A Study to Investigate the Effect of Single and Repeated Oral Doses of ACT-539313 on What the Body Does to Flurbiprofen, Omeprazole, Midazolam in Healthy Subjects

A Single-center, Open-label, Four-period, Fixed-sequence Study to Investigate the Effect of Single and Repeated Oral Doses of ACT-539313 on the Pharmacokinetics of Flurbiprofen, Omeprazole, Midazolam, and Their Respective Metabolites in Healthy Subjects

A study to investigate the effect of single and repeated oral doses of ACT-539313 on what the body does to flurbiprofen, omeprazole, midazolam in healthy participants.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: ACT-539313; Drug: Flurbiprofen; Drug: Omeprazole; Drug: Midazolam

Detailed Description

A screening evaluation will be performed within 3 to 28 days (or within 10 to 28 days for women of childbearing potential) before first study treatment administration. Prior to any screening assessment, participants must sign the informed consent form.

Eligibility will be based on the results of the Screening and Day -1 assessments.

The participants will be confined to the study site from the morning of Day -1 until the morning of Day 2, from the morning of Day 7 until the morning of Day 9 and from the morning of Day 14 until the morning of Day 16. Participants will return to the study site for the End of Study examination on Day 17.

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 13353
    • CRS Clinical Research Services Berlin GMBH

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Signed informed consent in a language understandable to the participant prior to any study-mandated procedure.
• Healthy male or female subjects aged between 18 and 45 years (inclusive) at Screening.
• Body Mass Index of 18.5 to 28.0 kg/m2 (inclusive) at Screening.
• Women of childbearing potential must have a negative serum pregnancy test at Screening and a negative urine pregnancy test on Day -1. They must consistently and correctly use (from Screening, during the entire study, and for at least 30 days after study treatment intake) a highly effective method of contraception with a failure rate of < 1% per year, be sexually inactive, or have a vasectomized partner. If a hormonal contraceptive is used, it must have been initiated at least 1 month before treatment administration.
• Women of non-childbearing potential, i.e., postmenopausal (defined as 12 consecutive months with no menses without an alternative medical cause, confirmed by a FSH 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.
• 12-lead ECG (including QT: < 450 milliseconds [for males] and < 470 milliseconds [for females] without clinically relevant abnormalities, measured after 5 min in the supine position at Screening and on Day -1.

Exclusion Criteria:

• Pregnant or lactating women.
• Any circumstances or conditions, which, in the opinion of the investigator, may affect full participation in the study or compliance with the protocol.
• Clinically relevant findings in clinical laboratory tests (hematology, clinical chemistry, and urinalysis, i.e. outside the reference ranges (< 0.9 lower limit of normal and > 1.1 upper limit of normal; except for relevant hepatic parameters [Alanine Aminotransferase (ALT), Aspartate Aminotransferase Test (AST), bilirubin] which must not exceed the upper limit of normal), at Screening and on Day -1.
• 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(s) (appendectomy and herniotomy allowed, cholecystectomy not allowed).
• Acute, ongoing, recurrent, or chronic systemic disease with the ability to interfere with the evaluation of the study results.
• Prior history of severe respiratory failure, acute respiratory depression, or sleep apnea.
• Prior history of peptic ulcer disease and/or gastrointestinal bleeding.
• Prior history of asthma, urticaria, or other allergic type reactions after taking acetylsalicylic acid or other NSAIDs.
• History of cardiovascular thrombotic events (including myocardial infarction and stroke) and coronary artery bypass graft surgery.
• Participation in a clinical study involving study treatment administered within 3 months (or 5 t 1/2 of the study treatment administered [whichever is longer]) prior to screening or in more than 4 clinical studies within 1 year prior to Screening.
• 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; with the exception of ibuprofen [1200 mg/day] or paracetamol [up to 1500 mg/day] up until Day -1) within 3 weeks (or 5 t1/2 [whichever is longer]) prior to first study treatment administration.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: OTHER
• Allocation: NA
• Interventional Model: SEQUENTIAL
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: ACT-539313 with or without a standard combination (probe substrate); Treatment arm has 4 in-house treatment periods. In Treatment Period 1, participants will receive a single oral dose of the standardized combination (probe substrate: containing flurbiprofen [50 mg], midazolam [2 mg] and omeprazole 20 [mg]) on Day 1. Participants will be discharged from the study site on Day 2 and will be re-admitted on Day 7. In Treatment Period 2 (morning of Day 8) a first oral dose of 100 mg ACT-539313 will be administered. One hour later a single oral dose of the probe substrate will be administered. In the evening of Day 8, a second oral dose of 100 mg ACT-539313 will be administered. During Treatment Period 3 (morning of Day 9, ending on the evening of Day 14) oral doses of 100 mg ACT-539313 will be administered in the morning and evening. In Treatment Period 4 (Day 15), a single oral dose of 100 mg ACT-539313 together with the probe substrate will be administered. The participants will receive the last dose of ACT-539313 in the evening of Day 15.

Drug: ACT-539313; 100 mg ACT-539313 (hard capsules) will be administered twice per day in period 2 (morning and evening of Day 8), period 3 (morning and evening of Day 9 to 14) and period 4 (morning and evening of Day 15).; Drug: Flurbiprofen; One daily dose of flurbiprofen 50 mg will be administered in period 1 (morning of Day 1), period 2 (morning of Day 8), and period 4 (morning of Day 15).; Drug: Omeprazole; A single dose of omeprazole 20 mg will be administered in period 1 (morning of Day 1), period 2 (morning of Day 8), and period 4 (morning of Day 15).; Drug: Midazolam; A single dose of midazolam 2 mg will be administered in period 1 (morning of Day 1), period 2 (morning of Day 8), and period 4 (morning of Day 15).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum plasma concentration (Cmax) of each probe substrate: flurbiprofen, midazolam and omeprazole.	In periods 1, 2 and 4 the plasma pharmacokinetic parameters of flurbiprofen, omeprazole, and midazolam will be derived by non-compartmental analysis of the plasma concentration-time profiles. Plasma pharmacokinetic samples will be collected at multiple predefined time points to analyze probe substrate: flurbiprofen, midazolam and omeprazole concentrations.	Pre-dose through to 24 hours post-dose.
Time to reach Cmax (tmax) of each probe substrate: flurbiprofen, midazolam and omeprazole.	In periods 1, 2 and 4 the plasma pharmacokinetic parameters of flurbiprofen, omeprazole, and midazolam will be derived by non-compartmental analysis of the plasma concentration-time profiles. Plasma pharmacokinetic samples will be collected at multiple predefined time points to analyze probe substrate: flurbiprofen, midazolam and omeprazole concentrations.	Pre-dose through to 24 hours post-dose.
The area under the plasma concentration-time curve from zero to 24 hours (AUC0-24) of flurbiprofen, midazolam and omeprazole.	In periods 1, 2 and 4 the plasma pharmacokinetic parameters of flurbiprofen, omeprazole, and midazolam will be derived by non-compartmental analysis of the plasma concentration-time profiles. Plasma pharmacokinetic samples will be collected at multiple predefined time points to analyze probe substrate: flurbiprofen, midazolam and omeprazole concentrations.	Pre-dose through to 24 hours post-dose.
The terminal elimination half-life (t½) of each probe substrate: flurbiprofen, midazolam and omeprazole.	In periods 1, 2 and 4 the plasma pharmacokinetic parameters of flurbiprofen, omeprazole, and midazolam will be derived by non-compartmental analysis of the plasma concentration-time profiles. Plasma pharmacokinetic samples will be collected at multiple predefined time points to analyze probe substrate: flurbiprofen, midazolam and omeprazole concentrations.	Pre-dose through to 24 hours post-dose.
ACT-539313 trough plasma concentrations (Ctrough)	In periods 2, 3 and 4 the plasma pharmacokinetic parameters of ACT-539313 will be measured prior to the next dose being administered in the morning.	Pre-dose through to 10 days after first dose.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment-emergent adverse events	All adverse events will be collected, however, adverse events occurring during the in-between period (from end of period 1 up to first study treatment administration in period 2, are not considered as treatment-emergent adverse events.	From study treatment administration on Day 1 up to last assessment at End of Study (Day 17).
Maximum plasma concentration (Cmax) of ACT-539313	In periods 2 (Day 8 and 9) and period 4 (Day 15, 16 and 17) the plasma pharmacokinetic parameters of ACT-539313 will be derived by non-compartmental analysis of the plasma concentration-time profiles. Cmax will be analyzed in periods 2 and 4 with the administration of probe substrate. In period 4 the Cmax will be determined after steady state ACT-539313 concentrations have been reached.	Pre-dose through to 24 hours post-dose.
Time to reach Cmax (tmax) of ACT-539313	In periods 2 (Day 8 and 9) and period 4 (Day 15, 16 and 17) the plasma pharmacokinetic parameters of ACT-539313 will be derived by non-compartmental analysis of the plasma concentration-time profiles. tmax will be analyzed in periods 2 and 4 with the administration of probe substrate. In period 4 the tmax will be determined after steady state ACT-539313 concentrations have been reached.	Pre-dose through to 24 hours after first dose.
Area under the plasma concentration-time curve [AUC(tau)] of ACT-539313	In periods 2 (Day 8 and 9), period 3 (Day 10 to Day 15) and period 4 (Day 15, 16 and 17) plasma pharmacokinetic samples will be collected at multiple predefined time points to analyze ACT-539313 concentrations. AUC(tau) will be calculated according to the linear trapezoidal rule using the measured concentration-time values above the limit of quantification.	Pre-dose through to 240 hours after first dose.

Collaborators and Investigators

• Sponsor: Idorsia Pharmaceuticals Ltd.

Study record dates

Study Major Dates

• Study Start (ACTUAL): February 18, 2022
• Primary Completion (ACTUAL): April 13, 2022
• Study Completion (ACTUAL): April 13, 2022

Study Registration Dates

• First Submitted: February 15, 2022
• First Submitted That Met QC Criteria: February 15, 2022
• First Posted (ACTUAL): February 24, 2022

Study Record Updates

• Last Update Posted (ACTUAL): May 4, 2022
• Last Update Submitted That Met QC Criteria: May 3, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Gastrointestinal Agents; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Anti-Ulcer Agents; Proton Pump Inhibitors; Midazolam; Omeprazole; Flurbiprofen
• Other Study ID Numbers: ID-082-103; 2021-006214-36 (EUDRACT_NUMBER)

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