To Study the Effect of Aprocitentan on the Electrical Activity of the Heart in Healthy Men and Women

Healthy Subjects Clinical Trial

Official title:

Prospective, Single-center, Randomized, Double-blind, Placebo- and Moxifloxacin-controlled, 4-way Crossover Phase 1 Study to Assess the Effect of Multiple Therapeutic and Supratherapeutic Doses of Aprocitentan on the QT Interval Duration in Healthy Subjects

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04281342
• Other study ID #: ID-080-108
• Secondary ID: 2019-003617-34
• Status: Completed
• Phase: Phase 1
• Start date: January 14, 2020
• Est. completion date: September 3, 2021

Study information

• Verified date: November 2022
• Source: Idorsia Pharmaceuticals Ltd.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

To demonstrate that multiple-dose administration of oral therapeutic and supratherapeutic doses of aprocitentan do not have a clinically relevant effect on the QT interval.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 48
• Est. completion date: September 3, 2021
• Est. primary completion date: August 3, 2021
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

Inclusion Criteria:

• Signed informed consent in a language understandable to the subject prior to any study-mandated procedure.

• Ability to communicate well with the investigator, in a language understandable to the subject, and to understand and comply with the requirements of the study.

• No clinically significant findings on the physical examination at screening.

• Body mass index 18.0 to 30.0 kg/m2 (inclusive) at screening.

• Systolic blood pressure 90-140 mmHg, diastolic blood pressure 50-90 mmHg, and pulse rate 50-90 bpm (all inclusive), measured on the same arm, after 5 minutes in the supine position at screening.

• 12-lead safety ECG: QTcF less than 450 ms for male subjects and less than 470 ms for female subjects, QRS less than 110 ms, PR less than 220 ms, and resting HR greater than 50 bpm and less than 90 bpm with no clinically relevant abnormalities on 12-lead ECG after at least 5 min in the supine position at Screening and on Day 1 pre-dose of Period 1.

• No clinically relevant findings in clinical laboratory tests (hematology, clinical chemistry) at screening.

• Negative results from urine drug screen, urine cotinine test, and breath alcohol tests at screening and on Day -1 of each period.

• A woman of childbearing potential (WoCBP) is eligible only if the following applies:

• Negative serum pregnancy test at screening.

• Negative urine pregnancy test on Day -1 of each period.

• Agreement to consistently and correctly use a highly effective method of contraception from screening up to at least 30 days after last study treatment administration in the last period with in-between periods included.

• Women of non-childbearing potential (WoNCBP) must meet at least one of the following criteria:

• Previous bilateral salpingectomy, salpingo-oophorectomy or hysterectomy,

• Confirmed premature ovarian failure,

• Post-menopausal.

Exclusion Criteria:

• Pregnant or lactating women.

• Previous exposure to aprocitentan or macitentan.

• Known hypersensitivity to aprocitentan or macitentan or any of the drug product excipients, or treatments of the same class.

• Any contraindication or known hypersensitivity to moxifloxacin or any of the drug product excipients or to other fluoroquinolone antibiotics.

• Known hypersensitivity or allergy to natural rubber latex.

• History of major medical or surgical disorders which, in the opinion of the investigator, are likely to interfere with the absorption, distribution, metabolism, or excretion of the study treatment (appendectomy and herniotomy allowed, cholecystectomy not allowed).

• Acute, ongoing, recurrent, or chronic systemic disease able to interfere with the evaluation of the study.

• 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 2 weeks or 5 t½ (whichever is longer) prior to first study treatment administration with the exception of contraceptives in female subjects.

• History or presence of rhythm disorders (e.g., sinoatrial heart block, sick-sinus syndrome, second- or third-degree atrioventricular block, long QT syndrome, symptomatic bradycardia, atrial flutter, or atrial fibrillation) or hypokalemia.

• Legal incapacity or limited legal capacity at screening.

Related Conditions & MeSH terms

• Healthy Subjects

Intervention

Drug:
• Aprocitentan 25 mg
Repeated administration of a 25 mg oral dose of aprocitentan, once daily from Day 1 to Day 10, followed by 18 days of observation.
• Aprocitentan 100 mg
Repeated administration of a 100 mg oral dose of aprocitentan, once daily from Day 1 to Day 10, followed by 18 days of observation.
• Matching placebo
Repeated administration of an oral dose of aprocitentan-matching placebo, once daily from Day 1 to Day 10, followed by 18 days of observation.

Other:
• Moxifloxacin control to establish assay sensitivity
Repeated administration of an oral dose of aprocitentan-matching placebo, once daily from Day 1 to Day 9. On Day 10, oral administration of one single 400 mg moxifloxacin tablet open-label, followed by 18 days of observation.

Locations

Country	Name	City	State
Germany	CRS Clinical Research Services Mannheim GmbH	Mannheim	Baden-Württemberg

Sponsors (1)

Lead Sponsor	Collaborator
Idorsia Pharmaceuticals Ltd.

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Placebo-corrected change from baseline in QT interval corrected with Fridericia's formula (??QTcF)		Multiple predefined time points related to study treatment administration on Day 1 and Day 10 to 11 of each treatment.
Secondary	Aprocitentan trough plasma concentrations (Ctrough)		Day 2 to Day 9
Secondary	Aprocitentan plasma Cmax, first dose		Pre-defined times on the first dosing day (Day 1) up to 15 hours after last dose
Secondary	Aprocitentan plasma Cmax, steady state		Pre-defined times on the last dosing day (Day 10) up to 15 hours after last dose
Secondary	Area under the plasma concentration-time curve (AUCt) during a dosage interval (t) of aprocitentan		Day 1 to Day 10
Secondary	Aprocitentan attainment of steady-state conditions		Day 1 to Day 10
Secondary	Accumulation index between the first and the last dosing day of aprocitentan		Day 1; Day 10