dose and 1 hour (h), 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 72h, 96h, 120h, 144h and 168h after drug administration]

   Cmax (Maximum measured concentration of the Nintedanib in plasma)

Secondary Outcome Measures

1. AUC (0-tz) of Nintedanib [Pre-dose and 1 hour (h), 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 72h, 96h, 120h, 144h and 168h after drug administration]

   AUC (0-tz) (Area under the concentration-time curve of the Nintedanib in plasma over the time interval from 0 to the last quantifiable drug plasma concentration)

2. Number (%) of Subjects With Drug-related Adverse Events (AEs) [(AEs) during the 'on-treatment' period (from administration of trial medication until the end of the 28-day residual effect period); Up to 29 days]

   Number (%) of subjects with drug-related Adverse events (AEs)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 79 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion criteria:

Healthy subjects:

• Male or female subject, healthy according to the investigator's judgement based on a complete medical history, including a physical examination, vital signs (BP, PR), 12-lead ECG, and clinical laboratory

• Age of 18 to 79 years at screening visit

Hepatically impaired patients as determined by a hepatologist/ gastroenterologist:

• A documented diagnosis of the impaired hepatic function, determined by hepatologist/gastroenterologist/specialist for internal medicine, must be available in the patient´s source data.

• Male or female chronic hepatically impaired patient as determined by screening results and classified as Child-Pugh A (Child-Pugh score of 5-6 points) or as Child-Pugh B (Child-Pugh score of 7-9 points). Hepatic insufficiency must be diagnosed at least 3 months before screening.

• Age of 18 to 79 years at screening visit

Exclusion criteria:

Healthy subjects:

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

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

• Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders judged as clinically relevant by the investigator

• Surgery of the gastrointestinal tract that could interfere with kinetics of the trial medication based on the investigator´s judgment

• Women who are breast feeding or of child-bearing potential not using a highly effective method of birth control for at least one month prior to inclusion and at least 3 month after administration of trial medication.

Hepatically impaired patients as determined by a hepatologist/gastroenterologist:

• Medical disorder, condition or history of such that would impair the patient's ability to participate or complete this study in the opinion of the investigator or the sponsor

• Patients with significant diseases other than underlying diagnose of hepatic impairment and concomitant diseases related to it. A significant disease is defined as a disease which in the opinion of the investigator:

• put the patient at risk because of participation in the study

• may influence the results of the study

• is not in a stable condition

• Surgery of the gastrointestinal tract that could interfere with the kinetics of the trial medication based on the investigator´s judgment

• Women who are breast feeding or of child-bearing potential not using a highly effective method of birth control for at least one month prior to inclusion and at least 3 month after administration of trial medication

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	1199.200.49001 Boehringer Ingelheim Investigational Site	Kiel		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: NCT02191865
• Other Study ID Numbers: 1199.200; 2014-000690-39
• First Posted: Jul 16, 2014
• Last Update Posted: Feb 1, 2016
• Last Verified: Dec 1, 2015

• Additional relevant MeSH terms: Hepatic Insufficiency; Liver Failure; Nintedanib

Study Results

Participant Flow

Recruitment Details	Healthy subjects were to be matched to subjects with hepatic impairment ((Child-Pugh A, score 5 or 6),(Child-Pugh B, score 7 to 9)) by age (±10 years), body weight (±10%), sex, race, and smoking habits (current vs. ex- and never smokers).

