Clinical trial NCT02381496: A Study to Assess the Tolerability, Safety, Pharmacodynamics, and Pharmacokinetics of Ascending Single Doses (Including Food Interaction) and Ascending Multiple Doses of ACT-453859, and Multiple Doses of Setipiprant (ACT-129968)
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Keywords: ACT-453859
ACT-463036
Setipiprant
Tolerability
safety
pharmacodynamics
pharmacokinetics
Lead sponsor: Idorsia Pharmaceuticals Ltd.
Sponsor class: INDUSTRY
First posted: 2015-03-06
Enrollment: 88
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

Brief summary: 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.

Detailed description: 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:

* Six male subjects will receive a single oral dose of ACT-453859, under fasted conditions.
* Two male subjects will receive matching placebo, under fasted conditions.

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:

* Three male subjects will receive ACT-453859.
* Three female subjects will receive ACT-453859.
* One male subject will receive matching placebo.
* One female subject will receive matching placebo.

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:

* Four male subjects will receive setipiprant 500 mg twice a day (b.i.d.) in TPI and 1000 mg b.i.d. in TPII.
* Four female subjects will receive setipiprant 500 mg b.i.d. in TPI and 1000 mg b.i.d. in TPII.

Eligibility criteria: Inclusion Criteria:

* Signed informed consent.
* Healthy male subjects (Part A), healthy male and female subjects for Parts B \& C.
* Hematology, coagulation (Part A and Part B only), clinical chemistry, and urinalysis test results not deviating from the normal range to a clinically relevant extent.
* No clinically significant findings on physical examination.
* Body mass index between 18.0 and 28.0 kg/m\^2.
* Systolic blood pressure 100-145 mmHg, diastolic blood pressure 50-90 mmHg, and heart rate 45-90 beats per minute.
* 12-lead electrocardiogram without clinically relevant abnormalities.
* Negative results from urine drug screen and alcohol breath test.
* Able and willing to refrain from sunbathing, prolonged sun exposure, and artificial sunlight exposure such as solarium, and to limit skin and eye exposure to sunlight using appropriate precautions from the first dose until safety follow-up visit for Parts A and B.
* Ability to communicate well with the investigator in the local language, and to understand and comply with the requirements of the study.
* For male subjects: consent that the female partner uses a medically acceptable method of contraception throughout the entire study period and for 90 days after the study is completed.
* For male subjects: agree not to donate sperm from the first drug administration until 90 days after completion of the study.
* For Part C, women of childbearing potential must have a negative serum pregnancy test and a negative urine pregnancy test pre-dose on Day 1 (of each treatment period for Part C). Women of childbearing potential must consistently and correctly use a reliable method of contraception, be sexually inactive or have a vasectomized partner.
* Willing to adhere to the prohibitions and restrictions specified in this protocol.

Exclusion Criteria:

* Previous history of fainting, collapses, syncope, orthostatic hypotension, or vasovagal reactions.
* Veins unsuitable for intravenous puncture on either arm.
* Treatment with any prescribed or over-the-counter medications within 2 weeks prior to first study drug administration.
* Treatment or substances known to inhibit cytochrome P (CYP) enzyme drug metabolism .
* Treatment or substances known to induce CYP enzyme drug metabolism.
* Treatment with another investigational drug within 3 months prior or participated in more than four investigational drug studies within 1 year prior to Screening. Subjects will not participate in more than one part of the study.
* History or clinical evidence of alcoholism or drug abuse within the 3-year period prior to Screening.
* History or clinical evidence of any disease, and/or existence of any surgical or medical condition, which might interfere with the absorption, distribution, metabolism or excretion of the study drugs.
* Excessive caffeine consumption.
* Smoking, tobacco use, or use of nicotine products within 3 months and inability to refrain from smoking during the course of the study.
* Loss of 250 mL or more of blood, or an equivalent amount of plasma, within 3 months prior to Screening.
* Positive results from the hepatitis serology, except for vaccinated subjects or subjects with past but resolved hepatitis.
* Positive results from human immunodeficiency virus serology.
* Any circumstances or conditions, which, in the opinion of the investigator, may affect full participation in the study or compliance with the protocol.
* Legal incapacity or limited legal capacity.
* Pregnant or lactating women.
* Known allergic reactions or hypersensitivity to any excipients of the drug formulations.
* Difficulty in fasting or consuming standardized meals.
* Difficulty in swallowing whole tablets or capsules.

Primary outcomes:
measure: Area under the plasma concentration-time curve (AUC(0-t)) for single doses of ACT-453859
timeFrame: 72 hours
measure: AUC(0-t) for the active metabolite ACT-463036 after single doses of ACT-453859
timeFrame: 72 hours
measure: Area under the plasma concentration-time curve (AUC(0-infinity)) for single doses of ACT-453859
timeFrame: 72 hours
measure: AUC(0-infinity) for the active metabolite ACT-463036 after single doses of ACT-453859
timeFrame: 72 hours
measure: Time to reach maximum plasma concentration (tmax) for single doses of ACT-453859
timeFrame: 72 hours
measure: tmax for the active metabolite ACT-463036 after single doses of ACT-453859
timeFrame: 72 hours
measure: Terminal elimination rate constant (λZ) for single doses of ACT-453859
timeFrame: 72 hours
measure: λZ for the active metabolite ACT-463036 after single doses of ACT-453859
timeFrame: 72 hours
measure: Plasma half life (t1/2) for single doses of ACT-453859
timeFrame: 72 hours
measure: t1/2 for the active metabolite ACT-463036 after single doses of ACT-453859
timeFrame: 72 hours
measure: Maximum plasma concentration (Cmax) for single doses of ACT-453859
timeFrame: 72 hours
measure: Cmax for the active metabolite ACT-463036 after single doses of ACT-453859
timeFrame: 72 hours
measure: Renal clearance (CLR) following single dose of ACT-453859 100 mg
timeFrame: 72 hours
measure: Percentage of ACT-453859 excreted unchanged in the urine following single dose of ACT-453859 100 mg
timeFrame: 72 hours
Secondary outcomes:
measure: Area under the plasma concentration-time curve (AUCτ) for multiple doses of ACT-453859 (Day 1 & Day 7)
timeFrame: 11 days
measure: AUCτ for the active metabolite ACT-463036 after multiple doses of ACT-453859 (Day 1 & Day 7)
timeFrame: 11 days
measure: Cmax for multiple doses of ACT-453859 (Day 1 & Day 7)
timeFrame: 11 days
measure: Cmax for the active metabolite ACT-463036 after multiple doses of ACT-453859 (Day 1 & Day 7)
timeFrame: 11 days
measure: tmax for multiple doses of ACT-453859 (Day 1 & Day 7)
timeFrame: 11 days
measure: tmax for the active metabolite ACT-463036 after multiple doses of ACT-453859 (Day 1 & Day 7)
timeFrame: 11 days
measure: λZ for multiple doses of ACT-453859
timeFrame: 11 days
measure: λZ for the active metabolite ACT-463036 after multiple doses of ACT-453859
timeFrame: 11 days
measure: t1/2 for multiple doses of ACT-453859
timeFrame: 11 days
measure: t1/2 for the active metabolite ACT-463036 after multiple doses of ACT-453859
timeFrame: 11 days
measure: CLR following multiple doses of ACT-453859 100 mg per day
timeFrame: 8 days
measure: Percentage of ACT-453859 excreted unchanged in the urine following multiple doses of ACT-453859 100 mg per day
timeFrame: 8 days
measure: AUCτ for setipiprant after multiple doses of 500 and 1000 mg b.i.d. setipiprant (Day 1 & Day 7)
timeFrame: 10 days
measure: Cmax for setipiprant after multiple doses of 500 and 1000 mg b.i.d. setipiprant (Day 1 & Day 7)
timeFrame: 10 days
measure: tmax for setipiprant after multiple doses of 500 and 1000 mg b.i.d. setipiprant (Day 1 & Day 7)
timeFrame: 10 days
measure: Chemoattractant receptor-homologous molecule expressed on T helper 2 cells (CRTH2) antagonist pharmacodynamic (PD) effect after single doses of ACT-453859
timeFrame: 72 hours
measure: CRTH2 antagonist PD effect after multiple doses of ACT-453859
timeFrame: 10 days
measure: CRTH2 antagonist PD effect after multiple doses of setipiprant
timeFrame: 10 days
measure: CRTH2 antagonist potency following administration of single and multiple doses of ACT-453859 and setipiprant
timeFrame: up to 10 days
measure: Change from baseline up to end of study in systolic blood pressure
timeFrame: up to 11 days
measure: Change from baseline up to end of study in diastolic blood pressure
timeFrame: up to 11 days
measure: Change from baseline up to end of study in heart rate
timeFrame: up to 11 days
measure: 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)
timeFrame: up to 11 days
measure: Change from baseline up to end of study in QTcB interval (QT interval corrected for heart rate according to Bazett's correction)
timeFrame: up to 11 days
measure: Change from baseline up to end of study in QTcF interval (QT interval corrected for heart rate according to Fridericia's correction)
timeFrame: up to 11 days
measure: Change from baseline up to end of study in heart rate
timeFrame: up to 11 days
measure: Number of subjects with treatment-emergent electrocardiogram abnormalities
timeFrame: up to 11 days
Other outcomes:
Locations:
Study officials:
affiliation: Actelion
name: Martine Géhin, PhD
role: STUDY_DIRECTOR
References: