Single-ascending Oral Dose Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ACT-281959 / ACT-246475 in Healthy Male Subjects
Status and phase
Completed
Phase 1
Conditions
Safety, Tolerability, Pharmacokinetics and Pharmacodynamics
Treatments
Drug: ACT-281959 prodrug formulation II (Group G dose to be defined)
Drug: Placebo (Groups A to F)
Drug: ACT-281959 prodrug formulation I (Groups C to G doses to be defined)
Drug: 20 mg ACT-281959 prodrug formulation I (Group B)
Drug: 5 mg ACT-281959 prodrug formulation I (Group A)
Drug: ACT-246475 (Group G dose to be defined)
Details and patient eligibility
About
Study Part I is a single-ascending dose study. Healthy male subjects to be included in the study and randomized in 6 dose groups, Groups A-F (8 subjects per group). Of the 8 subjects per group, 6 subjects receive the investigational drug and 2 subjects receive matching placebo. Study Part II is a 3-period, crossover, single dose study. Nine healthy male subjects to be enrolled in one group (Group G). Each subject to receive 2 different formulations of the prodrug and one formulation of the active drug in a randomized sequence.
Full description
Study Part I is a prospective, single-center, double-blind, randomized, placebo-controlled, single-ascending dose, Phase 1 study. Approximately 48 healthy male subjects to be included in the study and randomized in 6 dose groups, Groups A-F (8 subjects per group). Of the 8 subjects per group, 6 subjects are to receive the investigational drug and 2 subjects to receive matching placebo. Study Part II is a prospective, single-center, open-label, randomized, 3-period, crossover, single dose, Phase 1 study. Nine healthy male subjects to be enrolled in one group, Group G. Each subject to receive 2 different formulations of the prodrug and one formulation of the active drug in a randomized sequence.
Enrollment
49 patients
Sex
Male
Ages
18 to 45 years old
Volunteers
Accepts Healthy Volunteers
Inclusion criteria
- Signed informed consent in the local language prior to any study-mandated procedure.
- Healthy male subjects aged between 18 and 45 years (inclusive) at screening.
- No clinically significant findings on the physical examination at screening.
- Body mass index of 18.0 to 28.0 kg/m^2 (inclusive) at screening.
- Systolic blood pressure 100-145 mmHg, diastolic blood pressure 50-90 mmHg, and pulse rate 45-90 beats per minute (inclusive), measured on the dominant arm, after 5 minutes in the supine position at screening.
- 12-lead electrocardiogram without clinically relevant abnormalities, measured after 5 minutes in the supine position at screening.
- Hematology, coagulation, clinical chemistry, and urinalysis test results not deviating to a clinically relevant extent from the normal range at screening.
- Negative results from urine drug screen at screening.
- Baseline value for maximal (at peak) platelet aggregation ≥ 50% light transmission aggregometry upon 20 μM adenosine diphosphate (ADP) activation at screening.
- Baseline values of closure time tested with the platelet function analyser 100, for both cartridges Collagen/Epinephrine and Collagen/ADP below the upper limit of the normal range.
- Ability to communicate well with the investigator in the local language, and to understand and comply with the requirements of the study.
Exclusion criteria
- Known allergic reactions or hypersensitivity to any excipient of the drug formulation(s).
- History or clinical evidence of any disease and/or existence of any surgical or medical condition which would interfere with the absorption, distribution, metabolism, or excretion of the study drug (appendectomy and herniotomy were allowed, while cholecystectomy was not allowed).
- Previous history of fainting, collapse, orthostatic hypotension, or vasovagal reactions.
- Family or personal history of bleeding (e.g., stroke, major trauma, or surgical intervention), or bleeding disorders (e.g., thrombocytopenia, clotting disturbances, intracranial vascular diseases, peptic ulcers), or reasonable suspicion of vascular malformations.
- Platelet count ˂ 120x10^9/L at screening.
- Veins unsuitable for intravenous puncture on either arm (e.g., veins that were difficult to locate, access, or puncture, veins with a tendency to rupture during or after puncture).
- Treatment with another investigational drug within 3 months prior to screening or participation in more than four investigational drug studies within 1 year prior to screening.
- History or clinical evidence of alcoholism or drug abuse within the 3-year period prior to screening.
- Excessive caffeine consumption, defined as ≥ 800 mg per day at screening.
- Smoking within 3 months prior to screening and inability to refrain from smoking during the course of the study.
- Previous treatment with any prescribed or over-the-counter medications (including herbal medicines such as St. John's Wort) especially acetyl salicylic acid, non-steroidal anti-inflammatory, or any anticoagulant medication (e.g., heparin, warfarin), within 2 weeks prior to (the first) administration of study drug.
- Loss of 250 mL or more of blood within 3 months prior to screening.
- Positive results from the hepatitis serology, except for vaccinated subjects or subjects with past but resolved hepatitis, at screening.
- Positive results from the human immunodeficiency virus serology at screening.
- Any circumstances or conditions, which, in the opinion of the investigator, would affect full participation in the study or compliance with the protocol.
- Legal incapacity or limited legal capacity at screening.
Trial design
Primary purpose
Treatment
Allocation
Randomized
Interventional model
Parallel Assignment
Masking
Triple Blind
49 participants in 7 patient groups
Group A 5 mg ACT-281959 prodrug formulation I/placebo
Experimental group
Description:
6 subjects to receive a single, oral dose of 5 mg ACT-281959 prodrug formulation I and 2 subjects to receive a single, oral dose of matching placebo. Medication to be administered in the fasted state.
Treatment:
Drug: Placebo (Groups A to F)
Drug: 5 mg ACT-281959 prodrug formulation I (Group A)
Group B 20 mg ACT-281959 prodrug formulation I/placebo
Experimental group
Description:
6 subjects to receive a single, oral dose of 20 mg ACT-281959 prodrug formulation I and 2 subjects to receive a single, oral dose of matching placebo. Medication to be administered in the fasted state.
Treatment:
Drug: Placebo (Groups A to F)
Drug: 20 mg ACT-281959 prodrug formulation I (Group B)
Group C ACT-281959 prodrug formulation I/placebo
Experimental group
Description:
Group C: 6 subjects to receive a single, oral dose of ACT-281959 prodrug formulation I and 2 subjects to receive a single, oral dose of matching placebo. Medication to be administered in the fasted state. Dose selection will be based on pharmacokinetic data derived from Groups A-B.
Treatment:
Drug: Placebo (Groups A to F)
Drug: ACT-281959 prodrug formulation I (Groups C to G doses to be defined)
Group D ACT-281959 prodrug formulation I/placebo
Experimental group
Description:
6 subjects to receive a single, oral dose of ACT-281959 prodrug formulation I and 2 subjects to receive a single, oral dose of matching placebo. Medication to be administered in the fasted state. Dose selection will be based on pharmacokinetic data derived from Groups A-C.
Treatment:
Drug: Placebo (Groups A to F)
Drug: ACT-281959 prodrug formulation I (Groups C to G doses to be defined)
Group E ACT-281959 prodrug formulation I/placebo
Experimental group
Description:
6 subjects to receive a single, oral dose of ACT-281959 prodrug formulation I and 2 subjects to receive a single, oral dose of matching placebo. Medication to be administered in the fasted state. Dose selection will be based on pharmacokinetic data derived from Groups A-D.
Treatment:
Drug: Placebo (Groups A to F)
Drug: ACT-281959 prodrug formulation I (Groups C to G doses to be defined)
Group F ACT-281959 prodrug formulation I/placebo
Experimental group
Description:
Food effect dose group: 6 subjects to receive a single, oral dose ACT-281959 prodrug formulation I and 2 subjects to receive a single, oral dose of matching placebo. Medication to be administered in the fasted state. Following a 7-10 day washout period, subjects will receive the identical treatments administered in the first period. Medication to be administered in the fed state. Dose selection will be based on pharmacokinetic data derived from Groups A-E.
Treatment:
Drug: Placebo (Groups A to F)
Drug: ACT-281959 prodrug formulation I (Groups C to G doses to be defined)
Group G ACT-281959 prodrug formulation I & II/ACT-246475
Experimental group
Description:
9 subjects to receive a single, oral dose of ACT-281959 prodrug formulation I (Treatment A), a single, oral dose of ACT-281959 prodrug formulation II (Treatment B), and a single, oral dose of ACT-246475 (Treatment C). Subjects will be equally randomized to one of 3 treatment sequences: ABC, BCA, and CAB. Treatments will be separated by 7-10 day washout periods. Medication to be administered in the fasted state. Data from Groups A-E will be used for pharmacometric modeling to guide the selection of doses to be used in Group G.
Treatment:
Drug: ACT-281959 prodrug formulation II (Group G dose to be defined)
Drug: ACT-281959 prodrug formulation I (Groups C to G doses to be defined)
Drug: ACT-246475 (Group G dose to be defined)
Trial contacts and locations
1
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Data sourced from clinicaltrials.gov
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