Clinical trial NCT04281342: To Study the Effect of Aprocitentan on the Electrical Activity of the Heart in Healthy Men and Women
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Subjects
Lead sponsor: Idorsia Pharmaceuticals Ltd.
Sponsor class: INDUSTRY
First posted: 2020-02-24
Enrollment: 48
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Each subject will be randomized immediately prior to first study treatment administration on Day 1 Period 1 to one of 12 treatment sequences following a 3 × 4 × 4 Williams square design. Moxifloxacin will be open-label on Day 10 in one period.
Primary purpose: OTHER

Brief 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Placebo-corrected change from baseline in QT interval corrected with Fridericia's formula (ΔΔQTcF)
timeFrame: Multiple predefined time points related to study treatment administration on Day 1 and Day 10 to 11 of each treatment.
Secondary outcomes:
measure: Aprocitentan trough plasma concentrations (Ctrough)
timeFrame: Day 2 to Day 9
measure: Aprocitentan plasma Cmax, first dose
timeFrame: Pre-defined times on the first dosing day (Day 1) up to 15 hours after last dose
measure: Aprocitentan plasma Cmax, steady state
timeFrame: Pre-defined times on the last dosing day (Day 10) up to 15 hours after last dose
measure: Area under the plasma concentration-time curve (AUCτ) during a dosage interval (τ) of aprocitentan
timeFrame: Day 1 to Day 10
measure: Aprocitentan attainment of steady-state conditions
timeFrame: Day 1 to Day 10
measure: Accumulation index between the first and the last dosing day of aprocitentan
timeFrame: Day 1; Day 10
Other outcomes:
Locations:
city: Mannheim
country: Germany
facility: CRS Clinical Research Services Mannheim GmbH
state: Baden-Württemberg
Study officials:
affiliation: Idorsia Pharmaceuticals Ltd.
name: Clinical Trials
role: STUDY_DIRECTOR
References: