Multiple ascending dose study of HTL0018318

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.

"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 < 45 bpm) or tachycardia (HR > 100 bpm) at screening or
baseline visit;

7. A QTcF > 450 or < 300 msec at resting ECG at screening and baseline visit;

8. Personal or family history of congenital long QT syndrome or sudden death

9. Positive test for Hepatitis B surface antigen (HBsAg), Hepatitis C antibody (HCV Ab), or
human immunodeficiency virus antibody (HIV Ab) at screening;

10. Aspartate transaminase (AST), alanine transaminase (ALT), gamma glutamyl transferase
(GGT) or total bilirubin levels >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.,
ketoconazole, rifampicin, fluconazole, carbamazepine) from 21 days prior to study drug
administration;

17. Concomitant medication with a narrow therapeutic index that are substrates of CYP2C9 (e.g.
coumarin anticoagulants) or CYP3A4 (e.g. cyclosporine);

18. Intake of any food or any drinks containing cranberry, pomegranate, star fruit, grapefruit,
pomelos, exotic citrus fruits or Seville oranges (including marmalade and juices made from
these fruits) within 3 days before admission to the CRU and while subjects are confined to
the CRU;

19. Subject is unable to refrain from the use of concomitant medication which, in the opinion of
the investigator, interferes with their ability to participate in the trial, from 7 days prior to
dosing until the final follow-up study visit;

20. History of severe allergies, or history of an anaphylactic reaction to prescription or non prescription drugs or food (non-active hay-fever is acceptable);

21. History of epilepsy or seizures of any kind at any time;

22. 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 drugs;

23. Participation in an investigational drug trial in the 3 months prior to administration of the
initial dose of study drug or more than 4 times per year;

24. Donation or loss of blood of more than 500 mL within 3 months (males) or 4 months
(females) prior to screening;

25. Any other concomitant disease or condition that could interfere with, or for which the
treatment of might interfere with, the conduct of the study, or that would, in the opinion of the
Investigator, pose an unacceptable risk to the subject in this study.

Based on the results of the 24 hour period ECG Holter monitoring during screening, potential
subjects can be excluded based on the following exclusion criteria:

26. More than 200 ventricular ectopics in 24 hours;

27. Ventricular tachycardia (ventricular tachycardia was defined as being three or more
successive ventricular ectopic beats at a rate of at least 120 beats min-1);

28. Second degree heart block;

29. Sustained cardiac arrhythmias (atrial fibrillation, SVT, complete heart block);

30. Any symptomatic arrhythmia (except isolated extra systoles)."