Effect of CT1812 Treatment on Brain Synaptic Density

This is a single-center, randomized, double-blind, placebo-controlled, parallel group study of two doses of CT1812 in adults with mild to moderate Alzheimer's Disease to evaluate the safety and tolerability of oral CT1812, administered for up 180 days for the Primary study and another 180 days for the double-blind extension study.

Each participant and caregiver participated in a screening period of up to 60 days, followed by the primary double-blind treatment period of 24 weeks (169 days +/-2) followed by an optional double-blind extension treatment period of another 24 weeks (337 days +/-2).

Inclusion criteria

• Participants may be included in the study only if they meet all of the following criteria:

• 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.

• Non-childbearing potential for women is defined as postmenopausal [last natural menses greater than 24 months; in women under age 55, menopausal status will be documented with serum follicle stimulating hormone (FSH) test] or undergone a documented bilateral tubal ligation or hysterectomy.
• Male participants 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 abstinence, birth control pills, or any double combination of: intrauterine device (IUD), male or female condom, diaphragm, sponge, and cervical cap.
• Neuroimaging (MRI) obtained during screening consistent with the clinical diagnosis of Alzheimer's disease and without findings of significant exclusionary abnormalities (see exclusion criteria, number 3).
• MMSE 18-26 inclusive
• A positive amyloid (Pittsburgh imaging compound B) scan at screening, or history of a positive amyloid scan prior to study entry, or prior lumbar puncture with a CSF Abeta concentration consistent with Alzheimer's disease.
• Formal education of eight or more years.
• Must have a caregiver who sees them at least 10 hours per week, oversees the administration of study drug, and is willing and able to oversee administration of study medication and participate in all clinic visits and some study assessments. The caregiver must provide written informed consent to participate in the study.
• Living at home or in the community (assisted living acceptable)
• Able to swallow CT1812 capsules.
• Stable pharmacological treatment of any other chronic conditions for at least 30 days prior to screening.
• Capable of providing either written informed consent or oral assent to the study procedures and for use of protected health information [Health Insurance Portability and Accountability Act (HIPAA) Authorization, if applicable]. If the Participant can provide only assent, their legally authorized representative also must provide written informed consent. 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.
• Must consent to apolipoprotein E (ApoE) genotyping.
• 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.
• Able to complete all screening evaluations.

Exclusion criteria

• Participants will be excluded from the study if any of the following conditions apply:

• Hospitalization or change of chronic concomitant medication within one month prior to screening.
• Patients living in a continuous care nursing facility
• Screening MRI 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).
• MRI incompatible implants and other contraindications for MRI, such as pacemaker, artificial joints, non-removable body piercings, etc. Additionally, participants who meet the following imaging exclusion criteria will not be included in this study:

• Claustrophobia that will result in significant anxiety and difficulty lying still for brain imaging (MRI or PET).
• Participation in other research studies involving ionizing radiation within one year of the PET scans that would cause the participant to exceed the yearly dose limits for healthy volunteers.
• History of IV drug use that would prevent venous access for PET tracer injection.
• Severe motor problems that prevent the participant from lying still for brain imaging.
• Severe chronic pain (e.g., as the result of rheumatoid arthritis) that would prevent them from lying still during brain imaging.
• Clinical or laboratory findings consistent with:

• Other primary degenerative dementia, (dementia with Lewy bodies, fronto-temporal dementia, Huntington's disease, Jacob-Creutzfeld Disease, Down's syndrome, etc.)
• Other neurodegenerative condition (Parkinson's disease, amyotrophic lateral sclerosis, etc.)
• Seizure disorder
• Other infectious, metabolic or systemic diseases affecting the central nervous system (syphilis, present hypothyroidism, present vitamin B12 or folate deficiency, other laboratory values) etc.)
• A current DSM-V diagnosis of active major depression, schizophrenia or bipolar disorder. Patients with depressive symptoms successfully managed by a stable dose of an antidepressant are allowed entry.
• Clinically significant, advanced or unstable disease that may interfere with outcome evaluations, such as:

• Chronic liver disease, liver function test abnormalities or other signs of hepatic insufficiency (ALT, AST, total bilirubin > 1.5 x ULN)
• Respiratory insufficiency
• Renal insufficiency eGFR < 45 mL/min based on the CKD-EPI formula (https://www.questdiagnostics.com/home/physicians/egfr-calculator)Heart disease (myocardial infarction, unstable angina, heart failure, cardiomyopathy within six months before screening)
• Bradycardia (<45/min.) or tachycardia (>100/min.)
• 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)
• Uncontrolled diabetes defined by HbA1c >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.
• Seropositive for human immunodeficiency virus (HIV).
• 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).
• Clinically significant abnormalities in screening laboratory tests, including:

• hematocrit less than 33% for males and less than 30% for females
• absolute neutrophil cell count of 1200/uL (with the exception of a documented history of a chronic benign neutropenia), or platelet cell count of < 120,000/uL
• INR >1.4 or other coagulopathy, confirmed by repeat.
• Disability that may prevent the patient from completing all study requirements (e.g. blindness, deafness, severe language difficulty, etc.)
• Women who are fertile and of childbearing potential.
• Within 4 weeks of screening visit or during the course of the study, concurrent treatment with antipsychotic agents (except risperidone ≤1.5 mg/day, quetiapine ≤100 mg/day, olanzapine ≤5 mg/day, and aripiprazole ≤10 mg/day), antiepileptics (except gabapentin and pregabalin for nonseizure indications), centrally active anti-hypertensive drugs (e.g., clonidine, l-methyl dopa, guanidine, guanfacine, etc.), opiate analgesics, systemic corticosteroids, psychostimulants, antiparkinsonian medications (except for non-parkinsonian indications) and mood stabilizers (e.g., valproate, lithium), sedatives and anxiolytics with the exception that use of short- to medium-acting benzodiazepines for treatment of insomnia is permitted, however, use of sedatives or hypnotics should be avoided for 8 hours before administration of cognitive tests.
• 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.)
• Nootropic drugs except stable AD meds (acetylcholinesterase inhibitors and memantine
• 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.
• Suspected or known allergy to any components of the study treatments.
• 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.
• Previous exposure to anti Aβ vaccines
• Exposure to passive immunotherapies for AD (e.g. monoclonal antibodies) or BACE inhibitors within the previous 180 days.
• Contraindication to undergoing an LP including, but not limited to: inability to tolerate an appropriately flexed position for the time necessary to perform an LP; international normalized ratio (INR) > 1.4 or other coagulopathy; platelet count of < 120,000/μL; infection at the desired lumbar puncture site; taking anti-coagulant medication within 90 days of screening (Note: low dose aspirin is permitted); degenerative arthritis of the lumbar spine; suspected non-communicating hydrocephalus or intracranial mass; prior history of spinal mass or trauma.
• Use of NSAIDs more than 2 days in within any 7-day period. Each incidence of use must be recorded in the source and CRF.
• Any condition, which in the opinion of the investigator or the sponsor makes the patient unsuitable for inclusion.