A Drug-drug Interaction Trial in Healthy Female Participants to Investigate the Effect of Aprocitentan on Combined Hormonal Contraceptives

A Single-center, Open-label, Fixed-sequence Trial to Investigate the Effect of Multiple-dose Aprocitentan on the Single-dose Pharmacokinetics of Combined Oral Contraceptives in Healthy Female Participants

The goal of this clinical trial is to learn if drug aprocitentan has an effect on hormonal contraceptives in healthy female volunteers. The main question it aims to answer is:

Does aprocitentan modify the fate of hormonal contraceptives in the body?

Trial participants will:

• Take a single dose of hormonal contraceptives (fixed combination) alone
• Take aprocitentan every day for 2 weeks
• Take a single dose of the same hormonal contraceptives at the same time as the 10th administration of aprocitentan.

Study Overview

• Status: Completed
• Conditions: Drug Drug Interaction
• Intervention / Treatment: Drug: Ethinyl Estradiol / Levonorgestrel Oral Tablet; Drug: Aprocitentan

Detailed Description

The main objective of the trial is to evaluate the influence of aprocitentan at steady-state on the single-dose pharmacokinetics (PK) of combined oral contraceptives.

19 healthy female participants will be enrolled to have at least 16 evaluable participants.

Following a screening period (from full signature of the informed consent form [ICF] to enrollment; 10 to 28 days prior to first trial intervention administration), eligible participants (meeting all inclusion criteria and none of the exclusion criteria) will be enrolled in the trial to participate in two sequential trial periods, Trial Period A and Trial Period B, with an in-between period of at least 7 days. Trial Period B will be split into two sequential sub-periods, Trial Period B1 and Trial Period B2.

• Trial Period A: Starts with a single administration of trial intervention on Day 1 and ends with an End-of-Trial Period (EoTP) assessment on Day 5. Trial intervention administration on Day 1 will be followed by a 96-hour observation period for safety monitoring and PK sampling.
• Trial Period B1: Trial intervention will be administered from Day 1 to Day 9, with assessments for PK sampling and safety monitoring performed throughout.
• Trial Period B2: Starts with administration of trial intervention on Day 10 and ends with an EoTP assessment on Day 14. Trial intervention will be administered from Day 10 to Day 13, with assessments for PK sampling and safety monitoring performed throughout.

Trial participation of an individual participant ends with the completion of the Participant Last Visit, which will be performed 10-14 days after the last administration of trial intervention. A post-trial safety follow up is performed 30-40 days after last administration of trial intervention.

• Study Type: Interventional
• Enrollment (Actual): 19
• Phase: Phase 1

Contacts and Locations

Study Locations

• Czechia
  • Pilsen, Czechia, 323 00
    • CEPHA s.r.o.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Signed and dated informed consent form (ICF) prior to any trial-mandated procedure.
• Healthy female participants aged from 18 to 65 years at the time of signing the ICF.
• Ability to communicate well with the investigator, in a language understandable to the participant, and to understand and comply with the trial requirements.
• Body mass index (BMI) of 18.0 to 30.0 kg/m2 (inclusive) at Screening.
• Normal or not clinically significant abnormal systolic blood pressure (SBP) 100-139 mmHg, diastolic blood pressure (DBP) 50-90 mmHg, and pulse rate 45-90 bpm (inclusive), measured on either arm, after 5 min in the supine position at Screening and on Day 1 (predose) of Trial Period A (TP A).
• Participant of childbearing potential who has a negative serum pregnancy test at Screening and a negative urine pregnancy test on Day 1 (predose) of TP A.
• Participant of childbearing potential who agrees to use two reliable methods of non- hormonal contraception from Screening and for at least 30 days after the last trial intervention administration, or be sexually inactive, or have a vasectomized partner.
• Participant of non-childbearing potential, i.e., postmenopausal (defined as 12 consecutive months with no menses without an alternative medical cause, confirmed by an follicle stimulating hormone test), with previous bilateral salpingectomy, bilateral salpingo-oophorectomy, or hysterectomy, or with premature ovarian failure (confirmed by a specialist), XY genotype, Turner syndrome, uterine agenesis).

Exclusion Criteria:

• Known hypersensitivity to aprocitentan, ethinylestradiol, or levonorgestrel, or treatments of the same class, or any of their excipients.
• Clinically relevant findings on the physical examination at Screening.
• Clinically relevant abnormalities on 12-lead electrocardiogram (ECG), measured after 5 min in a supine position at Screening or on Day 1 (pre-dose) of TP A.
• Clinically relevant findings in clinical laboratory tests (hematology and clinical chemistry) at Screening.
• 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 trial interventions (appendectomy and herniotomy allowed if performed > 12 weeks prior to first trial intervention administration, cholecystectomy not allowed).
• Acute, ongoing, recurrent, or chronic systemic disease able to interfere with the evaluation of the trial results.
• Previous clinically relevant history of fainting, collapse, syncope, orthostatic hypotension, or vasovagal reactions.
• Previous therapy with hormonal contraceptives or hormone replacement therapy within 2 months prior to first trial intervention administration.
• Pregnant, planning to become pregnant during the trial, or lactating participant of childbearing potential.
• Participant presenting any contraindications for LOETTE®

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ethinyl estradiol/levonorgestrel (LOETTE); In Trial Period A, participants will receive a single oral dose of 20µg ethinyl estradiol/100 µg levonorgestrel in the morning of Day 1.	Drug: Ethinyl Estradiol / Levonorgestrel Oral Tablet; Coated tablet of 20 µg ethinyl estradiol and 100 µg levonorgestrel; Other Names: LOETTE
Experimental: Aprocitentan; In Trial Period B1, participants will receive a once daily oral dose of 25 mg aprocitentan in the morning of Day 1 to Day 9.	Drug: Aprocitentan; Film-coated tablet of aprocitentan 25 mg
Experimental: Aprocitentan and ethinyl estradiol/levonorgestrel (LOETTE); In Trial Period B2, participants will receive a once daily oral dose of 25 mg aprocitentan in the morning of Day 10 to Day 13. On Day 10, participants will receive a single oral dose of 20µg ethinyl estradiol/100 µg levonorgestrel, administered concomitantly to aprocitentan.	Drug: Ethinyl Estradiol / Levonorgestrel Oral Tablet; Coated tablet of 20 µg ethinyl estradiol and 100 µg levonorgestrel; Other Names: LOETTE; Drug: Aprocitentan; Film-coated tablet of aprocitentan 25 mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum plasma concentration (Cmax) of ethinyl estradiol/levonorgestrel	The measured individual plasma concentrations will be used to directly obtain Cmax.	TP A: On Day 1 (pre-dose) and predefined times up to 96 hours post-dose (Day 5); TP B2: On Day 10 (pre-dose) and predefined times up to 96 hours post-dose (Day 14)
Time to maximum plasma concentration (tmax) of ethinyl estradiol/levonorgestrel	The measured individual plasma concentrations will be used to directly obtain tmax.	TP A: On Day 1 (pre-dose) and predefined times up to 96 hours post-dose (Day 5); TP B2: On Day 10 (pre-dose) and predefined times up to 96 hours post-dose (Day 14)
Area under the Plasma Concentration-Time Curve (AUC 0-t) of ethinyl estradiol/levonorgestrel	Change to AUC 0-t will be derived by non compartmental analysis of the concentration-time profiles.	TP A: On Day 1 (pre-dose) and predefined times up to 96 hours post-dose (Day 5); TP B2: On Day 10 (pre-dose) and predefined times up to 96 hours post-dose (Day 14)
Area under the Plasma Concentration-Time Curve (AUC 0-infinity) of ethinyl estradiol/levonorgestrel	Change to AUC 0-infinity will be derived by non compartmental analysis of the concentration-time profiles.	TP A: On Day 1 (pre-dose) and predefined times up to 96 hours post-dose (Day 5); TP B2: On Day 10 (pre-dose) and predefined times up to 96 hours post-dose (Day 14)
Terminal half-life (t1/2) of ethinyl estradiol/levonorgestrel	t1/2 will be derived by non compartmental analysis of the concentration-time profiles.	TP A: On Day 1 (pre-dose) and predefined times up to 96 hours post-dose (Day 5); TP B2: On Day 10 (pre-dose) and predefined times up to 96 hours post-dose (Day 14)
Trough plasma concentration (Ctrough) of aprocitentan	Ctrough will be based on measured individual plasma concentrations of aprocitentan.	Prior to administration on Day 10, 11, 12 and 13 in TP B2

Collaborators and Investigators

• Sponsor: Idorsia Pharmaceuticals Ltd.
• Investigators: Study Director: Clinical Trials, Idorsia Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): January 18, 2025
• Primary Completion (Actual): February 21, 2025
• Study Completion (Actual): February 21, 2025

Study Registration Dates

• First Submitted: January 14, 2025
• First Submitted That Met QC Criteria: January 28, 2025
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 7, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Contraceptive Agents, Hormonal; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Reproductive Control Agents; Contraceptive Agents, Female; Contraceptive Agents; Estrogens; Contraceptives, Oral, Combined; Contraceptives, Oral; Contraceptives, Oral, Hormonal; Contraceptives, Oral, Synthetic; Estradiol; Levonorgestrel; Ethinyl Estradiol; Ethinyl estradiol, levonorgestrel drug combination
• Other Study ID Numbers: ID-080-111; 2024-517224-19-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No