A Randomized, Double-blind, Placebo-controlled, Phase 2, 6-month Study to Evaluate the Safety, Tolerability and Exploratory Efficacy of CT1812 in Subjects With Mild to Moderate Dementia With Lewy Bodies
Phase: PHASE2
Conditions: Dementia With Lewy Bodies
Sponsor: Cognition Therapeutics

 
 
     Cognition Therapeutics, Inc. 
 
 
2500 Westchester Avenue Suite 220 
Purchase, NY 10577 
 
 
412-481-2210 
 
 
  
Protocol COG1201  
  
Official Title: A Randomized, Double-Blind, Placebo-
Controlled, Phase 2, 6-Month Study to Evaluate the Safety, 
Tolerability and Exploratory Efficacy of CT1812 in Subjects 
with Mild to Moderate Dementia with Lewy Bodies 
  
ClinicalTrials.gov ID (NCT number): NCT05225415 
   
Document: Study Protocol V3.0 
 
Document Date: 20 September 2022 

 
 
 
 
 
 
 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PHASE 2, 6-MONTH STUDY 
TO EVALUATE THE SAFETY, TOLERABILITY AND EXPLORATORY EFFICACY OF CT1812 
IN SUBJECTS WITH MILD TO MODERATE DEMENTIA WITH LEWY BODIES 
Protocol Number: COG1201 
Official Short Title: 
Clinical Trial of CT1812 in Mild to Moderate Dementia with Lewy Bodies 
Clinical Study Protocol 
Version Number: 3.0 
Issue Date:  20 September 2022 
Confidentiality Statement: 
This document contains information proprietary to Cognition Therapeutics, Inc. and is intended 
solely for the purpose of this clinical investigation. It should be kept securely and its contents 
should not be disclosed to any third party without the prior written consent of Cognition 
Therapeutics, Inc. 
 
 
 
 
 
 
 
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SIGNATURE PAGE FOR SPONSOR 
Study No.  
 
COG1201 
 
Protocol Title:  
A randomized, double-blind, placebo-controlled, phase 2, 6-month 
study to evaluate the safety, tolerability and exploratory efficacy of 
CT1812 in subjects with mild to moderate Dementia with Lewy 
Bodies 
 
 
Approved by the following: 
 
 
__ 
 ______________   
Anthony O. Caggiano, MD, PhD.                          
 
 
Date 
Chief Medical Officer, Head of R&D 
Cognition Therapeutics, Inc. 
2500 Westchester Avenue 
Purchase, NY 10577 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DocuSign Envelope ID: 568644D8-058C-4B65-A816-080ED1534626
9/22/2022
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SIGNATURE PAGE FOR INVESTIGATOR 
 
Study No.  
 
COG1201 
 
Protocol Title:  
A randomized, double-blind, placebo-controlled, phase 2, 6-month 
study to evaluate the safety, tolerability and exploratory efficacy of 
CT1812 in subjects with mild to moderate Dementia with Lewy 
Bodies 
 
I have read this protocol and agree to conduct this study in accordance with all 
stipulations of the protocol and in accordance with all applicable regulations, ICH and 
the Declaration of Helsinki. 
 
 _____________________ 
 _____________________ 
 ______________  
 
Investigator Name 
 
Signature 
 
 
Date 
 
 
 
 
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1 
PROTOCOL SYNOPSIS  
 
TITLE:  A randomized, double-blind, placebo-controlled, phase 2, 6-month study to 
evaluate the safety, tolerability, and exploratory efficacy of CT1812 in subjects with mild 
to moderate Dementia with Lewy Bodies 
 
SPONSOR:  Cognition Therapeutics Inc. 
PROTOCOL NUMBER:  
COG1201 
CLINICAL STUDY PHASE: Phase 2 
STUDY DRUG PRODUCT: CT1812 
STUDY OBJECTIVES:  
Primary: 
• 
To assess the safety and tolerability of CT1812 as a treatment for mild to moderate 
Dementia with Lewy Bodies. 
Secondary: 
• 
To assess exploratory measures of efficacy at baseline, 3 months, and 6 months. 
• 
To assess pharmacodynamic target engagement and potential biomarker evidence of 
disease modification. 
Exploratory: 
• 
To evaluate the efficacy of two doses of once-daily oral CT1812, administered for 
6 - months in subjects with Dementia with Lewy Bodies. 
• 
To evaluate the change in ⍺-synuclein pathology in skin biopsies over the course 
of 6 months. 
STUDY DESIGN: 
This is a multi-center, randomized, double-blind, placebo-controlled, study in subjects 
with mild to moderate Dementia with Lewy Bodies. 
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Subjects will be screened for eligibility by physical, laboratory, psychometric and 
neurologic examinations, and neuroimaging. Subjects may opt into collection of -pre-dose 
CSF. If a subject opts into CSF collection, this is to be completed along with screening 
procedures < 42 days prior to randomization at Baseline/Day 1. After having met all 
inclusion criteria, and none of the exclusion criteria, subjects will be randomized equally 
to one of three treatment arms. On clinic visit days, study drug will be taken in the clinic 
after all baseline procedures have been conducted. For days where there are no clinic 
visits, subjects will ingest study drug each morning at home. Subjects and their 
caregivers/study partner will return to the clinic for repeat psychometric/neurologic testing, 
safety procedures and PK and PD sample collection at the intervals described below. 
• 
Subjects will return to the clinic approximately every 2 weeks after their baseline 
visit until Day 70, then every four weeks until Day 182 (See Table 1).  A safety 
follow-up visit will occur approximately 28 days after the end of treatment for all 
subjects that complete through Day 182. 
Subjects who prematurely discontinue the study for any reason will be asked to attend an 
early termination visit (within 2 weeks of last dose).  
     Safety Stopping Rules:    
Dosing may be terminated by the Sponsor at the recommendation of the DSMB (Data 
and Safety Monitoring Board) based on safety and tolerability data, or at the discretion of 
the Sponsor; therefore, there are no study-specific stopping rules defined in this 
protocol.  
The occurrence of any one of the following events will result in a review of study safety 
information to date by the Sponsor and DSMB.  
Two occurrences of the same or similar serious adverse event (SAE) assessed as 
probably or possibly related to dosing with investigational product. 
Two or more different subjects with the same or similar severe AE assessed as probably 
or possibly related to dosing with the investigational product. 
Four or more subjects with the same or similar moderate AE which is possibly or probably 
related to dosing with investigational product. 
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The Sponsor and DSMB will review the available safety data and recommend whether 
dosing should continue, study drug administration should be terminated, or additional 
monitoring procedures or safety precautions need to be employed.    
The study or a dose group may be terminated if the Sponsor and DSMB determine that 
any adverse event(s) are occurring that are intolerable or pose a medically unacceptable 
safety risk.For individual subjects: 
Any participant who develops the following liver function test (LFT) laboratory 
abnormalities will not receive any additional doses and will be monitored until resolution 
of the AE or the return of laboratory abnormality to the acceptable screening value(s) 
• 
Elevated ALT or AST greater than 5 X Upper Limits of Normal (ULN)  
• 
Elevated ALT or AST greater than 3 X ULN in combination with total bilirubin > 2 
X ULN or INR > 1.5 X ULN  
• 
ALT or AST > 3 X ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
Serial monitoring of ALT/AST/bilirubin and INR will be performed, initially with repeat 
values within 4 days of discontinuation of study drug. If LFTs are still elevated 4 days 
post-study drug interruption, participants should have LFTs checked again 4 days later 
(+/- 1 day). The site investigator and medical monitor should agree to a plan for further 
LFT monitoring depending on whether the LFTs are still increasing or trending towards 
normal.  Repeat testing should be carried out until LFTs have normalized. The LFTs in 
this instance can also be run locally for more rapid turnaround.  
In the event a reversible etiology is found to explain the elevated liver enzymes (such as 
a common bile duct stone), drug may be restarted following normalization of LFTs, and 
after discussion between the Medical Monitor and site PI.  
Study drug will be temporarily discontinued if a participant does not achieve the 
aforementioned levels of elevated LFTs but has an elevation of ALT or AST >3 X ULN. 
These participants will have LFTs retested within 4 days after their last dose of study 
drug. If LFTs are still elevated 4 days post-study drug interruption, participants will have 
LFTs checked again 4 days later (+/- 1 day), and the site PI and medical monitor will 
agree to a plan for further monitoring of the findings. The LFTs in this instance can also 
be run locally for more rapid turnaround. 
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LFTs do not need to be intensively monitored when ALT and AST are ≤ 3 X ULN with no 
elevation of bilirubin, however the investigator and the medical monitor will formulate a 
plan for serial testing of LFTs. Cessation of dosing is not required in this circumstance 
but may be temporarily interrupted at the discretion of the investigator. 
  
NUMBER OF SUBJECTS: 
Approximately 120 subjects randomized in a 1:1:1 ratio to 100 mg/day, 300 mg/day or 
placebo. 
TARGET POPULATION: 
INCLUSION CRITERIA: 
Subjects may be included in the study only if they meet all of the following criteria: 
1) Subjects or their Legally Authorized Representative (LAR) (or designee as applicable 
by local law) must provide written informed consent to the study procedures prior to 
any study procedures. 
2) Subjects 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. 
3) Men or women 50-85 years of age (inclusive), meeting criteria for probable DLB (as 
defined by the 4th report of the DLB Consortium- McKeith et al., 2017) 
4) Men willing to comply with acceptable form of contraception or women of non-
childbearing potential as defined below: 
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. 
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ii) Male subjects who are sexually active with a woman of childbearing 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. 
5) MRI, or CT scan due to contraindication of MRI if approved by medical monitor) 
obtained during screening consistent with the clinical diagnosis of DLB and without 
findings of significant exclusionary abnormalities. 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.  
6) MMSE 18-27 inclusive. 
7) If receiving acetylcholinesterase inhibitors (AChEI), memantine or a combination of 
the two, must have been on a stable dose for at least 12 weeks before the screening 
visit, with no plans for dose adjustment during the study. Treatment-naive subjects can 
be entered into the study, but there should be no plans to initiate treatment with 
AChEIs or memantine from Screening to the end of the study. 
8) Stable pharmacological treatment of any other chronic conditions for at least 30 days 
prior to screening. 
9) Formal education of eight or more years. 
10) Subjects living at home or in an assisted living facility.   
11) Ability to swallow capsules. 
12) Must consent to apolipoprotein E (ApoE) genotyping. 
13) Subjects 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. 
14) Must be able to complete all screening evaluations. 
 
 
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EXCLUSION CRITERIA: 
Subjects will be excluded from the study if any of the following conditions apply: 
1) Any neurological condition that may be contributing to cognitive impairment above 
and beyond those caused by the subject's DLB, including any co-morbidities 
detected by clinical assessment or MRI (or CT scan due to contraindication of MRI, 
if approved by medical monitor) 
2) History of transient ischemic attacks or stroke within 12 months of screening. 
3) Parkinsonian (extrapyramidal) features with Modified Hoehn and Yahr stage 4 or 
higher or any diagnosis of Parkinson’s disease or parkinsonism that preceded 
cognitive decline by more than one year. 
4) Hospitalization (except for planned procedures) or change of chronic concomitant 
medication within one month prior to screening. 
5) Any major psychiatric diagnosis, including schizophrenia, bipolar disorder, and 
current major depressive disorder as per Diagnostic and Statistical Manual of 
Mental Disorders Fifth Edition. 
6) Geriatric Depression Scale score >6. (Subjects with a GDS >6 may be allowable 
if the investigator does not believe the subject is clinically depressed. Investigators 
should contact the medical monitor to discuss eligibility.) 
7) Subjects living in a continuous care nursing facility. 
8) Contraindication to the MRI examination for any reason (CT scan may be 
substituted for an MRI if subjects are unable to tolerate an MRI or an MRI is 
contraindicated for medical reasons, if the proposed CT scan is discussed and 
approved by the medical monitor on a case-by-case basis).     
9) Screening MRI (or historical MRI or CT scan due to contraindication of MRI if 
approved by medical monitor) or historical MRI/CT scan, if applicable. 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 
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meningioma). If a small incidental meningioma is observed, the medical monitor 
may be contacted to discuss eligibility. 
10) Clinical, laboratory findings or medical history consistent with: 
a) Other primary degenerative dementia, (frontotemporal dementia, Huntington’s 
disease, Creutzfeldt-Jakob Disease, Down syndrome, etc.). 
b) Other neurodegenerative condition (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.). 
11) 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 which requires the use of supplemental oxygen. 
c) Renal insufficiency eGFR < 50 mL/min based on the CKD‐EPI formula.  
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 heart rate is 
below 50 beats/min or 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 subjects with diabetes, only 
those subjects with known diabetes are required to get a HbA1c at screen. 
12) 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. 
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13) Seropositive for human immunodeficiency virus (HIV). 
14) 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). 
15) Clinically significant abnormalities in screening laboratory tests, including:  
a) Hematocrit less than 35% for males and less than 32% for females, absolute 
neutrophil cell count of 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 
16) Disability that may prevent the subject from completing all study requirements 
(e.g. blindness, deafness, severe language difficulty, etc.). 
17) 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)  At the discretion of the investigator, lorazepam or another anxiolytic may be 
administered as per local standard of care prior to MRI scan or optional lumbar 
puncture. Note neurocognitive testing should not be done within 24 hours of 
administration of conscious sedation. 
b) Stable use of clonazepam for at least 30 days as indicated for REM Sleep 
Behavioral Disorder (RBD) 
c) Stable use of atypical antipsychotics (e.g., quetiapine, pimavanserin) for at least 
30 days as indicated for delusions and hallucinations secondary to DLB. 
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18) 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). 
19) Nootropic drugs except stable AD meds (acetylcholinesterase inhibitors or 
memantine). 
20) 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. 
21) Suspected or known allergy to any components of the study treatments. 
22) 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. 
23) 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. 
24) Any prior exposure to immunomodulators, anti Aβ vaccines, or passive Aβ 
immunotherapies (e.g., monoclonal antibodies) and/or exposure to BACE 
inhibitors within the past 30 days. 
25) Any condition, which in the opinion of the investigator or the sponsor makes the 
subject unsuitable for inclusion. 
26) Any vaccination within one week of the baseline visit. 
 
 
 
 
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LENGTH OF STUDY: 
Each subject and caregiver will participate in a screening period of up to 42 days, followed 
by a double-blind treatment period of 182 (+/- 2) days and a follow up visit at day 210 (+/- 
2) for a maximum of 254 days of study participation. 
DOSAGE, DOSE FORM, AND ROUTE OF ADMINISTRATION: 
CT1812, 100 mg or 300 mg 
Study Drug will be capsules of identical appearance containing either placebo or CT1812 
fumarate.  
Study drug will be taken by mouth once each morning with food. 
EVALUATION CRITERIA: 
A DSMB (Data and Safety and Monitoring Board) will oversee the safety of the trial. This 
committee will include independent experts, including an independent statistician. Safety 
data will be provided to the DSMB at quarterly intervals during the trial. The study clinician 
and study medical monitor will review trial safety data on a regular basis. Similarly, more 
frequent ad hoc meetings of the DSMB will occur if ongoing safety data indicate interim 
meetings are indicated. 
The DSMB will review the safety and tolerability of CT1812 of the subjects enrolled in the 
study. They may also recommend additional safety and/or monitoring measures.  
 
Safety and Tolerability Measures: 
• 
Adverse events. 
• 
Serious adverse events. 
• 
Physical and neurological examinations. 
• 
Vital signs - body temperature, systolic and diastolic blood pressure, pulse rate 
and respiration rate. 
• 
Electrocardiogram (ECG). 
• 
Clinical laboratory tests: hematology, biochemistry, coagulation, serology and 
urinalysis, complete lipid panel. 
• 
Columbia Suicide Severity Rating Scale (C-SSRS). 
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Efficacy Measures: 
• 
Montreal Cognitive Assessment (MoCA). 
• 
Cognitive Drug Research Battery (CDR).  
• 
Clinician Assessment of Fluctuation (CAF). 
• 
Epworth Sleepiness Scale (ESS).  
• 
Movement Disorder Society – Unified Parkinson’s Disease Rating Scale – Part 
III (MDS-UPDRS3). 
• 
The Alzheimer’s Disease Cooperative Study – Clinical Global Impression of 
Change (ADCS-CGIC). 
• 
ADCS-Activities of Daily Living (ADCS-ADL). 
• 
Neuropsychiatric Inventory (NPI). 
 
PK/PD Biomarkers: 
• 
Pharmacokinetic: Plasma and CSF CT1812. 
• 
Pharmacodynamic:  
o Plasma biomarkers such as Aβ, phospho-tau, ⍺-synuclein, phospho-⍺-
synuclein, ⍺-synuclein oligomers will be examined. Other exploratory 
biomarkers may also be evaluated. 
o Optional CSF- CSF biomarkers such as Aβ, tau, phospho-tau, 
neurogranin, synaptotagmin, SNAP25 (synaptosomal-associated protein 
25), Neuro Filament Light Chain (NFL), Aβ oligomers, ⍺-synuclein, 
phospho-⍺-synuclein, ⍺-synuclein oligomers will be examined. Other 
exploratory biomarkers may also be evaluated. 
 
STATISTICAL METHODS: 
Analysis Populations 
The populations for analysis will include the enrolled population, safety population, 
intent-to-treat (ITT) population, pharmacokinetic (PK) population, and the 
pharmacodynamic (PD) population. 
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Sample Size 
The sample size is not based on statistical considerations but was chosen to provide 
preliminary information on the safety and efficacy of CT1812 when administered 
according to this protocol. 
 
It should be noted that for the comparison of both active groups versus placebo a total 
sample size of 105 would have 80% power to detect a mean difference of 0.78 points in 
the change from baseline in MoCA score assuming a standard deviation of 1.32 points 
(PASS 2020: Two Sample T-Test, alpha=0.05). To account for potential dropouts, a 
sample size of 120 subjects (40 subjects per arm) is planned. 
 
Data Analysis 
All descriptive statistical analyses will be performed using SAS statistical software 
(Version 9.4 or higher), unless otherwise noted.  
AEs will be assessed by the investigator for severity and will be coded for summarization 
using Medical Dictionary for Regulatory Activities (MedDRA® Version 24 or higher). 
Adverse events will be summarized by Preferred Term and System Organ Class, for 
each dose group (including placebo). 
Laboratory measures will be summarized by treatment group and time-point both as 
absolute values and as change from baseline, with descriptive statistics summarizing 
each group and time point. Similar presentation will be used for vital signs and for ECG 
interval measurements, and changes from pre-treatment baseline. 
Concomitant medications will be coded using WHO Drug Dictionary (enhanced) version 
March 2021 or higher. Concomitant medications will be summarized and listed. 
Efficacy endpoints will be summarized by treatment group and time-point using 
descriptive statistics as both absolute values and as change from baseline. Differences 
between treatment groups will be assessed using a mixed model for repeated measures 
(MMRM). The difference between each treatment group and the placebo at each time-
point will be estimated based on the least square means (LSM) from the MMRM. 
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Exploratory analyses of potential pharmacodynamics markers in CSF and plasma will be 
conducted using appropriate statistical tests. 
Exploratory analyses of potential change in ⍺-synuclein pathology in skin biopsies over 
the course of 6 months will be conducted using appropriate statistical tests. 
Additional statistical details will be provided in a prospective statistical plan. 
 
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Table of Contents 
Table of Contents 
1 
PROTOCOL SYNOPSIS ...................................................................................................................... 4 
2 
GLOSSARY OF TERMS AND ABBREVIATIONS ............................................................................ 21 
3 
INTRODUCTION ................................................................................................................................. 25 
3.1 
BACKGROUND............................................................................................................................... 25 
3.2 
NONCLINICAL EXPERIENCE ............................................................................................................ 26 
3.2.1 
Nonclinical Pharmacology Studies .................................................................................... 26 
3.2.2 
Nonclinical Pharmacokinetic Studies................................................................................. 27 
3.2.3 
Nonclinical Safety Studies ................................................................................................. 28 
3.3 
CLINICAL EXPERIENCE .................................................................................................................. 29 
3.4 
RATIONALE FOR STUDY ................................................................................................................. 31 
3.5 
RATIONALE FOR SELECTED DOSES ................................................................................................ 32 
4 
STUDY OBJECTIVES ........................................................................................................................ 32 
4.1 
PRIMARY OBJECTIVES ................................................................................................................... 32 
4.2 
SECONDARY OBJECTIVES.............................................................................................................. 32 
4.3 
EXPLORATORY OBJECTIVES .......................................................................................................... 32 
5 
STUDY TYPE AND DESIGN .............................................................................................................. 32 
5.1 
STUDY TYPE ................................................................................................................................. 32 
5.2 
ENDPOINTS .................................................................................................................................. 33 
5.2.1 
Safety Endpoints ................................................................................................................ 33 
5.2.2 
Efficacy Endpoints ............................................................................................................. 33 
5.2.3 
Pharmacokinetic/Pharmacodynamic Endpoints ................................................................ 33 
5.3 
STUDY DESIGN ............................................................................................................................. 34 
5.3.1 
Re-screening Activities ...................................................................................................... 34 
6 
STUDY DRUG ..................................................................................................................................... 35 
6.1 
SUPPLY AND STORAGE ................................................................................................................. 35 
6.2 
PACKAGING AND LABELING ............................................................................................................ 35 
6.3 
ADMINISTRATION........................................................................................................................... 35 
6.3.1 
Safety Stopping Rules ....................................................................................................... 35 
6.4 
ACCOUNTABILITY .......................................................................................................................... 37 
6.5 
OVERDOSE/TOXICITY MANAGEMENT .............................................................................................. 38 
6.6 
BLINDING, RANDOMIZATION AND MATCHING SUBJECTS................................................................... 38 
7 
INVESTIGATORS, SITES AND DURATION ..................................................................................... 38 
7.1 
INVESTIGATOR AND SITE ............................................................................................................... 38 
7.2 
DURATION OF STUDY .................................................................................................................... 38 
7.3 
USE OF REMOTE MEASURES IN EXTENUATING CIRCUMSTANCES ..................................................... 38 
7.4 
TERMINATION OF STUDY ............................................................................................................... 39 
8 
STUDY POPULATION ....................................................................................................................... 39 
8.1 
NUMBER OF SUBJECTS ................................................................................................................. 39 
8.2 
INCLUSION CRITERIA ..................................................................................................................... 39 
8.3 
EXCLUSION CRITERIA .................................................................................................................... 41 
8.4 
WITHDRAWAL OF SUBJECTS .......................................................................................................... 44 
8.5 
SUBJECT WITHDRAWAL PROCEDURES ........................................................................................... 44 
8.5.1 
Follow-up Procedures for Subjects Who Withdraw Prematurely ...................................... 44 
8.6 
PROCEDURES FOR REPLACING SUBJECTS WHO WITHDRAW PREMATURELY .................................... 45 
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9 
TREATMENT PLAN AND METHODS ............................................................................................... 45 
9.1 
TABLE 1, SCHEDULE OF ASSESSMENTS ......................................................................................... 46 
9.2 
VISIT SPECIFIC PROCEDURES ........................................................................................................ 50 
9.2.1 
Visit 1 / Screening .............................................................................................................. 50 
9.2.2 
Visit 2 / Study Day 1 – Baseline ........................................................................................ 52 
9.2.3 
Visit 3 Study Day 14 .......................................................................................................... 53 
9.2.4 
Visit 4 Study Day 28 .......................................................................................................... 53 
9.2.5 
Visit 5 Subject Day 42 ........................................................................................................ 54 
9.2.6 
Visit 6 Study Day 56 .......................................................................................................... 55 
9.2.7 
Visit 7 Study Day 70 .......................................................................................................... 55 
9.2.8 
Visit 8 Study Day 98 .......................................................................................................... 56 
9.2.9 
Visit 9 Study Day 126 ........................................................................................................ 57 
9.2.10 
Visit 10 Study Day 154 ...................................................................................................... 57 
9.2.11 
Visit 11 Study Day 182 / Early Termination ....................................................................... 58 
9.2.12 
Study Day 210 / Safety Follow-up Visit ............................................................................. 59 
9.3 
CONCOMITANT MEDICATIONS AND OTHER RESTRICTIONS ............................................................... 60 
9.3.1 
Concomitant COVID-19 Treatment Restrictions ............................................................... 60 
10 
SAMPLE COLLECTION ..................................................................................................................... 61 
10.1 
BLOOD SAMPLING FOR PK AND EXPLORATORY PLASMA BIOMARKERS ............................................ 61 
10.2 
HANDLING, SHIPPING, STORAGE AND ANALYSIS OF BLOOD SAMPLES .............................................. 61 
10.3 
OPTIONAL CEREBROSPINAL FLUID ................................................................................................. 63 
10.3.1 
Collection ........................................................................................................................... 63 
10.3.2 
Timing of Optional CSF Collection .................................................................................... 63 
10.3.3 
Volume of Optional CSF Collected .................................................................................... 64 
10.3.4 
Handling, Shipping, Storage and Analysis of Optional CSF ............................................. 64 
10.4 
SYN-ONE TESTTM SKIN BIOPSY ..................................................................................................... 64 
10.4.1 
Results from the Syn-One TestTM ...................................................................................... 64 
10.4.2 
Handling, Shipping and Analysis of Syn-One Skin TestTM ................................................ 64 
11 
SCREENING, EFFICACY AND SAFETY ASSESSMENTS .............................................................. 65 
11.1 
AFFECTIVE AND COGNITIVE MEASURES ......................................................................................... 65 
11.1.1 
Modified Hoehn and Yahr .................................................................................................. 65 
11.1.2 
Clinician Assessment of Fluctuation (CAF) ....................................................................... 65 
11.1.3 
Epworth Sleepiness Scale (ESS) ...................................................................................... 65 
11.1.4 
Cognitive Drug Research Battery (CDR) ........................................................................... 66 
11.1.5 
Movement Disorder Society – Unified Parkinson’s Disease Rating Scale -Part III (MDS-
UPDRS3) 66 
11.1.6 
Montreal Cognitive Assessment (MOCA) .......................................................................... 66 
11.1.7 
Geriatric Depression Scale ................................................................................................ 67 
11.1.8 
Mini Mental State Exam ..................................................................................................... 67 
11.1.9 
Neuropsychiatric Inventory ................................................................................................ 67 
11.1.10 
ADCS-Clinical Global Impression of Change (CGIC)........................................................ 67 
11.1.11 
ADCS-Activities of Daily Living (ADL) ............................................................................... 68 
11.1.12 
Columbia Suicide Severity Rating Scale ........................................................................... 68 
12 
SAFETY ASSESSMENTS .................................................................................................................. 69 
12.1 
ASSESSMENT OF SAFETY .............................................................................................................. 69 
12.1.1 
Adverse Events .................................................................................................................. 69 
12.1.2 
Physical and Neurological Examinations........................................................................... 70 
12.1.3 
Vital Signs .......................................................................................................................... 70 
12.1.4 
Clinical Laboratory Tests ................................................................................................... 70 
12.1.5 
Screening Laboratory Tests............................................................................................... 71 
12.1.6 
Pregnancy Tests ................................................................................................................ 71 
12.1.7 
12-lead Electrocardiogram................................................................................................. 71 
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12.1.8 
MRI..................................................................................................................................... 71 
12.2 
ADVERSE EVENTS......................................................................................................................... 72 
12.2.1 
Definitions .......................................................................................................................... 72 
12.2.2 
Collection and Rating of Adverse Events .......................................................................... 73 
12.2.3 
Adverse Event Follow-up ................................................................................................... 75 
13 
SERIOUS AND OTHER SIGNIFICANT ADVERSE EVENTS ........................................................... 76 
13.1 
DEFINITION OF A SERIOUS ADVERSE EVENT ................................................................................... 76 
13.1.1 
Serious Adverse Event Reporting by the Investigator to the Sponsor .............................. 77 
13.1.2 
Handling of Follow-up Information ..................................................................................... 78 
13.2 
REPORTING AND FOLLOW-UP OF PREGNANCY ................................................................................ 78 
13.3 
EXPEDITED REPORTING OF SERIOUS ADVERSE EVENTS ................................................................. 79 
13.3.1 
Responsibilities .................................................................................................................. 79 
13.3.2 
Expedited Reporting .......................................................................................................... 79 
14 
STATISTICAL METHODS .................................................................................................................. 80 
14.1 
GENERAL OVERVIEW OF THE STATISTICAL ANALYSIS PLAN ............................................................. 80 
14.2 
SAMPLE SIZE ................................................................................................................................ 80 
14.3 
ANALYSIS POPULATIONS ............................................................................................................... 80 
14.4 
DATA ANALYSIS ............................................................................................................................ 81 
14.4.1 
Initial Subject Characteristics ............................................................................................ 81 
14.4.2 
Safety Analyses ................................................................................................................. 81 
14.4.3 
Efficacy Analyses ............................................................................................................... 82 
14.4.4 
Other Analyses .................................................................................................................. 82 
15 
MISSING, UNUSED AND SPURIOUS DATA .................................................................................... 82 
16 
STUDY MANAGEMENT ..................................................................................................................... 82 
16.1 
PROTOCOL AMENDMENT AND PROTOCOL DEVIATION ..................................................................... 82 
16.1.1 
Protocol Amendment ......................................................................................................... 82 
16.1.2 
Protocol Deviations ............................................................................................................ 83 
16.1.3 
Protocol Waivers ................................................................................................................ 83 
16.2 
ETHICS AND REGULATORY ASPECTS.............................................................................................. 83 
16.2.1 
Ethical Conduct of the Study and Regulatory Guidelines ................................................. 83 
16.2.2 
Institutional Review Board and Regulatory Approval ........................................................ 83 
16.2.3 
Subject and Caregiver Informed Consent ......................................................................... 84 
16.3 
END OF STUDY AND REGULATORY NOTIFICATION ........................................................................... 85 
16.4 
DATA PROTECTION AND CONFIDENTIALITY ..................................................................................... 85 
16.5 
MONITORING ................................................................................................................................ 85 
16.6 
QUALITY ASSURANCE AND QUALITY CONTROL ............................................................................... 85 
16.7 
SOURCE DATA .............................................................................................................................. 86 
17 
DATA AND RECORD KEEPING........................................................................................................ 86 
17.1 
CASE REPORT FORMS .................................................................................................................. 86 
17.2 
RECORD KEEPING......................................................................................................................... 87 
18 
FINANCING AND INSURANCE ......................................................................................................... 87 
19 
USE OF DATA AND PUBLICATION POLICY ................................................................................... 87 
20 
REFERENCES .................................................................................................................................... 88 
21 
APPENDICES ..................................................................................................................................... 93 
APPENDIX A – PROHIBITED MEDICATIONS .......................................................................................... 94 
APPENDIX B – KEY CRITERIA FROM DIAGNOSIS AND MANAGEMENT OF DEMENTIA WITH LEWY 
BODIES: FOURTH CONSENSUS REPORT OF THE DLB CONSORTIUM. ............................................ 97 
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List of Tables 
 
 
Table 1, Schedule of Assessments 
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2 
GLOSSARY OF TERMS AND ABBREVIATIONS 
 
Abbreviation Description 
(α-synO) 
α-synuclein oligomers 
Abeta/ Aβ 
Amyloid beta 
AChEI 
acetylcholinesterase inhibitors  
AD 
Alzheimer’s disease 
ADCS-CGIC  
Alzheimer’s Disease Cooperative Study – Clinical Global Impression of 
Change 
ADCS-ADL 
Alzheimer’s Disease Cooperative Study – Activities of Daily Living 
AE 
adverse event 
ALT 
alanine aminotransferase 
AKI 
acute kidney injury 
APOE 
gene which codes for apolipoprotein E 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
β-HCG 
beta human chorionic gonadotropin 
BACE 
beta secretase cleaving enzyme 
BP 
systolic and diastolic blood pressure 
BUN 
blood urea nitrogen 
C 
Celsius 
CAF 
Clinician Assessment of Fluctuation 
CDR 
Cognitive Drug Research Battery 
Cmax 
maximum concentration 
CNS 
central nervous system 
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Abbreviation Description 
CRF 
Case report form 
CSF 
cerebrospinal fluid 
Css 
steady state concentration 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CYP 
cytochrome P450 
DDI 
drug-drug interaction 
dL 
deciliter 
DLB 
Dementia with Lewy Bodies 
DSMB 
Data Safety Monitoring Board 
ESS 
Epworth Sleepiness Scale 
ECG 
electrocardiogram 
EOS 
end of study 
F 
Fahrenheit 
FBR 
Future Biomedical Research  
GCP 
Good Clinical Practice 
GDS 
Geriatric Depression Scale 
GFR 
glomerular filtration rate 
h 
hour(s) 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
hERG 
human Ether-à-go-go Related Gene 
Hgb 
hemoglobin 
HIV 
human immunodeficiency virus 
IC50 
half maximal inhibitory concentration 
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Abbreviation Description 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IRB 
Institutional Review Board 
IKr 
delayed rectifier potassium channels  
kg 
kilogram 
KIM-1 
kidney injury molecule -1 
LAR 
Legally Authorized Representative 
LBD 
Lewy body dementia 
LP 
lumbar puncture 
LSM 
Least square means 
MAD 
multiple ascending dose 
MCHC 
mean corpuscular hemoglobin concentration  
MCI 
mild cognitive impairment 
MDS UPDRS 
Part III 
Movement Disorder Society-United Parkinson’s Disease Rating Scale 
Part III 
MMRM 
mixed model for repeated measures  
MoCA 
Montreal cognitive assessment scale 
µg 
microgram 
mg 
milligram 
mL 
milliliter 
mM 
milimole 
mmol 
millimolar 
MMSE 
Mini Mental State Exam 
MRI 
Magnetic Resonance Imaging 
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Abbreviation Description 
MTD 
maximum tolerated dose 
NAG 
N-acetyl-beta-D-glucosaminidase (an indicator of renal damage) 
NIH 
National Institutes of Health 
NIA 
National Institute on Aging 
NPI 
Neuropsychiatric Inventory 
NSAIDs 
nonsteroidal anti-inflammatory drugs 
PD 
pharmacodynamics 
PDD 
Parkinson’s disease dementia 
P‐gp 
p‐glycoprotein  
PK 
pharmacokinetic 
PRO 
Patient reported outcome 
QD 
once daily 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
t1/2 
terminal half life 
TFF3 
trefoil factor 3 (an indicator of renal damage) 
TK 
toxicokinetic 
Tmax 
time to maximum concentration 
ULN 
upper limit of normal 
WOCBP 
Women of Childbearing Potential  
Vd 
volume of distribution 
 
