Afatinib in Subjects With Kidney Dysfunction

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02096718
• Collaborator: (none)
• Enrollment: 30
• Location: 1
• Arms: 3
• Duration (Months): 7
• Patients Per Site Per Month: 4.3

Study Details

Study Description

Brief Summary

The primary objective of the current study is to investigate the influence of moderate to severe renal impairment on the pharmacokinetics and safety of a single dose afatinib in comparison to a control group with normal renal function.

The assessment of safety and tolerability will be an additional objective of this trial and will be evaluated by descriptive statistics.

Condition or Disease	Intervention/Treatment	Phase
Renal Insufficiency	Drug: Afatinib healthy; Drug: Afatinib severe renally impaired; Drug: Afatinib moderate renally impaired	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 30 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Pharmacokinetics, Safety and Tolerability After Single Dose Administration of Afatinib in Moderate and Severe Renal Impairment in Comparison to Subjects With Normal Renal Function (a Mono-centric, Open-label Study in Matched-group Design)
• Study Start Date: May 1, 2014
• Actual Primary Completion Date: Dec 1, 2014
• Actual Study Completion Date: Dec 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Afatinib in moderate renal impaired Single Dose Afatinib in moderate renal impaired subjects	Drug: Afatinib moderate renally impaired
Experimental: Afatinib in severe renal impaired Single Dose Afatinib in severe renal impaired subjects	Drug: Afatinib severe renally impaired
Other: Afatinib in healthy subjects Single Dose Afatinib in healthy subjects matched by gender, race, age and BMI to moderate and severe renal impaired subjects	Drug: Afatinib healthy

Outcome Measures

Primary Outcome Measures

1. AUC 0-tz of Afatinib (BIBW 2992) [PK plasma samples were taken at: 1 hour before drug administration and 0.5 hour (h), 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 192h, 240h, 312h after first drug administration]

   Area under the concentration-time curve of the analyte in plasma over the time interval from 0 up to the last quantifiable data point

2. Cmax of Afatinib (BIBW 2992) [PK plasma samples were taken at: 1 hour before drug administration and 0.5 hour (h), 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 192h, 240h, 312h after first drug administration]

   Maximum measured concentration of the analyte in plasma

Secondary Outcome Measures

1. AUC 0-inf of Afatinib (BIBW 2992) [PK plasma samples were taken at: 1 hour before drug administration and 0.5 hour (h), 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 192h, 240h, 312h after first drug administration]

   Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity

Eligibility Criteria

Criteria

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

Inclusion criteria:

• Despite renal impairment (group 1 and 2) healthy males or females according to the investigators assessment, as based on the following criteria: a complete medical history including a physical examination, vital signs (Blood Pressure (BP), Pulse Rate (PR)), 12-lead Electrocardiogram (ECG), and clinical laboratory tests.

• Glomerular filtration rate (GFR), estimated according to:

-- MDRD (Modification of Diet in Renal Disease)-formula:

• eGFR (estimated Glomerular Filtration Rate) [ml/min/1.73m²]= 175 x Serum Creatinine-1.154 x age-0.203 (if male)

• eGFR[ml/min/1.73m²]= 175 x Serum Creatinine-1.154 x age-0.203 x 0.742 (if female)

• 30 to 59 mL/min for moderate renal impairment group 1

• 15 to 29 mL/min for severe renal impairment group 2

• = 90 mL/min for healthy volunteers group 3

• Age =18 and =79 years

Exclusion criteria:

• Any finding of the medical examination (including Blood Pressure (BP), Pulse Rate (PR) and Electrocardiogram (ECG)) deviating from normal and of clinical relevance, e.g. repeated measurement of systolic blood pressure < 90 mmHg (millimeter of mercury) or > 140 mmHg, diastolic blood pressure < 50 mmHg or > 90 mmHg, repeated measurement of pulse rate < 45 bpm (beats per minute) or > 90 bpm.

• Any evidence of a clinically relevant concomitant disease.

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

• Relevant gastrointestinal tract surgery (except appendectomy).

• Diseases of the central nervous system (such as epilepsy, seizures) or psychiatric disorders or neurological disorders.

• History of photosensitivity or recurrent rash.

• Diseases of the central nervous system (such as epilepsy) or psychiatric disorders or neurological disorders.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	1200.216.1 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: NCT02096718
• Other Study ID Numbers: 1200.216; 2013-004825-98
• First Posted: Mar 26, 2014
• Last Update Posted: Jan 14, 2016
• Last Verified: Nov 1, 2015

• Additional relevant MeSH terms: Renal Insufficiency; Afatinib

Study Results

Participant Flow

Recruitment Details	30 patients were entered, treated and analyzed.
Pre-assignment Detail	This was a non-randomised, non-controlled, open-label, single-dose trial with matched group design. Group 1 contained subjects with moderate renal impairment, Group 2 subjects with severe renal impairment, and Group 3 subjects with normal renal function; groups were dosed sequentially.

Arm/Group Title	Afatinib in Moderate Renal Impairment	Afatinib in Severe Renal Impairment	Afatinib in Healthy Subjects
Arm/Group Description	Single Dose of 40 mg Afatinib film-coated tablet was orally administered to moderately renally impaired subjects in fasted state with 240 mL of water	Single Dose of 40 mg Afatinib film-coated tablet was orally administered to severely renally impaired subjects in fasted state with 240 mL of water	Single Dose of 40 mg Afatinib film-coated tablet was orally administered to healthy subjects in fasted state with 240 mL of water; healthy subjects were matched by gender, race, age and BMI to moderate and severe renal impaired subjects
Period Title: Overall Study
STARTED	8	8	14
COMPLETED	8	8	14
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Afatinib in Moderate Renal Impairment	Afatinib in Severe Renal Impairment	Afatinib in Healthy Subjects	Total
Arm/Group Description	Single Dose of 40 mg Afatinib film-coated tablet was orally administered to moderately renally impaired subjects in fasted state with 240 mL of water	Single Dose of 40 mg Afatinib film-coated tablet was orally administered to severely renally impaired subjects in fasted state with 240 mL of water	Single Dose of 40 mg Afatinib film-coated tablet was orally administered to healthy subjects in fasted state with 240 mL of water; healthy subjects were matched by gender, race, age and BMI to moderate and severe renal impaired subjects	Total of all reporting groups
Overall Participants	8	8	14	30
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	68.6 (11.0)	61.0 (11.9)	62.1 (11.4)	63.6 (11.5)
Sex: Female, Male (Count of Participants)
Female	5 62.5%	2 25%	7 50%	14 46.7%
Male	3 37.5%	6 75%	7 50%	16 53.3%

Outcome Measures

1. Primary Outcome

Title	AUC 0-tz of Afatinib (BIBW 2992)
Description	Area under the concentration-time curve of the analyte in plasma over the time interval from 0 up to the last quantifiable data point
Time Frame	PK plasma samples were taken at: 1 hour before drug administration and 0.5 hour (h), 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 192h, 240h, 312h after first drug administration

Outcome Measure Data

Analysis Population Description

The pharmacokinetic set (PKS): included all patients in the treated set who provided evaluable data for at least one primary (PK) endpoint without important protocol violations relevant to the evaluation of PK.

Arm/Group Title	Afatinib in Moderate Renal Impairment	Afatinib in Severe Renal Impairment	Afatinib in Healthy Subjects Matched to Moderate	Afatinib in Healthy Subjects Matched to Severe
Arm/Group Description	Single Dose of 40 mg Afatinib film-coated tablet was orally administered to moderately renally impaired subjects in fasted state with 240 mL of water	Single Dose of 40 mg Afatinib film-coated tablet was orally administered to severely renally impaired subjects in fasted state with 240 mL of water	Single Dose of 40 mg Afatinib film-coated tablet was orally administered to healthy subjects in fasted state with 240 mL of water; healthy subjects were matched by gender, race, age and BMI to moderate renal impaired subjects	Single Dose of 40 mg Afatinib film-coated tablet was orally administered to healthy subjects in fasted state with 240 mL of water; healthy subjects were matched by gender, race, age and BMI to severe renal impaired subjects
Measure Participants	8	8	8	8
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	948 (32.9)	952 (31.3)	776 (22.9)	634 (50.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib in Moderate Renal Impairment, Afatinib in Healthy Subjects Matched to Moderate
	Comments	The ANOVA model was fitted using log-transformed values. The difference between the expected means of each comparison was estimated by the difference in the corresponding Least Square Means (point estimate), and 2-sided 90% confidence intervals based on the t-distribution. These quantities were then back-transformed to the original scale to give the point estimator (gMean), and interval estimates for the intersubject ratio of the gMeans for each renal function group.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of gmeans
	Estimated Value	122.23
	Confidence Interval	(2-Sided) 90%; 95.743 to 156.045
	Parameter Dispersion	Type: Standard Deviation; Value: 28.3
	Estimation Comments	Relative bioavailability comparison of afatinib for moderate vs. normal matched with moderate patients was estimated by the ratios of the geometric means (gMean). Standard deviation is actually Inter individual geometric coefficient variation (gCV).

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Afatinib in Severe Renal Impairment, Afatinib in Healthy Subjects Matched to Severe
	Comments	The ANOVA model was fitted using log-transformed values. The difference between the expected means of each comparison was estimated by the difference in the corresponding Least Square Means (point estimate), and 2-sided 90% confidence intervals based on the t-distribution. These quantities were then back-transformed to the original scale to give the point estimator (gMean), and interval estimates for the intersubject ratio of the gMeans for each renal function group.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of gmeans
	Estimated Value	149.97
	Confidence Interval	(2-Sided) 90%; 105.266 to 213.671
	Parameter Dispersion	Type: Standard Deviation; Value: 41.9
	Estimation Comments	Relative bioavailability comparison of afatinib for severe vs. normal matched with severe patients was estimated by the ratios of the geometric means (gMean). Standard deviation is actually Inter individual geometric coefficient variation (gCV).

2. Primary Outcome

Title	Cmax of Afatinib (BIBW 2992)
Description	Maximum measured concentration of the analyte in plasma
Time Frame	PK plasma samples were taken at: 1 hour before drug administration and 0.5 hour (h), 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 192h, 240h, 312h after first drug administration

Outcome Measure Data

Analysis Population Description

The pharmacokinetic set (PKS): included all patients in the treated set who provided evaluable data for at least one primary (PK) endpoint without important protocol violations relevant to the evaluation of PK.

Arm/Group Title	Afatinib in Moderate Renal Impairment	Afatinib in Severe Renal Impairment	Afatinib in Healthy Subjects Matched to Moderate	Afatinib in Healthy Subjects Matched to Severe
Arm/Group Description	Single Dose of 40 mg Afatinib film-coated tablet was orally administered to moderately renally impaired subjects in fasted state with 240 mL of water	Single Dose of 40 mg Afatinib film-coated tablet was orally administered to severely renally impaired subjects in fasted state with 240 mL of water	Single Dose of 40 mg Afatinib film-coated tablet was orally administered to healthy subjects in fasted state with 240 mL of water; healthy subjects were matched by gender, race, age and BMI to moderate renal impaired subjects	Single Dose of 40 mg Afatinib film-coated tablet was orally administered to healthy subjects in fasted state with 240 mL of water; healthy subjects were matched by gender, race, age and BMI to severe renal impaired subjects
Measure Participants	8	8	8	8
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	28.7 (44.0)	28.2 (24.5)	28.3 (32.2)	23.2 (42.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib in Moderate Renal Impairment, Afatinib in Healthy Subjects Matched to Moderate
	Comments	The ANOVA model was fitted using log-transformed values. The difference between the expected means of each comparison was estimated by the difference in the corresponding Least Square Means (point estimate), and 2-sided 90% confidence intervals based on the t-distribution. These quantities were then back-transformed to the original scale to give the point estimator (gMean), and interval estimates for the intersubject ratio of the gMeans for each renal function group.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of gmeans
	Estimated Value	101.16
	Confidence Interval	(2-Sided) 90%; 72.931 to 140.309
	Parameter Dispersion	Type: Standard Deviation; Value: 38.5
	Estimation Comments	Relative bioavailability comparison of afatinib for moderate vs. normal matched with moderate patients was estimated by the ratios of the geometric means (gMean). Standard deviation is actually Inter individual geometric coefficient variation (gCV).

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Afatinib in Severe Renal Impairment, Afatinib in Healthy Subjects Matched to Severe
	Comments	The ANOVA model was fitted using log-transformed values. The difference between the expected means of each comparison was estimated by the difference in the corresponding Least Square Means (point estimate), and 2-sided 90% confidence intervals based on the t-distribution. These quantities were then back-transformed to the original scale to give the point estimator (gMean), and interval estimates for the intersubject ratio of the gMeans for each renal function group.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of gmeans
	Estimated Value	121.71
	Confidence Interval	(2-Sided) 90%; 90.790 to 163.162
	Parameter Dispersion	Type: Standard Deviation; Value: 34.2
	Estimation Comments	Relative bioavailability comparison of afatinib for severe vs. normal matched with severe patients was estimated by the ratios of the geometric means (gMean). Standard deviation is actually Inter individual geometric coefficient variation (gCV).

3. Secondary Outcome

Title	AUC 0-inf of Afatinib (BIBW 2992)
Description	Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity
Time Frame	PK plasma samples were taken at: 1 hour before drug administration and 0.5 hour (h), 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 192h, 240h, 312h after first drug administration

Outcome Measure Data

Analysis Population Description

The pharmacokinetic set (PKS): included all patients in the treated set who provided evaluable data for at least one primary (PK) endpoint without important protocol violations relevant to the evaluation of PK.

Arm/Group Title	Afatinib in Moderate Renal Impairment	Afatinib in Severe Renal Impairment	Afatinib in Healthy Subjects Matched to Moderate	Afatinib in Healthy Subjects Matched to Severe
Arm/Group Description	Single Dose of 40 mg Afatinib film-coated tablet was orally administered to moderately renally impaired subjects in fasted state with 240 mL of water	Single Dose of 40 mg Afatinib film-coated tablet was orally administered to severely renally impaired subjects in fasted state with 240 mL of water	Single Dose of 40 mg Afatinib film-coated tablet was orally administered to healthy subjects in fasted state with 240 mL of water; healthy subjects were matched by gender, race, age and BMI to moderate renal impaired subjects	Single Dose of 40 mg Afatinib film-coated tablet was orally administered to healthy subjects in fasted state with 240 mL of water; healthy subjects were matched by gender, race, age and BMI to severe renal impaired subjects
Measure Participants	8	8	8	8
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	976 (32.5)	980 (31.9)	797 (22.7)	653 (49.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Afatinib in Moderate Renal Impairment, Afatinib in Healthy Subjects Matched to Moderate
	Comments	The ANOVA model was fitted using log-transformed values. The difference between the expected means of each comparison was estimated by the difference in the corresponding Least Square Means (point estimate), and 2-sided 90% confidence intervals based on the t-distribution. These quantities were then back-transformed to the original scale to give the point estimator (gMean), and interval estimates for the intersubject ratio of the gMeans for each renal function group.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of gmeans
	Estimated Value	122.44
	Confidence Interval	(2-Sided) 90%; 96.141 to 155.928
	Parameter Dispersion	Type: Standard Deviation; Value: 28.0
	Estimation Comments	Relative bioavailability comparison of afatinib for moderate vs. normal matched with moderate patients was estimated by the ratios of the geometric means (gMean). Standard deviation is actually Inter individual geometric coefficient variation (gCV).

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Afatinib in Severe Renal Impairment, Afatinib in Healthy Subjects Matched to Severe
	Comments	The ANOVA model was fitted using log-transformed values. The difference between the expected means of each comparison was estimated by the difference in the corresponding Least Square Means (point estimate), and 2-sided 90% confidence intervals based on the t-distribution. These quantities were then back-transformed to the original scale to give the point estimator (gMean), and interval estimates for the intersubject ratio of the gMeans for each renal function group.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of gmeans
	Estimated Value	150.08
	Confidence Interval	(2-Sided) 90%; 105.626 to 213.250
	Parameter Dispersion	Type: Standard Deviation; Value: 41.5
	Estimation Comments	Relative bioavailability comparison of afatinib for severe vs. normal matched with severe patients was estimated by the ratios of the geometric means (gMean). Standard deviation is actually Inter individual geometric coefficient variation (gCV).

Adverse Events

Time Frame	From first administration of trial medication until the end of trial examination, up to 17 days
Adverse Event Reporting Description	The residual effect period (REP) for afatinib in subjects with renal impairment (that is, the time period in which measurable drug levels were still likely to be present) was 17 days. Therefore, all AEs reported within 17 days of afatinib administration were to be considered as occurring on treatment.
Arm/Group Title	Afatinib in Healthy Subjects		Afatinib in Moderate Renal Impairment		Afatinib in Severe Renal Impairment
Arm/Group Description	Single Dose of 40 mg Afatinib film-coated tablet was orally administered to healthy subjects in fasted state with 240 mL of water; healthy subjects were matched by gender, race, age and BMI to moderate and severe renal impaired subjects		Single Dose of 40 mg Afatinib film-coated tablet was orally administered to moderately renally impaired subjects in fasted state with 240 mL of water		Single Dose of 40 mg Afatinib film-coated tablet was orally administered to severely renally impaired subjects in fasted state with 240 mL of water
All Cause Mortality
	Afatinib in Healthy Subjects		Afatinib in Moderate Renal Impairment		Afatinib in Severe Renal Impairment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Afatinib in Healthy Subjects		Afatinib in Moderate Renal Impairment		Afatinib in Severe Renal Impairment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/8 (0%)		0/8 (0%)
Other (Not Including Serious) Adverse Events
	Afatinib in Healthy Subjects		Afatinib in Moderate Renal Impairment		Afatinib in Severe Renal Impairment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/14 (28.6%)		2/8 (25%)		0/8 (0%)
Gastrointestinal disorders
Diarrhoea	1/14 (7.1%)		1/8 (12.5%)		0/8 (0%)
Nausea	0/14 (0%)		1/8 (12.5%)		0/8 (0%)
Vomiting	0/14 (0%)		1/8 (12.5%)		0/8 (0%)
Nervous system disorders
Headache	1/14 (7.1%)		0/8 (0%)		0/8 (0%)
Sciatica	1/14 (7.1%)		0/8 (0%)		0/8 (0%)
Vascular disorders
Phlebitis	1/14 (7.1%)		0/8 (0%)		0/8 (0%)

Limitations/Caveats

Two healthy volunteers were matched to 2 different groups i.e. subjects with moderate renal impairment and subjects with severe renal impairment.

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.