Alzheimer's disease dementia
Conditions
Interventions
In Part A of the study HTL0009936 will be administered IV and PO. In Part B
both HTL0009936 and physostigmine will be administered.
Sponsors
Heptares Therapeutics Ltd.
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: 1.Healthy male and female subjects from 65 and older, inclusive. 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;;2. BMI between 18 and 34 kg/m2, inclusive;;3. Ability to communicate well with the investigator in the Dutch language; ;4. Female participants should be post-menopausal;;5. Able to participate and willing to give written informed consent and to comply with the study restrictions; and;6. Intermediate (IM) or extensive (EM) metabolizer as determined by CYP2D6 genotype.;Additional inclusion criteria for Part B of the study only;1. A score of
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;;3. Any disease associated with cognitive impairment, including but not limited to schizophrenia and dementia;;4. Clinically relevant abnormal laboratory results, ECG and vital signs, or physical findings at screening and/or at the start of the first study day for each period;;5. Systolic blood pressure greater than 140 or less than 90 mm Hg, and diastolic blood pressure greater than 90 or less than 50 mm Hg;;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;;11. Evidence of significant renal insufficiency, indicated by a glomerular filtration rate lower than the lower limit of normal (related to age) at screening;;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, 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;;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) or alcohol or cotinine test at screening and/or pre-dose;;16. Concomitant use of drugs that are metabolised by and/or are inhibitors of CYP2D6 (e.g., quinidine, paroxetine, fluoxetine) or inhibitors/inducers of CYP3A4 (e.g., ketoconazole, ritonavir) from 21 days prior to study drug administration;;17. Concomitant use of drugs that are substrates for the organic cation transporter 2 (OCT 2), including amantadine, amiloride, cimetidine, dopamine, famotidine, memantine, metformin, pindolol, procainamide, ranitidine, varenicline, oxaliplatin and dofetilide;;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,
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, QTcB, QTcF) Pharmacokinetics A population approach PK model will be developed, describing the plasma HTL0009936 concentrations over time. Pharmacodynamics (Part B only) Adaptive Tracking test Visual Analogue Scale N-back test Verbal visual learning test Milner MAZE test Pupil size Pharmaco-EEG Leeds Sleep Evalaution Questionnaire Paired Associates Learning test Rapid Visual Information Processing test Spatial Working Memory test | — |
Secondary
| Measure | Time frame |
|---|---|
| • To assess the concentration of HTL0009936 and its R-enantiomer HTL0010042 in selected samples. • To undertake preliminary investigations into the metabolite(s) of HTL0009936 in selected and/or pooled samples. | — |
Countries
Netherlands
Outcome results
None listed