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Investigation of Drug-drug Interaction of Nintedanib and Ketoconazole in Healthy Male Volunteers

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ClinicalTrials.gov Identifier: NCT01679613
Recruitment Status : Completed
First Posted : September 6, 2012
Results First Posted : November 27, 2014
Last Update Posted : November 27, 2014
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Healthy
Interventions Drug: Nintedanib
Drug: Ketoconazole
Enrollment 34
Recruitment Details  
Pre-assignment Details This was a randomised, open-label trial with a 2-way cross-over Pilot part, followed by a 2-way cross-over Main part. Subjects participated either in the Pilot part with 2 treatment sequences (A_B and B_A) or in the Main part with treatment sequences (C_D and D_C) with wash-out period of at least 14 days between each sequence.
Arm/Group Title Nintedanib (Pilot Part)/ Nintedanib+Ketoconazole (Pilot Part) Nintedanib+Ketoconazole (Pilot Part)/ Nintedanib (Pilot Part) Nintedanib (Main Part)/ Nintedanib+Ketoconazole (Main Part) Nintedanib+Ketoconazole (Main Part)/ Nintedanib (Main Part)
Hide Arm/Group Description Nintedanib 50mg was given as a single dose (Treatment A). Following a wash out period of at least 14 days, ketoconazole 400mg was given once daily for three days and nintedanib 50 mg was given as a single dose 1 hour (h) after the ketoconazole administration with ketoconazole under steady-state conditions (Treatment B) Ketoconazole 400mg was given once daily for three days and nintedanib 50 mg was given as a single dose 1 hour (h) after the ketoconazole administration with ketoconazole under steady-state conditions (Treatment B). Following a wash out period of at least 14 days, nintedanib 50mg was given as a single dose (Treatment A). Based on the results from the Pilot part, nintedanib 50mg was given as a single dose (Treatment C). Following a wash out period of at least 14 days, ketoconazole 400mg was given once daily for 3 days followed by administration of nintedanib 50mg as a single dose 1h after administration of ketoconazole, based on the results from the Pilot part. Nintedanib administration was done under steady state ketoconazole (Treatment D) Ketoconazole 400mg was given once daily for 3 days followed by administration of nintedanib 50mg as a single dose 1h after administration of ketoconazole, based on the results from the Pilot part. Nintedanib administration was done under steady state ketoconazole (Treatment D). Following a wash out period of at least 14 days, nintedanib 50mg was given as a single dose, based on the results from the Pilot part (Treatment C).
Period Title: Overall Study
Started 4 4 13 13
Received Nintedanib (Pilot) 4 3 0 0
Received Nintedanib+Ketoconazole (Pilot) 4 4 [1] 0 0
Received Nintedanib (Main) 0 0 13 11
Received Nintedanib+Ketoconazole (Main) 0 0 13 [2] 13 [2]
Completed 4 3 11 11
Not Completed 0 1 2 2
Reason Not Completed
other than stated above             0             1             2             2
[1]
One subject received only ketoconazole not nintedanib
[2]
Two subjects received only ketoconazole not nintedanib
Arm/Group Title Overall Study
Hide Arm/Group Description This was a randomised, open-label trial in healthy male subjects with a 2-way cross-over Pilot part, followed by a 2-way cross-over Main part. Subjects participated either in the Pilot part with 2 treatments (A and B) given in 1 of the 2 treatment sequences (A_B and B_A) or in the Main part with also 2 treatments (C and D) given in 1 of the 2 treatment sequences (C_D and D_C). Nintedanib administrations of the 2 respective treatments (A and B or C and D) were to be separated by a wash-out period of at least 14 days. The Pilot part was separated from the Main part by at least 3 weeks to allow for interim analysis
Overall Number of Baseline Participants 34
Hide Baseline Analysis Population Description
The treated set (TS) includes all subjects who were dispensed study medication and were documented to have taken at least one dose of study medication (nintedanib or ketoconazole).
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 34 participants
35.9  (10.7)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 34 participants
Female
0
   0.0%
Male
34
 100.0%
1.Primary Outcome
Title Area Under the Curve From 0 Extrapolated to Infinity (AUC0-∞)
Hide 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 hour (h) before drug administration and 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 6h, 8h, 10h, 12h, 15h, 24h, 36h, 48h and 72h after the drug administration
Hide Outcome Measure Data
Hide Analysis Population Description
The treated set (TS) includes all subjects who were dispensed study medication and were documented to have taken at least one dose of study medication (nintedanib or ketoconazole).
Arm/Group Title Nintedanib Nintedanib + Ketoconazole
Hide Arm/Group Description:

In both parts (Pilot and Main) 50 mg of nintedanib were given as a single dose on Day 1.

In the Main part, alternatively, a single dose of 100mg could have been given. The chosen dosing scheme depended on the increase in nintedanib exposure due to ketoconazole co-administration observed in the Pilot part.

In both parts (Pilot and Main) of the study 400 mg ketoconazole were given once daily for 3 days starting on Day -2 and 50 mg nintedanib were given as a single dose 1 h after the ketoconazole administration on Day 1, with ketoconazole under steady-state conditions.

In the Main part, alternatively, a single dose of 100mg could have been given 1 h after the ketoconazole administration or 4 h before the ketoconazole administration on Day 1. The chosen dosing scheme depended on the increase in nintedanib exposure due to ketoconazole co-administration observed in the Pilot part.

Overall Number of Participants Analyzed 31 29
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*h/mL
38.6
(42.5%)
61.3
(40.4%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Nintedanib, Nintedanib + Ketoconazole
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
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 effects for sequence, period, and treatment. Subjects within sequences is included as random effect.
Method of Estimation Estimation Parameter Geometric Mean Ratio in percentage
Estimated Value 160.48
Confidence Interval (2-Sided) 90%
148.245 to 173.736
Parameter Dispersion
Type: Standard Deviation
Value: 17.9
Estimation Comments

Ratio calculated as nintedanib+ketoconazole divided by nintedanib (in %).

The standard deviation is actually the geometric coefficient of variation (gCV).

2.Primary Outcome
Title Maximum Measured Concentration (Cmax)
Hide 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 hour (h) before drug administration and 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 6h, 8h, 10h, 12h, 15h, 24h, 36h, 48h and 72h after the drug administration
Hide Outcome Measure Data
Hide Analysis Population Description
TS
Arm/Group Title Nintedanib Nintedanib + Ketoconazole
Hide Arm/Group Description:

In both parts (Pilot and Main) 50 mg of nintedanib were given as a single dose on Day 1.

In the Main part, alternatively, a single dose of 100mg could have been given. The chosen dosing scheme depended on the increase in nintedanib exposure due to ketoconazole co-administration observed in the Pilot part.

In both parts (Pilot and Main) of the study 400 mg ketoconazole were given once daily for 3 days starting on Day -2 and 50 mg nintedanib were given as a single dose 1 h after the ketoconazole administration on Day 1, with ketoconazole under steady-state conditions.

In the Main part, alternatively, a single dose of 100mg could have been given 1 h after the ketoconazole administration or 4 h before the ketoconazole administration on Day 1. The chosen dosing scheme depended on the increase in nintedanib exposure due to ketoconazole co-administration observed in the Pilot part.

Overall Number of Participants Analyzed 31 29
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL
4.19
(71.0%)
7.13
(44.4%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Nintedanib, Nintedanib + Ketoconazole
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
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 effects for sequence, period, and treatment. Subjects within sequences is included as random effect.
Method of Estimation Estimation Parameter Geometric Mean Ratio in percentage
Estimated Value 179.62
Confidence Interval (2-Sided) 90%
157.557 to 204.779
Parameter Dispersion
Type: Standard Deviation
Value: 29.9
Estimation Comments

The standard deviation is actually the gCV (in %).

Ratio calculated as nintedanib+ketoconazole divided by nintedanib

3.Secondary Outcome
Title Area Under the Curve From 0 to the Last Quantifiable Concentration (AUC0-tz)
Hide Description

AUC0-tz represents the area under the plasma concentration-time curve of nintedanib from time 0 to the last quantifiable nintedanib plasma concentration.

For this endpoint, the "measured values" show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities

Time Frame 1 hour (h) before drug administration and 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 6h, 8h, 10h, 12h, 15h, 24h, 36h, 48h and 72h after the drug administration
Hide Outcome Measure Data
Hide Analysis Population Description
TS
Arm/Group Title Nintedanib Nintedanib + Ketoconazole
Hide Arm/Group Description:

In both parts (Pilot and Main) 50 mg of nintedanib were given as a single dose on Day 1.

In the Main part, alternatively, a single dose of 100mg could have been given. The chosen dosing scheme depended on the increase in nintedanib exposure due to ketoconazole co-administration observed in the Pilot part.

In both parts (Pilot and Main) of the study 400 mg ketoconazole were given once daily for 3 days starting on Day -2 and 50 mg nintedanib were given as a single dose 1 h after the ketoconazole administration on Day 1, with ketoconazole under steady-state conditions.

In the Main part, alternatively, a single dose of 100mg could have been given 1 h after the ketoconazole administration or 4 h before the ketoconazole administration on Day 1. The chosen dosing scheme depended on the increase in nintedanib exposure due to ketoconazole co-administration observed in the Pilot part.

Overall Number of Participants Analyzed 31 29
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*h/mL
35.7
(47.8%)
59.4
(40.8%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Nintedanib, Nintedanib + Ketoconazole
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 1.000
Comments p-value for ratio outside interval 0.8 to 1.25
Method ANOVA
Comments The model includes fixed effects for sequence, period, and treatment. Subjects within sequences is included as random effect.
Method of Estimation Estimation Parameter Geometric Mean Ratio in percentage
Estimated Value 168.09
Confidence Interval (2-Sided) 90%
155.252 to 181.981
Parameter Dispersion
Type: Standard Deviation
Value: 17.9
Estimation Comments

The standard deviation is actually the gCV.

Ratio calculated as nintedanib+ketoconazole divided by nintedanib (in %).

Time Frame From the first trial drug administration until 18 days after the last trial drug administration, up to 32 days.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Ketoconazole Nintedanib Nintedanib + Ketoconazole
Hide Arm/Group Description In both parts (Pilot and Main) of the study 400 mg ketoconazole were given once daily for 3 days starting on Day -2

In both parts (Pilot and Main) 50 mg of nintedanib were given as a single dose on Day 1.

In the Main part, alternatively, a single dose of 100mg could have been given. The chosen dosing scheme depended on the increase in nintedanib exposure due to ketoconazole co-administration observed in the Pilot part.

In both parts (Pilot and Main) of the study 400 mg ketoconazole were given once daily for 3 days starting on Day -2 and 50 mg nintedanib were given as a single dose 1 h after the ketoconazole administration on Day 1, with ketoconazole under steady-state conditions.

In the Main part, alternatively, a single dose of 100mg could have been given 1 h after the ketoconazole administration or 4 h before the ketoconazole administration on Day 1. The chosen dosing scheme depended on the increase in nintedanib exposure due to ketoconazole co-administration observed in the Pilot part.

All-Cause Mortality
Ketoconazole Nintedanib Nintedanib + Ketoconazole
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Ketoconazole Nintedanib Nintedanib + Ketoconazole
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/34 (0.00%)   0/31 (0.00%)   0/29 (0.00%) 
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Ketoconazole Nintedanib Nintedanib + Ketoconazole
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   2/34 (5.88%)   6/31 (19.35%)   6/29 (20.69%) 
Infections and infestations       
Nasopharyngitis  1  0/34 (0.00%)  2/31 (6.45%)  1/29 (3.45%) 
Musculoskeletal and connective tissue disorders       
Back pain  1  0/34 (0.00%)  0/31 (0.00%)  2/29 (6.90%) 
Nervous system disorders       
Headache  1  2/34 (5.88%)  5/31 (16.13%)  5/29 (17.24%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MEDDRA 15.1
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.
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
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Boehringer Ingelheim Call Center
Organization: Boehringer Ingelheim Pharmaceuticals
Phone: 1-800-243-0127
EMail: clintriage.rdg@boehringer-ingelheim.com
Layout table for additonal information
Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT01679613     History of Changes
Other Study ID Numbers: 1199.161
2012-001009-26 ( EudraCT Number: EudraCT )
First Submitted: September 3, 2012
First Posted: September 6, 2012
Results First Submitted: November 14, 2014
Results First Posted: November 27, 2014
Last Update Posted: November 27, 2014