Trial Outcomes & Findings for Investigation of Drug-drug Interaction of Nintedanib and Ketoconazole in Healthy Male Volunteers (NCT NCT01679613)
NCT ID: NCT01679613
Last Updated: 2014-11-27
Results Overview
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
Recruitment status
COMPLETED
Study phase
PHASE1
Target enrollment
34 participants
Primary outcome timeframe
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
Results posted on
2014-11-27
Participant Flow
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.
Participant milestones
| Measure |
Nintedanib (Pilot Part)/ Nintedanib+Ketoconazole (Pilot Part)
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)
|
Nintedanib+Ketoconazole (Pilot Part)/ Nintedanib (Pilot Part)
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).
|
Nintedanib (Main Part)/ Nintedanib+Ketoconazole (Main Part)
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)
|
Nintedanib+Ketoconazole (Main Part)/ Nintedanib (Main Part)
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).
|
|---|---|---|---|---|
|
Overall Study
STARTED
|
4
|
4
|
13
|
13
|
|
Overall Study
Received Nintedanib (Pilot)
|
4
|
3
|
0
|
0
|
|
Overall Study
Received Nintedanib+Ketoconazole (Pilot)
|
4
|
4
|
0
|
0
|
|
Overall Study
Received Nintedanib (Main)
|
0
|
0
|
13
|
11
|
|
Overall Study
Received Nintedanib+Ketoconazole (Main)
|
0
|
0
|
13
|
13
|
|
Overall Study
COMPLETED
|
4
|
3
|
11
|
11
|
|
Overall Study
NOT COMPLETED
|
0
|
1
|
2
|
2
|
Reasons for withdrawal
| Measure |
Nintedanib (Pilot Part)/ Nintedanib+Ketoconazole (Pilot Part)
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)
|
Nintedanib+Ketoconazole (Pilot Part)/ Nintedanib (Pilot Part)
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).
|
Nintedanib (Main Part)/ Nintedanib+Ketoconazole (Main Part)
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)
|
Nintedanib+Ketoconazole (Main Part)/ Nintedanib (Main Part)
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).
|
|---|---|---|---|---|
|
Overall Study
other than stated above
|
0
|
1
|
2
|
2
|
Baseline Characteristics
Investigation of Drug-drug Interaction of Nintedanib and Ketoconazole in Healthy Male Volunteers
Baseline characteristics by cohort
| Measure |
Overall Study
n=34 Participants
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
|
|---|---|
|
Age, Continuous
|
35.9 years
STANDARD_DEVIATION 10.7 • n=5 Participants
|
|
Sex: Female, Male
Female
|
0 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
34 Participants
n=5 Participants
|
PRIMARY outcome
Timeframe: 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 administrationPopulation: 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).
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
Outcome measures
| Measure |
Nintedanib
n=31 Participants
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.
|
Nintedanib + Ketoconazole
n=29 Participants
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.
|
|---|---|---|
|
Area Under the Curve From 0 Extrapolated to Infinity (AUC0-∞)
|
38.6 ng*h/mL
Geometric Coefficient of Variation 42.5
|
61.3 ng*h/mL
Geometric Coefficient of Variation 40.4
|
PRIMARY outcome
Timeframe: 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 administrationPopulation: TS
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
Outcome measures
| Measure |
Nintedanib
n=31 Participants
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.
|
Nintedanib + Ketoconazole
n=29 Participants
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.
|
|---|---|---|
|
Maximum Measured Concentration (Cmax)
|
4.19 ng/mL
Geometric Coefficient of Variation 71.0
|
7.13 ng/mL
Geometric Coefficient of Variation 44.4
|
SECONDARY outcome
Timeframe: 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 administrationPopulation: TS
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
Outcome measures
| Measure |
Nintedanib
n=31 Participants
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.
|
Nintedanib + Ketoconazole
n=29 Participants
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.
|
|---|---|---|
|
Area Under the Curve From 0 to the Last Quantifiable Concentration (AUC0-tz)
|
35.7 ng*h/mL
Geometric Coefficient of Variation 47.8
|
59.4 ng*h/mL
Geometric Coefficient of Variation 40.8
|
Adverse Events
Ketoconazole
Serious events: 0 serious events
Other events: 2 other events
Deaths: 0 deaths
Nintedanib
Serious events: 0 serious events
Other events: 6 other events
Deaths: 0 deaths
Nintedanib + Ketoconazole
Serious events: 0 serious events
Other events: 6 other events
Deaths: 0 deaths
Serious adverse events
Adverse event data not reported
Other adverse events
| Measure |
Ketoconazole
n=34 participants at risk
In both parts (Pilot and Main) of the study 400 mg ketoconazole were given once daily for 3 days starting on Day -2
|
Nintedanib
n=31 participants at risk
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.
|
Nintedanib + Ketoconazole
n=29 participants at risk
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.
|
|---|---|---|---|
|
Infections and infestations
Nasopharyngitis
|
0.00%
0/34 • From the first trial drug administration until 18 days after the last trial drug administration, up to 32 days.
|
6.5%
2/31 • From the first trial drug administration until 18 days after the last trial drug administration, up to 32 days.
|
3.4%
1/29 • From the first trial drug administration until 18 days after the last trial drug administration, up to 32 days.
|
|
Nervous system disorders
Headache
|
5.9%
2/34 • From the first trial drug administration until 18 days after the last trial drug administration, up to 32 days.
|
16.1%
5/31 • From the first trial drug administration until 18 days after the last trial drug administration, up to 32 days.
|
17.2%
5/29 • From the first trial drug administration until 18 days after the last trial drug administration, up to 32 days.
|
|
Musculoskeletal and connective tissue disorders
Back pain
|
0.00%
0/34 • From the first trial drug administration until 18 days after the last trial drug administration, up to 32 days.
|
0.00%
0/31 • From the first trial drug administration until 18 days after the last trial drug administration, up to 32 days.
|
6.9%
2/29 • From the first trial drug administration until 18 days after the last trial drug administration, up to 32 days.
|
Additional Information
Boehringer Ingelheim Call Center
Boehringer Ingelheim Pharmaceuticals
Phone: 1-800-243-0127
Email: [email protected]
Results disclosure agreements
- Principal investigator is a sponsor employee 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
- Publication restrictions are in place
Restriction type: OTHER