| Eligibility |
Part 1 and Part 2 Only:
Inclusion Criteria:
1. Healthy as determined by the Investigator, based on a medical evaluation including
medical history, physical examination, neurological 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 (a) unlikely to introduce
additional risk to the subject, (b) will not interfere with study procedures or
confound study results, and (c) is not otherwise exclusionary (see Exclusion
Criteria).
2. Men and women aged 18-55 years, inclusive, at Screening (Part 1) or 55-80 years,
inclusive, at Screening (Part 2)
3. Subject must understand the nature of the study and provide signed and dated written
informed consent in accordance with local regulations before the conduct of any
study-related procedures.
4. Able to complete all study related testing and evaluations
5. Women (Part 1 only) and men of child-bearing potential with partners of child-bearing
potential must agree to use highly effective contraception. Contraception should
consist of: (1) a condom for the male participant or partner of a female participant,
combined with (2) a highly effective method of contraception (e.g., a hormonal method
associated with suppression of ovulation, an intrauterine device [IUD]) for the female
participant or partner of a male participant. Abstinence from heterosexual intercourse
should only be used in place of contraception when this is consistent with the usual
and preferred lifestyle of the participant. For male subjects, contraception should
continue for 90 days after the last dose of investigational medicinal product (IMP,
one spermatic cycle). Male subjects should agree to refrain from sperm donation
throughout this same period.
6. Women of non-childbearing potential must be post-menopausal (the last menstrual period
was at least 12 months ago, and follicle-stimulating hormone [FSH] at Screening
confirms post-menopausal status), or have no uterus, ovaries, or fallopian tubes (or
have their fallopian tubes tied). All women must have a negative pregnancy test result
before administration of test article. Women who are surgically sterile must provide
documentation of the procedure by an operative report or by ultrasound.
7. Body weight > 50.0 kg for men and > 50 kg for women and Body Mass Index (BMI) within
the range 18.5-30.0 kg/m2, inclusive.
8. Subject must be, in the opinion of the Investigator, able to participate in all
scheduled evaluations, likely to complete all required tests, and likely to be
compliant.
9. Subjects is fluent in the local language.
10. Subject agrees not to post any personal medical data related to the study or
information related to the study on any website or social media site (e.g., Facebook,
Twitter, etc.) until the trial has been completed, this does not include information
about participating in a clinical study in general.
11. [Part 2 only] Subject is able to undergo Lumbar Puncture (LP)
Exclusion Criteria:
1. A positive urine drug screen/alcohol breath test at Screening or Day -1.
2. Any history of intellectual disability or psychiatric disorders, including substance
use disorders, according to the Diagnostic and Statistical Manual of Mental Disorders,
5th Edition (DSM-5) criteria, except a history of mild depression/anxiety that has
been resolved for at least the past 12 months.
3. A positive Hepatitis B surface antigen, Hepatitis C antibody, or Human
Immunodeficiency Virus (HIV) antibody test at Screening.
4. Alanine aminotransferase or aspartate aminotransferase levels greater than 1.5 times
the upper limit of normal (ULN) at Screening or between Screening and first dose
administration.
5. Frequent use of any tobacco-containing (e.g., cigar, cigarette, or snuff) or
nicotine-containing product (e.g., nicotine chewing gum, nicotine plasters, or other
product used for smoking cessation) within 3 months prior to 1 week before study drug
administration. Frequent use is defined as more than 10 cigarettes or equivalent per
week. Use of any tobacco or nicotine-containing product is prohibited from 1 week
prior to study drug administration throughout the study (final visit).
6. History of regular alcohol consumption within the last 12 months, defined as an
average weekly intake of >21 alcoholic drinks/week for men or >14 alcoholic
drinks/week for women.
7. Regularly consumed (e.g., more days than not) excessive quantities of
xanthine-containing beverages (e.g., more than five cups of coffee or the equivalent
per day) within 30 days prior to Day -1.
8. Received or used an investigational product (including placebo) or device within the
following time period prior to Day -1 in the current study: 90 days, 5 half-lives, or
twice the duration of the biological effect of the investigational product (whichever
is longer).
9. Use of prescription or non-prescription drugs, vitamins, herbal, and dietary
supplements (including St John's Wort) within 7 days (or 28 days if the drug is a
potential hepatic enzyme inducer) or 5 half-lives (whichever is longer) prior to Day
-1.
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. Loss of more than 400 mL of blood within 3 months prior to Day -1, i.e., blood donor
12. A positive serum pregnancy test or lactation.
13. Hearing test result considered unacceptable for auditory ERP P300 assessment.
14. A history or presence of any disease, condition, or surgery likely to affect drug
absorption, distribution, metabolism, or excretion. Subjects with a history of
cholecystectomy should be excluded.
15. A history or presence of a clinically significant hepatic, renal, gastrointestinal,
cardiovascular, endocrine, pulmonary, ophthalmologic, immunologic, hematologic,
dermatologic, or neurologic abnormality.
16. A clinically significant abnormality on physical examination, neurological
examination, electrocardiogram (ECG), or laboratory evaluations at Screening or
between Screening and first dose administration.
17. A corrected QT interval measurement corrected according to the Fridericia rule (QTcF)
> 450 msec during controlled rest at screening or between screening and first dose
administration, or family history of long QT syndrome.
18. Any clinically significant abnormalities in rhythm, conduction, or morphology of the
resting ECG and any abnormalities in the 12-lead ECG that, in the judgement of the
Investigator or Medical Monitor, may interfere with the interpretation of QTc interval
changes, including abnormal ST-T-wave morphology or left ventricular hypertrophy.
19. PR (PQ) interval shortening < 120 msec (PR < 120 msec but > 110 msec is acceptable if
there is no evidence of ventricular pre-excitation).
20. PR (PQ) interval prolongation (> 220 msec), intermittent second- (Wenckebach block
while asleep or in deep rest is not exclusionary) or third-degree AV block.
21. Persistent or intermittent complete bundle branch block (BBB), incomplete bundle
branch block (IBBB), or intraventricular conduction delay (IVCD) with QRS > 120 msec.
22. A clinically significant vital signs abnormality at Screening or Day -1 This includes,
but is not limited to, the following, in the sitting position (3 measurements, each 5
minutes apart): (a) systolic blood pressure < 90 or >140 mmHg, (b) diastolic blood
pressure < 50 or > 95 mmHg, or (c) heart rate < 45 or > 100 beats per minute.
23. Significant (> 10%) weight loss or gain within 30 days prior to Day -1
24. A history of seizure.
25. A history of head trauma, with loss of consciousness, except for minor head trauma
that occurred at least 20 years prior to first dose.
26. A history of symptomatic orthostatic hypotension (i.e., postural syncope) or
symptomatic orthostatic hypotension at Screening.
27. A history of neuroleptic malignant syndrome.
28. A history of chronic urinary tract infections.
29. The subject is, in the opinion of the Investigator or Medical Monitor, unlikely to
comply with the protocol or is unsuitable for any reason, e.g., known issues with
ability to swallow size 00 capsules.
30. Currently employed by Asceneuron SA or by a clinical trial site participating in this
study, or a first-degree relative of an Asceneuron SA employee or of an employee at a
participating clinical trial site.
31. Unsatisfactory venous access.
32. Identification of suicide risk in the Columbia-Suicide Severity Rating Scale (C-SSRS).
33. Part 2 only: Abnormal exercise ECG in relation to age.
Part 3 Only:
Inclusion Criteria
1. Between 55-85 years of age, inclusive.
2. Mild cognitive impairment due to AD or Mild-to-moderate AD dementia, Mini-Mental State
Examination (MMSE) 14-27 and Clinical Dementia Rating (CDR) 0.5, 1 or 2 at the
Screening Visit.
3. Clinical diagnosis of mild cognitive impairment or dementia, due probably to AD, by
Revised National Institute on Aging-Alzheimer's Association criteria.
4. Reliable and capable support person/caregiver.
5. Able to undergo Lumbar Puncture (LP) and complete all study related testing and
evaluations.
6. Women of non-childbearing potential must be post-menopausal [the last menstrual period
was at least 12 months ago, and FSH at Screening confirms post-menopausal status], or
have no uterus, ovaries, or fallopian tubes; or have their fallopian tubes tied. All
women must have a negative pregnancy test result before administration of test
article. Women who are surgically sterile must provide documentation of the procedure
by an operative report or by ultrasound.
7. Women and men of child-bearing potential with partners of child-bearing potential must
agree to use highly effective contraception. Contraception should consist of: (1) a
condom for the male participant or partner of a female participant, combined with (2)
a highly effective method of contraception (e.g., a hormonal method associated with
suppression of ovulation, an IUD) for the female participant or partner of a male
participant. Abstinence from heterosexual intercourse should only be used in place of
contraception when this is consistent with the usual and preferred lifestyle of the
participant. For male subjects, contraception should continue for 90 days after the
last dose of IMP (one spermatic cycle). Male subjects should agree to refrain from
sperm donation throughout this same period.
8. Treatment-free or receiving stable acetylcholinesterase inhibitor (AChEI) treatment,
defined as:
- Subjects who are taking an approved AChEI for at least 2 weeks prior to the first
Screening biomarker for efficacy assessment at a dose that is not anticipated to
change through the study follow-up period, OR
- Subjects who received an AChEI in the past and discontinued, e.g., due to
tolerability issues, at least 5 half-lives or 30 days before the first Screening
biomarker or efficacy assessment, whichever is longer.
Exclusion Criteria:
1. Receipt of any investigational drug or device within 8 weeks or 4 half-lives,
whichever is longer, prior to randomization.
2. History of cardiovascular disease or at risk of stroke or heart attack, peripheral
vascular intervention, atrial fibrillation, clinically relevant cardiac arrhythmias,
or uncontrolled hypertension.
3. History within 2 years of Screening, or current diagnosis of the any of the following
psychiatric disorders: Schizophrenia, schizoaffective disorder, bipolar disorder I, or
alcohol abuse or dependence per DSM-5 criteria.
4. History of unexplained loss of consciousness, and seizures (excluding infant febrile
seizures)
5. Ongoing infectious, metabolic, or systemic diseases affecting the central nervous
system (CNS) (e.g. syphilis, untreated hypothyroidism, current vitamin B12 or folate
deficiency, potentially clinically significant serum electrolyte disturbances,
unstable diabetes mellitus (HbA1c > 10.5%); or other similar conditions.
6. History within 2 years of Screening, or current diagnosis of a chronic inflammatory
disease (i.e., rheumatoid arthritis, systemic lupus, erythematosus, Crohn's disease,
etc.).
7. A positive Hepatitis B surface antigen, Hepatitis C antibody, or Human
Immunodeficiency Virus (HIV) antibody test at Screening.
8. The subject has received active amyloid or tau immunization at any time, or passive
immunization within 12 months of Screening.
9. Intake of any of the prohibited medications listed below within the past 30 days or 5
half-lives, whichever is longer. Subjects need to stay off the medication during the
trial.
- For memantine, a 1-month drug-free period is required between the last dose
received and Screening
- Anticonvulsants
- Neuroleptics (quetiapine and clozapine are allowed)
- Centrally active anti-hypertensive drugs (e.g., clonidine, alpha-methyldopa,
guanidine, or guanfacine)
- Immunosuppressants or systemic corticosteroids >10 mg/day prednisone or
equivalent
- Anticoagulants
9. History or presence of brain MRI scans indicative of a neurologic disease other than AD
or any other significant abnormality.
10. Subject has an atypical variant presentation of AD, if known from medical history,
particularly non-amnestic AD.
11. History of treatment for cancer within the past 2 years. Subjects who have undergone
curative excision of basal cell carcinoma or squamous cell carcinoma of the skin within the
past 2 years are permitted.
12. Blood pressure and ECG parameters at Screening:
- Seated systolic blood pressure < 90 mmHg or > 150 mmHg; or diastolic blood pressure <
50 mmHg or > 95 mmHg
- ECG abnormalities on the screening ECG including: clinically significant conduction
abnormalities, ischemic changes (e.g., prior Q-wave myocardial infarction and/or
marked ischemic ST- and T-wave), arrhythmias (e.g., persistent or paroxysmal
ventricular or supraventricular arrhythmias, including atrial fibrillation), or other
ECG abnormalities that would pose unnecessary risk in the opinion of the Investigator
- QTc interval > 450 in males or > 470 in females utilizing Fredericia's correction
(QTcF)
13. Abnormal stress ECG in relation to age at Screening.
14. Renal insufficiency (serum creatinine >177 µmol/L).
15. Hepatic impairment with alanine aminotransferase or aspartate aminotransferase >
1.5 times the upper limit of normal, or Child-Pugh class B or C.
16. Hearing test result considered unacceptable for auditory ERP P300 assessment.
17. Positive urine or serum pregnancy test, lactating, or plans to become pregnant
during the trial.
18. Significant suicide risk as assessed by C-SSRS.
19. Any condition that in the judgement of the Investigator would interfere with the
ability to complete the trial, pose significant risk to subject safety, or potentially
confound interpretation of trial results, e.g., known issues with ability to swallow
size 5 capsules.
|
