Trial Outcomes & Findings for A Study to Test Whether Nintedanib Influences the Components of Birth-control Pills in Women With Systemic Sclerosis Associated Interstitial Lung Disease (SSc-ILD) (NCT NCT03675581)

Last Updated: 2020-11-09

Results Overview

Area under the concentration-time curve of ethinylestradiol in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz). For Microgynon (ethinylestradiol + levonorgestrel) alone (Reference treatment, R) and Microgynon (ethinylestradiol + levonorgestrel) + nintedanib (Test treatment, T) plasma concentrations of ethinylestradiol were measured 35 minutes (min) before and at 30 min, 1 hour (h), 1h 30 min, 2h, 3h, 4h, 6h, 8h, 11h 55 min, 23h 55 min, 47h 55 min after Microgynon administration alone or in combination with nintedanib.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

17 participants

Primary outcome timeframe

35 minutes (min) before and at 30 min, 1 hour (h), 1h 30 min, 2h, 3h, 4h, 6h, 8h, 11h 55 min, 23h 55 min, 47h 55 min after microgynon administration alone or in combination with nintedanib.

Results posted on

2020-11-09

Participant Flow

This is an open-label, 2-period, fixed-sequence, Phase I trial in order to investigate the effect of nintedanib on the pharmacokinetics of a combination of ethinylestradiol and levonorgestrel in female patients with Systemic Sclerosis associated Interstitial Lung Disease (SSc-ILD).

All patients were screened for eligibility prior to participation in the trial. Patients attended a specialist site which ensured that they (the patients) strictly met all inclusion and none of the exclusion criteria. Patients were not to be allocated to a treatment group if any of the entry criteria were violated.

Participant milestones

Participant milestones
Measure	Microgynon / Microgynon + Nintedanib Period 1 consisted of a Microgynon alone treatment. All patients received a single dose of Microgynon: 1 tablet of 30 μg ethinylestradiol and 150 μg levonorgestrel at trial Day -3 (Reference treatment, R). Period 2 consisted of a Microgynon + nintedanib combination treatment. All patients received a continuous stable dose of nintedanib, soft gelatine capsule of 150 milligrams (mg) twice daily (bid) (300 mg total per day), starting from trial Day 1 over a period of at least 14 days to approximately 28 days. After at least 10 days of nintedanib treatment, all patients received a second single dose of Microgynon: 1 tablet of 30 μg ethinylestradiol and 150 μg levonorgestrel on trial Day 11 (Test treatment, T). All treatments were to be taken with food, swallowed whole with approximately 250 milliliters (mL) of water and was not to be chewed or crushed.
Period 1: Microgynon Alone STARTED	17
Period 1: Microgynon Alone COMPLETED	17
Period 1: Microgynon Alone NOT COMPLETED	0
Period 2: Microgynon + Nintedanib STARTED	17
Period 2: Microgynon + Nintedanib COMPLETED	17
Period 2: Microgynon + Nintedanib NOT COMPLETED	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

A Study to Test Whether Nintedanib Influences the Components of Birth-control Pills in Women With Systemic Sclerosis Associated Interstitial Lung Disease (SSc-ILD)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Microgynon / Microgynon + Nintedanib n=17 Participants Period 1 consisted of a Microgynon alone treatment. All patients received a single dose of Microgynon: 1 tablet of 30 μg ethinylestradiol and 150 μg levonorgestrel at trial Day -3 (Reference treatment, R). Period 2 consisted of a Microgynon + nintedanib combination treatment. All patients received a continuous stable dose of nintedanib, soft gelatine capsule of 150 milligrams (mg) twice daily (bid) (300 mg total per day), starting from trial Day 1 over a period of at least 14 days to approximately 28 days. After at least 10 days of nintedanib treatment, all patients received a second single dose of Microgynon: 1 tablet of 30 μg ethinylestradiol and 150 μg levonorgestrel on trial Day 11 (Test treatment, T). All treatments were to be taken with food, swallowed whole with approximately 250 milliliters (mL) of water and was not to be chewed or crushed.
Age, Continuous	59.1 Years STANDARD_DEVIATION 13.2 • n=5 Participants
Sex: Female, Male Female	17 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	15 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants
Race (NIH/OMB) Asian	1 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	1 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants
Race (NIH/OMB) White	15 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: 35 minutes (min) before and at 30 min, 1 hour (h), 1h 30 min, 2h, 3h, 4h, 6h, 8h, 11h 55 min, 23h 55 min, 47h 55 min after microgynon administration alone or in combination with nintedanib.

Population: Pharmacokinetic parameter analysis set (PKS): The PKS included all subjects in the treated set (TS) who provided at least 1 pharmacokinetic (PK) endpoint that had been defined as primary or secondary and was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability.

Outcome measures

Outcome measures
Measure	Microgynon Alone (Reference Treatment, R) n=15 Participants Period 1 consisted of a Microgynon alone treatment. All patients received a single dose of Microgynon: 1 tablet of 30 μg ethinylestradiol and 150 μg levonorgestrel at trial Day -3 (Reference treatment, R). The treatment was to be taken with food, swallowed whole with approximately 250 milliliters (mL) of water and was not to be chewed or crushed.	Microgynon + Nintedanib (Test Treatment, T) n=15 Participants Period 2 consisted of a Microgynon + nintedanib combination treatment. All patients received a continuous stable dose of nintedanib, soft gelatine capsule of 150 milligrams (mg) twice daily (bid) (300 mg total per day), starting from trial Day 1 over a period of at least 14 days to approximately 28 days. After at least 10 days of nintedanib treatment, all patients received a second single dose of Microgynon: 1 tablet of 30 μg ethinylestradiol and 150 μg levonorgestrel on trial Day 11 (Test treatment, T). The treatment was to be taken with food, swallowed whole with approximately 250 milliliters (mL) of water and was not to be chewed or crushed.
Area Under the Concentration-time Curve of Ethinylestradiol in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz)	610.00 picograms * hours per milliliters Standard Error 1.16	618.28 picograms * hours per milliliters Standard Error 1.16

PRIMARY outcome

Area under the concentration-time curve of levonorgestrel in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz). For Microgynon (ethinylestradiol + levonorgestrel) alone (Reference treatment, R) and Microgynon (ethinylestradiol + levonorgestrel) + nintedanib (Test treatment, T) plasma concentrations of levonorgestrel were measured 35 minutes (min) before and at 30 min, 1 hour (h), 1h 30 min, 2h, 3h, 4h, 6h, 8h, 11h 55 min, 23h 55 min, 47h 55 min after Microgynon administration alone or in combination with nintedanib.

Outcome measures

Outcome measures
Measure	Microgynon Alone (Reference Treatment, R) n=15 Participants Period 1 consisted of a Microgynon alone treatment. All patients received a single dose of Microgynon: 1 tablet of 30 μg ethinylestradiol and 150 μg levonorgestrel at trial Day -3 (Reference treatment, R). The treatment was to be taken with food, swallowed whole with approximately 250 milliliters (mL) of water and was not to be chewed or crushed.	Microgynon + Nintedanib (Test Treatment, T) n=15 Participants Period 2 consisted of a Microgynon + nintedanib combination treatment. All patients received a continuous stable dose of nintedanib, soft gelatine capsule of 150 milligrams (mg) twice daily (bid) (300 mg total per day), starting from trial Day 1 over a period of at least 14 days to approximately 28 days. After at least 10 days of nintedanib treatment, all patients received a second single dose of Microgynon: 1 tablet of 30 μg ethinylestradiol and 150 μg levonorgestrel on trial Day 11 (Test treatment, T). The treatment was to be taken with food, swallowed whole with approximately 250 milliliters (mL) of water and was not to be chewed or crushed.
Area Under the Concentration-time Curve of Levonorgestrel in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz)	33062.73 picograms * hours per milliliters Standard Error 1.20	31872.47 picograms * hours per milliliters Standard Error 1.20

PRIMARY outcome

Maximum measured concentration of ethinylestradiol in plasma (Cmax). For Microgynon (ethinylestradiol + levonorgestrel) alone (Reference treatment, R) and Microgynon (ethinylestradiol + levonorgestrel) + nintedanib (Test treatment, T) plasma concentrations of ethinylestradiol were measured 35 minutes (min) before and at 30 min, 1 hour (h), 1h 30 min, 2h, 3h, 4h, 6h, 8h, 11h 55 min, 23h 55 min, 47h 55 min after Microgynon administration alone or in combination with nintedanib.

Outcome measures

Outcome measures
Measure	Microgynon Alone (Reference Treatment, R) n=15 Participants Period 1 consisted of a Microgynon alone treatment. All patients received a single dose of Microgynon: 1 tablet of 30 μg ethinylestradiol and 150 μg levonorgestrel at trial Day -3 (Reference treatment, R). The treatment was to be taken with food, swallowed whole with approximately 250 milliliters (mL) of water and was not to be chewed or crushed.	Microgynon + Nintedanib (Test Treatment, T) n=15 Participants Period 2 consisted of a Microgynon + nintedanib combination treatment. All patients received a continuous stable dose of nintedanib, soft gelatine capsule of 150 milligrams (mg) twice daily (bid) (300 mg total per day), starting from trial Day 1 over a period of at least 14 days to approximately 28 days. After at least 10 days of nintedanib treatment, all patients received a second single dose of Microgynon: 1 tablet of 30 μg ethinylestradiol and 150 μg levonorgestrel on trial Day 11 (Test treatment, T). The treatment was to be taken with food, swallowed whole with approximately 250 milliliters (mL) of water and was not to be chewed or crushed.
Maximum Measured Concentration of Ethinylestradiol in Plasma (Cmax)	54.75 picograms per milliliters Standard Error 1.11	63.89 picograms per milliliters Standard Error 1.11

PRIMARY outcome

Maximum measured concentration of levonorgestrel in plasma (Cmax). For Microgynon (ethinylestradiol + levonorgestrel) alone (Reference treatment, R) and Microgynon (ethinylestradiol + levonorgestrel) + nintedanib (Test treatment, T) plasma concentrations of levonorgestrel were measured 35 minutes (min) before and at 30 min, 1 hour (h), 1h 30 min, 2h, 3h, 4h, 6h, 8h, 11h 55 min, 23h 55 min, 47h 55 min after Microgynon administration alone or in combination with nintedanib.

Outcome measures

Outcome measures
Measure	Microgynon Alone (Reference Treatment, R) n=15 Participants Period 1 consisted of a Microgynon alone treatment. All patients received a single dose of Microgynon: 1 tablet of 30 μg ethinylestradiol and 150 μg levonorgestrel at trial Day -3 (Reference treatment, R). The treatment was to be taken with food, swallowed whole with approximately 250 milliliters (mL) of water and was not to be chewed or crushed.	Microgynon + Nintedanib (Test Treatment, T) n=15 Participants Period 2 consisted of a Microgynon + nintedanib combination treatment. All patients received a continuous stable dose of nintedanib, soft gelatine capsule of 150 milligrams (mg) twice daily (bid) (300 mg total per day), starting from trial Day 1 over a period of at least 14 days to approximately 28 days. After at least 10 days of nintedanib treatment, all patients received a second single dose of Microgynon: 1 tablet of 30 μg ethinylestradiol and 150 μg levonorgestrel on trial Day 11 (Test treatment, T). The treatment was to be taken with food, swallowed whole with approximately 250 milliliters (mL) of water and was not to be chewed or crushed.
Maximum Measured Concentration of Levonorgestrel in Plasma (Cmax)	3124.48 picograms per milliliters Standard Error 1.14	3152.35 picograms per milliliters Standard Error 1.14

SECONDARY outcome

Area under the concentration-time curve of ethinylestradiol in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞). For Microgynon (ethinylestradiol + levonorgestrel) alone (Reference treatment, R) and Microgynon (ethinylestradiol + levonorgestrel) + nintedanib (Test treatment, T) plasma concentrations of ethinylestradiol were measured 35 minutes (min) before and at 30 min, 1 hour (h), 1h 30 min, 2h, 3h, 4h, 6h, 8h, 11h 55 min, 23h 55 min, 47h 55 min after Microgynon administration alone or in combination with nintedanib.

Outcome measures

Outcome measures
Measure	Microgynon Alone (Reference Treatment, R) n=15 Participants Period 1 consisted of a Microgynon alone treatment. All patients received a single dose of Microgynon: 1 tablet of 30 μg ethinylestradiol and 150 μg levonorgestrel at trial Day -3 (Reference treatment, R). The treatment was to be taken with food, swallowed whole with approximately 250 milliliters (mL) of water and was not to be chewed or crushed.	Microgynon + Nintedanib (Test Treatment, T) n=15 Participants Period 2 consisted of a Microgynon + nintedanib combination treatment. All patients received a continuous stable dose of nintedanib, soft gelatine capsule of 150 milligrams (mg) twice daily (bid) (300 mg total per day), starting from trial Day 1 over a period of at least 14 days to approximately 28 days. After at least 10 days of nintedanib treatment, all patients received a second single dose of Microgynon: 1 tablet of 30 μg ethinylestradiol and 150 μg levonorgestrel on trial Day 11 (Test treatment, T). The treatment was to be taken with food, swallowed whole with approximately 250 milliliters (mL) of water and was not to be chewed or crushed.
Area Under the Concentration-time Curve of Ethinylestradiol in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞)	749.65 picograms * hours per milliliters Standard Error 1.14	758.95 picograms * hours per milliliters Standard Error 1.14

SECONDARY outcome

Area under the concentration-time curve of levonorgestrel in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞). For Microgynon (ethinylestradiol + levonorgestrel) alone (Reference treatment, R) and Microgynon (ethinylestradiol + levonorgestrel) + nintedanib (Test treatment, T) plasma concentrations of levonorgestrel were measured 35 minutes (min) before and at 30 min, 1 hour (h), 1h 30 min, 2h, 3h, 4h, 6h, 8h, 11h 55 min, 23h 55 min, 47h 55 min after Microgynon administration alone or in combination with nintedanib.

Outcome measures

Outcome measures
Measure	Microgynon Alone (Reference Treatment, R) n=15 Participants Period 1 consisted of a Microgynon alone treatment. All patients received a single dose of Microgynon: 1 tablet of 30 μg ethinylestradiol and 150 μg levonorgestrel at trial Day -3 (Reference treatment, R). The treatment was to be taken with food, swallowed whole with approximately 250 milliliters (mL) of water and was not to be chewed or crushed.	Microgynon + Nintedanib (Test Treatment, T) n=15 Participants Period 2 consisted of a Microgynon + nintedanib combination treatment. All patients received a continuous stable dose of nintedanib, soft gelatine capsule of 150 milligrams (mg) twice daily (bid) (300 mg total per day), starting from trial Day 1 over a period of at least 14 days to approximately 28 days. After at least 10 days of nintedanib treatment, all patients received a second single dose of Microgynon: 1 tablet of 30 μg ethinylestradiol and 150 μg levonorgestrel on trial Day 11 (Test treatment, T). The treatment was to be taken with food, swallowed whole with approximately 250 milliliters (mL) of water and was not to be chewed or crushed.
Area Under the Concentration-time Curve of Levonorgestrel in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞)	56311.68 picograms * hours per milliliters Standard Error 1.24	49605.41 picograms * hours per milliliters Standard Error 1.24

Adverse Events

Microgynon Alone (Reference Treatment, R)

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Nintedanib Alone (Before Combination Treatment)

Serious events: 0 serious events

Other events: 11 other events

Deaths: 0 deaths

Microgynon + Nintedanib (Test Treatment, T)

Serious events: 1 serious events

Other events: 3 other events

Deaths: 0 deaths

Nintedanib Alone (After Combination Treatment)

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Microgynon Alone (Reference Treatment, R) n=17 participants at risk Period 1 consisted of a Microgynon alone treatment. All patients received a single dose of Microgynon: 1 tablet of 30 μg ethinylestradiol and 150 μg levonorgestrel at trial Day -3 (Reference treatment, R). The treatment was to be taken with food, swallowed whole with approximately 250 milliliters (mL) of water and was not to be chewed or crushed.	Nintedanib Alone (Before Combination Treatment) n=17 participants at risk All patients received a continuous stable dose of nintedanib, 150 mg twice daily (bid) (300 mg total per day), soft gelatine capsule from trial Day 1 for at least 10 consecutive days. The treatment was to be taken with food, swallowed whole with approximately 250 mL of water and was not to be chewed or crushed.	Microgynon + Nintedanib (Test Treatment, T) n=17 participants at risk Period 2 consisted of a Microgynon + nintedanib combination treatment. All patients received a continuous stable dose of nintedanib, soft gelatine capsule of 150 milligrams (mg) twice daily (bid) (300 mg total per day), starting from trial Day 1 over a period of at least 14 days to approximately 28 days. After at least 10 days of nintedanib treatment, all patients received a second single dose of Microgynon: 1 tablet of 30 μg ethinylestradiol and 150 μg levonorgestrel on trial Day 11 (Test treatment, T). The treatment was to be taken with food, swallowed whole with approximately 250 mL of water and was not to be chewed or crushed.	Nintedanib Alone (After Combination Treatment) n=17 participants at risk All patients continued to receive a stable dose of nintedanib, 150 mg bid (300 mg total per day), soft gelatine capsule after the combination treatment on trial Days 12 and 13. The treatment was to be taken with food, swallowed whole with approximately 250 mL of water and was not to be chewed or crushed. AE's are considered to have occurred on nintedanib alone (after combination treatment) if occurring on Day 14 or later, i.e. at least 3 days after combination treatment.
Hepatobiliary disorders Drug-induced liver injury	0.00% 0/17 • The adverse events collection time frame started at the day of first administration of the treatment till 2 days after for Microgynon alone, till 10 days after for nintedanib (before combination treatment), till 2 days after for Microgynon + nintedanib and as from 3 days after the combination treatment for nintedanib alone. Treated set (TS): The TS included all subjects who had been enrolled and treated with at least 1 dose of study drug. The treated set was used for safety analyses.	0.00% 0/17 • The adverse events collection time frame started at the day of first administration of the treatment till 2 days after for Microgynon alone, till 10 days after for nintedanib (before combination treatment), till 2 days after for Microgynon + nintedanib and as from 3 days after the combination treatment for nintedanib alone. Treated set (TS): The TS included all subjects who had been enrolled and treated with at least 1 dose of study drug. The treated set was used for safety analyses.	5.9% 1/17 • The adverse events collection time frame started at the day of first administration of the treatment till 2 days after for Microgynon alone, till 10 days after for nintedanib (before combination treatment), till 2 days after for Microgynon + nintedanib and as from 3 days after the combination treatment for nintedanib alone. Treated set (TS): The TS included all subjects who had been enrolled and treated with at least 1 dose of study drug. The treated set was used for safety analyses.	0.00% 0/17 • The adverse events collection time frame started at the day of first administration of the treatment till 2 days after for Microgynon alone, till 10 days after for nintedanib (before combination treatment), till 2 days after for Microgynon + nintedanib and as from 3 days after the combination treatment for nintedanib alone. Treated set (TS): The TS included all subjects who had been enrolled and treated with at least 1 dose of study drug. The treated set was used for safety analyses.

Other adverse events

Additional Information

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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.
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