Clinical trial NCT01954615: Single-ascending Oral Dose Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ACT-281959 / ACT-246475 in Healthy Male Subjects
Official title: A Single-center, Double-blind, Randomized, Placebo-controlled, Single-ascending Oral Dose and Food Interaction Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ACT-281959 / ACT-246475 in Healthy Male Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Safety, Tolerability, Pharmacokinetics and Pharmacodynamics
Keywords: ACT-281959
ACT-246475
Lead sponsor: Idorsia Pharmaceuticals Ltd.
Sponsor class: INDUSTRY
First posted: 2013-10-07
Enrollment: 49
Sex: MALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Change in supine systolic blood pressure from baseline up to the end of study
timeFrame: 72 hours
measure: Change in supine diastolic blood pressure from baseline up to the end of study
timeFrame: 72 hours
measure: Change in supine pulse rate from baseline up to the end of study
timeFrame: 72 hours
measure: Change in body weight from baseline up to the end of study
timeFrame: 72 hours
measure: Change in PQ Interval from baseline up to the end of study
timeFrame: 72 hours
measure: Change in QRS Interval from baseline up to the end of study
timeFrame: 72 hours
measure: Change in QT Interval from baseline up to the end of study
timeFrame: 72 hours
Secondary outcomes:
measure: Maximum plasma concentration (Cmax) of ACT-246475
timeFrame: 72 hours
measure: Time to reach maximum plasma concentration (tmax) of ACT-246475
timeFrame: 72 hours
measure: Area under the plasma concentration-time curve (AUC) from time 0 to time t of the last measured concentration (AUC0-t) of ACT-246475
timeFrame: 72 hours
measure: AUC from time zero to infinity (AUC0-∞) of ACT-246475
timeFrame: 72 hours
measure: Terminal half-life (t1/2) of ACT-246475
timeFrame: 72 hours
measure: Percentage inhibition of platelet aggregation following administration of ACT-281959 as prodrug formulation I
timeFrame: 24 hours
measure: Percentage inhibition of platelet aggregation following administration of ACT-281959 as prodrug formulation II
timeFrame: 24 hours
measure: Percentage inhibition of platelet aggregation following administration of ACT-246475
timeFrame: 24 hours
Other outcomes:
Locations:
city: Rennes
country: France
facility: Biotrial
Study officials:
affiliation: Actelion
name: Daniela Baldoni, PharmD PhD
role: STUDY_DIRECTOR
References: