Clinical trial NCT04739423
Conditions: Mild Cognitive Impairment, Lewy Body Dementia, Parkinson's Disease Rapid Eye Movement Sleep Behavior Disorder, Parkinson's Disease Dementia
Sponsor: CuraSen Therapeutics, Inc.
Start date: 2021-06-28; Completion date: 2022-08-31
Enrollment: 41 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This is a Phase II, randomized, placebo-controlled, double-blind, crossover study on the CNS and pharmacodynamic effects of clenbuterol (CST-103) co-administered with nadolol (CST-107) in 4 subject populations with Neurodegenerative Disorders.

Detailed description:
Approximately 40 subjects with Parkinson's Disease (PD) with REM Sleep Behavior Disorder (RBD) and Depressive Symptoms, Mild Cognitive Impairment (MCI) with Depressive Symptoms, Dementia with Lewy Bodies (DLB) with Cognitive Fluctuations, and Parkinson's Disease Dementia (PDD) with Cognitive Fluctuations were to be enrolled in a 2 period, 2-way crossover design following study eligibility confirmation during the screening period. The number of subjects enrolled in each cohort could change as emerging data are reviewed from this and other studies.

During each treatment period, subjects received daily doses of clenbuterol (CST-103) co-administered with nadolol (CST-107) or matching placebo for 14 days. Each treatment period was separated by a washout period of 14 days (+5-day window).

All subjects completed clinical and pharmacodynamic assessments during each treatment period and PK blood samples were collected prior to, during and after study medication administration.

Arms: arm 1: Subjects will receive daily doses of CST-103 co-administered with CST-107 for 14 days, followed by a washout period of no drug for 14 days, followed by matching placebo for CST-103 and matching placebo for CST-107 for 14 days. arm 2: Subjects will receive daily doses of matching placebo for CST-103 co-administered with matching placebo for CST-107 for 14 days, followed by a washout period of no drug for 14 days, followed by daily doses of CST-103 co-administered with CST-107 for 14 days.
Interventions: intervention 1: clenbuterol (CST-103), nadolol (CST-107), matching placebo
Intervention descriptions: intervention 1: clenbuterol (CST-103) and matching placebo orange capsules; nadolol (CST-107) and matching placebo white capsules

Protocol documents:
Prot_000.pdf: 
 
 
 
Clinical Trial Protocol 
Clinical Trial Title 
A Phase II, Randomized, Placebo-Controlled, Double-Blind, Crossover, 
Study of the Pharmacodynamic Effects of CST-103 co-administered with 
CST-107 on the Central Nervous System in Subjects with 
Neurodegenerative Disorders  
Protocol Number 
CST103/CST107-CLIN-011 
EudraCT Number 
2020-006067-28 
Investigational Products 
CST-103, CST-107 
Indication 
Neurodegenerative disease 
Sponsor 
CuraSen Therapeutics, Inc. 
930 Brittan Avenue, #306 
San Carlos, CA 94070 
USA 
Phone: +1 650-475-2842 
 
Sponsor’s Medical Monitor 
(AUS/NZ)  
 
 
 
 
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 / 08 JAN 2021 
Version 1.1 / 27 JAN 2021, Amendment 1 
Version 2.0 / 14 MAY 2021, Amendment 2 AUS-NZ  
Version 3.0 / 18 JUL 2021, Amendment 3 AUS-NZ 
Version 4.0 / 23 AUG 2021, Amendment 4 AUS-NZ 
Version 5.0 / 19 OCT 2021, Amendment 5 AUS-NZ 
Version 6.0 / 18 FEB 2022, Amendment 6 AUS-NZ 
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 II, Randomized, Placebo-Controlled, Double-Blind, Crossover, Study of the 
Pharmacodynamic Effects of CST-103 co-administered with CST-107 on the Central Nervous 
System in Subjects with Neurodegenerative Disorders 
 
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. 
_____________________ 
Date 
 
 
21 February 2022


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INVESTIGATOR’S AGREEMENT 
Title:  
A Phase II, Randomized, Placebo-Controlled, Double-Blind, Crossover, Study of the 
Pharmacodynamic Effects of CST-103 co-administered with CST-107 on the Central Nervous 
System in Subjects with Neurodegenerative Disorders 
 
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’s Medical 
Monitor (AUS/
 
 
Phone: 
 
Email: 
 
 
  
 
 
 
 
 
 
 


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PROTOCOL SYNOPSIS 
Title 
A Phase II, Randomized, Placebo-Controlled, Double-Blind, 
Crossover, Study of the Pharmacodynamic Effects of CST-103 co-
administered with CST-107 on the Central Nervous System in 
Subjects with Neurodegenerative Disorders  
Sponsor 
CuraSen Therapeutics, Inc. 
Study Medication 
CST-103 and CST-107 
Primary Objectives 
The primary objective of this study is to identify a CNS signal in 
one of the planned pharmacodynamic measurements after multiple 
oral doses of CST-103 in the presence of CST-107 in four 
populations of subjects with Neurodegenerative Disorders (NDD): 
Cohort A 
1. Parkinson’s Disease (PD) with REM Sleep Behavior Disorder 
(RBD) and Depressive Symptoms 
2. Mild Cognitive Impairment (MCI) with Depressive Symptoms 
Cohort B 
1. Dementia with Lewy Bodies (DLB) with Cognitive 
Fluctuations  
2. Parkinson’s Disease Dementia (PDD) with Cognitive 
Fluctuations  
These pharmacodynamic assessments will compare the effect of 
CST-103 co-administered with CST-107 with that of placebo on the 
following:  
Cohort A: 
• Emotional Facial Processing  
Cohort B: 
• Cognitive fluctuations  
 
 


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Secondary Objectives 
The secondary objectives for all subjects include the comparison of 
the effect of CST-103 co-administered with CST-107 with that of 
placebo on the following:  
1. Cognition 
2. Movement and time spent sitting, standing and sleeping 
3. Sleep  
4. Pupillary reactivity  
5. Mood Assessment 
6. Safety and tolerability of CST-103 co-administered with 
CST-107 
7. The pharmacokinetic (PK) profiles of CST-103 and CST-
107 
Exploratory Objective 
 
The exploratory objectives are: 
1. To characterize the effect of CST-103 co-administered with 
CST-107 on inflammatory biomarkers in blood, such as C-
reactive protein and cytokine levels.  
2. To characterize the effect of CST-103 co-administered with 
CST-107 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. 
3. To characterize the effect of CST-103 co-administered with 
CST-107 on performance on a sustained attention task in 
subjects in Cohort B. 
4. To characterize the effect of CST-103 co-administered with 
CST-107 on Freezing of Gait (FOG) (for subjects with 
RBD+PD, PDD and DLB).  
5. To characterize the locus coeruleus volume and contrast 
ratio; this is an optional procedure based on imaging 
capabilities 
Primary Endpoints 
The primary endpoints include: 
Cohort A: 
Change in Negative Emotional Bias in the Facial Expression 
Recognition Task 
Cohort B: 
Cognitive Fluctuations as measured by: 
1. Spectral analysis of waking EEG  
2. Activity Tracking 
3. Pupillometry 
4. Dementia Cognitive Fluctuation Scale (DCFS) 


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Secondary Endpoints 
The secondary endpoints will compare the effect of CST-103 co-
administered with CST-107 with that of placebo on the following:  
1. Verbal fluency test (alphabet & category) and CANTAB 
cognitive assessments, which include the following:  
• Reaction Time (RTI) 
• Rapid Visual Information Processing (RVP) 
• Verbal Recognition Memory (VRM) Phase I 
• Adaptive Tracking Task (ATT) 
• Paired Associates Learning Task (PAL) 
• Stop Signal Task (SST) 
• Delayed Verbal Recall 
2. Digital wearable device (BioStamp) data, which includes 
four key measures of interest: 
a. Activity and posture classifications, durations, and 
temporal patterns 
b. Sleep (duration, posture transitions, and activity 
counts) 
c. Autonomic function – heart rate variability (HRV) 
d. Temporal pedometry (daily step count, and gait 
cadence) 
3. Assessment of sleep using digital device and Epworth 
Sleepiness Scale (ESS) 
4. Change in pupillary diameter as measured using the 
pupillary light reflex test 
5. Geriatric Depression Scale (GDS), Hospital Anxiety and 
Depression Scale (HADS) 
6. Adverse events (AE), electrocardiograms (ECGs), vital 
signs, laboratory safety tests (hematology, chemistry and 
urinalysis). 
7. Plasma PK parameters of CST-103 and CST-107 (including 
Cmax, tmax, AUCt, AUCinf, t1/2)  


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Exploratory Endpoints 
The exploratory endpoints are:  
1. Changes in inflammatory biomarkers, such as C-reactive 
protein and cytokine levels, as measured prior to and after 
CST-103 co-administered with CST-107 may be determined. 
2. 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 CST-103 co-administered with CST-107 may be 
evaluated.  
3. Performance on the SART as measured prior to and after 
CST-103 co-administered with CST-107. 
4. Assessment of FOG using the FOG-Q (for subjects with 
RBD+PD, PDD and DLB). 
5. The characterization of the brain imaging signal in the locus 
coeruleus complex using neuromelanin-sensitive MRI 
sequence.  This is an optional endpoint based on imaging 
capabilities. 
Methodology 
Study Design 
This is a Phase II, randomized, placebo-controlled, double-blind, 
crossover study on the CNS and pharmacodynamic effects of CST-
103 co-administered with CST-107 in 4 subject populations with 
Neurodegenerative Disorders. 
Approximately 40 subjects (approximately 20 subjects in Cohort A 
with RBD+PD or MCI and approximately 20 subjects in Cohort B 
with PDD or DLB) will be enrolled in a 2 period, 2-way crossover 
design following study eligibility confirmation during the screening 
period.  The number of subjects enrolled in each cohort may change 
as emerging data are reviewed from this and other studies.   
During each treatment period, subjects will receive daily doses of 
CST-103 co-administered with CST-107 or matching placebo for 14 
days. Each treatment period will be separated by a washout period 
of 14 days (+5-day window).    
All subjects will complete clinical 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.  


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Subjects will complete scheduled study assessments throughout the 
study duration according to the Schedule of Events.  
 
 
Safety Review Meetings (SRM) 
Safety Review Meetings (SRM) will be held to review blinded 
safety data (such as AEs, vital signs, ECGs, and safety labs), and PK 
(if available), when 25%, 50%, and 75% of the subjects have 
completed the study.   
The SRM members will be composed of the regional Lead 
Investigator(s) or delegated representative, CuraSen Chief Medical 
Officer, CuraSen Medical Monitor(s), and Clinical Research Study 
Manager(s).  Additional members may be added as needed (e.g., 
Biostatistics, PK scientist).   
Number of Subjects  
Approximately 40 subjects will be enrolled in this study: 
approximately 20 in Cohort A (RBD+PD or MCI) and 
approximately 20 subjects in Cohort B (PDD or DLB).  The number 
of subjects enrolled in each cohort may change as emerging data are 
reviewed from this and other studies.   
Number of Sites 
Subjects will be enrolled at up to 10 clinical sites.  


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Inclusion Criteria 
A subject will be considered eligible for enrollment if all of the 
following are met: 
Cohort A 
Subjects with RBD+PD: 
1. Male or female subjects ≥ 40 and ≤ 80 years of age, at time of 
informed consent. 
2. Subject diagnosed with Parkinson’s Disease, as defined by the 
United Kingdom Parkinson 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 REM Sleep Behavior Disorder 
Single-Question Screen (RBD1Q). 
3. Subject who is Modified Hoehn & Yahr ≥ stage 1 and ≤ stage 
3 during “On” period as documented in the 3 months prior to 
Screening or completed at Screening.  
4. Montreal Cognitive Assessment (MoCA) score ≥ 18 and ≤ 28. 
 
Subjects with MCI: 
6. Male or female subjects ≥ 50 and ≤ 80 years of age, at time of 
informed consent.  
7. Subjects who meet the criteria for amnestic Mild Cognitive 
Impairment (MCI) as per the National Institute on Aging-
Alzheimer's Association core clinical criteria. 
8. Montreal Cognitive Assessment (MoCA) score ≥ 18 and ≤ 26. 
9. No dementia according to the International Classifications of 
Diseases (ICD)-10 and Diagnostic and Statistical Manual of 
Mental Disorders (DSM)-IV. 
10. A memory complaint reported by the subject or his/her 
partner, family member or caregiver. 
11. A score of greater than or equal to one standard deviation 
below age and educational norms in the Digit Symbol 
Substitution Test (DSST) during Screening. 
12. Cognitive decline not primarily caused by vascular, traumatic, 
or medical problems (alternative causes of cognitive decline 
are ruled out). 
 
Cohort B 
Subjects with Dementia with Lewy Bodies (DLB) or Parkinson's 
Disease Dementia (PDD): 
14. Male or female subjects ≥ 50 and ≤ 80 years of age, at time of 
informed consent. 


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15. A diagnosis of dementia associated with Dementia with Lewy 
Bodies (McKeith 2017) or Parkinson’s disease (PDD) (Emre 
2007). 
16. Documented cognitive fluctuations endorsed on the Dementia 
Cognitive Fluctuation Scale (DCFS) with a combined score 
of  ≥8 in items 4, 11, 12 and 14 must be present.  
17. Montreal Cognitive Assessment (MoCA) score ≥ 18 and ≤ 26. 
18. Subject having informant or caregiver throughout the study 
who will submit written consent to cooperate with this study, 
who routinely accompanies and/or stays with subject 12 hours 
or more a week, assists with treatment compliance, provides 
assessments and is able to escort the subject on required visits 
to study institution. 
19. Subject who is Modified Hoehn & Yahr ≥ stage 1 and ≤ stage 
3 during “On” period as documented in the 3 months prior to 
Screening or completed at Screening. 
20. Stable concomitant medical and/or psychiatric illnesses in the 
judgement of the PI.  
 
For ALL Subjects: 
21. Unless confirmed to be azoospermic (vasectomized or 
secondary to medical cause), males must agree to use a male 
condom from Day 1 throughout the study 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 Follow-Up Visit. 
22. 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 reliable 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). 
23. Females of non-childbearing potential may be enrolled if it is 
documented that they are postmenopausal (refer to section 
5.6).  
24. Body weight greater or equal to 50 kg and body mass index 
(BMI) between 18 and 35 kg/m2, inclusive at Screening.  


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25. Stable medical conditions for 3 months prior to Screening 
visit (e.g., controlled hypertension, dyslipidemia). 
26. Willing to follow the protocol requirements and comply with 
protocol restrictions. 
27. Capable of providing informed consent and complying with 
study procedures (completion of self-assessment rating scales 
and use of wearable devices). Subjects who are unable to 
provide 
consent 
may 
use 
a 
Legally 
Authorized 
Representative.  
 


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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 if 
requiring the use of a β2-Adrenergic bronchodilator, 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 or history in past two years of epilepsy, 
focal brain lesion, head injury with loss of consciousness or 
meeting DSM-IV diagnostic criteria for psychotic disorders, 
such as Schizophrenia or Bipolar Disorder, or have unstable 
concomitant psychiatric symptomatology that is not believed 
by the Investigator to be associated with PDD or DLB.   
5. Evidence of any significant clinical disorder or laboratory 
finding (or in the case of potassium levels below normal 
range) that renders the participant unsuitable for receiving 
an investigational drug including clinically significant or 
unstable hematologic, hepatic, cardiovascular, pulmonary, 
gastrointestinal, endocrine (excluding managed hypo and 
hyperthyroidism), metabolic, renal, or other systemic 
disease or laboratory abnormality. 
6. Participants with a history of malignant disease, including 
solid tumors and hematologic malignancies (except basal 
cell and squamous cell carcinomas of the skin that have been 
completely excised and are considered cured) within 5 years 
prior to Screening. 
7. Any clinically significant illness or disease (apart from those 
typically associated with NDD) as determined by medical 
and surgical history, physical examination, 12-lead 
electrocardiogram (ECG) and clinical laboratory 
assessments conducted at Screening.   
8. Clinically significant abnormalities of ECG, including QTcF 
> 450 ms, for males and QTcF > 470 ms for females, and/or 
HR < 50 beats per minute, or evidence of clinically 
significant bundle branch blocks, as indicated by 12-lead 


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ECG in a supine position at Screening or during the Lead-In 
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/products 
(refer to section 5.4) during Screening or throughout study, 
unless approved by both the Investigator and the Sponsor 
Medical Monitor.  
11. Known hypersensitivity to Spiropent (clenbuterol), Corgard 
(nadolol) or intolerance to lactose. Subjects with hereditary 
galactose intolerance (e.g., galactosemia, lactase deficiency 
or glucose galactose malabsorption) should be excluded. 
12. Prior 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. 
13. Prior 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. 
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 hepatitis C antibody (HCV Ab) or 
current hepatitis B infection (defined as positive for hepatitis 
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. Positive screening test for human immunodeficiency virus 
(HIV). 
18. Current infection with severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2).  
19. Contraindications to wearing the BioStamp digital device 
sensors, which include but are not limited to implanted 


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pacemakers, defibrillators, or other active implantable 
devices. 
20. Known allergies or hypersensitivities to adhesives or 
hydrogel. 
21. Females who are breastfeeding. 
22. Any other reason for which the PI considers it is not in the 
best interest of the participant to undertake the study.  
23. Inability to undergo a clinical MRI of the brain due to 
claustrophobia, inability to lie supine for a prolonged time 
period, or other contraindications to undergoing an MRI of 
the brain including, but not limited to, pacemakers; 
implantable cardioverter defibrillators; cochlear implants; 
cerebral aneurysm clips; implanted infusion pumps; 
implanted nerve stimulators; metallic splinters in the eye; 
and, other magnetic, electronic or mechanical implants or 
clinical findings that in the judgment of the investigator 
would pose a potential hazard in combination with MRI. 
(NOTE: this is a procedural exclusion not a study 
exclusion). 
Description of Study 
Medications  
The study medications will be provided as oral capsules for CST-
103, CST-107 and corresponding matching placebos. 
During Treatment Periods 1 and 2, subjects will receive once daily 
oral doses of 80 µg CST-103 or matching placebo co-administered 
with 1 mg CST-107 or matching placebo on Days 1 – 14. 
A 14-day supply of study drug will be dispensed to the subject at the 
beginning of each treatment period, and the subject will be 
instructed to self-administer daily.   
Study Duration  
The study duration will be approximately 12 weeks, which includes 
a Screening period of up to 21 days, a Lead-In Period of up to 14 
days, the treatment/study period of 6 weeks (two 2-week treatment 
periods separated with a 2-week wash-out), and the Follow-Up Visit 
2 weeks 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 -8.  Subjects who meet eligibility criteria 
based on screening assessments may be enrolled in the study. 
 
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), creatinine 
clearance calculation, drug and alcohol tests, SARS-CoV-2 status 
assessment, serum HIV, and 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 for each population: DCFS, MHYS, MoCA, RBD1Q,  
and DSST. 
 
Once all screening visit procedures are completed and the subject 
meets all eligibility criteria, the subject will return to the site to 
begin the Lead-In Period (up to 14 days). At that time, the subject 
will be randomly assigned to treatment. During the Lead-In Period, 
the subject will be trained on and practice the CANTAB tests and 
verbal fluency test (alphabet & category), and complete the ESS. 
The Lead-In Period will also be used to establish a baseline activity 
profile using a digital device. The BioStamp digital device will be 
dispensed to the subject who will be instructed to wear it for 7 
consecutive days prior to the Treatment Period 1 – Day 1 Visit.   
 
At the conclusion of the Lead-In Period, subjects will return to the 
clinic to begin the treatment periods.  During each treatment period, 
subjects will receive daily doses of CST-103 co-administered with 
CST-107 or matching placebo for 14 days. Each treatment period 
will be separated by a washout period of 14 days (+5-day window). 
 
A comprehensive list of all study procedures is provided in the 
Schedule of Events. 


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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. 
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 40 subjects is planned, with approximately 
20 subjects with RBD+PD or MCI in Cohort A, and approximately 
20 subjects with DLB or PDD in Cohort B.  The sample size for the 
study parts is based on practical considerations. No formal 
hypothesis testing is planned. 
 


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Statistical Analysis 
Details of statistical parameters and methods to be used will be 
described in a Statistical Analysis Plan (SAP).  
Continuous data will display number of subjects, means, standard 
deviations, median, minimum, and maximum. Categorical data will 
display frequency counts and percentages. As this study is primarily 
descriptive in nature, no formal hypothesis testing will be 
performed. 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 
cohort (A or B), disease criteria within cohort (RBD+PD or MCI for 
Cohort A, and PDD or DLB for Cohort B), treatment sequence and 
overall.  Summaries of safety, PD, and PK will be presented by 
disease criteria, treatment (CST-103/CST-107 versus placebo) 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 will be summarized. An informal assessment of 
differences between CST-103/CST-107 and placebo may be 
performed. For continuous endpoints, the difference is defined as 
CST-103/CST-107 minus 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. 
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. 
All data will be listed. 
 
 
 
 


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STUDY SCHEMA – COHORT A IN RBD+PD OR MCI SUBJECTS 
  
   
 
 
 
 
STUDY SCHEMA – COHORT B IN DLB OR PDD SUBJECTS  
  
 


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SCHEDULE OF EVENTS FOR EACH TREATMENT PERIOD  
 
Screening 
Lead-In 
Treatment Periods 1 & 21 
Follow-Up 
Day -28 to 
Day -8 
Day -14 to 
Day -1 
Day 1 
Day 72 
(±1) 
Day 14/EW2,3, 4 
(±1) 
~2 Weeks after 
Last Dose of 
Study Drug or 
EW2,3 
Outpatient visit 
X 
X 
X 
X 
X 
X 
Informed consent 
X 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
Inclusion / Exclusion 
criteria valuation 
X 
X 
X29 
 
 
 
Medical history 
X 
 
 
 
 
 
Height and weight, BMI 
calculation 
X 
 
 
 
 
 
Vital signs5 
X 
 
X 
X 
X 
X 
ECG6 
X 
X 
X 
 
X 
X 
Physical exam, complete7 
X 
 
 
 
 
X 
Safety labs8 
X 
 
X 
 
 X 
X 
Urine drug screen 
X 
 
 
 
 
 
Alcohol test 
X 
 
X 
 
 
 
Hepatitis and HIV 
serologies 
X 
 
 
 
 
 
TSH 
X 
 
 
 
 
 
Serum FSH9 
X 
 
 
 
 
 
β-hCG pregnancy test9 
X 
 
 
 
 
 


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Screening 
Lead-In 
Treatment Periods 1 & 21 
Follow-Up 
Day -28 to 
Day -8 
Day -14 to 
Day -1 
Day 1 
Day 72 
(±1) 
Day 14/EW2,3, 4 
(±1) 
~2 Weeks after 
Last Dose of 
Study Drug or 
EW2,3 
Serum or urine pregnancy 
test9 
 
 
X 
 
X 
X 
SARS-CoV-2 status 
assessment10 
X 
X 
 
 
 
 
PK sample11 
 
 
X 
 
X 
 
APOE4 genotyping 
 
 
X28 
 
 
 
Pharmacodynamic sample 
collection27  
 
 
X 
 
X 
 
C-SSRS12 
X 
 
X25 
X 
X 
X 
DSST12, 13 
X 
 
 
 
 
 
Dementia Cognitive 
Fluctuation Scale (DCFS)12, 
14   
X 
 
X 
 
X 
 
Modified Hoehn & Yahr 
Scale (MHYS)12, 15 
X 
 
 
 
 
 
HADS16,18 
X 
 
X 
 
X 
 
Freezing of Gait 
Questionnaire (FOG-Q)12, 15 
 
 
X 
 
X 
 
RBD1Q17, 18 
X 
 
 
 
 
 
MoCA12 
X 
 
 
 
 
 
Epworth Sleepiness Scale 
(ESS)18 
 
X 
X 
X 
X 
 


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Screening 
Lead-In 
Treatment Periods 1 & 21 
Follow-Up 
Day -28 to 
Day -8 
Day -14 to 
Day -1 
Day 1 
Day 72 
(±1) 
Day 14/EW2,3, 4 
(±1) 
~2 Weeks after 
Last Dose of 
Study Drug or 
EW2,3 
Geriatric Depression Scale 
(GDS)18  
 
 
X 
X 
X 
 
CANTAB19 
 
X 
X 
X 
X 
 
Verbal fluency test 
(alphabet & category)12,19 
 
X 
X 
X 
X 
 
Pupillary Light Reflex 
(PLR) Test20 
 
 
X 
X 
 X 
 
EEG21 
 
 
X 
 
X 
 
Sustained Attention to 
Response Task (SART)22 
 
 
X 
 
X 
 
Facial Recognition Task 
(FERT) 16, 23  
 
 
X 
X 
X 
 
BioStamp digital device 24 
 
X 
 
 
 
 
CST-103+CST-107 or 
matching placebo 
administration  
 
 
 
 
 
 
Neuromelanin MRI scan 
X26 
 
 
 
 
X26 
Assessment of AEs 
 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
AE = adverse event; ECG = electrocardiogram; EEG = electroencephalogram; PK = pharmacokinetics 
 
1 Wash-out period between Treatment Periods 1 & 2 is 14 (+ 5) days.  The Wash-out period may be extended further with Medical Monitor approval. 
2 Visit to be conducted in the clinic, virtually, other off-site location, or at the subject’s home according to site and subject preference and capabilities. 
3 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.  


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4 Subjects who withdraw from the study prior to completion of dosing should complete Day 14 safety assessments at the time of withdrawal.  
5 Vital signs to include BP, HR, respiration rate, and oral/tympanic temperature; triplicate BP and HR measurements (separated by approximately 1 minute) after subject is supine for 5 
minutes; vital signs will be obtained at every study visit as follows:  
• 
Screening   
• 
Day 1 of each treatment period: 
1. 
Prior to dosing (within 15 minutes)  
2. 
1 hour (±30 mins) after dosing  
• 
Day 7 of each treatment period: 1 hour (±30 mins) after dosing 
• 
Day 14 of each treatment period: 1 hour (±30 mins) after dosing  
• 
Follow-Up Visit 
6 Subjects will be required to rest in a supine position for at least 5 minutes prior to the recording of ECG. ECGs to be obtained at the following timepoints:  
• 
Screening   
• 
Lead-In  
• 
Day 1 of each treatment period:   
1. 
Prior to dosing (within 15 minutes)  
2. 
1 hour (±30 mins) after dosing   
3. 
4 hours (±30 mins) after dosing 
• 
Day 14 of each treatment period: 
1. 
1 hour (±30 mins) after dosing  
2. 
4 hours (±30 mins) after dosing 
• 
Follow-Up Visit 
7 A complete physical examination (PE) (excluding genital, rectal and breast exams) is required at Screening; the Follow-Up PE will be symptom-driven based on subject complaints.  
8 Safety labs to include hematology, chemistries, and urinalysis. Subjects should be fasting for 8 hours for the safety labs.  
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 and at the Follow-Up visit.  
10 Subjects to be assessed for current infection per local site standard procedure. 
11 PK sample timepoints (CST-103/CST-107) in each treatment period:   
• 
Day 1: 
1. 
Prior to dosing 
2. 
4 hours (±10 mins) post dose 
• 
Day 14: 
1. 
Prior to dosing 
2. 
4 hours (±10 mins) post dose 
12 The DSST, DCFS, MHYS, FOG-Q, C-SSRS, verbal fluency, and MoCA to be done by a qualified clinical rater.  
13 MCI subjects only 
14 Cohort B only; DLB and PDD subjects 
15RBD+PD, DLB and PDD subjects only 
16 Cohort A only; MCI and RBD+PD subjects 
17 RBD+PD subjects only  
18 The RBD1Q, ESS, HADS, and GDS are per subject self-report.   
19  First administration of CANTAB and verbal fluency test is to familiarize the subject with the tests and equipment. The CANTAB and verbal fluency test should be administered after 
completion of FERT for Cohort A, and after completion of EEG for Cohort B at the following timepoints in each treatment period: 


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• 
Cohort A: 
o 
Day 1:  
1. 
Prior to first dose  
2. 
4 hours (±30 mins) after dosing 
o 
Day 7: After dosing (up to 4 hours) 
o 
Day 14: After dosing (up to 4 hours) 
• 
Cohort B: 
o 
Day 1: 
1. 
 Prior to first dose 
2. 
4 hours (±30 mins) after dosing 
o 
Day 7: After dosing (up to 4 hours) 
o 
Day 14: After dosing (up to 4 hours) 
20 The PLR test will be conducted after the CANTAB. The PLR test will be performed (twice for each eye) at the following timepoints in each treatment period: 
o 
Day 1:  
1. 
Prior to first dose  
2. 
After post dose CANTAB 
o 
Day 7: After post dose CANTAB 
o 
Day 14: After post dose CANTAB 
21 Cohort B only: First assessment with EEG on Day 1 pre-dose is to obtain a baseline for each period. The EEG will be conducted on Day 14 in clinic (~1 hour).   EEG will be conducted 
at the following timepoints in each treatment period: 
• 
Day 1:  
1. Prior to dosing  
2. 3 hours (±15 mins) after dosing 
• 
Day 14: After dosing (up to 3 hours)  
22Cohort B (select sites only): First administration of Sustained Attention to Response Task (SART) is to obtain baseline for each period (it will be conducted only at a subset of sites).  
SART will be conducted at the following timepoints in each treatment period: 
• 
Day 1:  
1. 
Prior to dosing  
2. 
3 hours (±15 mins) after dosing such as to occur during the EEG collection period 
• 
Day 14: After dosing (up to 3 hours) such as to occur during the EEG collection period 
23 Cohort A only: FERT will be conducted at the following timepoints in each treatment period: 
• 
Day 1: Prior to dosing  
• 
Day 7: After dosing   
• 
Day 14: After dosing   
24 Once all screening visit procedures are completed and the subject meets all eligibility criteria, the BioStamp device will be dispensed to the subject who will be instructed to wear for 7 
days prior to the Treatment Period 1 – Day 1 Visit.  The BioStamp device will be re-dispensed at 2 other timepoints (at each of the Day 1 Visits in Treatment Periods 1 and 2), worn 
for 14 days and removed on Day 14.   
25  C-SSRS not completed on Day 1 during Treatment Period 1. 
26  The neuromelanin sensitive MRI sequence is optional depending on the imaging facility’s capabilities.  If not performed at Screening, it may be performed at the Follow-up visit or at 
any other convenient time during the study. 


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27 The pharmacodynamic timepoints in each treatment period are: 
• 
Day 1: 
1. 
Prior to dosing 
• 
Day 14: 
1. 
4 hours (±10 mins) post dose 
28 Treatment period 1 only.  For ongoing subjects who have completed visits beyond Treatment Period 1, Day 1, the test may be done at any time during the study. 
29 Treatment period 1 only.   


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LIST OF ABBREVIATIONS  
Abbreviation 
Definition 
Aβ 
amyloid‐β 
α-syn 
α-synuclein 
β-AR 
Beta-adrenoceptor 
β-hCG 
Beta human chorionic gonadotropin 
AD 
Alzheimer’s Disease 
AE 
Adverse event 
APOE4 
Apolipoprotein E4 
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 
CANTAB 
Cambridge Neuropsychological Test Automated Battery 
CBF 
Cerebral blood flow  
CF 
Cognitive fluctuations 
cGCP 
Current Good Clinical Practice 
CLIN-001 
CST101/CST107-CLIN-001 
CLIN-002 
CST103/CST107/CST109-CLIN-002 
CLIN-003 
CST101/CST103/CST109-CLIN-003 
Cmax 
Maximum concentration  
CNS 
Central nervous system 
CRF 
Case report form 
CK 
Creatinine kinase 
C-SSRS 
CST-103 
Columbia-Suicide Severity Rating Scale 
Clenbuterol 
CST-107 
Nadolol 
CV 
Coefficients of variation 
DCFS 
Dementia Cognitive Fluctuation Scale 
DLB 
Dementia with Lewy Bodies  
DSST 
Digit Symbol Substitution Test 
EC 
Ethics Committee 
eCRF 
Electronic case report form 
ECG 
Electrocardiogram 
EEG 
Electroencephalogram 


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Abbreviation 
Definition 
ERP 
Event Related Potential 
ESS 
Epworth Sleepiness Scale 
EW 
Early withdrawal 
FAS 
Full analysis set 
FERT 
Facial Expression Recognition Task 
FOG 
FOG-Q 
FSH 
Freezing of Gait 
Freezing of Gait Questionnaire 
Follicle-stimulating hormone 
GDS 
Geriatric Depression Scale 
HADS 
Hospital Anxiety and Depression Scale 
HR 
Heart rate 
HbsAb 
Hepatitis B surface antibody 
HbsAg 
Hepatitis B surface antigen 
HCV Ab 
Hepatitis C antibody 
HIV 
Human immunodeficiency virus 
HRV 
Heart rate variability 
IB 
Investigator Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IRT 
Interactive response technology 
ITT 
Intent to treat 
IV 
Intravenous 
IWRS 
Interactive Web Response System 
LBD 
Lewy Body Dementia 
MCI 
Mild cognitive impairment  
MedDRA 
Medical Dictionary for Regulatory Activities 
MHYS 
Modified Hoehn & Yahr Scale 
MoCA 
MRI 
Montreal Cognitive Assessment 
Magnetic resonance imaging 
NDD 
Neurodegenerative disease 
PAL 
Paired Associates Learning 
PD 
Parkinson’s Disease 
PDD 
Parkinson’s Disease Dementia 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PKS 
PK set 
PLR 
Pupillary Light Reflex 


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Abbreviation 
Definition 
PO 
By mouth/oral administration 
PPS 
Per protocol set 
QD 
Once daily 
RBD1Q 
REM Sleep Behavior Disorder Single-Question Screen 
RBD+PD 
REM Sleep Behavior Disorder positive Parkinson’s Disease 
RTI 
Reaction Time Index 
RVP 
Rapid Visual information Processing 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SART 
SOC 
Sustained attention response task 
System organ class 
SOP 
Standard operating procedure 
SRM 
Safety review meeting 
SST 
Stop Signal Task 
t1/2 
Time to maximum observed drug concentration 
TEAE 
Treatment emergent adverse event 
tmax 
Time of maximum concentration 
TP 
Treatment Period 
TSH 
Thyroid-stimulating hormone 
VRM 
Verbal Recognition Memory 
WAIS-IV 
Wechsler Adult Intelligence Scale, Fourth Edition 
 
 
 
 


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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ................................................................................................................4 
STUDY SCHEMA – COHORT A IN RBD+PD OR MCI SUBJECTS ..................................18 
SCHEDULE OF EVENTS FOR EACH TREATMENT PERIOD .........................................19 
LIST OF ABBREVIATIONS ........................................................................................................25 
1. 
INTRODUCTION ..................................................................................................................31 
1.1. 
Background: Neurodegenerative Disease .....................................................................31 
1.1.1. 
Parkinson’s Disease .............................................................................................31 
1.1.2. 
Mild Cognitive Impairment .................................................................................31 
1.1.3. 
Lewy Body Dementias ........................................................................................32 
1.1.4. 
Dementia with Lewy Bodies ...............................................................................32 
1.1.5. 
Parkinson’s Disease Dementia ............................................................................32 
1.2. 
Rationale for Targeting Beta Adrenoceptors ................................................................33 
1.3. 
Overall Risk/Benefit Assessment ..................................................................................33 
1.4. 
Study Rationale .............................................................................................................34 
1.4.1. 
Rationale for Trial ...............................................................................................34 
1.4.2. 
Rationale for Dose Selection ...............................................................................35 
1.5. 
Rationale for CST-107 Dose Selection .........................................................................38 
1.6. 
Compliance Statement ..................................................................................................38 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..........................................................................38 
2.1. 
Study Objectives ...........................................................................................................38 
2.2. 
Primary Endpoints .........................................................................................................39 
2.3. 
Secondary Endpoints .....................................................................................................40 
2.4. 
Exploratory Endpoints ..................................................................................................40 
3. 
STUDY DESIGN ...................................................................................................................41 
3.1. 
Clinical Trial Design .....................................................................................................41 
3.2. 
Safety Review Meetings ...............................................................................................41 
3.3. 
Criteria for Termination of Study Medication ..............................................................42 
3.4. 
Criteria for Suspension of Trial ....................................................................................42 
4. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..........................................................42 
4.1. 
Study Participation ........................................................................................................42 
4.2. 
Inclusion Criteria ...........................................................................................................43 
4.3. 
Exclusion Criteria..........................................................................................................44 
4.4. 
Enrollment Procedures and Randomization ..................................................................46 
4.4.1. 
Screening .............................................................................................................46 
4.4.2. 
Subject Re-Screening ..........................................................................................46 
4.4.3. 
Randomization and Lead-In ................................................................................46 
4.5. 
Subject Withdrawal .......................................................................................................47 
4.5.1. 
Criteria for Withdrawal from Clinical Trial ........................................................47 
4.5.2. 
Follow-Up for Early Treatment Withdrawal Subjects ........................................47 
5. 
SCHEDULE OF EVENTS AND STUDY PROCEDURES ..................................................48 


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5.1. 
Visit Assessments .........................................................................................................48 
5.1.1. 
Cohort A – RBD+PD or MCI Subjects ...............................................................48 
5.1.2. 
Cohort B – DLB or PDD Subjects ......................................................................52 
5.2. 
Procedures for Monitoring Subject Compliance ...........................................................56 
5.3. 
Procedures and Specifications.......................................................................................56 
5.3.1. 
Medical History, Vital Signs, and Physical Exam ..............................................56 
5.3.2. 
12-Lead ECG .......................................................................................................57 
5.3.3. 
Clinical Laboratory Analysis ...............................................................................57 
5.3.4. 
Pregnancy Testing ...............................................................................................58 
5.3.5. 
Columbia Suicide Severity Rating Scale (C-SSRS) ............................................58 
5.3.6. 
Clinical/Disease and Cognitive Scales and Assessments ....................................58 
5.3.7. 
CANTAB Assessments .......................................................................................61 
5.3.8. 
Pupillary Light Reflex (PLR) Test ......................................................................62 
5.3.9. 
Neuromelanin MRI Scan .....................................................................................62 
5.3.10. 
Electroencephalogram (EEG) – DLB and PDD Subjects ...................................62 
5.3.11. 
Facial Expression Recognition Task (FERT) – MCI and RBD+PD 
Subjects ................................................................................................................63 
5.3.12. 
BioStamp nPoint Data Collection .......................................................................63 
5.4. 
Concomitant Medications .............................................................................................63 
5.5. 
Escape/Rescue Medications ..........................................................................................64 
5.6. 
Contraception ................................................................................................................65 
6. 
ASSESSMENT OF SAFETY .................................................................................................66 
6.1. 
Adverse Events..............................................................................................................66 
6.1.1. 
Definitions ...........................................................................................................66 
6.1.2. 
Assessment of Adverse Events ............................................................................67 
6.1.3. 
Reporting Serious Adverse Events ......................................................................68 
6.1.4. 
Follow-up of Adverse Events ..............................................................................68 
6.2. 
Clinical Safety Laboratory Abnormalities ....................................................................68 
6.3. 
ECG Abnormalities .......................................................................................................69 
6.4. 
Pregnancy ......................................................................................................................69 
7. 
STUDY MEDICATION .........................................................................................................69 
7.1. 
Study Medication ..........................................................................................................69 
7.2. 
Study Medication Dosing and Administration ..............................................................69 
7.2.1. 
Randomization .....................................................................................................70 
7.2.2. 
Blinding ...............................................................................................................70 
7.2.3. 
Packaging and Labeling ......................................................................................70 
7.2.4. 
Storage and Handling ..........................................................................................70 
7.2.5. 
Accountability and Disposition of Study Medication .........................................71 
8. 
STATISTICAL CONSIDERATIONS ...................................................................................71 
8.1. 
Sample Size ...................................................................................................................71 
8.2. 
Analysis Populations .....................................................................................................72 
8.3. 
Timing of Analyses .......................................................................................................72 
8.3.1. 
Safety Reviews ....................................................................................................72 


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8.3.2. 
Interim Analysis and Accruing Data Review ......................................................73 
8.3.3. 
Final Analysis ......................................................................................................73 
8.4. 
Multiplicity ....................................................................................................................73 
8.5. 
Statistical Methods ........................................................................................................73 
8.5.1. 
Subject Disposition ..............................................................................................73 
8.6. 
Subject Characteristics ..................................................................................................73 
8.7. 
Analysis of Primary Endpoints .....................................................................................74 
8.7.1. 
Cohort A: Negative Emotional Bias ....................................................................74 
8.7.2. 
Cohort B: Cognitive Fluctuations ........................................................................74 
8.8. 
Analysis of Secondary Endpoints .................................................................................74 
8.8.1. 
Cognition, Mood, and Physiological Symptoms .................................................74 
8.8.2. 
Pupillary-Related Endpoints ................................................................................74 
8.8.3. 
Epworth Sleepiness Scale ....................................................................................75 
8.8.4. 
Analysis of Safety ................................................................................................75 
8.8.5. 
Adverse Events ....................................................................................................75 
8.8.6. 
Concomitant Medications ....................................................................................75 
8.8.7. 
Study Drug Administration .................................................................................75 
8.8.8. 
Clinical Laboratory Results, Vital Signs, and ECGs ...........................................75 
8.8.9. 
Analysis Pharmacokinetic Endpoints ..................................................................76 
8.9. 
Analysis of Exploratory Endpoints ...............................................................................76 
8.10. Analysis of Other Endpoints .........................................................................................76 
9. 
ETHICAL, LEGAL AND ADMINISTRATIVE ASPECTS .................................................76 
9.1. 
Data Quality Assurance.................................................................................................76 
9.2. 
Case Report Forms and Source Documentation ...........................................................77 
9.3. 
Access to Source Data ...................................................................................................77 
9.4. 
Data Processing .............................................................................................................77 
9.5. 
Archiving Clinical Trial Records ..................................................................................78 
9.6. 
Good Clinical Practice ..................................................................................................78 
9.7. 
Informed Consent ..........................................................................................................78 
9.8. 
Protocol Approval and Amendment..............................................................................78 
9.9. 
Study Medication Accountability .................................................................................79 
9.9.1. 
Handling of Study Medications ...........................................................................79 
9.9.2. 
Disposition of Study Medications .......................................................................79 
9.9.3. 
Premature Termination of the Clinical Trial .......................................................79 
9.10. Confidentiality ..............................................................................................................79 
9.11. Publication Policy .........................................................................................................80 
10. REFERENCES .......................................................................................................................81 
 
 
 


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1. 
INTRODUCTION 
1.1. 
Background: Neurodegenerative Disease 
1.1.1. 
Parkinson’s Disease 
Parkinson’s disease (PD) was originally described by James Parkinson in the 19th century and 
named the “shaking palsy” (Parkinson 1817). PD affects 0.1% to 0.2% of the general population 
with increasing prevalence with age and up to 1% in individuals above 60 years of age, resulting 
in an estimated 7 to 10 million people with PD worldwide (Tysnes and Storstein 2017).  
PD is a common, progressive and debilitating neurodegenerative disease classically 
characterized by motor symptoms, including tremor, muscle rigidity, bradykinesia, and posture 
balance disorders (Kalia 2015). In addition to these classic motor symptoms, the physical 
burdens for PD patients include nonmotor symptoms, including cognitive dysfunction, 
neuropsychiatric symptoms, autonomic dysfunction, sleep disorder, and sensory dysfunction 
(Boland and Stacy 2012). An increasing amount of clinical and epidemiological data suggest that 
these nonmotor symptoms contribute throughout the entire course of PD.  
PD is characterized by the progressive loss of dopaminergic neurons in the substantia nigra and 
by the appearance of Lewy bodies, which are intracellular inclusions of aggregated α-syn, a 
protein that is considered to play an important role in the pathogenesis of PD (Dehay 2015).  
1.1.2. 
Mild Cognitive Impairment 
Alzheimer’s disease (AD) is a severe and life-threatening neurodegenerative disorder that affects 
approximately 44 million people in the world. Pathological hallmarks of AD include synaptic 
and neuronal loss, neuroinflammation, alterations of various neurotransmitter systems, and the 
accumulation of amyloid plaques and neurofibrillary tangles (Huang 2012). The approved 
medications that are currently available to treat AD provide transient palliative care for some 
patients but do not alter progression of the disease. Therefore, there is an urgent need for 
developing therapeutic agents capable of simultaneously addressing cognitive symptoms and 
pathology of AD and its precursor, amnestic mild cognitive impairment (MCI).  
Evidence from both genetic at-risk cohorts and clinically normal older individuals suggests that 
the pathophysiological process of AD begins years, if not decades, before the diagnosis of 
clinical dementia during the preclinical stage of AD (Sperling 2011). Preclinical AD is the stage 
where subjects have amyloid deposition but do not yet have any symptoms (Buckley 2018). In 
contrast, patients who are at the MCI stage have cognitive deficits. Of interest is that one of the 
early changes seen in the preclinical stage of AD are areas of decreased cerebral perfusion that 
are indicative of the diagnosis (Musiek 2012) and measurement of these hypoperfusion areas 
have been shown to be useful as a biomarker for AD (Jack 2013).  
Cerebral perfusion can be measured by arterial spin labeling perfusion magnetic resonance 
imaging (ASL MRI) (Fällmar 2017). ASL enables the measurement of brain perfusion non-
invasively at the tissue level (Haller 2016) by utilizing magnetically labeled blood water as an 
endogenous tracer.   


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1.1.3. 
Lewy Body Dementias 
Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are Lewy body-
related neurodegenerative disorders sharing common clinical and neuropathological findings 
(Sezgin 2019). The clinical features of both conditions include cognitive impairment, behavioral 
symptoms, autonomic dysfunction, sleep disorders, and parkinsonism. The cognitive profile of 
both disorders is characterized by particularly severe deficits in executive and visuospatial 
functions as well as attention. Clinical differentiation between DLB and PDD is based on an 
arbitrary distinction between the time of onset of parkinsonism and cognitive symptoms; 
extrapyramidal symptoms precede dementia in PDD, whereas it coincides with or follows 
dementia within 1 year in DLB. When the clinical picture is fully developed, DLB and PD-D are 
practically indistinguishable.  
1.1.4. 
Dementia with Lewy Bodies 
Dementia with Lewy bodies (DLB) is the third most common type of dementia in the world 
(Heidebrink 2002) with an annual incidence of 0.1% of the general population (Zaccai 2005). 
Essential for a diagnosis of DLB is dementia, defined as a progressive cognitive decline of 
sufficient magnitude to interfere with normal social or occupational functions, or with usual daily 
activities. Prominent or persistent memory impairment may not necessarily occur in the early 
stages but is usually evident with progression. Deficits on tests of attention, executive function, 
and visuoperceptual ability may be especially prominent and occur early (Chan 2018). 
DLB was first clearly defined in 1996, at the First International Workshop of the Consortium on 
Dementia with Lewy Bodies (McKeith 1996) and updated criteria were published in 2017 
(McKeith 2017). The clinical diagnostic criteria include rapid progressive mental impairment to 
dementia as the central feature of DLB. A core feature of DLB is “fluctuations” which can be 
defined as spontaneous alterations in cognition, attention, and arousal (Sezgin 2019). There is 
often no consistent fluctuation pattern even within the same patient; they may occur within a day 
or from day to day. Other core features include persistent well-formed visual hallucinations, and 
one or more spontaneous cardinal features of parkinsonism such as bradykinesia, rest tremor, and 
rigidity. Core clinical features may precede dementia including fluctuating cognition with 
pronounced variations in attention and alertness, recurrent well-formed and detailed visual 
hallucinations, and RBD (Iranzo 2014).  
1.1.5. 
Parkinson’s Disease Dementia  
Parkinson’s disease dementia (PDD) is a late complication of Parkinson’s disease, with a 
cumulative prevalence of 75–90% of those with a disease duration of 10 years or more (Buter 
2008; Hely., 2008; Aarsland and Kurz, 2010). It’s development negatively impacts activities of 
daily living (Rosenthal et al., 2010), and confers significantly increased morbidity and mortality 
(Reid, 1996; Levy et al., 2002). It is now widely recognized that the clinical phenotype of PD-D 
extends beyond the classical dysexecutive syndrome seen in early Parkinson’s disease to include 
additional deficits in recognition memory, attention processes and visual perception 
(Pagonabarraga and Kulisevsky, 2012; Kehagia 2013), as well as visual hallucinations and 
cognitive fluctuations (Emre, 2003, Emre 2007).  
 


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1.2. 
Rationale for Targeting Beta Adrenoceptors  
Both nonclinical and clinical data suggest a potential role for beta adrenoceptor (β-AR) agonists 
in the treatment of neurodegenerative diseases (Faizi 2012, Heneka 2002, Mittal 2017). Despite 
decades of clinical data on β-AR agonists, however, most studies have concentrated on the 
pulmonary and cardiovascular effects of this drug class and have provided minimal data on 
central nervous system (CNS) effects.  
A recent study published in Science (Mittal 2017) suggests that β2-adrenoceptors (β2-AR) are 
linked to the transcription of α-syn and increased risk of PD, therefore suggesting that they might 
represent novel targets for the development of therapeutics for this neurodegenerative disease. 
A high-throughput gene expression assay was developed for endogenous expression of human 
SNCA, the gene encoding α-syn. Researchers screened over a thousand compounds, including 
commercially available drugs. This screening led to the identification of 3 α-syn expression–
lowering compounds, the β2-AR agonists metaproterenol, salbutamol (also known as albuterol), 
and clenbuterol (CST-103). 
Additionally, a pharmacoepidemiology study performed in Norway, using the Norwegian 
national prescription database of 4.6 million subjects, found that use of the β2-AR agonist 
salbutamol was associated with decreased risk of PD (rate ratio of 0.66) while use of the β-AR 
antagonist propranolol was associated with a markedly increased risk of PD (rate ratio of 2.20) 
(Mittal 2017). Several additional epidemiology papers published subsequently suggest that 
treatment with β-AR agonists is protective against PD (Aaseth 2018, Clark and Vissel 2018, 
Gronich 2018, Magistrelli 2020, Searles 2018). Additional data also suggest that the effect of 
β-AR agonists may generalize to other neurodegenerative diseases such as mild cognitive 
impairment (MCI) and Alzheimer’s disease (AD) (Chalermpalanupap 2013, Coutellier 2014)  
Research from the Shamloo laboratory at Stanford University has demonstrated that the 
noradrenergic system, and β-ARs in particular, are promising therapeutic targets for AD. 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). The laboratory further discovered that in addition to the cognition-enhancing 
effects, xamoterol attenuates 3 major pathological hallmarks of AD: beta-amyloid burden, tau 
pathology, and neuroinflammation (Ardestani 2017).  
1.3. 
Overall Risk/Benefit Assessment 
While there will be no direct benefits for subjects participating in this study, the data generated 
will be valuable and beneficial for developing β-AR agonist therapies for neurodegenerative 
diseases.  
The adverse events (AEs) that are expected with use of CST-103 and CST-107 for their 
approved indications is provided in the Investigator Brochure (IB). The medications will be 
administered as daily doses in this study. 
Hypokalemia is a known effect of β2-AR-agonists, but its clinical significance is unclear since it 
appears to be a redistribution of potassium in the body rather than total body potassium depletion 
(Unwin 2011, Kardalas 2018).  


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In CuraSen studies, CLIN-002 and CLIN-003, in which a total of 19 healthy subjects and 
8 patients with PD were administered daily doses of 80 µg of CST-103 for 5-7 days only one 
case of mild hypokalemia was observed. It is therefore expected that hypokalemia will not be a 
safety concern with either β2-AR-agonist. However, in case hypokalemia is observed during this 
study, the subject should be managed based on their clinical needs and presentation as 
appropriate as per the Investigator’s discretion.  
In cohort 8 from CLIN-002 when CST-103 was co-administered daily for seven days with CST-
107 there were no clinically significant changes in vital signs, physical exam, ECGs, or 
laboratory values. Taken together with the decades of clinical safety data for CST-103 these 
safety results from our previous studies suggest that CST-103 will be generally well tolerated 
without any safety issues when co-administered with a 1 mg dose of CST-107.  
Suicide ideation is always a concern for CNS-active drugs. There have been no reports of suicide 
due to clenbuterol, but subjects in this study will be monitored for suicide ideation. 
Magnetic resonance imaging (MRI) is a painless and safe, non-invasive diagnostic procedure 
that uses a powerful magnet and radio waves to produce detailed images of the head or the 
body’s organs and structures without the use of X-rays or other radiation. 
There are no known harmful effects from the strong magnetic field used in MRI scans. However, 
the magnet is so powerful that it can affect any unsecured metal objects, which can be pulled 
toward the magnet. The magnet may affect pacemakers, artificial limbs, and other medical 
devices or implants that contain metal. The MRI will not be conducted if subjects have medical 
devices or implants. 
1.4. 
Study Rationale  
1.4.1. 
Rationale for Trial 
Nonclinical data for β-AR agonists demonstrate positive effects on cognition, inflammation, and 
biomarkers relevant to neurodegenerative disorders. The Science publication referenced above 
(Mittal 2017) using pharmaco-epidemiology suggested a protective effect of the β-AR agonist 
salbutamol on reducing the incidence of PD. Taken together with the nonclinical data on β-AR 
agonists (Faizi 2012, Heneka 2002) and the neuroanatomical data showing that the locus 
coeruleus (LC) is one of the first areas affected in neurodegeneration, the hypothesis suggesting 
that β-AR agonists may have a significant role in the therapy of a variety of neurodegenerative 
disorders is well founded. 
CuraSen’s ongoing and completed signal-seeking studies demonstrate that the β2-AR agonist 
CST-103 increases cerebral perfusion in healthy subjects and in patients with PD and MCI.  Data 
using a well-established cognitive battery suggests improved cognitive performance in healthy 
volunteers. This trial seeks to undertake further evaluation of the effects of CST-103 
administration on clinically relevant measures in patients with neurodegenerative disorders. 
These clinically relevant measures include effects of CST-103 on mood, arousal, cognitive 
performance, sleep, pupillary reactivity, and movement. 
Decreased cognitive performance is a hallmark of neurodegenerative diseases and very relevant 
to the ability of patients to conduct their activities of daily living. Cognitive performance will be 


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measured through the use of the Cambridge Neuropsychological Test Automated Battery 
(CANTAB), which is a standardized and automated administration of cognitive testing via touch 
tablet.  
Stimulation of the adrenergic system is well understood to have positive effects on attention, 
arousal and mood which maybe expected to have beneficial effects on clinical symptoms 
associated with these parameters such as cognition, depression and cognitive fluctuations. 
Cognitive fluctuations (CF) are one of the core features of Lewy Body dementias and are a set of 
symptoms that describe a spontaneous and time-varying alteration of cognitive abilities, often 
accompanied by disturbances in alertness or arousal. While such fluctuations have been reported 
across several dementia syndromes, they are considered to be the most characteristic and 
frequent symptom of Lewy body dementias—dementia with Lewy bodies (DLB) and 
Parkinson’s disease dementia (PDD)—where they are seen in up to 90% of patients (Walker 
2000). Since CF are related to arousal and the adrenergic system is intimately involved in arousal 
mechanisms it is our hypothesis that treatment with CST-103 will have an impact on CF. The 
effect of CST-103 on cognitive fluctuations will be assessed through the use of EEG, ERP, 
pupillometry and a digital device which measures activity. 
Depressed mood is a very common feature of neurodegenerative disorders. The impact of CST-
103 on mood will be measured through the use of an established facial emotional recognition 
task and clinical rating scales. 
β-AR agonists have been postulated to have anti-inflammatory properties and have been 
suggested to modulate the levels of various cytokines (Bissonnette and Befus 1997, 
Yamaguchi 2010). Therefore, pharmacodynamic blood samples will be collected in this study to 
investigate the effects of CST-103 on inflammatory biomarkers.  
1.4.2. 
Rationale for Dose Selection 
 
Rationale for CST-103 Dose Selection 
CuraSen has initiated 3 signal-seeking clinical studies – CST101/CST107-CLIN-001 (CLIN 
001), CST103/CST107/CST109-CLIN-002 (CLIN-002), and CST101/CST103/CST109-CLIN-
003 (CLIN-003) – to evaluate the effects of β-AR agonists on cerebral perfusion as measured by 
ASL MRI and cognition. Observations from those studies inform the trial design, endpoints, and 
doses of CST-103 planned for this study. 
The 80 µg CST-103 dose was selected based on data from 2 CuraSen clinical studies: 
• Study CST103/CST107/CST109-CLIN-002 (CLIN-002) evaluated single oral doses of 
20, 40, 80, and 160 µg CST-103 and once-daily oral doses of 80 µg CST-103 for 7 days 
in healthy male subjects aged 40 to 55 years. This study (Cohort 4) is currently evaluating 
single oral doses of 80 µg CST-103 administered a week apart in patients with MCI or 
PD. 
• Study CST101/CST103/CST109-CLIN-003 (CLIN-003) evaluated a single oral dose of 
160 µg CST-103 and once-daily oral doses of 80 µg CST-103 administered for five days 
after 2 days of dose titration in healthy male and female subjects and in patients with PD.  


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The daily 80 µg CST-103 dose is below the recommended maximum daily dose in Germany 
(100 µg) for the treatment of reactive airways diseases. Preliminary data from a cohort of healthy 
subjects (n=16) and patients with Parkinson’s disease (n=8) who were administered 80 µg 
CST-103 daily for 5 days after a two day dose titration in CLIN‑003 demonstrate that CST-103 
was in general well tolerated. There were no serious AEs, and all adverse events were rated as 
mild with the exception of two cases of musculoskeletal pain which were labeled as moderate. 
No clinically significant lab values were reported.  
A cohort of healthy subjects (n=4) in CLIN-002 were administered once-daily oral doses of 
80 µg CST-103 for 7 days without dose titration and this regimen was tolerated. There were no 
SAEs, no stopping criteria were met, and no rescue medications were used. All adverse events 
were rated as mild with the exception of a case of increased CK labeled as moderate. There were 
no clinically significant changes in vital signs, physical examinations, or ECGs. Hypokalemia 
(3.17 mg/dl) was observed in one subject but was transient.  
Data from Cohort 2 in CLIN-002, in which subjects received a single oral dose of 160 µg 
CST-103, demonstrated that CST-103 at this higher dose was generally well tolerated in the 
healthy subjects. Mild hypokalemia and hyperglycemia were observed with spontaneous 
recovery within the next few hours. One subject experienced mild sinus tachycardia and 
palpitations after dosing with CST-103. A favorable safety and tolerability profile of the planned 
CST-103 dose is also supported by published clinical studies, including a 52-week, double-blind, 
randomized, placebo-controlled study of CST-103 80 µg twice daily (Koeberl 2018).  
The neuroimaging data from CLIN-002 using ASL MRI demonstrated that doses of CST-103 
below 30 µg do not produce significant increases in cerebral perfusion and a dose of 40 µg 
produces a minimal increase while doses of 80 and 160 µg produce a robust global increase in 
cerebral perfusion, with a particularly robust increase of up to 15% in the thalamus and up to 
28% in the hippocampus, which are both areas of the brain relevant to neurodegenerative 
diseases (Figure 1, Bartsch 2015, Leh 2016).  


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Figure 1: 
CST-103 Produces a Dose-Dependent Increase in Cerebral Perfusion 
(measured as cerebral blood flow [CBF]) in the Thalamus and Hippocampus 
as Measured by ASL-MRI 
 
In Cohort 5 of CuraSen study CLIN-002, “estimated doses” of CST-103 were based on dose equivalents 
calculated from PK modeling of exposures at 24 hours (estimated dose of 50 µg) and 48 hours 
(estimated dose of 30 µg) after a single dose of 80 µg CST-103 administered to subjects on Day 1. On 
days when CST-103 was dosed ASL was conducted 3 hours post dosing. 
Our hypothesis is that by improving cerebral perfusion, particularly in areas of the brain that are 
relevant for symptoms that are commonly found in PD and MCI, the administration of a β-AR 
agonist will have a positive effect on clinically relevant symptoms such as memory and 
cognition. In particular for cognition, preliminary data from study CLIN-003 suggest that a daily 
dose of 80 µg of CST-103 improves cognitive performance in healthy subjects.  
Preliminary data show that once-weekly dosing of 80 µg CST-103 for 2 weeks resulted in 
increases of cerebral perfusion in three subjects with PD on Days 1 and 7.  Furthermore, 
persistent increases in cerebral perfusion were noted in healthy volunteers at 24 and 48 hours 
after administration of 80 µg CST-103 (CLIN-002, Cohort 5). Since a single dose of 80 µg of 
CST-103 produces a robust increase in cerebral perfusion which lasts a few days after dosing 
(Figure 1), the expectation is that the positive cognitive effects seen after administration of a 
single dose of either 80 or 160 µg CST-103 may also be demonstrated with the 80 µg dose of 
CST-103 administered daily. In summary, a dose of 80 µg of CST-103 administered daily has 
been shown to be safe and well tolerated from previous data from the literature and in the 
CuraSen clinical studies CLIN-002 and CLIN-003.  


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1.5. 
Rationale for CST-107 Dose Selection 
CST-107 is included in this study to attenuate the peripheral effects commonly caused by β2-AR 
agonists which include increased heart rate, palpitations, tremors, decreases in potassium and 
increases in blood glucose. Previous CuraSen studies exploring low doses of CST-107 co-
administered with 80 µg of CST-103 suggest that a 1 mg dose can attenuate these peripheral 
effects. This is in marked contrast to the usual initial dose for hypertension which is 40 mg CST-
107 tablets once daily. The usual maintenance dose is 40 or 80 mg administered once daily and 
doses up to 240 or 320 mg administered once daily may be needed. 
In the treatment of reactive airways disease, the use of a β-AR blocker is not normally 
recommended along with CST-103 in that the therapeutic effect of the agonist can be 
antagonized and would risk triggering a severe bronchospasm in patients with asthma. Since this 
study does not include patients with reactive airways disease and CST-103 is not being used for 
its bronchodilatory properties, this contraindication is not applicable to this study. 
 
1.6. 
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 identify a CNS signal in one of the planned 
pharmacodynamic measurements after multiple oral doses of CST-103 in the presence of CST-
107 in four populations of subjects with Neurodegenerative Disorders (NDD): 
 
Cohort A 
1. Parkinson’s Disease (PD) with REM Sleep Behavior Disorder (RBD) and Depressive 
Symptoms 
2. Mild Cognitive Impairment (MCI) with Depressive Symptoms 
Cohort B 
3. Dementia with Lewy Bodies (DLB) with Cognitive Fluctuations  
4. Parkinson’s Disease Dementia (PDD) with Cognitive Fluctuations  
These pharmacodynamic assessments will compare the effect of CST-103 co-administered with 
CST-107 with that of placebo on the following:  
 
Cohort A 
• Emotional Facial Processing  
 


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Cohort B 
• Cognitive fluctuations 
The secondary objectives for all subjects include the comparison of the effect of CST-103 co-
administered with CST-107 with that of placebo on the following: 
1. Cognition 
2. Movement and time spent sitting, standing and sleeping 
3. Sleep  
4. Pupillary reactivity  
5. Mood Assessment 
6. Safety and tolerability of CST-103 co-administered with CST-107  
7. The pharmacokinetic (PK) profiles of CST-103 and CST-107 
 
The exploratory objectives are to characterize the effect of CST-103 co-administered with CST-
107 on the following: 
1. To characterize the effect of CST-103 co-administered with CST-107 on inflammatory 
biomarkers in blood, such as C-reactive protein and cytokine levels may be measured.  
2. To characterize the effect of CST-103 co-administered with CST-107 on 
neurodegenerative biomarkers in the blood such as neurofilament light chain, total and 
phosphorylated tau protein, and amyloid‐β (Aβ) peptides may also be evaluated.  
3. To characterize the effect of CST-103 co-administered with CST-107 on performance of 
a sustained attention task in Cohort B subjects. 
4. To characterize the effect of CST-103 co-administered with CST-107 on Freezing of 
Gait (FOG) (for subjects with RBD+PD, PDD and DLB). 
5. To characterize the locus coeruleus volume and contrast ratio (this is an optional 
objective based on imaging capabilities). 
 
2.2. 
Primary Endpoints 
The primary endpoints include: 
Cohort A 
Comparison of the effects of CST-103 co-administered with CST-107 vs placebo on change in 
Negative Emotional Bias in the Facial Expression Recognition Task. 
Cohort B 
Comparison of the effects of CST-103 co-administered with CST-107 vs placebo on Cognitive 
Fluctuations as measured by: 
1. Spectral analysis of waking EEG  
2. Activity Tracking 
3. Pupillometry 
4. Dementia Cognitive Fluctuation Scale (DCFS) 


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2.3. 
Secondary Endpoints 
The secondary endpoints will compare the effect of CST-103 co-administered CST-107 with that 
of placebo on the following:  
1. Verbal fluency test (alphabet & category) CANTAB cognitive assessments, which 
include the following:  
• Reaction Time (RTI) 
• Rapid Visual Information Processing (RVP) 
• Verbal Recognition Memory (VRM) Phase I 
• Adaptive Tracking Task (ATT) 
• Paired Associates Learning Task (PAL) 
• Stop Signal Task (SST) 
• Delayed Verbal Recall 
2. Digital wearable device (BioStamp) data, which includes four key measures of 
interest: 
a. Activity and posture classifications, durations, and temporal patterns  
b. Sleep (duration, posture transitions, and activity counts) 
c. Autonomic function – heart rate variability (HRV) 
d. Temporal pedometry (daily step count, and gait cadence)  
3. Assessment of sleep using digital device and Epworth Sleepiness Scale (ESS) 
4. Change in pupillary diameter as measured using the pupillary light reflex test 
5. Geriatric Depression Scale (GDS), Hospital Anxiety and Depression Scale (HADS) 
6. Adverse events (AE), electrocardiograms (ECGs), vital signs, laboratory safety tests 
(hematology, chemistry and urinalysis). 
7. Plasma PK parameters of CST-103 and CST-107 (including Cmax, tmax, AUCt, AUCinf, 
t1/2)  
2.4. 
Exploratory Endpoints 
Exploratory endpoints may include:  
1. Changes in inflammatory biomarkers, such as C-reactive protein and cytokine levels, 
as measured prior to and after CST-103 co-administered with CST-107. 
2. 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 CST-103 co-administered with CST-107.  
3. Performance on the SART as measured prior to and after CST-103 co-administered 
with CST-107. 
4. Assessment of FOG using the FOG-Q (for subjects with RBD+PD, PDD and DLB). 


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5. The characterization of the brain imaging signal in the locus coeruleus complex using 
neuromelanin-sensitive MRI sequence. This is an optional endpoint based on imaging 
capabilities. 
3. 
STUDY DESIGN  
3.1. 
Clinical Trial Design 
This is a Phase II, randomized, placebo-controlled, double-blind, crossover study on the CNS 
and pharmacodynamics effects of CST-103 co-administered with CST-107 in 4 subject 
populations with Neurodegenerative Disorders.  
Approximately 40 subjects (approximately 20 subjects in Cohort A with RBD+PD or MCI and 
approximately 20 subjects in Cohort B with PDD or DLB) will be enrolled in a 2 period, 2-way 
cross over design following study eligibility confirmation during the screening period.  The 
number of subjects enrolled in each cohort may change as emerging data are reviewed from this 
and other studies.   
During each treatment period, subjects will receive daily doses of CST-103 co-administered with 
CST-107 or matching placebo for 14 days. Each treatment period will be separated by a washout 
period of 14 days (+5-day window).    
All subjects will complete clinical and pharmacodynamic assessments during each treatment 
period and at the Follow-Up Visit 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. 
Pharmacodynamic blood samples will be collected as indicated in the Schedule of Events to 
investigate the effects of CST-103 co-administered with CST-107 on inflammatory biomarkers.  
3.2. 
Safety Review Meetings  
Safety Review Meetings (SRMs) will be held to review blinded safety data (such as AEs, vital 
signs, ECGs, and safety labs), and PK (if available) when 25%, 50%, and 75%, of the subjects 
are completed. Data to be reviewed may not necessarily be validated and cleaned (data query 
resolution may be pending). Data will be reviewed blinded (treatment assignment will not be 
revealed) unless unblinding is deemed necessary for the SRM committee. 
The SRM members will include the regional Lead Investigator(s) or representative, CuraSen 
Chief Medical Officer, CuraSen Medical Monitor(s), and Clinical Research Study Manager. 
Additional members may be added as needed (e.g., statistician, PK scientist). The SRM 
committee will monitor subject safety and recommend whether to continue with dosing, to 
modify the protocol, to perform additional safety assessments and/or reviews, to delay or 
terminate subject enrollment, or to decrease and/or increase sample size based on emerging 


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safety data from this study or emerging safety, PK, and pharmacodynamics data from other 
ongoing and completed CuraSen studies.   
3.3. 
Criteria for Termination of Study Medication 
Dosing of the study medication will be terminated for any subject for whom the following 
circumstances apply: 
• 
Any subject experiences a serious adverse event (SAE) that is assessed to be related to 
study medication 
• 
Medical or ethical reasons affecting continuation of 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). 
A subject may be terminated at any point in time at the discretion of CuraSen Medical Monitor 
or PI.  
3.4. 
Criteria for Suspension of Trial 
The study will be stopped if either of the following occurs.  
• One or more serious adverse events (SAEs) considered to be related to study medication; 
or 
• Two or more severe or clinically significant adverse events (AEs) considered to be 
related to study medication  
If following an internal safety review, it is appropriate to restart the study, a substantial 
amendment will be submitted to the appropriate regulatory authorities and Ethics Committee 
(EC). The trial will not restart in each region until the amendment has been approved by the 
regional regulatory authorities and ECs. 
4. 
SELECTION AND WITHDRAWAL OF SUBJECTS  
4.1. 
Study Participation 
Approximately 40 subjects will be enrolled in this study. Approximately 20 subjects with 
RBD+PD or MCI will be enrolled in Cohort A. Cohort B of this study will include 
approximately 20 subjects with DLB or PDD.  The number of subjects enrolled in each cohort 
may change as emerging data are reviewed from this and other studies.   
All subjects must participate in the informed consent process and sign and date the informed 
consent before any study-related procedures are performed. Waivers for deviations from the 
eligibility criteria will not be granted. 
 
 


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4.2. 
Inclusion Criteria 
A subject will be considered eligible for enrollment if all of the following criteria are met: 
Cohort A 
Subjects with RBD+PD: 
1. Male or female subjects ≥ 40 and ≤ 80 years of age, at time of informed consent. 
2. Subject diagnosed with Parkinson’s Disease, as defined by the United Kingdom Parkinson 
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 REM Sleep Behavior Disorder Single-Question Screen (RBD1Q). 
3. Subject who is Modified Hoehn & Yahr ≥ stage 1 and ≤ stage 3 during “On” period as 
documented in the 3 months prior to Screening or completed at Screening.  
4. Montreal Cognitive Assessment (MoCA) score ≥ 18 and ≤ 28. 
Subjects with MCI: 
6. Male or female subjects ≥ 50 and ≤ 80 years of age, at time of informed consent.  
7. Subjects who meet the criteria for amnestic Mild Cognitive Impairment (MCI) as per the 
National Institute on Aging-Alzheimer's Association core clinical criteria. 
8. Montreal Cognitive Assessment (MoCA) score ≥ 18 and ≤ 26. 
9. No dementia according to the International Classifications of Diseases (ICD)-10 and 
Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV. 
10. A memory complaint reported by the subject or his/her partner, family member or 
caregiver. 
11. A score of greater than or equal to one standard deviation below age and educational norms 
in the Digit Symbol Substitution Test (DSST) during Screening. 
12. Cognitive decline not primarily caused by vascular, traumatic, or medical problems 
(alternative causes of cognitive decline are ruled out). 
 
Cohort B 
Subjects with Dementia with Lewy Bodies (DLB) or Parkinson's Disease Dementia (PDD): 
14. Male or female subjects ≥ 50 and ≤ 80 years of age, at time of informed consent. 
15. A diagnosis of dementia associated with Dementia with Lewy Bodies (McKeith 2017) or 
Parkinson’s disease (PDD) (Emre 2007). 
16. Documented cognitive fluctuations endorsed on the Dementia Cognitive Fluctuation Scale 
(DCFS) with a combined score of  ≥8 in items 4, 11, 12 and 14 must be present.  
17. Montreal Cognitive Assessment (MoCA) score ≥ 18 and ≤ 26. 
18. Subject having informant or caregiver throughout the study who will submit written 
consent to cooperate with this study, who routinely accompanies and/or stays with subject 
12 hours or more a week, assists with treatment compliance, provides assessments and is 
able to escort the subject on required visits to study institution. 
19. Subject who is Modified Hoehn & Yahr ≥ stage 1 and ≤ stage 3 during “On” period as 
documented in the 3 months prior to Screening or completed at Screening. 
20. Stable concomitant medical and/or psychiatric illnesses in the judgement of the PI.  


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For ALL Subjects: 
21. Unless confirmed to be azoospermic (vasectomized or secondary to medical cause), males 
must agree to use a male condom from Day 1 throughout the study 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 Follow-Up Visit. 
22. 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 reliable 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). 
23. Females of non-childbearing potential may be enrolled if it is documented that they are 
postmenopausal (refer to section 5.6).  
24. Body weight greater or equal to 50 kg and body mass index (BMI) between 18 and 35 
kg/m2, inclusive at Screening. 
25. Stable medical conditions for 3 months prior to Screening visit (e.g., controlled 
hypertension, dyslipidemia). 
26. Willing to follow the protocol requirements and comply with protocol restrictions. 
27. Capable of providing informed consent and complying with study procedures 
(completion of self-assessment rating scales and use of wearable devices). Subjects who 
are unable to provide consent may use a Legally Authorized Representative.  
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 if requiring the use of a β2-
Adrenergic bronchodilator, 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 or history in past two years of epilepsy, focal brain lesion, head injury 
with loss of consciousness or meeting DSM-IV diagnostic criteria for psychotic 
disorders, such as Schizophrenia or Bipolar Disorder, or have unstable concomitant 
psychiatric symptomatology that is not believed by the Investigator to be associated with 
PDD or DLB.   


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5. Evidence of any significant clinical disorder or laboratory finding (or in the case of 
potassium levels below normal range) that renders the participant unsuitable for 
receiving an investigational drug including clinically significant or unstable hematologic, 
hepatic, cardiovascular, pulmonary, gastrointestinal, endocrine (excluding managed hypo 
and hyperthyroidism), metabolic, renal or other systemic disease or laboratory 
abnormality. 
6. Participants with a history of malignant disease, including solid tumors and hematologic 
malignancies (except basal cell and squamous cell carcinomas of the skin that have been 
completely excised and are considered cured) within 5 years prior to Screening. 
7. Any clinically significant illness or disease (apart from those typically associated with 
NDD) as determined by medical and surgical history, physical examination, 12-lead 
electrocardiogram (ECG) and clinical laboratory assessments conducted at Screening.   
8. Clinically significant abnormalities of ECG, including QTcF > 450 ms, for males and 
QTcF > 470 ms for females, and/or HR < 50 beats per minute, or evidence of clinically 
significant bundle branch blocks, as indicated by 12-lead ECG in a supine position at 
Screening or during the Lead-In 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/products (refer to section 5.4), during Screening or throughout study, 
unless approved by both the Investigator and the Sponsor Medical Monitor.  
 
11. Known hypersensitivity to Spiropent (clenbuterol), Corgard (nadolol) or intolerance to 
lactose. Subjects with hereditary galactose intolerance (e.g., galactosemia, lactase 
deficiency or glucose galactose malabsorption) should be excluded. 
12. Prior 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. 
13. Prior treatment with any β-AR agonists or β-AR blockers (includes oral medications, IV 
or inhaled) or any medications that impact adrenergic signaling within the last month 
prior to Screening. 
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 acutal 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 hepatitis C antibody (HCV Ab) or current hepatitis B infection 
(defined as positive for hepatitis 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. Positive screening test for human immunodeficiency virus (HIV). 
18. Current infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). 


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19. Contraindications to wearing the BioStamp digital device sensors, which include but are 
not limited to implanted pacemakers, defibrillators, or other active implantable devices, 
and known allergies. 
20. Known hypersensitivities to adhesives or hydrogel. 
21. Females who are breastfeeding. 
22. Any other reason for which the PI considers it is not in the best interest of the participant 
to undertake the study.  
23. Inability to undergo a clinical MRI of the brain due to claustrophobia, inability to lie 
supine for a prolonged time period, or other contraindications to undergoing an MRI of 
the brain including, but not limited to, pacemakers; implantable cardioverter 
defibrillators; cochlear implants; cerebral aneurysm clips; implanted infusion pumps; 
implanted nerve stimulators; metallic splinters in the eye; and, other magnetic, electronic 
or mechanical implants or clinical findings that in the judgment of the investigator would 
pose a potential hazard in combination with MRI. (NOTE: this is a procedural exclusion, 
not a study exclusion.) 
 
4.4. 
Enrollment Procedures and Randomization  
4.4.1. 
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 -8.  
If a subject falls outside the Screening Period window, screening may be extended with prior 
approval by the CuraSen Medical Monitor. If extended beyond 21 days, some of the screening 
procedures and assessments may need to be repeated. 
4.4.2. 
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). The screening process for such 
subjects must be discussed with the CuraSen Medical Monitor.   
4.4.3. 
Randomization and Lead-In 
Once all Screening tests and procedures are completed and all eligibility criteria are met, subjects 
will return to the clinic for randomization and begin the Lead-In Period. The IWRS will provide 
the randomization number. The Lead-In tests and procedures listed in the Schedule of Events 
will be completed within 14 days prior to Day 1 of Treatment Period 1. If subjects fall outside 
the Lead-In Period window, the Lead-In Period may be extended with prior approval by the 
CuraSen Medical Monitor. 


