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Trial record 11 of 3092 for:    Area Under Curve AND Healthy

Influence of Mild and Moderate Hepatic Impairment on the Pharmacokinetics, Safety and Tolerability of Various Doses of Afatinib

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ClinicalTrials.gov Identifier: NCT01298063
Recruitment Status : Completed
First Posted : February 17, 2011
Results First Posted : October 17, 2013
Last Update Posted : December 31, 2013
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Liver Diseases
Healthy
Intervention Drug: Afatinib
Enrollment 35
Recruitment Details  
Pre-assignment Details  
Arm/Group Title 50 mg Afatinib Group A 30 mg Afatinib Group B1 50 mg Afatinib Group B2 50 mg Afatinib Group C 50 mg Afatinib Group D
Hide Arm/Group Description Group A: Mild hepatic impaired subjects with Child Pugh A were treated with 50 milligram (mg) Afatinib (One tablet qd in the morning). Group B1: Moderate hepatic impaired subjects with Child Pugh B were treated with 30 mg Afatinib (One tablet qd in the morning). Group B2: Moderate hepatic impaired subjects with Child Pugh B were treated with 50 mg Afatinib (One tablet qd in the morning). Group C: Subjects with normal hepatic function matching to subjects in group A were treated with 50 mg Afatinib (One tablet qd in the morning). Group D: Subjects with normal hepatic function matching to subjects in group B2 were treated with 50 mg Afatinib (One tablet qd in the morning).
Period Title: Overall Study
Started 8 3 8 8 8
Completed 8 3 8 8 8
Not Completed 0 0 0 0 0
Arm/Group Title 50 mg Afatinib Group A 30 mg Afatinib Group B1 50 mg Afatinib Group B2 50 mg Afatinib Group C 50 mg Afatinib Group D Total
Hide Arm/Group Description Group A: Mild hepatic impaired subjects with Child Pugh A were treated with 50 mg Afatinib (One tablet qd in the morning). Group B1: Moderate hepatic impaired subjects with Child Pugh B were treated with 30 mg Afatinib (One tablet qd in the morning). Group B2: Moderate hepatic impaired subjects with Child Pugh B were treated with 50 mg Afatinib (One tablet qd in the morning). Group C: Subjects with normal hepatic function matching to subjects in group A were treated with 50 mg Afatinib (One tablet qd in the morning). Group D: Subjects with normal hepatic function matching to subjects in group B2 were treated with 50 mg Afatinib (One tablet qd in the morning). Total of all reporting groups
Overall Number of Baseline Participants 8 3 8 8 8 35
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 8 participants 3 participants 8 participants 8 participants 8 participants 35 participants
53.9  (9.0) 64.3  (6.1) 54.8  (9.0) 55.9  (12.6) 53.1  (7.9) 55.3  (9.5)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 8 participants 3 participants 8 participants 8 participants 8 participants 35 participants
Female
2
  25.0%
0
   0.0%
3
  37.5%
2
  25.0%
3
  37.5%
10
  28.6%
Male
6
  75.0%
3
 100.0%
5
  62.5%
6
  75.0%
5
  62.5%
25
  71.4%
1.Primary Outcome
Title Area Under Curve From 0 to Infinity (AUC0-infinity)
Hide Description AUC0-infinity represents the area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity
Time Frame 30 minutes (min) prior to first dosing and 30 min, 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 12 h, 24 h, 36 h, 48 h, 72 h, 96 h, 120 h, 144 h, 168 h, 240 h after first dosing
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic (PK) analysis set includes all evaluable matched subjects in the treated set providing at least 1 observation for at least 1 PK endpoint without important protocol violations. Group B1 was not included in the primary analysis set for comparison.
Arm/Group Title 50 mg Afatinib Group A 30 mg Afatinib Group B1 50 mg Afatinib Group B2 50 mg Afatinib Group C 50 mg Afatinib Group D
Hide Arm/Group Description:
Group A: Mild hepatic impaired subjects with Child Pugh A were treated with 50 milligram (mg) Afatinib (One tablet qd in the morning).
Group B1: Moderate hepatic impaired subjects with Child Pugh B were treated with 30 mg Afatinib (One tablet qd in the morning).
Group B2: Moderate hepatic impaired subjects with Child Pugh B were treated with 50 mg Afatinib (One tablet qd in the morning).
Group C: Subjects with normal hepatic function matching to subjects in group A were treated with 50 mg Afatinib (One tablet qd in the morning).
Group D: Subjects with normal hepatic function matching to subjects in group B2 were treated with 50 mg Afatinib (One tablet qd in the morning).
Overall Number of Participants Analyzed 8 3 8 8 8
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*h/mL
886
(53.7%)
552
(42.1%)
934
(31.0%)
956
(22.7%)
985
(32.3%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection 50 mg Afatinib Group A, 50 mg Afatinib Group C
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments Relative bioavailability
Statistical Test of Hypothesis P-Value 0.1998
Comments P-value for ratio outside interval 80 - 125 percent
Method ANOVA
Comments Adjusted (by treatment) geometric mean ratio
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 92.64
Confidence Interval (2-Sided) 90%
67.960 to 126.270
Parameter Dispersion
Type: Standard Deviation
Value: 33.6
Estimation Comments The standard deviation is actually the intra individual geometric coefficient of variation
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection 50 mg Afatinib Group B2, 50 mg Afatinib Group D
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments Relative bioavailability
Statistical Test of Hypothesis P-Value 0.1440
Comments P-value for ratio outside interval 80 - 125 percent
Method ANOVA
Comments Adjusted (by treatment) geometric mean ratio
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 94.88
Confidence Interval (2-Sided) 90%
72.278 to 124.549
Parameter Dispersion
Type: Standard Deviation
Value: 31.6
Estimation Comments The standard deviation is actually the intra individual geometric coefficient of variation
2.Primary Outcome
Title Maximum Concentration (Cmax)
Hide Description Cmax represents the maximum measured concentration of the analyte in plasma
Time Frame 30 minutes (min) prior to first dosing and 30 min, 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 12 h, 24 h, 36 h, 48 h, 72 h, 96 h, 120 h, 144 h, 168 h, 240 h after first dosing
Hide Outcome Measure Data
Hide Analysis Population Description
PK analysis set. Group B1 was not included in the primary analysis set for comparison.
Arm/Group Title 50 mg Afatinib Group A 30 mg Afatinib Group B1 50 mg Afatinib Group B2 50 mg Afatinib Group C 50 mg Afatinib Group D
Hide Arm/Group Description:
Group A: Mild hepatic impaired subjects with Child Pugh A were treated with 50 mg Afatinib (One tablet qd in the morning).
Group B1: Moderate hepatic impaired subjects with Child Pugh B were treated with 30 mg Afatinib (One tablet qd in the morning).
Group B2: Moderate hepatic impaired subjects with Child Pugh B were treated with 50 mg Afatinib (One tablet qd in the morning).
Group C: Subjects with normal hepatic function matching to subjects in group A were treated with 50 mg Afatinib (One tablet qd in the morning).
Group D: Subjects with normal hepatic function matching to subjects in group B2 were treated with 50 mg Afatinib (One tablet qd in the morning).
Overall Number of Participants Analyzed 8 3 8 8 8
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL
33.7
(51.7%)
17.5
(44.1%)
39.5
(40.1%)
30.7
(33.7%)
31.1
(46.0%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection 50 mg Afatinib Group A, 50 mg Afatinib Group C
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments Relative bioavailability
Statistical Test of Hypothesis P-Value 0.2002
Comments P-value for ratio outside interval 80 - 125 percent
Method ANOVA
Comments Adjusted (by treatment) geometric mean ratio
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 109.47
Confidence Interval (2-Sided) 90%
82.683 to 144.947
Parameter Dispersion
Type: Standard Deviation
Value: 30.3
Estimation Comments The standard deviation is actually the intra individual geometric coefficient of variation
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection 50 mg Afatinib Group B2, 50 mg Afatinib Group D
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments Relative bioavailability
Statistical Test of Hypothesis P-Value 0.5281
Comments P-value for ratio outside interval 80 - 125 percent
Method ANOVA
Comments Adjusted (by treatment) geometric mean ratio
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 126.89
Confidence Interval (2-Sided) 90%
86.028 to 187.159
Parameter Dispersion
Type: Standard Deviation
Value: 42.8
Estimation Comments The standard deviation is actually the intra individual geometric coefficient of variation
3.Secondary Outcome
Title Area Under Curve From 0 to tz (AUC0-tz)
Hide Description AUC0-tz represents the area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the time of the last quantifiable data point
Time Frame 30 minutes (min) prior to first dosing and 30 min, 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 12 h, 24 h, 36 h, 48 h, 72 h, 96 h, 120 h, 144 h, 168 h, 240 h after first dosing
Hide Outcome Measure Data
Hide Analysis Population Description
PK analysis set. Group B1 was not included in the primary analysis set for comparison.
Arm/Group Title 50 mg Afatinib Group A 30 mg Afatinib Group B1 50 mg Afatinib Group B2 50 mg Afatinib Group C 50 mg Afatinib Group D
Hide Arm/Group Description:
Group A: Mild hepatic impaired subjects with Child Pugh A were treated with 50 mg Afatinib (One tablet qd in the morning).
Group B1: Moderate hepatic impaired subjects with Child Pugh B were treated with 30 mg Afatinib (One tablet qd in the morning).
Group B2: Moderate hepatic impaired subjects with Child Pugh B were treated with 50 mg Afatinib (One tablet qd in the morning).
Group C: Subjects with normal hepatic function matching to subjects in group A were treated with 50 mg Afatinib (One tablet qd in the morning).
Group D: Subjects with normal hepatic function matching to subjects in group B2 were treated with 50 mg Afatinib (One tablet qd in the morning).
Overall Number of Participants Analyzed 8 3 8 8 8
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*h/mL
842
(50.8%)
519
(39.1%)
904
(31.4%)
930
(22.5%)
956
(33.3%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection 50 mg Afatinib Group A, 50 mg Afatinib Group C
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments Relative bioavailability
Statistical Test of Hypothesis P-Value 0.2309
Comments P-value for ratio outside interval 80 - 125 percent
Method ANOVA
Comments Adjusted (by treatment) geometric mean ratio
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 90.61
Confidence Interval (2-Sided) 90%
66.915 to 122.705
Parameter Dispersion
Type: Standard Deviation
Value: 32.8
Estimation Comments The standard deviation is actually the intra individual geometric coefficient of variation
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection 50 mg Afatinib Group B2, 50 mg Afatinib Group D
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments Relative bioavailability
Statistical Test of Hypothesis P-Value 0.1546
Comments P-value for ratio outside interval 80 - 125 percent
Method ANOVA
Comments Adjusted (by treatment) geometric mean ratio
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 94.49
Confidence Interval (2-Sided) 90%
71.563 to 124.764
Parameter Dispersion
Type: Standard Deviation
Value: 32.4
Estimation Comments The standard deviation is actually the intra individual geometric coefficient of variation
4.Secondary Outcome
Title Clinical Relevant Abnormalitites for Physical Examination, Vital Signs, 12-lead ECG, Clinical Laboratory Tests, Adverse Event, Investigator's Global Tolerability
Hide Description Clinical relevant abnormalitites for physical examination, vital signs, 12-lead electrocardiogramm (ECG), clinical laboratory test (including hematology, clinical chemistry, coagulation, urinalysis), adverse event, investigator's global tolerability. New abnormal findings or worsening of baseline conditions were reported as Adverse Events.
Time Frame First administration of trial medication until 28 days after last administration of trial medication
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set
Arm/Group Title 50 mg Afatinib Group A 30 mg Afatinib Group B1 50 mg Afatinib Group B2 50 mg Afatinib Group C 50 mg Afatinib Group D
Hide Arm/Group Description:
Group A: Mild hepatic impaired subjects with Child Pugh A were treated with 50 mg Afatinib (One tablet qd in the morning).
Group B1: Moderate hepatic impaired subjects with Child Pugh B were treated with 30 mg Afatinib (One tablet qd in the morning).
Group B2: Moderate hepatic impaired subjects with Child Pugh B were treated with 50 mg Afatinib (One tablet qd in the morning).
Group C: Subjects with normal hepatic function matching to subjects in group A were treated with 50 mg Afatinib (One tablet qd in the morning).
Group D: Subjects with normal hepatic function matching to subjects in group B2 were treated with 50 mg Afatinib (One tablet qd in the morning).
Overall Number of Participants Analyzed 8 3 8 8 8
Measure Type: Number
Unit of Measure: participants
Lipase increased 1 0 0 0 0
Hyperlipasaemia 0 1 0 0 0
Time Frame First administration of trial medication until 28 days after last administration of trial medication
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title 50 mg Afatinib Group A 30 mg Afatinib Group B1 50 mg Afatinib Group B2 50 mg Afatinib Group C 50 mg Afatinib Group D
Hide Arm/Group Description Group A: Mild hepatic impaired subjects with Child Pugh A were treated with 50 mg Afatinib (One tablet qd in the morning). Group B1: Moderate hepatic impaired subjects with Child Pugh B were treated with 30 mg Afatinib (One tablet qd in the morning). Group B2: Moderate hepatic impaired subjects with Child Pugh B were treated with 50 mg Afatinib (One tablet qd in the morning). Group C: Subjects with normal hepatic function matching to subjects in group A were treated with 50 mg Afatinib (One tablet qd in the morning). Group D: Subjects with normal hepatic function matching to subjects in group B2 were treated with 50 mg Afatinib (One tablet qd in the morning).
All-Cause Mortality
50 mg Afatinib Group A 30 mg Afatinib Group B1 50 mg Afatinib Group B2 50 mg Afatinib Group C 50 mg Afatinib Group D
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
50 mg Afatinib Group A 30 mg Afatinib Group B1 50 mg Afatinib Group B2 50 mg Afatinib Group C 50 mg Afatinib Group D
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/8 (0.00%)   0/3 (0.00%)   0/8 (0.00%)   0/8 (0.00%)   0/8 (0.00%) 
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
50 mg Afatinib Group A 30 mg Afatinib Group B1 50 mg Afatinib Group B2 50 mg Afatinib Group C 50 mg Afatinib Group D
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   3/8 (37.50%)   1/3 (33.33%)   1/8 (12.50%)   1/8 (12.50%)   0/8 (0.00%) 
Gastrointestinal disorders           
Diarrhoea  1  1/8 (12.50%)  0/3 (0.00%)  0/8 (0.00%)  0/8 (0.00%)  0/8 (0.00%) 
Dyspepsia  1  0/8 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  1/8 (12.50%)  0/8 (0.00%) 
Nausea  1  1/8 (12.50%)  0/3 (0.00%)  0/8 (0.00%)  0/8 (0.00%)  0/8 (0.00%) 
Investigations           
Lipase increased  1  1/8 (12.50%)  0/3 (0.00%)  0/8 (0.00%)  0/8 (0.00%)  0/8 (0.00%) 
Metabolism and nutrition disorders           
Hyperlipasaemia  1  0/8 (0.00%)  1/3 (33.33%)  0/8 (0.00%)  0/8 (0.00%)  0/8 (0.00%) 
Nervous system disorders           
Headache  1  1/8 (12.50%)  0/3 (0.00%)  0/8 (0.00%)  0/8 (0.00%)  0/8 (0.00%) 
Vascular disorders           
Phlebitis  1  0/8 (0.00%)  0/3 (0.00%)  1/8 (12.50%)  0/8 (0.00%)  0/8 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 14.1
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS 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.
Any publication of the result of this trial must be consistent with the Boehringer Ingelheim publication policy. The rights of the investigator and of the sponsor with regard to publication of the results of this trial are described in the investigator contract.
Results Point of Contact
Name/Title: Boehringer Ingelheim Call Center
Organization: Boehringer Ingelheim Pharmaceuticals
Phone: 1-800-243-0127
Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT01298063     History of Changes
Other Study ID Numbers: 1200.86
2010-021140-18 ( EudraCT Number: EudraCT )
First Submitted: February 15, 2011
First Posted: February 17, 2011
Results First Submitted: August 8, 2013
Results First Posted: October 17, 2013
Last Update Posted: December 31, 2013