Clinical trial NCT05104463
Conditions: Mild Cognitive Impairment Dementia
Sponsor: CuraSen Therapeutics, Inc.
Start date: 2022-04-11; Completion date: 2024-02-01
Enrollment: 64 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This is a Phase 2a, randomized, placebo-controlled, double-blind, crossover study to evaluate the effects CST-2032 administered with CST-107 on cognition in participants with Mild Cognitive Impairment (MCI) or mild dementia.

Detailed description:
Approximately 60 participants will be enrolled in a 2 period, 2-way crossover design following study eligibility confirmation during the screening period. During each treatment period, subjects will receive daily doses of CST-2032 administered with CST-107 or matching placebo for 14 days. Each treatment period will be separated by a washout period of at least 7 days and up to 21 days.

All participants will complete clinical, cognitive and pharmacodynamic assessments during each treatment period. PK blood samples will be collected prior to, during and after study medication administration.

Arms: arm 1: Participants will receive daily doses of CST-2032 (3mg) co-administered with CST-107 (3mg) for 14 days, followed by a washout period of no drug for 7 days, followed by matching placebo for CST-2032 and matching placebo for CST-107 for 14 days. arm 2: Participants will receive matching placebo for CST-2032 and matching placebo for CST-107 for 14 days followed by a washout period of no drug for 7 days, followed by daily doses of CST-2032 (3mg) co-administered with CST-107 (3mg) for 14 days.
Interventions: intervention 1: CST-2032, matching placebo for CST-2032, CST-107, matching placebo for CST-107
Intervention descriptions: intervention 1: CST-2032 and matching placebo white tablets, CST-107 and matching placebo yellow tablets

Protocol documents:
Prot_000.pdf: 
Protocol CST2032/CST107-CLIN-015 
 
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Clinical Trial Protocol 
Clinical Trial Title 
A Phase 2a, Randomized, Placebo-Controlled, Double-Blind, Crossover Study to 
Evaluate the Safety, Tolerability and Effects of CST-2032 and CST-107 on 
Cognition in Subjects with Mild Cognitive Impairment or Mild Dementia due to 
Parkinson’s or Alzheimer’s Disease. 
Protocol Number 
CST2032/CST107-CLIN-015 
IND Number 
158123 
Clinicaltrials.gov NCT 
NCT05104463 
Investigational Products 
CST-2032, CST-107 
Indication 
Cognitive Impairment 
Sponsor 
CuraSen Therapeutics, Inc. 
930 Brittan Avenue, #306 
San Carlos, CA 94070, USA 
Phone: +1 650-475-2842 
Sponsor’s Medical Monitors 
 
 
 
 
 
Clinical Trial Compliance 
This clinical trial will be conducted in accordance with standards of Good Clinical 
Practice, as defined by the International Council for Harmonisation (ICH) and all 
applicable federal and local regulations. 
Version/Date  
Version 1.0 / November 8, 2021  
 
Amendment 1 / November 12, 2021  
 
Amendment 2 / November 17, 2021  
 
Amendment 3 / January 10, 2022 
 
Amendment 4 / February 28, 2022 
 
Amendment 5 / May 26, 2022 
 
Amendment 6 / August 04, 2022 
 
Amendment 7 / September 27, 2022 
 
Amendment 8 / December 09, 2022 
 
Amendment 9 / March 15, 2023 
 
Amendment 10 / July 11, 2023 
Confidential Information 
The confidential information in this document is provided to you as a Principal Investigator, potential Principal Investigator, or Consultant, for review by you, your 
staff, and applicable institutional review committees. This information will not be disclosed to others without written authorization from Sponsor except to the extent 
necessary to obtain informed consent from those persons to whom the drug may be administered. 


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SIGNATURE PAGE 
 
Declaration of Sponsor 
Title:  
A Phase 2a, Randomized, Placebo-Controlled, Double-Blind, Crossover Study to Evaluate 
the Safety, Tolerability and Effects of CST-2032 and CST-107 on Cognition in Subjects with 
Mild Cognitive Impairment or Mild Dementia due to Parkinson’s or Alzheimer’s Disease. 
 
This clinical trial protocol was subjected to critical review. The information it contains is 
consistent with current knowledge of the risks and benefits of the Investigational Products, 
with moral, ethical, and scientific principles governing clinical research and in accordance 
with Good Clinical Practice and applicable federal and local regulations. 
 
 
 
_____________________________________ 
_____________________ 
Name: 
  
Date 
Title: Chief Medical Officer 
 
CuraSen Therapeutics, Inc. 
 


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INVESTIGATOR’S AGREEMENT 
Title:  
A Phase 2a, Randomized, Placebo-Controlled, Double-Blind, Crossover Study to Evaluate 
the Safety, Tolerability and Effects of CST-2032 and CST-107 on Cognition in Subjects with 
Mild Cognitive Impairment or Mild Dementia due to Parkinson’s or Alzheimer’s Disease. 
I have read all pages of this clinical study protocol and any amendments for which CuraSen 
is the Sponsor. I agree to conduct the study as outlined in the protocol and to comply with all 
the terms and conditions set out therein. I confirm that I will conduct the study in accordance 
with Good Clinical Practice (cGCP) guidelines. I will also ensure that sub-investigator(s) and 
other relevant staff members have access to copies of this protocol and all other relevant 
information provided by Sponsor and the ICH cGCP guidelines to enable them to work in 
accordance with the provisions of these documents. 
 
Principal Investigator 
 
 
_____________________________________ 
_____________________ 
Name  
Date 
Title 
Institution 
 
CONTACTS IN CASE OF EMERGENCY 
Role in Study 
Name 
Telephone and Email 
CuraSen Medical Monitor 
(US) 
 
 
 
CuraSen Medical Monitor 
(NZ) 
 
 
 
 
 


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PROTOCOL SYNOPSIS 
Title 
A Phase 2a, Randomized, Placebo-Controlled, Double-Blind, 
Crossover Study to Evaluate the Safety, Tolerability and Effects 
of CST-2032 and CST-107 on Cognition in Subjects with Mild 
Cognitive Impairment or Mild Dementia due to Parkinson’s or 
Alzheimer’s Disease. 
Sponsor 
CuraSen Therapeutics, Inc. 
Study Medication 
CST-2032 co-administered with CST-107 
Primary Objective 
The primary objective of this study is to evaluate the safety and 
tolerability of CST-2032 when combined with CST-107.  
Secondary Objectives 
The secondary objectives of this study will evaluate the effects of 
CST-2032 when combined with CST-107 versus placebo on the 
following measures: 
1. Cognition 
2. Mood  
3. Attention Deficit  
4. Apathy 
5. Overall clinical improvement 
6. PK 
Exploratory 
Objectives 
The exploratory objectives are: 
• To evaluate whether baseline disease characteristics impact 
response to treatment. 
• To characterize the effects of treatment on 
neurodegenerative biomarkers in the blood such as 
neurofilament light chain, total and phosphorylated tau 
protein, and amyloid‐β (Aβ) peptides may also be measured. 
Primary Endpoint 
The primary endpoint is safety and tolerability of CST-2032 
including adverse event rates (AEs), serious adverse event rates 
(SAEs), study discontinuation rates, electrocardiograms (ECGs), 
vital signs, and laboratory safety observations. 
Secondary Endpoints 
The secondary endpoints will compare the effect of CST-2032 
administered with CST-107 versus placebo on the following:  
• Cognitive tasks in the Cambridge Neuropsychological 
Test Automated Battery (CANTAB) and other cognitive 
measures: 
o Reaction Time (RTI) - attention 
o Verbal Recognition Memory (VRM) – episodic 
memory (verbal stimuli) 
o Adaptive Tracking Task (ATT) – visuospatial 
with strong attentional demand 


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o Paired Associates Learning (PAL) – episodic 
memory (visual stimuli) 
o Delayed Verbal Recall - episodic memory (verbal 
stimuli) 
o Stop Signal Task (SST) – response inhibition 
(impulsivity), an aspect of executive function  
o Phonological verbal fluency (pVFT) 
o Digit symbol substitution test (DSST) 
o Color Trails Test (select sites only) 
• Facial expression recognition task (FERT)  
• Geriatric Depression Scale – 30 questions (GDS-30) 
• Conners Adult Attention Deficit Hyperactivity Disorder 
Scale (ADHD) Rating Scale, short form, self-report 
(CAARS) 
• Starkstein Apathy scale short form (SAS-6) 
• Alzheimer's Disease Cooperative Study-Clinical Global 
Impression of Change (ADCS-CGIC) 
• Suicidal ideation using the Columbia Suicide Severity 
Rating Scale (C-SSRS). 
• Plasma pharmacokinetics (PK) parameters of CST-2032 
and CST-107 (including Cmax, tmax, AUCt, t1/2).  
Exploratory Endpoints 
The following exploratory endpoints may be undertaken to 
evaluate:  
• Subgroup and/or correlation analyses of effects of treatment 
on baseline disease characteristics including but not limited 
to disease activity as determined from relevant disease 
scales at screening, genetic variants involved in 
neurodegenerative disease including but not limited to 
apolipoprotein E4 (APOE4), leucine rich repeat kinase 2 
(LRRK2), and glucocerebrosidase (GCase) protein (GBA) 
(optional and where applicable).  
• Changes in neurodegenerative biomarkers, such as 
neurofilament light chain, total and phosphorylated tau 
protein, and amyloid‐β (Aβ) peptides, as measured prior to 
and after treatment may be evaluated.  
• Change in average z-score for baseline-deficit cognitive 
tasks identified for each subject from the Cognitive tasks in 
the Cambridge Neuropsychological Test Automated Battery 
(CANTAB) and other cognitive measures. 
Methodology 
This is a Phase 2a, randomized, placebo-controlled, double-blind, 
crossover study to evaluate the safety, tolerability and effects 


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CST-2032 administered with CST-107 on cognition in subjects 
with MCI or mild dementia. 
Approximately 60 subjects will be enrolled in a 2 period, 2-way 
crossover design following study eligibility confirmation during 
the screening period. 
During each treatment period, subjects will receive 3 mg CST-
107 or matching placebo on Day -1, followed by daily doses of 
CST-2032 (co-administered with CST-107) or matching placebo 
on Day 1 through Day 14. Each treatment period will be 
separated by a washout period of at least 7 days and up to 21 
days.  
All subjects will complete clinical, cognitive and 
pharmacodynamic assessments during each treatment period as 
indicated in the Schedule of Events. 
PK blood samples will be collected prior to, during and after 
study medication administration, as indicated in the Schedule of 
Events. 
Number of Subjects  
Approximately 60 subjects will be enrolled in this study. 
Number of Sites 
Subjects will be enrolled at up to 20 clinical sites globally 


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Inclusion Criteria 
A subject will be considered eligible for enrollment if all of the 
following are met: 
1. Male or female subjects ≥ 50 and ≤ 85 years of age at time 
of informed consent. 
2. Diagnosis of mild cognitive impairment (per National 
Institute on Aging-Alzheimer's Association core clinical 
criteria [refer to Section 4.4]) OR mild dementia due to 
either: 
a. Parkinson's disease (as defined by the United 
Kingdom Parkinson’s Disease Brain Bank criteria) 
associated with REM sleep behavior disorder 
(RBD+PD) diagnosed according to the 
International Classification of Sleep Disorders, 
Third Edition (ICSD-3, albeit documentation by 
polysomnography is not required) and positive 
response to the RBD Single-Question Screen 
(RBD1Q) and without hallucinations [refer to 
Section 4.4], OR  
b. Alzheimer’s Disease (probable Alzheimer’s 
disease based on National Institute on Aging-
Alzheimer’s Association core clinical criteria 
[refer to Section 4.4]). 
3. If the subject is taking medications, they have been on a 
stable dose for at least 30 days (90 days for anti-psychotic 
medications) prior to Day -1, and the dose and regimen 
must remain unchanged through the End of Study Visit 
unless required for management of adverse events (AEs). 
4. Cognitive decline not primarily caused by vascular, 
traumatic, or medical problems (alternative causes of 
cognitive decline are ruled out). 
5. Adequate visual and auditory abilities and motor skills to 
perform all aspects of the cognitive and functional 
assessments. 
6. Has a partner or caregiver who can accompany the subject 
at specified study visits (if required based on cognitive 
function). 
7. MoCA score ≥ 14 and ≤ 26. 
8. Unless confirmed to be azoospermic (vasectomized or 
secondary to medical cause), males must agree to use a 
male condom from Day -1 until the End-of-Study visit 
when having penile-vaginal intercourse with a woman of 
childbearing potential who is not currently pregnant.  
Note: Men with a pregnant or breastfeeding partner must 
agree to remain abstinent from penile-vaginal intercourse 


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or use a condom during each episode of penile-vaginal 
penetration until after the End-of-Study Visit. 
9. Females of childbearing potential (i.e., not 
postmenopausal, or surgically sterile) who have a male 
partner must have a negative serum pregnancy test result 
and must agree to one of the following from start of 
Screening through 30 days after the last study medication 
administration: 
a. use a highly effective method of birth control 
(refer to Section 5.6), or 
b. monogamous relationship with a male partner of 
confirmed sterility, or 
c. practice complete abstinence (refer to 
Section 5.6). 
10. Females of non-childbearing potential may be enrolled if 
it is documented that they are postmenopausal (refer to 
Section 5.6). 
11. Body weight greater or equal to 50 kg and body mass 
index (BMI) between 18 and 35 kg/m2, inclusive at 
Screening.  
12. Stable medical conditions for 30 days prior to Screening 
visit (e.g., controlled hypertension, dyslipidemia). 
13. Willing to follow the protocol requirements and comply 
with protocol restrictions. 
14. Capable of providing informed consent and complying 
with study procedures. 
15. Able to speak, understand and read English. 


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Exclusion Criteria 
Subjects with any of the following will not be eligible for 
participation. 
1. Subjects with poorly controlled hypertension despite 
lifestyle modifications and/or pharmacotherapy. 
2. Subjects with pulmonary disease, including asthma, or 
evidence of clinically significant moderate or severe 
pulmonary symptoms. 
3. Clinical signs indicating syndromes such as corticobasal 
degeneration, supranuclear gaze palsy, multiple system 
atrophy, chronic traumatic encephalopathy, signs of 
frontotemporal dementia, history of stroke, head injury or 
encephalitis, cerebellar signs, early severe autonomic 
involvement, or Babinski sign. 
4. Current evidence of epilepsy, focal brain lesion, head 
injury with loss of consciousness or meeting DSM-V 
diagnostic criteria for psychotic disorders, such as 
schizophrenia or bipolar disorder, or have unstable 
concomitant psychiatric symptomatology (NOTE: 
Subjects with psychotic disorders may be enrolled if their 
condition is effectively managed (i.e., must be receiving 
stable doses of anti-psychotic medication(s) 90 daysprior 
to randomization and must remain on that dose 
throughout both treatment periods) 
5. Evidence of any significant clinical disorder or laboratory 
finding (e.g., potassium levels below normal range) that 
renders the participant unsuitable for receiving an 
investigational drug including clinically significant or 
unstable hematologic, moderate and severe impairment of  
hepatic function (as defined by the National Cancer 
Institute Organ Dysfunction Working 
Group),cardiovascular, pulmonary, gastrointestinal, 
endocrine (including thyrotoxicosis, excluding managed 
hypo- or hyper- thyroidism), immunologic, dermatologic, 
neurologic, musculoskeletal, metabolic, renal, or other 
systemic disease or laboratory abnormality. 
6. Participants with a history of malignant disease within 
5 years, including solid tumors and hematologic 
malignancies (exceptions: [a] basal cell and squamous 
cell carcinomas of the skin or solid tumors that have been 
completely excised and are considered cured; [b] low-
grade adenocarcinoma of the prostate, which are slow 
growing, and are unlikely to progress or metastasize 
during the clinical trial). 
7. Any current clinically significant medical condition or 
disease as determined by medical history, physical 


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examination, 12-lead electrocardiogram (ECG) and 
clinical laboratory assessments that, in the view of the 
Principal Investigator, will interfere with participation in 
the study or interpretation of results.  
8. Clinically significant abnormalities of 12-lead ECG (as 
determined by a central reader), including QTcF > 440 
ms, for males and females, and/or HR < 50 beats per 
minute, or evidence of bundle branch block, as indicated 
on the Mean ECG Analysis Report during the screening 
period.  
9. A calculated creatinine clearance of ≤ 60 mL/min 
according to the Cockcroft-Gault equation. 
10. Current use of any prohibited prescription medication, 
over-the-counter medication, or herbal supplements 
including green tea products (refer to Section 5.4) during 
Screening or throughout study, unless approved by both 
the Investigator and the Sponsor Medical Monitor.  
11. Prior and/or concurrent treatment with any investigational 
drug ≤ 90 days prior to dosing (Day -1), or ≤ 5 half-lives 
of the drug (whichever is longer), or current enrollment in 
any other study treatment or disease study, except for 
observational studies. 
12.  Prior and/or concurrent treatment with any β-AR 
agonists or β-AR blockers (includes oral meds, IV or 
inhaled) or any meds that impact adrenergic signaling 
within the last month prior to Screening. Subjects may be 
on stable doses of serotonin-selective reuptake inhibitor 
(SSRI) antidepressants but are prohibited to be on 
serotonin-noradrenaline reuptake inhibitors (SNRIs), or 
tricyclic antidepressants (TCAs), or any treatment for 
ADHD including noradrenaline reuptake inhibitors 
(NRIs), or amphetamines within the last month prior to 
Screening. 
13. A history of heart failure, sinus bradycardia, second- or 
third-degree heart block, hypokalemia, attack of 
unconsciousness possibly associated with torsades de 
pointes (TdP) or family history of Long QT Syndrome. 
14. Known or suspected alcohol or substance abuse within 
the past 12 months and/or positive test for alcohol or 
drugs of abuse at Screening or Day -1. 
15. Suicidal ideation with actual intent or plan (“Yes” answer 
on the C-SSRS ideation items 4 or 5) within 3 months 
prior to study Screening. 
16. Positive screening test for human immunodeficiency 
virus (HIV), hepatitis C antibody (HCV Ab) or current 
hepatitis B infection (defined as positive for hepatitis B 


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surface antigen [HBsAg] at Screening). Subjects with 
immunity to hepatitis B (defined as negative HbsAg and 
positive hepatitis B surface antibody [HbsAb]) are 
eligible to participate in the study. 
17. Current infection with severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2).  
18. Females who are breastfeeding. 
19. Any other reason for which the PI considers it is not in 
the best interest of the participant to undertake the study.  
Description of Study 
Medications  
In this study, subjects will be randomly assigned to one of 
2 treatment regimens: 
 
Treatment Period 1 
Treatment Period 2 
1 3 mg CST-2032 + 3 mg CST-107 Placebo (2032) + placebo (107) 
2 
Placebo (2032) + placebo (107) 3 mg CST-2032 + 3 mg CST-107 
On Day -1 of each treatment period, CST-107 or matching 
placebo will be administered after completion of all scheduled 
study assessments. On all other dosing days, CST-107 or placebo 
will be co-administered with CST-2032 or placebo. 
The study medications will be provided as oral tablets for 
CST-2032, CST-107, and corresponding matching placebos. All 
subjects will be administered the same number of tablets 
regardless of treatment regimen. 
During Treatment Periods 1 and 2, subjects will receive once 
daily oral doses of 3 mg CST-2032 or matching placebo and 
3 mg CST-107 or matching placebo on Days 1–14. 
Subjects will be given blister cards for CST-2032 or matching 
placebo and blister cards or bottles for CST-107 or matching 
placebo containing 10 repeat doses for a 1-week supply at study 
visits during each treatment period and will be instructed to self-
administer daily in the morning.  
Study Duration  
The study duration will be approximately 12 weeks, which 
includes a Screening period of up to 28 days, the treatment/study 
period of 7 weeks (two 2-week treatment periods separated by a 
washout period of at least 7 and up to 21 Days), and the 
End-of-Study Visit of up to 12 Days after the last study drug 
dose. 


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Study Procedures 
After informed consent, all subjects will complete screening 
procedures and tests to establish eligibility, which will be 
performed between Day -28 and Day -2. Subjects who meet 
eligibility criteria based on screening assessments may be 
enrolled in the study. 
Study Procedures 
(continued) 
Screening procedures include medical history evaluation, body 
weight and height measurements, physical exam, vital signs 
(including blood pressure, heart rate, respirations, temperature), 
ECGs, Columbia-Suicide Severity Rating Scale (C-SSRS), safety 
laboratory tests (chemistry, hematology, and urinalysis), blood 
draw for evaluation of genetic variants including but not limited 
to APOE4, and neurodegeneration biomarkers, creatinine 
clearance calculation, drug and alcohol breath tests, 
SARS-CoV-2 test, serum HIV, Hepatitis B and C screen. A 
serum β-hCG pregnancy test must be completed for women of 
childbearing potential. Postmenopausal women will need to 
complete a follicle-stimulating hormone (FSH) test. 
Subjects with a positive drug screen (including alcohol) at 
Screening will be rechecked and if positive will be excluded from 
participation in the study.  
During the Screening Visit, the following disease and cognitive 
assessments and measures will be completed as required to 
evaluate eligibility: RBD1Q (administered to all subjects but 
used for eligibility only in PD subjects), and MoCA. In addition, 
the modified Hoehn and Yahr Scale (MHYS) will be evaluated in 
subjects with PD for purposes of patient phenotyping. ADCS-
CGIC will also be completed.  
Once all screening visit procedures are completed and the subject 
meets all eligibility criteria, the subject will return to the site to 
be trained on and practice the CANTAB. Subjects will be 
randomly assigned to one of the two treatment regimens on Day -
1.  
A comprehensive list of all study procedures is provided in the 
Schedule of Events. 
Concomitant 
Medications 
Any concomitant therapy used from the time the subject signs the 
informed consent through the final visit must be recorded on the 
case report form (CRF) for all randomized subjects. In addition, 
any medication required for treatment of adverse events (AEs) or 
serious adverse events (SAEs) must be recorded on the CRF. 
Permitted and prohibited medications are listed in Section 5.4. 


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Sample Size 
Justification 
The sample size estimation is based on a crossover design with 
the assumption that carryover effects are equal. 
A total of approximately 60 subjects is planned. The sample size 
is based on practical considerations and is typical of studies 
whose objectives are to evaluate the safety and cognitive effects 
of a therapeutic intervention. The study is only powered for very 
large effect sizes. Lack of statistical significance will not be 
indicative of lack of a potentially meaningful treatment effect. 
Statistical Analysis 
Details of statistical parameters and methods to be used will be 
described in a Statistical Analysis Plan (SAP).  
Analysis of effects on baseline-deficit cognitive tasks will be 
based on an analysis of variance of the change from baseline, 
where baseline is the average of the two latest pre-treatment 
assessments in each treatment period with each patient used as 
their own control. This analysis will be described in more detail 
in the SAP. 
Continuous data will display number of subjects, means, standard 
deviations, median, minimum, and maximum. Categorical data 
will display frequency counts and percentages. Unless specified 
otherwise, confidence intervals will be displayed at the two-sided 
95% confidence level.  
Disposition and baseline data will be summarized by disease 
criteria (MCI and mild dementia combined and separately), 
treatment sequence and overall. Summaries of safety, 
pharmacodynamics and PK will be presented by disease criteria, 
treatment (active versus placebo), drug (CST-2032/ CST-107) 
and overall. A limited subset of summaries may be presented by 
treatment sequence and/or period and overall.  
For primary and secondary endpoints, observed values and 
changes from baseline, as well as the difference between change 
from baseline within subject, will be summarized. For continuous 
endpoints, the difference is defined as change from baseline on 
drug minus change from baseline on placebo. Comparisons may 
be made using a mixed model with factors for disease criteria, 
treatment, treatment sequence, subject nested in sequence (as a 
random effect), period, and baseline values as appropriate. 
Comparisons between treatments may also be compared using 
the paired t-test and/or nonparametric tests where appropriate. 


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Statistical Analysis 
(continued) 
All adverse events will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA) and will be summarized by 
system organ class and preferred term. 
Subgroup analyses may be conducted after study completion to 
evaluate whether effects of treatment are influenced by baseline 
disease characteristics including but not limited to disease 
activity as determined from relevant disease scales at screening, 
neurodegenerative biomarkers in plasma, and genetic variants 
including but not limited to APOE4, LRRK2, and GBA. All data 
will be listed. 
 


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STUDY SCHEMA 
 
Cognition tests to include (CANTAB), phonological verbal fluency test (pVFT), digit symbol substitution test (DSST).  
*Secondary endpoint measures include facial expression recognition task (FERT); Geriatric Depression Scale – 30 questions (GDS-30); Conners Adult Attention 
Deficit Hyperactivity Disorder Scale (ADHD) Rating Scale, short form, self-report (CAARS); Starkstein Apathy scale short form (SAS-6); and Alzheimer’s 
Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC).  ADCS-CGIC is not done on Day -1 or Day 1. 
 


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SCHEDULE OF EVENTS 
 
Screening 
Treatment Periods 1 & 21 
End of Study 
Days -28 to -2 
Day -1 
Day 1 
Day 7±12 
Day 14±1 or Early 
Withdrawal2,3 
7-12 Days after Last Dose of 
Study Drug or EW Visit2 
Outpatient visit 
X 
X 
X 
X 
X 
X 
Informed consent 
X 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
Assess Inclusion/Exclusion criteria 
X 
X21 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
Height, weight, BMI calculation 
X 
 
 
 
 
 
Vital signs5 
X 
X 
X 
X 
X3 
X 
ECG6 
X 
X 
X 
X 
X3 
X 
Physical exam7 
X 
 
 
 
 
X 
Safety labs8 
X 
 
X19 
X20 
X3, 20 
X 
Urine drug screen 
X 
 
 
 
 
 
Alcohol breath test 
X 
X 
 
 
 
 
HIV and Hepatitis serologies 
X 
 
 
 
 
 
Serum FSH9 
X 
 
 
 
 
 
β-hCG pregnancy test9 
X 
 
 
 
 
 
Serum or urine pregnancy test9 
 
X 
 
 
X3 
X 
SARS-CoV-2 assessment10 
X 
 
 
 
 
 
Genetic variants including but not limited 
to APOE4, LRRK2, GBA (optional and 
where applicable) 
X 
 
 
 
 
 
Neurodegeneration biomarkers 
X 
 
 
 
X 
 
PK sample11 
 
 
 
X 
 
 
RBD1Q, MHYS12 
X 
 
 
 
 
 
MoCA12 
X 
 
 
 
X 
 


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Screening 
Treatment Periods 1 & 21 
End of Study 
Days -28 to -2 
Day -1 
Day 1 
Day 7±12 
Day 14±1 or Early 
Withdrawal2,3 
7-12 Days after Last Dose of 
Study Drug or EW Visit2 
DSST12 
X 
X 
X 
X 
X 
 
FERT13 
 
X 
X 
 
X 
 
CANTAB, pVFT14 
X 
X 
X 
X 
X 
 
Color Trails Test4 
 
X 
 
X 
X 
 
SAS-6, CAARS, GDS-3015 
 
X 
X 
 
X 
 
C-SSRS12 
X 
X16 
 
X 
X3 
X 
ADCS-CGIC12,17 
X 
 
 
 
X 
 
Study drug administration18 
 
 
 
 
 
 
Provide subject dosing instructions and 
dispense dosing diary 
 
 
X 
 
 
 
Review dosing diary 
 
 
 
X 
X3 
 
Assessment of AEs 
 
X 
X 
X 
X3 
X 
Concomitant medications 
X 
X 
X 
X 
X3 
X 
AE = adverse event; ECG = electrocardiogram;  PK = pharmacokinetics 
 
Disease assessments should be conducted after the subjects have been provided with a light meal or snack without caffeinated beverages or high sugar content in 
the following order if possible: FERT before pVFT, then DSST and then CANTAB and Color Trails Test. ADCS-CGIC should be conducted last. 
1 Washout period between Treatment Periods 1 & 2 is 7 to 21 days. The washout period may be extended with prior approval by the CuraSen Medical Monitor, 
2 Visit to be conducted in the clinic, or other off-site location or at the subject’s home according to site preference and capabilities. In addition, should there be 
factors and/or conditions which would make a site visit unnecessarily difficult and/or potentially unsafe for a subject, some visits and/or procedures may be 
performed by alternate arrangement, e.g., visits in the subject’s home, virtual visits. The End of Study visit is to occur 7-12 days after last dose of study drug. 
3 Subjects who withdraw from the study prior to completion of dosing should complete these Day 14 safety assessments at the time of early withdrawal (EW). 
4 The Color Trails Test should be completed after the CANTAB assessments (select sites only). 
5 Vital signs to include orthostatic changes in BP and HR, respiratory rate, and oral/tympanic temperature. For assessments of orthostatic changes, BP and HR 
are obtained: a) after rest in a supine position for at least 5 minutes, and b) 1 minute after standing.  Vital signs will be obtained at every study visit as 
follows:  
• 
Screening 
• 
Day -1 prior to administration of CST-107 or matching placebo in each treatment period 
• 
Days 1, 7, and 14 of each treatment period:  
o 
Within 30 minutes prior to dosing of study drug (CST-2032+CST-107 or matching placebos),  
o 
Approximately 4 hours (± 30 minutes) after administration of study drug,  


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• 
End-of-Study Visit. 
6 ECGs to be obtained in triplicate (separated by approximately 1 minute) after subject is supine for 5 minutes at the following timepoints:  
• 
Screening 
• 
3 sets of triplicate ECG measures (i.e., 9 ECGs) on Day -1 prior to administration of CST-107 or matching placebo in each treatment period to 
thoroughly establish a baseline; the time between each set of 3 ECGs should be ≤5 minutes. 
• 
On Day 1 of each treatment period:  
o 
Within 30 minutes prior to dosing of study drug,  
o 
Approximately 1 hour after administration of study drug, 
o 
Approximately 2 hours after administration of study drug, 
o 
Approximately 4 hours after administration of study drug,  
• 
Days 7 and 14 of each treatment period:  
o 
Within 30 minutes prior to dosing study drug,  
o 
Approximately 1 hour after administration of study drug, 
o 
Approximately 2 hours after administration of study drug, 
o 
Approximately 4 hours after administration of study drug,  
• 
End-of-Study Visit, 
• 
All ECGs will be evaluated by a central ECG reader. 
7 A complete physical examination (PE) (excluding genital, rectal and breast exams) is required at Screening; the End-of-Study PE will be symptom-driven 
based on subject complaints.  
8 Safety labs to include hematology, chemistries, and urinalysis. Fasting safety labs to be conducted at Screening and EOS. 
9 At Screening, serum β-hCG pregnancy test for females of childbearing potential; an FSH test will be performed for postmenopausal women. Females of 
childbearing potential will have serum or urine pregnancy tests (per standard site practice) on Day -1, Day 14/EW and at the End-of-Study visit.  
10 Subjects to be tested for current SARS-CoV-2 infection at Screening. Additional evaluations of SARS-CoV-2 infection on other visit days should be 
according to site standard operating procedures. 
11 PK samples to be collected on Day 7 of each treatment period:  
• 
within 15 minutes prior to dosing study drug, 
• 
0.5+0.25 hour after administration of study drug, 
• 
1+0.5 hour after administration of study drug,  
• 
2+0.5 hour after administration of study drug, and  
• 
4+0.5 hours after administration of study drug. 
12 The DSST, C-SSRS, pVFT, ADCS-CGIC, MoCA and MHYS (if done within the past 3 months, MHYS does not have to be repeated) are to be administered 
by a qualified clinical rater. The MHYS will be recorded but not be used as an enrollment criterion. 
 
13 Facial Recognition Task (FERT) will be conducted at the following timepoints in each treatment period: 
• 
Day -1: Prior to administration of CST-107 or matching placebo,  
• 
Day 1: at least 2 hours after dosing of study drug, 
• 
Day 14: at least 2 hours after dosing of study drug. 


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14 First administration of CANTAB is to familiarize the subject with the tests and equipment. The CANTAB and phonological verbal fluency (pVFT) test and 
DSST should be administered after completion of FERT at the following timepoints in each treatment period: 
• 
CANTAB only to be administered twice, at least 1 hour apart during the final week (Day -8 to Day -2) before Treatment Period 1 to familiarize subjects 
with the CANTAB 
• 
CANTAB, pVFT and DSST to be administered on Day -1 prior to administration of CST-107 or matching placebo. These tests are to be administered in 
each treatment period at approximately the same time of day (±1 hour) and under approximately the same food status as planned for the tests on Days 1, 
7, and 14. 
• 
CANTAB, pVFT and DSST to be administered on Days 1, 7 and 14 of each treatment period:  
o 
3±0.5 hours after administration of study drug. Tests should be conducted at approximately the same time of day (±1 hour) and under the same 
food status on Days -1, 1, 7 and 14.  
15 SAS-6, CAARS, and GDS-30 are per subject self-report. These tests will be administered at the following timepoints in each treatment period: 
• 
Day -1: Prior to administration of CST-107 or matching placebo 
• 
Day 1: at least 2 hours after dosing of study drug, 
• 
Day 14: at least 2 hours after dosing of study drug. 
16 C-SSRS not completed on Day -1 during Treatment Period 1. 
17 The ADCS-CGIC will be administered at the following timepoints in each treatment period: 
• 
Screening 
• 
Day 14: at least 3 hours after dosing of study drug. 
18 On Day -1 only, CST-107 or matching placebo is to be administered upon completion of all scheduled study assessments. On all other dosing days, study 
drugs (CST-2032+CST-107 or matching placebos) are to be co-administered. On Days -1, 1, 7 and 14 the study drugs are administered in the clinic. 
19 On Day 1, safety labs will be collected pre-dose and approximately 4 hours post-dose (chemistry only at 4 hours post-dose). 
20 On Days 7 and 14, safety labs will be collected approximately 4 hours post-dose. 
21 Inclusion/exclusion criteria not re-assessed on Day -1 of Treatment Period 2. 
 


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LIST OF ABBREVIATIONS  
Abbreviation 
Definition 
ADCS-CGIC 
Alzheimer’s Disease Cooperative Study-Clinical Global Impression 
of Change 
APOE4 
Apolipoprotein E4  
β-AR 
Beta-adrenoceptor 
β-hCG 
Beta human chorionic gonadotropin 
AD 
Alzheimer’s Disease 
AE 
Adverse event 
ADHD 
Attention Deficit/Hyperactivity Disorder  
AS 
Apathy scale 
ASL MRI 
Arterial spin labelling magnetic resonance imaging 
ATT 
Adaptive tracking test 
AUCinf 
Area under the drug concentration-time curve from time zero to 
infinity 
AUCt 
Area under the drug concentration-time curve from time zero to 
time t 
BMI 
Body mass index  
BP 
Blood pressure 
CAARS 
Connors Adult Attention Deficit/Hyperactivity Disorder Scale – 
short form, self-report 
cAMP 
cyclic adenosine monophosphate 
CANTAB 
Cambridge Neuropsychological Test Automated Battery 
CBF 
Cerebral blood flow  
cGCP 
Current Good Clinical Practice 
CLIN-002 
CST103/CST107/CST109-CLIN-002 
CLIN-007 
CST2032-CLIN-007 
Cmax 
Maximum concentration  
CNR 
Contrast-to-noise ratio 
CNS 
Central nervous system 
CRF 
Case report form 
CST-107 
Nadolol 
DSMB 
Data and Safety Monitoring Board 
DSM-V 
Diagnostic and Statistical Manual of Mental Disorders 5 
DSST 
Digital Symbol Substitution Test 
eCRF 
Electronic case report form 
EC 
Ethics committee 


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Abbreviation 
Definition 
ECG 
Electrocardiogram 
EW 
Early withdrawal 
FERT 
Facial Expression Recognition Task 
FSH 
Follicle-stimulating hormone 
GBA 
Glucocerebrosidase (GCase) protein 
GDS-30 
Geriatric Depression Scale – 30 questions 
HR 
Heart rate 
HbsAb 
Hepatitis B surface antibody 
HbsAg 
Hepatitis B surface antigen 
HCV Ab 
Hepatitis C antibody 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
ICSD-3 
International Classification of Sleep Disorders, Third Edition 
IRB 
Institutional review board 
ISI 
Interstimulus interval 
ITT 
Intent to treat 
IV 
Intravenous 
IWRS 
Interactive Web Response System 
LC 
Locus coeruleus 
LRRK2 
Leucine rich repeat kinase 2 
MAOI 
Monoamine oxidase inhibitor 
MCI 
Mild cognitive impairment  
MedDRA 
Medical Dictionary for Regulatory Activities 
MHYS 
Modified Hoehn & Yahr Scale 
MoCA 
Montreal Cognitive Assessment 
PAL 
Paired Associates Learning 
PD 
Parkinson’s Disease 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PO 
By mouth/oral administration 
pVFT 
Phonological verbal fluency test 
QD 
Once daily 
QTcF 
QT interval corrected for changes in heart rate using the Fridericia 
equation 
RBD 
REM Sleep Behavior Disorder 


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Abbreviation 
Definition 
RBD1Q 
REM sleep behavior disorder (RBD) Single-Question Screen 
RTI 
Reaction Time Index 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SAS-6 
Starkstein apathy scale – short form (6 questions) 
SIR 
standard image recognition 
SNRI 
serotonin/noradrenaline reuptake inhibitors 
SOP 
Standard operating procedure 
SSRI 
Serotonin selective reuptake inhibitors 
SST 
Stop signal test 
t1/2 
Time to maximum observed drug concentration 
TEAE 
Treatment emergent adverse event 
tmax 
Time of maximum concentration 
VRM 
Verbal Recognition Memory 
WAIS-IV 
Wechsler Adult Intelligence Scale, Fourth Edition 
 
 
 
 


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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ............................................................................................ 4 
STUDY SCHEMA ................................................................................................... 15 
SCHEDULE OF EVENTS ...................................................................................... 16 
LIST OF ABBREVIATIONS .................................................................................... 20 
TABLE OF CONTENTS ........................................................................................... 23 
LIST OF FIGURES ................................................................................................... 25 
1. 
INTRODUCTION .............................................................................................. 26 
1.1. 
Rationale for Dose Selection ..................................................................... 29 
1.1.1. 
Rationale for CST-2032 Dose Selection ......................................... 29 
1.1.2. 
Rationale for CST-107 Dose Selection ........................................... 31 
1.2. 
Compliance Statement .............................................................................. 32 
2. 
STUDY OBJECTIVES AND ENDPOINTS ...................................................... 32 
2.1. 
Study Objectives ....................................................................................... 32 
2.2. 
Primary Endpoint ...................................................................................... 32 
2.3. 
Secondary Endpoints ................................................................................. 33 
2.4. 
Exploratory Endpoints .............................................................................. 33 
3. 
STUDY DESIGN ............................................................................................... 34 
3.1. 
Clinical Trial Design ................................................................................. 34 
3.2. 
Criteria for Termination of Study Medication .......................................... 34 
3.3. 
Criteria for Suspension/Termination of Trial ............................................ 35 
3.4. 
Data and Safety Monitoring Board (DSMB) ............................................ 35 
4. 
SELECTION AND WITHDRAWAL OF SUBJECTS ...................................... 35 
4.1. 
Study Participation .................................................................................... 35 
4.2. 
Inclusion Criteria ....................................................................................... 35 
4.3. 
Exclusion Criteria...................................................................................... 37 
4.4. 
Diagnostic criteria ..................................................................................... 38 
4.5. 
Enrollment Procedures and Randomization .............................................. 41 
4.5.1. 
Screening ......................................................................................... 41 
4.5.2. 
Subject Re-Screening ...................................................................... 41 
4.5.3. 
Randomization ................................................................................. 41 
4.6. 
Subject Withdrawal ................................................................................... 41 
4.6.1. 
Criteria for Withdrawal from Clinical Trial .................................... 41 
4.6.2. 
End-of-Study for Early Withdrawal Subjects .................................. 42 
5. 
SCHEDULE OF EVENTS AND STUDY PROCEDURES .............................. 42 
5.1. 
Visit Assessments ..................................................................................... 42 
5.1.1. 
Screening (Day -28 to Day -2) ........................................................ 42 
5.1.2. 
Day -1, one day before start of dosing of Study Drug in Treatment 
Periods 1 and 2 ................................................................................ 44 
5.1.3. 
Day 1, Treatment Periods 1 and 2 ................................................... 45 


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5.1.4. 
Day 7 (±1), Treatment Periods 1 and 2 ........................................... 46 
5.1.5. 
Day 14 (±1), Treatment Periods 1 and 2 / Early Withdrawal (EW*)
 ......................................................................................................... 47 
5.1.6. 
End-of-Study – Approximately 7-12 Days after Treatment Period 2 
Day 14 or EW Visit ......................................................................... 48 
5.2. 
Procedures for Monitoring Subject Compliance ....................................... 48 
5.3. 
Procedures and Specifications................................................................... 48 
5.3.1. 
Medical History, Vital Signs, and Physical Exam .......................... 48 
5.3.2. 
12-Lead ECG ................................................................................... 49 
5.3.3. 
–Clinical Laboratory Analysis ......................................................... 49 
5.3.4. 
Pregnancy Testing ........................................................................... 50 
5.3.5. 
Columbia Suicide Severity Rating Scale (C-SSRS) ........................ 50 
5.3.6. 
Clinical/Disease and Cognitive Scales and Assessments ................ 50 
5.4. 
Concomitant Medications ......................................................................... 54 
5.5. 
Escape/Rescue Medications ...................................................................... 55 
5.6. 
Contraception ............................................................................................ 55 
6. 
ASSESSMENT OF SAFETY ............................................................................. 56 
6.1. 
Adverse Events.......................................................................................... 56 
6.1.1. 
Definitions ....................................................................................... 56 
6.1.2. 
Assessment of Adverse Events ........................................................ 58 
6.1.3. 
Reporting Serious Adverse Events .................................................. 59 
6.1.4. 
Follow-up of Adverse Events .......................................................... 59 
6.2. 
Clinical Safety Laboratory Abnormalities ................................................ 60 
6.3. 
ECG Abnormalities ................................................................................... 60 
6.4. 
Pregnancy .................................................................................................. 60 
7. 
STUDY MEDICATION ..................................................................................... 60 
7.1. 
Study Medication ...................................................................................... 60 
7.2. 
Study Medication Dosing and Administration .......................................... 61 
7.2.1. 
Randomization ................................................................................. 61 
7.2.2. 
Blinding ........................................................................................... 62 
7.2.3. 
Packaging and Labeling .................................................................. 62 
7.2.4. 
Storage and Handling ...................................................................... 62 
8. 
STATISTICAL CONSIDERATIONS ............................................................... 63 
8.1. 
Sample Size ............................................................................................... 63 
8.2. 
Analysis Populations ................................................................................. 63 
8.3. 
Timing of Analyses ................................................................................... 64 
8.3.1. 
Interim Analysis .............................................................................. 64 
8.3.2. 
Final Analysis .................................................................................. 64 
8.4. 
Multiplicity ................................................................................................ 64 
8.5. 
Statistical Methods .................................................................................... 64 
8.5.1. 
Subject Disposition .......................................................................... 65 
8.6. 
Subject Characteristics .............................................................................. 65 


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8.7. 
Analysis of Primary Endpoint ................................................................... 65 
8.7.1. 
Analysis of Adverse Events ............................................................. 65 
8.8. 
Analysis of Secondary Endpoints ............................................................. 66 
8.8.1. 
CANTAB, pVFT, DSST, Color Trails Test .................................... 66 
8.8.2. 
Mood, Apathy and Disease Activity Scales .................................... 67 
8.8.3. 
Clinical Laboratory Results, Vital Signs, and ECGs ....................... 67 
8.8.4. 
Analysis Pharmacokinetic Endpoints .............................................. 67 
8.9. 
Analysis of Exploratory Endpoints ........................................................... 67 
8.10. Other Analyses .......................................................................................... 68 
8.10.1. 
Concomitant Medications ................................................................ 68 
8.10.2. 
Study Drug Administration ............................................................. 68 
9. 
ETHICAL, LEGAL AND ADMINISTRATIVE ASPECTS ............................. 68 
9.1. 
Data Quality Assurance............................................................................. 68 
9.2. 
Case Report Forms and Source Documentation ....................................... 68 
9.3. 
Access to Source Data ............................................................................... 69 
9.4. 
Data Processing ......................................................................................... 69 
9.5. 
Archiving Clinical Trial Records .............................................................. 69 
9.6. 
Good Clinical Practice .............................................................................. 69 
9.7. 
Informed Consent ...................................................................................... 70 
9.8. 
Protocol Approval and Amendment.......................................................... 70 
9.9. 
Study Medication Accountability ............................................................. 70 
9.9.1. 
Handling of Study Medications ....................................................... 70 
9.9.2. 
Disposition of Study Medications ................................................... 71 
9.10. Confidentiality .......................................................................................... 71 
9.11. Publication Policy ..................................................................................... 71 
10. REFERENCES ................................................................................................... 72 
 
LIST OF FIGURES 
Figure 1 
Heterocellular Role of Noradrenaline Projections from the Locus 
Coeruleus in Cognition ........................................................................... 27 
Figure 2. 
Effects of 1, 3, and 10mg CST-2032 Combined with 3 mg CST-107 on 
CANTAB Measures of Cognition in Healthy Volunteers Aged 50–75 
(N=8)....................................................................................................... 31 
 
 


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1. 
INTRODUCTION 
The noradrenergic system, and β-Ars in particular, are promising therapeutic targets for 
cognitive diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). In 
multiple transgenic mouse models of AD, xamoterol, a β-AR agonist, enhances cognitive 
function associated with the disease (Ardestani 2017, Coutellier 2014, Faizi 2011, 
Faizi 2012, Salehi 2009). Xamoterol additionally attenuates three major pathological 
hallmarks of AD: beta-amyloid burden, tau pathology, and neuroinflammation (Ardestani 
2017). Collectively, these data suggest that targeting β-AR may have the unique potential to 
provide comprehensive therapeutic benefits for the treatment of AD.  
Several epidemiologic studies additionally suggest that treatment with β-AR agonists may be 
more protective against development of PD (Aaseth 2018, Clark 2018, Gronich2018, 
Magistrelli 2020, Mittal 2017, Searles 2018). Additional data also suggest that the effect of 
β-AR agonists may generalize to other cognitive disorders such as mild cognitive impairment 
(MCI) and AD (Chalermpalanupap 2013, Coutellier 2014).  
The locus coeruleus (LC) is a small nucleus located in the pons and is the primary source of 
noradrenaline (norepinephrine) in the forebrain (Brunnström 2011). LC axons project to 
multiple cortical and subcortical regions that underlie memory, attention, and emotional 
processing, including the hippocampus, frontoparietal cortex, and amygdala (Berridge 2003). 
Through its binding to both α and β-adrenoceptors, noradrenaline plays a key role in a variety 
of essential central nervous system (CNS) functions such as learning and memory, arousal, 
attention, and cognition, and plays an important role in maintaining brain homeostasis by 
regulating neuroimmune responses.  
Neuroanatomical studies have identified the LC as one of the earliest sites in the brain 
affected in cognitive diseases including AD and PD (Braak 2011, Braak 2017). Consistent 
with this, profound degeneration of noradrenergic neurons is an established early finding of 
AD, and deficits in noradrenergic neurotransmission have been described both in human 
patients and mouse AD models (Adolfsson 1979, Bondareff 1987, Grudzien 2007, 
Hoogendijk 1999, Iversen 1983, Kalaria 1989, Tejani-Butt 1993). Importantly, the 
dysfunction of the noradrenergic system is tightly linked to both cognitive symptoms of AD 
and underlying disease progression at many levels such as neuroinflammation 
(Bondareff 1987, Heneka 2002, Jardanhazi-Kurutz 2010).  
Progressive and extensive degeneration of the LC is evident early in patients with AD or PD 
(Kalaria 1989, Vermeiren 2017), giving rise to a hypothesis that the LC is a “ground zero” 
for the pathology underlying the development of cognitive impairment, and nonmotor 
symptoms and can further complicate the lives of PD patients (Nahimi 2018).  
The role of β2-AR extends beyond neurotransmission (Figure 1). Expression of β2-Ars is 
observed across multiple cell types including neurons, nerve fibers, microglia, astrocytes, 
oligodendrocytes and blood vessels (Gao 2016). This diversity in cellular localization gives 
rise to a corresponding diversity of function. For example, β2-Ars have been shown to 
promote glycogenolysis and lactate release from astrocytes which contribute to memory 
consolidation and long-term potentiation of synaptic strength in hippocampal neurons 
(Sorg 1991, Gao 2016, Suzuki 2011). Hypometabolism is an early feature of 
neurodegeneration in Alzheimer’s and Parkinson’s diseases (Cunnane 2020, Sonninen 2020), 


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and it is thought that glial metabolic support of neurons is neuroprotective in the context of 
disease (Cai 2019, Cunnane 2020). A pro-metabolic role of β-AR stimulation has been 
variously demonstrated: adrenergic stimulation alters the cellular metabolism of astrocytes 
(Dienel 2016), increased cellular cyclic adenosine monophosphate (cAMP), the second 
messenger produced by β-AR signaling, is associated with enhanced glycolysis 
(Vardjan 2018), and stimulation of β-Ars increases cellular glucose uptake (Catus 2011) and 
glycogenolysis (Hertz 2010). 
Finally, it is hypothesized that normal noradrenergic signaling from the LC may protect 
against inflammation, and that neuroinflammation in degenerative diseases may result from 
the progressive damage to the LC. This is supported by nonclinical observations that 
neurotoxin-mediated lesioning of the LC induces neuroinflammation (Pugh 2007), while 
stimulation of β2-AR expressed on microglia and astrocytes appears to be anti-inflammatory 
effect (reviewed by O’Donnell 2012).  
Figure 1 
Heterocellular Role of Noradrenaline Projections from the Locus 
Coeruleus in Cognition 
 
Source: Giorgi 2019 
 
Clinical and nonclinical studies conducted by CuraSen provide supportive evidence that 
CST-2032 mediates the diverse cellular functions described above. Firstly, in vitro studies 
confirm that CST-2032 stimulates β2ARs endogenously expressed on neuronal cells, 
astrocytes, microglia, pericytes, cerebral microvascular endothelial cells and human brain 
vascular smooth muscle cells to produce cAMP with similar potencies. Furthermore, 
nonclinical studies with CST-2032 demonstrate its effects on aspects of the neuronal, 
metabolic, and inflammatory signaling as described above. Specifically, CST-2032 improves 
performance a rat model of attention and impulsivity, in the five-choice-serial reaction test. 
Anti-inflammatory effects of CST-2032 were demonstrated in mice in the form of a 
reduction in lipopolysaccharide-mediated increases in pro-inflammatory mediators including 
TNFα and IL-6 in plasma and brain, and a potentiation of the anti-inflammatory IL-10. 
Finally, in an astrocytoma cell line that endogenously expresses β2-AR, CST-2032 shifted 
cellular metabolism away from mitochondrial oxidative phosphorylation and towards 
glycolysis, increasing the total rate of cellular ATP production.  


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In humans, increases in cerebral perfusion, measured as cerebral blood flow (CBF) by 
arterial spin labelling magnetic resonance imaging (ASL MRI) in brain regions relevant to 
cognition, attention and arousal, the thalamus, hippocampus and amygdala, were observed 
following administration of a β2-AR agonist, clenbuterol, in a clinical study sponsored by 
CuraSen Therapeutics, Inc (CST103/CST107/CST-109-CLIN-002). Similarly, improvements 
in performance in CANTAB domains were observed following administration of CST-2032 
in healthy volunteers and subjects with MCI in the phase 1 study, CST2032-CLIN-007 
(Figure 2). Increases in cerebral perfusion are expected under conditions of increased 
neuronal activity. This phenomenon of neurovascular coupling arises from integrated 
responses from multiple cell types, many of which are known to express β2 receptors, 
including neurons, cerebral blood vessels, microglia, oligodendrocytes, and astrocytes 
(Giorgi 2020).  
Taken together, LC neuronal loss and the resulting widespread consequence of noradrenergic 
deficiency in neuronal transmission, metabolism and inflammation are believed to underpin 
cognitive impairment in neurodegenerative diseases. We hypothesize that this noradrenergic 
deficiency may be restored through exogenous adrenergic stimulation using the β2-AR 
agonist, CST-2032. 
The CLIN-015 study seeks to evaluate the safety and efficacy of CST-2032 when dosed with 
CST-107 in subjects with mild cognitive impairment or mild dementia where the disruptions 
in noradrenergic stimulation, metabolism and inflammation described above have been 
reported. In addition, secondary analyses will evaluate the effects of treatment on cognition, 
mood and attention, and the pharmacokinetic (PK) properties of CST-2032 when 
administered with CST-107. As exploratory objectives, this study may additionally evaluate 
whether baseline disease characteristics such as disease activity, neurodegenerative 
biomarkers in the plasma and Apolipoprotein E4 variant influence the effects of treatment. 
Use of an agonist for stimulating β2-ARs within the CNS represents a novel approach in any 
neuropsychiatric indication, largely due to concerns about how such an agonist action in the 
brain could be selectively precipitated, while sparing likelihood of excess stimulation of the 
same target in the periphery. Excess stimulation of β2-ARs in the periphery has the potential 
to cause AEs of cardiovascular and metabolic origin. Accordingly, the concept of co-
administering a β-AR antagonist (‘beta blocker’) that has both preference for the β2-AR 
subtype, and minimal CNS penetration, was developed. Examination of the large number of 
widely used β-AR antagonists revealed one established antagonist, nadolol (CST-107), as 
uniquely fitting this need, assuming that an optimal dose level could be identified that 
preferentially blocked only β2 AR function in the peripheral tissues, with low access to 
desired CNS targets. CuraSen’s data from the CLIN-007 study identified the doses of nadolol 
that effectively minimize the peripheral effects of CST-2032. These doses are less than 10% 
of the lowest dose for nadolol approved for treatment of angina or hypertension (40 mg) and 
are likely to preferentially inhibit β2-ARs. The CLIN-007 study additionally confirmed that 
only 2 to 3 % of the plasma concentration of nadolol is detected in the cerebrospinal fluid, 
supporting the use of this combination dosing therapeutic strategy, that will eventually 
require formulation of a fixed dose combination drug product. 


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1.1. 
Rationale for Dose Selection 
1.1.1. 
Rationale for CST-2032 Dose Selection 
β2-AR agonists have been used for decades as bronchodilators for treatment of bronchospasm 
in patients with obstructive airway disease. As such, peripherally mediated the 
pharmacologic effects and risks associated with this class of agent are well known, including 
increased heart rate, hyperglycemia, hypokalemia, muscle twitch and tremor, palpitations, 
and peripheral vasodilatation (see Ventolin [albuterol] HFA label).  
It is understood that these peripherally mediated effects may not be ideal properties for a 
medication for use in long-term patient studies. Accordingly, the use of doses of CST-2032 
that might produce significant changes in these peripheral measures can only be safely 
contemplated if simultaneously co-administered with a dose of an antagonist for these β2-AR 
mediated effects, but one that fails to significantly cross the blood brain barrier, thus leaving 
the cerebral β2-AR population sensitive to a CNS penetrant agonist such as CST-2032. The 
dose levels of CST-2032 proposed for this study therefore have been selected to be 
administered along with such peripherally restricted antagonist, thus attenuating any of the 
clinical effects listed above. 
At the doses of 3 mg of CST-2032 and 3 mg of nadolol planned for the CLIN-015 study, 
there were no clinically significant increases in heart rate, prolongation of QTcF, or 
decreases in potassium levels observed in the CLIN-007 study. Furthermore, there were no 
instances of tremor, palpitations, dizziness, or tachycardia. Therefore, it is expected that the 
combination of 3 mg CST-2032 with 3 mg of nadolol will be safe and well tolerated. 
In rats and dogs, the NOAELs observed with CST-2032 were determined to be 110 and 
15 mg/kg/day, respectively, the highest doses tested in the GLP 28-day repeated-dose 
toxicity studies. Based on the CLIN-007 study, the plasma exposures observed at the dose of 
3 mg CST-2032 are 588- and 193-fold below the AUC0-24 at the no-observed adverse event 
levels in 28-day toxicity studies in rat and dog (Investigator Brochure [IB]). 
The 3 mg dose of CST-2032 to be administered in CLIN-015 has previously been 
administered as single and once-daily doses for 7 days in the CLIN-007 study. Specifically, 
in the CLIN-007 study, CST-2032 (0.3 – 12 mg) was evaluated in healthy volunteers as 
monotherapy (0.3–- 6 mg, as an oral solution) or with co-administered or pre-administered 
CST-107 (nadolol, 1 – 40 mg, as oral capsules, or tablets). In addition, the effects on safety, 
PK and effects on cognition using the using measures from the CANTAB and cerebral 
perfusion (by ASL MRI) were evaluated in patients with MCI or PD following a single dose 
of 3 mg CST-2032, administered 2 hours after a single dose of 3 mg CST-107 (nadolol). 
The most common AEs with CST-2032 monotherapy (other than skin reactions to ECG 
electrodes) were increases in heart rate, tremor, palpitations, headache, dizziness and 
hypokalemia as well as the observed increases in QTc and glucose and decreases in 
potassium and are consistent with the β2-AR agonist drug class. Heart rate generally 
increased with dose when 1 – 6 mg CST-2032 was administered as monotherapy, with 
concomitant decreases in plasma potassium concentration. These responses, which are 
consistent with known effects of β2 AR agonists, were generally transient with maximal 
effects at approximately 2 to 3 hours after dosing, at the approximate plasma Tmax of 


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CST-2032, and returned to pre-dose levels within 1 day of dosing. These effects were 
observed at CST-2032 exposures similar to its in vitro β2-AR potency, and were minimized 
by low doses of nadolol at plasma exposures at or above the affinity constant for nadolol at 
β2-AR. 
Following CST-2032 monotherapy, increases in QTcF were observed, especially at time 
points at which decreases in potassium and increases in heart rate were most marked. The 
time-course of the QTc effects, generally followed the same profile as the changes in 
potassium and heart rate: with largest changes within the first 4 hours after administration of 
CST-2032 and returned to pre-dose levels within 1 day of dosing.  
Breakthrough increases in QTcF were also observed when sub-optimal doses of nadolol 
(1 mg) were used in combination with CST-2032. Effects of CST-2032 on potassium, heart 
rate, and QTcF were attenuated by co-administration and pre-administration of 1 mg of the 
peripherally restricted β2-AR preferring antagonist, nadolol, and essentially eliminated by 
pre-administration of > 1 mg nadolol. No instances of QTcF > 450 ms or ΔQTcF > 30 ms 
were observed in subjects who received ≥3 mg nadolol with CST-2032. The observed 
potassium concentrations range from 3.8 to 4.3 mml/L in subjects who received 1, 3, or 
10 mg CST-2032 with 3 mg nadolol.  
The observed increases in QTcF with CST-2032 monotherapy are suspected to be the result 
of concomitant decreases in potassium that were seen in some individuals. Additionally, it is 
possible that contribution to these increases arose from inadequate correction for associated 
heart rate increases using the Fridericia method. The observed increases in QTcF, whether 
they may be attributed to decreases in potassium or failure to adequately correct for increases 
in heart rate, are blocked by low doses of nadolol, and thus appear to derive from the primary 
pharmacological action on β2-ARs, consistent with established class effect. 
Nonclinical studies with CST-2032 are consistent with a low potential for delayed ventricular 
polarization. Specifically, from in vitro assessments at cardiac ion channels, a greater than 
3000-fold margin was observed between the Cmax following administration of 3 mg 
CST-2032 to humans and the potency at the hERG potassium channel. Similarly, a greater 
than 300-fold margin between was observed between the Cmax and other cardiac ion channels 
(Nav1.5, Nav1.5 (late), KCNQ1/mink, Kv4.3/kChIP2, Kir2.1, Cav1.2).  
While the data strongly suggest that the apparent QTcF prolongation seen with monotherapy 
is due to decreases in potassium or failure to adequately correct for increases in heart rate, in 
an overabundance of caution this study will exclude subjects who have a QTcF > 440 ms or 
have risk factors for TdP from participating. 
Preliminary observations from the CLIN-007 study found that a single dose of 3 mg 
CST-2032 was associated with improvements in cognition (by CANTAB, Figure 2) and 
cerebral perfusion (by ASL MRI, see IB) in healthy volunteers and patients with MCI. Safety 
and tolerability assessments of CST-2032 administered at a dose of 3 mg with CST-107 has 
shown a good safety and tolerability profile. Based on all data, a dose of 3 mg of CST-2032 
has been selected for this study and will be administered once-daily with a dose of 3 mg 
CST-107.  


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Figure 2. 
Effects of 1, 3, and 10mg CST-2032 Combined with 3 mg CST-107 on 
CANTAB Measures of Cognition in Healthy Volunteers Aged 50–75 
(N=8) 
 
Source: preliminary CANTAB data from CST2032-CLIN-007, Cohort D2. Scales are configured to show 
improvements as increases from zero. CST-107 dose = 3 mg. 
 
1.1.2. 
Rationale for CST-107 Dose Selection 
CST-107 (nadolol) is included in this study to attenuate the peripheral effects most 
commonly caused by CST-2032 and other β2-AR agonists. In the phase 1 clinical trial with 
CST-2032, a range of doses of CST-107 was evaluated to determine the minimum dose at 
which the observed peripheral β2-AR agonist clinical signs (including increased heart rate, 
palpitations, tremors, decreases in potassium and increases in blood glucose) were attenuated 
or eliminated. While the latter effects were substantially mitigated following 1 mg CST-107, 
more robust inhibition of the peripheral effects was observed with 3 mg CST-107. A dose 
level of 3 mg CST-107 (nadolol) is in marked contrast to the usual initial dose for 
hypertension which is 40 mg CST-107 tablets once daily. The usual maintenance dose for 
nadolol is 40 or 80 mg administered once daily and doses up to 240 or 320 mg administered 
once daily may be needed. 
Separate assessments in the CLIN-007 study show that only 2-3% of the plasma 
concentration of CST-107 is detected in cerebrospinal fluid of healthy volunteers. 
Furthermore, effects of CST-2032 on measures of cognition using CANTAB and cerebral 
perfusion were observed in the presence of CST-107.  
Taken together, these data support the use of CST-107 as a peripherally restricted β2-AR 
antagonist to mitigate peripheral effects of CST-2032, e.g., on heart rate, while preserving 
potential central effects on cerebral perfusion, cerebral metabolism, pupillary light reflex, and 
cognition.  
Based on the above experience, after completion of all scheduled assessments and baseline 
measures on Day -1, an initial dose of 3 mg CST-107 or matching placebo will be 
administered on Day -1 of each treatment period to provide systemic CST-107 exposure prior 
to the Tmax of CST-2032 on Day 1. On subsequent dosing days (Days 1 through 14) in 
1 mg
3 mg
10 mg
-5
0
5
10
15
3.75
8.75
-1.63
Paired Associates Learning
decrease in total errors adjusted
for difficulty level
1 mg
3 mg
10 mg
0.0
0.1
0.2
0.3
0.18
0.14
0.07
Adaptive Tracking
mean change in difficulty multiplier
1 mg
3 mg
10 mg
-20
0
20
40
4.8
24.3
9.8
4.4
Reaction  Time Index
mean decrease in reaction time (msec)
Reaction time
Movement time


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Treatment periods 1 and 2, 3 mg CST-107 will be co-administered with 3mg CST-2032 as, 
after the first dose, trough concentrations of CST-107 are predicted to be sufficient to 
attenuate peripheral effects of CST-2032.  
1.2. 
Compliance Statement 
The clinical trial will be conducted in accordance with standards of current Good Clinical 
Practices (cGCP), as defined by the International Council for Harmonisation (ICH) and all 
applicable national and local regulations. 
2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Study Objectives 
The primary objective of this study is to evaluate the safety and tolerability of CST-2032 
when combined with CST-107. 
The secondary objectives of this study will evaluate the effects of CST-2032 when combined 
with CST-107 versus placebo on the following measures: 
• Cognition.  
• Mood.  
• Attention Deficit.  
• Apathy. 
• Overall clinical improvement. 
• PK. 
 
The exploratory objectives are: 
• To evaluate whether baseline disease characteristics impact response to treatment.  
• To characterize the effects of treatment on neurodegenerative biomarkers in the blood 
such as neurofilament light chain, total and phosphorylated tau protein, and amyloid‐
β (Aβ) peptides may also be measured. 
 
2.2. 
Primary Endpoint 
The primary endpoint is safety and tolerability of CST-2032 administered with CST-107 
including adverse event rates (AEs), serious adverse event rates (SAEs), study 
discontinuation rates, electrocardiograms (ECGs), vital signs, laboratory safety observations. 


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2.3. 
Secondary Endpoints 
The secondary endpoints will compare the effect of CST-2032 administered with CST-107 
versus placebo on the following: 
• Cognitive tasks in Cambridge Neuropsychological Test Automated Battery 
(CANTAB) and other cognitive measures: 
o Reaction Time (RTI)–- attention 
o Verbal Recognition Memory (VRM) – episodic memory (verbal stimuli) 
o Adaptive Tracking Task (ATT) – visuospatial with strong attentional demand 
o Paired Associates Learning (PAL) – episodic memory (visual stimuli) 
o Delayed Verbal Recall–- episodic memory (verbal stimuli) 
o Stop Signal Task (SST) – response inhibition (impulsivity), an aspect of 
executive function 
o Phonological verbal fluency (pVFT) 
o Digit symbol substitution test (DSST) 
o Color Trails Test (select sites only) 
• Facial expression recognition task (FERT)  
• Geriatric Depression Scale – 30 questions (GDS-30) 
• Conners Adult Attention Deficit Hyperactivity Disorder Scale (ADHD) Rating Scale, 
short form, self-report (CAARS) 
• Starkstein Apathy scale short form (SAS-6) 
• Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change 
(ADCS-CGIC) 
•  Suicidal ideation using the Columbia Suicide Severity Rating Scale (C-SSRS). 
• Plasma pharmacokinetics (PK) parameters of CST-2032 and CST-107 (including 
Cmax, tmax, AUCt, t1/2). 
 
2.4. 
Exploratory Endpoints 
The following exploratory endpoints may be undertaken to evaluate:  
•  
• Subgroup and/or correlation analyses of effects of treatment on baseline disease 
characteristics including but not limited to disease activity as determined from relevant 
disease scales at screening, neurodegenerative biomarkers in plasma, and genetic 
variants including but not limited to APOE4, LRRK2, and GBA (optional and where 
applicable).  


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• Changes in neurodegenerative biomarkers, such as neurofilament light chain, total and 
phosphorylated tau protein, and amyloid‐β (Aβ) peptides, as measured prior to and after 
treatment may be evaluated. 
• Change in average z-score for baseline-deficit cognitive tasks identified for each subject 
from Cognitive tasks in the Cambridge Neuropsychological Test Automated Battery 
(CANTAB) and other cognitive measures. 
 
3. 
STUDY DESIGN  
3.1. 
Clinical Trial Design 
This is a Phase 2a, randomized, placebo-controlled, double-blind, crossover study to evaluate 
the safety, tolerability and effects of CST-2032 administered with CST-107 on cognition in 
subjects with MCI or mild dementia. 
Approximately 60 subjects will be enrolled in a 2 period, 2-way crossover design following 
study eligibility confirmation during the screening period. Subjects will be randomly 
assigned to receive once daily doses of (a) 3 mg CST-2032 with 3 mg CST-107 or (b) both 
matching placebos in a randomized sequence (see Study Schema). 
During each treatment period, subjects will receive 3 mg CST-107 or matching placebo on 
Day -1, followed by daily doses of CST-2032 (co-administered with CST-107) or matching 
placebo on Day 1 through Day 14. Each treatment period will be separated by a washout 
period of at least 7 days and up to 21 days.  The washout period may be extended with prior 
approval by the CuraSen Medical Monitor. 
All subjects will complete clinical, cognitive and pharmacodynamic assessments during each 
treatment period as indicated in the Schedule of Events. 
PK blood samples will be collected prior to, during and after study medication 
administration, as indicated in the Schedule of Events. 
3.2. 
Criteria for Termination of Study Medication 
Dosing of the study medication will be terminated for any subject for whom either of the 
following circumstances apply: 
• 
Subject experiences a serious adverse event (SAE) that is deemed by the investigator 
to be related to study medication 
• 
Medical or ethical reasons affecting continued participation in the study. 
• Dosing of the study medication may be stopped if treatment-related AEs, changes in 
vital signs, ECG or clinical laboratory results are observed and these changes pose a 
significant health risk, in the opinion of the CuraSen Medical Monitor or Principal 
Investigator (PI). 
 


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A subject may be terminated at any point in time at the discretion of CuraSen Medical 
Monitor or PI.  
3.3. 
Criteria for Suspension/Termination of Trial 
Administration of CST-2032 and CST-107 will be stopped if either of the following occurs:  
• Two serious adverse events (SAEs) within the same system organ class (SOC) 
considered to be related to study drug; or 
• Three severe or clinically significant adverse events (AEs) considered to be related to 
study drug. 
 
The Sponsor reserves the right to terminate this clinical trial at any time. If the clinical trial is 
terminated prior to scheduled completion, the Investigator will be notified and given any 
necessary instructions concerning final examinations that are required. If the Investigator, the 
Sponsor, or the Sponsor’s Medical Monitor becomes aware of conditions or events that 
suggest a possible hazard to subjects if the clinical trial continues, the clinical trial may be 
terminated after appropriate consultation with the relevant parties. 
3.4. 
Data and Safety Monitoring Board (DSMB) 
A DSMB will be established to assess participant safety at predetermined intervals (including 
an interim analysis – see Section 8.3.1) during the study as needed. Further details will be 
provided in the DSMB Charter. 
4. 
SELECTION AND WITHDRAWAL OF SUBJECTS  
4.1. 
Study Participation 
Approximately 60 subjects with MCI or mild dementia will be randomized in this study.  
All subjects must participate in the informed consent process and sign and date the informed 
consent before any study-related procedures are performed.  
4.2. 
Inclusion Criteria 
A subject will be considered eligible for enrollment if all the following criteria are met: 
1. Male or female subjects ≥ 50 and ≤ 85 years of age at time of informed consent. 
2. Diagnosis of mild cognitive impairment (per National Institute on Aging-Alzheimer’s 
Association core clinical criteria [refer to Section 4.4]) OR mild dementia due to 
either: 
a. Parkinson’s disease (as defined by the United Kingdom Parkinson’s Disease 
Brain Bank criteria) associated with REM sleep behavior disorder (RBD+PD) 
diagnosed according to the International Classification of Sleep Disorders, 
Third Edition (ICSD-3, (albeit documentation by polysomnography is not 
required for the purposes of this inclusion criteria) and positive response to the 


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RBD Single-Question Screen (RBD1Q) and without hallucinations [refer to 
Section 4.4],], OR  
b. Alzheimer’s Disease (probable Alzheimer’s disease based on National 
Institute on Aging-Alzheimer’s Association core clinical criteria [refer to 
Section 4.4]). 
3. If the subject is taking medications, they have been on a stable dose and regimen for 
at least 30 days (90 days for anti-psychotic medications) prior to Day -1, and the dose 
must remain unchanged through the End of Study Visit unless required for 
management of adverse events (AEs). 
4. Cognitive decline not primarily caused by vascular, traumatic, or medical problems 
(alternative causes of cognitive decline are ruled out). 
5. Adequate visual and auditory abilities and motor skills to perform all aspects of the 
cognitive and functional assessments. 
6. Has a partner or caregiver who can accompany the subject at specified study visits (if 
required based on cognitive function). 
7. MoCA score ≥ 14 and ≤ 26. 
8. Unless confirmed to be azoospermic (vasectomized or secondary to medical cause), 
males must agree to use a male condom from Day -1 until the End-of-Study visit when 
having penile-vaginal intercourse with a woman of childbearing potential who is not 
currently pregnant. 
Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a condom during each episode of penile-
vaginal penetration until after the End-of-Study Visit. 
9. Females of childbearing potential (i.e., not postmenopausal, or surgically sterile) who 
have a male partner must have a negative serum pregnancy test result and must agree 
to one of the following from start of Screening through 30 days after the last study 
medication administration: 
a. use a highly effective method of birth control (refer to Section 5.6), or 
b. monogamous relationship with a male partner of confirmed sterility, or 
c. practice complete abstinence (refer to Section 5.6). 
10. Females of non-childbearing potential may be enrolled if it is documented that they 
are postmenopausal (refer to Section 5.6).  
11. Body weight greater or equal to 50 kg and body mass index (BMI) between 18 and 
35 kg/m2, inclusive at Screening.  
12. Stable medical conditions for 30 days prior to Screening visit (e.g., controlled 
hypertension, dyslipidemia). 
13. Willing to follow the protocol requirements and comply with protocol restrictions. 
14. Capable of providing informed consent and complying with study procedures. 
15. Able to speak, understand and read English. 
 


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4.3. 
Exclusion Criteria 
A subject with any of the following criteria will not be eligible for participation: 
1. Subjects with poorly controlled hypertension despite lifestyle modifications and/or 
pharmacotherapy. 
2. Subjects with pulmonary disease, including asthma, or evidence of clinically 
significant moderate or severe pulmonary symptoms. 
3. Clinical signs indicating syndromes such as corticobasal degeneration, supranuclear 
gaze palsy, multiple system atrophy, chronic traumatic encephalopathy, signs of 
frontotemporal dementia, history of stroke, head injury or encephalitis, cerebellar 
signs, early severe autonomic involvement, or Babinski sign. 
4. Current evidence of epilepsy, focal brain lesion, head injury with loss of 
consciousness or meeting DSM-V diagnostic criteria for psychotic disorders, such as 
schizophrenia or bipolar disorder, or have unstable concomitant psychiatric 
symptomatology. (NOTE: Subjects with psychotic disorders may be enrolled if their 
condition is effectively managed (i.e., must be receiving stable doses of anti-
psychotic medication(s) 90 days prior to randomization and must remain on that dose 
throughout both treatment periods) 
5. Evidence of any significant clinical disorder or laboratory finding (e.g., potassium 
levels below normal range) that renders the participant unsuitable for receiving an 
investigational drug including clinically significant or unstable hematologic, 
moderate and severe impairment of  hepatic function (as defined by the National 
Cancer Institute Organ Dysfunction Working Group), cardiovascular, pulmonary, 
gastrointestinal, endocrine (including thyrotoxicosis, excluding managed hypo- or 
hyper- thyroidism), immunologic, dermatologic, neurologic, musculoskeletal, 
metabolic, renal, or other systemic disease or laboratory abnormality. 
6. Participants with a history of malignant disease within 5 years, including solid tumors 
and hematologic malignancies (exceptions: [a] basal cell and squamous cell 
carcinomas of the skin or solid tumors that have been completely excised and are 
considered cured; [b] low-grade adenocarcinoma of the prostate, which are slow 
growing, and are unlikely to progress or metastasize during the clinical trial). 
7. Any current clinically significant medical condition or disease as determined by 
medical history, physical examination, 12-lead electrocardiogram (ECG) and clinical 
laboratory assessments conducted that, in the view of the Principal Investigator, will 
interfere with participation in the study or interpretation of results.  
8. Clinically significant abnormalities of 12-lead ECG (as determined by a central 
reader), including QTcF > 440 ms, for males and females, and/or HR < 50 beats per 
minute, or evidence of bundle branch blocks, as indicated on the Mean ECG Analysis 
Report during the screening period.  
9. A calculated creatinine clearance of ≤ 60 mL/min according to the Cockcroft-Gault 
equation. 
10. Current use of any prohibited prescription medication, over-the-counter medication, 
or herbal supplements including green tea products (refer to Section 5.4) during 
Screening or throughout study, unless approved by both the Investigator and the 
Sponsor Medical Monitor.  


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11. Prior and/or concurrent treatment with any investigational drug ≤ 90 days prior to 
dosing (Day -1), or ≤5 half-lives of the drug (whichever is longer), or current 
enrollment in any other study treatment or disease study, except for observational 
studies. 
12. Prior and/or concurrent treatment with any β-AR agonists or β-AR blockers (includes 
oral meds, IV or inhaled) or any meds that impact adrenergic signaling within the last 
month prior to Screening. Subjects maybe on stable doses of serotonin-selective 
reuptake inhibitor (SSRI) antidepressants but are prohibited to be on serotonin-
noradrenaline reuptake inhibitors (SNRIs), or tricyclic antidepressants (TCAs), or 
any treatment for ADHD including noradrenaline reuptake inhibitors (NRIs), or 
amphetamines within the last month prior to Screening. 
13. A history of heart failure, sinus bradycardia, second- or third-degree heart block, 
hypokalemia, attack of unconsciousness possibly associated with torsades de pointes 
(TdP) or family history of Long QT Syndrome.  
14. Known or suspected alcohol or substance abuse within the past 12 months and/or 
positive test for alcohol or drugs of abuse at Screening or Day -1. 
15. Suicidal ideation with actual intent or plan (“Yes” answer on the C-SSRS ideation 
items 4 or 5) within 3 months prior to study Screening. 
16. Positive screening test for human immunodeficiency virus (HIV), hepatitis C 
antibody (HCV Ab) or current hepatitis B infection (defined as positive forhepatitis B 
surface antigen [HbsAg] at Screening). Subjects with immunity to hepatitis B 
(defined as negative HbsAg and positive hepatitis B surface antibody [HbsAb]) are 
eligible to participate in the study. 
17. Current infection with severe acute respiratory syndrome coronavirus 2 
(SARS-CoV-2).  
18. Females who are breastfeeding. 
19. Any other reason for which the PI considers it is not in the best interest of the 
participant to undertake the study. 
 
4.4. 
Diagnostic criteria 
The following diagnostic criteria are provided for identification of eligible subjects under 
inclusion criterion 2.  
• The National Institute on Aging-Alzheimer’s Association defines the core clinical 
criteria for diagnosis of MCI (Albert 2011) as follows:  
‒ Cognitive concern reflecting a change in cognition reported by patient or 
informant or clinician (i.e., historical or observed evidence of decline over 
time). 
‒ Objective evidence of impairment in one or more cognitive domains, typically 
including memory (i.e., formal or bedside testing to establish level of 
cognitive function in multiple domains). 
‒ Preservation of independence in functional abilities. 
‒ Not demented. 


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• The United Kingdom Parkinson’s Disease Brain Bank criteria for PD (Clark 2016) 
are: 
‒ Bradykinesia (slowness of initiation of voluntary movement with progressive 
reduction in speed and amplitude of repetitive actions). 
‒ And at least one of the following: 
1. muscular rigidity 
2. 4–6 Hz rest tremor 
3. postural instability not caused by primary visual, vestibular, cerebellar, 
or proprioceptive dysfunction. 
• RBD diagnosis will be evaluated in subjects with PD and recorded using the 
International Classification of Sleep Disorders, Third Edition (ICSD-3) criteria for 
RBD (albeit documentation by polysomnography is not required for the purposes of 
this inclusion criteria) as well as the RBD1Q. The ICSD-3 criteria for RBD are: 
‒ repeated times of arousal during sleep where the subject talks, makes noises or 
performs complex motor behaviors, such as punching, kicking, or running 
movements that often relate to the content of the subject’s dreams 
‒ the subject recalls dreams associated with these movements or sounds 
‒ if the subject awakens during the episode, they are alert and not confused or 
disoriented 
‒ the subject’s sleep disturbance is not caused by another sleep disturbance, a 
mental health disorder, medication, or substance abuse 
• The National Institute on Aging-Alzheimer’s Association defines the core clinical 
criteria for the diagnosis of probable Alzheimer’s disease (McKhann 2011) as:  
‒ Meets criteria for dementia, with cognitive or behavioral symptoms that: 
1. Interfere with the ability to function at work or at usual activities; and 
2. Represent a decline from previous levels of functioning and 
performing; and 
3. Are not explained by delirium or major psychiatric disorder; 
4. Cognitive impairment is detected and diagnosed through a 
combination of (1) history-taking from the patient and a 
knowledgeable informant and (2) an objective cognitive assessment, 
either a “bedside” mental status examination or neuropsychological 
testing. Neuropsychological testing should be performed when the 
routine history and bedside mental status examination cannot provide a 
confident diagnosis. 
5. The cognitive or behavioral impairment involves a minimum of two of 
the following domains: 


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a. Impaired ability to acquire and remember new information—
symptoms include repetitive questions or conversations, 
misplacing personal belongings, forgetting events or 
appointments, getting lost on a familiar route. 
b. Impaired reasoning and handling of complex tasks, poor 
judgment— symptoms include poor understanding of safety 
risks, inability to manage finances, poor decision-making 
ability, inability to plan complex or sequential activities. 
c. Impaired visuospatial abilities—symptoms include inability to 
recognize faces or common objects or to find objects in direct 
view despite good acuity, inability to operate simple 
implements, or orient clothing to the body. 
d. Impaired language functions (speaking, reading, writing)—
symptoms include difficulty thinking of common words while 
speaking, hesitations; speech, spelling, and writing errors. 
e. Changes in personality, behavior, or comportment—symptoms 
include uncharacteristic mood fluctuations such as agitation, 
impaired motivation, initiative, apathy, loss of drive, social 
withdrawal, decreased interest in previous activities, loss of 
empathy, compulsive or obsessive behaviors, socially 
unacceptable behaviors. 
‒ In addition to the criteria for dementia above, probable Alzheimer’s disease 
has the following characteristics: 
1. Insidious onset. Symptoms have a gradual onset over months to years, 
not sudden over hours or days; 
2. Clear-cut history of worsening of cognition by report or observation; 
and  
3. The initial and most prominent cognitive deficits are evident on history 
and examination in one of the following categories. 
a. Amnestic presentation: It is the most common syndromic 
presentation of AD dementia. The deficits should include 
impairment in learning and recall of recently learned 
information. There should also be evidence of cognitive 
dysfunction in at least one other cognitive domain, as defined 
earlier in the text. 
b. Nonamnestic presentations: 
• Language presentation: The most prominent deficits are 
in word-finding, but deficits in other cognitive domains 
should be present. 


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• Visuospatial presentation: The most prominent deficits 
are in spatial cognition, including object agnosia, 
impaired face recognition, simultanagnosia, and alexia. 
Deficits in other cognitive domains should be present. 
• Executive dysfunction: The most prominent deficits are 
impaired reasoning, judgment, and problem solving. 
Deficits in other cognitive domains should be present. 
 
4.5. 
Enrollment Procedures and Randomization  
4.5.1. 
Screening 
After informed consent, all subjects will complete screening procedures and tests to 
establish eligibility during the Screening Period, which will be performed between Day -28 
and Day -2. If a subject falls outside the Screening Period window, screening may be 
extended with prior approval by the CuraSen Medical Monitor. If extended beyond 28 days, 
some of the screening procedures and assessments may need to be repeated. 
4.5.2. 
Subject Re-Screening 
Subjects who have screen failed may be re-screened a second time if their eligibility 
characteristics have changed. Subjects who are re-screened must be assigned a new subject 
number within the Interactive Web Response System (IWRS) and repeat all Screening 
procedures. The screening process for such subjects must be discussed with the CuraSen 
Medical Monitor.  
4.5.3. 
Randomization 
Once all Screening tests and procedures are completed and all eligibility criteria are met, 
subjects will return to the clinic for randomization and begin dosing in Treatment Period 1. 
The IWRS will provide the randomization number.  
4.6. 
Subject Withdrawal 
At the time of early withdrawal, the subject should complete the Day 14/Early Withdrawal 
(EW) visit and return in 7 – 12 days for the End-of-Study Visit. A subject may withdraw 
from the clinical trial at any time without penalty and for any reason without prejudice to his 
or her future medical care. Subjects will be informed that the Investigator may withdraw any 
subject from the study without his/her consent for any reason if the Investigator thinks it is in 
the best interest of the subject. In such cases, the Investigator will contact the Sponsor’s 
Medical Monitor before subject withdrawal.  
4.6.1. 
Criteria for Withdrawal from Clinical Trial 
Reasons for subject withdrawal include, but are not limited, to the following: 
• Withdrawal of consent 


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• Adverse events 
• Pregnancy 
• Protocol violation/non-compliance 
• Study burden 
• Positive test for COVID-19 
• Fear of contracting COVID-19 
• Sponsor termination of the study 
• Investigator’s determination that it is in the best interest of the subject to discontinue  
• Lost to follow-up 
• Other (e.g., withdrawal of caregiver consent) 
 
The reason for withdrawal must be recorded on the case report form (CRF). Whenever 
possible, the subject should continue to be followed for safety assessments (if consent has not 
been withdrawn). The Sponsor’s Medical Monitor should be contacted before withdrawal 
whenever possible. 
4.6.2. 
End-of-Study for Early Withdrawal Subjects 
Subjects who discontinue the study after the Day -1 visit of either Treatment Period and who 
have received study drug will have Early Withdrawal and End-of-Study visits.  
5. 
SCHEDULE OF EVENTS AND STUDY PROCEDURES  
Assessments and procedures at each visit are summarized in the Schedule of Events. For 
visits in which multiple disease assessments are planned, efforts should be made to conduct 
them after the subjects have been provided with a light meal or snack (without caffeinated 
beverages or high sugar content) in the following order (as relevant): FERT before pVFT, 
then DSST and CANTAB.  The Color Trails Test should be conducted after the CANTAB 
assessments.  ADCS-CGIC should be conducted last. SAS-6, GDS-30 and CAARS may be 
administered at any time before ADCS-CGIC.  
5.1. 
Visit Assessments 
5.1.1. 
Screening (Day -28 to Day -2) 
The following procedures will be performed, and assessments/measurements recorded: 
• Consenting process and written informed consent 
• Obtain a subject number from the IWRS 
• Evaluation for inclusion/exclusion criteria 


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• Demographics (sex, age, race, ethnicity, years of education) 
• Medical history including concomitant medications 
• Height, body weight, BMI calculation 
• Vital signs (blood pressure [BP], heart rate [HR], respiration rate and oral/tympanic 
temperature); for assessments of orthostatic changes, BP and HR are obtained: a) 
after rest in a supine position for at least 5 minutes, and b) 1 minute after standing 
• 12-lead ECG, obtained 3 times (separated by approximately 1 minute) after the 
subject is supine for at least 5 minutes 
• Complete physical examination, excluding genital, rectal and breast exams  
• Laboratory tests 
1. Hematology, fasting chemistry (includes calculated creatinine clearance), and 
urinalysis 
2. Urine drug screen 
3. Alcohol breath test 
4. Serology for HIV, hepatitis B and C 
5. SARS-CoV-2 test 
6. Serum β-hCG test for females of childbearing potential 
7. FSH test for postmenopausal women 
8. Whole blood sample for determination of genetic variants including but not 
limited to APOE4, LRRK2, and GBA (optional and where applicable) 
9. Plasma sample for neurodegenerative biomarkers 
• CANTAB administered twice, at least 1 hour apart during the final week (Day -8 to 
Day -2) before Treatment Period 1 to familiarize subjects with the tests.  
• Other clinical and cognitive scales/assessments: 
1. MoCA 
2. ADCS-CGIC 
3. DSST 
4. RBD1Q (to be evaluated in all subjects, but to be used to assess eligibility for 
subjects with PD only)  
5. MHYS (only in subjects with PD; prior assessment within 3 months of 
Screening will suffice) 
6. C-SSRS 
 


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Subjects with a positive drug or alcohol screen at Screening will be rechecked once and if 
positive, the subject will be excluded from participation in the study. The drug and/or alcohol 
screen tests may be repeated per Investigator clinical judgement. 
Subjects who are eligible for study participation will be scheduled to return to the clinic for 
the start of Treatment Period 1.  
5.1.2. 
Day -1, one day before start of dosing of Study Drug in Treatment Periods 1 
and 2 
The following procedures will be performed, and assessments/measurements recorded: 
• Review of inclusion/exclusion criteria (Treatment Period 1 only) 
• Assessment of concomitant medications 
• Vital signs (BP, HR, respiration rate, and oral/tympanic temperature); for assessments 
of orthostatic changes, BP and HR are obtained: a) after rest in a supine position for 
at least 5 minutes, and b) 1 minute after standing 
• 3 sets of triplicate ECG measures (i.e., 9 ECGs) prior to dosing with study drug to 
thoroughly establish a baseline obtained after subject has rested in supine position for 
at least 5 minutes; the time between each set of 3 ECGs should be ≤5 minutes 
• Alcohol breath test prior to dosing CST-107 or matching placebo 
• Serum or urine pregnancy test (per standard site practice) prior to dosing CST-107 or 
matching placebo for females of childbearing potential; positive urine pregnancy 
result to be confirmed by serum test 
 
The following procedures will be administered (prior to dosing CST-107) at approximately 
the same time of day (±1 hour) and under approximately the same food status as planned for 
the tests on Days 1, 7, and 14: 
• FERT 
• pVFT 
• DSST 
• CANTAB 
• Color Trails Test (select sites only), administered after CANTAB 
• SAS-6 
• CAARS 
• GDS-30 
• C-SSRS in Treatment Period 2 only 


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Obtain the randomization number and the Days 1-7 blister card/bottle numbers for study drug 
(CST-2032+CST-107 or matching placebos) from the IWRS – do not dispense blister 
card/bottle to the subject 
Remove one CST-107 or matching placebo tablet from the bottle or the Day 10 well on the 
blister card and administer the dose to the subject after completion of all scheduled 
assessments  
5.1.3. 
Day 1, Treatment Periods 1 and 2 
The following procedures will be performed, and assessments/measurements recorded: 
• Assessment of concomitant medications 
• Vital signs (BP, HR, respiration rate, and oral/tympanic temperature); for assessments 
of orthostatic changes, BP and HR are obtained: a) after rest in a supine position for 
at least 5 minutes, and b) 1 minute after standing: 
1. Within 30 minutes prior to dosing of study drug 
2. 4 hours (±30 minutes) after dosing study drug 
• 12-lead ECG, obtained 3 times (separated by approximately 1 minute) after subject 
has rested in supine position for at least 5 minutes: 
1. Within 30 minutes prior to dosing study drug  
2. Approximately 1 hour after dosing study drug 
3. Approximately 2 hours after dosing study drug 
4. Approximately 4 hours after dosing study drug 
• Laboratory tests (hematology, chemistry, and urinalysis) 
1. Pre-dose and approximately 4 hours post-dose 
2. Chemistry only at 4 hours post-dose 
• Administer study medication (CST-2032 and CST-107 or matching placebos) from 
the blister card/bottle 
• FERT administered at least 2 hours after dosing study drug and prior to 
administration of the cognition tests (pVFT, DSST, CANTAB) 
• SAS-6, CAARS GDS-30 administered at least 2 hours after dosing study drug 
• pVFT, DSST, CANTAB tests at 3 hours (± 30 minutes) after dosing study drug. Tests 
should be conducted at approximately the same time of day (±1 hour) and under the 
same food status on Days -1, 1, 7 and 14. 
• Dispense study medication (Days 1-7 blister card/bottle) and provide dosing 
instructions to the subjects 
• Dispense dosing diary 
• Assessment of AEs 
• Schedule Day 7 Visit. Subjects should be instructed not to administer study drug prior 
to the clinic visit on Day 7 as study drug will be administered on site.  


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5.1.4. 
Day 7 (±1), Treatment Periods 1 and 2 
The following procedures will be performed, and assessments/measurements recorded: 
• Review subject dosing diary  
• Vital signs (BP, HR, respiration rate, and oral/tympanic temperature); for assessments 
of orthostatic changes, BP and HR are obtained: a) after rest in a supine position for 
at least 5 minutes, and b) 1 minute after standing: 
1. Within 30 minutes prior to dosing study drug  
2. Approximately 4 hours after dosing study drug 
• 12-lead ECG, obtained 3 times (separated by approximately 1 minute) after subject 
has rested in supine position for at least 5 minutes: 
1. Within 30 minutes prior to dosing study drug  
2. Approximately 1 hour after dosing study drug 
3. Approximately 2 hours after dosing study drug 
4. Approximately 4 hours after dosing study drug 
• C-SSRS 
• Laboratory tests (hematology, chemistry, and urinalysis) at approximately 4 hours 
post-dose 
• PK samples:  
1. Within 15 minutes prior to dosing study drug (CST-2032 and CST-107 or 
matching placebos) 
2. 30 minutes (+15 minutes) after administration of study drug 
3. 1 hour (+30 minutes) after dosing study drug 
4. 2 hours (+30 minutes) after dosing study drug 
5. 4 hours (+30 minutes) after dosing study drug 
• Administer study drug (CST-2032 and CST-107 or matching placebos) from the Days 
1-7 blister card/bottle 
• Collect study drug (CST-2032 and CST-107 or matching placebos) blister 
cards/bottles from Days 1-7 and conduct accountability  
• pVFT, DSST, CANTAB tests 3 hours (± 30 minutes) after dosing study drug. Tests 
should be conducted at approximately the same time of day (±1 hour) and under the 
same food status on Days -1, 1, 7 and 14. 
• Color Trails Test (select sites only), administered after CANTAB 
• Assessment of AEs 
• Assessment of concomitant medications 
• Obtain blister card numbers/bottle for study drug (CST-2032 and CST-107 or 
matching placebos) from the IWRS and dispense study medication for Days 8-14 
 
• Schedule Day 14 Visit. Subjects should be instructed not to administer study drug 
prior to the clinic visit on Day 14 as study drug will be administered on site. 
 


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5.1.5. 
Day 14 (±1), Treatment Periods 1 and 2 / Early Withdrawal (EW*) 
The following procedures will be performed, and assessments/measurements recorded at the 
Day 14 Visit of each Treatment Period. Subjects who withdraw prior to Day 14 should 
complete Day 14 safety assessments at the time of EW (identified with an asterisk [*]): 
• *Review subject dosing diary 
 
• *Vital signs (BP, HR, respiration rate, and oral/tympanic temperature); for 
assessments of orthostatic changes, BP and HR are obtained: a) after rest in a supine 
position for at least 5 minutes, and b) 1 minute after standing: 
1. Within 30 minutes prior to dosing study drug  
2. Approximately 4 hours after dosing study drug 
• *12-lead ECG, obtained 3 times (separated by approximately 1 minute) after subject 
has rested in supine position for at least 5 minutes: 
1. Within 30 minutes prior to dosing study drug  
2. Approximately 1 hour after dosing study drug 
3. Approximately 2 hours after dosing study drug 
4. Approximately 4 hours after dosing study drug 
• *C-SSRS 
• Laboratory tests approximately 4 hours post-dose 
1. *Hematology, chemistry, and urinalysis 
2. *Serum or urine pregnancy test (per standard site practice) prior to dosing 
study drug for females of childbearing potential; positive urine pregnancy 
result to be confirmed by serum test 
3. Plasma sample for neurodegenerative biomarkers 
• Administer study medication (CST-2032 and CST-107 or matching placebos) from 
the Days 8-14 blister cards or bottles 
• *Collect study drug (CST-2032 and CST-107 or matching placebos) blister cards/bottle 
from Days 8-14 and conduct accountability 
• FERT administered at least 2 hours after dosing study drug and prior to 
administration of the cognition tests (pVRT, DSST, CANTAB) 
• pVFT, DSST, CANTAB tests 3 hours (± 30 minutes) after dosing study drug. Tests 
should be conducted at approximately the same time of day (±1 hour) and under the 
same food status on Days -1, 1, 7 and 14. 
• Color Trails Test (select sites only), administered after CANTAB 
• SAS-6, CAARS, GDS-30 administered at least 2 hours after dosing study drug 
• MoCA 
• ADCS-CGIC 
• *Assessment of AEs  
• *Assessment of concomitant medications 
• *Register visit in IWRS 


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• Schedule End-of-Study Visit (TP2 Day 14 or EW Visit only) 
5.1.6. 
End-of-Study – Approximately 7-12 Days after Treatment Period 2 Day 14 
or EW Visit 
The following procedures will be performed, and assessments/measurements recorded: 
• Vital signs (BP, HR, respiration rate, and oral/tympanic temperature); for assessments 
of orthostatic changes, BP and HR are obtained: a) after rest in a supine position for 
at least 5 minutes, and b) 1 minute after standing 
• 12-lead ECG, obtained 3 times (separated by approximately 1 minute) after the 
subject is supine for at least 5 minutes 
• Symptom-driven physical examination 
• Laboratory tests 
1. Hematology, fasting chemistry, and urinalysis 
2. Serum or urine pregnancy test (per standard site practice) for females of 
childbearing potential; positive urine pregnancy result to be confirmed by 
serum test 
• C-SSRS 
• Assessment of AEs  
• Assessment of concomitant medications 
• Register visit in IWRS 
 
The End-of-Study Visit should be conducted in the clinic. However, should there be factors 
and/or conditions which would make the End-of-Study site visit unnecessarily difficult 
and/or potentially unsafe for a subject, this visit may be performed by alternate arrangement, 
e.g., visit in the subject’s home, virtual visit. 
5.2. 
Procedures for Monitoring Subject Compliance 
All study procedures are to be performed under the direct supervision of the Investigator and 
qualified healthcare professionals at the study site unless conditions prevent the subject from 
safely attending. In these cases, study procedures may be performed by alternate 
arrangement, e.g., visit to the subject’s home, virtual visit. The study site will maintain 
contact information for each subject; if a subject fails to return for study visits, the study site 
will make every attempt to contact the subject, including, but not limited to, sending 
registered letters.  
5.3. 
Procedures and Specifications  
5.3.1. 
Medical History, Vital Signs, and Physical Exam 
Medical history, including details regarding illnesses and allergies, date(s) of onset, and 
whether condition(s) is currently ongoing, and medication history, will be collected on all 
subjects during Screening. 
Subject height and body weight will be measured at Screening, and subject’s BMI will be 
calculated and recorded. 


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Assessment of vital signs will include BP, HR, respiration rate, and oral/tympanic 
temperature. All routine measures of BP and HR should be collected (a) after rest in a supine 
position for at least 5 minutes, and (b) 1 minute after standing, to assess orthostatic changes. 
Vital signs will be collected as indicated in the Schedule of Events. 
A complete physical exam will be performed at Screening and will include general 
appearance and examination of the following body systems (excludes breast, genital, and 
rectal exams): head, neck and thyroid, eyes, ears, nose, throat, mouth, chest, respiratory, 
cardiovascular, lymph nodes, abdomen, skin, nails, hair, musculoskeletal, and neurological. 
A symptom-driven physical exam based on subject complaints will be conducted at the 
End-of-Study Visit. 
5.3.2. 
12-Lead ECG 
A 12-lead ECG will be collected in triplicate as indicated in the Schedule of Events. Subjects 
will be required to rest in a supine position for at least 5 minutes prior to the recording of 
ECG. All ECGs will be reviewed by the Investigator or qualified study staff and will be read 
by a central reader. 
5.3.3. 
Clinical Laboratory Analysis 
The following laboratory assessments will be performed at timepoints detailed in the 
Schedule of Events: 
Hematology: hematocrit, hemoglobin, mean corpuscular hemoglobin (MCH), mean 
corpuscular hemoglobin concentration (MCHC), mean corpuscular volume (MCV), platelet 
count, red blood cell (RBC) count, and white blood cell (WBC) count with differential, 
reticulocyte count. 
Chemistry: albumin, alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), BUN, calcium, bicarbonate, serum creatinine, creatine 
phosphokinase (CPK), glucose, lipase, amylase, phosphate, potassium, sodium, total 
bilirubin, total cholesterol, total protein, triglycerides, and uric acid. 
Urinalysis: Appearance, occult blood, glucose, leukocyte esterase, nitrite, pH, protein, 
urobilinogen by dipstick; a reflex microscopic urinalysis will be performed if dipstick 
protein, nitrite, leukocyte esterase, or occult blood results are positive. 
Calculated creatinine clearance according to the Cockcroft-Gault equation: To be determined 
at Screening only. 
Serologies for HIV, hepatitis B, and hepatitis C: HbsAg, HbsAb, and HCV Ab (Screening 
only). If these results indicate potential infection, the PI must refer the subject for counselling 
and treatment as per institution policy and procedures. 
SARS-CoV-2: Conducted at Screening by central lab.  After Screening, the test may be 
conducted according to current local COVID management procedures. 
Pregnancy Tests: Serum β-hCG for all female subjects of childbearing potential at Screening; 
serum or urine pregnancy test for women of childbearing potential on days noted in the 
Schedule of Events. Positive urine pregnancy tests must be confirmed by a serum test. 


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Urine Drug Screen: Tests for drugs of abuse.  
Alcohol breath test. 
CST-2032 and CST-107 PK samples: Plasma samples will be collected for PK analysis on 
Day 7 of each treatment period for analysis of CST-2032, CST-107 and possible metabolites. 
Samples may be stored for up to 2 years. 
Disease Biomarkers: Whole blood will be collected for analysis of genetic variants including 
but not limited to APOE4, LRRK2, and GBA (optional and where applicable) during 
screening, and plasma will be collected during screening and on Day 14 for analysis of 
neurodegeneration biomarkers (may be stored for up to 5 years). 
Instructions on blood and plasma sample processing and shipping can be found in the 
Laboratory Manual. 
Retesting Procedures:  
Retesting of labs is only permitted if there is reason to believe that the retest value will be 
within acceptable parameters, such as if the initial test result was erroneous due to a sample 
processing error. 
5.3.4. 
Pregnancy Testing 
A serum β-hCG pregnancy test will be performed for all female subjects of childbearing 
potential at the Screening visit; female subjects may not be enrolled until the result of this 
test is known. FSH test will be performed for postmenopausal women. Women of 
childbearing potential will have serum or urine pregnancy tests on days noted in the Schedule 
of Events. Positive urine pregnancy tests will be confirmed by a serum test. 
5.3.5. 
Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS, is a suicidal ideation and behavior rating scale to evaluate suicide risk 
(Posner 2011). 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 and behaviors.” 
The scale identifies specific behaviors which may be indicative of an individual’s intent to 
complete suicide. The tool is administered by a qualified rater via interview with the subject. 
5.3.6. 
Clinical/Disease and Cognitive Scales and Assessments  
Clinical/disease and cognitive scales and assessments must be administered by an 
appropriately qualified rater. Clinical and cognitive scales will be conducted for all subjects 
unless otherwise stated and will be performed as outlined on the Schedule of Events. The 
descriptions of these clinical/disease and cognitive scales are noted below.  
 
Digital Symbol Substitution Test (DSST)  
The DSST integrates complex neuropsychological processes and measures aspects of 
cognitive function, including cognitive and psychomotor speed, attention, visual scanning, 
and executive function. The specific version of the DSST used in this study is the Coding 
subtest of the Wechsler Adult Intelligence Scale – 4th edition (WAIS-IV). 


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Subjects are asked to copy simple graphic symbols that are paired to the digits 1–9 within a 
specified time period. Using a key, the examinee is asked to draw each symbol under its 
corresponding number. The examinee’s score is determined by the number of symbols 
correctly drawn within a 90 or 120-second time limit. Higher scores indicate better 
performance; for a 120-second limit, the maximum attainable score is 135. Test scores can be 
benchmarked against published normative data by age group, and education level (2008 NCS 
Pearson, Inc.) as a means of evaluating test performance.  
 
Montreal Cognitive Assessment (MoCA)  
The MoCA (Nasreddine 2005) is a brief cognitive screening tool that is used in clinical 
research and practice. The scores range from 0 to 30 with scores lower than 26 suggesting 
cognitive disorder. The MoCA includes measures of expressive and receptive language, 
memory, and praxis. There are items that screen executive functions and working memory.  
 
Geriatric Depression Scale-30 (GDS-30) 
The GDS is a 30-item self-administered yes/no question test constructed for brief screening 
of depression in elderly persons (Yesavage 1983). Scores greater than 9 are considered 
suspect for depression. 
 
Alzheimer’s Disease Cooperative Study-Clinical Global Impression of 
Change (ADCS-CGIC) 
The ADCS-CGIC focuses on clinicians’ observations of change in the patient’s cognitive, 
functional, and behavioral performance since the beginning of a trial (Schneider 1997). It 
relies on both direct examination of the patient and interview of informants. Unlike a targeted 
symptom scale, it takes into account a subject’s overall function in the cognitive, behavioral, 
and functional activity domains. Scoring is based on an interview with the caregiver and 
examination of the patient by an independent evaluator.  The MoCA will be used to provide 
the cognitive assessment. The ADCS-CGIC requires the assessor to consider a number of 
cognitive, functional, and behavioral areas prior to providing an overall “global” assessment 
of clinical change. It is performed by interviewing the patient to assess function and mental 
status and the informant, using a worksheet that comprehensively lists relevant symptoms 
potentially useful in judging clinically meaningful change, and allows for notes for future 
reference.  
 
Starkstein Apathy Scale short form (SAS-6) 
The SAS-6 is a 6-item questionnaire to measure the severity of apathetic symptoms 
(Garofalo 2021, Starkstein 1992). In the SAS-6, each question is read by the examiner, and 
the patient is provided with four possible answers: “not at all,” “slightly,” “some,” or “a lot” 
which are scored on a 4-point Likert scale (range: 0–3). Scores range from 0 to 18; higher 
scores indicate more severe apathy.  
 
Connors Adult ADHD Rating Scale – self-report short form (CAARS) 
The CAARS is an 26-item scale designed to assess, diagnose, and monitor treatment of 
attention deficit/hyperactivity disorder (ADHD) in adults. The self-report short form contains 
factor-derived scales for inattention/memory, hyperactivity/restlessness, 


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impulsivity/emotional lability, and problems with self-concept (developed by Conners, 
Erhardt, and Sparrow, unpublished). 
 
REM Sleep Behavior Disorder Single-Question Screen (RBD1Q)  
The RBD1Q is a single “yes-no” question that queries the classic dream-enactment behavior 
of RBD (Postuma 2012) and will be administered at Screening to identify subjects with REM 
sleep behavior disorder. 
The RBD1Q consists of a single question, answered “yes” or “no,” as follows: “Have you 
ever been told, or suspected yourself, that you seem to ‘act out your dreams’ while asleep 
(for example, punching, flailing your arms in the air, making running movements, etc.)?” 
RBD1Q will be evaluated and recorded for all subjects, but to be used to assess eligibility for 
subjects with PD only.  
 
Modified Hoehn and Yahr Scale (MHYS) for subjects with PD only 
The MHYS is a clinician-completed rating scale that is used to describe the symptom 
progression of PD. Originally described in 1967, it parsed the progression of PD into 5 
stages. It has since been modified with the addition of stages 1.5 and 2.5 to account for the 
intermediate course of PD (Fahn 1987). As such, the MHYS is as follows: 
• Stage 0: No signs of disease. 
• Stage 1.0: Unilateral disease. 
• Stage 1.5: Unilateral plus axial involvement. 
• Stage 2: Bilateral disease, without impairment of balance. 
• Stage 2.5: Mild bilateral disease, with recovery on pull test. 
• Stage 3: Mild to moderate bilateral disease; some postural instability; physically 
independent. 
• Stage 4: Severe disability; still able to walk or stand unassisted. 
• Stage 5: Wheelchair bound or bedridden unless aided. 
 
The MHYS will be evaluated during screening (unless completed within the past 3 months) 
for purposes of phenotyping of subjects with PD. It will not be used as an enrollment 
criterion.  
 
CANTAB Assessments  
The CANTAB is a standardized and automated administration of cognitive testing via touch 
tablet, which will include the following: 
• The Reaction Time (RTI) task is a processing and psychomotor speed task. It begins 
with a simple stage with only one target and can be increased to 5 targets to increase 
demand. Once a yellow circle flashes on screen, subjects must select that circle as fast 
as possible. 
• The Verbal Recognition Memory (VRM) Phase I and Delayed Verbal Recall 
recognition measures the ability to encode and subsequently retrieve verbal 
information. Eighteen (18) words are presented, and subjects are subsequently asked 


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to recall them; this is repeated 2 times. Forty-five (45) minutes later free recall test 
and forced-choice recognition test are carried out. 
• The Adaptive Tracking Task (ATT) measures visuomotor coordination and vigilance. 
In this test, a small circle (target) will continuously move across the screen in a semi-
randomized fashion, so as to minimize the subject’s ability to predict the trajectory of 
the target. The subject is instructed to use his/her finger upon the touch screen to 
move a small dot so that it is consistently within the center of the moving target on 
the screen. During the test, the speed of the circle is adjusted in response to the 
subject’s ability to keep the dot in the circle, ensuring that the test is adapted to the 
individual subject.  
• The Paired Associates Learning (PAL) task is a measure of visuo-spatial episodic 
memory relying on the functional integrity of the hippocampus. The task becomes 
gradually more difficult, benchmarking a subject’s memory capacity. Subjects have to 
remember the location of an abstract pattern in a specific location. 
• The Stop Signal Task (SST) measures response inhibition (impulse control). The 
subject must respond to an arrow stimulus, by selecting one of two options, 
depending on the direction in which the arrow points. If an audio tone is present, the 
subject must withhold making that response (inhibition). 
 
 Phonological Verbal Fluency Test (pVFT) 
Verbal fluency tests are widely used for assessing executive function and requires the 
generation of words from initial letters (phonological verbal fluency) or belonging to a 
specific category (semantic fluency), under a time constraint (Harrison 2000). The specific 
versions of verbal fluency used in this study are the ‘ALPHABET’ and ‘CATEGORY’ tests 
from the Brief And Simple Index of Cognition (BASIC) (Metis Cognition, Ltd., Warminster, 
UK). 
For the ALPHABET task, subjects are given 1 minute to say aloud as many words they can 
think of that begin with the letter F, avoiding repetitions or the same words with different 
endings. The total score is the number of correct words generated. 
For the CATEGORY task, subjects are given 1 minute to say aloud as many animals they can 
think of, avoiding repetitions. The total score is the number of animals generated.  
 Facial Expression Recognition Task (FERT)  
The Facial Expression Recognition Task assesses the recognition of facial emotions. Faces 
with six different basic emotions (happiness, fear, anger, disgust, sadness, surprise) are 
briefly displayed on the screen and participants are required to indicate the expression of the 
face via a button-press. Different intensity levels of each emotion are presented, which 
increases the ambiguity of the facial expression and the sensitivity of the task. Early change 
in measures of emotional bias in depressed patients treated with antidepressants has been 
positively correlated with the improvement in patients’ symptoms of depression across a full 


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6–8 weeks of treatment (Tranter 2009) suggesting that such early changes detected through 
the use of the FERT may be predictive of antidepressant response. 
 Color Trails Test (Select Sites Only) 
The Color Trails Test consists of numbered circles printed with vivid pink or yellow 
backgrounds that are perceptible to color-blind individuals.  For Part 1, the respondent uses a 
pencil to rapidly connect circles numbered 1-25 in sequence.  For Part 2, the respondent 
rapidly connects numbered circles in sequence, but alternates between pink and yellow. The 
length of time to complete each trial is recorded. 
5.4. 
Concomitant Medications  
Subjects who require routine medication to manage and treat concurrent conditions 
(e.g., hyperlipidemia, diabetes, hypertension, Parkinson’s Disease, Alzheimer’s Disease) 
must be on stable doses 30 days prior to randomization and remain on those doses for the 
duration of the study. Any concomitant therapy taken from the time the subject signs the 
informed consent through the final visit must be recorded on the CRF for all enrolled 
subjects. The medication name, dosage, date, and indication for use must be recorded. The 
Medical Monitor or designee should be notified in advance of (or as soon as possible after) 
any instances in which prohibited therapies are administered. 
Prohibited concomitant medications include the following:  
• Monoclonal antibodies for treatment of MCI or mild dementia e.g., aducanumab. 
• Cannabis and products containing tetrahydro cannabinol (THC) and/or cannabidiol 
(CBD). 
• Hypnotics, such as zolpidem or zopiclone, within 48 hours prior to a study visit 
involving cognitive testing. 
• St. John’s Wort, green tea, green tea products, or Ginkgo Biloba during Screening or 
throughout the study.  
• Benzodiazepines from Screening throughout the study with the following exception: 
o Clonazepam is permitted when used for RBD at doses up to 1 mg at bedtime – 
subjects must be on a stable dose 90 days prior to randomization and remain on 
that dose throughout both treatment periods.   
• Anti-psychotic medication(s) are permitted at stable doses 90 days prior to 
randomization.  The doses must remain unchanged throughout both treatment 
periods. 
• Gabapentin 900 mg per day maximum, gabapentin enacarbil 600 mg per day 
maximum, pregabalin 300 mg per day maximum are permitted at stable doses 90 
days prior to randomization.  The doses must remain unchanged throughout both 
treatment periods. 
• Phenylephrine and pseudoephedrine are prohibited from Screening throughout the 
study. 


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• Any β-AR agonists or β-AR blockers (including oral medications, eye drops with 
adrenergic agents such as timolol or atenolol, IV, or inhaled), or any medications that 
impact adrenergic signaling within the last month prior to Screening and throughout 
the study, including:  
o β-AR agonists such as Ventolin (albuterol), Proventil (albuterol), Proair HFA 
(albuterol), Xopenex HFA (levalbuterol), Xopenex (levalbuterol), terbutaline, 
metaproterenol, Proair Respiclick  
o β-AR blockers such as Acebutolol, Atenolol (Tenormin), Bisoprolol (Zebeta), 
Metoprolol (Lopressor, Toprol XL), Nebivolol (Bystolic), Propranolol 
(Inderal, InnoPran XL. 
• Serotonin-noradrenaline reuptake inhibitors (SNRIs) such as desvenlafaxine (Pristiq, 
Khedezla), duloxetine (Cymbalta, Irenka), levomilnacipran (Fetzima), milnacipran 
(Savella), venlafaxine (Effexor XR). 
• Tricyclic antidepressants (TCAs) such as Amitriptyline, Amoxapine, Desipramine 
(Norpramin), Doxepin, Imipramine (Tofranil), Nortriptyline (Pamelor), Protriptyline, 
Trimipramine. 
• Noradrenaline reuptake inhibitors (NRIs) such as atomoxetine, maprotiline, 
reboxetine, and viloxazine. 
• Amphetamines such as dextroamphetamine, methylphenidate, dexmethylphenidate, 
methamphetamine, mixed amphetamine salts, amphetamine sulfate, 
lisdexamfetamine. 
• Subjects who had prior treatment with any investigational drug ≤90 days prior to 
dosing (Day -1), or ≤5 half-lives of the drug (whichever is longer) will be excluded. 
• Subjects should not receive the influenza vaccine within 2 weeks of the Screening 
visit through to the End-of-Study Visit. 
• Opioid use is prohibited within 30 days prior to Screening and throughout the study. 
 
5.5. 
Escape/Rescue Medications  
Since CST-2032 is being co-administered with the nonselective β-AR antagonist nadolol 
(CST-107), the typical β-AR agonist effects such as HR increases, are unlikely to occur. 
However, if there are intolerable HR/BP increases subjects may be administered rescue 
nadolol.  
Nadolol has been successfully used in ongoing or previous CuraSen studies to block the 
peripheral effects of CST-2032 and other β-AR agonists.  
5.6. 
Contraception 
Female subjects of childbearing potential (i.e., not postmenopausal or not surgically sterile) 
and all male participants with sexual partners of childbearing potential must use reliable 
methods of birth control during their participation in the study.  
Unless confirmed to be azoospermic (vasectomized or secondary to medical cause), male 
subjects must agree to use a male condom from Day -1 throughout the study when having 


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penile-vaginal intercourse with a woman of childbearing potential who is not currently 
pregnant. Men with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse or use a condom during each episode of penile-vaginal penetration 
until after the End-of-Study Visit.  
Female subjects of childbearing potential who have a male partner must agree to 
contraception from the start of Screening through 30 days after the last administration of 
study medication. 
Acceptable methods of contraception for female subjects of child-bearing potential study 
include the following:  
• Use of highly effective birth control, including hormonal prescription oral 
contraceptives, contraceptive injections, contraceptive patch, contraceptive implant, 
contraceptive ring, intrauterine device, intrauterine hormone-releasing system, dual 
barrier method (e.g., condoms, or diaphragm, or cervical cap when used with 
spermicide), or 
• monogamous relationship with a male partner of confirmed sterility, or 
• practice complete abstinence, i.e., refrain from sexual intercourse. 
 
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhoea method are not acceptable 
methods of contraception. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the subject. 
Females of non-childbearing potential may be enrolled if it is documented that they are 
postmenopausal (amenorrhea for ≥12 months) and follicle-stimulating hormone (FSH) ≥ 25 
IU/L, or have undergone surgical sterilization, including hysterectomy, bilateral 
oophorectomy, bilateral salpingectomy, or Essure procedure. Females with FSH <25 IU/L 
must agree to contraception from Day -1 through 30 days after the last administration of 
study medication, if they have a male partner. 
6. 
ASSESSMENT OF SAFETY 
Blinded safety data, including adverse events, vitals, ECG, clinical labs, will be monitored 
and evaluated on an ongoing basis throughout the study. 
6.1. 
Adverse Events 
6.1.1. 
Definitions 
Adverse Event 
An AE is any untoward medical occurrence associated with the use of a study drug in 
humans and which does not necessarily have a causal relationship with this treatment. AEs 


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may be reported by the subject, discovered through Investigator questioning, or detected 
through physical examination, laboratory test, or other means.  
AEs include: 
• Any new undesirable medical experience or an unfavorable and unintended change of 
an existing condition that occurs during or after treatment, whether or not considered 
related to study medication. 
• Abnormal laboratory findings considered by the Investigator to be clinically 
significant, i.e., those that are unusual for the population being studied or individual 
subject. 
• Complications and termination of pregnancy; uncomplicated pregnancies are not 
considered AEs but must still be reported. 
 
Additionally, events (including intercurrent illnesses) occurring from the time of 
randomization will be documented on the AE CRF. Concurrent illnesses, which existed prior 
to first dose in the clinical trial, will not be considered AEs unless they worsen during the 
treatment period.  
Serious Adverse Event 
An SAE is defined as any untoward medical occurrence that at any dose: 
• Results in death. 
• Is life-threatening (this means that the subject is at risk of death at the time of the 
event; it does not mean that the event hypothetically might have caused death if it 
were more severe). 
• Requires or prolongs subject hospitalization. 
• Results in persistent or significant disability or incapacity. 
• Is a congenital anomaly or birth defect. 
• Is an important medical event that does not otherwise meet the criteria for 
seriousness. 
 
Medical and scientific judgment should be exercised in deciding if an event is serious if it 
does not meet the above definitions, such as an important medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but that may jeopardize the 
subject or may require intervention to prevent one of the above outcomes. Specific examples 
of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias, or convulsions that do not result in hospitalization.  
A distinction should be drawn between seriousness and severity of an AE. An AE that is 
assessed as severe, for example, should not be confused with an SAE. Severity is a category 
utilized for rating the intensity of the event (see below); both AEs and SAEs will be assessed 


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for severity grading. An event is defined as “serious” when it meets one of the predefined 
outcomes as described above. 
6.1.2. 
Assessment of Adverse Events 
Each event recorded on the AE CRF will be assessed by the Investigator with regard to the 
following categories. 
 
Severity 
Severity of AEs will be graded as one of: 
• Mild: Awareness of signs or symptoms but easily tolerated. A type of AE that is 
usually transient and may require only minimal treatment or therapeutic intervention. 
The event does not generally interfere with usual activities of daily living. 
• Moderate: A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research subject. 
• Severe: Incapacitating the ability to do work or to do activities. A type of AE that 
interrupts usual activities of daily living, or significantly affects clinical status, or may 
require intensive therapeutic intervention. 
 
 
Relationship to Study Medication 
The Investigator or designee, using clinical judgment, will assess the causality/relationship 
between each AE and the most recently administered study medication (i.e., whether there is 
a reasonable possibility that the drug caused the event) and record that assessment in the 
CRF.  
Unrelated: The AE is clearly not related to the study medication. The AE is clearly explained 
by another cause, or exposure to the study medication has not occurred.  
Related: The AE may be related to the study medication. The AE and administration of the 
study medication are considered reasonably related in time, but the AE is more likely 
explained by the study medication than another cause. 
AE reporting will extend from randomization until completion of the End-of-Study Visit. 
AEs occurring after the end of the clinical trial must be reported if the Investigator considers 
there is a causal relationship with the study medication.  
All AEs, regardless of the relationship to study medication, will be recorded in the CRF.  
All reports should contain a brief description of the event, date of onset, date of resolution, 
severity, treatment required, relationship to study medication, outcome, and whether the 
event is classified as serious. Whenever possible, the Investigator should group signs or 
symptoms that constitute a single diagnosis into a single event term. For example, “cough, 
rhinitis, and sneezing” might be grouped together as “upper respiratory tract infection.” 
A treatment-emergent clinically significant abnormal laboratory value should be recorded as 
an AE. 


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6.1.3. 
Reporting Serious Adverse Events 
All SAEs that occur from time of informed consent until completion of the final visit, 
whether considered to be associated with the study medication or not, must be reported 
within 24 hours by telephone, e-mail, or fax to the Sponsor’s Medical Monitor and/or 
Sponsor’s designee using the appropriate contact details provided. The minimum information 
required for an initial report is: 
• Sender of report (name, address of Investigator), 
• Subject identification (subject number, NOT subject name), 
• Protocol number, 
• Description of SAE and date of onset, 
• Relationship assessment, 
• Date of visit and study visit number, 
• Current status of subject. 
 
However, whenever possible, all points on the SAE form should be completed and the form 
faxed or scanned and emailed to the Sponsor or designee. The site should also notify the 
Sponsor or designee by email or voicemail if the information was sent via facsimile. In 
addition, the event must be documented in the CRF. 
It is recognized that it may be difficult to differentiate the relationship of an adverse event to 
CST-2032 or to CST-107 (nadolol).  There is a long history of the clinical safety of nadolol 
and the dose of nadolol being administered in this study is less than 10% of the labeled 
starting dose for treatment of angina pectoris or hypertension (3 mg versus 40 mg).  
Therefore, unless the PI is confident in attribution of causality to CST-107 (e.g., for an AE 
that occurs prior to administration of CST-2032), all assessments of  related AEs will be 
attributed to CST-2032 for expedited reporting purposes. 
After receipt of the initial report, the Sponsor’s Medical Monitor or designee will review the 
information and, if necessary, contact the Investigator to obtain further information for 
assessment of the event. The Sponsor or designee will be responsible for all information 
processing and reporting according to local legal requirements.  
The Sponsor or designee will determine the SAEs requiring expedited reporting to regulatory 
agencies. The clinical trial site personnel are responsible for reporting these events to their 
Ethics Committee in accordance with applicable laws and regulations. 
6.1.4. 
Follow-up of Adverse Events 
All AEs and SAEs experienced by a subject, irrespective of the suspected causality, will be 
monitored until the event has resolved, until any abnormal laboratory values have returned to 
baseline or stabilized at a level acceptable to the Investigator and Medical Monitor. Any SAE 
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must be reported to Sponsor or designee and any necessary regulatory agencies and must be 
followed by the Investigator until resolution or stabilization. 
6.2. 
Clinical Safety Laboratory Abnormalities 
Blood and urine samples for routine safety laboratory parameters will be collected at 
timepoints specified in the Schedule of Events. The Investigator will document review of all 
labs and will determine and document clinical significance. All abnormal laboratory values 
that are clinically significant, treatment-emergent, and meet one of the following conditions 
(as determined by the Investigator) should be recorded as a single AE: 
• Accompanied by clinical symptoms, or 
• Requires a change in concomitant therapy 
 
6.3. 
ECG Abnormalities 
All ECGs  will be evaluated by a central ECG reader and the Investigator in consultation 
with the Sponsor’s Medical Monitor to determine if the abnormality is significant and 
whether it is safe for the subject to continue in the study. 
6.4. 
Pregnancy  
Female subjects who become pregnant during the study period must be discontinued from the 
study. Pregnancy in a study subject should be reported by the Investigator within 1 business 
day to the Sponsor’s Medical Monitor. Pregnancy in itself is not regarded as an AE unless 
there is a suspicion that an investigational product may have interfered with the effectiveness 
of a contraceptive medication.  
Any female subject or partner of a male study subject who becomes pregnant during the trial 
will be asked to agree to regular reporting of the progress and outcome of her pregnancy to 
the Investigator (or designee) and Sponsor. Monitoring of the pregnant subject or partner 
should continue until the outcome (spontaneous miscarriage, elective termination, normal 
birth, or congenital abnormality) of the pregnancy is known and documented even if 
the subject was discontinued from the study.  
All reports of congenital abnormalities/birth defects are SAEs.  Spontaneous miscarriages 
should also be reported and handled as SAEs.  Elective abortions without complications 
should not be handled as AEs. 
7. 
STUDY MEDICATION  
7.1. 
Study Medication  
CST-2032 is provided as white tablets containing 3 mg CST-2032 that are identical in 
appearance to the matching placebo. CST-2032 and matching placebo will be supplied in 
blister cards containing 10 repeat doses for a 1-week supply.  


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CST-107 is provided as yellow tablets containing 3 mg nadolol that are identical in 
appearance to the matching placebo. CST-107 and matching placebo will be supplied in 
blister cards or bottles containing 10 repeat doses for a 1-week supply. 
Additional details on the study medication can be found in the Investigator Brochure (IB).  
7.2. 
Study Medication Dosing and Administration 
The CST-2032 blister cards are designed for subjects to dispense 2 tablets on each dosing 
day according to the treatment the subject is randomized to receive and the treatment period 
in which they are participating, e.g.: 
• 2 placebo tablets for administration of blinded placebo, or  
• 1 tablet of 3 mg CST-2032 and 1 tablet of placebo for the blinded 3 mg dose. 
 
The CST-107 blister cards or bottles allow subjects to dispense 1 tablet on each dosing day 
according to the treatment the subject is randomized to receive and the treatment period in 
which they are participating, e.g.: 
• 1 placebo tablet for administration of blinded placebo, or 
• 1 tablet of 3 mg CST-107 for the blinded 3 mg dose. 
 
During each treatment period, subjects will receive CST-107 or matching placebo for 15 days 
and CST-2032 or matching placebo for 14 days:  
• On Day -1, CST-107 or matching placebo will be administered in clinic after 
completion of all scheduled assessments.  
• Study drug (CST-2032 and CST-107 or matching placebos) will be administered in 
clinic on Day 1 during which dispensing will be demonstrated to the subjects. 
 
Subjects will receive a 1-week supply of study drug on Days 1 and 7 of each treatment 
period. CST-107 or matching placebo and CST-2032 or matching placebo are to be taken 
together each day during both treatment periods.  
7.2.1. 
Randomization 
The designated Interactive Web Response System (IWRS) will be used to randomize subjects 
into the study on Day -1. Eligible subjects will be randomly assigned in a 1:1 ratio to one of 
the following 2 treatment regimens/sequences:  
 
Treatment Period 1 
Treatment Period 2 
1 
3 mg CST-2032 + 3 mg CST-107 
Placebo (2032) + placebo (107) 
2 
Placebo (2032) + placebo (107) 
3 mg CST-2032 + 3 mg CST-107 
 


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The IWRS will provide the randomization number. 
7.2.2. 
Blinding  
This clinical trial is a double-blinded study, with the Sponsor, subjects, and site personnel 
(e.g., study nurses, coordinators, investigators) blinded to treatment assignment. Limited staff 
will have access to treatment assignments, such as the unblinded statistical team, IWRS 
system administration, and drug supply management team.  
A subject’s treatment assignment should only be unblinded by the PI and/or by CuraSen’s 
Medical Monitor when knowledge of the treatment is essential for the further 
management of the subject or may impact the safety of subjects currently enrolled. 
Unblinding for any other reason will be considered a protocol violation. The PI is 
strongly encouraged to contact the CuraSen Medical Monitor before unblinding any 
subject’s treatment assignment but must do so within 1 working day after the event and 
must document the unblinding in the subject’s source records. 
CST-2032 matched placebo and CST-107 matched placebo will be packaged and color-, 
size-, and shape-matched to be indistinguishable from CST-2032 3 mg and CST-107 3 mg. 
7.2.3. 
Packaging and Labeling 
The color and labeling for tablets of CST-2032 and its matching placebo will be distinct from 
the packaging for color and labeling for tablets of CST-107 and its matching placebo:  
• CST-2032 and matching placebo will be supplied in blister cards with a white label 
containing 10 repeat doses. The blister cards are designed for subjects to dispense 2 
tablets on each dosing day according to the treatment the subject is randomized to 
receive and the treatment period in which they are participating. 
• CST-107 and matching placebo will be supplied in blister cards with a blue label 
containing 10 repeat doses or bottles with a yellow label containing 10 doses. The 
blister cards are designed for subjects to dispense 1 tablet on each dosing day 
according to the treatment the subject is randomized to receive and the treatment 
period in which they are participating. 
 
Each blister card will supply 1 week (+3 extra days) of dosing of CST-2032/placebo and 
1 week (+2 extra days) of dosing for CST-107/placebo blister or bottle.  
The clinical label will identify the product by name, lot number, Sponsor, and storage 
conditions. The blister or bottle labels will include the investigational drug caution statement: 
“Caution: New Drug - Limited by Federal (United States) Law to Investigational Use Only.” 
7.2.4. 
Storage and Handling 
Study medications will be stored in a secure, controlled-access location at the study site. 
Study medications will be stored and handled at the clinical site in accordance with 
instructions in the Pharmacy Manual.  


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CST-2032/matching placebo will be stored at refrigerated temperature 36°F–46°F (2–8°C).  
Minor excursions are permitted (down to 0°C and up to 25°C for up to 60 minutes) and 
should be recorded within the pharmacy temperature logs.  Excursions longer than 15 
minutes must be reported to CuraSen but the product is still suitable for use.  If temperature 
excursions are greater than 60 minutes, CuraSen must be informed within 24 hours so that 
study medication can be quarantined.   
CST-107/matching placebo will be stored at controlled room temperature 59°F–77°F (15–
25°C) with excursions allowed up to 86°F (30°C) for not longer than 48 hours (continuous). 
The Sponsor must be notified immediately of any temperature excursions or damage to study 
medications.  
Temperature monitoring is required at the storage location to ensure that the study 
medications are maintained within an established temperature range. The Investigator(s) is 
responsible for ensuring that the temperature is monitored throughout the total duration of the 
trial and that records are maintained; the temperature should be monitored continuously by 
using either in house validated data acquisition system, a mechanical recording device, such 
as a calibrated chart recorder, or by manual means, such that minimum and maximum 
thermometric values over a specific time period can be recorded and retrieved as required. 
8. 
STATISTICAL CONSIDERATIONS  
Details of statistical parameters and methods to be used will be described in a Statistical 
Analysis Plan (SAP). The SAP will be developed and finalized prior to database lock. The 
SAP will describe the statistical methodology to assess differences between treatment groups, 
all data handling procedures and definitions, including the methods for managing missing 
data.  
8.1. 
Sample Size 
A total of approximately 60 subjects is planned. Although formal hypothesis testing is 
planned, the study is underpowered for detecting meaningful cognitive benefits and lack of 
significance will not be interpreted as lack of a treatment effect. The sample size is based on 
practical considerations and is typical of studies whose objectives are to evaluate the safety 
and cognitive effects of a therapeutic intervention.  
8.2. 
Analysis Populations 
The analysis populations are as follows: 
Intent to Treat Set (ITT): All subjects who have signed informed consent and have been 
randomized to a treatment sequence. Subjects will be analyzed according to the treatment 
sequence assigned at randomization. The ITT will be the analysis set for disposition and 
select baseline characteristic analyses. 
Safety Set: All subjects who received at least 1 dose of study drug (either CST-2032 or 
CST-107 or placebo). Subjects will be reported based on treatment and dose received. The 
Safety Set will be used for reporting of safety analyses.  


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Full Analysis Set (FAS): All randomized subjects who have taken at least 1 dose of blinded 
study drug (CST-2032+CST-107 or Placebo). Subjects will be analyzed according to the 
treatment assigned at randomization. The Full Analysis Set will be used for evaluating the 
cognitive endpoints, pharmacodynamic endpoints and selected secondary endpoints.  
Per-Protocol Set (PPS): A subset of the Full Analysis Set who sufficiently complied with 
the protocol. Details of the evaluability criteria will be determined prior to study unblinding 
and specified in the SAP. The Per Protocol Set may be used for selected safety analyses. 
Pharmacokinetic Set (PKS): All subjects in the Safety Set who have at least one valid 
plasma concentration assessment for CST-2032 or CST-107. Subjects will be analyzed 
according to the treatment received. The PKS will be the analysis set for PK concentration 
and PK parameter analyses. 
Additional analysis populations may be defined in the Statistical Analysis Plan. 
8.3. 
Timing of Analyses 
8.3.1. 
Interim Analysis 
An unblinded interim analysis may be conducted by the DSMB after approximately 40  
subjects have completed Treatment Period 1.  
If conducted, this will be an unblinded analysis, but patient level treatment assignments will 
continue to be blinded.  
Details of the interim analysis will be provided in the Statistical Analysis Plan and DSMB 
Charter.  
8.3.2. 
Final Analysis  
The final analysis will be performed after the last subject completes their End-of-Study visit 
or their last scheduled assessment per the Schedule of Events, or the sponsor terminates the 
study for any reason.  
8.4. 
Multiplicity 
This study is descriptive in nature and informal testing of multiple endpoints may be 
performed. Given the exploratory nature of the comparisons, no adjustment of Type I error is 
planned. 
8.5. 
Statistical Methods 
Statistical analyses will be performed using SAS 9.4 or higher. Continuous data will display 
number of subjects, means, standard deviations, median, minimum, and maximum. 
Categorical data will display frequency counts and percentages. Unless specified otherwise, 
confidence intervals will be displayed at the two-sided 95% confidence level.  
Summaries of disposition and baseline data will be summarized by treatment, disease criteria 
(MCI vs. mild dementia), treatment sequence and overall. Summaries of safety, and 
pharmacodynamic measures (e.g., effects of treatment on CANTAB, pVFT, DSST, Color 


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Trails Test, FERT, GDS-30, SAS-6, CAARS, ADCS-CGIC) will be presented by treatment 
overall. PK of CST-2032 and CST-107 will be presented by treatment and treatment 
sequence. A limited subset of summaries may be presented by treatment and treatment 
sequence and/or period and overall.  
For analysis purposes, Baseline will be defined as either the pre-dose measurement(s) taken 
within each of the study periods, or as the last measurement(s) before the first dose received. 
This will be detailed in the SAP for each parameter. All data will be listed. 
Any changes in the planned analysis will be described and documented in the SAP and/or 
clinical study report. 
8.5.1. 
Subject Disposition 
Subject disposition will be summarized by LC integrity as determined by baseline disease 
characteristics, treatment, treatment sequence and overall using the ITT. Summaries will 
include the number and percent of subjects: in each analysis population, entering the 
treatment period, completing each period, completing the study, and discontinuing study 
prematurely, including a description of the reason for early withdrawal. All data will be 
listed. 
8.6. 
Subject Characteristics 
Demographic and other baseline characteristics will be summarized by disease criteria, 
treatment, treatment sequence and overall using the ITT. Select summaries may also be 
repeated in the FAS and Safety Set, if the Safety Set differs from the FAS. All data will be 
listed.  
8.7. 
Analysis of Primary Endpoint 
Primary endpoint data will be summarized by treatment using the Safety Set. Selected 
summaries may be repeated in the PPS. All data will be listed. 
8.7.1. 
Analysis of Adverse Events  
Safety endpoints will be summarized by disease criteria, treatment, treatment sequence and 
overall using the Safety Set. Additional summaries may be performed by treatment, treatment 
sequence and/or period. A limited set of endpoints may also be summarized using other 
analysis populations.  
All reported AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Adverse event collection will begin during screening and will be collected up to 
14 days after the last dose of study drug. All AEs collected on/after first dose of study drug 
will be considered treatment emergent (TEAE). Each TEAE will further be attributed to a 
treatment (CST2032+CST-107 or placebo) based on the AE start date. If a TEAE start date is 
prior to the first dose in Treatment Period 2, the AE will be attributed to the treatment 
received in Period 1. If a TEAE start date is on/after the first dose in Treatment Period 2, the 
AE will be attributed to the treatment received in Period 2.  


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An overall summary of the number and percentage of subjects experiencing TEAEs, serious 
AEs (SAEs), treatment-related AEs, AEs by maximum severity and AEs leading to treatment 
withdrawal will be provided. TEAEs, SAEs, and treatment-related AEs will be further 
summarized by MedDRA system organ class and preferred term and reported by treatment.  
All AEs will be listed. Separate listings may be prepared for SAEs, AEs leading to study 
drug termination, and treatment-related AEs. Individual ECG results will be listed for each 
subject. Summaries of ECGs by treatment will include observed data and changes from 
baseline for each parameter including heart rate, QT, and QTcF. The number and percentage 
of subjects with abnormal ECGs will be summarized by treatment. 
Additional analyses may be performed and will be described in the SAP. 
8.8. 
Analysis of Secondary Endpoints 
Differences between CST-2032+CST-107 and placebo in performance in cognitive tasks will 
be assessed using the FAS. For continuous endpoints, the difference is defined as CST-
2032+CST-107 minus placebo except as defined in the SAP (e.g., for certain CANTAB test 
[PAL, RTI, and SSRT]). Comparisons may be made using a mixed model with factors for 
disease criteria, treatment, treatment sequence, subject nested in sequence (as a random 
effect), period, and baseline values as appropriate. Comparisons between treatments may also 
be compared using the paired t-test and/or nonparametric tests where appropriate and as 
specified in the SAP. These analyses will be conducted for all subjects in the study and also 
for each disease subset (PD/AD). 
Secondary endpoints related to cognition, physiological symptoms, mood and will be 
summarized by disease criteria, treatment, treatment sequence and overall using the FAS. 
Select summaries may be repeated in the PPS. Comparisons between treatments will be 
performed similarly for all secondary endpoints. All data will be listed. 
8.8.1. 
CANTAB, pVFT, DSST, Color Trails Test  
Absolute values and changes from baseline will be summarized by baseline disease 
characteristics, treatment and overall. In addition, comparisons of effects of CST-2032+CST-
107 vs placebo may be undertaken.  
Pre-dose measures of cognitive performance may be used to identify the cognitive domains 
for which each subject is deficient based on available population data generated outside of 
this protocol, as available.  
A responder analysis may be performed based on whether the subject meets pre-defined 
criteria for one or more of the cognitive tests.  
The responder criteria for will be defined after review of emerging data from ongoing 
CuraSen clinical trials (e.g., CST103/CST107-CLIN-010, CST103/CST107-CLIN-011, and 
CST2032-CLIN-007). Methods and responder criteria will be described in more detail in the 
SAP prior to database lock.  


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8.8.2. 
Mood, Apathy and Disease Activity Scales 
The absolute values and change from baseline in overall scores and sub-domain scores where 
applicable will be summarized by baseline disease characteristics, treatment and overall for 
FERT, GDS-30, CAARS, SAS-6, ADCS-CGIC using the FAS.  
All results will be listed. 
8.8.3. 
Clinical Laboratory Results, Vital Signs, and ECGs 
Absolute values and changes from baseline will be summarized by disease criteria, treatment 
and overall. In addition, clinical laboratory results, ECG categorical analyses, and ECG shift 
tables may be generated.  
All results will be listed. Laboratory values outside of normal ranges and clinically 
significant ECG abnormalities will be flagged.  
8.8.4. 
Analysis Pharmacokinetic Endpoints 
PK endpoints will be summarized by disease criteria, treatment and overall using the PKS. 
All PK endpoints will be listed. 
Individual plasma CST-2032 and CST-107 concentrations will be listed for each subject and 
summarized by nominal sampling timepoint with descriptive statistics (sample size [N], 
arithmetic mean, standard deviation, median, minimum, maximum, geometric mean and 
coefficient of variation). Individual and mean CST-2032 and CST-107 concentration-time 
profiles will also be presented graphically on both a linear and log-linear scale. 
All PK parameters will be computed from the individual plasma CST-2032 and CST-107 
concentrations using an appropriate noncompartmental or compartmental approach. The 
actual PK sampling timepoints will be used for the PK analysis if available, and there are 
significant deviations from the nominal collection times.  
The PK parameters that may be determined (including Cmax, tmax, AUCt, AUCinf, t1/2) will be 
calculated.  
Additional analyses will be performed as deemed necessary upon review of the data. 
8.9. 
Analysis of Exploratory Endpoints 
Subgroup analyses may be conducted after study completion to evaluate whether effects of 
treatment are influenced by baseline disease characteristics including but not limited to 
disease activity as determined from relevant disease scales at screening, neurodegenerative 
biomarkers (such phosphorylated tau, neurofilament light chain, total and phosphorylated tau 
protein, and amyloid‐β (Aβ) peptides) in plasma, and genetic variants including but not 
limited to APOE4, LRRK2, and GBA.  Additionally, change in average z-score for baseline-
deficit cognitive tasks identified for each subject from Cognitive tasks in the CANTAB and 
other cognitive measures may be evaluated. 
All exploratory endpoints will be listed. 


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8.10. 
Other Analyses  
Medical history, physical examination, C-SSRS, protocol deviations, screening clinical & 
cognitive scales (e.g., MoCA, RBD1Q, MHYS), neurodegenerative biomarkers, and genetic 
variants including but not limited to APOE4, LRRK2, and GBA will be listed. 
8.10.1. 
Concomitant Medications 
Concomitant medications will be coded using the World Health Organization Drug 
Dictionary. Medications taken on or after the first day of the treatment period through the end 
of treatment will be considered on-treatment medications and will be summarized. All 
medications will be listed. 
8.10.2. 
Study Drug Administration 
Subject exposure to study drug and compliance will be summarized by treatment and 
treatment sequence. All study medication dispensed and returned, exposure, and compliance 
data will be listed. 
9. 
ETHICAL, LEGAL AND ADMINISTRATIVE ASPECTS 
9.1. 
Data Quality Assurance 
The Sponsor or designee will conduct either an in-person or virtual site visit to verify the 
qualifications of each Investigator, according to Sponsor’s or designee’s applicable standard 
operating procedure, inspect the site facilities, and inform the Investigator of responsibilities 
and the procedures for ensuring adequate and correct documentation. 
The Investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the clinical trial for each 
clinical trial subject. All information recorded on the CRFs for this clinical trial must be 
consistent with the subjects’ source documentation (i.e., medical records). 
9.2. 
Case Report Forms and Source Documentation 
Data obtained during this clinical trial should be promptly entered in the electronic CRF 
(eCRF). All source documents from which eCRF entries are derived will be placed in the 
subject’s medical records. An eCRF will be completed for every subject who was screened 
for participation in the clinical trial. Measurements for which source documents are available 
include vital signs, physical exams, laboratory assessments and ECG recordings. 
A representative of the Sponsor or designee (a Site Monitor) will visit the clinical trial center 
periodically to monitor adherence to the protocol and to applicable regulatory regulations, 
and the maintenance of adequate and accurate clinical records. The eCRFs will be reviewed 
in detail, for which the Site Monitor will have access to subject medical records, laboratory 
data, and other source documentation. Remote monitoring may be utilized in some 
circumstances. The Site Monitor will make a decision as to their acceptability. If errors or 
omissions are found in the course of a data review, or if clarification of data is required, the 
eCRFs in question will be corrected by the Investigator or designee. 


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After full review by the Site Monitor and resolution of any data clarifications, the 
Investigator will sign and date the completed eCRF. This signature will indicate that 
thorough inspection of the data therein has been made and will thereby certify the contents of 
the form. 
9.3. 
Access to Source Data 
During the course of the clinical trial, Sponsor representatives, Site Monitors, FDA, EC/IRB, 
and/or the Sponsor’s Quality Assurance Group or designee must have direct access to source 
data to review protocol compliance, compare CRFs and individual subject’s medical records, 
assess drug accountability, and ensure that the clinical trial is being conducted according to 
pertinent regulatory requirements. 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. The Investigator will ensure that the Sponsor is provided with 
all necessary support at all times. 
9.4. 
Data Processing 
All data will be entered using an appropriate data entry system, following standard 
procedures. 
The data review and data-handling document will include specifications for consistency and 
plausibility checks of data and will also include data-handling rules for obvious data errors.  
9.5. 
Archiving Clinical Trial Records 
According to ICH guidelines, essential documents will be retained for a minimum of 2 years 
after the last approval of a marketing application in an ICH region.  
It is the responsibility of the Investigator and clinical trial staff to maintain a comprehensive 
and centralized filing system of all clinical trial-related documentation. This centralized file 
should be available for inspection at any time by the Sponsor, Site Monitor or the Sponsor’s 
Quality Assurance staff or designee for monitoring or auditing by the Sponsor and regulatory 
authorities. Elements of clinical trial documentation will include: 
• Subject files containing the completed eCRF supporting source documentation and the 
signed informed consent form (ICF). 
• Clinical trial files, containing the protocol with all amendments, the IB, copies of all 
clinical trial documentation, and all correspondence to and from the EC/IRB and the 
Investigator. 
• Pharmacy files, containing the Study Medication Accountability Records or dispensation 
logs and all clinical trial agent-related correspondence. 
 
9.6. 
Good Clinical Practice 
The procedures set out in this clinical trial protocol are designed to ensure that the Sponsor 
and Investigator abide by the principles of the cGCP guidelines of the ICH and applicable 


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federal/national and local regulations. The clinical trial also will be carried out in keeping 
with local legal requirements. 
9.7. 
Informed Consent 
Before each subject is screened, written informed consent must be obtained from the subject. 
The informed consent forms (ICFs) must be signed and dated and retained by the Investigator 
as part of the clinical trial records. The Investigator will not undertake any investigation 
specifically required for the clinical trial until valid consent has been obtained. The terms of 
the consent and when it was obtained must also be documented in the CRF. Each subject will 
receive a fully signed copy of each consent form that he/she signs for the clinical trial. 
If a protocol amendment is required, the ICF may need to be revised to reflect the changes to 
the protocol. If the consent form is revised, it must be reviewed and approved by the 
appropriate EC/IRB and signed by all subjects subsequently enrolled in the clinical trial, as 
well as those currently enrolled in the clinical trial. 
9.8. 
Protocol Approval and Amendment 
Before the start of the clinical trial, the clinical trial protocol and/or other relevant documents 
will be approved by the EC/IRB in accordance with legal and regulatory requirements. The 
Sponsor must ensure that all ethical and legal requirements have been met before the first 
subject is screened for the clinical trial. 
The procedures outlined in the protocol and eCRFs will be reviewed by the Investigator and 
staff prior to clinical trial initiation to ensure appropriate interpretation and implementation. 
No deviations from the protocol should be made except in emergency situations in which 
alternative treatment is necessary for the protection, proper care, and well-being of subjects. 
To alter the protocol, amendments must be written, and approvals must be received from the 
appropriate personnel. Amendments will originate from Sponsor and will be provided to the 
Investigator for submission to the EC/IRB for review and approval prior to implementation. 
If a protocol amendment substantially alters the clinical trial design or increases potential risk 
to the study subject, the ICF should be revised and, if applicable, subject’s consent to 
continue participation should be obtained. 
Administrative changes may be made without the need for a formal amendment.  
9.9. 
Study Medication Accountability 
9.9.1. 
Handling of Study Medications 
The Investigator shall take adequate precautions, including storage of the study medications 
in a securely locked, substantially constructed cabinet or other securely locked, substantially 
constructed enclosure (or a locked refrigerator for CST-2032), access to which is limited, to 
prevent theft or diversion of the substances into illegal channels of distribution. 


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9.9.2. 
Disposition of Study Medications 
The Investigator is required to maintain adequate records of the disposition of the study 
medications, including dates, quantity, and use by subjects. If the investigation is terminated, 
suspended, discontinued, or completed, the Investigator shall return the unused supplies to 
the Sponsor or designee or dispose in accordance with established site procedures. When the 
Sponsor has indicated in writing that study medication is to be destroyed on site, destruction 
must be in accordance with local regulations for the product type and a destruction certificate 
must be provided to the Sponsor.  
9.10. 
Confidentiality 
All clinical trial findings and documents will be regarded as confidential. The Investigator 
and members of his/her research team must not disclose such information without prior 
written approval from the Sponsor. 
The anonymity of participating subjects must be maintained, and national requirements and 
guidelines must be followed. Subjects will be identified on eCRFs and other documents by 
their subject number, sex and/or birth date, not by name and subject to local requirements. 
Documents that identify the subject (e.g., the signed informed consent) must be maintained in 
confidence by the Investigator.  
9.11. 
Publication Policy 
By signing the clinical trial protocol, the Investigator agrees with the use of results of the 
clinical trial for the purposes of national and international registration, publication, and 
information for medical and pharmaceutical professionals. If necessary, the authorities will 
be notified of the Investigator's name, address, qualifications, and extent of involvement. 
All information not previously published concerning CST-2032 and/or CST-107 and the 
Sponsor’s operations, including, but not limited to, patent applications, formulas, 
manufacturing processes, basic scientific data, and formulation information, supplied by the 
Sponsor to the Investigator is considered confidential and shall remain the sole property of 
Sponsor. The Investigator agrees to use and maintain the confidentiality of this information 
in accordance with the provisions contained in the clinical trial agreement. Any use or 
reproduction thereof, including, but not limited to, publications or presentations by the 
Investigator or his/her associates, must be submitted to the Sponsor for review and approval 
in accordance with the provisions contained in the relevant agreement governing the conduct 
of this trial. All publications must acknowledge the sponsorship of Sponsor. 


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10.1176/appi.ajp.2011.10111704. PMID: 22193671; PMCID: PMC3893686. 
Postuma RB, Arnulf I, Hogl B, et al. A single-question screen for rapid eye movement sleep 
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Pugh PL, Vidgeon-Hart MP, Ashmeade T, Culbert AA, Seymour Z, Perren MJ, Joyce F, 
Bate ST, Babin A, Virley DJ, Richardson JC, Upton N, Sunter D. Repeated administration of 
the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) 
modulates neuroinflammation and amyloid plaque load in mice bearing amyloid precursor 
protein and presenilin-1 mutant transgenes. J Neuroinflammation. 2007 Feb 26;4:8. 
Salehi A, Faizi M, Colas D, et al. Restoration of norepinephrine-modulated contextual 
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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 
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10.1097/00002093-199700112-00004. PMID: 9236949. 
Searles Nielsen S, Gross A, Camacho-Soto A, et al. β2-adrenoreceptor medications and risk 
of Parkinson disease. Ann Neurol. 2018 Nov;84(5):683-693.  
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S, Puttonen K, Naumenko N, Goldsteins G, Laham-Karam N, Lehtonen M, Tavi P, 
Koistinaho J, Lehtonen Š. Metabolic alterations in Parkinson's disease astrocytes. Sci Rep. 
2020 Sep 2;10(1):14474.  
Sorg O & Magistretti PJ. Characterization of the glycogenolysis elicited by vasoactive 
intestinal peptide, noradrenaline and adenosine in primary cultures of mouse cerebral cortical 
astrocytes. Brain Research 1991 563(1-2), 227–233.  
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Neuropsychiatry Clin Neurosci. 1992 Spring;4(2):134-9. 
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Astrocyte-neuron lactate transport is required for long-term memory formation. Cell. 2011 
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Protocol CST2032/CST107-CLIN-015 
 
July 11, 2023 
Amendment 10 
CuraSen Therapeutics, Inc. 
 
 
CONFIDENTIAL  
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10.3389/fnmol.2018.00148. PMID: 29867342; PMCID: PMC5953330. 
Vermeiren Y, De Deyn PP Targeting the norepinephrinergic system in Parkinson’s disease 
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SAP_001.pdf: 
 
 
CONFIDENTIAL 
           Page 1 of 41 
 
 
Statistical Analysis Plan 
 
A PHASE 2A, RANDOMIZED, PLACEBO-
CONTROLLED, DOUBLE-BLIND CROSSOVER STUDY 
TO EVALUATE THE SAFETY, TOLERABILITY AND 
EFFECTS OF CST-2032 AND CST-107 ON COGNITION 
IN SUBJECTS WITH MILD COGNITIVE IMPAIRMENT 
OR MILD DEMENTIA DUE TO PARKINSON’S OR 
ALZHEIMER’S DISEASE 
 
Protocol Number: CST2032/CST107-CLIN-015 
 
SAP Version and date:  Draft 3.0, 25-July-2023 
 
STUDY DRUG:  
CST-2032, CST-107 
 
PREPARED FOR: 
CuraSen Therapeutics, Inc. 
930 Brittan Avenue, #306 
San Carlos, CA 94070, USA 
 
PREPARED BY: 
 
 
 
 


Sponsor: CuraSen Therapeutics, Inc. 
 
Statistical Analysis Plan 
Protocol Number: CST2032/CST107-CLIN-015  
Draft Version 3.0, 25Jul2023 
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           Page 2 of 41 
 
 
Approval Signature Page  
 
 
 
 
 
 
 
 
 
 
Document Author: 
 
Biostatistician II 
Signature by Manager: 
 
Director, Biostatistics 
 
Date 
 
 
 
 
 
 
 
 
Document Reviewer: 
 
Senior Biostatistician I 
 
Date 
 
 
 
 
CuraSen Therapeutics, Inc. 
 
 
 
 
 
 
 
 
Document Reviewer:  
 
Chief Medical Officer 
 
Date 
 
 
 


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Draft Version 3.0, 25Jul2023 
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           Page 3 of 41 
 
Revision History 
SAP Revision Chronology: 
 
 
Version 1.0 
16-February-2023 
 
Version 2.0 
25-April-2023 
Amend Section 4.5 Timing of 
Analysis for adjusted interim 
analysis timing. 
Version 3.0 
25-July-2023 
Amend Section 2 Introduction 
for updated protocol and CRF 
versions. 
Amend Section 4.5 Timing of 
Analysis to include additional 
outputs. 
Amend Section 9.2 Secondary 
Endpoints and Analyses for 
planned analyses in case of 
model convergence issues, 
repeat analyses on the per 
protocol set, and addition of 
MoCA analyses. 
 
 
 


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Statistical Analysis Plan 
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           Page 4 of 41 
 
 
Contents 
1 
ABBREVIATIONS ................................................................................................................ 6 
2 
Introduction ............................................................................................................................. 8 
2.1 
Changes to the Planned Analysis.................................................................................. 8 
3 
Study Objectives and Endpoints ............................................................................................. 8 
4 
Study Design ......................................................................................................................... 10 
4.1 
General Description .................................................................................................... 10 
4.2 
Randomization and Blinding ...................................................................................... 11 
4.3 
Sample Size ................................................................................................................ 11 
4.4 
Study Committees....................................................................................................... 12 
4.4.1 
Data and Safety Monitoring Board ......................................................................... 12 
4.5 
Timing of Analyses .................................................................................................... 12 
5 
Analysis Sets/Populations ..................................................................................................... 14 
6 
Data Analysis Considerations ............................................................................................... 15 
6.1 
General Data Handling ............................................................................................... 15 
6.2 
Stratification and Covariates ...................................................................................... 15 
6.3 
Evaluation of Subgroups ............................................................................................ 16 
6.4 
Multiple Comparisons and Multiplicity ..................................................................... 16 
7 
General Considerations ......................................................................................................... 16 
7.1 
Reference Dates .......................................................................................................... 16 
7.2 
Study Day and Duration Variables ............................................................................. 16 
7.3 
Baseline and Post-Baseline Changes .......................................................................... 16 
7.4 
Missing Data and Data Imputation Rules ................................................................... 17 
7.5 
Multiple Assessments and Visit Windows ................................................................. 17 
8 
Study Subject Data ................................................................................................................ 17 
8.1 
Subject Enrollment and Disposition ........................................................................... 17 
8.2 
Protocol Deviations .................................................................................................... 18 
8.3 
Demographic and Baseline Characteristics ................................................................ 18 
8.4 
Clinical and Cognitive Scales ..................................................................................... 18 
8.5 
Medical History .......................................................................................................... 18 
8.6 
Prior, Concomitant, and Rescue Medication .............................................................. 19 
8.7 
Study Drug Exposure and Compliance ...................................................................... 19 
9 
Endpoint Analyses ................................................................................................................ 19 


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9.1 
Primary Endpoint and Analyses ................................................................................. 20 
9.2 
Secondary Endpoints and Analyses ............................................................................ 20 
9.3 
Exploratory Endpoints and Analyses ......................................................................... 27 
10 PHARMACOKINETICS ...................................................................................................... 28 
11 Safety .................................................................................................................................... 28 
11.1 
Adverse Events ........................................................................................................... 28 
11.2 
Clinical Laboratory Evaluations ................................................................................. 29 
11.3 
Vital Signs .................................................................................................................. 30 
11.4 
Electrocardiogram (ECG) ........................................................................................... 30 
11.5 
Physical Examinations ................................................................................................ 31 
11.6 
Columbia-Suicide Severity Rating Scale (C-SSRS) .................................................. 31 
12 References ............................................................................................................................. 32 
13 APPENDICES ...................................................................................................................... 34 
13.1 
APPENDIX 1: Partial Date Conventions ................................................................... 34 
Algorithm for Treatment Emergence of Adverse Events: ........................................................ 34 
Algorithm for Prior / Concomitant Medications:...................................................................... 35 
13.2 
APPENDIX 2: Protocol Schedule of Events .............................................................. 36 
13.3 
APPENDIX 3: Normative Data for Cognition Tests Used in this SAP ..................... 41 
 
 
 
 


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1 ABBREVIATIONS 
ADCS-CGIC 
Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change 
APOE4 
Apolipoprotein E4 
β-AR  
Beta-adrenoceptor  
β-hCG  
Beta human chorionic gonadotropin  
AD 
Alzheimer’s Disease 
AE  
Adverse event  
ADHD  
Attention Deficit/Hyperactivity Disorder  
AS  
Apathy scale  
ATT  
Adaptive tracking test  
AUCinf  
Area under the drug concentration-time curve from time zero to infinity  
AUCt  
Area under the drug concentration-time curve from time zero to time t  
BMI  
Body mass index  
BP  
Blood pressure  
CAARS 
Connors Adult Attention Deficit/Hyperactivity Disorder Scale – short form, 
self-report 
cAMP  
cyclic adenosine monophosphate 
CANTAB  
Cambridge Neuropsychological Test Automated Battery  
CBF  
Cerebral blood flow  
cGCP  
Current Good Clinical Practice  
Cmax  
Maximum concentration  
CNR 
Contrast-to-noise ratio 
CNS  
Central nervous system  
CRF  
Case report form  
C-SSRS  
Columbia-Suicide Severity Rating Scale  
CST-107  
Nadolol  
DSMB 
Data and Safety Monitoring Board  
DSM-V 
Diagnostic and Statistical Manual of Mental Disorders 5  
DSST  
Digital Symbol Substitution Test  
EC  
Ethics Committee  
eCRF  
Electronic case report form  
ECG  
Electrocardiogram  
EW  
Early withdrawal  
FAS  
Full analysis set  
FERT  
Facial Expression Recognition Task  
FSH  
Follicle-stimulating hormone  
GBA 
Glucocerebrosidase (GCase) protein 
GDS-30 
Geriatric Depression Scale – 30 questions 
HR  
Heart rate  
HbsAb  
Hepatitis B surface antibody  
HbsAg  
Hepatitis B surface antigen  
HCV Ab  
Hepatitis C antibody  
HIV  
Human immunodeficiency virus  
IB  
Investigator Brochure  
ICF  
Informed consent form  
ICH  
International Council for Harmonisation  


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ICSD-3 
International Classification of Sleep Disorders, Third Edition  
IRB 
Institutional review board  
ISI 
Interstimulus interval  
ITT  
Intent to treat  
IV  
Intravenous  
IWRS  
Interactive Web Response System  
LC  
Locus coeruleus  
LRRK2 
Leucine rich repeat kinase 2 
MAOI 
Monoamine oxidase inhibitor  
MCI  
Mild cognitive impairment  
MD 
Mild Dementia  
MedDRA  
Medical Dictionary for Regulatory Activities  
MHYS  
Modified Hoehn & Yahr Scale  
MoCA  
Montreal Cognitive Assessment  
PAL  
Paired Associates Learning  
PD  
Parkinson’s Disease  
PI  
Principal Investigator  
PK  
Pharmacokinetic  
PKS  
PK set  
PO  
By mouth/oral administration  
PPS  
Per protocol set  
pVFT 
Phonological verbal fluency test 
QD  
Once daily  
QTcF 
QT interval corrected for changes in heart rate using the Fridericia equation 
RBD 
REM Sleep Behavior Disorder  
RBD1Q  
REM Sleep Behavior Disorder Single-Question Screen  
RTI  
Reaction Time Index  
SAE  
Serious adverse event  
SAP  
Statistical analysis plan  
SARS-CoV-2  
Severe acute respiratory syndrome coronavirus 2  
SAS-6 
Starkstein apathy scale – short form (6 questions) 
SIR 
standard image recognition 
SNRI 
serotonin/noradrenaline reuptake inhibitors 
SOP  
Standard operating procedure  
SSRI 
Serotonin selective reuptake inhibitors 
SST 
Stop signal test 
t1/2  
Time to maximum observed drug concentration  
TEAE  
Treatment emergent adverse event  
tmax  
Time of maximum concentration  
VRM  
Verbal Recognition Memory  
WAIS-IV  
Wechsler Adult Intelligence Scale, Fourth Edition  
 
 


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           Page 8 of 41 
 
2 INTRODUCTION 
The statistical analysis plan (SAP) details the planned statistical analysis methods required to 
address the study objectives as described in CuraSen’s protocol CST2032/CST-107-CLIN-015:  A 
Phase 2a, Randomized, Placebo-Controlled, Double-Blind, Crossover Study to Evaluate the 
Safety, Tolerability and Effects of CST-2032 and CST-107 on Cognition in Subjects with Mild 
Cognitive Impairment or Mild Dementia due to Parkinson’s or Alzheimer’s Disease.   
This SAP should be read in conjunction with the study protocol, case report form (CRF), and any 
other applicable study documents. This version of the SAP is based on the protocol CST2032-
CST107-CLIN-015, Amendment 10 dated 11Jul2023 and CRF version 7.0 dated 31Mar2023.  
Changes to these documents may result in subsequent changes to the SAP. The final, sponsor-
approved version of the SAP must occur prior to database lock.  
2.1 
Changes to the Planned Analysis 
There is still no adjustment of Type I error but hypotheses are not designated in priority order for 
hierarchical testing. 
3 STUDY OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
The primary objective of this study is to 
evaluate the safety and tolerability of CST-
2032 when combined with CST-107. 
The primary endpoint is safety and tolerability 
of CST-2032 including adverse event rates 
(AEs), serious adverse event rates (SAEs), 
study 
discontinuation 
rates, 
electrocardiograms (ECGs), vital signs, and 
laboratory safety observations. 
Secondary 
The secondary objectives of this study will 
evaluate the effects of CST-2032 when 
combined with CST-107 versus placebo on the 
following measures: 
1. Cognition 
2. Mood 
3. Attention Deficit 
4. Apathy 
5. Overall clinical improvement 
6. PK 
The secondary endpoints will compare the 
effect of CST-2032 administered with CST-
107 versus placebo on the following: 
• Cognitive tasks in the Cambridge 
Neuropsychological Test Automated 
Battery 
(CANTAB) 
and 
other 
cognitive measures: 
o Reaction 
Time 
(RTI) 
– 
attention 
o Verbal Recognition Memory 
(VRM) – episodic memory 
(verbal stimuli) 
o Adaptive Tracking Task (ATT) 
– visuospatial with strong 
attentional demand 
o Paired 
Associates 
Learning 
(PAL) – episodic memory 
(visual stimuli) 


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o Delayed 
Verbal 
Recall 
– 
episodic 
memory 
(verbal 
stimuli) 
o Stop Signal Task (SST) – 
response 
inhibition 
(impulsivity), an aspect of 
executive function 
o Phonological verbal fluency 
(pVFT) 
o Digit symbol substitution test 
(DSST) 
o Color Trails Test (select sites 
only) 
• Facial expression recognition task 
(FERT). 
• Geriatric Depression Scale – 30 
questions (GDS-30). 
• Conners 
Adult 
Attention 
Deficit 
Hyperactivity 
Disorder 
(ADHD) 
Rating Scale, short form, self-report 
(CAARS). 
• Starkstein Apathy scale short form 
(SAS-6). 
• Alzheimer’s 
Disease 
Cooperative 
Study-Clinical Global Impression of 
Change (ADCS-CGIC). 
• Suicidal ideation using the Columbia 
Suicide Severity Rating Scale (C-
SSRS). 
• Plasma 
pharmacokinetics 
(PK) 
parameters of CST-2032 and CST-107 
(including Cmax, tmax, AUCt, t1/2). 
Exploratory 
The exploratory objectives are: 
• To evaluate whether baseline disease 
characteristics impact response to 
treatment. 
• To characterize the effects of treatment 
on neurodegenerative biomarkers in 
the blood such as neurofilament light 
chain, total and phosphorylated tau 
protein, and amyloid-β (Aβ) peptides 
may also be measured. 
The following exploratory endpoints may be 
undertaken to evaluate: 
• Subgroup and/or correlation analyses 
of effects of treatment on baseline 
disease characteristics including but 
not limited to disease activity as 
determined from relevant disease 
scales at screening, genetic variants 
involved in neurodegenerative disease  
including 
but 
not 
limited 
to 
apolipoprotein E4 (APOE4), leucine 
rich repeat linase2 (LRRK2), and 
glucocerebrosidase (GCase) protein 


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Protocol Number: CST2032/CST107-CLIN-015  
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(GBA) 
(optional 
and 
where 
applicable). 
• Changes 
in 
neurodegenerative 
biomarkers, such as neurofilament 
light chain, total and phosphorylated 
tau protein, and amyloid-β (Aβ) 
peptides, as measured prior to and after 
treatment may be evaluated. 
• Change in average z-score for baseline-
deficit cognitive tasks identified for each 
subject from the Cognitive tasks in the 
Cambridge Neuropsychological Test 
Automated Battery (CANTAB) and 
other cognitive measures.  
 
4 STUDY DESIGN 
4.1 
General Description 
This is a Phase 2a, randomized, placebo-controlled, double-blind crossover study to evaluate the 
safety, tolerability and effects CST-2032 administered with CST-107 on cognition in subjects with 
MCI or mild dementia. 
Approximately 60 subjects will be enrolled in a 2 period, 2-way crossover design following study 
eligibility confirmation during the screening period. 
During each treatment period, subjects will receive 3 mg CST-107 or matching placebo on Day -
1, followed by daily doses of 3 mg CST-2032 (co-administered with 3 mg CST-107) or matching 
placebo on Day 1 through Day 14. The study medications will be provided as oral tablets for CST-
2032, CST-107, and corresponding matching placebos. Each treatment period will be separated by 
a washout period of at least 7 days and up to 21 days. 
All subjects will complete clinical, cognitive and pharmacodynamic assessments during each 
treatment period as indicated in the Scheduled of Events in Appendix 2 of this SAP. 
PK blood samples will be collected prior to, during and after study medication administration, as 
indicated in the Schedule of Events. 
The study duration will be approximately 12 weeks, which includes a Screening period of up to 
28 days, the treatment/study period of 7 weeks (two 2-week treatment periods separated by a 
washout period of at least 7 and up to 21 Days), and the End-of-Study Visit of up to 12 Days after 
the last study drug dose. 
Subjects will be enrolled at up to 20 clinical sites in the USA and New Zealand. 
 


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Study Schema 
 
4.2 
Randomization and Blinding 
The designated Interactive Web Response System (IWRS) will be used to randomize subjects into 
the study on Day -1. Eligible subjects will be randomly assigned in a 1:1 ratio to one of the 
following 2 treatment regimens/sequences: 
 
Treatment Period 1 
Treatment Period 2 
1 
3 mg CST-2032 + 3 mg CST-107 
Placebo (2032) + placebo (107) 
2 
Placebo (2032) + placebo (107) 
3 mg CST-2032 + 3 mg CST-107 
 
The IWRS will provide the randomization number. 
This clinical trial is a double-blinded study, with the Sponsor, subjects, and site personnel (e.g., 
study nurses, coordinators, investigators) blinded to treatment assignment. Limited staff will have 
access to treatment assignments, such as the unblinded statistical team, IWRS system 
administration, and drug supply management team. 
CST-2032 matched placebo and CST-107 matched placebo will be packaged and color-, size-, and 
shape-matched to be indistinguishable from CST-2032 3 mg and CST-107 3 mg. 
4.3 
Sample Size  
A total of approximately 60 subjects is planned. Although formal hypothesis testing is planned, 
the study is underpowered for detecting meaningful cognitive benefits and lack of significance will 
not be interpreted as lack of a treatment effect. The sample size is based on practical considerations 
and is typical of studies whose objectives are to evaluate the safety and cognitive effects of a 
therapeutic intervention. 


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4.4 
Study Committees 
4.4.1 Data and Safety Monitoring Board 
A Data and Safety Monitoring Board (DSMB) will be established to assess participant safety at 
predetermined intervals (including an optional interim analysis) during the study as needed. 
Further details will be provided in the DSMB Charter. 
4.5 
Timing of Analyses 
An unblinded interim analysis may be conducted after approximately 50% of subjects have 
completed Treatment Period 1. A subset of the analysis will be reviewed in closed DSMB sessions 
and all results will be reviewed by the unblinded CuraSen team. Results reviewed by the DSMB 
are marked in the table below with asterisks. All efforts will be made by data management to clean 
the data as much as possible for this analysis. It is expected that the following set of 24 outputs 
will be generated: 
Number 
Title 
Population 
14.1.1* 
Subject Disposition 
Intent to Treat Set 
14.1.2* 
Demographics and Baseline Characteristics 
Intent to Treat Set 
14.2.2.1.1* Secondary Endpoint: CANTAB Observed and Change from 
Baseline Results by Timepoint 
Full Analysis Set 
14.2.2.1.2 
Secondary Endpoint: CANTAB Observed and Change from 
Baseline Results by Timepoint – Subgroup Analysis 
Full Analysis Set 
14.2.2.1.3* Secondary Endpoint: CANTAB Observed and Change from 
Baseline Results by Timepoint during Treatment Period 1 
Full Analysis Set 
14.2.2.1.4* Secondary Endpoint: CANTAB Observed and Change from 
Baseline Results by Timepoint during Treatment Period 2 
Full Analysis Set 
14.2.2.1.5* Secondary Endpoint: CANTAB Observed and Change from 
Baseline Results by Timepoint 
Per Protocol Set 
14.2.2.1.6 
Secondary Endpoint: CANTAB Observed and Change from 
Baseline Results by Timepoint – Subgroup Analysis 
Per Protocol Set 
14.2.2.1.7* Secondary Endpoint: CANTAB Observed and Change from 
Baseline Results by Timepoint during Treatment Period 1 
Per Protocol Set 
14.2.2.1.8* Secondary Endpoint: CANTAB Observed and Change from 
Baseline Results by Timepoint during Treatment Period 2 
Per Protocol Set 


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14.2.2.2.1* Secondary Endpoint: Verbal Fluency Test Observed and Change 
from Baseline Results by Timepoint 
Full Analysis Set 
14.2.2.2.2 
Secondary Endpoint: Verbal Fluency Test Observed and Change 
from Baseline Results by Timepoint – Subgroup Analysis 
Full Analysis Set 
14.2.2.3.1* Secondary Endpoint: Digital Symbol Substitution Test Observed 
and Change from Baseline Results by Timepoint 
Full Analysis Set 
14.2.2.3.2 
Secondary Endpoint: Digital Symbol Substitution Test Observed 
and Change from Baseline Results by Timepoint – Subgroup 
Analysis 
Full Analysis Set 
14.2.2.9.1* Secondary Endpoint: Montreal Cognitive Assessment Observed and 
Change from Baseline Results by Timepoint 
Full Analysis Set 
14.2.2.9.2 
Secondary Endpoint: Montreal Cognitive Assessment Observed and 
Change from Baseline Results by Timepoint – Subgroup Analysis 
Full Analysis Set 
14.3.1.1* 
Overall Summary of Adverse Events 
Safety Set 
14.3.1.2* 
Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term 
Safety Set 
14.3.1.3* 
Treatment-Emergent Serious Adverse Events by System Organ 
Class and Preferred Term 
Safety Set 
14.3.4.1.1* Hematology – Observed Results and Change from Baseline by 
Timepoint 
Safety Set 
14.3.4.2.1* Clinical Chemistry – Observed Results and Change from Baseline 
by Timepoint 
Safety Set 
14.3.4.2.2 
Clinical Chemistry – Shifts from Baseline by Timepoint 
Safety Set 
14.3.5.1* 
Vital Signs – Observed Results and Change from Baseline by 
Timepoint 
Safety Set 
14.3.6.1* 
Electrocardiogram (ECG) – Observed Results and Change from 
Baseline by Timepoint 
Safety Set 
* denotes outputs to be reviewed by the DSMB 
The efficacy analyses may be performed on all subjects included in the interim analysis and/or, 
separately, for AD and/or PD subgroups in this set. Additionally, further analyses of PD-MCI, PD-
MD, AD-MCI, and AD-MD subgroups may be undertaken in the efficacy analyses if sufficient 
subjects are enrolled. A final decision on the populations to be analyzed will be made prior to the 


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interim analysis based on the number of subjects enrolled with PD or AD, and within the further 
MCI or MD groups. For example, the Sponsor may elect to exclude a patient population from the 
interim analysis if the post-dose data are available for fewer than e.g., 25 subjects. The baseline 
and safety summaries will be performed on all subjects included in the interim analysis regardless 
of the patient population(s) selected for efficacy analysis. 
To produce these outputs, a biostatistician and a statistical programmer from 
, separate 
from the primary study team, will be unblinded to treatment assignments and work within a 
restricted domain inaccessible to all other 
 members. No additional team members from 
 or CuraSen will become unblinded until after database lock and release of the live 
randomization list at the time of study completion. The unblinded statistician will be in attendance 
during the closed DSMB sessions for the purpose of presenting and interpreting the interim 
analysis results. Additional information regarding the roles, responsibilities, and objectives for the 
DSMB will be outlined within a DSMB charter, separate from this SAP. 
The final analysis will be performed after the last subject completes their End-of-Study visit or 
their last scheduled assessment per the Schedule of Events, or the sponsor terminates the study for 
any reason. The full set of analyses summarized in this SAP will be generated upon final study 
database lock. 
5 ANALYSIS SETS/POPULATIONS 
 
Intent to Treat Set (ITT): All subjects who have signed informed consent and have been 
randomized to a treatment sequence. Subjects will be analyzed according to the treatment sequence 
assigned at randomization. The ITT will be the analysis set for disposition and select baseline 
characteristic analyses. 
Safety Set (SAF): All subjects who received at least 1 dose of study drug (either CST-2032 or 
CST-107 or placebo). Subjects will be reported based on treatment and dose received. The Safety 
Set will be used for reporting safety analyses. 
Full Analysis Set (FAS): All randomized subjects who have taken at least 1 dose of blinded study 
drug (CST-2032+CST-107 or Placebo). Subjects will be analyzed according to the treatment 
assigned at randomization. The Full Analysis Set will be used for evaluating the cognitive 
endpoints, pharmacodynamic endpoints and selected secondary endpoints. 
Per-Protocol Set (PPS): A subset of the Full Analysis Set who sufficiently complied with the 
protocol (i.e., has no protocol deviations labeled as “major”). The Per Protocol Set may be used 
for selected safety analyses. 
Pharmacokinetic Set (PKS): All subjects in the Safety Set who have at least one valid plasma 
concentration assessment for CST-2032 or CST-107. Subjects will be analyzed according to the 
treatment received. The PKS will be the analysis set for PK concentration and PK parameter 
analyses. 


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6 DATA ANALYSIS CONSIDERATIONS 
 
6.1 
General Data Handling 
All analyses will be conducted based on SAS 9.4 or higher. 
Study data will be recorded in eCRFs for all screened and randomized patients. The EDC vendor 
for this study is MedNet Solutions.  
Unless otherwise stated, all listings will be sorted by disease type, treatment sequence, subject 
number, and assessment date (and time, if available). 
Unless stated otherwise, continuous data will be summarized by disease type, treatment sequence, 
and overall using n, mean, median, standard deviation (SD), minimum value, and maximum value.  
Unless stated otherwise, categorical data will be summarized by disease type, treatment sequence, 
and overall using frequency counts and percentages. Where applicable, 95% confidence intervals 
(CIs) will be provided. Unless otherwise stated, the denominator of percentages will be the number 
of participants in the population/treatment arm or the number with non-missing data.   
• The number of missing values will be presented as a separate category with no percentage, 
but only if one or more subjects are missing data. 
• Counts of zero will be presented without percentages. 
Relative to the number of digits after the decimal in the raw data, summary statistics will have the 
following number of digits after the decimal:  
• Minimum and Maximum: same number of significant digits as the raw data 
• Mean and Median: one additional decimal place to that reported for Minimum and 
Maximum 
• SD or Standard Error (SE): two additional decimal places than the Minimum and 
Maximum 
• Percentages: reported to one decimal place  
• P-values will be reported to four decimal places. If the value is below 0.0001 it will be 
noted as < 0.0001; if the value is above 0.9999 it will be noted as > 0.9999. 
Unless otherwise noted, statistical inference will be based on a 5% significance level (i.e. 95% 
confidence intervals will be produced). 
All data up to the time of study completion/withdrawal from the study will be included in the 
analysis, regardless of duration of treatment. 
Numbering for data displays will be based on ICH E3. 
6.2 
Stratification and Covariates 
There are no formal plans for analysis stratification.  


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6.3 
Evaluation of Subgroups  
All summaries and analyses will be performed by (PD) and (AD). Select secondary efficacy 
endpoints will be further analyzed by MCI and MD categories (PD-MCI, PD-MD, AD-MCI, and 
AD-MC).  
6.4 
Multiple Comparisons and Multiplicity 
This study is descriptive in nature and informal testing of multiple endpoints may be performed. 
Given the exploratory nature of the comparisons, no adjustment of Type I error is planned. 
7 GENERAL CONSIDERATIONS 
 
7.1 
Reference Dates  
• Screening date is defined as the eCRF provided date on which a subject was screened for 
trial entry and informed consent was obtained.  
• Treatment start date is defined as the date of first dose of CST-2032 or matching placebo. 
Each treatment period will have a treatment start date (i.e., in order to determine AEs 
occurring during a treatment). Subjects commence dosing of CST-107 or matching 
placebo 1 day earlier and this will be considered Day -1. 
• Treatment end date is defined as the date of last dose of study drug.  
• Safety data, such as AEs and laboratory assessments will use the treatment start date as a 
reference date.  
• Study day will be based on treatment start date as a reference date.  
7.2 
Study Day and Duration Variables  
Study day or duration calculations will generally be defined as the following, assuming non 
missing dates:   
• date of interest – reference date + 1, when the date of interest >= reference date;  
• otherwise, date of interest – reference date.  
If either date is missing, reference day or duration calculations will not be performed.  Date 
imputation will be performed as identified in Section 6.4. In general, study day will be based on 
the treatment start date as the reference. As such, study day would either have a negative value if 
collected before dosing or a positive value if collected on or after the day of drug dosing; there 
will be no study day zero.   
Duration of time is dependent on reference dates and will be calculated in a manner similar to 
that of the reference date calculation, assuming that dates of interest will strictly follow reference 
dates (e.g., no negative values).  For example, duration of time in study is defined as the end of 
study date – informed consent date + 1. Duration of treatment is defined as treatment end date – 
treatment start date + 1, where treatment end date is the date of last dose of study drug.  
7.3 
Baseline and Post-Baseline Changes 
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• Baseline will be based on the last non-missing value collected prior to or on the treatment 
start date and time.  Post-baseline values will be those collected after the treatment start 
date and time.    
• Change from baseline is defined as: value – baseline value.  
7.4 
Missing Data and Data Imputation Rules 
All attempts will be made by the Data Management team to ensure completeness of data. 
Generally, missing data will not be imputed, and will be presented as collected in the study 
database.  
In cases where adverse event (AE) or medication dates are missing, the imputation methods 
described in Appendix 1 will be used to determine flags for treatment-emergent events, and 
concomitant medications.  
Other missing data methods will be proposed within the respective analysis section, as needed.  
7.5 
Multiple Assessments and Visit Windows 
Nominal visits (e.g. those identified by the study CRF) will be the basis of summarization and 
statistical analysis; no visit date windowing will be conducted. Unscheduled data may be 
included in summaries of specific abnormalities any time post-baseline and in subject data 
listings.   
8 STUDY SUBJECT DATA  
8.1 
Subject Enrollment and Disposition 
Subject disposition will be summarized using the ITT set. Summaries will include the number 
and percent of subjects: screened, enrolled, in each analysis population, completing the study, 
and discontinuing study prematurely, including a description of the reason for early withdrawal. 
Reasons for withdrawal will include the following:  
• Adverse Event  
• Lost to follow-up  
• Subject withdrew consent  
• Protocol violation/non-compliance  
• Investigator decision  
• Study terminated by sponsor  
• Pregnancy  
• Study burden  
• Tested positive for COVID-19  
• Fear of contracting COVID-19  
• Other  
Data will be presented by disease criteria and sequence.  


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Screen failures, analysis populations, and final subject disposition status will be listed. Visit 
dates and reasons for visits not done will also be listed. 
8.2 
Protocol Deviations  
Protocol deviations will be recorded and detailed in a data listing. Protocol deviations will be 
identified and classified as minor or major, as evaluated by the monitoring team. 
Protocol waiver data will also be recorded and detailed in a data listing. 
8.3 
Demographic and Baseline Characteristics  
Subject demographics using the ITT set will be summarized. These will include age, sex (Male / 
Female), child-bearing potential (Yes / No), ethnicity (Hispanic or Latino / Not Hispanic or 
Latino), race (American Indian or Alaska Native / Asian / Black or African American / Native 
Hawaiian or Pacific Islander / White / Other), years of education, baseline height (cm), baseline 
weight (kg), and BMI (kg/m2).  Data will be presented by disease criteria and sequence.  
8.4 
Clinical and Cognitive Scales  
The Montreal Cognitive Assessment (MoCA) is a brief cognitive screening tool and includes 
measures of expressive and receptive language, memory, and praxis. There are items that screen 
executive functions and working memory. The scores range from 0 to 30 with scores lower than 
26 suggesting cognitive disorder.  
 
The Digital Symbol Substitution Test (DSST) integrates complex neuropsychological processes 
and measures aspects of cognitive function, including cognitive and psychomotor speed, attention, 
visual scanning, and executive function. The maximum attainable score is 135, with higher scores 
indicating better performance. Further details of the test can be found in Section 5.3.6.1 of the 
study protocol.  
 
The Modified Hoehn and Yahr Scale (MHYS, for PD subjects only) is a clinician-completed rating 
scale that is used to describe the symptom progression of PD. It parses PD into 5 stages, with the 
additional of stages 1.5 and 2.5 to account for the intermediate course of PD. Details on staging 
can be found in Section 5.3.6.8 of the study protocol.  
 
The REM Sleep Behavior Disorder Single-Question Screen (RBD1Q) is a single “yes-no” question 
as follows: “Have you ever been told, or suspected yourself, that you seem to ‘act out your dreams’ 
while asleep (for example, punching, flailing your arms in the air, making running movements, 
etc.)?”  RBD1Q will be evaluated for all subjects but used to assess eligibility for only PD subjects. 
 
MoCA, DSST, MHYS, and RBD1Q data will be summarized in the demographics and baseline 
characteristics tables and listed by subject.  
8.5 
Medical History 
Medical history among the ITT set will be summarized and listed by Medical Dictionary for 
Regulatory Activities (MedDRA 24.1) system organ class (SOC) and preferred term (PT), and 
verbatim term as collected in the study database. 


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8.6 
Prior, Concomitant, and Rescue Medication  
The incidence of medication use will be summarized by WHO Drug Dictionary (B3 2021-09-01) 
anatomic therapeutic chemical (ATC) Level 2 classification (i.e. therapeutic main group) and 
preferred name. A subject will be counted only once at each level of reporting.  Prior medications 
are those which have been identified to have been discontinued prior to the treatment start date 
(e.g. taken exclusively during the pre-therapy period and prior to the start of CST-2032 or matching 
placebo on Day 1).  Concomitant medications are those which have been identified to have been 
taken at any point after first dose. Subjects who are administered rescue medications are those 
which have been administered rescue nadolol when there is an intolerable HR/BP increase. Prior, 
concomitant, and rescue medication use will be summarized separately and presented by disease 
and treatment group.  
All prior, concomitant, and rescue medication data will be listed including the verbatim and 
preferred drug name and ATC Level 2. Procedures and non-medication therapies will also be 
listed. 
8.7 
Study Drug Exposure and Compliance 
Drug exposure will be summarized as a continuous variable in the Safety Set. The duration of drug 
exposure will be calculated as follow: 
Duration of Exposure (days) = Date of Last Dose – Date of First Dose + 1 
In addition, subjects will be assessed for compliance to drug dosing for CST-2032 and CST-107 
based on number of tablets dispensed and returned will be provided. The total number of tablets 
taken will be calculated as the sum of tablets dispensed minus the sum of tablets returned. 
• 
28 CST-2032 or placebo tablets are expected to be taken during each treatment period, per 
protocol (i.e., two tablets once daily beginning on Day 1). Summaries will be presented by 
treatment (i.e., Placebo and CST-2032/CST-107) based on each subject’s exposure to each 
treatment.  
 
• 
15 CST-107 or placebo tablets are expected to be taken during each treatment period, per 
protocol (i.e., one tablet once daily beginning on Day -1). Summarized will be presented 
by treatment (i.e., Placebo and CST-2032/CST-107) based on each subject’s exposure to 
each treatment. 
Drug exposure will be summarized by disease type and treatment taken at time of data collection. 
Study drug administration data, including date and time of doses, location of dosing, total number 
of tablets dispensed and returned, and compliance will be listed. 
9 ENDPOINT ANALYSES 
 
All inferential analyses are exploratory in nature given that this study was not powered based on 
any statistical assumptions. All efficacy data will be presented by cohort, disease type, and 
treatment assigned at the time of data collection. 


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9.1 
Primary Endpoint and Analyses 
 
The SAF will be used for all primary endpoint analyses unless otherwise stated otherwise. The 
primary objective of this study is to evaluate the safety and tolerability of CST-2032 when 
combined with CST-107. Further details regarding safety analyses can be found in Section 11. 
9.2 
Secondary Endpoints and Analyses 
 
The FAS will be used for all secondary endpoint analyses unless stated otherwise. All inferential 
analyses are exploratory in nature given that this study was not powered based on any statistical 
assumptions.  
 
CANTAB  
Cognition function is assessed using the following CANTAB tests:  
• Reaction Time (RTI)  
• Verbal Recall Memory (VRM)  
• Adaptive Tracking Task (ATT)  
• Paired Associates Learning Task (PAL)  
• Stop Signal Task (SST) 
• Delayed Verbal Recall 
The cognitive assessments measured as part of the CANTAB tests will be administered on Day -
1 (Baseline), and 3 hours after dosing on Days 1, 7, and 14 of each treatment period. Summaries 
will be presented by disease type and treatment sequence.  
There are eighteen key measures based on the Measures Description downloaded from the 
CANTAB portal and as described by Cambridge Cognition, which are:  
• RTI Median Five-Choice Movement Time: The median time taken for a subject to release the 
response button and select the target stimulus after it flashed yellow on screen, measured in 
milliseconds. The measurement name for this parameter in the files downloaded from the 
CANTAB portal is RTIFMDMT.  
• RTI Median Five-Choice Reaction Time: The median duration it took for a subject to release 
the response button after the presentation of a target stimulus, measured in milliseconds. The 
measurement name for this parameter in the files downloaded from the CANTAB portal is 
RTIFMDRT.  
• PAL First Attempt Memory Score: The number of times a subject chose the correct box on 
their first attempt when recalling the pattern locations. The measurement name for this 
parameter in the files downloaded from the CANTAB portal is PALFAMS.  
• PAL Number of Patterns Reached: The number of patterns presented to the subject on the 
last problem they reached. The measurement name for this parameter in the files downloaded 
from the CANTAB portal is PALNPR.  
• PAL Total Errors (Adjusted): The number of times the subject chose the incorrect box for a 
stimulus on assessment problems (PALTE), plus an adjustment for the estimated number of 


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errors they would have made on any problems, attempts and recalls they did not reach. The 
measurement name for this parameter in the files downloaded from the CANTAB portal is 
PALTEA.  
• VRM Free Recall Distinct Stimuli – P1.1: The total number of distinct words that are 
correctly recalled from the presentation phase by the subject during the P1.1 immediate free 
recall stage. The measurement name for this parameter in the files downloaded from the 
CANTAB portal is VRMFR11D.  
• VRM Free Recall Distinct Stimuli – P1.2: The total number of distinct words that are 
correctly recalled from the presentation phase by the subject during the P1.2 immediate free 
recall stage. The measurement name for this parameter in the files downloaded from the 
CANTAB portal is VRMFR12D.  
• VRM Free Recall Distinct Stimuli – P1.3: The total number of distinct words that are 
correctly recalled from the presentation phase by the subject during the P1.3 immediate free 
recall stage. The measurement name for this parameter in the files downloaded from the 
CANTAB portal is VRMFR13D.  
• VRM Delayed Free Recall Distinct Stimuli – P2.1: The total number of distinct words that 
are correctly recalled from the presentation phase by the subject during the P2.1 delayed free 
recall stage. The measurement name for this parameter in the files downloaded from the 
CANTAB portal is VRMFR21D.  
• VRM Delayed Recognition Total Correct – P2.2: The total number of target words that the 
subject correctly recognizes, plus the total number of distractor words that the subject 
correctly rejects in the P2.2 delayed recognition phase. The measurement name for this 
parameter in the files downloaded from the CANTAB portal is VRMD22TC.  
• VRM Free Recall Distinct Stimuli Mean – P1.1-1.3: The mean of times a subject repeats a 
word that was shown during the presentation phase in the P1.3 immediate free recall stage. 
The measurement name for this parameter in the files downloaded from the CANTAB portal 
is VRMFRDM. 
• VRM Free Recall Distinct Stimuli Median – P1.1-1.3: The median number of distinct words 
that are correctly recalled from the presentation phase by the subject during the P1.1-1.3 
immediate free recall stages. The measurement name for this parameter in the files 
downloaded from the CANTAB portal is VRMFRDMD. 
• ATT Euclidean Distance Mean (Phase 2B): The mean Euclidean distance between Target x/y 
and Finger Touch x/y coordinates, calculated in pixel over the entire 2B assessed phase of the 
task. This measure is only calculated during the times that either ‘Finger Lift’ and/or Multi-
touch’ are not occurring. The measurement name for this parameter in the files downloaded 
from the CANTAB portal is ATT2BEM.  
• ATT Euclidian Distance Standard Deviation (Phase 2B): The standard deviation of the 
Euclidean distance between Target x/y and Finger Touch x/y coordinates, calculated in pixels 
over the entire 2B assessed phase of the task. This measure is only calculated during the 
times that either ‘Finger Lift’ or ‘Multi-touch’ are not occurring. The measurement name for 
this parameter in the files downloaded from the CANTAB portal is ATT2BESD.  
• ATT Difficulty Multiplier Mean (Phase 2B): The mean of the difficulty multiplier calculated 
over the entire 2B assessed phase of the task. This measure is only calculated during the 
times that either ‘Finger/Lift’ and/or ‘Multi-touch’ are not occurring. The measurement name 
for this parameter in the files downloaded from the CANTAB portal is ATT2BDM.  


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• ATT Difficulty Multiplier Standard Deviation (Phase 2B): The standard deviation of the 
difficulty multiplier calculated over the entire 2B assessed phase of the task. This measure is 
only calculated during the times that either ‘Finger Lift’ and/or ‘Multi-touch’ are not 
occurring. The measurement name for this parameter in the files downloaded from the 
CANTAB portal is ATT2BDSD.  
• SST Stop Signal Reaction Time: The estimate of time where an individual can successfully 
inhibit their responses 50% of the time. This covert measurement is sampled from the length 
of time between the go stimulus and the stop stimulus at which the subject is able to 
successfully inhibit their response on 50% of the trials. We can infer that this is the time 
before which all actions become ballistic and the subject is no longer able to cancel their 
action selection. The measurement name for this parameter in the files downloaded from the 
CANTAB portal is SSTSSRT.  
• SST Median RT: All Go Trials: The median reaction time taken across all the valid Go trials 
in the task. The measurement name for this parameter in the files downloaded from the 
CANTAB Portal is SSTMRTG. 
Additionally, 3 more verbal recall parameters will be derived for analysis: 
• VRM Free Recall Distinct Stimuli Mean Errors – P1.1-1.3: For each recording of 
VRMFRDM, a new record will be derived as the value of VRMFRDM subtracted from 18. 
The parameter decode will be VRMFRDME. 
• VRM Delayed Free Recall Distinct Stimuli Errors – P2.1: For each recording of 
VRMFR21D, a new record will be derived as the value of VRMFR21D subtracted from 18. 
The parameter decode will be VRMFR21E. 
• VRM Delayed Recognition Total Correct Errors – P2.2: For each recording of VRMD22TC, 
a new record will be derived as the value of VRMD22TC subtracted from 36. The parameter 
decode will be VRMD22TE. 
For all 21 parameters, observed values at each assessment and changes from baseline will be 
summarized using descriptive statistics on the FAS and PPS. In addition to the descriptive 
statistic summaries, for each parameter, a mixed effects model approach will be used to evaluate 
treatment effect. The model will include change from baseline as the dependent variable, 
baseline as a covariate, treatment sequence, period, timepoint (i.e., Day 1: 3 hrs post-dose, Day 
7: 3 hrs post-dose, Day 14: 3 hrs post-dose), disease type, and treatment as fixed effects, and 
subject as a random effect. The least square means will be summarized, as well as the least 
square mean difference between treatments, where the corresponding p-value for this LS mean 
difference will be provided. If there are convergence issues, alternative covariance structures 
may be used including autoregressive of order 1 (AR1) and compound symmetry (CS). The 
effect size will be estimated using Cohen’s D: difference in means / pooled SD. This analysis 
will be performed using AD and PD as subgroups, and again using AD-MCI, AD-MD, PD-MCI, 
and PD-MD as subgroups. 
Additionally, using treatment period 1 and treatment period 2 data separately, all 21 parameters 
will have observed value and change from baseline summarized, and a mixed effects model with 
change from baseline as the dependent variable, baseline as a covariate, timepoint (i.e., Day 1:3 
hrs post-dose, Day 7: 3 hrs post-dose, Day 14: 3 hrs post-dose), disease type, and treatment as 
fixed effects, and subject as a random effect will be evaluated. The least square means, least 


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square mean differences, and associated p-values will be presented. AR1 and CS covariance 
structures may be explored if there are convergence issues. The effect size will be estimated 
using Cohen’s D: difference in means / pooled SD. These analyses will be presented by AD and 
PD subgroups and no further subgroup categorization. The analyses will be presented on the 
FAS and repeated on the PPS. 
Bar plots of the arithmetic mean of observed values with error bars of the standard error of the 
mean, arithmetic mean of change from baseline with error bars of the standard error bars of the 
mean change, and least square mean change with error bars of the standard error will be 
produced for the following CANTAB parameters: 
• VRM Free Recall Distinct Stimuli Mean – P1.1-1.3 (VRMFRDM) 
• VRM Free Recall Distinct Stimuli – P1.1 (VRMFR11D) 
• VRM Free Recall Distinct Stimuli – P1.2 (VRMFR12D) 
• VRM Free Recall Distinct Stimuli – P1.3 (VRMFR13D) 
• VRM Delayed Free Recall Distinct Stimuli – P2.1 (VRMFR21D) 
• VRM Delayed Recognition Total Correct – P2.2 (VRMD22TC) 
Bar plots of the least square mean change with error bars of the standard error only will be 
produced for the following CANTAB parameters: 
• PAL Total Errors (Adjusted) (PALTEA) 
• RTI Median Five-Choice Reaction Time (RTIFMDRT) 
• RTI Median Five-Choice Movement Time (RTIFMDMT) 
• ATT Difficulty Multiplier Mean (ATT2BDM) 
• SST Stop Signal Reaction Time (SSTSSRT) 
All plots will be presented separately for AD and PD subjects. 
All CANTAB data, which includes 80 total measurements, will be listed on the FAS. 
Phonological verbal fluency (pVFT) 
The pVFTs are widely used for assessing executive function and requires the generation of 
words from initial letters (phonological verbal fluency) or belonging to a specific category 
(semantic fluency), under a time constraint. The specific versions of verbal fluency tests in this 
study are the ‘ALPHABET’ and ‘CATEGORY’ tests from the Brief And Simple Index of 
Cognition (BASIC).  
For the ALPHABET task, subjects are given 1 minute to say aloud as many words they can think 
of that begin with the letter F, avoiding repetitions or the same words with different endings. The 
total score is the number of correct words generated. For the CATEGORY task, subjects are 
given 1 minute to say aloud as many animals they can think of, avoiding repetitions. The total 
score is the number of animals generated. 
The pVFTs will be administered on Day -1 (Baseline), Day 1, Day 7, and Day 14 of each 
treatment period. Summary statistics of observed values and change from baseline will be 


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presented. A mixed model with change from baseline as the outcome, baseline as a covariate, 
fixed effects for treatment sequence, period, timepoint (i.e., Day 1, Day 7, Day 14), disease type, 
and treatment, and subject as a random effect will be analyzed. LS mean, LS mean difference 
and its associated p-value will be reported. AR1 and CS covariance structures may be explored if 
there are convergence issues. The effect size will be estimated using Cohen’s D: difference in 
means / pooled SD. This analysis will be performed using AD and PD as subgroups, and again 
using AD-MCI, AD-MD, PD-MCI, and PD-MD as subgroups. The analysis will be presented on 
the FAS and repeated on the PPS. 
Bar plots of the least square mean change of Alphabet and Category scores with error bars of the 
standard error will be produced, separated by AD and PD. 
  
All pVFT data will be listed. 
Facial Expression Recognition Task (FERT) 
Analyses of FERT data will be summarized in a separate analysis plan. 
Digital Symbol Substitution Test (DSST) 
The DSST will be administered on Day -1 (Baseline), Day 1, Day 7, and Day 14 of each 
treatment period. Summary statistics of the total score observed values and change from baseline 
will be presented. A mixed model with change from baseline as the outcome, baseline as a 
covariate, fixed effects for treatment sequence, period, timepoint (i.e., Day 7, Day 14), disease 
type, and treatment, and subject as a random effect will be analyzed. LS mean, LS mean 
difference and its associated p-value will be reported. AR1 and CS covariance structures may be 
explored if there are convergence issues. The effect size will be estimated using Cohen’s D: 
difference in means / pooled SD. This analysis will be performed using AD and PD as 
subgroups, and again using AD-MCI, AD-MD, PD-MCI, and PD-MD as subgroups. The 
analysis will be presented on the FAS and repeated on the PPS. 
 
A bar plot of the least square mean change of DSST total score with error bars of the standard 
error will be produced, separated by AD and PD. 
 
All DSST data will be listed. 
 
Geriatric Depression Scale – 30 questions (GDS-30)  
The GDS is a 30-item self-administered yes/no question test constructed for brief screening of 
depression in elderly persons. Total scores are the summation of scored responses (responses 
indicating worsening depression equate to 1, and responses indicating lessening depression 
equate to 0) from each question. Scores greater than 9 are considered suspect for depression. The 
GDS will be administered on Day -1 (Baseline), Day 1, and Day 14 of each treatment period. 
Summary statistics of total scores and change from baseline will be presented. A mixed model 
with change from baseline as the outcome, baseline as a covariate, fixed effects for treatment 
sequence, period, timepoint (i.e., Day 1, Day 14), disease type, and treatment, and subject as a 
random effect will be analyzed. LS mean, LS mean difference and its associated p-value will be 


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reported. AR1 and CS covariance structures may be explored if there are convergence issues. 
The effect size will be estimated using Cohen’s D: difference in means / pooled SD. 
All GDS data, included responses to individual questions, will be listed. 
Conners Adult Attention Deficit Hyperactivity Disorder Scale (ADHD) Rating Scale, short form, 
self-report (CAARS) 
The CAARS is a 26-item scale designed to assess, diagnose, and monitor treatment of attention 
deficit/hyperactivity disorder (ADHD) in adults. The self-report short form contains  
factor-derived scales for inattention/memory, hyperactivity/restlessness,  
impulsivity/emotional lability, and problems with self-concept. Individuals are asked to rate 
themselves on a range of symptoms and behaviors associated with ADHD as adults using a 4-point 
scale: 0=Not at all/never; 1=Just a little/once in a while; 2=Pretty much/often; 3=Very much/very 
frequently. The CAARS will be administered on Day -1 (Baseline), Day 1, and Day 14 of each 
treatment period. Total score will be derived as the sum of results from the 26 questions at each 
visit and can range from 0 to 78. Subscales will be derived as follows: 
• Inattention/Memory Problems: sum of scores from questions 3, 5, 17, 18, and 21 
• Hyperactivity/Restlessness: sum of scores from questions 4, 6, 10, 11, and 23 
• Impulsivity/Emotional Lability: sum of scores from questions 1, 7, 8, 13, and 20 
• Problems with Self-Concept: sum of scores from questions 9, 15, 16, 25, and 26 
• ADHD Index: sum of scores from questions 2, 7, 8, 9, 11, 12, 14, 17, 19, 22, 24, and 26 
 
Summary statistics of the 5 subscales and total scores and change from baseline will be presented. 
A mixed model with change from baseline as the outcome, baseline as a covariate, fixed effects 
for treatment sequence, period, timepoint (i.e., Day 1, Day 14), disease type, and treatment, and 
subject as a random effect will be analyzed. LS mean, LS mean difference and its associated p-
value will be reported. AR1 and CS covariance structures may be explored if there are convergence 
issues. The effect size will be estimated using Cohen’s D: difference in means / pooled SD. 
 
All CAARS data, including responses to individual questions, will be listed. 
Starkstein Apathy scale short form (SAS-6) 
 
The SAS-6 is a 6-item questionnaire read by an examiner to measure the severity of apathetic 
symptoms. Each question has four possible answers: “not at all,” “slightly,” “some,” or “a lot” 
which are scored on a 4-point Likert scale (range: 0–3). Total scores will be derived the 
summation of scored responses (higher scores indicate more severe apathy) from each question 
and can range from 0 to 18. The SAS-6 will be administered on Day -1 (Baseline), Day 1, and 
Day 14 of each treatment period. Summary statistics of total scores and change from baseline 
will be presented. A mixed model with change from baseline as the outcome, baseline as a 
covariate, fixed effects for treatment sequence, period, timepoint (i.e., Day 1, Day 14), disease 
type, and treatment, and subject as a random effect will be analyzed. LS mean, LS mean 
difference and its associated p-value will be reported. AR1 and CS covariance structures may be 
explored if there are convergence issues. The effect size will be estimated using Cohen’s D: 
difference in means / pooled SD. 


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All SAS-6 data, included responses to individual questions, will be listed. 
Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) 
 
The ADCS-CGIC requires the assessor to consider a number of cognitive, functional, and 
behavioral areas prior to providing an overall “global” assessment of clinical change. It is 
performed by interviewing the patient to assess function and mental status and the informant, 
using a worksheet that comprehensively lists relevant symptoms potentially useful in judging 
clinically meaningful change, and allows for notes for future reference. Further details of the test 
can be found in Section 5.3.7.4 of the study protocol. The ADCS-CGIC will be administered on 
Screening (Baseline) and Day 14 of each treatment period. Scores range from 1 (marked 
improvement) to 7 (marked worsening), where 4 indicates no change. Summary statistics of 
scores at Day 14 will be presented. A mixed model with the score as the outcome,  fixed effects 
for treatment sequence, period, timepoint (i.e., Day 14), disease type, and treatment, and subject 
as a random effect will be analyzed. LS mean, LS mean difference and its associated p-value will 
be reported. AR1 and CS covariance structures may be explored if there are convergence issues. 
The effect size will be estimated using Cohen’s D: difference in means / pooled SD. 
All ADCS-CGIC data will be listed. 
 
Color Trails Test (Select Sites Only) 
 
The Color Trails Test consists of numbered circles printed with vivid pink or yellow backgrounds 
that are perceptible to color-blind individuals. For Part 1, the respondent uses a pencil to rapidly 
connect circles numbered 1-25 in sequence. For Part 2, the respondent rapidly connects numbered 
circles in sequence, but alternates between pink and yellow. The length of time to complete each trial 
is recorded. The Color Trails Test will be administered on Day -1 (Baseline), Day 7, and Day 14 
of each treatment period at selected sites. Summary statistics of completion times for Part 1, Part 
2, and their time difference and change from baseline will be presented. A mixed model with 
change from baseline as the outcome, baseline as a covariate, fixed effects for treatment 
sequence, period, timepoint (i.e., Day 7 and Day 14), disease type, and treatment, and subject as 
a random effect will be analyzed. LS mean, LS mean difference and its associated p-value will 
be reported. AR1 and CS covariance structures may be explored if there are convergence issues. 
The effect size will be estimated using Cohen’s D: difference in means / pooled SD. 
A bar plot of the least square mean change of the Part 2 completion time with error bars of the 
standard error will be produced, separated by AD and PD. 
 
All Color Trails Test data will be listed. 
 
Montreal Cognitive Assessment (MoCA) 
 
Details of MoCA are outlined in section 8.4 of this SAP. The MoCA will be collected at Screening 
(Baseline) and Day 14 of each treatment period. Summary statistics of the MoCA-MIS Score and 
MoCA Total Score and change from baseline will be presented. A mixed model with change from 
baseline as the outcome, baseline as a covariate, fixed effects for treatment sequence, period, 
timepoint (i.e., Day 14), disease type, and treatment, and subject as a random effect will be 


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analyzed. LS mean, LS mean difference and its associated p-value will be reported. AR1 and CS 
covariance structures may be explored if there are convergence issues. The effect size will be 
estimated using Cohen’s D: difference in means / pooled SD. This analysis will be performed using 
AD and PD as subgroups, and again using AD-MCI, AD-MD, PD-MCI, and PD-MD as subgroups. 
 
All MoCA data will be listed. 
9.3 
Exploratory Endpoints and Analyses 
The FAS will be used for all exploratory endpoint analyses unless stated otherwise. 
Neurodegenerative Biomarkers  
Neurodegenerative biomarkers including neurofilament light chain, total and phosphorylated tau 
protein, and amyloid-β (Aβ) peptides will also be collected at Screening and Day 14 of each 
treatment period. If data is available descriptive statistics of the neurodegenerative biomarkers 
and change from baseline to Day 14 will be summarized. Additionally, genetic biomarkers 
including APOE4, LRRK2, and GBA may be collected at Screening and descriptive statistics 
may be tabulated if numeric. All biomarker data will be listed. 
Z-scores 
Z-scores will be calculated for the observed values of select CANTAB, pVFT, and DSST 
endpoints using the formula: z = (observed value - normative mean) / normative SD. Normative 
means and standard deviations can be found in Appendix 3, and specifics on which parameters 
will be used in z-score derivations (ATT2BDM, PALTEA, RTIFMDRT, SSTSSRT, and 
VRMFR11D) are in section 9.2 in the CANTAB section. Z-scores will also be derived for the 
Alphabet and Category total scores of pVFT and the DSST total score.  For the endpoints of 
PALTEA, RTIFMDRT and SSTSSRT, in which higher scores reflect poor performance, the sign 
of z-scores will be reversed by multiplying the calculated z-score by -1. Hence a positive z-score 
will reflect an outcome better than the norm and a negative z-score will reflect an outcome worse 
than the norm. In the case of the adaptive tracking test in the CANTAB, normative data are from 
prior studies conducted by CuraSen. For endpoints for which multiple norms are shown in 
Appendix 3, pooled estimates of the normal mean and SD, weighted by the sample size, will be 
used to calculate the z-scores. Z-scores for DSST will use norms based on the age of the subject. 
Normative data for the CANTAB, VFT, and DSST endpoints are summarized in Appendix 3. 
Normative data for the verbal fluency tests, DSST and most of the tests within the CANTAB are 
defined from published studies in which the tests were administered in an approximately similar 
manner as the CLIN-011 study. Normative data are based on untreated, approximately age 
matched cognitively normal populations, except for the Stop Signal Test where data are only 
available for a young adult population are available. 
 
Summary statistics of z-scores and change from baseline for subjects with a baseline deficit will 
be presented for each of the 5 CANTAB parameters marked. Baseline deficit is defined as 
having a baseline z-score less than -0.5. Subjects with baseline values greater than or equal to -
0.5 will not be summarized. Additionally, a mixed model approach will be used to evaluate 
treatment effect. The model will include change from baseline in z-score as the dependent 
variable, baseline as a covariate, treatment sequence, period, timepoint (i.e., Day 1: 3 hrs post-


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hose, Day 7: 3 hrs post-dose, Day 14: 3 hrs post-dose), disease type, and treatment as fixed 
effects, and subject as a random effect. The least square means will be summarized, as well as 
the least square mean difference between treatments, where the corresponding p-value for this 
LS mean difference will be provided.  
 
Summary statistics of z-scores and change from baseline for subjects with a baseline deficit for 
the two pVFT parameters will also be presented. Baseline deficit is defined as having a baseline 
z-score less than -0.5, and subjects with baseline values greater than or equal to -0.5 will not be 
summarized. Additionally, a mixed model with z-score change from baseline as the dependent 
variable, baseline as a covariate, treatment sequence, period, timepoint (i.e., Day 1, Day 7, Day 
14), disease type, and treatment as fixed effects, and subject as a random effect will be analyzed, 
with the least square means, least square mean difference, and corresponding p-value will be 
provided. 
 
Summary statistics of z-scores and change from baseline for subjects with a baseline deficit for 
DSST total score will be presented. Baseline deficit is defined as having a baseline z-score less 
than -0.5, and subjects with baseline values greater than or equal to -0.5 will not be summarized. 
Additionally, a mixed model with z-score change from baseline as the dependent variable, 
baseline as a covariate, treatment sequence, period, timepoint (i.e., Day 1, Day 7, Day 14), 
disease type, and treatment as fixed effects, and subject as a random effect will be analyzed, with 
the least square means, least square mean difference, and corresponding p-value will be 
provided. 
 
10 PHARMACOKINETICS 
Details regarding PK sampling, including scheduled timepoint and actual date and time of blood 
draws will be listed. Additional analyses of PK data will be summarized in a separate analysis 
plan. 
11 SAFETY 
11.1 Adverse Events 
Adverse events (AEs) will be recorded from the time of randomization through end of study.   
AEs will also be assessed for severity, relationship to study drug, and seriousness.  AEs will be 
considered treatment-emergent if their onset occurs following the date and time of first dose of 
CST-2032 or matching placebo up to the study completion date.  Each TEAE will also be 
categorized according to the treatment period in which it occurs, in order to attribute and 
summarize an AE based on treatment received at time of event (i.e., during placebo or active 
treatment).  Events that occur during the washout period between Treatment Period 1 and 2 will 
be attributed to the treatment received in Period 1, and events occurring after Treatment Period 2 
up to the End of Study visit will be attributed to the treatment received in Period 2.  
Any missing severity assessments will be assumed to be severe, missing relationship assessments 
will be assumed to be related, and missing seriousness assessments will be assumed as serious.   


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An overview of AEs will be produced, including counts and percentages of subjects with any 
incidences of: treatment-emergent AEs (TEAEs), serious AEs (SAEs), related AEs, unrelated 
AEs, AEs by maximum severity, AEs leading to treatment withdrawal and AEs leading to death. 
Adverse events will be coded based on the Medical Dictionary for Regulatory Affairs (MedDRA 
24.1) for reporting by system organ class (SOC) and preferred term (PT) in descending order of 
overall incidence.  
Summaries of adverse events by SOC and PT will include the following types:   
• TEAEs;  
• SAEs; and  
• Related AEs.  
A summary of TEAEs by SOC, PT, and maximum severity will also be prepared.  
A comprehensive listing of all AEs will be provided in a by-subject data listing. In addition, the 
following listings will be provided:   
• SAEs;  
• Related AEs; and  
• AEs leading to study drug termination 
11.2 Clinical Laboratory Evaluations 
Hematology and clinical chemistry will be reported based on the International System of Units 
(SI). The following laboratory evaluations will be summarized using descriptive statistics:  
• Hematology: hematocrit, hemoglobin, mean corpuscular hemoglobin (MCH), mean 
corpuscular hemoglobin concentration (MCHC), mean corpuscular volume (MCV), 
platelet count, red blood cell (RBC) count, and white blood cell (WBC) count with 
differential, reticulocyte count. 
• Clinical chemistry: albumin, alkaline phosphatase (ALP), alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), BUN, calcium, bicarbonate, serum creatinine, 
creatinine phosphokinase (CPK), glucose, lipase, amylase, phosphate, potassium, sodium, 
total bilirubin, total cholesterol, total protein, triglycerides, and uric acid.  Additionally, 
the following chemistry parameters collected at Screening only will be included in these 
outputs: calculated creatinine clearance according to the Cockcroft-Gault equation.   
• Urinalysis and microscopy: appearance, occult blood, glucose, leukocyte esterase, nitrite, 
pH, protein, urobilinogen by dipstick, a reflex microscopic urinalysis will be performed if 
dipstick protein, nitrite, leukocyte esterase, or occult blood results are positive.  
Observed values and changes from screening/baseline, when applicable, for the above laboratory 
evaluations will be summarized at each visit.    
This data will also be summarized in shift tables of baseline to each visit based on range 
categories of low (below lower limit of normal [LLN], normal, and high [above upper limit of 
normal [ULN]).   


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All laboratory results will be provided in subject data listings. The following additional results 
will be included in these listings: 
• Serology: HIV Ab, HbsAg, HbsAb, and HCV Ab (Screening only).  
• Immunology: SARS-CoV-2 (Screening only).  
• Pregnancy and FSH Tests: Both urine and serum pregnancy tests will be presented.  
• Urine Drug and Alcohol tests: Drug tests will include amphetamine, barbiturates, 
cocaine, opiates. 
• COVID-19: SARS-CoV-2 (Screening only) 
Box plots of observed results or change from baseline at each visit for potassium, glucose, lipase, 
amylase, and creatinine kinase results for each treatment group may be generated. 
11.3 Vital Signs 
Vital signs will include the following: systolic and diastolic blood pressure (mmHg); heart rate 
(beats/min), temperature (oC), and respiratory rate (breaths/min).  
Observed values and changes from screening/baseline for vital signs will be summarized at each 
visit and time point. Summaries will be presented by treatment at the time of data collected (i.e., 
Placebo and CST-2032/CST-107). If multiple collections occur for the same visit and timepoint 
in two positions, the values will be averaged.  
All vital sign data will be listed.  
Box plots of observed results or change from baseline at each visit for heart rate, systolic blood 
pressure, and diastolic blood pressure results for each treatment group may be generated. 
11.4 Electrocardiogram (ECG) 
ECG parameters include:  Heart rate, PR interval, RR interval, QRS interval, QT interval, QTcB 
interval, and QTcF interval. Observed values and changes from baseline for ECG parameters 
will be summarized at each visit and time point.  The baseline measurement may include up to 9 
repeat observations, and all repeats will be averaged to obtain a single baseline value. Any ECG 
parameters taken in triplicate post-baseline will be averaged within timepoint. 
Electrocardiograms (ECGs) will be interpreted using the following categories: Normal; 
Abnormal Not Clinically Significant; and Abnormal, Clinically Significant.  Clinical 
interpretation will also be summarized at each visit and time point.  
Additionally, the number and percentage of subjects in each of the following QTcF categories 
will be tabulated by visit and timepoint:  
• QTcF ≤ 450 msec  
• 450 msec < QTcF ≤ 480 msec 
• 480 msec < QTcF ≤ 500 msec  
• QTcF > 500 msec  
• QTcF change from baseline of ≤ 30 msec  


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• QTcF change from baseline of > 30 msec and ≤ 60 msec  
• QTcF change from baseline of > 60 msec  
For parameters collected as triplicate measurements, the average of the non-missing 
measurements will be summarized. 
Box plots of observed results or change from baseline at each visit for QTcF pressure results for 
each treatment group may be generated. 
11.5 Physical Examinations 
Physical examination abnormalities will be presented in subject data listings. The following body 
systems will be assessed:   
• General appearance  
• Head, Neck, Thyroid  
• Ears, Eyes, Nose, Throat, Mouth  
• Chest (excluding breasts)  
• Respiratory  
• Cardiovascular  
• Lymph nodes  
• Abdomen  
• Skin, Hair, Nails  
• Musculoskeletal  
• Neurological  
• Other 
11.6 Columbia-Suicide Severity Rating Scale (C-SSRS) 
The Columbia-Suicide Severity Rating Scale measures four elements: the severity of ideation, 
the intensity of ideation, behavior and lethality. The C-SSRS consists of 10 categories, with a 
binary response option (yes/no). Categories include:  
1. Wish to be Dead  
2. Non-specific Active Suicidal Thoughts  
3. Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act  
4. Active Suicidal Ideation with Some Intent to Act, without Specific Plan  
5. Active Suicidal Ideation with Specific Plan and Intent  
6. Preparatory Acts or Behavior  
7. Aborted Attempt  
8. Interrupted Attempt  
9. Actual Attempt (nonfatal)  
10. Completed Suicide. 
The C-SSRS will be completed at Screening(Baseline), Day 7, Day 14, and Follow-Up. The 
outcome of the C-SSRS is a numerical score obtained from the 10 categories stated above.  
In addition, three C-SSRS composite indicator variables will be calculated as follows:  


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(1) C-SSRS suicidal ideation indicator  
A composite indicator of C-SSRS suicidal ideation (Items 1-5 above) will be calculated as:  
• IF the response to any one of the five suicidal ideation questions is “Yes”, THEN set 
the suicidal ideation indicator equal to 1.  
• OTHERWISE, set the suicidal ideation indicator equal to 0.  
(2) C-SSRS suicidal behavior indicator  
A composite indicator of C-SSRS behavior ideation (Items 6-10 above) will be calculated as:   
• IF the response to any one of the five suicidal behavior questions is “Yes”, THEN set the 
suicidal behavior indicator equal to 1.  
• OTHERWISE, set the suicidal behavior indicator equal to 0.  
(3) C-SSRS suicidal ideation or behavior indicator  
A composite indicator of C-SSRS suicidal ideation or behavior will be calculated as:  
• IF the response to any one of the 5 suicidal ideation questions or any of the 5 suicidal 
behavior questions is “Yes”, THEN set the suicidal ideation or behavior indicator equal 
to 1.  
• OTHERWISE, set the suicidal ideation or behavior indicator equal to 0.  
The C-SSRS will be evaluated in the Safety Set based on methods described by Nilsson. The 
number and percentage of subjects with any suicidal ideation and/or suicidal behavior following 
the first dose of study drug will be tabulated.   
For the composite endpoint of suicidal ideation, the number and percent of subjects who 
experience any one of the five suicidal ideation events at least once during treatment through 
follow-up will be tabulated.  
For the composite endpoint of suicidal behavior, the number and percent of subjects who 
experience any one of the five suicidal behavior events at least once during treatment through 
follow-up will be tabulated.  
For the composite endpoint of suicidal ideation or behavior, the number and percent of subjects 
who experience any one of the ten suicidal ideation or behavior events at least once during 
treatment through follow-up will be tabulated.  
Results from the C-SSRS will be presented in a listing. 
12 REFERENCES 
 
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use.  ICH E3 Guideline: Structure and content of clinical study reports 
questions & answers (R1). 2012.            


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http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E3/E3_QAs_
R1_Step4.pdf.  Accessed 13 Jan 2016. 
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use.  ICH Harmonised Tripartite Guideline: Structure and content of 
clinical 
study 
reports 
E3. 
Step 
4. 
1995. 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E3/E3_Guide
line.pdf. Accessed 13 Jan 2016. 
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use.  ICH E9: Statistical principles for clinical trials. 1998. 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E9/Step4/E9
_Guideline.pdf . Accessed 15 June 2016. 
PhUSE CSS Development of Standard Scripts for Analysis and Programming Working Group.  
Analyses and Displays Associated with Demographics, Disposition, and Medications in Phase 2-
4 
Clinical 
Trials 
and 
Integrated 
Summary 
Documents. 
 
2014. 
http://www.phusewiki.org/wiki/images/c/c9/CSS_WhitePaper_DemoDispMed_v1.0.pdf 
. 
Accessed 03 Jan 2017. 
PhUSE CSS Development of Standard Scripts for Analysis and Programming Working Group.  
Analyses and Displays Associated to NonCompartmental Pharmacokinetics – With a Focus on 
Clinical 
Trials. 
2014. 
http://www.phusewiki.org/wiki/images/e/ed/PhUSE_CSS_WhitePaper_PK_final_25March2014.
pdf . Accessed 31 Dec 2016. 
Nilsson ME, Suryawanshi S, Gassmann‐Mayer C, Dubrava S, McSorley P, and Jiang K. (2013).  
Columbia–Suicide Severity Rating Scale Scoring and Data Analysis Guide. Retrieved from 
http://www.cssrs.columbia.edu/documents/ScoringandDataAnalysisGuide_Feb2013.pdf. 
 
 


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13 APPENDICES 
13.1 APPENDIX 1: Partial Date Conventions  
ALGORITHM FOR TREATMENT EMERGENCE OF ADVERSE EVENTS: 
START DATE 
STOP DATE 
ACTION 
Known 
Known/Partial/
Missing 
If start date < study drug start date, then not TEAE  
If start date >= study drug start date, then TEAE   
 
 
 
Partial, but known components 
show that it cannot be on or 
after study drug start date 
Known/Partial/
Missing 
Not TEAE 
 
 
 
Partial, could be on or after 
study drug start date 
Known 
If stop date < study drug start date, then not TEAE  
If stop date >= study drug start date, then TEAE 
 
Partial 
Impute stop date as latest possible date (i.e., last day 
if day unknown or 31st December if day and month 
unknown), then:  
If stop date < study drug start date, then not TEAE  
If stop date >= study drug start date, then TEAE 
 
Missing 
Assumed TEAE 
 
 
 
Missing 
Known 
If stop date < study drug start date, then not TEAE  
If stop date >= study drug start date, then TEAE 
 
Partial 
Impute stop date as latest possible date (i.e., last day of month  
if day unknown or 31st December if day and month are  
unknown), then:  
If stop date < study drug start date, then not TEAE  
If stop date >= study drug start date, then TEAE 
 
Missing  
Assumed TEAE 
 
 
 


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ALGORITHM FOR PRIOR / CONCOMITANT MEDICATIONS: 
START DATE 
STOP DATE 
ACTION 
Known 
Known 
If stop date < study drug start date, assign as prior  
If stop date >= study drug start date and start date <= follow-up / end of study,  
assign as concomitant 
 
Partial 
Impute stop date as latest possible date (i.e., last day of month if day unknown  
or 31st December if day and month are unknown), then:  
If stop date < study drug start date, assign as prior  
If stop date >= study drug start date and start date <= follow-up / end of study,  
assign as concomitant 
 
Missing 
If stop date is missing, assign as concomitant 
 
 
 
Partial 
Known 
Impute start date as earliest possible date (i.e., first day of month if day unknown  
or 1st January if day and month are unknown), then:  
If stop date < study drug start date, assign as prior  
If stop date >= study drug start date and start date <= follow-up / end of study,  
assign as concomitant 
 
Partial 
Impute start date as earliest possible date (i.e., first day of month if day unknown  
or 1st January if day and month are unknown) and impute stop date as latest  
possible date (i.e., last day of month if day unknown or 31st December if day  
and month are unknown), then:  
If stop date < study drug start date, assign as prior  
If stop date >= study drug start date and start date <= follow-up / end of study,  
assign as concomitant 
 
Missing 
If stop date is missing, assign as concomitant 
 
 
 
Missing 
Known 
If stop date < study drug start date, assign as prior  
If stop date >= study drug start date, assign as concomitant 
 
Partial 
 
 
Impute stop date as latest possible date (i.e., last day of month if day unknown 
or 31st December if day and month are unknown), then:  
If stop date < study drug start date, assign as prior  
If stop date >= study drug start date, assign as concomitant 
 
Missing 
If stop date is missing, assign as concomitant 
 
 


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13.2 APPENDIX 2: Protocol Schedule of Events 
 
Screening 
Treatment Periods 1 & 21 
End of Study 
Day -28 to -2 
Day -1 Day 1 Day 7 ±12 Day 14±1 or Early 
Withdrawal2,3 
7-12 Days after Last Dose of 
Study Drug or EW Visit2 
Outpatient visit  
X 
X 
X 
X 
X 
X 
Informed consent  
X 
 
 
 
 
 
Randomization  
 
X 
 
 
 
 
Assess Inclusion/Exclusion criteria  
X 
X21 
 
 
 
 
Demographics  
X 
 
 
 
 
 
Medical history  
X 
 
 
 
 
 
Height, weight, BMI calculation  
X 
 
 
 
 
 
Vital signs5 
X 
X 
X 
X 
X3 
X 
ECG6 
X 
X 
X 
X 
X3 
X 
Physical exam7  
X 
 
 
 
 
X 
Safety labs8 
X 
 
X19 
X20 
X3, 20 
X 
Urine drug screen  
X 
 
 
 
 
 
Alcohol breath test  
X 
X 
 
 
 
 
HIV and Hepatitis serologies  
X 
 
 
 
 
 
Serum FSH9 
X 
 
 
 
 
 
β-hCG pregnancy test9 
X 
 
 
 
 
 
Serum or urine pregnancy test9 
 
X 
 
 
X3 
X 
SARS-CoV-2 assessment10 
X 
 
 
 
 
 
Genetic variants including but not limited  
to APOE4 genetic variant, LRRK2, GBA   
(optional and where applicable) 
X 
 
 
 
 
 
Neurodegeneration biomarkers 
X 
 
 
 
X 
 
PK sample11 
 
 
 
X 
 
 
RBD1Q, MHYS12 
X 
 
 
 
 
 
 


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Statistical Analysis Plan 
Protocol Number: CST2032/CST107-CLIN-015  
Draft Version 3.0, 25Jul2023 
CONFIDENTIAL 
           Page 37 of 41 
 
 
Screening 
Treatment Periods 1 & 21 
End of Study 
Day -28 to -2 Day -1 Day 1 Day 7 ±12 Day 14±1 or Early 
Withdrawal2,3 
7-12 Days after Last Dose of 
Study Drug or EW Visit2 
MoCA12 
X 
 
 
 
X 
 
DSST12 
X 
X 
X 
X 
X 
 
FERT13 
 
X 
X 
 
X 
 
CANTAB, pVFT14 
X 
X 
X 
X 
X 
 
Color Trails Test4 
 
X 
 
X 
X 
 
SAS-6, CAARS, GDS-3015 
 
X 
X 
 
X 
 
C-SSRS12 
X 
X16 
X 
X 
X3 
X 
ADCS-CGIC12,17 
X 
 
 
 
X 
 
Study drug administration18 
 
 
 
 
 
 
Provide subject dosing instructions and  
dispense dosing diary 
 
 
X 
 
 
 
Review dosing diary 
 
 
 
X 
X3 
 
Assessment of AEs 
 
X 
X 
X 
X3 
X 
Concomitant medications 
X 
X 
X 
X 
X3 
X 
    AE = adverse event; ECG = electrocardiogram;; PK = pharmacokinetics  
Disease assessments should be conducted after the subjects have been provided with a light meal or snack without caffeinated 
beverages or high sugar content in the following order if possible: FERT before pVFT, then DSST then CANTAB and Color 
Trails Test. ADCS-CGIC should be conducted last.  
1 Washout period between Treatment Periods 1 & 2 is 7 to 21 days. The washout period may be extended with prior approval by the 
CuraSen Medical Monitor,  
2 Visit to be conducted in the clinic, or other off-site location or at the subject’s home according to site preference and capabilities. In 
addition, should there be factors and/or conditions which would make a site visit unnecessarily difficult and/or potentially unsafe for a 
subject, some visits and/or procedures may be performed by alternate arrangement, e.g., visits in the subject’s home, virtual visits. The 
End of Study visit is to occur 7-12 days after last dose of study drug.  
3 Subjects who withdraw from the study prior to completion of dosing should complete these Day 14 safety assessments at the time of 


Sponsor: CuraSen Therapeutics, Inc. 
 
Statistical Analysis Plan 
Protocol Number: CST2032/CST107-CLIN-015  
Draft Version 3.0, 25Jul2023 
CONFIDENTIAL 
           Page 38 of 41 
 
early withdrawal (EW).  
4 The Color Trails Test should be completed after the CANTAB assessments (select sites only). 
5 Vital signs to include orthostatic changes in BP and HR, respiratory rate, and oral/tympanic temperature. For assessments of 
orthostatic changes, BP and HR are obtained: a) after rest in a supine position for at least 5 minutes, and b) 1 minute after standing.  
Vital signs will be obtained at every study visit as follows: 
• Screening  
• Day -1 prior to administration of CST-107 or matching placebo in each treatment period  
• Days 1, 7, and 14 of each treatment period:  
o Within 30 minutes prior to dosing of study drug (CST-2032+CST-107 or matching placebos),  
o Approximately 4 hours (± 30 minutes) after administration of study drug,  
• End-of-Study Visit.  
6 ECGs to be obtained in triplicate (separated by approximately 1 minute) after subject is supine for 5 minutes at the following 
timepoints:  
• Screening  
• 3 sets of triplicate ECG measures (i.e., 9 ECGs) on Day -1 prior to administration of CST-107 or matching placebo in each 
treatment period to thoroughly establish a baseline; the time between each set of 3 ECGs should be ≤5 minutes.   
• On Day 1 of each treatment period:  
o Within 30 minutes prior to dosing of study drug,  
o Approximately 1 hour after administration of study drug,  
o Approximately 2 hours after administration of study drug,  
o Approximately 4 hours after administration of study drug,  
• Days 7 and 14 of each treatment period:  
o Within 30 minutes prior to dosing study drug,  
o Approximately 1 hour after administration of study drug,  
o Approximately 2 hours after administration of study drug,  
o Approximately 4 hours after administration of study drug,  
• End-of-Study Visit,  
• All ECGs will be evaluated by a central ECG reader.  
7 A complete physical examination (PE) (excluding genital, rectal and breast exams) is required at Screening; the End-of-Study PE 
will be symptom-driven based on subject complaints.   
8 Safety labs to include hematology, chemistries, and urinalysis. Fasting safety labs to be conducted at Screening and EOS.  
9 At Screening, serum β-hCG pregnancy test for females of childbearing potential; an FSH test will be performed for postmenopausal 
women. Females of childbearing potential will have serum or urine pregnancy tests (per standard site practice) on Day -1, Day 14/EW 


Sponsor: CuraSen Therapeutics, Inc. 
 
Statistical Analysis Plan 
Protocol Number: CST2032/CST107-CLIN-015  
Draft Version 3.0, 25Jul2023 
CONFIDENTIAL 
           Page 39 of 41 
 
and at the End-of-Study visit.   
10 Subjects to be tested for current SARS-CoV-2 infection at Screening. Additional evaluations of SARS-CoV-2 infection on other 
visit days should be according to site standard operating procedures.  
11 PK samples to be collected on Day 7 of each treatment period:   
• within 15 minutes prior to dosing study drug,  
• 0.5+0.25 hour after administration of study drug,  
• 1+0.5 hour after administration of study drug,  
• 2+0.5 hour after administration of study drug, and  
• 4+0.5 hours after administration of study drug.  
12 The DSST, C-SSRS, pVFT, ADCS-CGIC, MoCA and MHYS (if done within the past 3 months, MHYS does not have to be 
repeated) are to be administered by a qualified clinical rater. The MHYS will be recorded but not be used as an enrollment criterion. 
13 Facial Recognition Task (FERT) will be conducted at the following timepoints in each treatment period:  
• Day -1: Prior to administration of CST-107 or matching placebo,  
• Day 1: at least 2 hours after dosing of study drug,  
• Day 14: at least 2 hours after dosing of study drug.  
14 First administration of CANTAB is to familiarize the subject with the tests and equipment. The CANTAB and phonological verbal 
fluency (pVFT) test and DSST should be administered after completion of FERT at the following timepoints in each treatment period:  
• CANTAB only to be administered twice, at least 1 hour apartduring the final week (Day -8 to Day -2) before Treatment Period 
1 to familiarize subjects with the CANTAB  
• CANTAB, pVFT and DSST to be administered on Day -1 prior to administration of CST-107 or matching placebo. These tests 
are to be administered in each treatment period at approximately the same time of day (±1 hour) and under approximately the 
same food status as planned for the tests on Days 1, 7, and 14.  
• CANTAB, pVFT and DSST to be administered on Days 1, 7 and 14 of each treatment period:  
o 3±0.5 hours after administration of study drug. Tests should be conducted at approximately the same time of day (±1 
hour) and under the same  
food status on Days -1, 1, 7 and 14.   
15 SAS-6, CAARS, and GDS-30 are per subject self-report. These tests will be administered at the following timepoints in each 
treatment period:  
• Day -1: Prior to administration of CST-107 or matching placebo  
• Day 1: at least 2 hours after dosing of study drug,  
• Day 14: at least 2 hours after dosing of study drug.  
16 C-SSRS not completed on Day -1 during Treatment Period 1.  
17 The ADCS-CGIC will be administered at the following timepoints in each treatment period:  


Sponsor: CuraSen Therapeutics, Inc. 
 
Statistical Analysis Plan 
Protocol Number: CST2032/CST107-CLIN-015  
Draft Version 3.0, 25Jul2023 
CONFIDENTIAL 
           Page 40 of 41 
 
• Screening  
• Day 14: at least 3 hours after dosing of study drug.  
18 On Day -1 only, CST-107 or matching placebo is to be administered upon completion of all scheduled study assessments. On all 
other dosing days, study drugs (CST-2032+CST-107 or matching placebos) are to be co-administered. On Days -1, 1, 7 and 14 the 
study drugs are administered in the clinic.  
19 On Day 1, safety labs will be collected pre-dose and approximately 4 hours post-dose (chemistry only at 4 hours post-dose).  
20 On Days 7 and 14, safety labs will be collected approximately 4 hours post-dose.  
21 Inclusion/exclusion criteria not re-assessed on Day -1 of Treatment Period 2.  
 
 


Sponsor: CuraSen Therapeutics, Inc. 
 
Statistical Analysis Plan 
Protocol Number: CST2032/CST107-CLIN-015  
Draft Version 3.0, 25Jul2023 
CONFIDENTIAL 
           Page 41 of 41 
 
13.3 APPENDIX 3: Normative Data for Cognition Tests Used in this SAP 
Test 
Test Code 
Mean Result 
Standard Deviation 
N 
Population 
Reference 
DSST (2 min) 
N/A 
70.0 
16.3 
Subset of 
N=2200, 
from 
Wechsler 
2008 
35-44y 
Wisdom et al 2012 
65.0 
16.0 
45-54y 
59.5 
15.5 
55-64y 
54.4 
15.5 
65-69y 
49.5 
15.5 
70-74y 
44.5 
16.0 
75-79y 
Verbal Fluency – Alphabet 
(items per minute) 
AAACCPT 
15.3 
4.6 
365 
Healthy adults, mean age 41y, average 14.2 
years of edu, 55% female 
Harrison et al 2000 
Verbal Fluency – Category 
(items per minute) 
CAACCPT 
17.9 
6.8 
46 
Healthy adults >=65y 
Adaptive Tracking Test 
ATT2BDM 
4.8 
0.45 
8 
Healthy 55-75y 
CST2032-CLIN-001 (Cohort D2) 
5.2 
0.29 
16 
Healthy 55-75y 
CST103-CST139-CLIN-010 (Part D) 
Paired associates learning test 
(PAL) 
PALTEA 
34.3 
16.7 
1349 
Healthy adults 57-84y 
Abbott et al 2018 
25.8 
18.9 
1204 
Atherosclerosis and LDL >70mg/dL, 40-85y 
(mean=62.7y), 72% male, 92% white, 12.7y 
education, 74% on beta blockers. Excl: 
dementia and MCI 
Guigliano et al 2017 
5-choise Reaction time interval 
(TRI) 
RTIFMDRT 
327.7 
43.6 
1502 
Healthy adults 57-84y 
Abbott et al 2018 
355.9 
71.7 
1204 
Atherosclerosis and LDL >70mg/dL, 40-85y 
(mean=62.7y), 72% male, 92% white, 12.7y 
education, 74% on beta blockers. Excl: 
dementia and MCI 
Guigliano et al 2017 
370 
54.5 
488 
Female twins, 42-72y at BL, mean age 55.5y 
Stop signal test – reaction time 
SSTSSRT 
180.09 
32.08 
36 
Control group: 72% men, mean age=31.6y 
Martoni et al 2018 
Immediate Verbal Recall 
VRMFR11D 
8.15 
2.32 
91 
Healthy, 29% male, mean age=65y 
Bensalem et al 2019 
8.43 
2.18 
98