Dementia, pharmacokinetics, pharmacodynamics
Conditions
Interventions
In this study HTL0018318 will be administered in a oral solution
Sponsors
Heptares Therapeutics Ltd.
Eligibility
Inclusion criteria
Inclusion criteria: 1. Younger adults: age 18-55 inclusive. Elderly adults: age ≥65 years, inclusive. 2. Healthy young and elderly male and female subjects. Healthy status is defined by absence of evidence of any active or chronic disease following a detailed medical and surgical history, a complete physical examination including vital signs, 12-lead ECG, haematology, blood chemistry, and urinalysis; 3. BMI between 18 and 34 kg/m2, inclusive; 4. Ability to communicate well with the investigator in the Dutch language; 5. Young female subjects (18-55 years inclusive) must have a negative serum pregnancy test at screening and urine pregnancy test pre-dose on Day 1. Women of childbearing potential must consistently and correctly use (from screening, during the entire study, and for at least 90 days after last study drug intake) double barrier contraception (a condom combined with a 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 postmenopausal (i.e., amenorrhea for at least 1 year without an alternative medical cause), or surgically or naturally sterile. Male subjects must consistently and correctly use (from screening, during the entire study, and for at least 90 days after last study drug intake) double barrier contraception (a condom combined with spermicide), be sexually inactive, or have a sterilized partner. 6. Able to participate and willing to give written informed consent and to comply with the study restrictions; 7. Willing and able to perform the cognitive tests, as evidenced by performance on the training session of the cognitive tests.
Exclusion criteria
Exclusion criteria: "1. Legal incapacity or inability to understand or comply with the requirements of the study; 2. Clinically relevant history of abnormal physical or mental health interfering with the study as determined by medical history taking and physical examinations obtained during the screening visit and/or at the start of the first study day for each period as judged by the investigator (including (but not limited to), neurological, psychiatric, endocrine, cardiovascular, respiratory, gastrointestinal, hepatic, or renal disorder); 3. Any disease associated with cognitive impairment, including but not limited to schizophrenia and dementia; 4. Clinically relevant abnormal laboratory results (including hepatic and renal panels, complete blood count, chemistry panel and urinalysis), electrocardiogram (ECG) and vital signs, or physical findings at screening and/or at the start of the first study day for each period (as judged by the investigator). In case of uncertain or questionable results, tests performed during screening may be repeated before randomization to confirm eligibility or judged to be clinically irrelevant for healthy subjects; 5. Systolic blood pressure (SBP) greater than 140 or less than 90 mm Hg, and/or diastolic blood pressure (DBP) greater than 90 or less than 50 mm Hg at screening and baseline or a history of a significant period of hypertension as judged by the principal investigator; 6. Notable resting bradycardia (HR 100 bpm) at screening or baseline visit; 7. A QTcF > 450 or 1.5 times the upper limit of normal at screening and baseline. 11. Evidence of significant renal insufficiency, indicated by a glomerular filtration rate lower than the lower limit of normal (related to age) at screening and baseline. 12. Presence or history (within 3 months of screening) of alcohol abuse confirmed by medical history, or daily alcohol consumption exceeding 2 standard drinks per day on average for females or exceeding 3 standard drinks per day on average for males (1 standard drink = 10 grams of alcohol), or a positive breath alcohol test at screening or upon admission to the Clinical Research Unit (CRU), and the inability to refrain from alcohol use from 24 hours before screening, dosing and each scheduled visit until discharge from the clinical research unit (CRU) (alcohol consumption will be prohibited during study confinement) 13. Use of tobacco and/or nicotine-containing products within 90 days of dosing; 14. Habitual and heavy consumption of caffeinated beverages (more than 8 cups of coffee or equivalent/day) at screening and/or unable to refrain from use of (methyl) xanthine (e.g. coffee, tea, cola, chocolate) from 24 hours prior to dosing until discharge from the CRU; 15. Positive urine drug screen (UDS), serum/urine pregnancy test for females of child-bearing potential or alcohol or cotinine test at screening and/or pre-dose; 16. Concomitant use of drugs that are inhibitors/inducers of CYP3A4 and CYP2C9 (e.g.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Safety and tolerability endpoints - Treatment-emergent (serious) adverse events ((S)AEs) - Concomitant medication - Clinical laboratory tests (Haematology, Chemistry, Urinalysis) - Vital signs (Pulse Rate (bpm), Systolic blood pressure (mmHg), Diastolic blood pressure (mmHg)) - Electrocardiogram (ECG) (Heart Rate (HR) (bpm), PR, QRS, QT, QTcF) - pulmonary function test - salivary flow rate. Pharmacokinetics - A population approach PK model will be developed, describing the plasma HTL0018318 concentrations over time. Pharmacodynamics - Adaptive Tracking -Pupillometry-left pupil/iris ratio; right pupil/iris ratio -Milner Maze test (immediate, delayed and reversed condition) -N-back (0-back, 1-back and 2-back condition) -Electroencephalography (EEG): 21-lead EEG recordings (standard power spectrum analysis; optional EEG analysis by NBT analytics) -Event related potentials (ERPs) (i.e. P50, N100, P300 and mismatch-negativity (MMN) tasks) -Visual Analogue Scales according to Bond and Lader (alertness, mood, calmness) -Visual Analogue Scale for nausea. -Leeds Sleep Evaluation Questionnaire" | — |
Contacts
Public ContactG.J. Groeneveld
Centre for Human Drug Research
Outcome results
None listed