Arm/Group Title	Child Pugh A	Child Pugh B	Healthy
Arm/Group Description	Oral administration of 1 soft gelatin capsule of Nintedanib 100 mg with 240 ml of water under fed conditions in patients with mild hepatic impairment (Child-Pugh A). Subjects were dosed in a 3 plus 5 design, where a subgroup of 3 subjects was dosed and safety was evaluated formally at a safety meeting prior to dosing the remaining 5 subjects in the group.	Oral administration of 1 soft gelatin capsule of Nintedanib 100 mg with 240 ml of water under fed conditions in patients with moderate hepatic impairment (Child-Pugh B). Subjects were dosed in a 3 plus 5 design, where a subgroup of 3 subjects was dosed and safety was evaluated formally at a safety meeting prior to dosing the remaining 5 subjects in the group.	Oral administration of 1 soft gelatin capsule of Nintedanib 100 mg with 240 ml of water under fed conditions in subjects with normal hepatic function.
Period Title: Overall Study
STARTED	8	8	17
COMPLETED	8	8	17
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Child Pugh A	Child Pugh B	Healthy	Total
Arm/Group Description	Oral administration of 1 soft gelatin capsule of Nintedanib 100 mg with 240 ml of water under fed conditions in patients with mild hepatic impairment (Child-Pugh A). Subjects were dosed in a 3 plus 5 design, where a subgroup of 3 subjects was dosed and safety was evaluated formally at a safety meeting prior to dosing the remaining 5 subjects in the group.	Oral administration of 1 soft gelatin capsule of Nintedanib 100 mg with 240 ml of water under fed conditions in patients with moderate hepatic impairment (Child-Pugh B). Subjects were dosed in a 3 plus 5 design, where a subgroup of 3 subjects was dosed and safety was evaluated formally at a safety meeting prior to dosing the remaining 5 subjects in the group.	Oral administration of 1 soft gelatin capsule of Nintedanib 100 mg with 240 ml of water under fed conditions in subjects with normal hepatic function.	Total of all reporting groups
Overall Participants	8	8	17	33
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60.6 (8.1)	56.6 (6.5)	57.6 (8.4)	58.1 (7.8)
Sex: Female, Male (Count of Participants)
Female	3 37.5%	3 37.5%	7 41.2%	13 39.4%
Male	5 62.5%	5 62.5%	10 58.8%	20 60.6%

Outcome Measures

1. Primary Outcome

Title	AUC (0-inf) of Nintedanib
Description	AUC (0-inf) (Area under the concentration-time curve of the Nintedanib in plasma over the time interval from 0 extrapolated to infinity)
Time Frame	Pre-dose and 1 hour (h), 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 72h, 96h, 120h, 144h and 168h after drug administration

Outcome Measure Data

Analysis Population Description

Pharmacokinetic set (PKS): The PKS included all subjects of the TS who provided at least 1 observation for at least 1 primary PK endpoint, which was judged as PK evaluable and was not affected by important protocol violation(s) relevant to the evaluation of PK.

Arm/Group Title	Child-Pugh A	Child-Pugh B	Healthy Matched Child-Pugh A	Healthy Matched Child-Pugh B
Arm/Group Description	Oral administration of 1 soft gelatin capsule of Nintedanib 100 mg with 240 ml of water under fed conditions in patients with mild hepatic impairment (Child-Pugh A).	Oral administration of 1 soft gelatin capsule of Nintedanib 100 mg with 240 ml of water under fed conditions in patients with moderate hepatic impairment (Child-Pugh B).	Oral administration of 1 soft gelatin capsule of Nintedanib 100 mg with 240 ml of water under fed conditions in healthy control subjects matched with hepatic (Child pugh A) impaired subjects	Oral administration of 1 soft gelatin capsule of Nintedanib 100 mg with 240 ml of water under fed conditions in healthy control subjects matched with hepatic (Child pugh B) impaired subjects .
Measure Participants	8	8	8	8
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	200 (87.7)	674 (66.3)	92.7 (58.5)	77.8 (38.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Child-Pugh A, Healthy Matched Child-Pugh A
	Comments	The statistical model used for the analysis of AUC (0-inf) was an ANOVA (analysis of variance) model on the logarithmic scale. Observations from a subject with hepatic impairment and the matched healthy control subject were analysed as a matched pair.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	215.39
	Confidence Interval	(2-Sided) 90%; 120.71 to 384.32
	Parameter Dispersion	Type: Standard Deviation; Value: 73.5
	Estimation Comments	Ratio of Child Pugh A (Test): Healthy Child Pugh A (Reference). The Standard deviation is the Intra-individual gCV

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Child-Pugh B, Healthy Matched Child-Pugh B
	Comments	The statistical model used for the analysis of AUC (0-inf) was an ANOVA (analysis of variance) model on the logarithmic scale. Observations from a subject with hepatic impairment and the matched healthy control subject were analysed as a matched pair.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of geometric means
	Estimated Value	867.13
	Confidence Interval	(2-Sided) 90%; 572.93 to 1312.41
	Parameter Dispersion	Type: Standard Deviation; Value: 45.9
	Estimation Comments	Ratio of Child Pugh B (Test): Healthy Child Pugh B (Reference). The Standard deviation is the Intra-individual gCV

2. Primary Outcome

Title	Cmax of Nintedanib
Description	Cmax (Maximum measured concentration of the Nintedanib in plasma)
Time Frame	Pre-dose and 1 hour (h), 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 72h, 96h, 120h, 144h and 168h after drug administration

Outcome Measure Data

Analysis Population Description

Pharmacokinetic set (PKS): The PKS included all subjects of the TS who provided at least 1 observation for at least 1 primary PK endpoint, which was judged as PK evaluable and was not affected by important protocol violation(s) relevant to the evaluation of PK.

Arm/Group Title	Child-Pugh A	Child-Pugh B	Healthy Matched Child-Pugh A	Healthy Matched Child-Pugh B
Arm/Group Description	Oral administration of 1 soft gelatin capsule of Nintedanib 100 mg with 240 ml of water under fed conditions in patients with mild hepatic impairment (Child-Pugh A).	Oral administration of 1 soft gelatin capsule of 100 mg Nintedanib with 240 ml of water under fed conditions in patients with moderate hepatic impairment (Child-Pugh B).	Oral administration of 1 soft gelatin capsule of Nintedanib 100 mg with 240 ml of water under fed conditions in healthy control subjects matched with hepatic (Child pugh A) impaired subjects	Oral administration of 1 soft gelatin capsule of Nintedanib 100 mg with 240 ml of water under fed conditions in healthy control subjects matched with hepatic (Child pugh B) impaired subjects .
Measure Participants	8	8	8	8
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	20.5 (68.4)	59.4 (87.0)	9.25 (54.1)	7.81 (49.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Child-Pugh A, Healthy Matched Child-Pugh A
	Comments	The statistical model used for the analysis of Cmax was an ANOVA (analysis of variance) model on the logarithmic scale. Observations from a subject with hepatic impairment and the matched healthy control subject were analysed as a matched pair.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	221.76
	Confidence Interval	(2-Sided) 90%; 134.73 to 365.01
	Parameter Dispersion	Type: Standard Deviation; Value: 61.4
	Estimation Comments	Ratio of Child Pugh A (Test): Healthy Child Pugh A (Reference). The Standard deviation is the Intra-individual gCV

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Child-Pugh B, Healthy Matched Child-Pugh B
	Comments	The statistical model used for the analysis of Cmax was an ANOVA (analysis of variance) model on the logarithmic scale. Observations from a subject with hepatic impairment and the matched healthy control subject were analysed as a matched pair.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of geometric means
	Estimated Value	761.01
	Confidence Interval	(2-Sided) 90%; 439.01 to 1319.18
	Parameter Dispersion	Type: Standard Deviation; Value: 69.1
	Estimation Comments	Ratio of Child Pugh B (Test): Healthy Child Pugh B (Reference). The Standard deviation is the Intra-individual gCV

3. Secondary Outcome

Title	AUC (0-tz) of Nintedanib
Description	AUC (0-tz) (Area under the concentration-time curve of the Nintedanib in plasma over the time interval from 0 to the last quantifiable drug plasma concentration)
Time Frame	Pre-dose and 1 hour (h), 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 72h, 96h, 120h, 144h and 168h after drug administration

Outcome Measure Data

Analysis Population Description

Pharmacokinetic set (PKS): The PKS included all subjects of the TS who provided at least 1 observation for at least 1 primary PK endpoint, which was judged as PK evaluable and was not affected by important protocol violation(s) relevant to the evaluation of PK.

Arm/Group Title	Child-Pugh A	Child-Pugh B	Healthy Matched Child-Pugh A	Healthy Matched Child-Pugh B
Arm/Group Description	Oral administration of 1 soft gelatin capsule of Nintedanib 100 mg with 240 ml of water under fed conditions in patients with mild hepatic impairment (Child-Pugh A).	Oral administration of 1 soft gelatin capsule of 100 mg Nintedanib with 240 ml of water under fed conditions in patients with moderate hepatic impairment (Child-Pugh B).	Oral administration of 1 soft gelatin capsule of Nintedanib 100 mg with 240 ml of water under fed conditions in healthy control subjects matched with hepatic (Child pugh A) impaired subjects	Oral administration of 1 soft gelatin capsule of Nintedanib 100 mg with 240 ml of water under fed conditions in healthy control subjects matched with hepatic (Child pugh B) impaired subjects .
Measure Participants	8	8	8	8
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	193 (89.5)	652 (66.2)	89.2 (59.6)	74.8 (38.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Child-Pugh A, Healthy Matched Child-Pugh A
	Comments	The statistical model used for the analysis of AUC (0-tz) was an ANOVA (analysis of variance) model on the logarithmic scale. Observations from a subject with hepatic impairment and the matched healthy control subject were analysed as a matched pair.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	ratio of the geometric means
	Estimated Value	216.79
	Confidence Interval	(2-Sided) 90%; 120.37 to 390.45
	Parameter Dispersion	Type: Standard Deviation; Value: 75.0
	Estimation Comments	Ratio of Child Pugh A (Test): Healthy Child Pugh A (Reference). The Standard deviation is the Intra-individual gCV

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Child-Pugh B, Healthy Matched Child-Pugh B
	Comments	The statistical model used for the analysis of AUC (0-tz) was an ANOVA (analysis of variance) model on the logarithmic scale. Observations from a subject with hepatic impairment and the matched healthy control subject were analysed as a matched pair.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of geometric means
	Estimated Value	870.74
	Confidence Interval	(2-Sided) 90%; 576.36 to 1315.49
	Parameter Dispersion	Type: Standard Deviation; Value: 45.7
	Estimation Comments	Ratio of Child Pugh B (Test): Healthy Child Pugh B (Reference). The Standard deviation is the Intra-individual gCV

4. Secondary Outcome

Title	Number (%) of Subjects With Drug-related Adverse Events (AEs)
Description	Number (%) of subjects with drug-related Adverse events (AEs)
Time Frame	(AEs) during the 'on-treatment' period (from administration of trial medication until the end of the 28-day residual effect period); Up to 29 days

Outcome Measure Data

Analysis Population Description

TS

Arm/Group Title	Child-Pugh A	Child-Pugh B	Healthy
Arm/Group Description	Oral administration of 1 soft gelatin capsule of Nintedanib 100 mg with 240 ml of water under fed conditions in patients with mild hepatic impairment (Child-Pugh A).	Oral administration of 1 soft gelatin capsule of 100 mg Nintedanib with 240 ml of water under fed conditions in patients with moderate hepatic impairment (Child-Pugh B).	Oral administration of 1 soft gelatin capsule of Nintedanib 100 mg with 240 ml of water under fed conditions in subjects with normal hepatic function.
Measure Participants	8	8	17
Number [percentage of participants]	0.0 0%	37.5 468.8%	17.6 103.5%

Adverse Events

Time Frame	AEs during the 'on-treatment' period (from administration of trial medication until the end of the 28-day residual effect period); up to 29 days
Arm/Group Title	Child Pugh A		Child Pugh B		Healthy
Arm/Group Description	Oral administration of 1 soft gelatin capsule of Nintedanib 100 mg with 240 ml of water under fed conditions in patients with mild hepatic impairment (Child-Pugh A).		Oral administration of 1 soft gelatin capsule of Nintedanib 100 mg with 240 ml of water under fed conditions in patients with moderate hepatic impairment (Child-Pugh B).		Oral administration of 1 soft gelatin capsule of Nintedanib 100 mg with 240 ml of water under fed conditions in subjects with normal hepatic function.
All Cause Mortality
	Child Pugh A		Child Pugh B		Healthy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Child Pugh A		Child Pugh B		Healthy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/8 (0%)		0/17 (0%)
Other (Not Including Serious) Adverse Events
	Child Pugh A		Child Pugh B		Healthy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		3/8 (37.5%)		3/17 (17.6%)
Gastrointestinal disorders
Diarrhoea	0/8 (0%)		1/8 (12.5%)		0/17 (0%)
Nausea	0/8 (0%)		1/8 (12.5%)		2/17 (11.8%)
Vomiting	0/8 (0%)		0/8 (0%)		1/17 (5.9%)
Nervous system disorders
Headache	0/8 (0%)		0/8 (0%)		1/17 (5.9%)
Skin and subcutaneous tissue disorders
Pruritus	0/8 (0%)		1/8 (12.5%)		0/17 (0%)
Skin irritation	0/8 (0%)		1/8 (12.5%)		0/17 (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