A randomized, double-blind, placebo-controlled, parallel-group, phase 2 study to evaluate the safety and efficacy of CT1812 in subjects with mild to moderate Alzheimer's disease

1. Men, and women of non-childbearing potential, 50-85 years of age
inclusively, with a
diagnosis of mild to moderate Alzheimer*s disease according to the 2011 NIA-AA
criteria
and at least a 6 month decline in cognitive function documented in the medical
record.
i) Non-childbearing potential for women is defined as postmenopausal (last
natural
menses greater than 24 months) or undergone a documented bilateral tubal
ligation
or hysterectomy. If last natural menses less than 24 months, a serum FSH value
confirming post-menopausal status can be employed.
ii) Male subjects who are sexually active with a woman of child-bearing
potential
must agree to use condoms during the trial and for 3 months after last dose
unless
the woman is using an acceptable means of birth control. Acceptable forms of
birth
control include, birth control pills, or any double combination of:
intrauterine device (IUD), diaphragm, sponge, and cervical cap. Periodic
abstinence, coitus interruptus, exclusive use of spermicides and lactational
amenorrhea method (LAM) are not acceptable contraceptive methods.
2) Diagnostic confirmation by amyloid PET with florbetaben or another approved
amyloid PET
ligand. Previous amyloid imaging study with a positive result will be accepted.
If none is
available, then amyloid PET will be conducted during screening. Diagnostic
confirmation by
a CSF sample collected at the optional screening visit lumbar puncture in place
of amyloid PET will
also be acceptable. Inclusion via CSF samples requires: low Aβ 42
OR low Aβ 42/40 ratio AND either increased total-tau OR increased phospho-tau
based on the ranges established by the central lab.
3) Neuroimaging (MRI, or CT scan due to contraindication of MRI is approved by
Medical Monitor) obtained during screening consistent with the clinical
diagnosis of
Alzheimer*s disease and without findings of significant exclusionary
abnormalities (see
exclusion criteria, number 4). An historical MRI, (or CT scan),up to 1 year
prior to screening, may be
used if there is no history of intervening neurologic disease or clinical
events
(such as a stroke, head trauma etc.) and the subject is without clinical
symptoms or signs
suggestive of such intervening events.
4) MMSE 18-26 inclusive.
5) No active depression and a GDS <=6 (see exclusion criteria number 6).
Subjects with a GDS >6 may be allowed to enroll if the investigator does not
believe the subject is clinically depressed. Investigators must contact the
Medical Monitor to discuss eligibility.
6) Modified Hachinski <=4.
7) Formal education of eight or more years.
8) Participants must have a caregiver/ study partner who in the opinion of the
site principal
investigator, has contact with the study subject for a sufficient number of
hours per week
to provide informative responses on the protocol assessments, oversee the
administration
of study drug, and is willing and able to participate in all clinic visits and
some study
assessments. The caregiver/ study partner must provide written informed consent
to
participate in the study.
9) Participants living at home or in the community (assisted living
acceptable).
10) Ability to swallow CT1812 capsules.
11) Stable pharmacological treatment of any other chronic conditions for at
least 30 days prior
to screening.
12) Participants must be capable of providing written informed consent to the
study procedures
and for use of protected health information [Health Insurance Portability and
Accountability
Act (HIPAA) and European General Data Protection Regulation (GDPR) if
applicable]. Written informed consent also shall be obtained from the
responsible caregiver. All consent processes must be undertaken in the presence
of a
witness and prior to any study procedures.
13) Must consent to apolipoprotein E (ApoE) genotyping for data analysis
stratification.
14) Participants shall be generally healthy with mobility (ambulatory or
ambulatory-aided, i.e.,
walker or cane), vision and hearing (hearing aid permissible) sufficient for
compliance with
testing procedures.
15) Must be able to complete all screening evaluations.

1) Hospitalization (except for planned procedures) or change of chronic
concomitant
medication within one month prior to screening.
2) Participants living in a continuous care nursing facility.
3) Contraindications to the MRI examination for any reason. CT scan may be
substituted for an MRI if a subject is unable to tolerate an MRI or an MRI is
contraindicated for medical reasons. The proposed CT scan will be approved by
the Medical Monitor on a case-by-case basis.
4) Screening MRI (or historical MRI, or CT scan due to contraindication of MRI
if approved by medical monitor)) of the brain indicative of significant
abnormality, including, but not limited to, prior hemorrhage or infarct >1 cm3,
>3 lacunar infarcts, cerebral contusion, encephalomalacia, aneurysm, vascular
malformation, subdural hematoma, hydrocephalus, space-occupying lesion (e.g.
abscess or brain tumor such as meningioma). If a small incidental meningioma is
observed, the Medical Monitor may be contacted to discuss eligibility.
5) Clinical or laboratory findings consistent with:
a) Other primary degenerative, (dementias such as dementia with Lewy bodies,
frontotemporal
dementia, Huntington*s disease, Creutzfeldt-Jakob Disease, Down syndrome,
etc.).
b) Other neurodegenerative condition (Parkinson*s disease, amyotrophic lateral
sclerosis,
etc.).
c) Seizure disorder.
d) Other infectious, metabolic or systemic diseases affecting the central
nervous system
(syphilis, present hypothyroidism, present vitamin B12 or folate deficiency,
other
laboratory values etc.).
6) A current DSM-V diagnosis of active major depression, schizophrenia or
bipolar disorder.
Subjects with depressive symptoms successfully managed by a stable dose of an
antidepressant or antipsychotic would be allowed to enroll
7) Clinically significant, advanced or unstable disease that may interfere with
outcome
evaluations, such as:
a) Chronic liver disease, liver function test abnormalities or other signs of
hepatic
insufficiency (ALT, AST, alkaline phosphatase > 1.5 ULN, lactate dehydrogenase
(LDH)
> 1.5 x ULN).
b) Respiratory insufficiency.
c) Renal insufficiency eGFR < 50 mL/min based on the CKD*EPI formula, as
calculated by
the central laboratory.
d) Heart disease (myocardial infarction, unstable angina, heart failure,
cardiomyopathy
within six months before screening).
e) Bradycardia (<50 beats/min.) or tachycardia (>100 beats/min.). If the heart
rate is below 50 beats/min the subject may be eligible to enroll if the
Investigator has determined that the heart rate < 50 beats/min is stable and
not clinically significant. If the heart rate is above 100 beats/min, the heart
rate assessment may be repeated to assess eligibility.
f) Poorly managed hypertension (systolic >160 mm Hg and/or diastolic >95 mm Hg)
or
hypotension (systolic <90 mm Hg and/or diastolic <60 mm Hg).
g) Uncontrolled diabetes defined by HbA1c >7.5% in participants with diabetes,
Only those
subjects with known diabetes are required to get a HbA1c at screen.
8) History of cancer within 3 years of screening with the exception of fully
excised non-melanoma skin cancers or non-metastatic prostate cancer that has
been stable for at least 6
months.
9) Seropositive for human immunodeficiency virus (HIV).
10) History of acute/chronic hepatitis B or C and/or carriers of hepatitis B
(seropositive for
hepatitis B surface antigen [HbsAg] or anti-hepatitis C [HCV]
antibody).Subjects who have evidence of resolved Hepatitis C infection (HCV RNA
negative) may be considered following discussion with the Medical Monitor.
11) Clinically significant abnormalities in screening laboratory tests,
including:
d) Hematocrit less than 35% for males and less than 32% for females, absolute
neutrophil
cell count < 1500/uL (with the exception of a documented history of a chronic
benign neutropenia),absolute lymphocyte count <900/ul or platelet cell count of
<120,000/uL; INR >1.4 or other coagulopathy,
confirmed by repeat assessment of:
i) Hematocrit.
ii) Neutrophil count.
iii. Lymphocyte count
iv. Platelet count
v. PT/INR
12) Disability that may prevent the subject from completing all study
requirements (e.g.
blindness, deafness, severe language difficulty, etc.).
13) Within 4 weeks of screening visit or during the course of the study,
concurrent treatment with
antipsychotic agents, antiepileptics, centrally active anti-hypertensive drugs
(e.g., clonidine,
l-methyl dopa, guanidine, guanfacine, etc.), sedatives, opioids, mood
stabilizers (e.g.,
valproate, lithium); or benzodiazepines, with the following exceptions:
a. Low dose lorazepam may be used for sedation prior to MRI scan for those
participants
requiring sedation. At the discretion of the investigator, 0.5 to 1 mg may be
given orally
prior to the scan with a single repeat dose given if the first dose is
ineffective. No more than
a total of 2 mg lorazepam may be used for the MRI scan.
b) Stable use of eszopiclone or zolpidem for sleep is allowed. Stable use of
short-acting benzodiazepines and trazadone specifically as sleep aids are
allowed.
14) Any disorder that could interfere with the absorption, distribution,
metabolism or excretion of
drugs (e.g. small bowel disease, Crohn*s disease, celiac disease, or liver
disease).
15) Nootropic drugs except stable AD meds (acetylcholinesterase inhibitors or
memantine.
16) Suspected or known drug or alcohol abuse, i.e. more than approximately 60 g
alcohol
(approximately 1 liter of beer or 0.5 liter of wine) per day indicated by
elevated MCV
significantly above normal value at screening.
17) Suspected or known allergy to any components of the study treatments.
18) Enrollment in another investigational study or intake of investigational
drug within the
previous 30 days or five half-lives of the investigational drug, whichever is
longer.
19) Intake of drugs or substances potentially involved in clinically
significant induction or
inhibition of CYP3A4 or P-gp mediated drug interactions with CT1812, within 4
weeks or five
half-lives of the interacting drug prior to administration of CT1812 and
throughout the course
of the study. Grapefruit juice should be avoided in the two weeks prior to
dosing and throughout the course of the study. See Appendix A for a complete
list of prohibited substances. See Section 9.3.1 for handling of Paxlovid *
administration for COVID infection during the study.
20) Any prior exposure to immunomodulators, anti Aβ vaccines, or passive Aβ
immunotherapies for
AD (e.g. monoclonal antibodies) and/or exposure to BACE inhibitors within the
past 30 days.
21) Any vaccination within one week of the baseline visit.
22) Any condition, which in the opinion of the investigator or the sponsor
makes the participant
unsuitable for inclusion.