Clinical trial NCT03359291: Clinical Study to Investigate the Effect of Macitentan on the Concentrations of Rosuvastatin in the Blood of Healthy Male Subjects
Official title: A Single-center, Open-label, One-sequence, Two-treatment Study to Investigate the Effect of Macitentan at Steady State on the Pharmacokinetics of Rosuvastatin in Healthy Male Subjects.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Subjects
Keywords: macitentan
rosuvastatin
pharmacokinetics
Lead sponsor: Actelion
Sponsor class: INDUSTRY
First posted: 2017-12-02
Enrollment: 20
Sex: MALE
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: All subjects will receive rosuvastatin alone (treatment A) or with macitentan at steady state (treatment B). A fixed sequence design was selected to avoid a lengthy washout period and unnecessary prolongation of subjects' participation in the study.
Primary purpose: OTHER

Brief summary: The aim of this Phase 1 trial is to study a potential drug-drug interaction between macitentan and rosuvastatin, a model substrate of various transporter proteins (e.g. in the gut).

Detailed description: Rosuvastatin is a substrate of various transporter proteins including breast cancer resistance protein (BCRP) and organic anion-transporting polypeptides (OATP). It is unknown to which extent macitentan has an effect, if any, on BCRP transporters, especially intestinal BCRP. The primary purpose of this Phase 1 study is to investigate the effect of macitentan on the pharmacokinetics of rosuvastatin, a model BCRP substrate.

Eligibility criteria: Principal Inclusion Criteria:

* Signed informed consent in the local language prior to any study-mandated procedure.
* Healthy male subjects aged between 18 and 55 years (inclusive) at screening.
* No clinically significant findings on the physical examination at screening.
* Body mass index of 18.0 to 30.0 kg/m2 (inclusive) at screening.
* Systolic blood pressure 100-140 mmHg, diastolic blood pressure 60-90 mmHg, and pulse rate 50-90 beats per minute (inclusive), measured on the dominant arm, after 5 min in the supine position at screening.
* 12-lead electrocardiogram (ECG) without clinically relevant abnormalities, measured after 5 min in the supine position at screening.
* Hematology and clinical chemistry test results not deviating from the normal range to a clinically relevant extent at screening.
* Negative results from urine drug screen and alcohol breath test at screening and Day -1.
* Ability to communicate well with the investigator, in the local language, and to understand and comply with the requirements of the study.

Principal Exclusion Criteria:

* Known allergic reactions or hypersensitivity to macitentan, rosuvastatin, any drug of the same classes, or any of their excipients.
* Any contraindication for rosuvastatin treatment.
* History or clinical evidence of myopathy.
* Subjects of Asian race.
* Known hypersensitivity or allergy to natural rubber latex.
* Values of hepatic aminotransferase (alanine aminotransferase and aspartate aminotransferase) outside of the normal range at screening.
* Hemoglobin or hematocrit outside of the normal range at screening.
* History or clinical evidence of any disease and/or existence of any surgical or medical condition, which might interfere with the absorption, distribution, metabolism or excretion of the study treatment(s) (appendectomy and herniotomy allowed, cholecystectomy not allowed).
* Previous history of fainting, collapse, syncope, orthostatic hypotension, or vasovagal reactions.
* Veins unsuitable for intravenous puncture on either arm (e.g., veins that are difficult to locate, access or puncture, veins with a tendency to rupture during or after puncture).
* Previous exposure to macitentan.
* Previous exposure to rosuvastatin.
* Treatment with another investigational drug within 3 months prior to screening or participation in more than 3 investigational drug studies within 1 year prior to screening.
* History or clinical evidence of alcoholism or drug abuse within the 3-year period prior to screening.
* Excessive caffeine consumption, defined as ≥ 800 mg per day at screening.
* Nicotine intake (e.g., smoking, nicotine patch, nicotine chewing gum or electronic cigarettes) within 3 months prior to screening and inability to refrain from nicotine intake from screening until End-Of-Study (EOS).
* Previous treatment with any prescribed medications (including vaccines) or over-the-counter (OTC) medications (including herbal medicines such as St John's Wort, homeopathic preparations, vitamins, and minerals) within 3 weeks prior to first study treatment administration.
* Loss of 250 mL or more of blood within 3 months prior to screening.
* Positive results from the hepatitis serology, except for vaccinated subjects or subjects with past but resolved hepatitis, at screening.
* Positive results from the HIV serology at screening.
* Any circumstances or conditions, which, in the opinion of the investigator, may affect full participation in the study or compliance with the protocol.
* Legal incapacity or limited legal capacity at screening.

Primary outcomes:
measure: AUC(0-inf) of rosuvastatin following administration of rosuvastatin alone (treatment A) and in combination with macitentan (treatment B)
timeFrame: From Day1 to Day17 (treatment A: from Day1-Day5 and treatment B: from Day10-Day17)
measure: Cmax of rosuvastatin following administration of rosuvastatin alone (treatment A) and in combination with macitentan (treatment B)
timeFrame: From Day1 to Day17 (treatment A: from Day1-Day5 and treatment B: from Day10-Day17)
Secondary outcomes:
measure: tmax of rosuvastatin following administration of rosuvastatin alone (treatment A) and in combination with macitentan (treatment B)
timeFrame: From Day1 to Day17 (treatment A: from Day1-Day5 and treatment B: from Day10-Day17)
measure: t½ of rosuvastatin following administration of rosuvastatin alone (treatment A) and in combination with macitentan (treatment B)
timeFrame: From Day1 to Day17 (treatment A: from Day1-Day5 and treatment B: from Day10-Day17)
measure: AUC(0-t) of rosuvastatin following administration of rosuvastatin alone (treatment A) and in combination with macitentan (treatment B)
timeFrame: From Day1 to Day17 (treatment A: from Day1-Day5 and treatment B: from Day10-Day17)
measure: Trough plasma concentrations of macitentan and its metabolite ACT-132577
timeFrame: From Day5 to Day17
measure: Change from baseline in supine blood pressure
timeFrame: From Day1 to end-of-study visit (Day 26-28)
measure: Change from baseline in pulse rate
timeFrame: From Day1 to end-of-study visit (Day 26-28)
measure: Change from baseline in heart rate (HR)
timeFrame: From Day1 to end-of-study visit (Day 26-28)
measure: Change from baseline in ECG variables
timeFrame: From Day1 to end-of-study visit (Day 26-28)
measure: Change from baseline to end-of-study (EOS) in body weight
timeFrame: From Day1 to end-of-study visit (Day 26-28)
measure: Change from baseline in clinical laboratory tests
timeFrame: From Day1 to end-of-study visit (Day 26-28)
measure: Incidence rate of treatment-emergent treatment-emergent adverse events (AEs) and serious adverse events (SAEs)
timeFrame: From Day1 to follow-up period (Day46-48)
Other outcomes:
Locations:
city: Mannheim
country: Germany
facility: CRS Clinical Research Services Mannheim
Study officials:
affiliation: Actelion
name: Shirin Bruderer, PhD
role: STUDY_DIRECTOR
References: