Alzheimer's disease dementia
Conditions
Interventions
Pharmacodynamics
Pharmacokinetics
Safety
Tolerability
Sponsors
Axovant Scienced GmbH
Eligibility
Age
18 Years to 64 Years
Inclusion criteria
Inclusion criteria: 1. Healthy as determined by the Investigator, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. A subject with a clinical abnormality or laboratory parameters outside the reference range for the population being studied may be included only if, in the opinion of the Investigator, the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures. The Medical Monitor may be consulted as needed. 2. Male or female age 55 and above at screening. 3. A female subject is eligible to participate if she is of: * Non-childbearing potential defined as pre-menopausal females with a documented bilateral tubal ligation, bilateral oophorectomy (removal of the ovaries) or hysterectomy; hysteroscopic sterilization, or postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 mIU/ml is confirmatory]. Documented verbal history from the subject is acceptable. * Child-bearing potential and agrees to use one of the contraception methods listed in Section 5.6.1 for an appropriate period of time (as determined by the product label or Investigator) prior to the start of dosing to sufficiently minimize the risk of pregnancy at that point. Female subjects must agree to use contraception until the follow-up visit. 4. Male subjects must agree to use one of the contraception methods listed in Section 5.6.1. This criterion must be followed from the time of the first dose of study medication until 14 days after the last dose of study medication. 5. Body weight * 50 kg for men and * 45 kg for women and Body Mass Index within the range 18.5 31.0 kg/m2 (inclusive). 6. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
Exclusion criteria
Exclusion criteria: 1. The subject has a positive drug/alcohol screen at screening or Day 1. A minimum list of drugs that will be screened for is included in Section 7.3.4. 2. A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result at screening. 3. A positive pre-study test for human immunodeficiency virus (HIV) antibody. 4. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), direct bilirubin values greater than 1.25x the upper limit of normal (ULN) at screening or Day 1. A single repeat is allowed for eligibility determination. 5. Current use of tobacco/nicotine/vaping/e-cig/ products within 1 month prior to screening. 6. History of regular alcohol consumption within 6 months of the study defined as: * An average weekly intake of >14 drinks/week for men or >7 drinks/week for women. One drink is equivalent to (12 g alcohol) = 5 ounces (150 ml) of wine or 12 ounces (360 ml) of beer or 1.5 ounces (45 ml) of 80 proof distilled spirits. 7. The subject has received an investigational product (including placebo) within the following time period prior to the first dosing day in the current study: 60 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer). 8. Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John*s Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator and Medical Monitor the medication will not interfere with the study procedures or compromise subject safety (Section 6.9.2). 9. Consumption of Seville oranges or grapefruit (or their juices) from 7 days prior to the first dose of study medication. 10. History of clinically significant sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the Investigator or Medical Monitor, contraindicates their participation. 11. If heparin is used during PK sampling, subjects with a history of sensitivity to heparin or heparin-induced thrombocytopenia should not be enrolled. 12. Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 60 day period. 13. Pregnant females as determined by positive serum or urine human chorionic gonadotropin test at screening or prior to dosing. 14. Lactating females. 15. Subjects with a pre-existing condition interfering with normal gastrointestinal anatomy, function, or motility, hepatic and/or renal function that could interfere with the absorption, metabolism, and/or excretion of the study drugs. Subjects with a history of cholecystectomy, peptic ulceration, inflammatory bowel disease or pancreatitis should be excluded. 16. History of significant pulmonary, renal, gastrointestinal, ophthalmologic, genitourinary, or hepatic diseases. 17. History/evidence of symptomatic arrhythmia, angina/ischemia, coronary artery bypass grafting surgery or percutaneous transluminal coronary angioplasty or any clinically significant cardiac disease. 18. Exclusion criteria for screening ECG (a single repeat is allowed for eligibility determination): Heart rate 100 bpm PR Interval 220 msec QRS duration 120 msec QTcF interval >450 msec ;* Any
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| * Number of subjects completing full dose escalation * Number of subjects in each group completing the 6 mg BID dosing period | — |
Secondary
| Measure | Time frame |
|---|---|
| * Highest dose achieved before stopping due to intolerability * Nausea score by visual analog scale * Number of vomiting episodes and time to first vomiting episode * Abdominal pain score by visual analog scale * Number of diarrhea episodes * Percent of subjects reporting nausea * Percent of subjects reporting vomiting * Percent of subjects reporting diarrhea * Percent of subjects reporting dizziness * Other AEs * General safety and tolerability parameters also include adverse events, clinical laboratory, electrocardiogram (ECG), and vital sign assessments * Plasma PK parameters of rivastigmine and metabolite as data permit * Change from baseline in REM sleep parameters, including shortening of REM latency, increase in REM density and increase in the percentage duration of REM sleep during the night * Spectral parameters in non-REM sleep (spindle power, spindle density) * Change from baseline in nausea intensity based on a Visual Analog Scale (VAS) assessment * Change from baseline in abdominal pain based on a VAS assessment | — |
Countries
The Netherlands
Outcome results
None listed