A Clinical Study to Compare the Impact of Multiple-dose Oral Administration of Macitentan, 10 mg versus 75 mg on Endothelin-1 Clearance, Endothelial Function, and Hemodynamics in Healthy Participants

Prior treatment

• Nicotine intake (eg, smoking, nicotine patch, nicotine chewing gum, or electronic cigarettes) within 3 months prior to screening, inability to refrain from nicotine from screening until completion of the end-of-study visit, or positive test result for cotinine at screening and on Day 1. Note:A positive cotinine test may be repeated once (as soon as possible and within the screening period or on Day 1) to exclude a technical error. Participants with a negative cotinine test at retest may be included
• Donated blood or blood products or had substantial loss of blood (more than 500 mL) within 3 months before the first administration of study intervention or intention to donate blood or blood products during the study
• Had major surgery (eg, requiring general anaesthesia) within 6 months before screening, or will not have fully recovered from surgery, or has surgery planned during the time the participant is expected to participate in the study or within 4 weeks after the last dose of study intervention administration
• Taken any disallowed therapies, Concomitant Therapy, before the planned first dose of study intervention
• Received an investigational intervention (including investigational vaccines) or used an invasive investigational medical device within 30 days or 5 half-lives (whichever is longer) before study intervention intake in the first treatment period, or received a biological product within 3 months or 5 half-lives (whichever is longer) before study intervention intake in the first treatment period, or is currently enrolled in an investigational study

Other illness

• 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 intervention(s)
• Positive results from the HIV-1 and HIV-2 serology at screening
• Positive results from the hepatitis serology (ie, hepatitis A IgM antibody, HBsAg, and/or anti-HCV) at screening
• History of drug or alcohol abuse according to DSM-V criteria within 3 years before screening or positive test result(s) for alcohol or drugs of abuse (including barbiturates, opiates, cocaine, cannabinoids, amphetamines and benzodiazepines) at screening and on Day 1. Note: A positive urine drug test and/or alcohol breath test may be repeated once (as soon as possible and within the screening period or on Day 1) to exclude a technical error. Participants with a negative urine drug and/or alcohol breath test at retest may be included
• History of malignancy within 5 years before screening (exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy, which is considered cured with minimal risk of recurrence)
• Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments
• Known allergies, hypersensitivity, or intolerance to macitentan (Opsumit®) or its excipients. For further information refer to the IB of macitentan (IB macitentan)

Lab values

• A hemoglobin value of ≤11 g/dL at screening
• Values of hepatic aminotransferase (ALT and/or AST) >1.5×ULN at screening

Other

• Employee of the investigator or study site, with direct involvement in the proposed study or other studies under the direction of that investigator or study site, as well as family members of the employees or the investigator
• Unable to swallow solid, oral dosage forms whole with the aid of water (participants may not chew, divide, dissolve, or crush the study intervention)
• Pregnant, or breast-feeding, or planning to become pregnant while enrolled in this study or within 30 days after the last dose of study intervention
• Plans to father a child while enrolled in this study or within 90 days after the last dose of study intervention
• Orthostatic hypotension (>20 mmHg decrease in SBP or >10 mmHg decrease in DBP after 3 minutes of standing compared to supine blood pressure)
• Contraindications to the use of macitentan (Opsumit®) per local prescribing information

• 18 to 55 years of age, inclusive.
• A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for at least 30 days after the last study intervention intake
• During the study (from the day of first study intervention intake onwards) and for a minimum of one spermatogenesis cycle (defined as approximately 90 days) after receiving the last dose of study intervention, a male participant must agree: a. To wear a condom when engaging in any activity that allows for passage of ejaculate to another person b. Not to donate sperm for the purpose of reproduction Contraceptive use should be consistent with local regulations regarding the use of contraceptive methods for participants participating in clinical studies
• Must sign an ICF indicating that the participant understands the purpose of, and procedures required for, the study and is willing to participate in the study, before starting any screening activities
• Able to communicate well with the investigator or a member of the study-site personnel, in the local language, and to understand and comply with the requirements of the study
• Willing and able to adhere to the lifestyle restrictions specified in this protocol
• Healthy on the basis of physical examination and medical and surgical history performed at screening. If there are any abnormalities, the participant may be included only if the investigator judges the abnormalities to be not clinically significant. This determination must be recorded in the participant's source documents and initialed by the investigator
• Healthy on the basis of clinical laboratory tests performed at screening. If the results of the serum chemistry panel, hematology, or urinalysis are outside the normal reference ranges, the participant may be included only if the investigator judges the abnormalities or deviations from normal to be not clinically significant or to be appropriate and reasonable for the population under study. This determination must be recorded in the participant's source documents and initialed by the investigator
• SBP between 100 and 145 mmHg (inclusive), DBP between 50 and 90 mmHg (inclusive), and pulse rate between 45 and 90 beats per minute (inclusive), after the participant is supine for at least 5 minutes, at screening
• Twelve-lead ECG without clinically relevant abnormalities, at the discretion of the investigator, and without any of the following findings listed below measured after the participant is supine for at least 5 minutes, at screening only. a. Heart rate >90 beats per minute or <45 beats per minute b. PR >210 milliseconds c. QTcF ≥450 milliseconds for males and QTcF ≥460 milliseconds for females (corrected cf. Fridericia 1920) d. Clinically significant abnormal ECG intervals
• Body weight not less than 50 kg and BMI (weight [kg]/height^2 [m]^2) within the range 18.0 - 25.0 kg/m^2 (inclusive)
• Man or woman
• All women must have a negative highly sensitive serum (β-hCG) at screening and a negative urine pregnancy test on Day 1
• A woman must be: a. Not of childbearing potential or b. Of childbearing potential and practicing an acceptable birth control method and agree to remain on an acceptable birth control method throughout the study from signing of the ICF onwards and for at least 30 days after the last study intervention intake