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This is a three-part study to assess the tolerability, safety, pharmacodynamics, and pharmacokinetics of ascending single doses (including food interaction) of ACT-453859 in healthy male subjects, of ascending multiple doses of ACT-453859 in healthy male and female subjects, and of multiple doses of setipiprant (ACT-129968) in healthy male and female subjects.
Part A of this study is a single-center, randomized, double-blind, placebo-controlled, single-ascending dose (SAD) design in healthy male subjects. In each cohort, eight subjects will be randomized as follows:
The doses of ACT-453859 were 1, 3, 10, 30, 100, 300, and 800 mg. Subjects in only one cohort (100 mg dose cohort) will come back for a second period of treatment under fed conditions.
Part B is a single-center, randomized, double-blind, placebo-controlled multiple-ascending dose (MAD) design in healthy male and female of subjects.
In each of 3 cohorts, eight subjects will be randomized to receive multiple doses of ACT-453859 or placebo once a day for 7 days as follows:
The doses of ACT-453859 will be 10, 100, and 800 mg per day.
Part C is a single-center and open-label design consisting of multiple oral doses of setipiprant given in a sequential design in healthy male and female subjects.
Eight subjects will be randomized to receive multiple doses of setipiprant for 7 days (only a single dose on Day 7), in Treatment Period I (TPI) and Treatment Period II (TPII), as follows:
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Part A: Cohort A1: ACT-453859 1 mg | Experimental | ACT-453859 1 mg or placebo, single dose, administered orally in the fasted state
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| Part A: Cohort A2: ACT-453859 3 mg | Experimental | ACT-453859 3 mg or placebo, single dose, administered orally in the fasted state
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| Part A: Cohort A3: ACT-453859 10 mg | Experimental | ACT-453859 10 mg or placebo, single dose, administered orally in the fasted state
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| Part A: Cohort A4: ACT-453859 30 mg | Experimental | ACT-453859 30 mg or placebo, single dose, administered orally in the fasted state
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| Part A: Cohort A5: ACT-453859 100 mg | Experimental |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| ACT-453859 1 mg | Drug | Capsule |
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| ACT-453859 3 mg |
| Measure | Description | Time Frame |
|---|---|---|
| Area under the plasma concentration-time curve (AUC(0-t)) for single doses of ACT-453859 | Blood samples for pharmacokinetic assessments will be collected at various time points over the study period. AUC(0-t) will be calculated according to the linear trapezoidal rule using the measured concentration-time values above the limit of quantification (LOQ). | 72 hours |
| AUC(0-t) for the active metabolite ACT-463036 after single doses of ACT-453859 | Blood samples for pharmacokinetic assessments will be collected at various time points over the study period. AUC(0-t) will be calculated according to the linear trapezoidal rule using the measured concentration-time values above the LOQ. | 72 hours |
| Area under the plasma concentration-time curve (AUC(0-infinity)) for single doses of ACT-453859 | Blood samples for pharmacokinetic assessments will be collected at various time points over the study period. AUC(0-infinity) will be calculated by combining AUC(0-t) and AUC(extra). AUC(extra) represents an extrapolated value obtained by Ct/λz, where Ct is the last plasma concentration measured above the LOQ and λZ represents the terminal elimination rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal elimination phase. | 72 hours |
| AUC(0-infinity) for the active metabolite ACT-463036 after single doses of ACT-453859 | Blood samples for pharmacokinetic assessments will be collected at various time points over the study period. AUC(0-infinity) will be calculated by combining AUC(0-t) and AUC(extra). AUC(extra) represents an extrapolated value obtained by Ct/λz, where Ct is the last plasma concentration measured above the LOQ and λZ represents the terminal elimination rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal elimination phase. | 72 hours |
| Measure | Description | Time Frame |
|---|---|---|
| Area under the plasma concentration-time curve (AUCτ) for multiple doses of ACT-453859 (Day 1 & Day 7) | Blood samples for pharmacokinetic assessments will be collected at various time points over the study period. AUCτ will be calculated according to the linear trapezoidal rule using the measured concentration-time values above the LOQ during one dosing interval. | 11 days |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Martine Géhin, PhD | Actelion | Study Director |
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ACT-453859 100 mg or placebo, single dose, administered orally in the fasted state
After a washout period of 10-20 days subjects will return for a second study period to receive the same treatment received in the first session but under fed conditions |
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| Part A: Cohort A6: ACT-453859 300 mg | Experimental | ACT-453859 300 mg or placebo, single dose, administered orally in the fasted state
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| Part A: Cohort A7: ACT-453859 800 mg | Experimental | ACT-453859 800 mg or placebo, single dose, administered orally in the fasted state
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| Part B: Cohort B1: ACT-453859 10 mg | Experimental | ACT-453859 10 mg or placebo, once a day for 7 days, administered orally in the fasted state
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| Part B: Cohort B2: ACT-453859 100 mg | Experimental | ACT-453859 100 mg or placebo, once a day for 7 days, administered orally in the fasted state
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| Part B: Cohort B3: ACT-453859 800 mg | Experimental | ACT-453859 800 mg, once a day for 7 days, administered orally in the fasted state
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| Part C: Treatment Periods I & II: Setipiprant | Experimental | Setipiprant 500 mg, twice daily for 7 days, administered orally in Treatment Period I (TPI) and setipiprant 1000 mg, twice daily for 7 days, administered orally in Treatment Period II (TPII)
There will be a washout period of 10 days between TPI and TPII |
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| Drug |
Capsule |
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| ACT-453859 10 mg | Drug | Capsule |
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| ACT-453859 30mg | Drug | Capsule |
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| ACT-453859 100 mg | Drug | Capsule |
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| ACT-453859 300 mg | Drug | Capsule |
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| ACT-453859 800 mg | Drug | Capsule |
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| Placebo | Other | Matching ACT-453859 placebo capsule |
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| Setipiprant 500 mg | Drug | Capsule |
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| Setipiprant 1000 mg | Drug | Capsule |
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| Time to reach maximum plasma concentration (tmax) for single doses of ACT-453859 |
Blood samples for pharmacokinetic assessments will be collected at various time points over the study period. The measured individual plasma concentrations of ACT-453859 will be used to directly obtain tmax. |
| 72 hours |
| tmax for the active metabolite ACT-463036 after single doses of ACT-453859 | Blood samples for pharmacokinetic assessments will be collected at various time points over the study period. The measured individual plasma concentrations of ACT-463036 will be used to directly obtain tmax. | 72 hours |
| Terminal elimination rate constant (λZ) for single doses of ACT-453859 | Blood samples for pharmacokinetic assessments will be collected at various time points over the study period. λZ will be determined by log-linear regression analysis of the measured plasma concentrations of the terminal elimination phase. | 72 hours |
| λZ for the active metabolite ACT-463036 after single doses of ACT-453859 | Blood samples for pharmacokinetic assessments will be collected at various time points over the study period. λZ will be determined by log-linear regression analysis of the measured plasma concentrations of the terminal elimination phase. | 72 hours |
| Plasma half life (t1/2) for single doses of ACT-453859 | Blood samples for pharmacokinetic assessments will be collected at various time points over the study period. t1/2 will be calculated as follows: t½ = ln 2/λZ. | 72 hours |
| t1/2 for the active metabolite ACT-463036 after single doses of ACT-453859 | Blood samples for pharmacokinetic assessments will be collected at various time points over the study period. t1/2 will be calculated as follows: t½ = ln 2/λZ. | 72 hours |
| Maximum plasma concentration (Cmax) for single doses of ACT-453859 | Blood samples for pharmacokinetic assessments will be collected at various time points over the study period. The measured individual plasma concentrations of ACT-453859 will be used to directly obtain Cmax. | 72 hours |
| Cmax for the active metabolite ACT-463036 after single doses of ACT-453859 | Blood samples for pharmacokinetic assessments will be collected at various time points over the study period. The measured individual plasma concentrations of ACT-463036 will be used to directly obtain Cmax. | 72 hours |
| Renal clearance (CLR) following single dose of ACT-453859 100 mg | Urine samples for pharmacokinetic assessments will be collected at various time points over the study period. CLR will be calculated by dividing the total amount of unchanged ACT-453859 excreted in urine during the collection interval by AUC(0-t). | 72 hours |
| Percentage of ACT-453859 excreted unchanged in the urine following single dose of ACT-453859 100 mg | Urine samples for pharmacokinetic assessments will be collected at various time points over the study period.The percentage of total dose excreted unchanged in urine will be calculated by the total amount excreted, divided by the dose administered, multiplied by 100. | 72 hours |
| AUCτ for the active metabolite ACT-463036 after multiple doses of ACT-453859 (Day 1 & Day 7) | Blood samples for pharmacokinetic assessments will be collected at various time points over the study period. AUCτ will be calculated according to the linear trapezoidal rule using the measured concentration-time values above the LOQ during one dosing interval. | 11 days |
| Cmax for multiple doses of ACT-453859 (Day 1 & Day 7) | Blood samples for pharmacokinetic assessments will be collected at various time points over the study period. The measured individual plasma concentrations of ACT-453859 will be used to directly obtain Cmax. | 11 days |
| Cmax for the active metabolite ACT-463036 after multiple doses of ACT-453859 (Day 1 & Day 7) | Blood samples for pharmacokinetic assessments will be collected at various time points over the study period. The measured individual plasma concentrations of ACT-463036 will be used to directly obtain Cmax. | 11 days |
| tmax for multiple doses of ACT-453859 (Day 1 & Day 7) | Blood samples for pharmacokinetic assessments will be collected at various time points over the study period. The measured individual plasma concentrations of ACT-453859 will be used to directly obtain tmax. | 11 days |
| tmax for the active metabolite ACT-463036 after multiple doses of ACT-453859 (Day 1 & Day 7) | Blood samples for pharmacokinetic assessments will be collected at various time points over the study period. The measured individual plasma concentrations of ACT-463036 will be used to directly obtain tmax. | 11 days |
| λZ for multiple doses of ACT-453859 | Blood samples for pharmacokinetic assessments will be collected at various time points over the study period. λZ will be determined by log-linear regression analysis of the measured plasma concentrations of the terminal elimination phase. | 11 days |
| λZ for the active metabolite ACT-463036 after multiple doses of ACT-453859 | Blood samples for pharmacokinetic assessments will be collected at various time points over the study period. λZ will be determined by log-linear regression analysis of the measured plasma concentrations of the terminal elimination phase. | 11 days |
| t1/2 for multiple doses of ACT-453859 | Blood samples for pharmacokinetic assessments will be collected at various time points over the study period. t1/2 will be calculated as follows: t½ = ln 2/λZ. | 11 days |
| t1/2 for the active metabolite ACT-463036 after multiple doses of ACT-453859 | Blood samples for pharmacokinetic assessments will be collected at various time points over the study period. t1/2 will be calculated as follows: t½ = ln 2/λZ. | 11 days |
| CLR following multiple doses of ACT-453859 100 mg per day | Urine samples for pharmacokinetic assessments will be collected at various time points over the study period. CLR will be calculated by dividing the total amount of unchanged ACT-453859 excreted in urine during the collection interval by AUC(0-t). | 8 days |
| Percentage of ACT-453859 excreted unchanged in the urine following multiple doses of ACT-453859 100 mg per day | Urine samples for pharmacokinetic assessments will be collected at various time points over the study period. The percentage of total dose excreted unchanged in urine will be calculated by the total amount excreted, divided by the dose administered, multiplied by 100. | 8 days |
| AUCτ for setipiprant after multiple doses of 500 and 1000 mg b.i.d. setipiprant (Day 1 & Day 7) | Blood samples for pharmacokinetic assessments will be collected at various time points over the study period. AUCτ will be calculated according to the linear trapezoidal rule using the measured concentration-time values above the LOQ during one dosing interval. | 10 days |
| Cmax for setipiprant after multiple doses of 500 and 1000 mg b.i.d. setipiprant (Day 1 & Day 7) | Blood samples for pharmacokinetic assessments will be collected at various time points over the study period. The measured individual plasma concentrations of setipiprant will be used to directly obtain Cmax. | 10 days |
| tmax for setipiprant after multiple doses of 500 and 1000 mg b.i.d. setipiprant (Day 1 & Day 7) | Blood samples for pharmacokinetic assessments will be collected at various time points over the study period. The measured individual plasma concentrations of setipiprant will be used to directly obtain tmax. | 10 days |
| Chemoattractant receptor-homologous molecule expressed on T helper 2 cells (CRTH2) antagonist pharmacodynamic (PD) effect after single doses of ACT-453859 | Blood samples for PD assessment will be collected at various time points over the study period. The CRTH2 receptor level on eosinophils and basophils will be measured with flow cytometry and the percentage of eosinophil and basophil CRTH receptors blocked determined. | 72 hours |
| CRTH2 antagonist PD effect after multiple doses of ACT-453859 | Blood samples for PD assessment will be collected at various time points over the study period. The CRTH2 receptor level on eosinophils and basophils will be measured with flow cytometry and the percentage of eosinophil and basophil CRTH receptors blocked determined. | 10 days |
| CRTH2 antagonist PD effect after multiple doses of setipiprant | Blood samples for PD assessment will be collected at various time points over the study period. The CRTH2 receptor level on eosinophils and basophils will be measured with flow cytometry and the percentage of eosinophil and basophil CRTH receptors blocked determined. | 10 days |
| CRTH2 antagonist potency following administration of single and multiple doses of ACT-453859 and setipiprant | Study drug concentration that elicits 50% blockade (IC50) of eosinophil and basophil CRTH receptors. | up to 10 days |
| Change from baseline up to end of study in systolic blood pressure | Blood pressure and heart rate will be measured using an automatic oscillometric device, always on the dominant arm (i.e., dominant arm right = writing with right hand). Measurements will be recorded from the subject in the supine and standing position after having rested for a 5-minute period, except for Part C in which only supine position measurements will be performed. Standing position measurements will be performed after one minute standing. | up to 11 days |
| Change from baseline up to end of study in diastolic blood pressure | Blood pressure and heart rate will be measured using an automatic oscillometric device, always on the dominant arm (i.e., dominant arm right = writing with right hand). Measurements will be recorded from the subject in the supine and standing position after having rested for a 5-minute period, except for Part C in which only supine position measurements will be performed. Standing position measurements will be performed after one minute standing. | up to 11 days |
| Change from baseline up to end of study in heart rate | Blood pressure and heart rate will be measured using an automatic oscillometric device, always on the dominant arm (i.e., dominant arm right = writing with right hand). Measurements will be recorded from the subject in the supine and standing position after having rested for a 5-minute period, except for Part C in which only supine position measurements will be performed. Standing position measurements will be performed after one minute standing. | up to 11 days |
| Change from baseline up to end of study in QT interval (Time interval from beginning of the Q wave until end of the T wave) | Standard 12-lead electrocardiograms will be recorded at rest with the subject in the supine position for at least a 5-minute period at various time points throughout the study. | up to 11 days |
| Change from baseline up to end of study in QTcB interval (QT interval corrected for heart rate according to Bazett's correction) | Standard 12-lead electrocardiograms will be recorded at rest with the subject in the supine position for at least a 5-minute period at various time points throughout the study. The QTcB interval is the QT interval corrected for heart rate with Bazett's formula (QTcB = QT/RR^0.5 where RR is 60/heart rate). | up to 11 days |
| Change from baseline up to end of study in QTcF interval (QT interval corrected for heart rate according to Fridericia's correction) | Standard 12-lead electrocardiograms will be recorded at rest with the subject in the supine position for at least a 5-minute period at various time points throughout the study. The QTcF interval is the QT interval corrected for heart rate with Fridericia's formula (QTcF = QT/RR^0.33 where RR is 60/heart rate). | up to 11 days |
| Change from baseline up to end of study in heart rate | Standard 12-lead electrocardiograms will be recorded at rest with the subject in the supine position for at least a 5-minute period at various time points throughout the study. | up to 11 days |
| Number of subjects with treatment-emergent electrocardiogram abnormalities | Standard 12-lead electrocardiograms will be recorded at rest with the subject in the supine position for at least a 5-minute period at various time points throughout the study. Treatment-emergent electrocardiogram abnormalities are defined as abnormalities occurring after study drug administration up to end of study and which were not observed either at pre-dose or screening. | up to 11 days |
| ID | Term |
|---|---|
| C000605759 | ACT-453859 |
| C583159 | 2-(2-(1-naphthoyl)-8-fluoro-3,4-dihydro-1H-pyrido(4,3-b)indol-5(2H)-yl)acetic acid |
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