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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Group A 5 mg ACT-281959 prodrug formulation I/placebo | Experimental | 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. |
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| Group B 20 mg ACT-281959 prodrug formulation I/placebo | Experimental | 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. |
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| Group C ACT-281959 prodrug formulation I/placebo | Experimental | 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. |
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| Group D ACT-281959 prodrug formulation I/placebo | Experimental | 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. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 5 mg ACT-281959 prodrug formulation I (Group A) | Drug |
| ||
| 20 mg ACT-281959 prodrug formulation I (Group B) |
| Measure | Description | Time Frame |
|---|---|---|
| Change in supine systolic blood pressure from baseline up to the end of study | Blood pressure to be measured using an automatic oscillometric device. Measurements to be taken with the subject in the supine position after a resting period of at least 5 min. The dominant (writing) arm will be used for all measurements. Measurements to be taken at 1, 2, 4, 8, 24, 48, and 72 hours post-dose. | 72 hours |
| Change in supine diastolic blood pressure from baseline up to the end of study | Blood pressure to be measured using an automatic oscillometric device. Measurements to be taken with the subject in the supine position after a resting period of at least 5 min. The dominant (writing) arm will be used for all measurements. Measurements to be taken at 1, 2, 4, 8, 24, 48, and 72 hours post-dose. | 72 hours |
| Change in supine pulse rate from baseline up to the end of study | Pulse rate to be measured using an automatic oscillometric device. Measurements to be taken with the subject in the supine position after a resting period of at least 5 min. The dominant (writing) arm will be used for all measurements. Measurements to be taken at 1, 2, 4, 8, 24, 48, and 72 hours post-dose. | 72 hours |
| Change in body weight from baseline up to the end of study | Body weight will be measured using the same weighing scale for all subjects and throughout the study. The weighing scale should have a precision of at least 0.5 kg. | 72 hours |
| Change in PQ Interval from baseline up to the end of study | A standard 12-lead electrocardiogram (ECG) will be recorded in supine position after a 5-min rest period. The PQ interval is the time interval from the beginning of the P wave to the beginning of the QRS complex. Measurements to be taken at 1, 2, 4, 8, 24, 48 and 72 hours post-dose. |
| Measure | Description | Time Frame |
|---|---|---|
| Maximum plasma concentration (Cmax) of ACT-246475 | Blood samples for pharmacokinetic analysis taken immediately prior to dosing and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours, after dosing. Cmax calculated on the basis of the blood sampling time points. | 72 hours |
| Time to reach maximum plasma concentration (tmax) of ACT-246475 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Daniela Baldoni, PharmD PhD | Actelion | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Biotrial | Rennes | 35000 | France |
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| Group E ACT-281959 prodrug formulation I/placebo | Experimental | 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 F ACT-281959 prodrug formulation I/placebo | Experimental | 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 G ACT-281959 prodrug formulation I & II/ACT-246475 | Experimental | 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. |
|
| Drug |
|
| ACT-281959 prodrug formulation I (Groups C to G doses to be defined) | Drug |
|
| ACT-281959 prodrug formulation II (Group G dose to be defined) | Drug |
|
| ACT-246475 (Group G dose to be defined) | Drug |
|
| Placebo (Groups A to F) | Drug |
|
| 72 hours |
| Change in QRS Interval from baseline up to the end of study | A standard 12-lead electrocardiogram (ECG) will be recorded in supine position after a 5-min rest period. The QRS interval is the time interval from the beginning of the Q wave to the end of the S wave.Measurements to be taken at 1, 2, 4, 8, 24, 48 and 72 hours post-dose. | 72 hours |
| Change in QT Interval from baseline up to the end of study | A standard 12-lead electrocardiogram (ECG) will be recorded in supine position after a 5-min rest period. The QT interval is the time interval from beginning of the Q wave until end of the T wave. Measurements to be taken at 1, 2, 4, 8, 24, 48 and 72 hours post-dose. | 72 hours |
Blood samples for pharmacokinetic analysis taken immediately prior to dosing and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours, after dosing. tmax calculated on the basis of the blood sampling time points. |
| 72 hours |
| Area under the plasma concentration-time curve (AUC) from time 0 to time t of the last measured concentration (AUC0-t) of ACT-246475 | Blood samples for pharmacokinetic analysis taken immediately prior to dosing and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours, after dosing. AUC0-t calculated on the basis of the blood sampling time points, according to the linear trapezoidal rule using the measured concentration-time values above the limit of quantification. | 72 hours |
| AUC from time zero to infinity (AUC0-∞) of ACT-246475 | Blood samples for pharmacokinetic analysis taken immediately prior to dosing and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours, after dosing. AUC0-∞ was calculated by combining AUC0-t and AUCextra. AUCextra is an extrapolated value obtained by Ct/λz, where Ct is the last plasma concentration measured above the limit of quantification and λz represents the terminal elimination rate constant determined by log-linear regression analysis of the measured plasma concentrations in the terminal elimination phase. | 72 hours |
| Terminal half-life (t1/2) of ACT-246475 | Blood samples for pharmacokinetic analysis taken immediately prior to dosing and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours, after dosing. t1/2 calculated on the basis of the blood sampling time points. | 72 hours |
| Percentage inhibition of platelet aggregation following administration of ACT-281959 as prodrug formulation I | Adenosine diphosphate(ADP)-induced platelet aggregation will be measured using 2 different assays: Light transmission aggregometry (20 μM ADP) and VerifyNow P2Y12 (ADP receptor) assays Blood samples taken prior to dosing and at 1, 2, 3, 4, 8, 12 and 24 hours post-dosing. | 24 hours |
| Percentage inhibition of platelet aggregation following administration of ACT-281959 as prodrug formulation II | Adenosine diphosphate(ADP)-induced platelet aggregation will be measured using 2 different assays: Light transmission aggregometry (20 μM ADP) and VerifyNow P2Y12 (ADP receptor) assays Blood samples taken prior to dosing and at 1, 2, 3, 4, 8, 12 and 24 hours post-dosing. | 24 hours |
| Percentage inhibition of platelet aggregation following administration of ACT-246475 | Adenosine diphosphate(ADP)-induced platelet aggregation will be measured using 2 different assays: Light transmission aggregometry (20 μM ADP) and VerifyNow P2Y12 (ADP receptor) assays Blood samples taken prior to dosing and at 1, 2, 3, 4, 8, 12 and 24 hours post-dosing. | 24 hours |
| ID | Term |
|---|---|
| C000601315 | selatogrel |
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