Trial Outcomes & Findings for Investigation of the Effect of Nintedanib on the Pharmacokinetics of a Combination of Ethinylestradiol and Levonorgestrel in Patients With Non-small Cell Lung Cancer (NCT NCT02751385)

Last Updated: 2019-03-14

Results Overview

Area under the concentration-time curve in plasma over the time interval from 0 to the time of the last quantifiable data point (AUC 0-tz) for ethinylestradiol and levonorgestrel after a single dose of the combination of ethinylestradiol and levonorgestrel. In Period 1, blood samples were collected at pre-dose at 0.35 hour (h) and at 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h, 48h and 72h after drug administration of Microgynon®. Nintedanib in Period 2 was started at least 7 days before Microgynon® administration. In Period 2, blood samples were collected at pre-dose at 0.35 hour (h) and at 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 11.55h, 23.55h, 47.55h and 71.55h after drug administration of Microgynon®.

Recruitment status

TERMINATED

Study phase

PHASE1

Target enrollment

2 participants

Primary outcome timeframe

Please refer to description section for the details about the actual sampling time points

Results posted on

2019-03-14

Participant Flow

Phase I study to investigate the effect of multiple oral doses of nintedanib on the single dose kinetics of a combination of ethinylestradiol and levonorgestrel (Microgynon®) in patients with non-small cell lung cancer.

All patients were screened for eligibility to participate in the trial. Patients attended specialist sites to ensure that all subjects met all inclusion/exclusion criteria. Patients were not to be entered to trial treatment if any one of the specific entry criteria were not met.

Participant milestones

Participant milestones
Measure	Microgynon® Patients were orally administered one tablet of Microgynon® (combination of 30 microgram ethinylestradiol and 150 microgram levonorgestrel per tablet) after a standardised breakfast in Period 1.	Microgynon® With Nintedanib Patients were orally administered one tablet of Microgynon® after continuous 2x2 nintedanib soft gelatine capsule containing 100 mg per day (with dose reduction to 2x1 capsule containing 150 mg, if required) for at least 7 consecutive days in Period 2. Nintedanib was to be taken continuously throughout Period 2. In case of a temporary interruption of nintedanib intake, patients could receive Microgynon® in Period 2 only if they had taken nintedanib for at least 7 consecutive days before intake of Microgynon®.
Period 1 STARTED	2	0
Period 1 COMPLETED	2	0
Period 1 NOT COMPLETED	0	0
Period 2 STARTED	0	2
Period 2 COMPLETED	0	2
Period 2 NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	All Patients n=2 Participants Patients were orally administered one tablet of Microgynon® (combination of 30 microgram ethinylestradiol and 150 microgram levonorgestrel per tablet) after a standardised breakfast in Period 1. Patients were orally administered one tablet of Microgynon® after continuous 2x2 nintedanib soft gelatine capsule containing 100 mg per day (with dose reduction to 2x1 capsule containing 150 mg, if required) for at least 7 consecutive days in Period 2. Nintedanib was to be taken continuously throughout Period 2. In case of a temporary interruption of nintedanib intake, patients could receive Microgynon® in Period 2 only if they had taken nintedanib for at least 7 consecutive days before intake of Microgynon®. Same subjects were continued to Period 2, hence baseline characteristics are presented by Period 1.
Age, Continuous	67.0 years STANDARD_DEVIATION 11.3 • n=5 Participants • TS
Sex: Female, Male Female	2 Participants n=5 Participants • TS
Sex: Female, Male Male	0 Participants n=5 Participants • TS
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants • TS
Ethnicity (NIH/OMB) Not Hispanic or Latino	2 Participants n=5 Participants • TS
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants • TS
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants • TS
Race (NIH/OMB) Asian	0 Participants n=5 Participants • TS
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants • TS
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants • TS
Race (NIH/OMB) White	2 Participants n=5 Participants • TS
Race (NIH/OMB) More than one race	0 Participants n=5 Participants • TS
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants • TS

PRIMARY outcome

Timeframe: Please refer to description section for the details about the actual sampling time points

Population: Pharmacokinetic Set (PKS): This analysis set includes all patients in the Treated Set (TS) who contributes only one PK parameter value for one period to the statistical assessment.

Outcome measures

Outcome measures
Measure	Microgynon® n=2 Participants Patients were orally administered one tablet of Microgynon® (combination of 30 microgram ethinylestradiol and 150 microgram levonorgestrel per tablet) after a standardised breakfast in Period 1.	Microgynon® With Nintedanib n=2 Participants Patients were orally administered one tablet of Microgynon® after continuous 2x2 nintedanib soft gelatine capsule containing 100 mg per day (with dose reduction to 2x1 capsule containing 150 mg, if required) for at least 7 consecutive days in Period 2. Nintedanib was to be taken continuously throughout Period 2. In case of a temporary interruption of nintedanib intake, patients could receive Microgynon® in Period 2 only if they had taken nintedanib for at least 7 consecutive days before intake of Microgynon®.
Area Under the Concentration-time Curve of the the Ethinylestradiol and Levonorgestrel in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) Ethinylestradiol	410 picogram*hour/mililiter Geometric Coefficient of Variation 6.61	348 picogram*hour/mililiter Geometric Coefficient of Variation NA Only one patient was analysed, thus Geometric coefficient of variation (gCV) was not calculated.
Area Under the Concentration-time Curve of the the Ethinylestradiol and Levonorgestrel in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) Levonorgestrel	41500 picogram*hour/mililiter Geometric Coefficient of Variation 11.0	43600 picogram*hour/mililiter Geometric Coefficient of Variation NA Only one patient was analysed, thus Geometric coefficient of variation (gCV) was not calculated.

PRIMARY outcome

Timeframe: Please refer to description section for the details about the actual sampling time points

Population: Pharmacokinetic Set (PKS): This analysis set includes all patients in the TS who contributes only one PK parameter value for one period to the statistical assessment.

Maximum blood concentrations (Cmax) for ethinylestradiol and levonorgestrel after a single dose of the combination of ethinylestradiol and levonorgestrel. In Period 1, blood samples were collected at pre-dose at 0.35 hour (h) and at 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h, 48h and 72h after drug administration of Microgynon®. Nintedanib in Period 2 was started at least 7 days before Microgynon® administration. In Period 2, blood samples were collected at pre-dose at 0.35 hour (h) and at 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 11.55h, 23.55h, 47.55h and 71.55h after drug administration of Microgynon®.

Outcome measures

Outcome measures
Measure	Microgynon® n=2 Participants Patients were orally administered one tablet of Microgynon® (combination of 30 microgram ethinylestradiol and 150 microgram levonorgestrel per tablet) after a standardised breakfast in Period 1.	Microgynon® With Nintedanib n=2 Participants Patients were orally administered one tablet of Microgynon® after continuous 2x2 nintedanib soft gelatine capsule containing 100 mg per day (with dose reduction to 2x1 capsule containing 150 mg, if required) for at least 7 consecutive days in Period 2. Nintedanib was to be taken continuously throughout Period 2. In case of a temporary interruption of nintedanib intake, patients could receive Microgynon® in Period 2 only if they had taken nintedanib for at least 7 consecutive days before intake of Microgynon®.
Maximum Measured Concentration (Cmax) of Ethinylestradiol and Levonorgestrel Ethinylestradiol	32.6 picogram/milliliter[pg/mL] Geometric Coefficient of Variation 3.04	36.9 picogram/milliliter[pg/mL] Geometric Coefficient of Variation NA Only one patient was analysed, thus Geometric coefficient of variation (gCV) was not calculated.
Maximum Measured Concentration (Cmax) of Ethinylestradiol and Levonorgestrel Levonorgestrel	2680 picogram/milliliter[pg/mL] Geometric Coefficient of Variation 23.2	1630 picogram/milliliter[pg/mL] Geometric Coefficient of Variation NA Only one patient was analysed, thus Geometric coefficient of variation (gCV) was not calculated.

SECONDARY outcome

Timeframe: Please refer to description section for the details about the actual sampling time points

Population: Pharmacokinetic Set (PKS): This analysis set includes all patients in the TS who contributes only one PK parameter value for one period to the statistical assessment.

Area under curve from zero to infinity (AUC0-∞) for ethinylestradiol and for levonorgestrel after intake of a single dose of the combination of ethinylestradiol and levonorgestrel. In Period 1, blood samples were collected at pre-dose at 0.35 hour (h) and at 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h, 48h and 72h after drug administration of Microgynon®. Nintedanib in Period 2 was started at least 7 days before Microgynon® administration. In Period 2, blood samples were collected at pre-dose at 0.35 hour (h) and at 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 11.55h, 23.55h, 47.55h and 71.55h after drug administration of Microgynon®.

Outcome measures

Outcome measures
Measure	Microgynon® n=2 Participants Patients were orally administered one tablet of Microgynon® (combination of 30 microgram ethinylestradiol and 150 microgram levonorgestrel per tablet) after a standardised breakfast in Period 1.	Microgynon® With Nintedanib n=1 Participants Patients were orally administered one tablet of Microgynon® after continuous 2x2 nintedanib soft gelatine capsule containing 100 mg per day (with dose reduction to 2x1 capsule containing 150 mg, if required) for at least 7 consecutive days in Period 2. Nintedanib was to be taken continuously throughout Period 2. In case of a temporary interruption of nintedanib intake, patients could receive Microgynon® in Period 2 only if they had taken nintedanib for at least 7 consecutive days before intake of Microgynon®.
Area Under the Concentration-time Curve of the Ethinylestradiol and Levonorgestrel in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-infinity). Levonorgestrel	54500 pg*h/mL Geometric Coefficient of Variation 9.52	57600 pg*h/mL Geometric Coefficient of Variation NA Only one patient was analysed, thus Geometric coefficient of variation (gCV) was not calculated.
Area Under the Concentration-time Curve of the Ethinylestradiol and Levonorgestrel in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-infinity). Ethinylestradiol	503 pg*h/mL Geometric Coefficient of Variation 0.394	580 pg*h/mL Geometric Coefficient of Variation NA Only one patient was analysed, thus Geometric coefficient of variation (gCV) was not calculated.

Adverse Events

Microgynon®

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

Loading Nintedanib

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

Nintedanib+Microgynon®

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

Nintedanib

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	Microgynon® n=2 participants at risk Patients were orally administered one tablet of Microgynon® (combination of 30 microgram ethinylestradiol and 150 microgram levonorgestrel per tablet) after a standardised breakfast in Period 1.	Loading Nintedanib n=2 participants at risk Patients on nintedanib loading phase	Nintedanib+Microgynon® n=2 participants at risk Patients were orally administered one tablet of Microgynon® after continuous 2x2 nintedanib soft gelatine capsule containing 100 mg per day (with dose reduction to 2x1 capsule containing 150 mg if required) for at least 7 consecutive days in Period 2. Nintedanib was to be taken continuously throughout in Period 2. In case of a temporary interruption of nintedanib intake, patients could receive Microgynon® in Period 2 only if they have taken nintedanib for at least 7 consecutive days before intake of Microgynon®.	Nintedanib n=2 participants at risk Patients administered with nintedanib
Gastrointestinal disorders Diarrhoea	0.00% 0/2 • From first drug administration until 3 days after the last drug administration. Up to 13 days for Microgynon. From first drug administration until 30 days after the last drug administration. Up to 34 days for nintedanib.	50.0% 1/2 • From first drug administration until 3 days after the last drug administration. Up to 13 days for Microgynon. From first drug administration until 30 days after the last drug administration. Up to 34 days for nintedanib.	0.00% 0/2 • From first drug administration until 3 days after the last drug administration. Up to 13 days for Microgynon. From first drug administration until 30 days after the last drug administration. Up to 34 days for nintedanib.	0.00% 0/2 • From first drug administration until 3 days after the last drug administration. Up to 13 days for Microgynon. From first drug administration until 30 days after the last drug administration. Up to 34 days for nintedanib.
Investigations Hepatic enzyme increased	0.00% 0/2 • From first drug administration until 3 days after the last drug administration. Up to 13 days for Microgynon. From first drug administration until 30 days after the last drug administration. Up to 34 days for nintedanib.	0.00% 0/2 • From first drug administration until 3 days after the last drug administration. Up to 13 days for Microgynon. From first drug administration until 30 days after the last drug administration. Up to 34 days for nintedanib.	50.0% 1/2 • From first drug administration until 3 days after the last drug administration. Up to 13 days for Microgynon. From first drug administration until 30 days after the last drug administration. Up to 34 days for nintedanib.	0.00% 0/2 • From first drug administration until 3 days after the last drug administration. Up to 13 days for Microgynon. From first drug administration until 30 days after the last drug administration. Up to 34 days for nintedanib.
Musculoskeletal and connective tissue disorders Pain in extremity	50.0% 1/2 • From first drug administration until 3 days after the last drug administration. Up to 13 days for Microgynon. From first drug administration until 30 days after the last drug administration. Up to 34 days for nintedanib.	0.00% 0/2 • From first drug administration until 3 days after the last drug administration. Up to 13 days for Microgynon. From first drug administration until 30 days after the last drug administration. Up to 34 days for nintedanib.	0.00% 0/2 • From first drug administration until 3 days after the last drug administration. Up to 13 days for Microgynon. From first drug administration until 30 days after the last drug administration. Up to 34 days for nintedanib.	0.00% 0/2 • From first drug administration until 3 days after the last drug administration. Up to 13 days for Microgynon. From first drug administration until 30 days after the last drug administration. Up to 34 days for nintedanib.

Additional Information

Boehringer Ingelheim, Call Center

Boehringer Ingelheim

Phone: 1-800-243-0127

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Other - 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.
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