Single-ascending Oral Dose Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ACT-281959 / ACT-246475 in Healthy Male Subjects

NCT ID: NCT01954615

Last Updated: 2018-07-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 49 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-10-31
• Study Completion Date: 2012-03-31

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.

Conditions

Safety, Tolerability, Pharmacokinetics and Pharmacodynamics

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Group A 5 mg ACT-281959 prodrug formulation I/placebo

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.

Group Type: EXPERIMENTAL

5 mg ACT-281959 prodrug formulation I (Group A)

Intervention Type: DRUG

Placebo (Groups A to F)

Intervention Type: DRUG

Group B 20 mg ACT-281959 prodrug formulation I/placebo

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.

Group Type: EXPERIMENTAL

20 mg ACT-281959 prodrug formulation I (Group B)

Intervention Type: DRUG

Placebo (Groups A to F)

Intervention Type: DRUG

Group C ACT-281959 prodrug formulation I/placebo

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.

Group Type: EXPERIMENTAL

ACT-281959 prodrug formulation I (Groups C to G doses to be defined)

Intervention Type: DRUG

Placebo (Groups A to F)

Intervention Type: DRUG

Group D ACT-281959 prodrug formulation I/placebo

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.

Group Type: EXPERIMENTAL

ACT-281959 prodrug formulation I (Groups C to G doses to be defined)

Intervention Type: DRUG

Placebo (Groups A to F)

Intervention Type: DRUG

Group E ACT-281959 prodrug formulation I/placebo

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.

Group Type: EXPERIMENTAL

ACT-281959 prodrug formulation I (Groups C to G doses to be defined)

Intervention Type: DRUG

Placebo (Groups A to F)

Intervention Type: DRUG

Group F ACT-281959 prodrug formulation I/placebo

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.

Group Type: EXPERIMENTAL

ACT-281959 prodrug formulation I (Groups C to G doses to be defined)

Intervention Type: DRUG

Placebo (Groups A to F)

Intervention Type: DRUG

Group G ACT-281959 prodrug formulation I & II/ACT-246475

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.

Group Type: EXPERIMENTAL

ACT-281959 prodrug formulation I (Groups C to G doses to be defined)

Intervention Type: DRUG

ACT-281959 prodrug formulation II (Group G dose to be defined)

Intervention Type: DRUG

ACT-246475 (Group G dose to be defined)

Intervention Type: DRUG

Interventions

5 mg ACT-281959 prodrug formulation I (Group A)

Intervention Type: DRUG

20 mg ACT-281959 prodrug formulation I (Group B)

Intervention Type: DRUG

ACT-281959 prodrug formulation I (Groups C to G doses to be defined)

Intervention Type: DRUG

ACT-281959 prodrug formulation II (Group G dose to be defined)

Intervention Type: DRUG

ACT-246475 (Group G dose to be defined)

Intervention Type: DRUG

Placebo (Groups A to F)

Intervention Type: DRUG

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 45 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: Yes

Sponsors

Idorsia Pharmaceuticals Ltd.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Daniela Baldoni, PharmD PhD

Role: STUDY_DIRECTOR

Actelion

Locations

Biotrial

Rennes, , France

Countries

France

Other Identifiers

AC-075-101

Identifier Type: -

Identifier Source: org_study_id