A Study to Test Whether Nintedanib Influences the Components of Birth-control Pills in Women With Systemic Sclerosis Associated Interstitial Lung Disease (SSc-ILD)
Sponsor
Boehringer Ingelheim (Industry)
Overall Status
Completed
CT.gov ID
NCT03675581
Collaborator
(none)
17
10
1
11
1.7
0.2
Study Details
Study Description
Brief Summary
The main objective is to assess the potential influence of continuous intake of nintedanib on the systemic exposure of ethinylestradiol and levonorgestrel when administered in combination.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1 |
Study Design
Study Type:
Interventional
Actual Enrollment
:
17 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase I Trial 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)
Actual Study Start Date
:
Nov 8, 2018
Actual Primary Completion Date
:
Oct 9, 2019
Actual Study Completion Date
:
Oct 10, 2019
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: All subjects
|
Drug: Microgynon
fixed sequence trial
Drug: Nintedanib
fixed sequence trial
|
Outcome Measures
Primary Outcome Measures
- Area Under the Concentration-time Curve of Ethinylestradiol in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) [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.]
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.
- Area Under the Concentration-time Curve of Levonorgestrel in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) [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.]
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.
- Maximum Measured Concentration of Ethinylestradiol in Plasma (Cmax) [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.]
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.
- Maximum Measured Concentration of Levonorgestrel in Plasma (Cmax) [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.]
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.
Secondary Outcome Measures
- Area Under the Concentration-time Curve of Ethinylestradiol in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) [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.]
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.
- Area Under the Concentration-time Curve of Levonorgestrel in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) [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.]
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.
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
and Older
Sexes Eligible for Study:
Female
Accepts Healthy Volunteers:
No
Inclusion Criteria:
-
Age >= 18 years
-
A woman of non-child bearing potential, i.e. being postmenopausal1 or permanently sterilised (e.g. hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or a woman of childbearing potential correctly and consistently using a highly effective method of non-hormonal birth control (i.e. IUD or bilateral tubal ligation) together with barrier methods at least 30 days prior to first administration of Microgynon® (Visit 2), during the trial and for 3 months after last intake of nintedanib.
-
2013 American College of Rheumatology (ACR) / European League against Rheumatism (EULAR) classification criteria for Systemic Sclerosis associated Interstitial Lung Disease (SSc) fulfilled
-
SSc related Interstitial Lung Disease confirmed by High Resolution Computer Tomography (HRCT); Extent of fibrotic disease in the lung >= 10%
-
Forced Vital Capacity (FVC) >= 40% of predicted normal
-
Carbon Monoxide Diffusion Capacity (DLCO) 30% to 89% of predicted normal
-
Further inclusion criteria apply
Exclusion criteria:
-
Aspartate Transaminase (AST), Alanine Transaminase (ALT) >1.5 x Upper Level of Normal (ULN).
-
Bilirubin >1.5 x ULN
-
Creatinine clearance <30 mL/min
-
Clinically relevant anaemia at investigators discretion
-
Airway obstruction (pre-bronchodilator Forced Expiratory Volume in 1 second (FEV1)/Forced Vital Capacity (FVC) <0.7)
-
Other clinically significant pulmonary abnormalities
-
Significant Pulmonary Hypertension (PH)
-
Cardiovascular diseases
-
More than 3 digital fingertip ulcers or a history of severe digital necrosis requiring hospitalization or severe other ulcers
-
Bleeding risk (such as predisposition to bleeding, fibrinolysis, full-dose anticoagulation, high dose antiplatelet therapy, history of hemorrhagic central nervous system (CNS) event within last year
-
International normalised ratio (INR) >2, prolongation of prothrombin time (PT) and partial thromboplastin time (PTT) by >1.5 x ULN)
-
History of thrombo-embolic event within last year
-
Previous or planned hematopoietic stem cell transplantation
-
Clinical signs of malabsorption or needing parenteral nutrition
-
Patients with underlying chronic liver disease (Child Pugh A, B, C hepatic impairment)
-
Previous treatment with nintedanib or pirfenidone
-
Further exclusion criteria apply
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | UNIV UZ Gent | Gent | Belgium | 9000 | |
| 2 | HOP Avicenne | Bobigny | France | 93009 | |
| 3 | HOP Bichat | Paris | France | 75018 | |
| 4 | Universitätsklinikum Erlangen | Erlangen | Germany | 91054 | |
| 5 | Thoraxklinik-Heidelberg gGmbH am Universitätsklinikum Heidelberg | Heidelberg | Germany | 69126 | |
| 6 | Radboud Universitair Medisch Centrum | Nijmegen | Netherlands | 6525 GL | |
| 7 | Hospital Garcia de Orta, EPE | Almada | Portugal | 2801-951 | |
| 8 | Hospital Fernando Fonseca, EPE | Amadora | Portugal | 2720-276 | |
| 9 | Hospital Santa Creu i Sant Pau | Barcelona | Spain | 08026 | |
| 10 | Hospital Vall d'Hebron | Barcelona | Spain | 08035 |
Sponsors and Collaborators
- Boehringer Ingelheim
Investigators
None specified.Study Documents (Full-Text)
More Information
Additional Information:
Publications
None provided.Responsible Party:
Boehringer Ingelheim
ClinicalTrials.gov Identifier:
NCT03675581
Other Study ID Numbers:
- 1199-0340
- 2018-001177-24
First Posted:
Sep 18, 2018
Last Update Posted:
Nov 9, 2020
Last Verified:
Nov 1, 2020
Individual Participant Data (IPD) Sharing Statement:
Undecided
Plan to Share IPD:
Undecided
Studies a U.S. FDA-regulated Drug Product:
No
Studies a U.S. FDA-regulated Device Product:
No
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | 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). |
|---|---|
| Pre-assignment Detail | 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. |
| Arm/Group Title | Microgynon / Microgynon + Nintedanib |
|---|---|
| Arm/Group Description | 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 Title: Period 1: Microgynon Alone | |
| STARTED | 17 |
| COMPLETED | 17 |
| NOT COMPLETED | 0 |
| Period Title: Period 1: Microgynon Alone | |
| STARTED | 17 |
| COMPLETED | 17 |
| NOT COMPLETED | 0 |
Baseline Characteristics
| Arm/Group Title | Microgynon / Microgynon + Nintedanib |
|---|---|
| Arm/Group Description | 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. |
| Overall Participants | 17 |
| Age (Years) [Mean (Standard Deviation) ] | |
| Mean (Standard Deviation) [Years] |
59.1
(13.2)
|
| Sex: Female, Male (Count of Participants) | |
| Female |
17
100%
|
| Male |
0
0%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |
| Hispanic or Latino |
2
11.8%
|
| Not Hispanic or Latino |
15
88.2%
|
| Unknown or Not Reported |
0
0%
|
| Race (NIH/OMB) (Count of Participants) | |
| American Indian or Alaska Native |
0
0%
|
| Asian |
1
5.9%
|
| Native Hawaiian or Other Pacific Islander |
1
5.9%
|
| Black or African American |
0
0%
|
| White |
15
88.2%
|
| More than one race |
0
0%
|
| Unknown or Not Reported |
0
0%
|
Outcome Measures
| Title | Area Under the Concentration-time Curve of Ethinylestradiol in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) |
|---|---|
| Description | 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. |
| Time Frame | 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 Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Microgynon Alone (Reference Treatment, R) | Microgynon + Nintedanib (Test Treatment, T) |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 15 | 15 |
| Geometric Mean (Standard Error) [picograms * hours per milliliters] |
610.00
(1.16)
|
618.28
(1.16)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Microgynon Alone (Reference Treatment, R), Microgynon + Nintedanib (Test Treatment, T) |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | Relative systemic exposure | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Ratio of the geometric means (T/R) % |
| Estimated Value | 101.36 | |
| Confidence Interval |
(2-Sided) 90% 92.83 to 110.67 |
|
| Parameter Dispersion |
Type: Standard Deviation Value: 13.7 |
|
| Estimation Comments | The standard deviation is actually the geometric coefficient of variation (gCV) T=Test, R=Reference | |
| Title | Area Under the Concentration-time Curve of Levonorgestrel in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) |
|---|---|
| Description | 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. |
| Time Frame | 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 Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Microgynon Alone (Reference Treatment, R) | Microgynon + Nintedanib (Test Treatment, T) |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 15 | 15 |
| Geometric Mean (Standard Error) [picograms * hours per milliliters] |
33062.73
(1.20)
|
31872.47
(1.20)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Microgynon Alone (Reference Treatment, R), Microgynon + Nintedanib (Test Treatment, T) |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | Relative systemic exposure | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Ratio of the geometric means (T/R) % |
| Estimated Value | 96.40 | |
| Confidence Interval |
(2-Sided) 90% 91.48 to 101.58 |
|
| Parameter Dispersion |
Type: Standard Deviation Value: 8.2 |
|
| Estimation Comments | The standard deviation is actually the geometric coefficient of variation (gCV) T = Test, R = Reference | |
| Title | Maximum Measured Concentration of Ethinylestradiol in Plasma (Cmax) |
|---|---|
| Description | 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. |
| Time Frame | 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 Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Microgynon Alone (Reference Treatment, R) | Microgynon + Nintedanib (Test Treatment, T) |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 15 | 15 |
| Geometric Mean (Standard Error) [picograms per milliliters] |
54.75
(1.11)
|
63.89
(1.11)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Microgynon Alone (Reference Treatment, R), Microgynon + Nintedanib (Test Treatment, T) |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | Relative systemic exposure | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Ratio of the geometric means (T/R) % |
| Estimated Value | 116.69 | |
| Confidence Interval |
(2-Sided) 90% 107.63 to 126.51 |
|
| Parameter Dispersion |
Type: Standard Deviation Value: 12.6 |
|
| Estimation Comments | The standard deviation is actually the geometric coefficient of variation (gCV) T=Test, R=Reference | |
| Title | Maximum Measured Concentration of Levonorgestrel in Plasma (Cmax) |
|---|---|
| Description | 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. |
| Time Frame | 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 Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Microgynon Alone (Reference Treatment, R) | Microgynon + Nintedanib (Test Treatment, T) |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 15 | 15 |
| Geometric Mean (Standard Error) [picograms per milliliters] |
3124.48
(1.14)
|
3152.35
(1.14)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Microgynon Alone (Reference Treatment, R), Microgynon + Nintedanib (Test Treatment, T) |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | Relative systemic exposure | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Ratio of the geometric means (T/R) % |
| Estimated Value | 100.89 | |
| Confidence Interval |
(2-Sided) 90% 89.90 to 113.23 |
|
| Parameter Dispersion |
Type: Standard Deviation Value: 18.1 |
|
| Estimation Comments | The standard deviation is actually the geometric coefficient of variation (gCV) T=Test, R=Reference | |
| Title | Area Under the Concentration-time Curve of Ethinylestradiol in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) |
|---|---|
| Description | 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. |
| Time Frame | 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 Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Microgynon Alone (Reference Treatment, R) | Microgynon + Nintedanib (Test Treatment, T) |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 15 | 15 |
| Geometric Mean (Standard Error) [picograms * hours per milliliters] |
749.65
(1.14)
|
758.95
(1.14)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Microgynon Alone (Reference Treatment, R), Microgynon + Nintedanib (Test Treatment, T) |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | Relative systemic exposure | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Ratio of the geometric means (T/R) % |
| Estimated Value | 101.24 | |
| Confidence Interval |
(2-Sided) 90% 93.95 to 109.10 |
|
| Parameter Dispersion |
Type: Standard Deviation Value: 11.7 |
|
| Estimation Comments | The standard deviation is actually the geometric coefficient of variation (gCV) T=Test, R=Reference | |
| Title | Area Under the Concentration-time Curve of Levonorgestrel in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) |
|---|---|
| Description | 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. |
| Time Frame | 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 Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Microgynon Alone (Reference Treatment, R) | Microgynon + Nintedanib (Test Treatment, T) |
|---|---|---|
| Arm/Group Description | 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. | 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. |
| Measure Participants | 15 | 15 |
| Geometric Mean (Standard Error) [picograms * hours per milliliters] |
56311.68
(1.24)
|
49605.41
(1.24)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Microgynon Alone (Reference Treatment, R), Microgynon + Nintedanib (Test Treatment, T) |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | Relative systemic exposure | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Ratio of the geometric means (T/R) % |
| Estimated Value | 88.09 | |
| Confidence Interval |
(2-Sided) 90% 80.03 to 96.96 |
|
| Parameter Dispersion |
Type: Standard Deviation Value: 15.0 |
|
| Estimation Comments | The standard deviation is actually the geometric coefficient of variation (gCV) T=Test, R=Reference | |
Adverse Events
| Time Frame | 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. | |||||||
|---|---|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | 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. | |||||||
| Arm/Group Title | Microgynon Alone (Reference Treatment, R) | Nintedanib Alone (Before Combination Treatment) | Microgynon + Nintedanib (Test Treatment, T) | Nintedanib Alone (After Combination Treatment) | ||||
| Arm/Group Description | 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. | 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. | 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. | 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. | ||||
All Cause Mortality |
||||||||
| Microgynon Alone (Reference Treatment, R) | Nintedanib Alone (Before Combination Treatment) | Microgynon + Nintedanib (Test Treatment, T) | Nintedanib Alone (After Combination Treatment) | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/17 (0%) | 0/17 (0%) | 0/17 (0%) | 0/17 (0%) | ||||
Serious Adverse Events |
||||||||
| Microgynon Alone (Reference Treatment, R) | Nintedanib Alone (Before Combination Treatment) | Microgynon + Nintedanib (Test Treatment, T) | Nintedanib Alone (After Combination Treatment) | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/17 (0%) | 0/17 (0%) | 1/17 (5.9%) | 0/17 (0%) | ||||
| Hepatobiliary disorders | ||||||||
| Drug-induced liver injury | 0/17 (0%) | 0/17 (0%) | 1/17 (5.9%) | 0/17 (0%) | ||||
Other (Not Including Serious) Adverse Events |
||||||||
| Microgynon Alone (Reference Treatment, R) | Nintedanib Alone (Before Combination Treatment) | Microgynon + Nintedanib (Test Treatment, T) | Nintedanib Alone (After Combination Treatment) | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 3/17 (17.6%) | 11/17 (64.7%) | 3/17 (17.6%) | 2/17 (11.8%) | ||||
| Gastrointestinal disorders | ||||||||
| Nausea | 0/17 (0%) | 6/17 (35.3%) | 0/17 (0%) | 0/17 (0%) | ||||
| Vomiting | 0/17 (0%) | 5/17 (29.4%) | 1/17 (5.9%) | 0/17 (0%) | ||||
| Diarrhoea | 0/17 (0%) | 4/17 (23.5%) | 1/17 (5.9%) | 0/17 (0%) | ||||
| Abdominal pain upper | 0/17 (0%) | 2/17 (11.8%) | 1/17 (5.9%) | 0/17 (0%) | ||||
| Abdominal pain | 0/17 (0%) | 1/17 (5.9%) | 0/17 (0%) | 0/17 (0%) | ||||
| General disorders | ||||||||
| Fatigue | 1/17 (5.9%) | 0/17 (0%) | 0/17 (0%) | 0/17 (0%) | ||||
| Malaise | 1/17 (5.9%) | 0/17 (0%) | 0/17 (0%) | 0/17 (0%) | ||||
| Infections and infestations | ||||||||
| Bronchitis | 0/17 (0%) | 1/17 (5.9%) | 0/17 (0%) | 0/17 (0%) | ||||
| Respiratory tract infection | 0/17 (0%) | 1/17 (5.9%) | 0/17 (0%) | 0/17 (0%) | ||||
| Rhinitis | 0/17 (0%) | 1/17 (5.9%) | 0/17 (0%) | 0/17 (0%) | ||||
| Investigations | ||||||||
| Aspartate aminotransferase increased | 0/17 (0%) | 0/17 (0%) | 0/17 (0%) | 1/17 (5.9%) | ||||
| Musculoskeletal and connective tissue disorders | ||||||||
| Musculoskeletal pain | 0/17 (0%) | 1/17 (5.9%) | 0/17 (0%) | 0/17 (0%) | ||||
| Pain in extremity | 0/17 (0%) | 1/17 (5.9%) | 0/17 (0%) | 0/17 (0%) | ||||
| Nervous system disorders | ||||||||
| Headache | 2/17 (11.8%) | 1/17 (5.9%) | 1/17 (5.9%) | 0/17 (0%) | ||||
| Dizziness | 1/17 (5.9%) | 1/17 (5.9%) | 0/17 (0%) | 0/17 (0%) | ||||
| Reproductive system and breast disorders | ||||||||
| Vaginal discharge | 0/17 (0%) | 1/17 (5.9%) | 0/17 (0%) | 1/17 (5.9%) | ||||
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
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
| Name/Title | Boehringer Ingelheim, Call Center |
|---|---|
| Organization | Boehringer Ingelheim |
| Phone | 1-800-243-0127 |
| clintriage.rdg@boehringer-ingelheim.com |
Responsible Party:
Boehringer Ingelheim
ClinicalTrials.gov Identifier:
NCT03675581
Other Study ID Numbers:
- 1199-0340
- 2018-001177-24
First Posted:
Sep 18, 2018
Last Update Posted:
Nov 9, 2020
Last Verified:
Nov 1, 2020