Clinical trial NCT02099201: Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ACT-389949 in Healthy Subjects
Official title: A Single-center, Double-blind, Parallel-group, Randomized, Placebo-controlled, Multiple-ascending Oral Dose Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ACT-389949 in Healthy Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Subjects
Keywords: ACT-389949
Lead sponsor: Idorsia Pharmaceuticals Ltd.
Sponsor class: INDUSTRY
First posted: 2014-03-28
Enrollment: 65
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

Brief summary: This is a single-center, double-blind, parallel-group, randomized, placebo-controlled, multiple-ascending oral dose study to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of ACT-389949 in healthy subjects.

Part A of the study will evaluate the safety and tolerability following once a day oral dosing of ACT-389949 for 9 days and investigate ACT-389949 pharmacokinetics and pharmacodynamics.

Part B of the study will evaluate the safety and tolerability of ACT-389949 following a maximum of two different oral dosing regimens: ACT-389949 given either every 3 days for 13 days or every 2 days for 9 days (5 doses for each regimen).

Part C of the study, if required, will provide additional information to that obtained from Parts A and B in terms of safety, tolerability, pharmacokinetics, and pharmacodynamics of ACT-389949.


Eligibility criteria: Inclusion Criteria:

* Signed informed consent in local language.
* Healthy Caucasian male subjects and female subjects of non-childbearing potential.
* Men with female partners of childbearing potential must agree to use 2 reliable methods of contraception from first drug administration up to a minimum of 90 days after the end of treatment.
* Male subjects must agree not to donate sperm from the first drug administration until 90 days after the end of treatment.
* Non-smokers, defined as never smoked or achieved cessation ≥ 12 months prior to screening.
* Body mass index of 18.0 to 28.0 kg/m\^2 (inclusive) at screening.
* No clinically significant findings on the physical examination at screening.
* Negative results from urine alcohol and drug screen at screening and on Day -1.
* Systolic blood pressure 100-145 mmHg, diastolic blood pressure 50-90 mmHg, and pulse rate 45-90 beats per minute (inclusive) measured at screening.
* 12-Lead electrocardiogram without clinically relevant abnormalities at screening.
* Body temperature 35.5-37.7 °C at screening and prior to first dosing.
* C-reactive protein (CRP) and total and differential white blood cell (WBC)count within the local laboratory normal ranges at screening and on Day -1.
* Hematology, coagulation, clinical chemistry, and urinalysis results (other than total differential WBC and CRP), not deviating to a clinically relevant extent from the normal local laboratory range(s) at screening.
* Forced expiratory volume in 1 second (FEV1) ≥ 80% of predicted, FEV1 / Forced vital capacity ≥ 70%.
* Subjects must be able to provide adequate sputum following induction with hypertonic saline at screening.
* Able to communicate well with the investigator, in the local language, and to understand and comply with the requirements of the study.
* Able to stay in the unit for the entire duration required and undertake all study related procedures.

Exclusion Criteria:

* Circumstances or conditions, which, in the opinion of the investigator, may affect full participation in the study or compliance with the protocol.
* 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.
* Previous history of fainting, collapse, syncope, orthostatic hypotension, or vasovagal reactions.
* Veins unsuitable for intravenous puncture on either arm.
* Loss of 250 mL or more of blood or blood donation, within 3 months prior to screening.
* Known allergic reactions or hypersensitivity to any excipient of the drug formulation(s).
* Previous exposure to ACT-389949.
* Exposure to lipopolysaccharide within the last year.
* Treatment with another investigational drug within 3 months 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.
* Use of regular medication or therapy (including vaccines) or over-the-counter medications within 2 weeks prior to first study drug administration or 5 half-lives of the medication, whichever is longer.
* 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 serology at screening.
* Vaccinations within the previous 6 months or foreign travel to areas within the last 6 months where infectious diseases are prevalent.
* Signs or symptoms suggestive of infection within 2 weeks prior to study screening and between screening and dosing.
* Signs of respiratory tract infections within 2 weeks prior to screening and between screening and dosing.
* History of atopic allergy.
* Hay fever, if within active season.
* Chronic diseases including those with recurring periods of flare-ups and remission.
* Legal incapacity or limited legal capacity at screening.

Primary outcomes:
measure: Change from baseline up to end of study in supine systolic blood pressure
timeFrame: Up to 13 days
measure: Change from baseline up to end of study in supine diastolic blood pressure
timeFrame: Up to 13 days
measure: Change from baseline up to end of study in pulse rate
timeFrame: Up to 13 days
measure: Change from baseline up to end of study in body temperature
timeFrame: Up to 13 days
measure: Change from baseline up to end of study in body weight
timeFrame: Up to 13 days
measure: Change from baseline up to end of study in PQ/PR interval (time interval from the beginning of the P wave to the beginning of the QRS complex)
timeFrame: Up to 13 days
measure: Change from baseline up to end of study in QRS duration (time interval from the beginning of the Q wave to the end of the S wave)
timeFrame: Up to 13 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 13 days
measure: Change from baseline up to end of study in QTcB interval according to Bazett's correction (QTcB)
timeFrame: Up to 13 days
measure: Change from baseline up to end of study in QTcF interval according to Fridericia's correction (QTcF)
timeFrame: Up to 13 days
measure: Frequency of treatment-emergent ECG abnormalities from baseline up to end of study
timeFrame: Up to 13 days
Secondary outcomes:
measure: Area under the plasma concentration-time curve of ACT-389949 during the dosing interval (AUCτ,Dayx)
timeFrame: Up to 13 days
measure: Maximum plasma ACT-389949 concentration during the dosing interval (Cmax,Dayx)
timeFrame: Up to 13 days
measure: Average plasma ACT-389949 concentration during the dosing interval (Cav,Dayx)
timeFrame: Up to 13 days
measure: Time to reach maximum plasma ACT-389949 concentration (tmax,Dayx)
timeFrame: Up to 13 days
measure: Accumulation index (AI) of ACT-389949
timeFrame: Up to 13 days
measure: Trough concentration (Ctrough,Dayx) of ACT-389949
timeFrame: Up to 13 days
Other outcomes:
Locations:
city: Belfast
country: United Kingdom
facility: Celerion
Study officials:
affiliation: Actelion
name: Alison Mackie, MSc
role: STUDY_DIRECTOR
References: