Clinical trial NCT05225389
Conditions: Alzheimer Disease
Sponsor: Cognition Therapeutics
Start date: 2021-12-31; Completion date: 2022-01-24
Enrollment: 8 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Open-label, single-dose study to assess the absorption, metabolism, excretion and mass balance of \[C14\] CT1812

Detailed description:
Open-label, single-dose study to assess the absorption, metabolism, excretion and mass balance of \[C14\] CT1812 in 8 healthy male subjects

Subjects will be screened 28-days prior to dosing to determine eligibility.

Eligible subjects will be admitted to the clinical research unit (CRU) on Day -1. On Day 1, subjects will receive a single dose of CT1812 with a microtracer dose of \[14C\] CT1812. Whole blood, plasma, urine and fecal samples will be collection during the confinement period. Safety will be monitored throughout the study by repeated clinical and laboratory evaluations.

Subjects will be and discharged from the CRU following completion of procedures 168 hours post dose (Day 8)

Arms: arm 1: Investigational Drug
Interventions: intervention 1: 300 mg [C14] CT1812
Intervention descriptions: intervention 1: Single dose of 300 mg CT1812 with microtracer dose of \[C14\]

Protocol documents:
Prot_000.pdf: 
 
 
     Cognition Therapeutics, Inc. 
 
 
2500 Westchester Avenue Suite 220 
Purchase, NY 10577 
 
 
412-481-2210 
 
 
 
  
Protocol COG0108  
  
Official Title: A Phase 1, Open-Label Study to Assess the 
Absorption, Metabolism, Excretion, and Mass Balance of a 
Single Oral Dose of [14C]-CT1812 in Healthy Adult Male 
Subjects  
  
ClinicalTrials.gov ID (NCT number): NCT05225389  
  
Document Date: 15 December 2021  
  
Document: Redacted Protocol  
 


Page 1 
Clinical Protocol 
A Phase 1, Open-Label Study to Assess the Absorption, Metabolism, Excretion, and 
Mass Balance of a Single Oral Dose of [14C]-CT1812 in Healthy Adult Male Subjects 
Celerion Project No.: CA35306  
Sponsor Project No.: COG0108 
Good Clinical Practices (GCP) Statement 
This study is to be performed in full compliance with the protocol, GCP, and applicable 
regulatory requirements. All required study documentation will be archived as required by 
regulatory authorities. 
Confidentiality Statement 
This document is confidential. It contains proprietary information of Cognition 
Therapeutics, Inc. and/or Celerion. Any viewing or disclosure of such information that is 
not authorized in writing by Cognition Therapeutics, Inc. and/or Celerion is strictly 
prohibited. Such information may be used solely for the purpose of reviewing or 
performing this study. 
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2 
PRINCIPAL INVESTIGATOR AND SPONSOR – SIGNATORIES 
A Phase 1, Open-Label Study to Assess the Absorption, Metabolism, Excretion, and 
Mass Balance of a Single Oral Dose of [14C]-CT1812 in Healthy Adult Male Subjects 
CELERION CLINICAL SITE AND PRINCIPAL INVESTIGATOR: 
 
 
Signature:  
Date: _________________ 
PI’s name:_______________________ 
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Signature Page for VV-57813 v2.0
Reason for signing: Approve
gator
Date of signature: 17-Dec-2021 14:05:21 GMT+0000
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4 
TABLE OF CONTENTS 
1 PROTOCOL REVISION HISTORY ............................................................................. 2 
2 PRINCIPAL INVESTIGATOR AND SPONSOR – SIGNATORIES ......................... 3 
3 ADDITIONAL KEY CONTACTS FOR THE STUDY ................................................ 5 
4 TABLE OF CONTENTS ................................................................................................. 7 
5 SYNOPSIS ....................................................................................................................... 10 
6 STUDY EVENTS FLOW CHART ............................................................................... 13 
7 ABBREVIATIONS ......................................................................................................... 15 
8 INTRODUCTION........................................................................................................... 17 
8.1 
Background ............................................................................................................. 17 
8.1.1 
Nonclinical ................................................................................................ 17 
8.1.2 
Clinical ...................................................................................................... 20 
8.2 
Rationale .................................................................................................................. 22 
8.2.1 
Rationale for this Study and Study Design ............................................... 22 
8.2.2 
Rationale for the Dose Selection............................................................... 22 
8.3 
Risks and/or Benefits to Subjects ............................................................................ 23 
9 OBJECTIVES AND ENDPOINTS ............................................................................... 24 
10 STUDY DESIGN ............................................................................................................. 26 
10.1 Overall Study Design and Plan ............................................................................... 26 
10.1.1 
Confinement and Follow-Up .................................................................... 26 
10.1.2 
End of Study Definition ............................................................................ 26 
11 STUDY POPULATION ................................................................................................. 27 
11.1 Inclusion Criteria ..................................................................................................... 27 
11.2 Exclusion Criteria .................................................................................................... 27 
11.3 Early Termination of Subjects from the Study ........................................................ 29 
11.4 Lifestyle Considerations .......................................................................................... 30 
11.4.1 
Medications and Supplements Restrictions .............................................. 30 
11.4.2 
Meals and Dietary Restrictions ................................................................. 30 
11.4.2.1 Meals ........................................................................................ 30 
11.4.2.2 Dietary Restrictions .................................................................. 30 
11.4.3 
Caffeine, Alcohol, and Tobacco Restrictions ........................................... 31 
11.4.4 
Activity Restrictions ................................................................................. 31 
11.4.5 
Contraception Requirements ..................................................................... 31 
11.4.5.1 Guidance for Subjects .............................................................. 31 
12 TREATMENTS............................................................................................................... 32 
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12.1 Treatments Administered ........................................................................................ 32 
12.2 Dose Modification ................................................................................................... 32 
12.3 Method of Treatment Assignment ........................................................................... 32 
12.4 Blinding ................................................................................................................... 32 
12.5 Treatment Compliance ............................................................................................ 32 
13 STUDY ASSESSMENTS AND PROCEDURES ......................................................... 33 
13.1 Screening ................................................................................................................. 33 
13.2 Safety Assessments ................................................................................................. 33 
13.2.1 
Physical Examination................................................................................ 33 
13.2.2 
Standard Vital Signs ................................................................................. 33 
13.2.3 
ECG Monitoring ....................................................................................... 34 
13.2.4 
Ophthalmic Examinations ......................................................................... 34 
13.2.5 
Body Weight ............................................................................................. 34 
13.2.6 
Columbia Suicide Severity Rating Scale .................................................. 34 
13.2.7 
Clinical Laboratory Tests .......................................................................... 35 
13.2.8 
Adverse Events ......................................................................................... 36 
13.2.8.1 Adverse Event Definition ......................................................... 36 
13.2.8.2 Monitoring ............................................................................... 36 
13.2.8.3 Reporting .................................................................................. 36 
13.2.8.4 Serious Adverse Event ............................................................. 37 
13.3 Pharmacokinetic Assessments ................................................................................. 38 
13.3.1 
Blood Sampling and Processing ............................................................... 38 
13.3.2 
Pharmacokinetic Parameters ..................................................................... 38 
13.3.3 
Whole Blood to Plasma Partitioning Ratio ............................................... 39 
13.3.4 
Urine Sampling and Processing ................................................................ 39 
13.3.5 
Urine Pharmacokinetic Parameters ........................................................... 40 
13.3.6 
Fecal Sampling and Processing ................................................................ 40 
13.3.7 
Fecal Pharmacokinetic Parameters ........................................................... 40 
13.3.8 
Emesis ....................................................................................................... 41 
13.3.9 
Future Research ........................................................................................ 41 
13.3.10 Analytical Method .................................................................................... 41 
13.4 Blood Volume Drawn for Study Assessments ........................................................ 42 
14 STATISTICAL CONSIDERATIONS .......................................................................... 43 
14.1 Sample Size Determination ..................................................................................... 43 
14.2 Population for Analyses .......................................................................................... 43 
14.3 Statistical Analyses ................................................................................................. 43 
14.3.1 
Pharmacokinetic Analyses ........................................................................ 43 
14.3.1.1 Descriptive Statistics ................................................................ 43 
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14.3.1.2 Mass Balance ........................................................................... 43 
14.3.1.3 Metabolite Profiling ................................................................. 44 
14.3.1.4 Whole Blood and Plasma Partitioning Ratio ........................... 44 
14.3.2 
Safety Analyses ......................................................................................... 44 
15 STUDY ADMINISTRATION ....................................................................................... 45 
15.1 Ethics ....................................................................................................................... 45 
15.1.1 
Ethical Conduct of the Study .................................................................... 45 
15.1.2 
Subject Information and Consent.............................................................. 45 
15.1.3 
Confidentiality .......................................................................................... 45 
15.2 Termination of the Study ......................................................................................... 46 
15.3 Data Quality Assurance ........................................................................................... 46 
15.4 Direct Access to Source Data/Documents .............................................................. 46 
15.5 Drug Supplies, Packaging and Labeling ................................................................. 46 
15.6 Data Handling and Record Keeping ........................................................................ 47 
15.7 Report Format ......................................................................................................... 47 
15.8 Publication Policy ................................................................................................... 47 
16 REFERENCES ................................................................................................................ 48 
 
LIST OF TABLES 
Table 1: 
Blood Volume during the Study .................................................................... 42 
 
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5 
SYNOPSIS 
Compound: 
CT1812 
Clinical Indication: 
Alzheimer’s Disease (AD) dementia or prodromal mild cognitive 
impairment (MCI) due to AD 
Study Phase and 
Type: 
Phase 1 – absorption, metabolism, excretion, and mass balance study  
Study Objectives: 
Primary objectives: 
• To determine the route(s) of elimination and the overall mass 
balance of CT1812 following a single oral dose of 
[14C]-CT1812 administered in healthy adult male subjects. 
• To quantitate total radioactivity (TRA) concentration 
equivalents in whole blood, plasma, urine, and feces 
following a single oral dose of [14C]-CT1812 administered in 
healthy adult male subjects. 
• To characterize the PK profile of CT1812 and its metabolite, 
M6, in plasma following a single oral dose of [14C]-CT1812 
administered in healthy adult male subjects. 
• To characterize the metabolite profile of CT1812 in plasma, 
urine, and feces following a single oral dose of [14C]-CT1812 
in healthy adult male subjects and identify the chemical 
identity of each metabolite accounting for more than 10% of 
circulating TRA. 
Secondary objectives: 
• 
 
 
 
 
Summary of Study 
Design: 
This is an open-label, single-dose study to assess the absorption, 
metabolism, excretion, and mass balance for [14C]-CT1812. 
Subjects will be admitted to the 
 on Day -1 and discharged from 
the 
following completion of 168 hours postdose procedures 
(Day 8). 
On Day 1, subjects will receive a single oral dose of 300 mg CT1812 
(2 capsules) with a microtracer dose of ~1 μCi [14C]-CT1812 
(1 capsule). Whole blood, plasma, urine, and fecal samples will be 
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• TRA concentration equivalents
 
 
• CT1218 and M6 concentrations in plasma 
 
 
• Ratio of plasma CT1812 to TRA fo
 
. 
Metabolite profiling: 
CT1812 metabolite profiling will be performed on plasma, urine, and 
fecal samples. The percent of dose represented by each of the 
metabolites, if any, will be calculated using the radioactive 
concentration equivalent data combined with the metabolite profiling 
data. The percentage of each identified metabolite, if any, to TRA in 
the plasma will be estimated based on plasma metabolite profiling 
data. Metabolites accounting for more than 10% of circulating TRA 
will be identified. 
Whole blood to plasma partitioning ratio: 
The percentage of TRA in whole blood relative to plasma will be 
estimated at each time-matched determination of TRA in whole 
blood and plasma. 
Safety: 
Safety will be monitored through AEs, 12-lead electrocardiograms 
(ECGs), vital sign measurements, clinical laboratory tests, physical 
examinations, ophthalmic examinations, and Columbia-Suicide 
Severity Rating Scale (C-SSRS). AEs will be tabulated and summary 
statistics for the 12-lead ECGs, vital signs, and clinical laboratory 
tests may be computed and provided, as deemed clinically 
appropriate. 
 
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7 
ABBREVIATIONS 
Pharmacokinetic parameter abbreviations and definitions may be found in Sections 13.3.2, 
13.3.5, and 13.3.7  
 
µCi 
Microcurie 
Abeta 
Beta amyloid 
AD 
Alzheimer’s Disease 
AE 
Adverse event 
AMS 
Accelerator mass spectrometry 
BMI 
Body mass index 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CFR 
Code of Federal Regulations 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration  
CNS 
Central nervous system 
COVID-19 
Coronavirus Disease-2019 
CRF 
Case report form 
 
 
CSF 
Cerebrospinal fluid 
%CV 
Coefficient of variation 
CYP 
Cytochrome P450 
ECG 
Electrocardiogram 
EDTRS 
Early Treatment Diabetic Retinopathy Study 
F 
Absolute bioavailability 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HPBCD 
Hydroxypropyl-β-cyclodextrin  
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
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ICH 
International Council for Harmonisation 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IV 
Intravenous  
KRBC/PL 
Ration of partitioning between red blood cells and plasma 
LLOQ 
Lower level of quantitation 
MAD 
Multiple ascending dose 
MCI 
Mild cognitive impairment 
n 
Sample size 
No. 
Number 
P-gp 
P-glycoprotein 
PI 
Principal Investigator 
PK 
Pharmacokinetic(s) 
PO 
Per os; oral 
QA 
Quality Assurance 
QD 
Once daily 
QTcF 
Corrected value of the interval between the Q and T waves on the 
electrocardiogram tracing, corrected QT interval by Fredericia. 
SAD 
Single ascending dose 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SEDDS 
Self-emulsifying drug delivery system 
TEAE 
Treatment-emergent adverse events 
TRA 
Total radioactivity 
US 
United States 
USA 
United States of America 
 
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8 
INTRODUCTION 
8.1 
Background  
CT1812 is an oral formulation in current development for the treatment of Alzheimer’s 
Disease (AD) dementia and Mild cognitive impairment (MCI) due to AD. Cognition 
Therapeutics, Inc., has discovered that oligomeric forms of the beta amyloid 1-42 (Abeta) 
protein binds specifically and reversibly to a single, saturable receptor site on neuronal 
synapses (Izzo 2014a; Cahill et al, 2016) and that brain penetrant small molecules that act as 
antagonists at the sigma-2 receptor can both prevent oligomer binding in vitro and displace 
bound oligomers from these receptor sites and stop synapse loss in vitro. Currently, there are 
no approved products for the treatment of MCI or established AD that function by blocking 
the binding and pathological activity of soluble Abeta oligomers. CT1812 is a brain penetrant 
drug designed to selectively target and displace the oligomeric form of Abeta (Abeta 
oligomers) bound to neuronal receptors at synapses by a new and differentiated mechanism 
of action. CT1812 not only prevents and displaces binding of amyloid-beta oligomers to 
neuronal synapses, but was shown to prevent and restore Abeta oligomer-induced synapse 
loss and reverses downstream alterations in neuronal trafficking in cultured rat neurons. 
8.1.1 
Nonclinical  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
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8.1.2 
Clinical 
Phase I clinical trial for single ascending dose (SAD) and multiple ascending dose (MAD) 
studies have been completed in healthy subjects (study number COG0101). This double-blind, 
placebo controlled, ascending dose, multi-cohort trial included a food effect arm at the 90 mg 
dose. 
Pharmacokinetics 
In the SAD part, each cohort consisted of 6 subjects who received a single dose of CT1812 and 
2 subjects who received matching placebo. Following single-dose administration (10 mg, 
30 mg, 90 mg [fed and fasted], 180 mg, 450 mg, and 1120 mg), Tmax was reached in 60 to 
90 minutes. The median t½ ranged from 11.1 to 14.0 hours (coefficient of variance [%CV] 
from 14% to 39%) across the dose groups with no dose dependence. Individual t½ ranged 
from 7.1 to 19.3 hours. Plasma exposure (AUCinf) and Cmax were approximately dose 
proportional across 2 orders of magnitude. No appreciable differences in plasma AUC or 
Cmax were observed between fed and fasted cohorts given a 90 mg oral dose. No gender 
differences were detected. 
In the MAD part, each cohort consisted of 8 subjects who received CT1812 and 2 subjects who 
received matching placebo once daily (QD) for up to 14 days. Following multiple-dose 
administration (280 mg and 560 mg [younger cohorts] and 560 mg [older cohort]), PK 
profiling was performed on samples drawn from participants on Day 3 and Day 14 of dosing. 
Tmax ranged from 0.5 to 4.0 hours with the median Tmax for each cohort ranging from 0.88 
to 2.0 hours. The t½ ranged from 8.93 to 12.3 hours with no linear correlation with dose. 
Individual t½ ranged from 6.14 to 21.7 hours. Plasma exposure (AUC0-24,) and Cmax were 
approximately dose-proportional and showed modest accumulation compared to QD dosing 
in the SAD part. The healthy elderly subjects dosed with 560 mg of CT1812 for 14 days 
demonstrated mean plasma concentrations of CT1812 between that of the 560 mg and the 
840 mg doses in healthy young subjects. Mean Cmax was 31% above, Tmax similar, and 
AUC0-24 was 58% above the 560 mg dose parameters in normal healthy young subjects. 
Cerebrospinal fluid (CSF) was drawn from participants in the 560 mg and 840 mg cohorts 
23 hours after dosing on Days 7, 8, or 9 for determination of CT1812 concentrations. 
Subjects dosed with 560 mg had a mean (± standard deviation) CSF concentration of 8.01 
(4.26) ng/mL. Subjects in the 840 mg cohort had a mean CSF concentration of 23.3 ng/mL. 
These results indicate CNS penetration of CT1812 following oral dosing. Multiple dose 
exposure of CT1812 corresponded to more than 20 times the expected minimum therapeutic 
dose (34 to 38 mg) while CSF analysis indicated that brain concentrations exceeded the 
minimum target expected to improve memory (>80% receptor occupancy). 
Following CT1812 (90, 280, and 560 mg) administered QD to patients with mild to moderate 
AD for 28 days, preliminary PK analysis showed evidence of modest accumulation of 
CT1812 as indicated by plasma AUC values. Both AUC0-24 and Cmax estimates were 
higher on Day 28 than on Day 1, and pre-dose trough concentrations increased across the 
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dosing course, with steady-state levels generally attained by Day 7. Systemic exposure, as 
indicated by Cmax and AUC, increased approximately proportionally with dose; variability 
in PK parameters was high, with some individual values overlapping between dose groups. 
Lumbar punctures were performed on Day 28, 24 hours after the Day 27 dose. Mean 
steady-state predose CT1812 concentrations in the CSF increased with dose. Neurogranin 
levels, a synaptic damage marker that increases in the CSF of AD patients, significantly 
declined relative to screening levels in CT1812-treated patients by 17.6% compared to 
placebo-treated individuals, this finding is consistent with CT1812’s mechanism of action 
and preclinical studies demonstrating the drug can prevent Abeta oligomer-induced synapse 
loss and return synapse number to normal. Synaptotagmin-1 levels, synaptic damage 
biomarker that is elevated in the CSF of AD patients, significantly declined by a mean of 
63% in CT1812-treated patients on Day 28 compared to baseline values, whereas placebo 
treated values increased by a mean of 24%. 
A fixed-sequence study to examine the effect of multiple-dose CT1812 administration on 
standard probes of CYP2C19 (Omeprazole), CYP2C9 (Tolbutamide), CYP2D6 
(Dextromethorphan), and CYP3A4/5 (Midazolam) activity in healthy adult subjects was also 
conducted. Based on the small magnitude of change in PK parameters observed in this study 
for the isoenzymes CYP2D6 and CYP3A4, clinically meaningful interactions are unlikely 
except possibly for narrow therapeutic range CYP3A4 substrates. No significant interaction 
was observed for isoenzymes CYP2C19 and CYP2C9. 
Safety 
Single dose administration up to 1120 mg, and 14-day administration up to 840 mg/day were 
well tolerated. Adverse events reported to date have all been mild to moderate in severity, 
(with the exception of one serious adverse event [SAE] considered unrelated to study drug) 
and have mainly 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 one SAE following the 840 mg/day dose of the MAD investigation, an 
upper respiratory infection believed to be unrelated to study drug. There was one subject in 
the MAD investigation who developed a rash and showed improvement after discontinuing 
CT1812. Four (4) subjects in the MAD investigation showed an increase in liver function 
tests (LFTs) below 3 times the upper limit of normal (including one subject receiving 
placebo). These abnormalities resolved after the 14-day dosing period, with the exception of 
one subject who had an isolated rise of LFTs at Day 35. Lymphocytopenia was observed, at 
approximately Day 14 of dosing, in all cases it resolved with continuation of treatment 
except in one subject whose resolution was associated with drug cessation related to liver 
function test elevation. These cases were isolated to the 560 mg QD dose, and in 75% of 
cases were associated with non-specific malaise, which may suggest a stress-related 
response. 
Refer to the Investigator’s Brochure (IB) for detailed background information on CT1812 
(IB, Version 5.0). 
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8.2 
Rationale 
8.2.1 
Rationale for this Study and Study Design 
The disposition of any drug in the body is controlled by physiological processes affecting 
absorption, metabolism, and excretion. The most efficient and well-established approach to 
elucidate these processes is a mass balance study in which the drug dose is administered in 
radiolabeled form, followed by collection and analysis of different biological matrices for 
radioactivity using liquid scintillation count and determination of drug concentration using 
conventional liquid chromatography-tandem mass spectrometry and metabolite profile using 
liquid chromatography with radiometric detection. The PK, metabolic pathways, and routes 
of elimination of CT1812 have been evaluated in vitro and in vivo in preclinical species 
(IB, Version 5.0). In this study the TRA of [14C]-CT1812 will be measured using accelerator 
mass spectrometry (AMS). 
Additionally, the PK profile of CT1812 in humans has been evaluated in healthy subjects (in 
a SAD and MAD investigation [Study COG0101]). Currently, the 
biotransformation/metabolism and excretory pathways of CT1812 in humans are not known. 
The aim of this study is to characterize the plasma exposure, clearance pathways, and 
excretion routes for CT1812 and its metabolites in healthy male subjects following oral 
administration. Based on data in healthy subjects, the average t½ of CT1812 following single 
oral administration in the fasted state for doses from 10 mg to 1120 mg (Study COG0101) 
ranged from 11.1 to 14 hours, thus, it is expected that more than 90% of the radioactivity 
should be eliminated within 168 hours postdose, the sampling duration in this study. 
8.2.2 
Rationale for the Dose Selection  
The single dose consisting of 300 mg (~1 μCi) [14C]-CT1812 oral capsules chosen for this 
study is expected to provide sufficient mass of drug, and sufficient specific radioactivity 
(using AMS analysis), for detection and analysis of parent drug and/or metabolites in whole 
blood, plasma, urine, and fecal samples, as applicable, with CT1812 exposures that are in a 
safe and pharmacologically active range. Single doses of CT1812 (10 mg – 1120 mg), 
administered previously to healthy subjects appeared to be safe and well tolerated with the 
majority of events reported being mild in severity. 
The effective dose of radiation for a human male following a single oral administration of 
1 µCi of [14C]-CT1812, was calculated to be 0.036 mrem. The effective dose is <20 x than 
what the average American receives in one day from natural background radiation (NCRP, 
2009). Estimated radiation doses from a 1 μCi oral administration of [14C]-CT1812 are below 
the radiation dose limits set forth in 21 Code of Federal Regulations (CFR) 361 for the whole 
body, active blood-forming organs, lens of the eye, gonads, and any other organ. The 
extrapolated 0.036 mrem effective dose represents 0.0012% of the FDA limit (3000 mrem to 
the whole body, active blood-forming organs, lens of the eye, or gonads). Based on these 
results, a dose of 1 µCi of [14C]-CT1812 can be administered to a human and be recognized 
as safe under FDA guidelines (CFR Title 21, 2019). 
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8.3 
Risks and/or Benefits to Subjects 
Based on the clinical safety data available from healthy subject studies, the oral dose of 
CT1812 administered in this study is not anticipated to induce any potential risk or benefit to 
subjects participating in this study, as it is a single dose administered according to the dosing 
recommendations in the IB and was found to be safe and well tolerated (IB, Version 5.0). 
The estimated total radiation dose and the tissue specific exposure from a single oral 
administration of ~1 µCi [14C]-CT1812 are below the radiation dose limits set forth by the 
Food and Drug Administration (FDA) (see Section 8.2.2). Thus, the health risk resulting 
from exposure to radiation in the study drug is very low. 
The safety monitoring practices employed by this protocol (i.e., AE questioning, 12-lead 
ECG, vital signs, clinical laboratory tests, ophthalmic examinations, and C-SSRS) are 
adequate to protect the subjects’ safety and should detect all expected treatment-emergent 
AEs (TEAEs). 
There will be no direct health benefit for study participants from receipt of study drug. An 
indirect health benefit to the healthy subjects enrolled in this study is the free medical tests 
received at screening and during the study. 
 
 
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10 STUDY DESIGN 
10.1 Overall Study Design and Plan 
This is an open-label, single-dose study to assess the absorption, metabolism, excretion, and 
mass balance for [14C]-CT1812. 
Eight (8) healthy male subjects will be enrolled. 
Screening of subjects will occur within 28 days prior to dosing. 
Subjects will be admitted to the 
 on Day -1 and discharged from the 
 following 
completion of 168 hours postdose procedures (Day 8). 
On Day 1, subjects will receive a single oral dose of 300 mg CT1812 (2 capsules) with a 
microtracer dose of ~1 µCi [14C]-CT1812 (1 capsule). Whole blood, plasma, urine, and fecal 
samples will be collected over 168 hours postdose (Day 8) to measure TRA (all samples), 
CT1812 and M6 metabolite concentrations (plasma), and for metabolite profiling and 
identification (plasma, urine, and fecal samples). 
Safety will be monitored throughout the study by repeated clinical and laboratory 
evaluations. 
Discontinued subjects may be replaced at the discretion of the Sponsor. 
10.1.1 
Confinement and Follow-Up 
Subjects will be housed on Day -1, at the time indicated by the 
, until completion of 
168 hour procedures. Subjects may be admitted earlier than Day -1 for Coronavirus 
Disease-2019 (COVID-19) testing not related to study protocol as per 
 requirements. A 
subject may be required to remain at the 
for longer at the discretion of the Principal 
Investigator (PI) or designee. 
The 
 will attempt to contact all subjects who received the study drug (including subjects 
who terminate early) using their standard procedures approximately 14 days after dosing to 
determine if any AE has occurred since the last visit.  
10.1.2 
End of Study Definition 
The end of study is defined as the date of the last scheduled study procedure, i.e., the 
follow-up contact, outlined in the Study Events Flow Chart (Section 6). 
A subject is considered to have completed the study if he has completed the last scheduled 
procedure, i.e., the follow-up contact, shown in the Study Events Flow Chart (Section 6). 
 
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11 STUDY POPULATION 
11.1 Inclusion Criteria 
Subjects must fulfill all of the following inclusion criteria to be eligible for participation in 
the study: 
1. Healthy, adult, male, 19-55 years of age, inclusive, at the Screening visit. 
2. Male subjects must follow protocol specified contraception guidance as described in 
Section 11.4.5. 
3. Continuous non-smoker who has not used tobacco/nicotine-containing products for at 
least 3 months prior to dosing. 
4. Body mass index (BMI) ≥18.0 and ≤30.0 kg/m2 at the Screening visit (subjects must not 
have experienced a weight loss or gain of >10% within 4 weeks of dosing). 
5. Medically healthy with no clinically significant medical history, physical examination, 
laboratory profiles, vital signs or ECGs, as deemed by the PI/designee at the Screening 
visit. 
6. History of a minimum of 1 bowel movement per day. 
7. Able to swallow multiple capsules. 
8. Understands the study procedures in the informed consent form (ICF), and be willing and 
able to comply with the protocol. 
11.2 Exclusion Criteria 
Subjects must not be enrolled in the study if they meet any of the following criteria: 
1. Evidence of disease that, in the opinion of the PI/designee, may influence the outcome of 
the study within 4 weeks before dosing; e.g., psychiatric disorders, cancer, seizures, or 
disorders of the GI tract, liver, kidney, respiratory system, endocrine system, 
hematological system, neurological system, or cardiovascular system, or subjects who 
have a congenital abnormality in metabolism. 
2. Clinically significant illness, in the opinion of the PI/designee, that requires medical 
treatment within 8 weeks prior to dosing, or a clinically significant infection that requires 
medical treatment within 4 weeks prior to dosing. 
3. Any history of GI surgery that may affect PK profiles of CT1812, e.g., hepatectomy, 
nephrectomy, gastric bypass, digestive organ resection. Subjects with a history of 
appendectomy may be included at the discretion of the PI/designee and Sponsor. 
4. Has evidence of a clinically significant abnormality in physical examination findings, 
vital signs, or clinical laboratory determinations (congenital nonhemolytic 
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hyperbilirubinemia [e.g., suspicion of Gilbert’s syndrome is not acceptable]) at the 
Screening visit or Check-in. 
5. Has a clinically significant ECG abnormality, including a marked prolonged QT interval 
corrected by Fridericia’s method (QTcF; e.g., a repeated demonstration of a QTcF 
interval >450 msec) at the Screening visit or Check-in, or a family history of prolonged 
QTc syndrome or sudden death or angina, or has history of congestive heart failure, 
poorly controlled hypertension, clinically significant arrhythmia, hypotension, any form 
of heart block (history of or on ECG at the Screening visit or Check-in), bundle branch 
block, symptomatic ectopy, unstable arrhythmias including atrial fibrillation, frequent 
supraventricular or ventricular ectopy, or a PR >210 msec or QRS duration >120 msec on 
ECG at the Screening visit or Check-in. 
6. Estimated creatinine clearance <80 ml/min/1.73 m2 at the Screening visit by Chronic 
Kidney Disease Epidemiology Collaboration (CKD-EPI) formula. 
7. Known history of clinically significant allergy to CT1812 or excipients at the Screening 
visit.  
8. Has been diagnosed with acquired immune deficiency syndrome, or tests positive for 
human immunodeficiency virus (HIV), Hepatitis B virus surface antigen (HBsAg), or 
Hepatitis C virus (HCV) at the Screening visit. 
9. Has a history of alcohol use disorder within the 2 years before the Screening visit.  
10. Positive urine drug or alcohol results at the Screening visit or Check-in. 
11. Positive cotinine result at the Screening visit. 
12. Unable to refrain from or anticipates the use of: 
• Any drugs, including prescription and non-prescription medications, herbal remedies, 
or vitamin supplements beginning 14 days prior to dosing except for those allowed in 
Section 11.4.1. 
• Any drugs known to be significant inducers of CYP2D6 and CYP3A4 and/or P-gp, 
including St. John’s Wort, for 28 days prior to dosing. Appropriate sources (e.g., 
Flockhart TableTM) will be consulted to confirm lack of PK/pharmacodynamic 
interaction with study drug. 
13. Donation of blood or significant blood loss within 56 days prior to dosing. 
14. Plasma donation within 7 days prior to dosing. 
15. Poor peripheral venous access. 
16. Recent history (within 2 weeks of Day -1) of abnormal bowel movements, such as 
diarrhea, loose stools, or constipation. 
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17. Has exposure to significant diagnostic or therapeutic radiation (e.g., serial X-ray, 
computed tomography scan, barium meal) or current employment in a job requiring 
radiation exposure monitoring within 12 months prior to Check-in. 
18. Has participated in a radiolabeled drug study where exposures are known to the PI within 
the previous 3 months prior to admission to the clinic for this study or participated in a 
radiolabeled drug study where exposures are not known to the PI within the previous 
6 months prior to admission to the clinic for this study. The total 12-month exposure from 
this study and a maximum of 3 other previous radiolabeled studies within 3 to 12 months 
prior to this study will be within the CFR recommended levels considered safe, per 
United States (US) Title 21 CFR 361.1 i.e., less than 5000 mrem whole-body annual 
exposure with consideration given to the half-lives of the previous radiolabeled study 
drugs received. 
19. Has previously participated in a CT1812 investigational study. 
20. Evidence or history of active suicidal thoughts (Type 4 or 5 on the C-SSRS) in the 
6 months preceding the screening visit; or have a history of a suicide attempt in the 
previous 2 years, or more than 1 lifetime suicide attempt; or are at serious suicide risk per 
the PIs clinical judgment. 
21. Has any condition that would, in the opinion of the PI/designee or Sponsor, make the 
subject unsuitable for the study or is, in the opinion of the PI/designee, not likely to 
complete the study for any reason. 
22. Participation in another clinical study within 30 days prior to dosing. The 30-day window 
will be derived from the date of the last blood collection or dosing, whichever is later, in 
the previous study to Day 1 of the current study. 
11.3 Early Termination of Subjects from the Study 
Subjects are free to withdraw from the study at any time for any reason. 
In addition, subjects may be withdrawn from the study by the PI or designee for the 
following reasons: 
• AEs. 
• Difficulties in blood collection. 
A subject may be withdrawn by the PI (or designee) or the Sponsor if enrollment into the 
study is inappropriate, the study plan is violated, or for administrative and/or other safety 
reasons. 
Subjects who withdraw from the study early following dosing will be requested to remain 
confined to the 
at least until Day 8. 
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11.4 Lifestyle Considerations 
11.4.1 
Medications and Supplements Restrictions 
Prior concomitant medications (including prescription and non-prescription medications, 
herbal remedies, or vitamin supplements) will be prohibited as listed in the exclusion criteria 
in Section 11.2 and throughout the study. 
After dosing, acetaminophen (up to 2 g per 24 hours) may be administered at the discretion 
of the PI or designee. 
A mild laxative (i.e., Milk of Magnesia®, Colace®) or prune juice may be used to help with 
bowel movements if necessary, at the discretion of the PI/designee, except for the first 
4 hours postdose. 
Eye drops for retinal examination will be permitted to facilitate the ophthalmic assessments. 
If deviations occur, the PI or designee in consultation with the Sponsor if needed will decide 
on a case by case basis whether the subject may continue participation in the study. 
All medications taken by subjects during the course of the study will be recorded. 
11.4.2 
Meals and Dietary Restrictions 
11.4.2.1 
Meals 
Water (except water provided with dosing) will be restricted 1 hour prior to and 1 hour after 
dosing, but will be allowed ad libitum at all other times. Other fluids may be given as part of 
meals and snacks but will be restricted at all other times throughout the confinement period. 
Subjects will fast overnight for at least 10 hours prior to dosing. Subjects will continue the 
fast for at least 4 hours postdose.  
When confined, standard meals and snacks will be provided at appropriate times, except 
when they are required to fast. When confined in the 
, subjects will be required to fast 
from all food and drink except water between meals and snacks (with exception for mild 
laxative [i.e., Milk of Magnesia®, Colace®] or prune juice which may be given at the 
discretion of the PI/designee at any time excluding the first 4 hours following dosing). 
Each meal and/or snack served at the 
will be standardized and will be similar in caloric 
content and composition and will be taken at approximately the same time. 
11.4.2.2 
Dietary Restrictions 
The consumption of foods and beverages containing the following substances will be 
prohibited as indicated: 
• Grapefruit/Seville orange (or products containing these): 14 days prior to dosing and 
throughout the period of sample collection. 
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11.4.3 
Caffeine, Alcohol, and Tobacco Restrictions 
Subjects will refrain to use the following: 
• Xanthines/Caffeine-containing foods or beverages: 24 hours prior to dosing and 
throughout the period of sample collection (small amounts of caffeine derived from 
normal foodstuffs e.g., 250 mL/8 oz./1 cup decaffeinated coffee or other 
decaffeinated beverage, per day, with the exception of espresso; 45 g/1.5 oz. 
chocolate bar, per day, would not be considered a deviation to this restriction). 
• Alcohol-containing foods or beverages: 48 hours prior to dosing and throughout the 
period of sample collection. 
• Tobacco/nicotine containing products: at least 3 months prior to dosing and 
throughout the period of sample collection. 
11.4.4 
Activity Restrictions 
Subjects will remain ambulatory or seated upright for the first 4 hours postdose, except when 
they are supine or semi-reclined for study procedures. Should AEs occur at any time, subjects 
may be placed in an appropriate position or will be permitted to lie down on their right side. 
Specific measures will be taken to prevent the subject from missing a urine collection by 
strictly controlling and providing access to designated restrooms only. Subjects will be asked 
to void prior to entering the shower. 
Subjects will be instructed to refrain from strenuous physical activity which could cause 
muscle aches or injury, including contact sports at any time from the Screening visit until 
completion of the study. 
Should any subject withdraw or be withdrawn from the study, he will be cautioned against 
activities requiring mental alertness, judgment and physical coordination such as driving, 
operating machinery, or power equipment for a period of 24 hours postdose. 
11.4.5 
Contraception Requirements 
11.4.5.1 
Guidance for Subjects 
Subjects must agree to the following method of contraception: 
A non-vasectomized subject must agree to use a condom with spermicide or abstain from 
sexual intercourse during the study from dosing until 90 days after dosing. No restrictions are 
required for a vasectomized subject provided his vasectomy has been performed 4 months or 
more prior to dosing.  
A subject who has been vasectomized less than 4 months prior to dosing must follow the 
same restrictions as a non-vasectomized subject. 
The subject must agree not to donate sperm from dosing until 90 days after dosing. 
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12 TREATMENTS 
12.1 Treatments Administered 
Study drug will be supplied as capsules of nonradiolabeled CT1812 (powder) and capsules of 
radiolabeled [14C]-CT1812 (powder/suspension).  
The study treatment will consist of 3 capsules: 2 capsules containing CT1812 (
 
  and 1 capsule 
containing ~1 μCi [14C]-CT1812 (
).  
Capsules will be administered orally under fasting conditions on Day 1 at Hour 0 with 
approximately 240 mL of water. Additional water, up to 50 mL, is permissible to facilitate 
swallowing multiple capsules. 
The pharmacy at the 
 will provide the [14C]-CT1812 dose in individual unit dose 
containers for each subject.  
Subjects will be instructed not to crush, split, or chew the capsules.  
The exact clock time of dosing will be recorded. 
12.2 Dose Modification 
The dose and administration of the study drug to any subject may not be modified. If 
necessary a subject must be discontinued for the reasons described in Section 11.3. 
12.3 Method of Treatment Assignment 
Each subject will be assigned a unique identification number upon the Screening visit. 
Subjects who complete the study screening assessments and meet all the eligibility criteria 
will be assigned a unique identification number at the time of dosing, different from the 
screening number.  
If replacement subjects are used, the replacement subject number will be 100 more than the 
original (e.g., Subject No. 101 will replace Subject No. 1). Subjects will be replaced at the 
discretion of the Sponsor if less than 6 subjects are available for evaluation. 
12.4 Blinding 
This is an open-label study.  
12.5 Treatment Compliance  
A qualified designee will be responsible for monitoring the administration of the timed oral 
doses. A mouth check will be performed by the qualified designee to ensure that the subjects 
have swallowed the study drug. Once a subject has finished the dosing water, the qualified 
designee will use a flashlight and a tongue depressor to check the subject’s mouth. Subjects’ 
hands will also be verified to ensure that the study drug was ingested. 
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13 STUDY ASSESSMENTS AND PROCEDURES 
The Study Events Flow Chart (Section 6) summarizes the clinical procedures to be 
performed at each visit. Individual clinical procedures are described in detail below. 
Additional evaluations/testing may be deemed necessary by the PI or designee and/or the 
Sponsor for reasons related to subject safety. 
For this study, the blood (for whole blood and/or plasma), urine, and feces collections for 
TRA, the blood (for plasma) CT1812 and M6 concentrations, and the blood (for plasma), 
urine, and feces collections for metabolite profiling, as applicable, are the critical parameters 
and need to be collected as close to the exact time point as possible. All other procedures 
should be completed as close to the prescribed/scheduled time as possible, but can be 
performed prior or after the prescribed/scheduled time. 
Any nonscheduled procedures required for urgent evaluation of safety concerns take 
precedence over all routine scheduled procedures. 
13.1 Screening 
Within 28 days prior to dosing, medical history and demographic data, including name, sex, 
age, race, ethnicity, body weight (kg), height (cm), BMI (kg/m2) and history of tobacco use 
will be recorded. Each subject will have a 12-lead ECG, vital sign measurements (pulse rate, 
blood pressure, temperature, and respiratory rate), clinical laboratory tests, ophthalmic, 
C-SSRS, and physical examination. 
13.2 Safety Assessments 
13.2.1 
Physical Examination 
Full and abbreviated physical examinations and symptom driven physical examination(s) will 
be performed as outlined in the Study Events Flow Chart (Section 6). Additional 
symptom-driven physical examinations may be performed at other times, if deemed 
necessary by the PI or designee.  
An abbreviated physical examination will include at the minimum, examination of 
respiratory, cardiovascular, and GI systems, with the option for further examination of 
additional systems as necessary based on reported symptoms/AEs. 
13.2.2 
Standard Vital Signs 
Single measurements of body temperature, respiratory rate, blood pressure, and pulse rate 
will be measured as outlined in the Study Events Flow Chart (Section 6). Additional vital 
signs may be taken at any other times, if deemed necessary by the PI or designee. 
Blood pressure and heart rate measurements will be performed with subjects in a seated 
position, except when they are supine or semi-reclined because of study procedures and/or 
AEs (e.g. nausea, dizziness) or if deemed necessary by the PI or designee. 
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Vital signs will be measured within 24 hours prior to Day 1 dosing for the predose time 
point. When scheduled postdose, vital signs will be performed within approximately 
15 minutes of the scheduled time point.  
13.2.3 
ECG Monitoring 
Single 12-lead ECGs will be performed as outlined in the Study Events Flow Chart 
(Section 6). Additional ECGs may be taken at any other times, if deemed necessary by the PI 
or designee. 
ECGs will be performed with subjects in a supine position. All ECG tracings will be 
reviewed by the PI or designee. 
ECGs will be measured within 24 hours prior to Day 1 dosing for the predose time point. 
When scheduled postdose, ECGs will be performed within approximately 20 minutes of the 
scheduled time point. 
13.2.4 
Ophthalmic Examinations 
Ophthalmic examinations will be performed as outlined in the Study Events Flow Chart 
(Section 6). Additional ophthalmic examinations may be taken at any other times, if deemed 
necessary by the PI or designee. Ophthalmic examinations will include the following tests:  
− Best-corrected visual acuity using Early Treatment Diabetic Retinopathy Study 
(ETDRS) charts (refraction only required if subjects does not have his corrective lenses 
or contact lenses) 
− Slit lamp exam 
− Intraocular pressure measurement with applanation tonometry 
− Dilated fundus retinal exam 
13.2.5 
Body Weight 
Body weight (kg) will be reported as outlined in the Study Events Flow Chart (Section 6).  
13.2.6 
Columbia Suicide Severity Rating Scale 
The C-SSRS is a questionnaire scale to detect emergent suicide symptoms (suicidal ideation 
or actual suicidal behavior) during the course of this study. Assessments will be performed 
according to the Study Events Flow Chart (Section 6). At Screening, the C-SSRS 
Baseline/Screening version will be administered; at all other time points, as applicable, the 
Since Last Visit version will be administered. Additional C-SSRS assessments may be 
performed at other times if deemed necessary. The C-SSRS is to be administered at the site 
by an appropriately qualified/trained individual and a copy of the questionnaire to be used 
will be kept in the study binder. In addition, subjects who at any time during this study 
spontaneously report AEs of suicidal ideation or suicidal behavior, either as an outpatient or 
during visit interviews, must be assessed by the PI or designee and referred for further mental 
health evaluation as clinically indicated. 
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13.2.7 
Clinical Laboratory Tests 
All tests listed below will be performed as outlined in the Study Events Flow Chart 
(Section 6). In addition, laboratory safety tests may be performed at various unscheduled 
time points, if deemed necessary by the PI or designee.  
Hematology 
 
Serum Chemistry * 
• 
Hemoglobin 
• 
Hematocrit  
• 
Total and differential leukocyte 
count 
• 
Red blood cell count 
• 
Platelet count 
 
 
 
• 
Blood Urea Nitrogen 
• 
Bilirubin (total and direct) 
• 
Alkaline phosphatase 
• 
Aspartate aminotransferase 
• 
Alanine aminotransferase 
• 
Albumin 
• 
Sodium 
• 
Potassium 
• 
Chloride 
• 
Calcium 
• 
Glucose (fasting) 
• 
Creatinine ** 
• 
Lactic dehydrogenase 
• 
Creatine phosphokinase 
 
Urinalysis 
 
Additional Tests 
• 
pH 
• 
Specific gravity 
• 
Protein *** 
• 
Glucose 
• 
Ketones 
• 
Bilirubin 
• 
Blood *** 
• 
Nitrite*** 
• 
Urobilinogen 
• 
Leukocyte esterase *** 
 
• 
HIV test 
• 
HBsAg 
• 
HCV 
• 
Urine drug screen 
 Opiates  
 Amphetamines  
 Barbiturates  
 Benzodiazepines  
 Cocaine  
 Cannabinoids  
• 
Urine alcohol screen 
• 
Urine cotinine 
 
* 
Serum chemistry tests will be performed after at least an 8-hour fast; however, in case of dropouts or 
rechecks, subjects may not have fasted for 8 hours prior to the serum chemistry sample is taken.  
** At the Screening visit, creatinine clearance will be calculated using the CKD-EPI formula. 
*** If urinalysis is positive for protein, blood, nitrite and/or leukocyte esterase, a microscopic examination 
(for red blood cells, white blood cells, bacteria, casts, and epithelial cells) will be performed. 
 
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13.2.8 
Adverse Events  
13.2.8.1 
Adverse Event Definition 
An AE means any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related. 
A suspected adverse reaction means any AE for which there is a reasonable possibility that 
the drug caused the AE. Reasonable possibility means there is evidence to suggest a causal 
relationship between the drug and the AE.  
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product. 
13.2.8.2 
Monitoring 
Subjects will be monitored for adverse reactions to the study formulations and/or procedures 
throughout the study, from the time of signing the ICF until the follow-up contact. Prior to 
release, subjects will be asked how they are feeling. At the follow-up contact, subjects will be 
queried with an open-ended question such as: ‘How have you been feeling since your last 
visit?’  
AEs (whether serious or non-serious) and clinically significant abnormal laboratory test 
value(s) will be evaluated by the PI or designee and treated and/or followed up until the 
symptoms or value(s) return to normal, or acceptable levels, as judged by the PI or designee.  
Treatment of serious adverse events (SAEs) will be performed by a licensed health care 
professional, either at Celerion or at a nearby hospital emergency room where appropriate 
medical test(s) and/or examination(s) will be performed to document resolution of event(s). 
Outcome may be classified as fatal, not recovered/not resolved recovered/resolved, 
recovered/resolved with sequelae, recovering/resolving. 
13.2.8.3 
Reporting 
All AEs that occurred during this clinical study will be recorded. All clinically significant 
abnormal laboratory results should be reported as AEs.  
The PI or designee will review each event and assess its relationship to drug treatment 
(likely, probably, possibly, unlikely or unrelated).  
Each sign or symptom reported will be graded on a 3-point severity scale (mild, moderate, or 
severe), and the date of onset, time of onset, and outcome of each event will be noted. 
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The following definitions will be used for rating the severity of AEs: 
Mild 
The AE is easily tolerated and does not interfere with daily activity. 
Moderate 
The AE interferes with daily activity, but the subject is still able to function. 
Medical intervention may be considered. 
Severe 
The AE is incapacitating and requires medical intervention. 
13.2.8.4 
Serious Adverse Event 
If any AEs are serious, as defined by the Food and Drug Administration (FDA) CFR, 
Chapter 21, special procedures will be followed. All SAEs will be reported to the Sponsor 
via fax or e-mail within one working day of becoming aware of the event, whether or not the 
serious events are deemed drug-related. All serious event reporting will adhere to 
21 CFR 312.32 for Investigational New Drugs (IND) and to the Guidance for Industry and 
Investigators: Safety Reporting Requirements for INDs and BA/BE, dated December 2012. 
The institutional review board (IRB) will be notified of the Alert Reports as per FDA 
regulations. 
A SAE is any AE or suspected adverse reaction that in the view of either the PI (or designee) 
or Sponsor, results in any of the following outcomes: Death, a life-threatening adverse event, 
inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions, or a 
congenital anomaly/birth defect. Important medical events that may not result in death, be 
life-threatening, or require hospitalization may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in the above definition. 
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse.  
Life-threatening is defined as an AE or suspected adverse reaction that in the view of the PI 
(or designee) or Sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it occurred 
in a more severe form, might have caused death. 
Unexpected is defined as an AE or suspected adverse reaction that is not listed in the IB or is 
not listed at the specificity or severity that has been observed; or is not consistent with the 
risk information described in the general investigational plan or elsewhere in the current 
application, as amended. 
If a SAE occurs to a subject on this study, contact the Sponsor personnel listed in Section 3. 
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13.3 Pharmacokinetic Assessments 
13.3.1 
Blood Sampling and Processing 
Blood samples for the determination of TRA in whole blood and plasma, CT1812 and M6 
concentrations in plasma, and metabolite profiling in plasma will be collected at scheduled 
time points as delineated in the Study Events Flow Chart (Section 6). 
Predose samples should be handled, processed, analyzed, and stored separately away from 
the postdose samples to avoid cross contamination. 
Instruction for blood sampling, collection, processing, and sample shipment will be provided 
separately. 
13.3.2 
Pharmacokinetic Parameters  
PK parameters for whole blood and plasma TRA concentration equivalents and for plasma 
CT1812 and metabolite M6, will be calculated, as appropriate: 
AUC0-t: 
The area under the concentration versus time curve, from time 0 
to the time of the last common time point “t”, where t is the last 
common time point at which plasma TRA and plasma CT1812 
are quantifiable in all subjects.  
AUC0-24: 
The area under the concentration versus time curve, from time 0 
to the 24-hour time point.  
AUC0-last: 
The area under the concentration-time curve, from time 0 to the 
last observed non-zero concentration, as calculated by the linear 
trapezoidal method.  
AUC0-inf: 
The area under the concentration-time curve from 
time 0 extrapolated to infinity. AUC0-inf is calculated as the sum 
of AUC0-last plus the ratio of the last measurable concentration 
to the elimination rate constant. 
AUC%extrap: 
Percent of AUC0-inf extrapolated, represented as 
(1 - AUC0-last/AUC0-inf)*100. 
Cmax: 
Maximum observed concentration. 
Tmax: 
Time to reach Cmax. If the maximum value occurs at more than 
one time point, Tmax is defined as the first time point with this 
value. 
Kel: 
Apparent first-order terminal elimination rate constant calculated 
from a semi-log plot of the concentration versus time curve. The 
parameter will be calculated by linear least-squares regression 
analysis using the maximum number of points in the terminal 
log-linear phase (e.g., three or more non-zero concentrations). 
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t½: 
Apparent first-order terminal elimination half-life will be 
calculated as 0.693/Kel. 
CL/F: 
Apparent total clearance after oral (extravascular) administration, 
calculated as Dose/AUC0-inf (parent only). 
Vz/F: 
Apparent volume of distribution during the terminal elimination 
phase after oral (extravascular) administration, calculated as 
Dose/(AUC0-inf x Kel) (parent only). 
No value for Kel, AUC0-inf, AUC%extrap, CL/F, Vz/F, or t½ will be reported for cases that 
do not exhibit a terminal log-linear phase in the concentration-time profile. 
No PK parameters will be calculated for subjects with 2 or fewer consecutive time points 
with detectable concentrations, or who have an AE of vomiting that occurs at or before 2 
times the median Tmax. 
13.3.3 
Whole Blood to Plasma Partitioning Ratio 
The percentage of TRA in whole blood relative to plasma (i.e., whole blood:plasma 
partitioning ratio) will be estimated at each time-matched determination of TRA in whole 
blood and plasma collected at the scheduled time points as delineated in the Study Events 
Flow Chart (Section 6). 
13.3.4 
Urine Sampling and Processing 
Urine for determination of TRA and metabolite profiling will be collected at the specified 
intervals delineated in the Study Events Flow Chart (Section 6). 
Prior to the predose sample collection, each subject will be instructed as to urine collection 
methods. All urine during an interval is to be collected.  
On Day 1, a spot collection will be obtained prior to dosing for the predose sample. Subjects 
will be asked again to empty their bladder within approximately 15 minutes prior to dosing, 
and no urine will be collected at this time unless it is needed for the predose sample. Only 
one predose urine sample will be collected on Day 1. 
Subjects will be encouraged to void at the end of each collection interval. If they do void at 
any time during the collection interval, the time should be documented. Should this be the 
case, subjects need to void again at the end of the collection period, as scheduled. However, 
should subjects be unable to void, this will be documented as well.  
Urine will be refrigerated during the collection intervals. At the end of each interval, urine 
will be pooled and thoroughly mixed. Total urine volume will be weighed and recorded.  
Predose samples should be handled, processed, analyzed, and stored separately away from 
the postdose samples to avoid cross contamination. 
Instructions for urine sampling, collection, processing, and sample shipment will be provided 
separately. 
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13.3.5 
Urine Pharmacokinetic Parameters 
PK parameters for urine TRA will be calculated as follows: 
Ae(u): 
Amount of TRA excreted in urine within a given collection 
interval.  
CumAe(u): 
Cumulative amount of TRA excreted in urine. 
%Dose(u): 
Percent of administered radioactive dose excreted in urine within a 
given collection interval. 
Cum%Dose(u): 
Cumulative percent of administered radioactive dose recovered in 
urine. 
CLr: 
Renal clearance. CLr = CumAe(u)/AUC0-inf, where both CumAe 
and AUC are determined over matched time interval. 
13.3.6 
Fecal Sampling and Processing 
Fecal samples for the determination of TRA and metabolite profiling will be collected at the 
specified intervals delineated in the Study Events Flow Chart (Section 6). 
The predose fecal sample is to be obtained within 48 hours prior to dosing. Subjects will be 
asked to bring a fecal sample at Check-in (if produced within 48 hours prior to dosing). Feces 
produced between Check-in and dosing will also be collected as a predose sample with the 
sample produced nearest to dosing to be retained as the only predose sample. 
All fecal samples will be collected and stored individually for analysis of TRA and for 
metabolite profiling. The samples will be weighed at the time of collection. Multiple fecal 
samples from a given subject in a given interval will be pooled into a single sample at the 
time of homogenization. 
Predose samples should be handled, processed, analyzed, and stored separately away from 
the postdose samples to avoid cross contamination. 
Instructions for fecal sampling, collection, processing, and sample shipment will be provided 
separately. 
13.3.7 
Fecal Pharmacokinetic Parameters 
PK parameters for feces TRA will be calculated as follows: 
Ae(f): 
Amount of TRA excreted in feces within a given collection 
interval.  
CumAe(f): 
Cumulative amount of TRA excreted in feces. 
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%Dose(f): 
Percent of administered radioactive dose excreted in feces within 
a given collection interval. 
Cum%Dose(f): 
Cumulative percent of administered radioactive dose recovered in 
feces. 
13.3.8 
Emesis 
Collection containers (pre-weighed) for emesis will be available for subjects participating in 
the study at all times following dosing until discharge from the clinic. Subjects will be 
instructed at the beginning of the study that they should use one of the designated containers 
if emesis occurs following [14C]-CT1812 dosing. If emesis occurs following [14C]-CT1812 
dosing and the subject has been able to collect the emesis in the designated container, it will 
be weighed and recorded, labeled with subject identification, time, and date, and analyzed for 
TRA. The subject may continue the study with permission from the Sponsor; however, 
subject data will be excluded from the PK or mass balance calculations if the AE of vomiting 
occurs at or before 2 times the median Tmax. 
13.3.9 
Future Research 
No additional analysis is planned to be performed on the PK blood/urine samples for possible 
future research. Any additional research on these samples unspecified by this protocol will 
require approval from the subjects. 
13.3.10 Analytical Method 
Samples from all subjects will be assayed even if the subjects do not complete the study.  
Plasma concentrations of CT1812 and metabolite M6 will be determined using validated 
analytical methods. Whole blood, plasma, urine, and feces TRA will be determined with 
liquid scintillation counting or AMS detection. Profiling and identification of metabolites in 
plasma, urine, and where possible, feces will be conducted using standard laboratory 
procedures. Specifics of the analytical methods will be provided in separate documents. 
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13.4 Blood Volume Drawn for Study Assessments 
Table 1: Blood Volume during the Study 
Sample Type 
Number of 
Time 
Points 
Approximate 
Volume per 
Time Point * 
(mL) 
Approximate 
Volume per Aliquot 
(mL) 
Approximate 
Sample 
Volume Over 
Course of 
Study (mL) 
Screening laboratory safety 
tests (including hematology, 
serum chemistry, and serology) 
1 
12.5 
- 
12.5 
On-study hematology and 
serum chemistry 
3 
12.5 
- 
37.5 
Blood for plasma CT-1812 and 
M6 PK  
18 
6 
2 mL 
(1 mL primary 
+1 mL backup) 
108 
Blood for plasma TRA 
18 
3 
1 mL  
(0.5 mL primary and 
0.5 mL backup) 
54 
Blood for plasma metabolite 
profiling and identification 
18 
10 
4 mL 
(2 mL primary 
+2 mL backup) 
180 
Blood for whole blood TRA 
18 
2 
2 mL 
(1 mL primary 
1 mL backup) 
36 
Total Blood Volume (mL)→ 
 
428** 
* 
Represents the largest collection tube that is expected to be used (a smaller tube may be used). 
** 
If additional PK and safety analysis is required to obtain sufficient plasma/serum for analysis, additional 
blood may be obtained (up to a maximum of 50 mL).  
. 
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14 STATISTICAL CONSIDERATIONS 
Data will be handled and processed according to Celerion Standard Operating Procedures, 
which are written based on the principles of GCP. 
14.1 Sample Size Determination 
The sample size of 8 healthy male subjects was selected without statistical considerations and 
in order to have complete data from 6 subjects available for evaluation. It has been 
determined adequate to meet the study objectives. This sample size is limited based on 
clinical considerations for this type of study and in order to limit exposure to radioactivity. 
14.2 Population for Analyses 
PK Population: All subjects who comply sufficiently with the protocol and display an 
evaluable PK profile (e.g., exposure to treatment, availability of measurements and absence 
of major protocol violations or an AE of vomiting as described) will be included in the 
statistical analysis. 
Safety Population: All subjects who received the dose of the study drug will be included in 
the safety analysis. 
14.3 Statistical Analyses 
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a Statistical Analysis Plan (SAP). The SAP will be prepared by 
Celerion and agreed upon with the Sponsor. This document may modify the plans outlined in 
the protocol; however, any major modifications of the primary endpoints definition and/or its 
analysis will also be reflected in a protocol amendment. Additional statistical analyses other 
than those described in this section may be performed if deemed appropriate.  
14.3.1 
Pharmacokinetic Analyses 
14.3.1.1 
Descriptive Statistics 
The TRA (whole blood, plasma, urine, feces, and if applicable emesis), CT1812 and M6 
metabolite concentrations (plasma), and PK parameters listed in Sections 13.3.2, 13.3.5 and 
13.3.7 will be summarized using appropriate descriptive statistics which will be fully 
outlined in the SAP.  
14.3.1.2 
Mass Balance 
Total radioactivity recovery and the percent of the radioactive dose excreted in the urine and 
feces will be assessed. Mass balance will be calculated as a sum of the percent of the TRA 
recovered in urine and feces relative to the administered radioactive dose minus any 
radioactive dose lost due to emesis (if any occurred). 
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14.3.1.3 
Metabolite Profiling 
CT1812 metabolite profiling will be performed on plasma, urine, and fecal samples 
containing sufficient amounts of radioactivity. The percent of dose represented by each of the 
metabolites, if any, will be calculated using the radioactive concentration equivalent data 
combined with the metabolite profiling data. The percentage of each identified metabolite, if 
any, to TRA in the plasma will be estimated based on plasma metabolite profiling data. 
Metabolites accounting for more than 10% of circulating TRA will be identified. 
14.3.1.4 
Whole Blood and Plasma Partitioning Ratio 
The percentage of TRA in whole blood relative to plasma will be estimated at each 
time-matched determination of TRA in whole blood and plasma. 
14.3.2 
Safety Analyses 
All safety data will be populated in the individual case report forms (CRFs), and will be 
listed by subject in the final report. 
AEs will be coded using the most current version of Medical Dictionary for Regulatory 
Activities® available at Celerion and summarized by treatment for the number of subjects 
reporting the TEAE and the number of TEAEs reported. A by-subject AE data listing 
including verbatim term, coded term, severity, and relationship to treatment will be provided.  
Safety data including ECGs, vital signs assessments, ophthalmic examinations, and clinical 
laboratory results will be summarized by time point of collection. 
C-SSRS data will be listed by subject.  
Quantitative safety data as well as the difference to baseline, when appropriate, will be 
summarized using the appropriate descriptive statistics.  
Prior and concomitant medications will be listed by subject and coded using the most current 
version of the World Health Organization drug dictionary available at Celerion.  
Medical history will be listed by subject. 
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15 STUDY ADMINISTRATION  
15.1 Ethics 
Institutional Review Board  
This protocol will be reviewed by Advarra IRB, and the study will not start until the IRB has 
approved the protocol or a modification thereof. The IRB is constituted and operates in 
accordance with the principles and requirements described in the US Code of Federal 
Regulations (21 CFR Part 56). The IRB is compliant to International Council for 
Harmonisation (ICH) guidelines, and may be reached at: 
Advarra IRB  
6100 Merriweather Drive, Suite 600 
Columbia, Maryland 21044, USA 
Tel.: +1 410 884-2900 
15.1.1 
Ethical Conduct of the Study 
This research will be carried out in accordance with the protocol, US Code of Federal 
Regulations, 21 CFR Parts 50, 56, and 312, the ethical principles set forth in the Declaration 
of Helsinki, GCP, and the ICH harmonized tripartite guideline regarding GCP (E6[R2] Good 
Clinical Practice: Integrated Addendum to E6 [R1], November 2016). 
15.1.2 
Subject Information and Consent 
The purpose of the study, the procedures to be carried out and the potential hazards will be 
described to the subjects in non-technical terms. Subjects will be required to read, sign and 
date an ICF summarizing the discussion prior to screening, and will be assured that they may 
withdraw from the study at any time without jeopardizing their medical care. 
Subjects will be given a copy of their signed ICF. 
15.1.3 
Confidentiality 
All members of the PI’s staff have signed confidentiality agreements with Celerion. By 
signing this protocol, the PI and Celerion staff will regard all information provided by the 
Sponsor and all information obtained during the course of the study as confidential.  
The PI must guarantee the privacy of the subjects taking part in the study. Subjects will be 
identified throughout documentation and evaluation by a unique subject study number. 
Throughout the study, a subject’s source data will only be linked to the Sponsor’s clinical 
study database or documentation via a unique identification number. If subject name appears 
on any study document, it must be redacted before the copy of the documents is supplied to 
the Sponsor. Any information concerning the subjects (clinical notes, identification numbers, 
etc.) must be kept on file by the PI who will ensure that it is revealed only to the Sponsor, 
IRB, or regulatory authorities for the purposes of trial monitoring, auditing or official 
inspections. As required, in the case of an event where medical expenses are the 
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responsibility of the Sponsor, personal information i.e., full name, social security details etc. 
may be released to the Sponsor. Appropriate precautions will be taken to maintain 
confidentiality of medical records and personal information in strictest confidence and in 
accordance with local data protection laws. 
15.2 Termination of the Study 
Celerion reserves the right to terminate the study in the interest of subject welfare. 
The Sponsor reserves the right to suspend or terminate the study at any time. 
15.3 Data Quality Assurance 
Standard operating procedures are available for all activities performed at Celerion relevant 
to the quality of this study. Designated personnel of Celerion will be responsible for 
implementing and maintaining quality assurance (QA) and quality control systems to ensure 
that the study is conducted, and that data are generated, documented and reported in 
compliance with the study protocol, and GCP requirements as well as applicable regulatory 
requirements and local laws, rules and regulations relating to the conduct of the clinical 
study. 
The Clinical Study Report will be audited by the QA department and the QA audit certificate 
will be included in the study report. 
Clinical data will undergo quality control prior to clinical database lock. Edit checks are 
performed for appropriate databases as a validation routine using SAS® or comparable 
statistical program to check for missing data, data inconsistencies, data ranges, etc. 
Corrections are made prior to database lock. 
15.4 Direct Access to Source Data/Documents 
Celerion will ensure that the Sponsor, IRB and inspection by domestic and foreign regulatory 
authorities will have direct access to all study-related sites, source data/documents, and 
reports for the purpose of monitoring and auditing (ICH[E6][R2] 5.1.2 & 6.10). In the event 
that other study-related monitoring should be done by other parties, they will be required to 
sign a confidentiality agreement prior to any monitoring and auditing. 
15.5 Drug Supplies, Packaging and Labeling 
The Sponsor will supply sufficient quantities of CT1812 and [14C]-CT1812 to allow 
completion of this study. The lot numbers and expiration dates (where available) of the study 
drugs supplied will be recorded in the final report. 
Records will be made of the receipt and dispensing of the study drugs supplied. At the 
conclusion of the study, any unused CT1812 and [14C]-CT1812 will be retained by Celerion, 
returned to the Sponsor or designee, or destroyed, as per Sponsor instructions. If no supplies 
remain, this fact will be documented in the pharmacy product accountability records. 
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15.6 Data Handling and Record Keeping 
Celerion standard CRFs will be supplied. CRFs are produced, stored electronically, and are 
available to the designated study team members. Each CRF is reviewed and signed by the PI. 
The final signed CRFs are provided to the Sponsor in the format as decided between Celerion 
and the Sponsor (e.g., electronically, compact disc, flashdrive, secure file transfer protocol). 
This will be documented in the data management plan (if applicable).  
All raw data generated in connection with this study, together with the original copy of the 
final report, will be retained by Celerion until at least 5 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 5 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents 
should be retained for a longer period however if required by the applicable regulatory 
requirements or by an agreement with the sponsor. It is the responsibility of the Sponsor to 
inform the PI/Institution as to when these documents no longer need to be retained. 
15.7 Report Format 
According to the ICH Harmonized Tripartite Guideline (Organization of the Common 
Technical Document for the Registration of Pharmaceuticals for Human Use M4 and the 
ICH M2 Expert Working Group), the final report will be written according to the 
ICH E3 Guideline (Structure and Content of Clinical Study Reports).  
15.8 Publication Policy 
All unpublished information given to Celerion by the Sponsor shall not be published or 
disclosed to a third party without the prior written consent of the Sponsor. 
The data generated by this study are considered confidential information and the property of 
the Sponsor. This confidential information may be published only in collaboration with 
participating personnel from the Sponsor or upon Sponsor’s written consent to publish the 
article. 
 
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16 REFERENCES 
Cahill MA, Jazayeri JA, Catalano SM, et al. 2016. The emerging role of progesterone 
receptor membrane component 1 (PGRMC1) in cancer biology. Biochim Biophys Acta. pii: 
S0304-419X(16)30049-X. doi: 10.1016/j.bbcan.2016.07.004. [Epub ahead of print] Review. 
PMID: 27452206).  
Food and Drug Administration: Code of Federal Regulation (CFR) Title 21. Part 361 
Prescription Drugs for Human Use Generally Recognized as Safe and Effective and not 
Misbranded: Drugs Used in Research (April 2019). Available at: 
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=361.1. 
Accessed on 17Dec2020. 
Investigator’s Brochure (Version 5). Cognition Therapeutics, Inc., CT1812, September 2021. 
Izzo NJ, Staniszewski A, To L et al. 2014(a). 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. 
 
National Council on Radiation Protection and Measurements (NCRP) Report No. 160, 
Ionizing Radiation Exposure of the Population of the United State, National Council on 
Radiation Protection and Measurements, March 2009. 
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