Clinical trial NCT03675581: A Study to Test Whether Nintedanib Influences the Components of Birth-control Pills in Women With Systemic Sclerosis Associated Interstitial Lung Disease (SSc-ILD)
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Scleroderma, Systemic
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
First posted: 2018-09-18
Enrollment: 17
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Area Under the Concentration-time Curve of Ethinylestradiol in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz)
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.
measure: Area Under the Concentration-time Curve of Levonorgestrel in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz)
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.
measure: Maximum Measured Concentration of Ethinylestradiol in Plasma (Cmax)
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.
measure: Maximum Measured Concentration of Levonorgestrel in Plasma (Cmax)
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.
Secondary outcomes:
measure: Area Under the Concentration-time Curve of Ethinylestradiol in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞)
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.
measure: Area Under the Concentration-time Curve of Levonorgestrel in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞)
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.
Other outcomes:
Locations:
city: Gent
country: Belgium
facility: UNIV UZ Gent
city: Bobigny
country: France
facility: HOP Avicenne
city: Paris
country: France
facility: HOP Bichat
city: Erlangen
country: Germany
facility: Universitätsklinikum Erlangen
city: Heidelberg
country: Germany
facility: Thoraxklinik-Heidelberg gGmbH am Universitätsklinikum Heidelberg
city: Nijmegen
country: Netherlands
facility: Radboud Universitair Medisch Centrum
city: Almada
country: Portugal
facility: Hospital Garcia de Orta, EPE
city: Amadora
country: Portugal
facility: Hospital Fernando Fonseca, EPE
city: Barcelona
country: Spain
facility: Hospital Santa Creu i Sant Pau
city: Barcelona
country: Spain
facility: Hospital Vall d'Hebron
Study officials:
References:
citation: Vonk MC, Guillen-Del-Castillo A, Kreuter M, Avis M, Marzin K, Mack SR, Wind S, Gahlemann M. A Drug-Drug Interaction Study to Investigate the Effect of Nintedanib on the Pharmacokinetics of Microgynon (Ethinylestradiol and Levonorgestrel) in Female Patients with Systemic Sclerosis-Associated Interstitial Lung Disease. Eur J Drug Metab Pharmacokinet. 2022 Jan;47(1):81-89. doi: 10.1007/s13318-021-00728-7. Epub 2021 Oct 18.