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3 
INTRODUCTION 
3.1 
Background 
Dementia with Lewy bodies (DLB) is one of the most common causes of dementia. DLB, together 
with Parkinson’s disease dementia (PDD), is a form of Lewy body dementia (LBD). Approximately 
1.4 million Americans suffer from LBD, making it the second most common cause of 
neurodegenerative dementia after Alzheimer’s disease (AD). In addition to progressive dementia 
and motor deficits, patients with DLB endure a wide range of debilitating symptoms including 
cognitive fluctuations, recurrent visual hallucinations, and rapid-eye movement sleep behavior 
disorder. DLB patients have a short lifespan and rapid cognitive decline compared to AD and PDD 
patients. As a result, DLB is also associated with greater healthcare costs and caregiver burden 
than other forms of dementia. Unfortunately, no treatments are available to cure or slow the 
progression of DLB, making disease-modifying therapies for DLB a critical unmet medical need 
(Goldman 2020). 
A hallmark of DLB is the accumulation of abnormal protein aggregates called Lewy bodies. Lewy 
bodies are primarily composed of α-synuclein fibrils and oligomers. Although the processes by 
which these aggregates form and spread through the brain are poorly understood, it is widely 
thought that the accumulation of α-synuclein is linked to synaptic dysfunction, neurodegeneration, 
and neuronal death.  
Amyloid β (Aβ) is also linked to cognitive decline and markers of neurodegeneration in persons 
with DLB. While synucleinopathy is the defining feature of LBDs, amyloid plaques characteristic 
of AD are associated with the cognitive impairment in DLB. Approximately 80% of patients 
suffering from DLB have significant concentrations of Aβ-rich plaque deposits in their brains, in 
addition to α-synuclein pathology, at autopsy Aβ deposition correlates with cortical thinning, the 
severity of neurofibrillary tangles, and Lewy body inclusions. The combination of Aβ and α-
synuclein deposition in PDD patients is associated with a shorter interval between  development 
of dementia and onset of motor symptoms, as well as a shorter life span. Aβ deposition was linked 
to cognitive impairment in patients with DLB and PDD. Thus, Aβ-targeted therapies could limit 
cognitive decline in individuals with DLB. 
The Sponsor (Cognition Therapeutics, Inc. [CogRx]) is developing CT1812, a first-in-class brain-
penetrant small molecule that selectively clears toxic Aβ oligomers from the brain. CT1812 was 
identified through a phenotypic screening approach, in which it demonstrated an ability to prevent 
the binding and effects of Aβ oligomers (AβO) on mature neurons in culture (Izzo et al., 2014a; 
Izzo et al., 2014b). It displaces AβO bound to neuronal receptors at synapses and protects 
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synapses from toxic AβO effects. CT1812 accomplishes this by allosterically modulating a key 
protein regulator of oligomer receptors, the sigma-2 receptor complex, thus destabilizing the 
oligomer binding site and increasing the off-rate of AβO, which are then cleared into the 
cerebrospinal fluid (CSF). By inhibiting oligomer binding, CT1812 blocks downstream 
synaptotoxicity and restores memory to normal in aged transgenic mouse models of AD.  
The sigma-2 receptor complex protein PGRMC1 also binds to α-synuclein monomer and oligomer 
in synaptosomes. Evidence suggests that α-synuclein oligomers (α-synO) are toxic to synaptic 
function and the process of autophagy, a vital cellular damage response mechanism. Importantly, 
CT1812 partially attenuates α-synO binding and internalization. By displacing both α-synO and 
AβO from neurons, CT1812 may relieve the synaptotoxic effects of these oligomers in DLB 
patients and is therefore a clinical candidate for this disease. 
CT1812 is currently in clinical development for the treatment of AD. CT1812 has been 
demonstrated to be generally safe and well tolerated in Phase 1 trials in healthy volunteers 
(NCT02570997) and AD patients (NCT02907567). When administered once daily for 28 days to 
mild to moderate AD patients, CT1812 significantly reduces concentrations of synaptic 
degeneration markers in AD patient CSF (NCT02907567). The CT1812 mechanism of action has 
the potential to halt or slow cognitive decline, which will significantly alleviate the suffering of 
patients. This hypothesis is being tested in an ongoing six-month trial in mild to moderate AD 
patients (NCT03507790). The proposed clinical study in DLB patients will leverage these ongoing 
development efforts for AD and provide an opportunity to investigate a novel therapeutic 
candidate in an indication for which no disease-modifying treatments exist. 
3.2 
Nonclinical Experience 
3.2.1 Nonclinical Pharmacology Studies 
CT1812 is a lipophilic isoindoline formulated as a fumarate salt and is the result of a 
structure-based medicinal chemistry optimization program comprised of over 300 analogs. 
CT1812’s properties are fully described along with all preclinical studies in the Investigator 
Brochure. CT1812 has a high affinity at the target receptor sigma-2/PGRMC1 (S2) and is >100-
fold selective for this receptor over other receptors and ion channels. Dose-limiting toxicities at 
higher doses in both species appear to be hypercalcemia and renal tubular damage, both of which 
are non-invasively monitored via measurement of serum calcium and urinary markers of renal 
tubular injury such as kidney injury molecule 1 (KIM-149,50).  
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In vitro pharmacodynamic (PD) studies confirmed CT1812 target binding specificity, affinity and 
engagement, including the prevention and reversal of Aβ oligomer binding and the prevention of 
Aβ oligomer-induced synapse loss. 
In vivo PD studies confirmed the desired consequences of target engagement, including cognitive 
improvements in an aged transgenic mouse model of AD following oral administration of an 
apparently tolerated dose of CT1812 daily for 9 weeks. Additional in vivo PD studies, using an Aβ 
oligomer detecting microelectrode in an aged transgenic mouse model of AD, demonstrated that 
administration of CT1812 caused an acute increase in soluble Aβ oligomers in the interstitial fluid 
of the hippocampus and a sustained increased in soluble Aβ oligomers in the CSF of the lateral 
ventricle of the brain. These increases in soluble Aβ oligomers occurred without a change in the 
amount of soluble Aβ 1-40, indicating that displacement of Aβ oligomers occurred following 
treatment with CT1812. 
3.2.2 Nonclinical Pharmacokinetic Studies 
Absorption of CT1812 following oral gavage administration to mice, rats and dogs appears to be 
very rapid, with brain concentrations exceeding those concurrently measured in plasma. The drug 
is highly protein-bound in plasma from rat, mouse, dog, and human, but only weakly bound to 
blood cells. Systemic exposures to CT1812 following oral administration to rats and dogs were 
greater than dose-proportional at high, toxicologically relevant dosages. Extensive first-pass 
metabolism appears to be via oxidation and/or direct glucuronidation. 
Studies with human recombinant cytochrome P450 (CYP) isoforms show rapid metabolism (t1/2 
of 6.8 min) by CYP3A4, and slower metabolism (t1/2 of 57 and 81 minutes) by CYP2D6 and 
CYP2C19. A direct glucuronide conjugate was also observed in vitro in human hepatocyte 
incubations, consistent with that observed in vivo in rats and dogs.  
CT1812 was not an inhibitor of CYP1A2, CYP2B6, or CYP2C8, with less than 50% inhibition of 
activity observed at the highest concentration evaluated (10 μM). CT1812 was a weak inhibitor of 
CYP2C9, CYP2C19, CYP2D6, and CYP3A4, with IC50 values ranging from 4.4 to 38 μM. 
However, when evaluated in the context of systemic exposure data in humans, the drug‐drug 
interaction liability from these effects was considered to be minimal. CT1812 was found to be an 
inducer of CYP3A4 (≥ 0.3 μM), suggesting a potentially clinically significant risk of drug-drug 
interactions with this isoform, but induction of CYP2B6 and CYP1A2 appear less likely. CT1812 
does appear to be a substrate for p‐glycoprotein (P‐gp), and inhibits P‐gp with an IC50 of 10 μM. 
This is considered to be potentially clinically significant, primarily due to the possibility of 
interactions in the gastrointestinal (GI) tract. In vitro inhibition of the OATP1B1 transporter (IC50 
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of 11.5 µM) by CT1812 does not appear to be clinically relevant, when evaluated in the context 
of systemic exposure data in humans. As assessed per the FDA 2012 draft guidance for drug-
drug interaction (DDI) evaluations, clinically relevant DDI are suggested via CT1812 effects on 
CYP3A4 and P-gp. 
3.2.3 Nonclinical Safety Studies 
Two hERG (human Ether-à-go-go Related Gene) assays were performed to assess effects of 
CT1812 on the rapidly activating delayed rectifier potassium channels (IKr) using channels stably 
transfected and over-expressed in Chinese Hamster Ovary cells. Using whole-cell patch clamp 
electrophysiology, CT1812 was tested in both studies in duplicate at concentrations of 1, 3, 10, 
and 30 mM. Mean IC50 values of 26 mM and 0.6 mM were determined in the first and second 
assay, respectively. Reasons for the differing results are unknown. However, no ECG effects 
were noted in the telemeterized dog cardiovascular safety study or in the multiple-dose dog pivotal 
toxicology study when tested up to high-dose mean Cmax values of approximately 4 µM. 
Safety pharmacology studies with rats revealed no apparent effects on CNS or pulmonary 
parameters following single oral dosages that exceeded the maximum tolerated dose in this 
species. 
General toxicology studies with rats and dogs following oral dosing of CT1812 revealed dose-
limiting toxicity that manifested as degenerative changes in the proximal tubules of kidney, 
hypercalcemia, and vascular mineralization and/or degeneration involving multiple tissues and 
organs in each species. Tolerable and intolerable dosages and exposures, characterized with 
each species, informed the selection of dosages for this trial. 
Additionally, toxicology studies revealed several test article-related clinical laboratory changes, 
including elevated serum creatinine and/or BUN that correlated with mild weight loss, elevated 
serum calcium and reduced urinary specific gravity. The exact mechanism for these changes 
cannot be determined from those studies. Serum and urine tests will be performed in this trial to 
evaluate the effect of study drug administration on renal function (including serum creatinine, 
serum calcium, urine calcium).  
Genetic toxicology studies revealed no positive responses in bacterial and mammalian in vitro 
assays, or in an in vivo mouse bone marrow micronucleus assay when tested up to maximally 
feasible dosages. 
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3.3 
Clinical Experience 
CT1812 has been administered safely with good tolerability in over 60 healthy volunteers in a 
placebo-controlled Phase 1a trial (COG0101).  Six single (10-1120 mg) and three multiple dose 
cohorts (QD, 14 days, 280-840 mg) were observed under close inpatient stay (N=6-8 treated, 2 
placebo per cohort). Plasma concentrations of drug were shown to be approximately dose 
proportional across two orders of magnitude [0.13-14.93 mg (free base equivalent)/kg], and 
accumulation was minimal. Peak concentrations of CT1812 were reached within 1 to 2 hours and 
the plasma half-life was shown to be approximately 12 hours. Adverse events were mostly mild 
to moderate in severity and principally included headache, nausea, vomiting, diarrhea, 
constipation, abdominal pain, dyspepsia, upper respiratory tract infection, lightheadedness, 
syncope, myalgia, dizziness, rash and pain at the lumbar puncture site in those subjects who had 
lumbar punctures. There was only one AE of severe intensity, being an SAE of upper respiratory 
tract infection, occurring in one subject in the 840 mg dose of the MAD study, believed to be 
unrelated to study drug based on a similar pattern of URTIs in subjects receiving drugs other than 
CT1812 in the study unit during the same time period. One subject in the multiple dose cohort 
study developed a rash while on study drug. This subject showed improvement after discontinuing 
CT1812.  
No evidence of renal toxicity was observed based on routine measures of renal function (serum 
creatinine, BUN) or cystatin C. 
Four subjects in the MAD study showed an increase in liver function tests below 3X the upper 
limit of normal (including one subject on placebo). Subsequent studies will closely monitor liver 
enzyme parameters to determine if these were sporadic findings or possibly drug related. 
A fed cohort (280 mg) single dose was compared to the fasting cohort of 280 mg and no significant 
food effect was observed. A multiple dose cohort of elderly (≥65 years old) healthy volunteers 
was dosed at 560 mg x 14 days, and their exposures were similar to the 840 mg younger healthy 
volunteer subjects. 
In COG0103 15 healthy volunteers evaluated potential effects of CT1812 on the disposition of 
sensitive substrates of selected CYP isoenzymes CYP2C19 (omeprazole), CYP2C9 
(tolbutamide), CYP2D6 (dextromethorphan), and CYP3A4/5 (midazolam). Subjects were 
administered the probe drugs on Day -2 and PK evaluations performed. On Days 1 through 6, 
each subject took CT1812 560 mg. The CT1812 dose on Day 6 was taken concomitantly with the 
probe drug cocktail, and PK evaluation was conducted. No significant interaction was observed 
for isoenzymes 2C19 and 2C9. A weak drug interaction was observed between steady-state 
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CT1812 and midazolam 4 mg (CYP3A4).  Midazolam AUClast and the AUClast ratio (parent to 
metabolite) decreased by 24% and 28%, respectively, when midazolam 4 mg was taken with 
steady state CT1812 than when midazolam was taken alone. A weak drug interaction was 
observed between steady-state CT1812 and dextromethorphan 50 mg (CYP2D6), as indicated 
by a 1.75-fold and 2-fold increase in dextromethorphan AUClast and Cmax, respectively, following 
the 
combination 
treatment 
relative 
to 
dextromethorphan 
alone; 
however, 
the 
dextromethorphan/dextrorphan AUClast ratio was similar between treatments.  Based on the small 
magnitude of the interactions observed in this study for the isoenzymes CYP2D6 and CYP3A4, 
clinically meaningful implications are unlikely.  
A Phase 1a/2 trial (COG0102), evaluated the safety and pharmacokinetics of three doses of once-
a-day CT1812 (90 mg, 280 mg, 560 mg) dosed for 28 days in subjects with mild to moderate 
Alzheimer’s disease. This study enrolled 19 subjects in a 1:1:1:1 ratio of these doses vs. placebo. 
In general, all doses were relatively well tolerated, with no SAEs. All AEs were considered mild 
or moderate. While there was an increased frequency observed in total AEs with increasing dose, 
the small number of treated subjects does not permit definitive conclusions regarding the 
incidence of AEs by dose in a larger study population. Specific AEs which were noted to occur 
with greater frequency at the 560 mg dose included transient lymphocytopenia, nausea, vomiting, 
headache, fatigue, and depression. These AEs resolved in most instances while treatment was 
ongoing; one subject at the 560 mg dose experienced an ALT increase of 4.7 X ULN which 
resolved to normal levels after discontinuation of study drug. Cognitive outcomes were similar 
across the treatment groups. Plasma CT1812 concentration increased approximately dose 
proportionally, with a dose dependent increase in CSF concentration. CSF concentrations at all 
tested doses were > 80% of estimated brain PGRMC-1 receptor occupancy, which was the 
threshold associated with efficacy in preclinical studies.  
A Phase 1 trial (COG0105) was a pilot study of Synaptic Vesicle Glycoprotein 2A (SV2A) PET 
ligand 11C-UCB-J to evaluate the effect of CT1812 treatment on synaptic density in subjects with 
Mild to Moderate Alzheimer’s Disease. Eligible subjects were randomized in a 1:1:1 (300 mg 
CT1812: 100 mg CT1812: placebo) ratio. This was a 24-week treatment period, with an optional 
24-week double blind extension period which was instituted after study startup; 23 subjects were 
dosed, 18 completed the original trial, and 13 rolled over to the double-blind extension.   
Overall, CT1812 was generally well tolerated when delivered daily over a 24- or 48-week period 
in subjects with mild to moderate AD. 
The most common TEAE in the CT1812 treatment arms was headache. Two subjects were 
withdrawn from the study due to TEAEs of liver function test increased (mild, probably related to 
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study treatment). In the CT1812 100 mg arm, two cases of post-dose neurological examination 
findings were assessed as clinically significant for coordination (bilateral ideomotor apraxia) and 
mental state (presence of delusions). There were 2 subjects (CT1812 100 mg and 300 mg 
treatment arms) with suicidal ideation as assessed by the C-SSRS. 
A Phase 1 trial (COG0104) was a pilot study to evaluate the effect of CT1812 treatment on Aβ 
oligomer displacement into CSF in subjects with Mild to Moderate Alzheimer’s Disease. Subjects 
were randomized to CT1812 560 mg/280 mg or placebo in a 1:1 ratio.  A single dose was 
administered following insertion of an indwelling CSF lumbar catheter, and hourly CSF and 
plasma sampling was performed over a period of 24 hours to assess for oligomer displacement. 
Overall, CT1812 was generally well tolerated in mild to moderate AD patients when delivered as 
a single dose of 560 mg.  
There are several ongoing studies. COG0201 is a Phase 2 randomized, 6 month double-blind, 
placebo-controlled, parallel-group, study to evaluate the safety and efficacy of CT1812 in subjects 
with mild to moderate Alzheimer’s disease with a target enrollment of 120 subjects. Subjects are 
randomized to one of three treatment arms (CT1812 at doses of 100 or 300 mg/d or placebo, 
n=40/group).  To date 62 subjects have randomized. There have been several episodes of LFT 
elevation at various timepoints that have resolved following drug discontinuation or 
spontaneously.  No SAEs have been considered drug-related.  
COG0202 is a Phase 2 randomized, double-blind, placebo-controlled electroencephalography 
(EEG) study to evaluate the Effect of CT1812 Treatment on Synaptic Activity in Subjects with Mild 
to Moderate Alzheimer’s Disease.   This is a single-site, 16 subject, 29-day, 2-period crossover 
Phase 2 study of 1 dose level of CT1812 (300 mg) or placebo randomized in a 1:1 ratio. The 
purpose is to evaluate the efficacy of CT1812 in restoring synaptic function in subjects with mild 
to moderate Alzheimer’s disease (AD) through quantitative EEG measurements, as reflected by 
relative theta power. 
3.4 
Rationale for Study 
CT1812 was shown to be safe and well tolerated in a study of healthy volunteers and in Phase 1 
studies of subjects with mild to moderate Alzheimer’s disease. This Phase 2 study is designed to 
evaluate the safety of two doses of CT1812 administered once daily for 6 months in adults aged 
50 to 85 who have been diagnosed with mild to moderate DLB (the targeted clinical indication for 
CT1812). Randomized subjects will receive 100 mg of CT1812, 300 mg of CT1812, or placebo 
once daily for 182 days. Exploratory endpoints that evaluate the effect of CT1812 on biomarkers 
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and potential change in ⍺-synuclein pathology in skin biopsies over the course of 6-months are 
also included. 
3.5 
Rationale for Selected Doses 
Based on brain receptor occupancy studies in animals, the daily dose of 300 mg/day is projected 
to exceed 95% occupancy while the 100 mg/day dose is projected to exceed 80% receptor 
occupancy. In the Phase 1 multiple dose 2-week trial, doses exceeding 300 mg/day were well-
tolerated in both younger (≤ 64 years of age) and older (≥ 65 years of age) subjects. Transient 
increases in LFTS were noted in some subjects.  Subjects were discontinued and LFTs returned 
to normal after discontinuation.  In the phase 1 AD trial tolerability was also acceptable with no 
severe or serious adverse events observed at doses exceeding 300 mg/day. 
4 
STUDY OBJECTIVES 
4.1 
Primary Objectives 
• 
To assess the safety and tolerability of CT1812 as a treatment for mild to moderate Dementia 
with Lewy Bodies. 
4.2 
Secondary Objectives 
• 
To assess exploratory measures of efficacy at baseline, 3 months, and 6 months. 
• 
To assess pharmacodynamic target engagement and potential biomarker evidence of disease 
modification. 
4.3 
Exploratory Objectives 
• 
To evaluate the efficacy of two doses of once-daily oral CT1812, administered for 6 - months 
in subjects with Dementia with Lewy Bodies. 
5 
STUDY TYPE AND DESIGN 
5.1 
Study Type 
This is a multi-center, randomized, double-blind, placebo-controlled, study of 120 subjects with 
three dose arms: 100 mg/day and 300 mg/day of CT1812, vs  placebo. 
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5.2 
Endpoints 
5.2.1 Safety Endpoints 
• 
The incidence and severity of adverse events. 
• 
The change in usage of concomitant medications. 
• 
Changes in vital signs. 
• 
Changes in physical exam findings. 
• 
Changes in electrocardiogram findings. 
• 
Changes in clinical laboratory testing (serum chemistry, hematology, urinalysis). 
• 
Changes in the Columbia Suicide Severity Rating Scale (C-SSRS). 
5.2.2 Efficacy Endpoints 
• 
Montreal Cognitive Assessment Scale (MoCA) 
• 
Epworth Sleepiness Scale (ESS) 
• 
Clinician Assessment of Fluctuation (CAF) 
• 
ADCS-Clinical Global Impression of Change (CGIC). 
• 
ADCS-Activities of Daily Living (ADCS-ADL). 
• 
Movement Disorder Society – United Parkinson’s Disease Rating Scale Part III (MDS-
UPDRS Part III) 
• 
Cognitive Drug Research Battery (CDR) 
• 
Neuropsychiatric Inventory (NPI) 
5.2.3 Pharmacokinetic/Pharmacodynamic Endpoints 
• 
Pharmacokinetics:  
o CT1812 CSF/plasma concentration ratio (end of study only). 
o Changes in pre-dose CT1812 plasma concentrations. 
• 
Pharmacodynamics:  
o Plasma - Aβ, phospho-tau, ⍺-synuclein, phospho-⍺-synuclein, ⍺-synuclein 
oligomers. Other exploratory biomarkers may also be evaluated. 
o Optional CSF- Aβ, tau, phospho-tau, neurogranin, synaptotagmin, SNAP25 
(synaptosomal-associated protein 25), Neuro Filament Light Chain (NFL), Aβ 
oligomers, ⍺-synuclein, phospho-⍺-synuclein, ⍺-synuclein oligomers. Other 
exploratory biomarkers may also be evaluated. 
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5.3 
Study Design 
This is a multi-center, randomized, double-blind, placebo-controlled, study of 120 subjects has 
three dose arms: 100 mg/day and 300 mg/day of CT1812, vs placebo. 
Subjects will be screened for eligibility by physical, laboratory, psychometric and neurologic 
examinations, and neuroimaging. Subjects may opt into collection of pre-dose CSF. If a subject 
opts into CSF collection, this is to be completed along with screening procedures < 42 days prior 
to randomization at Baseline/Day 1. After having met all inclusion criteria, and none of the 
exclusion criteria, subjects will be randomized equally to one of three treatment arms (CT1812 at 
doses of 100 mg/day, 300 mg/day or placebo, up to n=40 group). On clinic visit days, study drug 
will be taken in the clinic after all baseline procedures been conducted. On days where there are 
no clinic visits, subjects will take study drug each morning at home. Subjects and their 
caregivers/study partner will return to the clinic for repeat psychometric/neurologic testing, safety 
procedures and PK and PD sample collection at the intervals described below. 
• 
Subjects will return to the clinic approximately every 2 weeks after their baseline visit until 
Day 70, then every four weeks until Day 182 (See Table 1). A safety follow-up visit will 
occur approximately 28 days after the end of treatment for all subjects that complete 
through Day 182. 
Subjects who prematurely discontinue the study for any reason will be asked to attend an early 
termination visit within 2 weeks of the last dose of study drug.  
5.3.1 
Re-screening Activities 
Subjects who initially screen fail for this study may be permitted to re-screen.  Re-screening may 
be permitted on a case-by-case basis following PI discussion with the Medical Monitor regarding 
whether a subject remains potentially eligible to participate in the study. A subject who is re-
screened is not required to sign another ICF if the re-screening occurs within 30 days from the 
previous ICF signature date. There is no minimum period of time a subject must wait to re-screen 
for the study. The subject must meet all eligibility criteria at the time of re-screening in order to 
qualify for the study. Depending on the time from last screening, the medical monitor will 
determine what assessments need to be repeated. 
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6 
STUDY DRUG 
6.1 
Supply and Storage 
Study drug formulated in hydroxypropyl methylcellulose (HPMC) capsules will be provided in 
bottles containing 65 capsules of 50 mg dose or 150 mg dose (based on freebase CT1812 
fumarate salt) or its matching placebo.  The bottles (original container) are induction sealed, 
child proof screw-top bottles with desiccant packs.  
All study drug (unopened and opened bottles) will be stored refrigerated between 2°C to 8°C 
[35.6°F to 46.4°F] in their original bottles. 
6.2 
Packaging and Labeling 
The treatment label will include a study reference code, drug identifier, quantity of dosage units, 
and lot number at a minimum, as well as other pertinent information according to US FDA or 
local regulations.  The expiry or use-by date will be stored in the IRT/IVRS/IWRS or according to 
local regulations. Study drug should not be used after the expiry or use-by date. All packaged 
and labelled supplies will be formally released in accordance with both Good Manufacturing 
Practice (GMP) and Good Clinical Practice (GCP) guidelines. 
6.3 
Administration 
CT1812 or matching placebo will be administered orally as a single daily dose for 6 months. All 
subjects will take the first dose in the clinic with food and be observed for 2 hours. A single daily 
dose consists of 2 capsules of study drug. Two (2) capsules to be taken with food. Daily 
outpatient dosing should occur in the morning (i.e., prior to 12 pm). To ensure appropriate 
specimen collection times relative to dosing on clinic days, subjects will be asked to bring their 
study medication to clinic visits and to take their medication at the clinic upon the instruction of 
the site staff. On “Drug Dispensation” clinic visits drug accountability will be completed for the 
bottle returned by the subject and the “in office dose administration” will be taken for that visit 
from the newly assigned bottle. 
6.3.1 Safety Stopping Rules 
Dosing may be terminated by the Sponsor at the recommendation of the DSMB (Drug Safety 
and Monitoring Board) based on safety and tolerability data, or at the discretion of the Sponsor; 
as a result, there are no study-specific stopping rules defined in this protocol. 
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The occurrence of any one of the following events will result in a review of study safety 
information to date by the Sponsor and DSMB. 
• 
Two occurrences of the same or similar serious adverse event (SAE) assessed as 
probably or possibly related to dosing with investigational product. 
• 
Two or more different subjects with the same or similar severe AE assessed as probably 
or possibly related to dosing with the investigational product. 
• 
Four or more subjects with the same or similar moderate AE which is possibly or 
probably related to dosing with investigational product. 
 
