Clinical trial NCT02068235: Study to Investigate the Absolute Bioavailability of a Single Oral Dose of Ponesimod in Healthy Male Subjects
Official title: Single-center, Open-label, Randomized, Two-way Crossover Study to Investigate the Absolute Bioavailability of a Single Oral Dose of Ponesimod in Healthy Male Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Keywords: Ponesimod
Bioavailability
Pharmacokinetics
Safety
Lead sponsor: Actelion
Sponsor class: INDUSTRY
First posted: 2014-02-21
Enrollment: 17
Sex: MALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER

Brief summary: This study consists of a single-dose pilot phase and a randomized, two-way crossover, single-dose main phase.The aim of this study is to evaluate the absolute bioavailability of the oral formulation (tablet) of ponesimod compared to an intravenous (i.v.) ponesimod formulation. Three subjects will be included in the pilot phase and 12 subjects in the main crossover phase.


Eligibility criteria: Inclusion Criteria:

* Signed informed consent in the local language prior to any study-mandated procedure.
* Body mass index ≥ 18 and ≤ 28 kg/m\^2 at screening.
* No clinically significant findings on the physical examination at screening.
* Systolic blood pressure (SBP) 100-145 mmHg and diastolic blood pressure (DBP) 50-90 mmHg, measured on the dominant arm, after 5 min in the supine position at screening and Day -1 of pilot phase/ first treatment period in main phase.
* 12-lead ECG without clinically relevant abnormalities at screening and Day -1 pilot phase / first treatment period in main phase.
* Negative results from urine drug screen at screening and Day -1 pilot phase / first treatment period in main phase.
* Hematology and clinical chemistry variables not deviating from the normal range to a clinically relevant extent at screening.
* 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 the active compound or any excipients 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).
* Veins unsuitable for i.v. puncture on either arm (e.g., veins that are difficult to locate, access, or puncture or veins with a tendency to rupture during or after puncture).
* Heart rate \< 50 or \> 95 beats per minute (bpm) at screening or Day -1 of pilot phase / first treatment period in main phase on 12-lead ECG measured after 5 min in the supine position.
* PR interval (time interval from the beginning of the P wave to the beginning of the QRS complex) \> 200 ms at screening and Day -1 of pilot phase / first treatment period in main phase.
* Subjects with personal or family history of long QT (time interval from beginning of the Q wave until end of the T wave) syndrome or hypokalemia.
* Previous history of fainting, collapse, syncope, orthostatic hypotension, or vasovagal reactions.
* Previous exposure to the study medication within 3 months prior to screening.
* Any immunosuppressive treatment within 6 weeks or 5 half-lives of the drug, whichever is longer, before study drug administration.
* Treatment with another investigational drug within 3 months or 10 half-lives of the drug, whichever is longer, prior to screening or participation in more than 4 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 (7 cups of coffee or 14 cups of tea) per day at screening.
* Smoking within the last 3 months prior to screening and inability to refrain from smoking during the course of the study.
* Treatment with any prescribed medications (including vaccines) or over-the-counter (OTC) medications (including herbal medicines) within 2 weeks prior to screening.
* Loss of 250 mL or more of blood within 3 months prior to screening.
* Lymphopenia (\< 1000 cells/μL) at screening or Day -1 of pilot phase / first treatment period in main phase.
* Viral, fungal (with exception of onychomycosis and dermatomycosis), bacterial, or protozoal infection within 4 weeks before the first study drug administration.
* 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 (HIV) 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.

Primary outcomes:
measure: Area under the plasma concentration-time curve (AUC(0-144h)) of ponesimod
timeFrame: 7 Days
measure: Area under the plasma concentration-time curve (AUC(0-infinity)) of ponesimod
timeFrame: 7 Days
measure: Maximum plasma concentration (Cmax) of ponesimod
timeFrame: 7 Days
measure: Plasma half life (t1/2) of ponesimod
timeFrame: 7 Days
measure: Time to maximum plasma concentration (tmax) after oral administration of ponesimod
timeFrame: 7 Days
measure: Total body clearance (CL) after intravenous administration of ponesimod
timeFrame: 7 Days
measure: Volume of distribution (Vss) after intravenous administration of ponesimod
timeFrame: 7 Days
measure: Absolute bioavailability (F) of after oral administration of ponesimod
timeFrame: 7 Days
Secondary outcomes:
measure: Change from baseline up to Day 7 in systolic blood pressure
timeFrame: 7 Days
measure: Change from baseline up to Day 7 in diastolic blood pressure
timeFrame: 7 Days
measure: Change from baseline up to Day 7 in pulse rate
timeFrame: 7 Days
measure: Change from baseline up to Day 7 in heart rate
timeFrame: 7 Days
measure: Change from baseline up to Day 7 in PR interval (time interval from the beginning of the P wave to the beginning of the QRS complex)
timeFrame: 7 Days
measure: Change from baseline up to Day 7 in QRS duration (time interval from the beginning of the Q wave to the end of the S wave)
timeFrame: 7 Days
measure: Change from baseline up to Day 7 in QT interval (time interval from beginning of the Q wave until end of the T wave)
timeFrame: 7 Days
measure: Change from baseline up to Day 7 in QT interval according to Bazett's correction (QTcB)
timeFrame: 7 Days
measure: Change from baseline up to Day 7 in QT interval according to Fridericia's correction (QTcF)
timeFrame: 7 Days
measure: Frequency of treatment-emergent ECG abnormalities from up to Day 7
timeFrame: 7 Days
Other outcomes:
Locations:
city: Merthyr Tydfil
country: United Kingdom
facility: Simbec Research Limited
Study officials:
affiliation: Actelion
name: Daniela Baldoni, PharmD, PhD
role: STUDY_DIRECTOR
References: