Clinical Study to Assess the Pharmacokinetics, Safety, and Tolerability of ACT-129968 in Healthy Subjects

Study Overview
=================
Brief Summary
-----------------
To explore the pharmacokinetics (PK) of a single dose of two different formulations of ACT-129968, i.e., tablet versus capsule and to evaluate the safety and tolerability of a single dose of two different formulations of ACT-129968, i.e., tablet versus capsule.

Detailed Description
-----------------
A total of 10 female and 10 male healthy subjects will be enrolled and will attend two treatment periods, separated by a 7-9 day washout. Over these two periods, two formulations of ACT-129968 (Treatment A: two capsules, 250 mg each; Treatment B: one tablet, 500 mg) will be administered in the sequence A/B or B/A to 10 subjects (5 females and 5 males) per sequence as determined by randomization.

Official Title
-----------------
A Single-center, Open-label, Two-period, Two-treatment, Crossover, Single-dose Study in Healthy Female and Male Subjects to Assess the Pharmacokinetics, Safety, and Tolerability of Two Different Formulations of ACT-129968

Conditions
-----------------
Healthy Subjects

Intervention / Treatment
-----------------
* Drug: ACT-129968 500 mg tablet
* Drug: ACT-129968 250 mg capsule


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Signed informed consent in the local language prior to any study-mandated procedure. Women must have a negative serum pregnancy test at screening and a negative urine pregnancy test pre-dose on Day-1 of each treatment period. Women of childbearing potential must consistently and correctly use (from screening, during the entire study, and for at least 28 days after last study drug intake) a reliable method of contraception with a failure rate of < 1% per year, be sexually inactive, or have a vasectomized partner. Women not of childbearing potential are defined as post-menopausal (i.e., spontaneous amenorrhea for at least 1 year without an alternative medical cause) or surgically or naturally sterile. No clinically significant findings on the physical examination at screening. Body mass index (BMI) of 18.0 to 28.0 kg/m^2 (inclusive) at screening. Systolic blood pressure (SBP) 100-145 mmHg, diastolic blood pressure (DBP) 50-90 mmHg, and pulse rate (PR) 45-90 bpm (inclusive), measured on the dominant arm (dominant arm = writing arm) after 5 minutes in the supine position at screening. 12-lead electrocardiogram (ECG) without clinically relevant abnormalities, measured after 5 minutes in the supine position at screening. Hematology, clinical chemistry, and urinalysis test results not deviating from the normal range to a clinically relevant extent at screening. Negative results from urine drug screen and breath alcohol test at screening and on admission to the unit (Day-1) in Period 1 and Period 2. Ability to communicate well with the investigator, in the local language, and to understand and comply with the requirements of the study. Exclusion Criteria: Pregnant or lactating women. 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 might interfere with the absorption, distribution, metabolism, or excretion of the study drug (appendectomy and herniotomy allowed, cholecystectomy not allowed). Previous history of fainting, collapse, syncope, orthostatic hypotension, or vasovagal reactions. History or clinical evidence of allergic rhinitis or asthma. Veins unsuitable for intravenous puncture on either arm (e.g., veins that are difficult to locate, access, or puncture, veins with a tendency to rupture during or after puncture). Previous exposure to the study medication. 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. Alcohol consumption of > 21 units/week or > 3 units/day. Smoking within 3 months prior to screening. Previous treatment with any prescribed or over-the-counter medications (including herbal medicines such as St John's Wort) within 2 weeks prior to first study drug administration. Loss of 250 mL or more of blood within 3 months prior to screening. Positive results from the hepatitis serology (Hepatitis B surface antigen and anti-hepatitis C virus), except for vaccinated subjects or subjects with past but resolved hepatitis (defined as positive finding for antibodies but negative findings for antigens), at screening. Positive results from the human immunodeficiency virus serology at screening. 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 at screening.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ACT-129968 tablet/capsules<br>Subjects attend two treatment periods. In the first treatment period subjects receive a single, oral dose of ACT-129968 500 mg administered as a tablet (1 tablet, 500 mg) in the fasted state. In the second treatment period subjects receive a single, oral dose of ACT-129968 500 mg administered as capsules (2 capsules, 250 mg each) in the fasted state. There is a 7-9 day washout period between the first treatment period and the second treatment period. | Drug: ACT-129968 500 mg tablet<br>* ACT-129968, a tetrahydropyridoindole derivative, is a chemoattractant receptor homologous molecule expressed on T helper 2 cells (CRTH2) antagonist<br>Drug: ACT-129968 250 mg capsule<br>* ACT-129968, a tetrahydropyridoindole derivative, is a chemoattractant receptor homologous molecule expressed on T helper 2 cells (CRTH2) antagonist<br>|
| Experimental: ACT-129968 capsules/tablet<br>Subjects attend two treatment periods. In the first treatment period subjects receive a single, oral dose of ACT-129968 500 mg administered as capsules (2 capsules, 250 mg each) in the fasted state. In the second treatment period subjects receive a single, oral dose of ACT-129968 500 mg administered as a tablet (1 tablet, 500 mg each) in the fasted state. There is a 7-9 day washout period between the first treatment period and the second treatment period. | Drug: ACT-129968 500 mg tablet<br>* ACT-129968, a tetrahydropyridoindole derivative, is a chemoattractant receptor homologous molecule expressed on T helper 2 cells (CRTH2) antagonist<br>Drug: ACT-129968 250 mg capsule<br>* ACT-129968, a tetrahydropyridoindole derivative, is a chemoattractant receptor homologous molecule expressed on T helper 2 cells (CRTH2) antagonist<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The area under the plasma concentration-time curve from time zero to time t of the last measured concentration above the limit of quantification (AUC0-t). | The plasma PK parameters for ACT-129968 will be derived by non-compartmental analysis of the plasma concentrationtime profiles. | Up to 48 h in each treatment period (1 and 2) | 
| The area under the plasma concentration-time curve from zero to infinity (AUC0-infinity). | The plasma PK parameters for ACT-129968 will be derived by non-compartmental analysis of the plasma concentrationtime profiles. | Up to 48 h in each treatment period (1 and 2) | 
| The maximum plasma concentration (Cmax) | The plasma PK parameters for ACT-129968 will be derived by non-compartmental analysis of the plasma concentrationtime profiles. | Up to 48 h in each treatment period (1 and 2) | 
| The time to reach maximum plasma concentration (tmax) | The plasma PK parameters for ACT-129968 will be derived by non-compartmental analysis of the plasma concentrationtime profiles. | Up to 48 h in each treatment period (1 and 2) | 
| The terminal elimination half-life (t½) | The plasma PK parameters for ACT-129968 will be derived by non-compartmental analysis of the plasma concentrationtime profiles. | Up to 48 h in each treatment period (1 and 2) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline to each time point of measurement during each treatment period and to EOS in supine blood pressure | mmHg | Up to 13 days | 
| Change from baseline to each time point of measurement during each treatment period and to EOS in pulse rate | bpm | Up to 13 days | 
| Body weight at baseline and end of study visit |  | Up to 13 days | 
| Change from baseline to EOS for hematology |  | Up to 13 days | 
| Change from baseline to EOS for clinical chemistry |  | Up to 13 days | 
| Change from baseline to EOS for pregnancy serum test |  | Up to 13 days | 
| Change from baseline to EOS for virus serology |  | Up to 13 days | 
| Change from baseline to each time point of measurement during each treatment period and to EOS in ECG variables | ECG variables are to be recorded at rest using a standard 12-lead ECG | Up to 13 days | 
| Number of patients with treatment-emergent ECG abnormalities for each treatment period |  | from study drug administration on Day 1 up to 48 hours post-dose | 
| Number of patients with treatment-emergent physical examination abnormalities at EOS |  | Up to 13 days | 
| Number of patients with treatment-emergent AEs and SAEs for each treatment period |  | from study drug administration on Day 1 up to 48 hours post-dose | 
| Number of patients with AEs leading to premature discontinuation of study drug |  | Entire duration of study | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Pharmacokinetics, Tolerability, Safety, ACT-129968