The Sponsor and DSMB will review the available safety data and recommend whether dosing 
should continue, or if study drug administration should be terminated, or if additional monitoring 
procedures or safety precautions need to be employed.  
The study or a dose group may also be terminated if the Sponsor and DSMB determine that any 
adverse event(s) are occurring that are intolerable or pose a medically unacceptable safety risk. 
For individual subjects: 
Any participant who develops the following liver function test (LFT) laboratory abnormalities will 
not receive any additional doses and will be monitored until resolution of the AE or the return of 
laboratory abnormality to the acceptable screening value(s) 
• 
Elevated ALT or AST greater than 5 X Upper Limits of Normal (ULN)  
• 
Elevated ALT or AST greater than 3 X ULN in combination with total bilirubin > 2 X ULN 
or INR > 1.5 X ULN  
• 
ALT or AST > 3 X ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
Serial monitoring of ALT/AST/bilirubin and INR will be performed, initially with repeat values 
within 4 days of discontinuation of study drug. If LFTs are still elevated 4 days post-study drug 
interruption, participants should have LFTs checked again 4 days later (+/- 1 day). The site 
investigator and medical monitor should agree to a plan for further LFT monitoring depending on 
whether the LFTs are still increasing or trending towards normal.  Repeat testing should be 
carried out until LFTs have normalized. The LFTs in this instance can also be run locally for 
more rapid turnaround.  
In the event a reversible etiology is found to explain the elevated liver enzymes (such as a 
common bile duct stone), drug may be restarted following normalization of LFTs, and after 
discussion between the Medical Monitor and site PI.  
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Study drug will be temporarily discontinued if a participant does not achieve the aforementioned 
levels of elevated LFTs but has an elevation of ALT or AST >3 X ULN. These participants will 
have LFTs retested within 4 days after their last dose of study drug. If LFTs are still elevated 4 
days post-study drug interruption, participants will have LFTs checked again 4 days later (+/- 1 
day), and the site PI and medical monitor will agree to a plan for further monitoring of the 
findings. The LFTs in this instance can also be run locally for more rapid turnaround. 
LFTs do not need to be intensively monitored when ALT and AST are ≤ 3 X ULN with no 
elevation of bilirubin, however the investigator and the medical monitor will formulate a plan for 
serial testing of LFTs. Cessation of dosing is not required in this circumstance but may be 
temporarily interrupted at the discretion of the investigator. 
 
6.4 
Accountability 
Subjects will return all study bottles and unused study drug at each clinic visit for drug 
accountability to be performed. The Investigator or their appointed designee is responsible for 
ensuring that deliveries of study drug are correctly dispensed and recorded, that the product is 
handled and stored safely and properly, and that it is only being given to subjects in accordance 
with this protocol.   
Sites will keep a current log of drug accountability recording:  
• 
Temperature logs for on-site storage refrigerator. 
• 
What drug supply was received from the Sponsor. 
• 
What drug supply was dispensed to each subject. 
• 
What drug supply is current in inventory. 
• 
What drug supply was destroyed or returned to the Sponsor for destruction. 
Note: Drug accountability is the responsibility of the Investigator; a written account will be required 
for all discrepancies. 
The Sponsor’s designated Monitor must verify all accountability records during periodic 
monitoring visits.  Unused and used study drug must be stored on site until such accountability 
has taken place and authorization is received from the Sponsor or Sponsor’s designee that the 
study drug may be returned or destroyed. 
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6.5 
Overdose/Toxicity Management 
No specific pharmacologic antagonist or antidote exists for CT1812.  Therefore, overdose or 
clinical toxicity should be managed with supportive care and pharmacologic treatments directed 
at specific symptoms (i.e., benzodiazepines for agitation or antipyretics for fever). 
6.6 
Blinding, Randomization and Matching Subjects 
This is a double-blind, placebo-controlled study. Study drug will consist of CT1812 and a matching 
placebo. The placebo will be identical in appearance to the active CT1812. 
The non-blinded statistician assigned to the trial will generate a list with the appropriate number 
of multiple digit individual study IDs for each arm, randomly assigned to either active or placebo 
treatment. 
7 
INVESTIGATORS, SITES AND DURATION 
7.1 
Investigator and Site 
This is a multi-center trial and will include up to approximately 30 qualified investigator sites.   
7.2 
Duration of Study 
Screening procedures will occur on Days -42 to -1. Eligible subjects will return to the clinic at 
Baseline/Day 1 visit for randomization into the trial. Daily dosing will continue through Day 182. 
The maximum total duration of subject participation in the study is up to 254 days including 
screening. 
7.3 
Use of Remote Measures in Extenuating Circumstances 
Study visits should be performed in the clinic as specified in Section 9 and Table 1 if possible. 
However, under extenuating circumstances, after consultation with and approval by the medical 
monitor, specific alternative measures may be implemented (e.g., if a subject is unable to travel 
to the study site due to safety concerns and/or local restrictions related to COVID-19 or other 
emerging events) in order to ensure the safety of subjects, site investigators, and site personnel 
while maintaining compliance with GCP and minimizing impact to the integrity of the study. The 
Screening Visit, Day 1 (Baseline), Days 28, 56, 70, 154 and 182 must be performed in the clinic. 
The following remote measures may be implemented. Additional details can be found in the 
Study Reference Manual. 
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• 
Consent or reconsent may be obtained remotely in writing (or verbally, with follow-up written 
confirmation), as allowed by local regulations.  
• 
Study drug may be shipped directly from the site to the subject, as applicable and as 
allowed by local regulations. 
• 
Study visits (except for those noted above) may be conducted as in-home visits by qualified 
personnel. 
• 
Study assessments to evaluate safety may be performed or overseen by qualified personnel 
conducting the in-home visits.  
 
7.4 
Termination of Study 
This study may be terminated at the discretion of the Sponsor.  
8 
STUDY POPULATION 
8.1 
Number of Subjects 
Approximately 120 subjects will be randomized.  
8.2 
Inclusion Criteria 
Subjects may be included in the study only if they meet all of the following criteria: 
1) 
Subjects or their Legally Authorized Representative (LAR) (or designee as applicable by 
local law) must provide written informed consent to the study procedures prior to any study 
procedures. 
2) 
Subjects 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. 
3) 
Men or women 50-85 years of age (inclusive), meeting criteria for probable DLB (as 
defined by the 4th report of the DLB Consortium, McKeith et al., 2017).  
4) 
 Men willing to comply with acceptable form of contraception or women of non-childbearing 
potential as defined below: 
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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 childbearing 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. 
5) 
MRI (or CT scan due to contraindication of MRI, if approved by medical monitor) obtained 
during screening consistent with the clinical diagnosis of DLB and without findings of 
significant exclusionary abnormalities. An historical MRI (or CT scan), up to 1 year prior to 
screening, may be used as long as 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.  
6) 
MMSE 18-27 inclusive. 
7) 
If receiving acetylcholinesterase inhibitors (AChEI), memantine or a combination of the two, 
must have been on a stable dose for at least 12 weeks before the screening visit, with no 
plans for dose adjustment during the study. Treatment-naive subjects can be entered into 
the study, but there should be no plans to initiate treatment with AChEIs or memantine from 
Screening to the end of the study. 
8) 
Stable pharmacological treatment of any other chronic conditions for at least 30 days prior 
to screening. 
9) 
Formal education of eight or more years. 
10) Subjects living at home or in an assisted living facility.   
11) Ability to swallow capsules. 
12) Must consent to apolipoprotein E (ApoE) genotyping. 
13) Subjects 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. 
14) Must be able to complete all screening evaluations. 
 
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8.3 Exclusion Criteria 
Subjects will be excluded from the study if any of the following conditions apply: 
1) 
Any neurological condition that may be contributing to cognitive impairment above and 
beyond those caused by the subject's DLB, including any co-morbidities detected by clinical 
assessment or MRI (or CT scan due to contraindication of MRI, if approved by medical 
monitor). 
2) 
History of transient ischemic attacks or stroke within 12 months of screening. 
3) 
Parkinsonian (extrapyramidal) features with Modified Hoehn and Yahr stage 4 or higher or 
any diagnosis of Parkinson’s disease or parkinsonism that preceded cognitive decline by 
more than one year. 
4) 
Hospitalization (except for planned procedures) or change of chronic concomitant 
medication within one month prior to screening. 
5) 
Any major psychiatric diagnosis, including schizophrenia, bipolar disorder, and current 
major depressive disorder as per Diagnostic and Statistical Manual of Mental Disorders 
Fifth Edition. 
6) 
Geriatric Depression Scale score > 6. (Subjects with a GDS >6 may be allowable if the 
investigator does not believe the subject is clinically depressed. Investigators should contact 
the medical monitor to discuss eligibility.) 
7) 
Subjects living in a continuous care nursing facility. 
8) 
Contraindication to the MRI examination for any reason or, in lieu of an MRI, if the subject 
is unwilling or unable to undergo a CT scan, or if the CT scan is not approved by the 
medical monitor. (Note:  CT scan may be substituted for an MRI if subjects are unable to 
tolerate an MRI or an MRI is contraindicated for medical reasons, if the proposed CT scan 
is discussed and approved by the medical monitor on a case-by-case basis). 
9) 
Screening MRI (or CT scan due to contraindication of MRI if approved by medical monitor) 
or historical MRI/CT scan, if applicable, 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. 
10) Clinical, laboratory findings or medical history consistent with: 
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a) Other primary degenerative dementia, (frontotemporal dementia, Huntington’s disease, 
Creutzfeldt-Jakob Disease, Down syndrome, etc.). 
b) Other neurodegenerative condition (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.). 
11) 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 which requires the use of supplemental oxygen. 
c) Renal insufficiency eGFR < 50 mL/min based on the CKD‐EPI formula.  
d) Heart disease (myocardial infarction, unstable angina, heart failure, cardiomyopathy 
within six months before screening). 
e) Bradycardia (<50 beats/min.) or tachycardia (>100beats/min.). If heart rate is below 50 
beats/min or 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 subjects with diabetes, Only those 
subjects with known diabetes are required to get a HbA1c at screen. 
12) 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. 
13) Seropositive for human immunodeficiency virus (HIV). 
14) 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). 
15) Clinically significant abnormalities in screening laboratory tests, including:  
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a) Hematocrit less than 35% for males and less than 32% for females, absolute neutrophil 
cell count of 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 
16) Disability that may prevent the subject from completing all study requirements (e.g. 
blindness, deafness, severe language difficulty, etc.). 
17) 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) At the discretion of the investigator, lorazepam or another anxiolytic may be 
administered as per local standard of care prior to MRI scan or optional lumbar puncture. 
Note neurocognitive testing should not be done within 24 hours of administration of 
conscious sedation.. 
b) Stable use of clonazepam for at least 30 days as indicated for REM Sleep Behavioral 
Disorder (RBD) 
c) Stable use of atypical antipsychotics (e.g., quetiapine, pimavanserin) for at least 30 days 
as indicated for delusions and hallucinations secondary to DLB. 
18) 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). 
19) Nootropic drugs except stable doses of acetylcholinesterase inhibitors or memantine. 
20) 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. 
21) Suspected or known allergy to any components of the study treatments. 
22) 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. 
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23) 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 course of study. 
24) Any prior exposure to immunomodulators, anti Aβ vaccines, passive anti Aβ 
immunotherapies (e.g., monoclonal antibodies) and/or exposure to BACE inhibitors within 
the past 30 days. 
25) Any condition, which in the opinion of the investigator or the sponsor makes the subject 
unsuitable for inclusion. 
26) Any vaccination within one week of the baseline visit. 
 
8.4 
Withdrawal of Subjects 
A subject should be withdrawn from the study if any of the following occur: 
1) 
Withdrawal of subject consent. 
2) 
Investigator determines that withdrawal from the study is in the best interest of the subject. 
3) 
Major protocol violation (i.e., circumstances where confounding conditions make it 
impossible to derive sound scientific or medical conclusions from the primary endpoint 
data generated on a subject).  
4) 
Any condition, injury, or disease that becomes apparent during the study and necessitates 
the termination of the subject from the study; including events detailed in Section 6.3.1- 
Safety Stopping Rules. 
5) 
Administrative reason (e.g., termination of the clinical study by a Regulatory Agency or the 
Sponsor). 
8.5 
Subject Withdrawal Procedures 
8.5.1 Follow-up Procedures for Subjects Who Withdraw Prematurely 
The date and the reason for study drug discontinuation or subject withdrawal from the study must 
be recorded on the Case Report Form.  If the subject has received one or more doses of study 
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drug, and has not withdrawn consent, the subject shall return for the Early Termination Visit. The 
Early Termination Visit will occur within 2 weeks of the last dose. 
8.6 
Procedures for Replacing Subjects Who Withdraw Prematurely 
Subjects who withdraw from the study will not be replaced.  
9 
TREATMENT PLAN AND METHODS
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9.1 
Table 1, Schedule of Assessments  
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Key for Table 1, Schedule of Assessments 
Abbreviations: DLB = Dementia with Lewy Bodies, PROs= Patient Reported Outcomes, MoCA = Montreal Cognitive 
Assessment Scale, CAF= Clinician Assessment of Fluctuation, ESS = Epworth Sleepiness Scale, MDS-UPDRS part III =  
Movement Disorder Society – United Parkinson’s Disease Rating Scale Part III, ADCS-CGIC = The Alzheimer’s Disease 
Cooperative Study – Clinical Global Impression of Change, ADCS-ADL= The Alzheimer’s Disease Cooperative Study - 
Activities of Daily Living, MMSE = Mini Mental State Exam, CDR= Cognitive Drug Research Battery,  ApoE = 
apolipoprotein E,  C-SSRS = Columbia Suicide Severity Rating Scale, ECG=electrocardiogram, GDS = Geriatric 
Depression Scale, PK=pharmacokinetic, NPI = Neuropsychiatric Inventory 
1. Informed consent for subject and caregiver must be obtained prior to the subject undergoing any study-specific 
procedures. 
2. Review of all criteria detailed in Sections 8.2 and 8.3 
3. Record demographic information, confirm ethnicity and obtain medical history, drug and alcohol history, and education 
history. 
4. Confirm DLB diagnosis in accordance with criteria based on the 4th report of the DLB Consortium (McKeith et al., 
2017). See Appendix B. 
5. Perform MMSE and GDS (see sections 11.1.8 and 11.1.7). 
6. APOE genetic testing is required for all subjects (see section 9.2.1). 
7. Screening labs include viral serology, TSH, FSH (for female subjects that are not surgically sterile) and HbA1c (for 
diabetic subjects only).  
8. Complete physical examination = thorough examination of all body systems (including neurological exam), including 
height and weight. Weight should be measured on the same scale each time. Height measured only at screening (see 
section 12.1.2). 
9. Brief physical examination = inquire about signs/symptoms, review of general appearance and brief review of body 
systems, including weight. Weight should be measured on the same scale each time (see section 12.1.2). 
10. ECG to be conducted during screening period, and approximately one to two hours post-dose at specified visits (see 
section 12.1.7). 
11. MRI (or CT scan due to contraindication of MRI if approved by medical monitor) performed at screen (if an historical 
MRI/CT scan is not used) (see section 12.1.8). 
12. Vital Signs:  body temperature, systolic and diastolic blood pressure, pulse rate and respiration rate 
 
13. Safety labs – Blood Chemistry, Hematology and Urinalysis – Blood should be drawn within an hour of urine collection 
(see section 12.1.4). 
 
14. Collect PK samples. See Section (see section 10.2) for timing of sample collection. See Laboratory Procedures 
Manual for sample handling.  
15. Collect PD plasma biomarker samples. See Section (see section 10.2) for timing of sample collection. See Laboratory 
Procedures Manual for sample handling. If the PD sample cannot be collected prior to dosing on Day 1 baseline, the 
subject may not receive the first dose of study drug.  Dosing will be delayed until this successful collection of this pre-
dose baseline sample. 
16. Whole blood sample collected for future biologic research (see section 10) See Laboratory Procedures Manual for 
sample handling 
17. Coagulation testing includes prothrombin time (PT) and INR (see section 12.1.4). 
18. Optional lumbar puncture: For subjects opting to undergo lumbar puncture, the procedure should be performed at 
least 24 hours before the Baseline visit and again at Day 182 (the end of the dosing period). LP on the Day 182 visit 
should be performed within t–e – 2-day visit window minimally 24 hours prior to the Day 182 visit procedures (e.g., 
Day 181) and prior to dosing on that day (see section 10.3).  
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19. If adequate volume is available, CSF will be stored for future evaluation of biomarkers of target engagement or 
disease modification. See Laboratory Procedures Manual for sample handling (see section 10.3) 
CSF should be sent for cell counts, if such testing is available (white blood cells and red blood cells, with differential if 
either of the counts is abnormal), CSF protein, and CSF glucose at Screening and Day 182. If abnormalities are 
observed at Screening, they should be discussed with the medical monitor before randomizing the subject. 
20. Subjects will undergo Syn-One TestTM punch biopsy during the screening period once all other screening procedures 
are complete with this procedure to occur at least 24 hours before the Baseline visit. 
21. Pregnancy testing for female subjects that are not surgically sterile (see section 12.1.6) 
22. C-SSRS Screening/Baseline version used at screening visit, Since Last Visit version used at all other visits and will be 
administered prior to dosing (see section 11.1.12). 
23. The CDR system requires two training sessions to be conducted at least 30 minutes apart during the screening 
period. These trainings can be done at the screening visit or scheduled on separate days during the screening period. 
24. The PROs/assessments will all be completed prior to dosing and procedures during the study visit (see section 11.1). 
25. The CAF and ESS will be administered prior to dosing and procedures during the study visit (see section 11.1.2 and 
11.1.3). 
26. The Modified Hoehn and Yahr will be administered at screening prior to other procedures (see section 11.1.1). 
27. All concomitant medications will be recorded from screening through Day 210 (see section 9.3). 
28. During Screening (post-consent), only SAEs related to a study-specific procedure will be collected. For all related AEs 
of moderate or severe intensity ongoing at the end of the study, follow-up will continue until the event has resolved to 
baseline severity, the event is assessed as stable by the Investigator, or the patient is lost to follow-up or the patient 
withdraws consent (see section 12). 
29. Drug accountability must be performed at each visit with the exception of screening, baseline and day 210 (safety 
follow up) (see section 6.4). 
30. Where drug is dispensed, the remainder of the previous bottle should be collected and retained by the site. 
31. Study drug should be administered in clinic with food. 
 
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9.2 
Visit Specific Procedures 
9.2.1 Visit 1 / Screening  
The Screening visit must be performed within 42 days prior to Day 1 – Baseline. The following 
procedures will be performed at the Screening visit: 
• 
Subjects or their Legally Authorized Representative (LAR) (or designee as applicable by 
local law) must provide written informed consent to the study procedures prior to any study 
procedures. The caregiver must also provide written informed consent at this time. 
• 
Evaluate subject eligibility against study inclusion/exclusion criteria. 
• 
Confirm DLB diagnosis (see section Appendix B). 
• 
Record demographic information, confirm ethnicity, alcohol and drug history, educational 
history and obtain medical history. 
• 
Administer the Mini-Mental State Exam (MMSE) and Geriatric Depression Scale (GDS)  
• 
Administer Modified Hoehn and Yahr  
• 
Administer CAF and ESS  
• 
Administer C-SSRS Screening/Baseline version  
• 
Perform complete physical examination with neurological examination  
• 
Measure and record vital signs  
• 
Perform 12-lead ECG  
• 
MRI (or CT scan due to contraindication of MRI, if approved by medical monitor), unless an 
historical MRI/CT scan is used. 
• 
Draw blood and prepare samples for APOE status. Apolipoprotein E (ApoE) genotype is 
associated with the risk and age of onset of DLB.  Blood samples (approximately 10 mL) to 
perform this testing will be collected and will be utilized to further understanding of response 
to CT1812. The genotyping is mandatory for participation in the study and the results will not 
be revealed to either the investigator or subject and caregiver. 
• 
Draw blood and prepare samples for coagulation testing (PT/INR), serum chemistry, 
hematology, viral serology, TSH, FSH (in women who had their last natural menses less 
than 24 months prior to screening and who are not surgically sterile) and HbA1c (in known 
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diabetics), Blood should be drawn within an hour of urine collection. Abnormal results at 
screening will exclude a subject unless the investigator is aware of a specific reason that 
can explain the abnormality (e.g., elevated CPK 24 hours after strenuous exercise). Should 
an abnormal lab remain abnormal on repeat the subject will be excluded. Collect blood 
sample for exploratory biomarker samples 
• 
Collect blood samples for exploratory plasma biomarker analysis 
• 
Collect urine sample for β-HCG pregnancy test for women who are not postmenopausal 
(last natural menses was less than 24 months ago) that are not surgically sterile.  
• 
Collect urine sample for urinalysis  
• 
Record concomitant medications  
• 
Once all above screening assessments are completed, complete the subject eligibility form 
located in the study manual and submit to the medical monitor.  
• 
If a subject opts in to the lumbar puncture, the subject should undergo the lumbar puncture 
(CSF biomarkers to be collected during this procedure) at least 24 hours before the Baseline 
visit.  
• 
Once all other screening activities are complete, the subject should undergo the Syn-One 
TestTM skin biopsy at least 24 hours prior to the baseline visit. 
• 
During the screening period, subjects will need to be trained on how to use the CDR system. 
This is an automated battery amenable to measurement of cognitive deficits in patients with 
DLB (McKeith et al. 2000; Wesnes et al. 2014). It consists of 10 performance tasks 
measuring attention, working memory, episodic memory, and executive function, performed 
by the patient on a laptop. Two training sessions need to be conducted at least 30 minutes 
apart during the screening period to allow patients to become familiar with the procedure, 
reduce test anxiety, reduce learning effects, and produce a stable baseline. These trainings 
can be done at the screening visit or scheduled on separate days during the screening 
period. 
• 
If eligible, schedule subject to return to the clinic on Day 1 to initiate CT1812 dosing. 
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9.2.2 Visit 2 / Study Day 1 – Baseline 
The following procedures will be conducted on Day 1: 
Pre-dose Assessments:  
• 
Confirm continued eligibility prior to dosing.  
• 
Administer MOCA, CDR, ADCS-ADL, NPI, ADCS-CGIC, MDS-UPDRS Part III, 
CAF and ESS  
• 
Administer C-SSRS Since Last Visit version  
• 
Perform complete physical examination with neurological examination  
• 
Measure and record vital signs  
• 
Draw blood and prepare sample for serum chemistry and hematology   Blood 
should be drawn within an hour of urine collection. 
• 
Collect whole blood sample for future biomedical research including potential 
genetic analyses  
• 
Collect blood samples for PK and exploratory plasma biomarker analysis  
• 
Collect urine samples for urinalysis  
• 
Record any new medical conditions, AEs, or changes in medications since the 
Screening visit. 
• 
Administer study drug with food. 
Post-dose Assessments 
• 
Record ECG ~1- 2 hours post-dose  
• 
Dispense study drug supply and instructions for at home dosing.  
• 
Instruct subject to return for Day 14 visit including instructions to bring study drug 
to the Day 14 visit 
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9.2.3 Visit 3 Study Day 14 
The subject will return to the clinic for the following assessments: 
 
• 
Measure and record vital signs  
• 
Draw blood and prepare sample for serum chemistry and hematology. Blood 
should be drawn within an hour of urine collection. 
• 
Collect urine samples for urinalysis, 
• 
Record any AEs. 
• 
Record changes in medications. 
• 
Conduct drug accountability, return study drug to the subject for continued dosing 
• 
Instruct subject to return for Day 28 visit including instructions to hold dose on 
morning of Day 28 visit and to bring study drug with them 
9.2.4 Visit 4 Study Day 28 
The subject will return to the clinic for the following assessments: 
Pre-dose Assessments:  
• 
Administer MOCA, CDR, ADCS-ADL, NPI, ADCS-CGIC, MDS-UPDRS Part III, CAF and 
ESS  
• 
Administer C-SSRS Since Last Visit version   
• 
Perform brief physical examination  
• 
Measure and record vital signs  
• 
Draw blood and prepare sample for serum chemistry and hematology.) Blood should be 
drawn within an hour of urine collection 
• 
Collect blood samples for PK and exploratory plasma biomarker analysis  
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• 
Collect urine samples for urinalysis  
• 
Record any AEs. 
• 
Record changes in medications. 
• 
Conduct drug accountability  
• 
Collect remaining drug in old bottle.  
• 
Administer Day 28 dose with food. 
Post-dose Assessments:  
• 
Record ECG ~1- 2 hours post -dose).  
• 
Dispense study drug supply and instructions for at home dosing  
• 
Instruct subject to return for Day 42 visit including instructions to bring study drug with 
them to the Day 42 visit 
9.2.5 Visit 5 Subject Day 42 
The subject will return to the clinic for the following assessments: 
 
• 
Measure and record vital signs  
• 
Draw blood and prepare sample for serum chemistry and Blood should be drawn within 
an hour of urine collection. 
• 
Collect urine samples for urinalysis  
• 
Record any AEs. 
• 
Record changes in medications. 
• 
Conduct drug accountability, return study drug to the subject for continued dosing 
• 
Instruct subject to return for Day 56 visit including instructions to hold dose on morning 
of Day 56 visit and to bring study drug with them 
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9.2.6 Visit 6 Study Day 56 
The subject will return to the clinic. 
Pre-dose Assessments:  
• 
Administer C-SSRS Since Last Visit version  
• 
Perform brief physical examination  
• 
Measure and record vital signs  
• 
Draw blood and prepare sample for serum chemistry and hematology Blood should be 
drawn within an hour of urine collection. 
• 
Collect blood samples for PK  
• 
Collect urine samples for urinalysis  
• 
Record any AEs. 
• 
Record changes in medications. 
• 
Conduct drug accountability  
• 
Administer Day 56 dose with food. 
Post-dose Assessments:  
• 
Dispense study drug supply and instructions for at home dosing  
• 
Instruct subject to return for Day 70 visit including instructions to bring study drug with 
them to the Day 70 visit 
9.2.7 Visit 7 Study Day 70 
The subject will return to the clinic for the following assessments: 
 
• 
Measure and record vital signs  
• 
Draw blood and prepare sample for serum chemistry and hematology   Blood should be 
drawn within an hour of urine collection. 
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• 
Collect urine samples for urinalysis  
• 
Record any AEs. 
• 
Record changes in medications. 
• 
Conduct drug accountability, return study drug to the subject for continued dosing 
• 
Instruct subject to return for Day 98 visit including instructions to hold dose on morning 
of Day 98 visit and to bring study drug with them 
9.2.8 Visit 8 Study Day 98  
The subject will return to the clinic. 
Pre-dose Assessments:  
• 
Administer MOCA, CDR, ADCS-ADL, NPI, ADCS-CGIC, MDS-UPDRS Part III, CAF and 
ESS  
• 
Administer C-SSRS Since Last Visit version  
• 
Perform brief physical examination  
• 
Measure and record vital signs  
• 
Draw blood and prepare sample for serum chemistry and hematology.  Blood should be 
drawn within an hour of urine collection. 
• 
Collect blood samples for PK and exploratory plasma biomarker analysis  
• 
Collect urine samples for urinalysis  
• 
Record any AEs 
• 
Record changes in medications 
• 
Conduct drug accountability  
• 
Collect any remaining drug in old bottle  
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• 
Administer Day 98 dose with food 
Post-dose Assessments:  
• 
Record ECG ~1- 2 hours post-dose  
• 
Dispense study drug supply and instructions for at home dosing  
• 
Instruct subject to return for the Day 126 Study Visit  
9.2.9 Visit 9 Study Day 126 
The subject will return to the clinic for the following assessments: 
 
• 
Measure and record vital signs  
• 
Draw blood and prepare sample for serum chemistry and hematology   Blood 
should be drawn within an hour of urine collection. 
• 
Collect urine samples for urinalysis 
• 
Record any AEs 
• 
Record changes in medications 
• 
Conduct drug accountability, return study drug to the subject for continued dosing 
• 
Instruct subject to return for Day 154 visit including instructions to hold dose on 
morning of Day 154 visit and to bring study drug with them 
9.2.10 Visit 10 Study Day 154 
The subject will return to the clinic. 
Pre-dose Assessments:  
• 
Administer C-SSRS Since Last Visit version  
• 
Perform brief physical examination  
• 
Measure and record vital signs  
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• 
Draw blood and prepare sample for serum chemistry and hematology. Blood should be 
drawn within an hour of urine collection 
• 
Draw blood for coagulation testing  
• 
Collect blood samples for PK   
• 
Collect urine samples for urinalysis  
• 
Record any AEs 
• 
Record changes in medications 
• 
Conduct drug accountability  
• 
 Administer Day 154 dose with food 
Post-dose Assessments:  
• 
Dispense study drug supply and instructions for at home dosing   
• 
Instruct subject to return for the relevant Day 182 Study Visit Including instructions to 
hold dose on morning of next visit and to bring remaining study drug with them 
9.2.11 Visit 11 Study Day 182 / Early Termination 
The subject will return to the clinic. 
• 
Within the -2-day window for scheduling assessments: 
• 
If the subject opted into the lumbar puncture, perform lumbar puncture, and collect CSF a 
minimum of 24 hours before the Day 182 / Early Termination Visit 
• 
The subject should undergo the Syn-One TestTM skin biopsy at least 24 hours prior to the Day 
182 / Early Termination Visit 
Pre-dose Assessments:  
• 
Administer MOCA, CDR, ADCS-ADL, NPI, ADCS-CGIC, MDS-UPDRS Part III, 
CAF and ESS  
• 
Administer C-SSRS Since Last Visit version  
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• 
Perform complete physical examination with neurological examination  
• 
Measure and record vital signs  
• 
Draw blood and prepare sample for serum chemistry and hematology. Blood 
should be drawn within an hour of urine collection. 
• 
Collect blood samples for PK and exploratory biomarker analysis  
• 
Collect urine samples for urinalysis  
• 
Record any AEs 
• 
Record changes in medications 
• 
Conduct drug accountability) and collect all remaining drug from subject 
• 
Administer last dose of study drug with food 
Post-dose Assessments 
• 
Record ECG ~1-2 hours post-dose  
• 
Instruct subject to return for Day 210, safety follow up visit 
Any subject that discontinues prematurely should complete Visit 11/Day 182 as an Early 
Termination visit. For subjects prematurely discontinuing, an early termination visit should be 
scheduled within 2 weeks of the last dose of study medication. If early termination visit is 3 or 
more days from the last dose, PK sampling should not be done. The remainder of the 
assessments below should be performed. 
9.2.12 Study Day 210 / Safety Follow-up Visit 
The subject will return to the clinic. 
• 
Administer C-SSRS Since Last Visit version 
• 
Measure and record vital signs 
• 
Draw blood and prepare sample for serum chemistry and hematology 
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• 
Collect urine samples for urinalysis 
• 
Record any AEs 
• 
Record changes in medications 
9.3 
Concomitant Medications and Other Restrictions 
All medications mentioned in the exclusion criteria (Section 8.3) are expressly prohibited at any 
time during the study. Exceptions to the list of excluded medications may be made on a case-by-
case basis if discussed and approved by the medical monitor in advance. Intake of drugs or 
substances potentially involved in clinically significant 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 are prohibited. Grapefruit juice should be avoided 
in the two weeks prior to dosing and throughout the course of the study. See Appendix A for a list 
of these prohibited substances. As noted in Appendix A, The P-glycoprotein (P-gp) substrate 
drugs loperamide and talinolol must be separated from dosing of CT1812 (before or after) by 6 
hours. If this is not feasible, the subject cannot participate in the study. 
Subjects may be on stable doses (at least 30 days prior to screening) of an acetylcholinesterase 
inhibitor and/or memantine and continue these medications during the study. Subjects may be 
enrolled on stable doses (at least 30 days prior to screening) of atypical antipsychotics (e.g., 
quietapine, pimavanserin) and clonazepam; however, such subjects should be monitored for 
potential changes in symptoms related to the use of these medications as a result of possible 
drug-drug interactions. Dose adjustments to these medications may be considered if indicated. 
9.3.1 
Concomitant COVID-19 Treatment Restrictions  
• 
If a subject is treated for COVID-19 infection, the following recommendations would allow 
the subject to remain in the trial. 
o If the subject is prescribed Paxlovid ™, CT1812 dosing should be held coinciding 
with the day Paxlovid ™ is first administered. CT1812 should not be administered 
for the 5-day course of Paxlovid ™, in addition to 7 additional days (12 days total 
holding of CT1812) to allow for regeneration of the 3A4 isoenzyme.  Normal dosing 
of CT1812 can then resume. 
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o If a subject is prescribed Lagevrio ™ (molnupiravir),the preclinical data indicates it 
is neither metabolized by CYP isoenzymes, nor does it interact with them. 
Therefore, no cessation of CT1812 is required if Lagevrio ™ is employed. 
 
10 SAMPLE COLLECTION 
10.1 Blood Sampling for PK and Exploratory Plasma Biomarkers 
Blood samples for the measurement of plasma CT1812 levels and exploratory plasma biomarkers 
will be drawn at the following times during the study: 
• 
Day 1 (baseline) whole blood sample collection for Future Biomedical Research (FBR) 
(pharmacogenomics) including potential genetic analyses (see section 10.2). Within 1.25 
hours prior to dosing 
• 
PK:  Days: 1, 28, 56, 98, 154, and 182: within 1.25 hours prior to dosing.  
• 
PD plasma biomarkers: Screening and Days: 1, 28, 98, and 182: within 1.25 hours prior 
to dosing 
o Note: If the PD sample cannot be collected prior to dosing on Day 1 baseline, the 
subject may not receive the first dose of study drug. Dosing will be delayed until 
this successful collection of this pre-dose baseline sample.   
 
10.2 Handling, Shipping, Storage and Analysis of Blood Samples 
Please refer to the Laboratory Procedures Manual for the processing of blood samples for PK 
and PD plasma biomarker analyses. 
Subject blood specimens collected during this study may be stored for up to 15 years and used 
to further the knowledge of CT1812. The whole blood sample (~10 mL) for Future Biomedical 
Research (FBR) will be collected at Day 1 from subjects. Research performed on this sample may 
include genetic analyses (e.g., DNA, gene expression profiling [ribonucleic acid], proteomics, 
metabolomics, or other analytes). Banked blood specimens may be used in the future to 
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determine whether certain genotypes are correlated with the safety or efficacy of CT1812 or to 
answer emerging research questions not described elsewhere in the protocol.  
Specimens obtained for FBR will be collected, tracked in a manner consistent with Good Clinical 
Practice by a quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as adherence to 
authorized use of specimens as specified in this protocol and in the Informed Consent Form.  
Subjects in this study will not be identified by name in case report forms (CRFs), study-related 
forms, study reports, or any related publications and this deidentification applies to all FBR 
specimens.  
Consistent with all patient information, information related to FBR specimens is confidential and 
may only be disclosed to third parties as permitted by the Informed Consent Form signed by the 
patient, unless permitted or required by law. 
Data derived from FBR specimen analysis on individual subjects will generally not be provided 
to study investigators unless a request for research use is granted.  
After collection at the site, deidentified specimens obtained for FBR will be transferred to 
Cognition Therapeutics and stored in a secure, long-term storage facility at -80° C for up to 15 
years.  After 15 years, the samples will be destroyed, and archived information will be discarded 
per local/country regulation. Sampling procedures, storage conditions, and shipment 
instructions are provided to the sites in the separate laboratory procedures manual.  
 
Data generated from deidentified FBR specimens will be available for inspection upon request 
by representatives of national and local health authorities, and monitors, representatives, and 
collaborators, as appropriate. 
Samples of deidentified FBR specimens, genetic research data and associated clinical data 
derived from the deidentified FBR samples may be shared with researchers who are not 
participating in the study or submitted to government or other health research databases for 
sharing with other researchers for the purpose of better understanding Alzheimer’s disease 
and/or the study drug and/or other treatments. 
In the event of death or loss of competence of a subject who is participating in the Research, 
the subject’s specimen and data will continue to be used unless permission to use the 
deidentified FBR specimens is withdrawn. 
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10.3 Optional Cerebrospinal Fluid 
10.3.1 Collection 
Cerebrospinal fluid (CSF) is being collected from subjects that consent to this optional procedure 
at screen and Day 182. This is being collected to evaluate CSF concentrations of CT1812 
following repeated dosing of CT1812 and potential effects on CSF biomarkers [Aβ, tau, phospho-
tau, neurogranin, synaptotagmin, SNAP25 (synaptosomal-associated protein 25), Neuro Filament 
Light Chain (NFL), Aβ oligomers, ⍺-syn, phospho-⍺-syn, ⍺-syn oligomers]. Other exploratory 
biomarkers may also be evaluated. 
As an optional procedure, CSF will be collected via lumbar puncture (LP). A qualified clinician will 
perform the LPs. 
Before commencing the LP, the clinician will ensure that there are no contraindications to the 
procedure.  
Obtained CSF collected at Screen and Day 182 should be sent to a local lab for cell counts (white 
blood cells and red blood cells, with differential if either of the counts is abnormal), CSF protein, 
and CSF glucose, if such testing is available.  If abnormalities at screen are observed, they should 
be discussed with the medical monitor before randomizing the subject. 
The investigator may in the event of a failed LP elect to attempt a repeat LP under fluoroscopy or 
CT scan or to obtain the assistance of an anesthesiologist, if these options are available at their 
IRB approved facility. Fluoroscopy or CT can be used during the first attempt if that is the standard 
of care at the institution, or the subject's anatomy suggests use of these measures would be 
prudent.. 
10.3.2 Timing of Optional CSF Collection 
After a subject has consented to participate in the optional lumbar puncture, samples for the 
measurement of CT1812 levels in CSF will be collected via lumbar puncture at least 24 hours 
before the Baseline visit, pre-dose, at least 24 hours prior to the Day 182 visit (within the visit 
window) in order to not impact the cognitive assessments performed on those visit days.  
Regardless of which day the LP is performed, study drug dosing for that day should be 
completed in the clinic, following the LP.  
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10.3.3 Volume of Optional CSF Collected 
The volume of CSF collected from each subject during this study will be approximately 10- 12 mL 
at each of the specified time points. 
10.3.4 Handling, Shipping, Storage and Analysis of Optional CSF 
Please refer to the Laboratory Procedures Manual for the handling of CSF samples. Subject CSF 
will be stored for future evaluation of biomarkers of target engagement or disease modification. 
Specimens collected during this study may be stored for up to 15 years and used to further the 
knowledge of CT1812. 
10.4 Syn-One TestTM Skin Biopsy 
Using biopsy kits provided by CND Life Sciences, Inc. (CND), punch biopsies will be taken to 
assess presence of phosphorylated alpha-synuclein. The biopsy will be performed during the 
screening period once all other screening procedures are complete with this procedure to occur 
at least 24 hours before the Baseline visit. Three-millimeter punch biopsies will be taken from 
the distal leg, the distal thigh, and the posterior cervical region after local anesthesia with 1% 
lidocaine. Given the national lidocaine shortage, suitable substitutes are lidocaine with 
epinephrine (1.0% or 2.0% lidocaine with 1:100,000 epinephrine), lidocaine without epinephrine, 
or bupivacaine.   
Any subject with a history of reaction to local anesthetic will be exempt from the procedure. 
Any subject that as previously had a Syn-One TestTM does not need to have this procedure 
repeated. Results from this biopsy will be entered into the eCRF by the site staff. 
Any subject that was randomized into the study prior to the implementation of the Syn-One 
TestTM  is exempt from this procedure. 
10.4.1 Results from the Syn-One TestTM   
Subjects and study site staff will be blinded to the results of the Syn-One TestTM until after the 
subject has completed their participation in the study.   
 
10.4.2 Handling, Shipping and Analysis of Syn-One Skin TestTM  
Please refer to the standard practice guidelines provided by CND Life Sciences, Inc. (CND), for 
detailed instructions for processing and shipping biopsy samples. 
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Samples will be placed in labeled tubes of Zamboni fixative and shipped overnight to CND. The 
skin biopsies will be dual immunostained for protein gene product 9.5 and phosphorylated 
alpha-synuclein. 
11 SCREENING, EFFICACY AND SAFETY ASSESSMENTS 
11.1 Affective and Cognitive Measures 
11.1.1 Modified Hoehn and Yahr 
The Modified Hoehn and Yahr Scale (Yahr and Hoehn 1967) is used to measure how Parkinson’s 
symptoms progress and to stage the level of disability. The scale includes stages 0 to 5 with 0 
being no signs of disease and 5 indicating the person is wheelchair or bedbound and in need of 
assistance.  
11.1.2 Clinician Assessment of Fluctuation (CAF) 
Cognitive fluctuations are a core feature of DLB (McKeith et al., 2017) characterized by 
alterations in attention, alertness, and consciousness. The CAF is a screening questionnaire 
asked of an informant to capture frequency and duration of episodes to calculate a severity 
score (range 0-16 with higher scores representing more severe fluctuations (Walker et al., Sep 
2000). The CAF is highly correlated with electrophysiologic measures and with computerized 
tests of cognitive performance (the CDR) (Walker et al., Apr 2000). 
11.1.3 Epworth Sleepiness Scale (ESS) 
Excessive daytime sleepiness is a common feature in DLB and is a major component of the 
symptoms of cognitive fluctuations (Ferman et al., 2004, 2014). The Epworth Sleepiness Scale 
(ESS) is a measure that assesses subjective sleepiness over the prior two weeks (Johns, 1991, 
1997). The ESS is a scale that queries the likelihood of dozing (i.e., 0= no chance of dozing, 1= 
slight chance of dozing, 2= moderate chance of dozing or sleeping, 3= high chance of dozing) in 
eight different circumstances. An ESS score ≥10 is considered abnormal and consistent with 
excessive daytime sleepiness. DLB patients have higher mean ESS scores compared to 
dementia etiologies (DLB 13.9 ± 5, bvFTD 9.6 ± 8, AD 8.8 ± 5, p<0.05). An ESS score ≥10 was 
significantly more likely to occur in DLB compared to bvFTD or AD (DLB 81% vs. bvFTD 47% 
vs. AD 45%, p<0.01) (Boeve et al., 2019). 
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11.1.4 Cognitive Drug Research Battery (CDR) 
Marked impairments in and fluctuation of attention are characteristic of dementia with Lewy 
bodies (DLB) (Ballard et al., 2001). Cognitive correlates of fluctuations may be best captured 
with computerized assessments of attention, reaction time, and vigilance.  The CDR is a 
computerized battery that captures simple and choice reaction time, cognitive reaction time, 
vigilance, and power of attention (Ballard et al., 2002). The CDR has been used in dementia 
clinical trials for DLB (Wesnes et al., 2002) and AD (Simpson, Surmon, Wesnes, & Wilcock, 
1991).. The CDR should be administered at the time points listed in the Schedule of Activities. 
Baseline visit should be schedule at a time of the day that is repeatable for the following visits. 
Additionally, two training sessions will be conducted at least 30 minutes apart during the 
screening period to allow patients to become familiar with the procedure, reduce test anxiety, 
reduce learning effects, and produce a stable baseline. These trainings can be done at the 
screening visit or scheduled on separate days during the screening period. 
11.1.5 Movement Disorder Society – Unified Parkinson’s Disease Rating Scale -Part III 
(MDS-UPDRS3) 
The MDS-UPDRS3 is a gold standard assessment of the motor examination of parkinsonism 
(Goetz et al., 2008), a core feature of DLB (McKeith et al., 2017). The motor exam covers 18 
motor signs associated with parkinsonism covering bradykinesia, rigidity, tremor, and gait with a 
range of scores from 0-136, with higher scores supporting more severe symptoms. A score of 6 
or greater suggest the presence of parkinsonism (Goetz et al., 2008) 
 
11.1.6 Montreal Cognitive Assessment (MOCA) 
The MOCA is a brief dementia screening assessment that covers nine domains (Nasredinne et 
al., 2005).  It has been validated for use in detecting cognitive impairment in Parkinson’s 
disease (Gill, Freshman, Blender & Ravina, 2008), Parkinson’s disease dementia (Biundo et al., 
2016 & Wang et al., 2013) and DLB (Biundo et al., 2016). The MOCA has a 0-30 range with 
lower scores meaning more impairment. During 1-year of follow-up, the percentage of relative 
standard deviation was 21% and the MOCA may be better suited to study cognitive change in 
DLB than tests such as the Mini Mental State Exam (Folstein, Folstein & McHugh, 1975) due to 
the lack of ceiling and floor effects (Biundo et al., 2016). 
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11.1.7 Geriatric Depression Scale 
The Geriatric Depression Scale (GDS) (Sheikh & Yesavage, 1986) is a depression screening 
assessment designed to identify depression in the elderly. The short-form 15-item questionnaire 
with Yes and No answers queries subject’s energy, attitude toward life, mood, etc. Subjects 
eligible for this study must not have a score above 6 out of 15. Often symptoms of depression can 
mask or mimic some symptoms of Dementia, therefore it is important to rule out participation of 
those who may be suffering from acute depression. Subjects with a GDS >6 may be allowable if 
the investigator does not believe the subject is clinically depressed. Investigators should contact 
the medical monitor to discuss eligibility. 
11.1.8 Mini Mental State Exam 
The Mini Mental State Exam (MMSE) (Folstein et al., 1975, 2010) is a brief, screening instrument 
often used in clinical trials to assess dementia severity. The MMSE assess several aspects of 
memory and cognitive functioning including orientation, attention, concentration, comprehension, 
recall, and praxis. The total possible score is 30, with high scores indicating less impairment.  
11.1.9 Neuropsychiatric Inventory 
The Neuropsychiatric Inventory (NPI) (Cummings et al., 1994, 1997) was developed to assess 
for common behaviors associated with dementia. A structured interview of the caregiver is used 
to assess 12 behavior domains including delusions, hallucinations, dysphoria, euphoria, anxiety, 
agitation/aggression, apathy, irritability/lability, disinhibition, and aberrant motor behavior as well 
as sleep and appetite/eating disorders. Screening questions are asked regarding behaviors 
which have occurred over the past month. If an affirmative response is given, more detailed 
information is acquired pertaining to the frequency on a 4-point scale and severity on a 3-point 
scale of the behavior. There is also a 6-point caregiver distress scale.  
11.1.10 
ADCS-Clinical Global Impression of Change (CGIC) 
The Alzheimer’s Disease Cooperative Study – Clinical Global Impression of Change (ADCS-
CGIC) was developed by the Alzheimer’s Disease Cooperative study (ADCS) (Schneider et al., 
1997). The scale consists of a format with which a clinician may address clinically relevant 
overall change, including 15 areas under the domains of cognition, behavior, and social and 
daily functioning. The rater, at baseline, interviews the subject and caregiver/informant, using a 
form that comprehensively lists relevant symptoms potentially useful in judging change, and 
makes notes for future reference. There are few requirements to fulfill during the interview, but 
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clinical assessment of mental status is to be made. By allowing raters to use the forms in an 
unstructured manner, this scale may facilitate clinical judgments with face validity. At follow-up 
visits, the clinician uses a similar set of forms to re-interview the patient and caregiver/informant.  
 
The ADCS-CGIC rating is made on a 7-point scale similar to other global change scales, where 
a higher score indicates marked improvement. The ADCS-CGIC value is a measure of the 
change from baseline and therefore the algebraic change from baseline is not calculated for the 
ADCS-CGIC. The ADCS-CGIC will be completed by an independent rater (not the rater 
completing the cognitive or other assessments) where available at the site. 
11.1.11 
 ADCS-Activities of Daily Living (ADL) 
The ADCS-ADL (Galasko et al., 1997) is a 23-item informant-administered assessment of 
functional impairment in terms of activities of daily living. Informants respond to 23 questions 
about the patient’s involvement and level of performance across items representing daily living. 
The questions range from basic to instrumental activities of daily living. Each item is rated from 
the highest level of independent performance to complete loss. The total score range is from 0-
78 with lower scores indicating greater functional impairment.  
11.1.12 
Columbia Suicide Severity Rating Scale  
Consistent with FDA regulatory guidance (FDA 2012), any occurrence of suicide-related thoughts 
and behaviors will be assessed. The Columbia Suicide Severity Rating Scale (C-SSRS) (Posner 
et al., 2011) includes suggested questions to elicit the type of information needed to determine if 
a suicide-related thought or behavior occurred. It rates an individual's degree of suicidal ideation 
on a scale, ranging from "wish to be dead" to "active suicidal ideation with specific plan and intent."  
The scale identifies behaviors that may be indicative of an individual's intent to commit suicide. If 
a suicide-related thought or behavior is identified at any time during the study, a thorough 
evaluation will be performed by a qualified study clinician and appropriate action undertaken.  The 
Screening/Baseline version will be used during the screening visit, and the Since Last Visit version 
will be used at all subsequent visits. 
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12  SAFETY ASSESSMENTS 
12.1 Assessment of Safety 
A DSMB (Drug Safety and Monitoring Board) will oversee the safety of the trial. This committee 
will include independent experts, including an independent statistician. Safety data will be 
provided to the DSMB at quarterly intervals during the trial. The study clinician and study medical 
monitor will review trial safety data biweekly and more frequently as the safety data warrant. 
Similarly, more frequent ad hoc meetings of the DSMB will occur if ongoing safety data indicate 
interim meetings are indicated. 
 
 
EVALUATION CRITERIA: 
The DSMB will review the safety and tolerability of CT1812 of the subjects enrolled in the study. 
They may also recommend monitoring and reporting of additional safety and/or tolerability 
measures such as: 
• 
Adverse events. 
• 
Serious Adverse Events. 
• 
Physical and neurological examinations. 
• 
Vital signs - body temperature, systolic and diastolic blood pressure, pulse rate and 
respiration rate. 
• 
Electrocardiogram (ECG). 
• 
Clinical laboratory tests: hematology, biochemistry, coagulation, serology and urinalysis. 
• 
Columbia Suicide Severity Rating Scale (C-SSRS). 
12.1.1 Adverse Events  
Adverse events will be captured from the start of study-related procedures at Visit 1 (including 
diagnostic assessments or signing of ICF) and during the study. Important medical events and 
conditions occurring prior to this period are not AEs; they will be captured within the medical chart 
and in the Medical History section of the Case Report Form. 
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12.1.2 Physical and Neurological Examinations 
At study visits in which a complete physical examination is required, the investigator should 
perform a thorough examination of all body systems (exception: genitourinary and reproductive 
should be symptom-directed).  At study visits in which a brief physical examination is required, 
the investigator should inquire about signs/symptoms, general appearance, eyes (pupillary 
reaction, ophthalmoscopy, eye movements), oral mucosa, heart and pulses, lungs, abdomen 
(liver/spleen), kidneys, and neurological (symptom-directed and may include mental state, 
speech, gait/posture, arm swinging, facial movements, tongue, muscle wasting (power and tone), 
coordination, reflexes, and sensation). 
Height should be measured at Screening. Weight should be measured on the same scale at each 
visit. The Investigator must ensure that the scale is properly calibrated prior to study initiation.  
12.1.3 Vital Signs 
Vital signs include body temperature, systolic and diastolic blood pressure, pulse rate and 
respiration rate. Body temperature will only be recorded once daily. Blood pressure and pulse rate 
recordings will be made after the study patient has been at rest for ≥5 minutes in either a sitting 
or a semi-supine position. As part of vital signs, the subject’s weight should be measured. 
12.1.4 Clinical Laboratory Tests 
Hematology testing will include red blood cell count, erythrocyte mean corpuscular hemoglobin 
concentration (MCHC), erythrocyte mean corpuscular volume (MCV), hematocrit, hemoglobin, 
leukocyte count, and absolute counts of monocytes, neutrophils, basophils, eosinophils and 
platelets. Coagulation testing (prothrombin time [PT/INR]) will be performed at screening and Day 
154 only.  
Serum chemistry analyses will include glucose, calcium, albumin, total protein, sodium, 
potassium, bicarbonate, chloride, magnesium, blood urea nitrogen (BUN), creatinine, creatine 
kinase, alkaline phosphatase, ALT, AST, bilirubin, lipase, lactate dehydrogenase (LDH) and 
phosphorus.  
In instances where either the AST or ALT are 2x the ULN these tests will be repeated and 
documented as an unscheduled visit.  
Blood draws should occur within 1 hour of urine collection. 
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Urinalysis will include osmolality, creatinine, calcium, sodium, turbidity, color, specific gravity, pH, 
protein, glucose, ketones, bilirubin, blood, urobilinogen, nitrite, leukocytes, and microscopic 
particles. Urine should not be first morning void. Microscopic examination will be performed if 
urinalysis results are abnormal for bacteria, casts, epithelial cells, erythrocytes, or leukocytes. 
Urine should be collected within one hour of blood draws for hematology and chemistry panels. It 
should not be first morning void. Trace protein will be considered positive. 
12.1.5 Screening Laboratory Tests 
The following will be performed to confirm subject eligibility at screening: 
• 
Viral serology: hepatitis B antigen, anti-hepatitis C antibody and anti-HIV antibodies 
• 
Thyroid stimulating hormone (TSH) 
• 
Follicle-stimulating hormone (FSH) testing will be conducted in women who had their last 
natural menses less than 24 months prior to screening) and who are not surgically sterile 
• 
HbA1c will be conducted in known diabetics 
• 
Folate and B12 are optional at discretion of the investigator if there is suspicion of 
deficiency 
12.1.6 Pregnancy Tests 
A urine pregnancy test and FSH will be performed at screening to rule out existing pregnancy in 
women who had their last natural menses less than 24 months prior to screening and who are 
not surgically sterile. to document a postmenopausal state. Subjects may not enter or continue in 
the study if pregnant. Additionally, women with an FSH test that is inconsistent with a 
postmenopausal state may not participate in the study.  
12.1.7 12-lead Electrocardiogram  
ECGs will be recorded using a digital ECG to provide machine-generated interval measurements.  
12.1.8 MRI 
The imaging specialist at the study site’s MRI facility is responsible for determining if a patient is 
contraindicated from having this procedure. The following is a list of some common conditions 
that may preclude the patient from having MRI scans. However, this should not be used as a 
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substitute for local clinical standards of care. The ultimate decision to perform the MRI rests with 
the site radiologist, the investigator, and the standard set by the local IRB/IEC: 
• 
Subjects who have a history of claustrophobia 
• 
Subjects with a pacemaker, epicardial pacemaker wires, MRI-incompatible cardiac valve 
prostheses, and MRI-incompatible vascular clips less than 2 months old or MRI-
incompatible aneurysm clips of any age 
• 
Subjects with MRI-incompatible cochlear implants 
• 
Subjects with spinal nerve stimulators 
• 
Subjects with an infusion pump 
• 
Subjects with metallic fragments in the eyes/orbits or in the vicinity of the brain or major 
neurovascular structures of the body. Subjects with an employment history that involves 
exposure to welding, unless absence of metallic fragments is documented by X-ray 
examination as per institutional practice. Subjects who have shrapnel at any place in 
their body. 
In lieu of an MRI, a CT scan may be substituted for an MRI if subjects are unable to tolerate an 
MRI or an MRI is contraindicated for medical reasons. Any proposed CT scan must be 
discussed with and approved by the medical monitor on a case-by-case basis). 
12.2  Adverse Events  
12.2.1 Definitions  
Adverse Event  
An Adverse Event (AE) is any untoward medical occurrence in a subject or clinical investigation 
subject undergoing a study procedure or administration of a study drug. An AE can therefore be 
any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of the study drug, whether considered related to the 
study drug or not. 
Related Adverse Event  
A related AE is an AE with a causality rating of “possible” or “probable”. 
Not related Adverse Event  
A not related AE is an AE with a causality rating of “unlikely” or “unrelated”. 
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Laboratory Abnormality 
A laboratory abnormality is any clinically significant laboratory abnormality suggesting a disease 
or organ toxicity and which is of a severity requiring active management (i.e., changes of dose, 
discontinuation of drug, more frequent follow-up, medical treatment, or a diagnostic investigation). 
Laboratory abnormalities are also considered AEs, if clinically significant. 
Pretreatment Adverse Events  
A pretreatment AE is any AE occurring during the pretreatment period (between informed consent 
and initiation of a study drug).   
Post-study Adverse Event  
A post-study AE is an AE occurring up to 30 days after the treatment period. 
 
Treatment-emergent Adverse Events  
Treatment-emergent adverse events (TEAEs) are all AEs occurring during the treatment period 
or a pretreatment AE that worsens in intensity during the treatment period. 
Treatment Period 
The treatment period is the period during which a subject receives study drug (i.e., first dose 
through last dose). 
Serious Adverse Event 
A serious adverse event (SAE) is any untoward medical occurrence that results in death, is life-
threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results 
in persistent or significant disability/incapacity, is a congenital anomaly/birth defect observed in 
any offspring of the subject conceived during treatment with the study drug or is an important 
medical event. See Section 14 for more details on SAEs. 
12.2.2 Collection and Rating of Adverse Events  
During the course of the study (i.e., from the signing of the ICF through the Follow-up Visit) all 
AEs, irrespective of the relatedness to the study drug, will be collected and reported on the 
Adverse Event Report Form.  The seriousness criteria should not be confused with the intensity 
of the event.  In case of an SAE, a Serious Adverse Event Report Form must be completed and 
transmitted to the Sponsor or designee.   
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Overdoses and medication errors in the presence of clinical consequences should be recorded 
as AEs.  The clinical consequence should be reported as “[enter AE] due to overdose”. 
12.2.2.1 Onset Date 
The onset date is the date when the first sign(s) or symptom(s) were first noted. For example, if 
the AE is an abnormal laboratory test (such as “platelets low”), the onset date is the date when 
the sample was taken. If the subject was hospitalized for meningitis, and symptoms such as fever, 
headache and nausea started the day before the hospitalization, the onset date is the day 
symptoms presented versus day of hospitalization. 
12.2.2.2 Assessment of Intensity 
The intensity of each AE will be rated according to the following 3-point scale: 
• 
Mild:  
Awareness of signs or symptoms, but no disruption of usual activity. 
• 
Moderate:  
Event sufficient to affect usual activity (disturbing). 
• 
Severe:  Inability to work or perform usual activities (unacceptable). 
12.2.2.3 Relationship to Study Drug 
The causal relationship of the study drug to an AE will be rated according to the following 4-
point scale: 
• 
Unrelated: Clearly and incontrovertibly due only to extraneous causes and does not 
meet criteria listed under possible or probable. 
• 
Unlikely: Does not follow a reasonable temporal sequence from administration; may 
have been produced by the subject’s clinical state or by environmental factors or 
other therapies administered. 
• 
Possible:  Follows a reasonable temporal sequence from administration; may have 
been produced by the subject’s clinical state or by environmental factors or other 
therapies administered. 
• 
Probable:  Clear temporal association with improvement on cessation of study drug 
or reduction in dose.  Reappears upon re-challenge or follows a known pattern of 
response to the study drug. 
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12.2.2.4 Action Taken  
The action taken toward the study drug in response to an AE will be listed as one of the following:  
• 
None: No change in study drug dosage was made. 
• 
Reduced: Dose of study drug was reduced. 
• 
Discontinued: 
The study drug was permanently stopped. 
12.2.2.5 Outcome of Adverse Event  
The outcome of an AE will be recorded as one of the following:  
• 
Recovered: fully recovered or the condition has returned to the level observed at 
baseline. 
• 
Recovered with sequelae: resulted in persistent or significant disability or incapacity; 
the nature of the sequelae should be specified. 
• 
Not recovered 
• 
Death 
12.2.3 Adverse Event Follow-up 
Adverse events requiring therapy must be treated with recognized standards of medical care to 
protect the health and well-being of the subject. 
Any subject who has any AE (whether serious or non-serious) or clinically significant (in the 
Investigator’s opinion) abnormal laboratory test values will be evaluated by the Investigator or a 
monitoring physician and will be treated and followed up until the symptoms or values return to 
normal or acceptable levels, as judged by the Investigator and the Sponsor.  
Adverse events that are unresolved at end of study or upon early withdrawal will be tracked at 
least weekly by site staff until resolution, for 30 days, or until the subject is lost to follow-up 
(defined as failure to respond to three phone messages left on separate days and one certified 
letter requesting follow-up).   
Subjects will be instructed to inform site staff of any AEs occurring during the 30-day period after 
discharge or early withdrawal. 
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Any follow-up information available at the time of the subject’s end of study will be included in the 
clinical study report. 
Any SAE that is considered to be unexpected and related to the study drug occurring after the 
end of study should be forwarded to the Sponsor.  These cases will be handled and submitted as 
expedited reports but will not be included in the clinical study report. 
Note: Any SAE will be reported to NIH by the sponsor within 48 hours of the time when the 
Sponsor becomes aware of the event. 
13 Serious And Other Significant Adverse Events  
13.1 Definition of a Serious Adverse Event 
A serious adverse event is any untoward medical occurrence that: 
• 
Results in death. Death is not an event per se but rather an outcome. Note that any 
event resulting in a fatal outcome must be fully documented and reported, including 
deaths that occur within 30 days after treatment ends and irrespective of the causal 
relationship to the study drug. 
• 
Is life-threatening. Life-threatening refers to an AE in which the subject was at 
immediate risk of death at the time of the event. It does not refer to an event, which may 
have caused death, if it was more severe. 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization.  
Hospitalization means that the subject was admitted to hospital, or that existing 
hospitalization was extended as a result of an event. Hospitalization describes a period 
of at least 24 hours. Over-night stays for observation; stays at the emergency room or 
treatment on an outpatient basis do not constitute a hospitalization. However, medical 
judgment must always be exercised and, when in doubt, the case should be considered 
serious (i.e., if the case fulfills the criterion for a medically important event). 
Hospitalization for administrative or social purposes does not constitute an SAE. 
Hospital admissions and/or surgical operations planned before study inclusion are not 
considered AEs if the illness or disease existed before the subject were enrolled in the 
study, provided that the condition did not deteriorate during the study. 
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• 
Results in persistent or significant disability/incapacity. Disability/incapacity means 
a substantial disruption of a person’s ability to conduct normal life functions. If in doubt, 
the decision should be left to medical judgment by the Investigator. 
• 
Is a congenital anomaly/birth defect. Any congenital anomaly or birth defect observed 
in any offspring of the subject conceived during treatment with the study drug. 
• 
Is an important medical event. Important medical events are events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require intervention to prevent one of the other outcomes listed in the 
definition above. Examples of important medical events include AEs that suggest a 
significant hazard, contraindication or precaution, occurrence of malignancy or 
development of drug dependency or drug abuse. Medical and scientific judgment should 
be exercised in deciding whether events qualify as medically important. 
An AE caused by an overdose or medical error is considered serious if a criterion listed in the 
definitions above is fulfilled. 
The following are not considered SAEs: 
• 
A pre-existing condition that is present prior to or at the start of the study that did not 
worsen. 
• 
Hospitalizations for treatment which were elective or preplanned, for a pre-existing 
condition unrelated to the indication under study that did not worsen. 
• 
Admission to a hospital or other institution for general care, not associated with any 
deterioration in condition. 
13.1.1 Serious Adverse Event Reporting by the Investigator to the Sponsor 
Any SAE that occurs after a subject has entered the study, whether related to study drug or not, 
must be reported to the CRO immediately (within 24 hours) via e-mail at the address noted below. 
A completed Serious Adverse Event Report Form with as much detail as possible must be 
included with the email. The Investigator must report all SAEs occurring from the time the subject 
signs the ICF until 30 days after last treatment with the study drug. 
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Sponsor Representative and Contact Information for SAE Reporting: 
safety.fax@synteract.com 
13.1.2  Handling of Follow-up Information 
Follow-up information may be required, or additional information may be received by the Sponsor 
(e.g., evolution of the SAE, other signs or symptoms, final diagnosis, final outcome, hospital 
discharge summary, or autopsy report). The same procedures and timelines as for initial 
reporting, listed above, should be followed for any follow-up information. If necessary, the study 
site will be visited to collect additional information. 
Follow-up information is required on all SAEs until one of the following criteria is satisfied: 
• 
The final outcome of the case is known. 
• 
The event is resolved, or the medical condition of the subject is stabilized. 
• 
No further information is available. 
• 
Sponsor assessment has been finalized. 
13.2 Reporting and Follow-up of Pregnancy 
If an Investigator becomes aware of the pregnancy of a female subject, the Investigator must 
withdraw the subject from the study and follow the pregnancy until termination or until the child is 
1 month old.  Pregnancy in a study participant or in a partner of a study participant, occurring after 
randomization although is not an AE, it is considered an immediately reportable event and must 
be reported immediately by telephone and by faxing a completed Pregnancy Report to the 
Sponsor within 24 hours of knowledge of the event. The pregnancy will not be processed as an 
SAE; however, the Investigator should notify the Sponsor or the Sponsor’s agent of the outcome 
of the pregnancy by submitting a follow-up Pregnancy Report. Additionally, if the outcome of the 
pregnancy meets the criteria for immediate classification of an SAE (e.g., spontaneous or 
therapeutic abortion, stillbirth, neonatal death, or congenital anomaly), the Investigator will report 
the event by phone and by faxing a completed SAE Report Form to the Sponsor within 24 hours 
of knowledge of the event. 
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13.3 Expedited Reporting of Serious Adverse Events  
13.3.1 Responsibilities 
The Sponsor is responsible for ensuring the timely reporting of SAEs to Regulatory Authorities 
and all Investigators who participate in the clinical development program of the study drug. It is 
the responsibility of the Investigator to provide the Sponsor with the case information such that 
reporting timeline demands of applicable Regulatory Authorities can be met. 
13.3.2 Expedited Reporting 
All AEs that are serious, unexpected, and considered related to the study drug judged by either 
Sponsor or the Investigator require expedited reporting. All available information relevant to the 
evaluation of the SAE will be reported. Serious adverse events will be considered reportable 
regardless of whether or not the study drug was used in accordance with the provisions in the 
protocol. 
Adverse events which are serious, but expected, or those which are not associated with the study 
drug will only be subject to expedited reporting if they are required to be reported to an authority 
according to national requirements.  
In addition, any unanticipated serious adverse events (SAEs) that are ‘related’ will be reported by 
the sponsor to the United States National Institutes of Health within 48 hours of knowledge of the 
same. 
13.3.2.1 Timelines 
Fatal or life-threatening serious unexpected and related cases require rapid reporting.  Regulatory 
Authorities shall be notified as soon as possible but no later than 7 calendar days after first 
knowledge by the Sponsor representative, followed by as complete a report as possible within 8 
additional calendar days.   
Serious unexpected and related cases that are not fatal or life-threatening must be submitted as 
soon as possible, but no later than 15 calendar days after first knowledge by the Sponsor 
representative that the case meets the minimum criteria for expedited reporting. 
It is the responsibility of the Investigator to support Sponsor activities needed to meet the 
aforementioned timelines for Regulatory Authority reporting in the event of an SAE. 
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14 Statistical Methods 
14.1 General Overview of the Statistical Analysis Plan 
Descriptive statistical methods will be used to summarize the data from this study. Unless stated 
otherwise, the term “descriptive statistics” refers to number of subjects (n), mean, median, 
standard deviation (SD), minimum, and maximum for continuous data and frequencies and 
percentages for categorical data. Individual data for all enrolled subjects will be presented in 
data listings, sorted by dosing arm and subject. 
 
The statistical analyses will be conducted with the SAS® software package version 9.4 or 
higher. 
The remainder of this section is a summary of the planned statistical analyses for the efficacy 
and safety data collected in this protocol. Full details of these analyses will be included in the 
statistical analysis plan (SAP). The SAP will be developed and finalized before database lock 
and will include the subject populations for analyses, and procedures for accounting for missing 
data.   
 
14.2 Sample Size 
The sample size is not based on statistical considerations but was chosen to provide preliminary 
information on the safety and efficacy of CT1812 when administered according to this protocol. 
 
It should be noted that for the comparison of both active groups versus placebo a total sample 
size of 105 would have 80% power to detect a mean difference of 0.78 points in the change 
from baseline in MoCA score assuming a standard deviation of 1.32 points (PASS 2020: Two 
Sample T-Test, alpha=0.05). To account for potential dropouts, a sample size of 120 subjects 
(40 subjects per arm) is planned. 
14.3 Analysis Populations 
The populations for analysis will include the enrolled population, intent-to-treat (ITT) population, 
safety population, pharmacokinetic (PK) population, and the pharmacodynamic (PD) population. 
 
The enrolled population represents all subjects that signed the informed consent form. This 
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population is being used for presentation of subject disposition, as well as for all listings. 
 
The ITT population will include all subjects that were randomly assigned to study drug. Subjects 
in this population will be analyzed according to the treatment to which they were randomized, 
regardless of what treatment they received. All efficacy analyses will be based on this 
population and treatment assignment. 
  
The safety population includes all subjects in the ITT population who received at least one dose 
of study treatment. Subjects in this population will be analyzed according to the treatment they 
received, regardless of which treatment they were randomly assigned. All safety and tolerability 
analyses will be based on this population and treatment 
assignment. 
 
The PK population will include all subjects in the safety population who had at least 1 
quantifiable concentration of CT1812. 
 
The PD population will include all subjects in the safety population who had an exploratory 
biomarker evaluation. 
14.4 Data Analysis 
14.4.1 Initial Subject Characteristics 
Demographic data and baseline characteristics will be listed for each subject and summarized 
descriptively by treatment group. 
14.4.2 Safety Analyses 
Adverse events (AEs) will be assessed by the investigator for severity and will be coded for 
summarization using Medical Dictionary for Regulatory Activities (MedDRA® Version 24 or 
higher).  The occurrence of AEs will be summarized by treatment using MedDRA system organ 
classification, preferred terms, and severity. Separate summaries of AEs, serious AEs, AEs 
related to study drug, and AEs leading to study discontinuation will be summarized by Preferred 
Term and System Organ Class. 
Concomitant medications will be coded using WHO Drug Dictionary (enhanced) March 2021 or 
higher and summarized. 
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Laboratory measures will be summarized by treatment group and time-point both as absolute 
values and as change from baseline, with descriptive statistics summarizing each group and time 
point.  Similar presentation will be used for vital signs and for ECG interval measurements, and 
changes from pre-treatment baseline. 
Results from Columbia Suicide Severity Rating Scale (C-SSRS) will be listed. 
Results from physical exam findings will be listed. 
14.4.3 Efficacy Analyses 
Continuous efficacy endpoints will be summarized by treatment group and time-point using 
descriptive statistics as both absolute values and change from baseline. Differences between 
treatment groups will be assessed using a mixed model for repeated measures (MMRM) with 
treatment group, time-point, and a treatment group by time-point interaction as fixed effects, 
subject as a random effect, and baseline value as a covariate. The difference between the 
combined CT1812 group versus placebo at each time-point will be estimated based on the least 
square means (LSM) from the MMRM. The pairwise comparisons of each CT1812 group and 
placebo will be created in a similar manner. 
 
Each efficacy endpoint will be listed. 
14.4.4 Other Analyses 
Pharmacokinetic and exploratory biomarker analyses will be described in the SAP. 
15 MISSING, UNUSED AND SPURIOUS DATA  
No imputation will be applied for missing data. Only non-missing values will be used for analyses. 
16 STUDY MANAGEMENT 
16.1 Protocol Amendment and Protocol Deviation 
16.1.1 Protocol Amendment 
Administrative amendments to the protocol will be classed as amendment of typographical errors, 
clarifications of confusing wording, and other minor modifications including but not limited to 
name, address, and contact information changes that have no impact on the safety of the subject 
or the science of the study. Administrative amendments will be submitted to the Institutional 
Review Board (IRB) for information only. The Sponsor will ensure that acknowledgement is 
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received and filed. Otherwise, an amendment will be classed as a substantial amendment and 
will be submitted to the appropriate Regulatory Authorities and the IRB for approval. 
16.1.2 Protocol Deviations 
No deviations from the protocol are anticipated. Should a non-anticipated protocol deviation 
occur, the Sponsor must be informed as soon as possible. All deviations and the reasons for the 
deviation will be documented by the Investigator or designated staff. Reporting of protocol 
deviations to the IRB and in accordance with applicable Regulatory Authority mandates is an 
Investigator responsibility. 
16.1.3 Protocol Waivers 
Protocol waivers will not be granted by the Sponsor in this study. 
16.2 Ethics and Regulatory Aspects 
16.2.1 Ethical Conduct of the Study and Regulatory Guidelines 
To ensure the ethical conduct of this clinical study, each Investigator is expected to conduct the 
study in accordance with the protocol; the United States IND regulations specified under 21 CFR 
11, 50, 54, 56, and 312; the International Conference on Harmonisation (ICH) Harmonised 
Tripartite Guideline for Good Clinical Practice (GCP); and the Guidelines of the Declaration of 
Helsinki. The Investigator will conduct all aspects of the study in accordance with all national, 
state and local laws of applicable Regulatory Authorities.   
The responsibilities of the Sponsor, the Study Monitor and the Investigator will be as defined in 
the ICH GCP consolidated guideline, and applicable regulatory requirements in the country where 
the study takes place. The Investigator is responsible for adhering to the GCP responsibilities of 
Investigators, for dispensing the study drug in accordance with the approved protocol or a signed 
amendment, and for its secure storage and safe handling throughout the study. 
16.2.2 Institutional Review Board and Regulatory Approval 
The study protocol and any amendments will be reviewed by an Independent Review Board. The 
IRB will review the written subject information sheet and the Informed Consent Form (ICF), their 
updates (if any), and any written materials given to the subjects. A listing of the membership of 
the IRB consulted and the name of the committee chair(s) or IRB registry (accreditation) number 
will be documented within the Investigator File and Trial Master File of the Sponsor. 
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The Regulatory permission to perform the study must be obtained in accordance with applicable 
regulatory requirements. All ethics approvals must be obtained, and regulatory obligations met 
before a subject is exposed to any study-related procedure, including screening tests for eligibility. 
16.2.3 Subject and Caregiver Informed Consent 
Potential subjects and his/her caregiver will be informed about the study both verbally and in 
writing. Each subject and his/her caregiver will be provided with a written subject information sheet 
that has been approved by the IRB and will be given a reasonable time to consider the study and 
to ask any questions they have regarding the study. The caregiver will consent to providing 
information about the subject, managing drug administration, and attending all clinic visits. The 
written subject information sheet and ICF must be in a language that the subject can understand.  
Only the Investigator, a medically qualified Sub-investigator or a suitably qualified and trained 
authorized person may be involved in the informed consent process.  
The Investigator or their suitable designee will obtain a freely given, written consent from each 
subject and his/her caregiver after an appropriate explanation of the aims, methods, potential 
hazards, and any other aspects of the study which are relevant to the decision of the subject to 
participate. The Investigator will explain that the subject is completely free to refuse to enter the 
study or to withdraw from it at any time, without any consequences for their further care and 
without the need to justify.  
The ICF and caregiver consents must be signed and dated by the subject and caregiver before 
exposure to any study-related procedure, including screening tests for eligibility. The subject and 
caregiver will receive copies of the written subject information sheet and the ICF and caregiver 
consent form. 
Each subject will be informed that a Study Monitor, a Quality Assurance Auditor mandated by the 
Sponsor, or a Health Authority Inspector, in accordance with applicable regulatory requirements, 
may review his or her source records and health data. Data protection will be handled in 
compliance with national and local regulations. 
If new safety information becomes available and results in significant changes in the risk to benefit 
assessment, the written subject information sheet will be revised or updated where necessary.  
Under these circumstances, all subjects (including those already being treated) should be 
informed of the new information, given a copy of the revised form and allowed to reevaluate their 
consent to continue in the study. 
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16.3 End of Study and Regulatory Notification 
The study can be terminated in part or in whole at the discretion of the FDA, an applicable 
Regulatory Authority, or the Sponsor.   
At the end of the study, the IRBs and Regulatory Authorities will be notified by the Sponsor 
according to applicable Regulatory requirements. 
16.4 Data Protection and Confidentiality 
The confidentiality of records that could identify subjects should be protected, respecting the 
privacy and confidentiality rules in accordance with applicable regulatory requirement(s). 
16.5 Monitoring 
The study will be monitored to ensure that the study is conducted and documented properly 
according to the protocol, GCP, and all applicable regulatory requirements.  
On-site visits will be made at appropriate times during the study.  Study Monitors must have direct 
access to source documentation in order to check the consistency of the data recorded in the 
Case Report Forms (CRF). 
The Investigator will make available to the Study Monitor source documents, medical records, 
and source data necessary to complete CRFs. In addition, the Investigator will work closely with 
the Study Monitor as needed and provide them appropriate evidence that the conduct of the study 
is being done in accordance with applicable regulations and GCP guidelines. 
16.6 Quality Assurance and Quality Control 
The Sponsor or its designee will perform the quality assurance and quality control activities of this 
study; however, responsibility for the accuracy, completeness, and reliability of the study data 
presented to the Sponsor lies with the Principal or Qualified Investigator generating the data.   
Prior to the study initiation, the Sponsor will explain the protocol, Investigator’s Brochure, and 
CRFs to Investigators. In addition, the Study Monitor will be available to explain applicable 
regulations and to answer any questions regarding the conduct of the study. 
At its discretion, the Sponsor may conduct audits as part of the implementation of quality 
assurance to ensure that the study is being conducted in compliance with the protocol, Standard 
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Operating Procedures, GCP, and all applicable regulatory requirements. Audits will be 
independent of and separate from the routine monitoring and quality control functions. 
The study center may also be compelled to an inspection by a Regulatory Authority. 
16.7 Source Data 
Source data are defined as information in original records and certified copies of original records 
of clinical findings, observations, data, or other activities in a clinical study necessary for the 
reconstruction and evaluation of the study.   
Source documents are the original data, documents, and records. Examples include hospital 
records, laboratory reports, clinical and office charts, laboratory notes, memoranda, evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate copies, microfiches, photographic 
negatives, microfilm or magnetic media, x-rays, other radiographic depictions or displays, subject 
files, and records kept at the pharmacy, at the laboratories and at medico-technical departments 
involved in the clinical study. All source documents must be reviewed by the PI and the sponsor 
(or designee) for compliance with GCP. 
Study-specific data sheets may be used to document source information that would not normally 
be collected and documented in the routine management of the subject. Data sheets used for 
source documentation must be verified and signed by the Investigator or a delegated study site 
team member and must be stored and archived in the subject’s clinic records (preferably) or in 
the Investigator File. 
The Investigator will permit study-related monitoring, audit(s), IRB review(s), and regulatory 
inspection(s), with a direct access to all the required source documents and associated records. 
17 Data and Record Keeping 
17.1 Case Report Forms 
All data will be entered in a validated electronic data capture system using single data entry. 
Standard procedures (including following data review guidelines, manual clinical review based on 
subject profiles, computerized validation to produce queries, and maintenance of an audit file 
which includes all database modifications) will be followed to ensure accurate data.  
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During the study, a study monitor (CRA) will make site visits to review protocol compliance, 
compare eCRFs against individual subject’s medical records, assess drug accountability, and 
ensure that the study is being conducted according to pertinent regulatory requirements. 
Electronic CRF entries will be verified with source documentation. The review of medical records 
will be performed in a manner to ensure that subject confidentiality is maintained. Checking the 
eCRFs for completeness, clarity and cross checking with source documents is required to monitor 
the progress of the study. Direct access to source data is also required for inspections and audits 
and will be carried out giving due consideration to data protection and medical confidentiality. 
17.2 Record Keeping 
Study records and source documents need to be preserved for at least 15 years after the 
completion or discontinuation of/withdrawal from the study or 2 years after the last approval of a 
marketing application of CT1812 in an ICH region, whichever is the longest time period. The 
sponsor will be notified prior to the planned destruction of any study related source documents. 
18 Financing and Insurance 
Financial aspects of the study are addressed in a separate clinical study agreement. The 
Investigator is required to have adequate current insurance to cover claims for negligence and/or 
malpractice. The Sponsor will provide insurance coverage for the clinical study as required by 
national regulations. 
19 Use of Data and Publication Policy 
Both the use of data and the publication policy are detailed within the clinical study agreement. 
The Investigator should be aware that intellectual property rights (and related matters) generated 
by the Investigator and others performing the clinical study will be subject to the terms of a clinical 
study agreement that will be agreed between the Institution and the Sponsor or their designee. 
With respect to such rights, the Sponsor or their designee will solely own all right and interest in 
any materials, data and intellectual property rights developed by the Investigator and others 
performing the clinical study described in this protocol, subject to the terms of any such 
agreement. To facilitate such ownership, the Investigator will be required to assign all such 
inventions either to the Institution where the study is conducted or directly to the Sponsor or their 
designee, as will be set forth in the clinical study agreement. This agreement will not preclude the 
reporting of any required data to Regulatory Authorities.
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20 REFERENCES 
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dementia with Lewy bodies: a multicenter 1-year follow-up study. J Neural Transm (Vienna). 2016 
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Boeve A, Ferman TJ, Aakre J, St Louis E, Silber M, Machulda M, Fields J, Graff-Radford N, Mielke 
M, Geda Y, Jones D, Graff-Radford J, Knopman D, Petersen R, Boeve B. Excessive Daytime 
Sleepiness in Major Dementia Syndromes. Am J Alzheimers Dis Other Demen. 2019 
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Brott DA, Adler SA, Arani R, Lovick SC, Pinches M, Furlong ST. (2014) Characterization of renal 
biomarkers for use in clinical trials: biomarker evaluation in healthy volunteers. Drug Des Devel 
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Cummings JL. The Neuropsychiatric Inventory: Assessing psychopathology in dementia patients. 
Neurology 1997; 48 (Suppl. 6): S10-S16 
 
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Cummings, JL, Mega, M, Gray, K, Rosenberg-Thompson, S, Carusi, DA and Gornbein, J. (1994) 
The Neuropsychiatric Inventory: Comprehensive Assessment of Psychopathology in Dementia. 
Neurology, 44, 2308-2314. 
FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. 
Available at: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractio
nsLabeling/ucm093664.htm#4. Accessed April 26, 2016. 
Ferman T, Smith G, Dickson D, et al. Abnormal daytime sleepiness in dementia with Lewy bodies 
compared to Alzheimer’s disease using the Multiple Sleep Latency Test. Alzheimer Res 
Ther 2014;16:76. 
Ferman TJ, Smith GE, Boeve BF, Ivnik RJ, Petersen RC, Knopman D, Graff-Radford N, Parisi J, 
Dickson DW. DLB fluctuations: specific features that reliably differentiate DLB from AD and 
normal aging. Neurology. 2004 Jan 27;62(2):181-7. 
Flockhart DA. (2007) Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana 
University 
School 
of 
Medicine. 
“http://medicine.iupui.edu/clinpharm/ddis/clinical-table”  
Accessed [17 April, 2016]. 
Folstein MF, Folstein SE, McHugh PR. (1975) “Mini-mental state”. A practical method for grading 
the cognitive state of patients for the clinician. J Psychiatr Res. 12(13):189-198. 
Folstein, MF and Folstein, SE. User's Manual by Marshal F. Folstein, MD, Susan E. Folstein, MD, 
Travis White, PhD, and Melissa A. Messer, MHS (2010). Mini-Mental State Examination, 2nd 
Edition. PAR. 
 
Galasko D, Bennett D, Sano M, Ernesto C, Thomas R, Grundman M, Ferris S. An inventory to 
assess activities of daily living for clinical trials in Alzheimer's disease. The Alzheimer's Disease 
Cooperative Study Alzheimer Dis Assoc Disord. 1997;11 Suppl 2:S33-9. 
Gill DJ, Freshman A, Blender JA, Ravina B The Montreal cognitive assessment as a screening 
tool for cognitive impairment in Parkinson's disease. Mov Disord. 2008 May 15; 23(7):1043-1046. 
Goetz CG, Tilley BC, Shaftman SR, Stebbins GT, Fahn S, Martinez-Martin P, Poewe W, Sampaio 
C, Stern MB, Dodel R, Dubois B, Holloway R, Jankovic J, Kulisevsky J, Lang AE, Lees A, 
Leurgans S, LeWitt PA, Nyenhuis D, Olanow CW, Rascol O, Schrag A, Teresi JA, van Hilten JJ, 
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LaPelle N; Movement Disorder Society UPDRS Revision Task Force. Movement Disorder 
Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS): 
scale presentation and clinimetric testing results. Mov Disord. 2008 Nov 15;23(15):2129-70. 
Goetz CG, Poewe W, Rascol O, Sampaio C, Stebbins GT, Counsell C, Giladi N, Holloway RG, 
Moore CG, Wenning GK, Yahr MD, Seidl L (2004). "Movement Disorder Society Task Force 
Report on the Hoehn and Yahr Staging Scale: Status and Recommendations. The Movement 
Disorder Society Task Force on Rating Scales for Parkinson's Disease". Movement Disorders. 19 
(9): 1020–1028. 
 
Goldman JG, Forsberg LK, Boeve BF, Armstrong MJ, Irwin DJ, Ferman TJ, Galasko D, Galvin 
JE, Kaufer D, Leverenz J, Lippa CF, Marder K, Abler V, Biglan K, Irizarry M, Keller B, Munsie L, 
Nakagawa M, Taylor A, Graham T: Challenges and opportunities for improving the landscape for 
Lewy body dementia clinical trials. Alzheimers Res Ther 2020; 12:137. 
Hsieh H, Boehm J, Sato C, Iwatsubo T, Tomita T, Sisodia S, Malinow. (2006) AMPAR Removal 
Underlies Ab-Induced Synaptic Depression and Dendritic Spine Loss. Neuron 52:831 – 843. 
Izzo NJ, Staniszewski A, To L, Fa M, Teich AF, Saeed F, Wostein H, Walko T, Vaswani A, Wardius 
M, Syed Z, Ravenscroft J, Mozzoni K, Silky C, Rehak C, Yurko R, Finn P, Look G, Rishton G, 
Safferstein H, Miller M, Johanson C, Stopa E, Windisch M, Hutter-Paier B, Shamloo M, Arancio 
O, LeVine H, Catalano SM. (2014a) Alzheimer’s therapeutics targeting Amyloid beta 1-42 
oligomers I: Abeta 42 oligomer binding to specific neuronal receptors is displaced by drug 
candidates that improve cognitive deficits. PLoS ONE 9(11):e0111898. 
Izzo NJ, Xu J, Zeng C, Kirk MJ, Mozzoni K, Silky C, Rehak C, Yurko R, Look G, Rishton G, 
Safferstein H, Cruchaga C, Goate A, Cahill MA, Arancio O, Mach RH, Craven R, Head E, LeVine 
H, Spires-Jones TL, Catalano SM. (2014b) Alzheimer’s therapeutics targeting Amyloid beta 1-42 
oligomers II: sigma-2/PGRMC1 receptors mediate Abeta 42 oligomer binding and synaptotoxicity. 
PLoS ONE;9(11):e0111899. 
Johns M, A new method for measuring daytime sleepiness: the Epworth Sleepiness 
Scale. Sleep 1991;14:540–545. 
 
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Johns MW, Hocking B.  Daytime sleepiness and sleep habits of Australian workers.  Sleep 1997: 
20(10):844-949. 
Lacor PN, Buniel MC, Furlow PW, Sanz Clemente A, Velasco PT, Wood M, Viola KL, Klein WL. 
(2007) A Oligomer-Induced Aberrations in Synapse Composition, Shape, and Density Provide a 
Molecular Basis for Loss of Connectivity in Alzheimer’s Disease. J Neurosci. 27(4):796 – 807. 
McKeith IG, Boeve BF, Dickson DW, Halliday G, Taylor JP, Weintraub D, Aarsland D, Galvin J, 
Attems J, Ballard CG, Bayston A, Beach TG, Blanc F, Bohnen N, Bonanni L, Bras J, Brundin P, 
Burn D, Chen-Plotkin A, Duda JE, El-Agnaf O, Feldman H, Ferman TJ, Ffytche D, Fujishiro H, 
Galasko D, Goldman JG, Gomperts SN, Graff-Radford NR, Honig LS, Iranzo A, Kantarci K, Kaufer 
D, Kukull W, Lee VMY, Leverenz JB, Lewis S, Lippa C, Lunde A, Masellis M, Masliah E, McLean 
P, Mollenhauer B, Montine TJ, Moreno E, Mori E, Murray M, O'Brien JT, Orimo S, Postuma RB, 
Ramaswamy S, Ross OA, Salmon DP, Singleton A, Taylor A, Thomas A, Tiraboschi P, Toledo 
JB, Trojanowski JQ, Tsuang D, Walker Z, Yamada M, Kosaka K. Diagnosis and management of 
dementia with Lewy bodies: Fourth consensus report of the DLB Consortium. Neurology. 2017 
Jul 4;89(1):88-100. 
Nasreddine ZS, Phillips NA, Bédirian V, Charbonneau S, Whitehead V, Collin I, Cummings JL, 
Chertkow H The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive 
impairment. J Am Geriatr Soc. 2005 Apr; 53(4):695-9. 
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, Currier GW, Melvin GA, 
Greenhill L, Shen S, Mann JJ.  (2011) The Columbia-Suicide Severity Rating Scale: initial validity 
and internal consistency findings from three multisite studies with adolescents and adults. Am J 
Psychiatry. 168(12):1266 – 1277. 
Schneider LS, Olin JT, Doody RS, Clark CM, Morris JC, Reisberg B, Schmitt FA, Grundman 
M, Thomas RG, Ferris SH. Validity and reliability of the Alzheimer's Disease Cooperative Study-
Clinical Global Impression of Change. The Alzheimer's Disease Cooperative Study. Alzheimer 
Dis Assoc Disord. 1997;11 Suppl 2:S22-S32.  
Sheikh JI, Yesavage JA. Geriatric Depression Scale (GDS): recent evidence and development of 
a shorter version. In: Brink TL, ed. Clinical Gerontology: A Guide to Assessment and Intervention. 
New York, NY: The Haworth Press; 1986:165-173. 
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Simpson PM, Surmon DJ, Wesnes KA, Wilcock GK (February 1991). "The Cognitive Drug 
Research 
Computerized 
Assessment 
System 
for 
Demented 
Patients: 
A 
Validated 
Study". International Journal of Geriatric Psychiatry. 6 (2): 95–102.  
United States Food and Drug Administration. Guidance for Industry. Suicidal Ideation and 
Behavior:  Prospective Assessment of Occurrence in Clinical Trials [draft guidance], August 2012. 
Available at: http://www.fda.gov/downloads/Drugs/Guidances/UCM225130.pdf  Accessed 
February 4, 2013. 
Walker MP, Ayre GA, Cummings JL, Wesnes K, McKeith IG, O'Brien JT, Ballard CG. The Clinician 
Assessment of Fluctuation and the One Day Fluctuation Assessment Scale. Two methods to 
assess fluctuating confusion in dementia. Br J Psychiatry. 2000 Sep;177:252-6. 
 
Walker MP, Ayre GA, Cummings JL, Wesnes K, McKeith IG, O'Brien JT, Ballard CG. Quantifying 
fluctuation in dementia with Lewy bodies, Alzheimer's disease, and vascular dementia. 
Neurology. 2000 Apr 25;54(8):1616-25 
 
Wang CS, Pai MC, Chen PL, Hou NT, Chien PF, Huang YC Montreal Cognitive Assessment and 
Mini-Mental State Examination performance in patients with mild-to-moderate dementia with 
Lewy bodies, Alzheimer's disease, and normal subjects in Taiwan. Int Psychogeriatr. 2013 Nov; 
25(11):1839-48. 
 
Wesnes, K.A.; McKeith, I.G.; Ferrara, R.; Emre, M.; Del Ser, T.; Spano, P.F.; Cicin-Sain, A.; 
Anand, R.; Spiegel, R. (March 2002). "Effects of Rivastigmine on Cognitive Function in Dementia 
with Lewy Bodies: A Randomised Placebo-Controlled International Study Using the Cognitive 
Drug Research Computerised Assessment System". Dementia and Geriatric Cognitive 
Disorders. 13 (3): 183–192. 
 
Wesnes, K. A., Aarsland, D., Ballard, C., & Londos, E. (2014). Memantine improves attention and 
episodic memory in Parkinson's disease dementia and dementia with Lewy bodies. International 
Journal of Geriatric Psychiatry, 30(1), 48-54. https://doi.org/10.1002/gps.4109 
 
 
 
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21 Appendices 
Appendix A - Prohibited Medications 
Appendix B - Key Criteria from Diagnosis and management of dementia with Lewy bodies: Fourth 
consensus report of the DLB Consortium. 
 
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Appendix A – Prohibited Medications  
The following medications are restricted within 4 weeks of screening visit and during the 
course of the study. Exceptions to the list of excluded medications may be made on a case‐by‐
case basis if discussed and approved by the medical monitor in advance. 
 
• 
Antipsychotic agents with the exception of atypical antipsychotic agents e.g., quetiapine and 
pimavanserin (see exclusion criteria and concomitant medications sections) 
• 
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: 
 At the discretion of the investigator, low dose lorazepam or another anxiolytic may be 
administered as per local standard of care prior to MRI scan or optional lumbar puncture. 
At the discretion of the investigator. Note neurocognitive testing should not be done 
within 24 hours of administration of conscious sedation. 
• 
Nootropic drugs (except stable doses of acetylcholinesterase inhibitors or  memantine), e.g., 
Gingko biloba extract. 
• 
Moderate to strong inhibitors or inducers of CYP3A4. See the table below for a complete list 
of restricted medications. 
• 
All hormonal contraceptives and hormone replacement therapies (oral, injectable, 
transdermal or implanted) 
• 
Calcium channel blockers (only diltiazem and verapamil are excluded) 
• 
Coumadin® or other anticoagulant medications (Prohibited only for subjects participating in 
optional lumbar puncture) 
• 
Digoxin 
• 
Inability to separate dosing by at least 6 hours (before or after) of CT1812 from subject 
medications which are sensitive or narrow therapeutic index substrates of CYP3A4, or 
substrates of P‐glycoprotein (P‐gp); Loperamide, Vinblastine or Talinolol. See Section 9.3.1 
for handling of Paxlovid ™ administration for COVID infection during the course of study. 
• 
Any prior exposure to immunomodulators, anti Aβ vaccines, anti Aβ passive 
immunotherapies for (e.g monoclonal antibodies) and/or exposure to BACE inhibitors within 
the past 30 days. 
 
 
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Below is a partial list of specific medications excluded unless otherwise noted. This list may 
not be all-inclusive for specific categories of medications. Check with the Medical 
Monitor if there are questions. 
 
Barbiturates 
 
Benzylbutylbarbiturate 
Butalbital 
Amobarbital 
Pentobarbital 
Secobarbital 
Sodium thiopental 
Phenobarbital 
 
Benzodiazepines 
 
Diazepam 
Estazolam 
Flunitrazepam 
Lorazepam 
Midazolam 
Nitrazepam 
Oxazepam 
Triazolam 
Temazepam 
Chlordiazepoxide 
Alprazolam 
Clobazam 
Clorazepate 
Etizolam 
 
Nonbenzodiazepine 
Hypnotics 
 
Eszopiclone 
Zaleplon 
Zolpidem 
Zopiclone 
 
Opioids 
 
Tramadol 
Tapentadol 
Morphine 
Hydromorphone 
Oxymorphone 
Oxycodone 
Hydrocodone 
Methadone 
Propoxyphene 
Meperidine 
Fentanyl 
Codeine 
Carfentanil 
 
Antipsychotics  
 
Olanzapine 
Clozapine 
Thiothixene 
Haloperidol 
Fluphenazine 
Prochlorperazine 
Trifluoperazine 
Loxapine 
Asenapine 
 
Other 
 
Glutethimide 
sodium oxybate (Xyrem®)  
 
First Generation 
Antihistamines 
 
Should not be used within 24 
hours of cognitive testing 
Diphenhydramine 
Dimenhydrinate 
Doxylamine 
Promethazine 
Hydroxyzine 
Brompheniramine 
Chlorpheniramine 
 
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3A4,5,7 
INHIBITORS 
3A4,5,7 
INDUCERS 
CYP3A Substrates with narrow therapeutic 
range 
HIV Antivirals: 
indinavir 
nelfinavir 
ritonavir 
 
clarithromycin 
itraconazole 
ketoconazole 
nefazodone 
erythromycin 
grapefruit juice 
verapamil 
 
suboxone 
diltiazem 
 
Carbamazepine 
efavirenz 
nevaripine 
phenobarbital 
phenytoin 
pioglitazone 
rifabutin 
rifampin 
St. John’s Wort 
troglitazone 
alfentanil 
 astemizole 
 cisapride 
 cyclosporine 
 dihydroergotamine 
 ergotamine 
 fentanyl 
 pimozide 
 quinidine 
 sirolimus 
 tacrolimus 
 terfenadine 
 
Sensitive P-gp Substrate 
Digoxin 
 
 
 
From:  Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana 
University School of Medicine (2007). "http://medicine.iupui.edu/clinpharm/ddis/clinical-table”  
Accessed [17 April, 2016]. 
 
 
 
 
 
 
 
 
 
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Appendix B – Key Criteria from Diagnosis and Management 
of Dementia with Lewy Bodies: Fourth consensus report of 
the DLB Consortium.  
 
Probable DLB can be diagnosed if: 
a. Two or more core clinical features of DLB are present, with or without the presence of 
indicative biomarkers, or 
b. Only one core clinical feature is present, but with one or more indicative biomarkers. 
 
Core clinical features (The first 3 typically occur early and may persist throughout the course.) 
• 
Fluctuating cognition with pronounced variations in attention and alertness. 
• 
Recurrent visual hallucinations that are typically well formed and detailed. 
• 
REM sleep behavior disorder, which may precede cognitive decline. 
• 
One or more spontaneous cardinal features of parkinsonism: these are bradykinesia 
(defined as slowness of movement and decrement in amplitude or speed), rest tremor, 
or rigidity. 
 
Indicative biomarkers 
• 
Reduced dopamine transporter uptake in basal ganglia demonstrated by SPECT or 
PET.  
• 
Abnormal (low uptake) 123iodine-MIBG myocardial scintigraphy. 
• 
Polysomnographic confirmation of REM sleep without atonia. 
 
 
McKeith IG et al. Diagnosis and management of dementia with Lewy bodies: Fourth consensus 
report of the DLB Consortium. Neurology. 2017 Jul 4;89(1):88-100 
 
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