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

Study Overview
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Brief Summary
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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.

Official Title
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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)

Conditions
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Scleroderma, Systemic

Intervention / Treatment
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* Drug: Microgynon
* Drug: Nintedanib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: All subjects<br> | Drug: Microgynon<br>* fixed sequence trial<br>Drug: Nintedanib<br>* fixed sequence trial<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Concentration-time Curve of Ethinylestradiol in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 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. | 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) | 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. | 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) | 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. | 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) | 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. | 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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Concentration-time Curve of Ethinylestradiol in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 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. | 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-∞) | 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. | 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. |