Healthy Subjects
Conditions
Keywords
ACT-389949
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.
Interventions
DRUGACT-389949 40 mg
Predicted dose
DRUGACT-389949 800 mg
Predicted dose
DRUGACT-389949 (Group C1 dose to be selected)
DRUGACT-389949 (Group C2 dose to be selected)
DRUGPlacebo
Sponsors
Idorsia Pharmaceuticals Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Frequency of treatment-emergent ECG abnormalities from baseline up to end of study | Up to 13 days | Treatment-emergent abnormalities will be determined from standard 12-lead ECGs recorded in the supine position, after a 5-minute period of resting. |
| Change from baseline up to end of study in body weight | Up to 13 days | Body weight will be measured where possible using the same weighing scale for all subjects throughout the study. The weighing scale should have a precision of at least 0.5 kg. |
| 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) | Up to 13 days | PQ/PR interval will be determined from standard 12-lead electrocardiogram (ECG) recorded in the supine position, after a 5-minute period of resting. |
| 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) | Up to 13 days | QRS duration will be determined from standard 12-lead ECG recorded in the supine position, after a 5-minute period of resting. |
| 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) | Up to 13 days | QT interval will be determined from standard 12-lead ECG recorded in the supine position, after a 5-minute period of resting. |
| Change from baseline up to end of study in QTcB interval according to Bazett's correction (QTcB) | Up to 13 days | QTcB interval will be determined from standard 12-lead ECG recorded in the supine position, after a 5-minute period of resting. 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) |
| Change from baseline up to end of study in QTcF interval according to Fridericia's correction (QTcF) | Up to 13 days | QTcF interval will be determined from standard 12-lead ECG recorded in the supine position, after a 5-minute period of resting. The QTcB interval is the QT interval corrected for heart rate with Fridericia's formula (QTcB = QT/RR\^0.33 where RR is 60/heart rate) |
| Change from baseline up to end of study in supine systolic blood pressure | Up to 13 days | Blood pressure will be measured using an automatic oscillometric device, always on the dominant arm (i.e., dominant arm right = writing with right hand) |
| Change from baseline up to end of study in supine diastolic blood pressure | Up to 13 days | Blood pressure will be measured using an automatic oscillometric device, always on the dominant arm (i.e., dominant arm right = writing with right hand) |
| Change from baseline up to end of study in pulse rate | Up to 13 days | Pulse rate will be measured using an automatic oscillometric device, always on the dominant arm (i.e., dominant arm right = writing with right hand) |
| Change from baseline up to end of study in body temperature | Up to 13 days | Body temperature will be measured in the ear, where possible using the same thermometer(s) for all the subjects throughout the study. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum plasma ACT-389949 concentration during the dosing interval (Cmax,Dayx) | Up to 13 days | Blood samples for pharmacokinetic analysis will be taken immediately prior to dosing with ACT-389949, and at various time points after dosing. Cmax,Dayx will be calculated on the basis of the blood sampling time points. |
| Average plasma ACT-389949 concentration during the dosing interval (Cav,Dayx) | Up to 13 days | Blood samples for pharmacokinetic analysis will be taken immediately prior to dosing with ACT-389949, and at various time points after dosing. Cav,Dayx will be calculated by dividing AUCτ,Dayx by the dosing interval. |
| Time to reach maximum plasma ACT-389949 concentration (tmax,Dayx) | Up to 13 days | Blood samples for pharmacokinetic analysis will be taken immediately prior to dosing with ACT-389949, and at various time points after dosing. tmax,Dayx will be calculated on the basis of the blood sampling time points. |
| Accumulation index (AI) of ACT-389949 | Up to 13 days | Blood samples for pharmacokinetic analysis will be taken immediately prior to dosing with ACT-389949, and at various time points after dosing. The AI will be calculated as follows: AUCτDayx / AUCτDay1. |
| Trough concentration (Ctrough,Dayx) of ACT-389949 | Up to 13 days | Blood samples for pharmacokinetic analysis will be taken immediately prior to dosing with ACT-389949, and at various time points after dosing. Ctrough,Dayx of ACT-389949 will be taken directly from the measured plasma concentration-time values. |
| Area under the plasma concentration-time curve of ACT-389949 during the dosing interval (AUCτ,Dayx) | Up to 13 days | Blood samples for pharmacokinetic analysis will be taken immediately prior to dosing with ACT-389949, and at various time points after dosing. AUCτ,Dayx will be calculated according to the linear trapezoidal rule using the measured concentration-time values above the lower limit of quantification during the dosing interval. |
Countries
United Kingdom
Outcome results
None listed