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4.5. 
Subject Withdrawal 
At the time of early withdrawal, the subject should complete the Day 14/Early Withdrawal (EW) 
visit and return in 2 weeks for the Follow-Up 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.  
4.5.1. 
Criteria for Withdrawal from Clinical Trial 
Reasons for subject withdrawal include, but are not limited, to the following: 
• Withdrawal of consent 
• 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. 
4.5.2. 
Follow-Up for Early Treatment 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 Follow-Up visits.  
 
 


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5. 
SCHEDULE OF EVENTS AND STUDY PROCEDURES  
Assessments and procedures at each visit are summarized in the Schedule of Events.  Certain 
visits (Days 7, 14, and/or Follow-up) may be conducted virtually, at another off-site location, or 
at the subject’s home according to site and subject preference and capabilities.  
5.1. 
Visit Assessments 
5.1.1. 
Cohort A – RBD+PD or MCI Subjects 
 
Screening (Day -28 to Day -8) 
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 
• Demographics (sex, age, race, ethnicity, years of education) 
• Medical history including concomitant medications 
• Height, body weight, BMI calculation 
• Clinical and cognitive scales/assessments: 
o All subjects: 
• HADS 
• MoCA 
o MCI subjects: 
• DSST 
o RBD+PD subjects 
• RBD1Q 
• MHYS 
• Vital signs (blood pressure [BP], heart rate [HR], respiration rate and oral/tympanic 
temperature); BP and HR measurements obtained 3 times (separated by approximately 1 
minute) after the subject is supine for 5 minutes 
• 12-lead ECG, obtained after subject has rested in supine position for at least 5 minutes 
• C-SSRS 
• Complete physical examination, excluding genital, rectal and breast exams  
• SARS-CoV-2 status assessment, per local site standard procedure 
• Laboratory tests – subjects should be fasting for 8 hours prior to the safety labs 
o Hematology, chemistry (includes calculated creatinine clearance), and urinalysis 
o Urine drug screen 
o Alcohol test 
o TSH   
o Serology for HIV, hepatitis B and C 
o Serum β-hCG test for females of childbearing potential 
o FSH test for postmenopausal women 


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• Neuromelanin scan (optional depending on imaging capabilities).  If not performed at 
Screening, it may be performed at the Follow-up visit or at any other convenient time 
during the study. 
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 
Lead-In Period assessments.  
 
Lead-in Period (Day -14 to Day -1) 
The following procedures will be performed, and assessments/measurements recorded: 
• Review of inclusion/exclusion criteria 
• SARS-CoV-2 status assessment, per local site standard procedure 
• Randomization 
• ECG 
• Verbal fluency test (alphabet & category) and CANTAB familiarization  
• ESS 
• BioStamp digital device dispensed – to be worn for 7 days prior to Treatment Period 1 
Day 1 Visit 
• Assessment of AEs 
• Assessment of concomitant medications 
 
Day 1, 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 
• Obtain bottle numbers (for CST-103 and CST-107) from the IWRS and dispense study 
medication 
• Vital signs (BP, HR, respiration rate, and oral/tympanic temperature); BP and HR 
measurements obtained 3 times (separated by approximately 1 minute) after the subject is 
supine for 5 minutes: 
1. Prior to dosing (within 15 minutes)  
2. 1 hour (±30 minutes) after dosing  
• 12-lead ECG, obtained after subject has rested in supine position for at least 5 minutes: 
1. Prior to dosing (within 15 minutes)  
2. 1 hour (±30 minutes) after dosing  
3. 4 hours (±30 minutes) after dosing 
• C-SSRS (not required during Treatment Period 1) 
• Laboratory tests – subjects should be fasting for 8 hours prior to the safety labs 
o Hematology, chemistry, and urinalysis 


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o Serum or urine pregnancy test (per standard site practice) for females of 
childbearing potential; positive urine pregnancy result to be confirmed by serum 
test 
• Alcohol test 
• Blood sample collection for pharmacodynamic biomarkers 
• Blood sample for APOE4 genetic test (Treatment Period 1 only; for ongoing subjects 
who have completed visits beyond Treatment Period 1, Day 1, the test may be done at 
any time during the study) 
• PK samples:  
1. Prior to dosing 
2. 4 hours (±10 minutes) post dose 
• Pharmacodynamic sample collection prior to dosing 
• FERT, administered prior to dosing 
• CANTAB tests and verbal fluency test (alphabet & catgory): 
1. Prior to dosing 
2. 4 hours (±30 minutes) post dose 
• Pupillary light reflex (PLR) tests (twice for each eye): 
1. Prior to dosing 
2. After the post dose CANTAB 
• HADS 
• GDS 
• ESS 
• FOG-Q (RBD+PD subjects only) 
• BioStamp dispensed – to be worn daily throughout each Treatment Period and removed 
on Day 14 
• Administer study medication  
• Provision of subject dosing diary  
• Assessment of AEs 
• Schedule Day 7 Visit 
 
Day 7 (±1), Treatment Periods 1 and 2 
The following procedures will be performed, and assessments/measurements recorded: 
• Assessment of concomitant medications 
• Assessment of AEs 
• Administer study medication and conduct a dosing compliance check 
• Vital signs (BP, HR, respiration rate, and oral/tympanic temperature); BP and HR 
measurements obtained 3 times (separated by approximately 1 minute) after the subject is 
supine for 5 minutes: 
o 1 hour (±30 minutes) after dosing  
• C-SSRS 
• FERT, administered after dosing 
• CANTAB and verbal fluency test alphabet & category): 
o Up to 4 hours post dose 


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• PLR test (twice for each eye), after the post dose CANTAB 
• GDS 
• ESS 
 
Day 14 (±1), Treatment Periods 1 and 2 / Early Withdrawal (EW) 
The following procedures will be performed, and assessments/measurements recorded: 
• Assessment of concomitant medications 
• Assessment of AEs  
• Collection of subject dosing diary 
• Administer study medication and collect bottles for accountability 
• Vital signs (BP, HR, respiration rate, and oral/tympanic temperature); BP and HR 
measurements obtained 3 times (separated by approximately 1 minute) after the subject is 
supine for 5 minutes: 
o 1 hour (±30 minutes) after dosing  
• 12-lead ECG, obtained after subject has rested in supine position for at least 5 minutes: 
o 1 hour (±30 minutes) after dosing 
o 4 hours (±30 minutes) after dosing 
• C-SSRS 
• Laboratory tests – subjects should be fasting for 8 hours prior to the safety labs 
o Hematology, chemistry, and urinalysis 
o Serum or urine pregnancy test (per standard site practice) for females of 
childbearing potential; positive urine pregnancy result to be confirmed by serum 
test  
• PK samples: 
o Prior to dosing 
o 4 hours (±10 minutes) post dose 
• Pharmacodynamic sample collection 4 hours (±10 minutes) post dose 
• BioStamp collected 
• FERT, administered after dosing 
• CANTAB and verbal fluency (alphabet & category)  
o Up to 4 hours post dose 
• PLR test (twice for each eye), after the post dose CANTAB  
• HADS 
• GDS  
• ESS  
• FOG-Q (RBD+PD subjects only) 
• Schedule Follow-Up Visit 
 
Follow-Up – 14 (±3) 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); BP and HR 
measurements obtained 3 times (separated by approximately 1 minute) after the subject is 
supine for 5 minutes 


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• 12-lead ECG, obtained after subject has rested in supine position for at least 5 minutes  
• Symptom-driven physical examination 
• C-SSRS 
• Laboratory tests – subjects should be fasting for 8 hours prior to the safety labs 
o Hematology, chemistry, and urinalysis 
o Serum or urine pregnancy test (per standard site practice) for females of 
childbearing potential; positive urine pregnancy result to be confirmed by serum 
test 
• Assessment of concomitant medications 
• Assessment of AEs  
• Register visit in IWRS 
• Neuromelanin scan (optional depending on imaging capabilities) if not performed at 
Screening or any other time during the study. 
 
The Follow-Up Visit should be conducted in the clinic. However, should there be factors and/or 
conditions which would make the Follow-Up 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. 
5.1.2. 
Cohort B – DLB or PDD Subjects 
 
Screening (Day -28 to Day -8) 
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 
• Demographics (sex, age, race, ethnicity, years of education) 
• Medical history including concomitant medications 
• Height, body weight, BMI calculation 
• MoCA 
• MHYS 
• DCFS 
• Vital signs (blood pressure [BP], heart rate [HR], respiration rate and oral/tympanic 
temperature); BP and HR measurements obtained 3 times (separated by approximately 1 
minute) after the subject is supine for 5 minutes 
• 12-lead ECG, obtained after subject has rested in supine position for at least 5 minutes 
• C-SSRS 
• Complete physical examination, excluding genital, rectal and breast exams 
• SARS-CoV-2 status assessment, per local site standard procedure 
• Laboratory tests – subjects should be fasting for 8 hours prior to the safety labs 
o Hematology, chemistry (includes calculated creatinine clearance), and urinalysis 
o Urine drug screen 
o Alcohol test 
o TSH  


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o Serology for HIV, hepatitis B and C 
o Serum β-hCG test for females of childbearing potential 
o FSH test for postmenopausal women 
• Neuromelanin scan (optional depending on imaging capabilities).  If not performed at 
Screening, it may be performed at the Follow-up visit or at any other convenient time 
during the study. 
Subjects with a positive drug or alcohol test at Screening will be rechecked once and if positive, 
the subject will be excluded from participation in the study. The drug and/or alcohol tests may be 
repeated per Investigator clinical judgement. 
Subjects who are eligible for study participation will be scheduled to return to the clinic for 
Lead-In Period assessments.  
 
Lead-in Period (Day -14 to Day -1) 
The following procedures will be performed, and assessments/measurements recorded: 
• Review of inclusion/exclusion criteria  
• SARS-CoV-2 status assessment, per local site standard procedure 
• Randomization 
• ECG 
• Verbal fluency test (alphabet & category) and CANTAB familiarization 
• ESS 
• BioStamp digital device dispensed – to be worn for 7 days prior to Treatment Period 1 
Day 1 Visit 
• Assessment of AEs 
• Assessment of concomitant medications 
 
Day 1, 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 
• Obtain bottle numbers (for CST-103 and CST-107) from the IWRS and dispense study 
medication 
• Vital signs (BP, HR, respiration rate, and oral/tympanic temperature); BP and HR 
measurements obtained 3 times (separated by approximately 1 minute) after the subject is 
supine for 5 minutes: 
1. Prior to dosing (within 15 minutes)  
2. 1 hour (±30 minutes) after dosing  
• 12-lead ECG, obtained after subject has rested in supine position for at least 5 minutes: 
1. Prior to dosing (within 15 minutes)  
2. 1 hour (±30 minutes) after dosing 
3. 4 hours (±30 minutes) after dosing  
• C-SSRS (not required during Treatment Period 1) 
• Laboratory tests – subjects should be fasting for 8 hours prior to the safety labs 


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o Hematology, chemistry, and urinalysis 
o Serum or urine pregnancy test (per standard site practice) for females of 
childbearing potential; positive urine pregnancy result to be confirmed by serum 
test 
• Alcohol test 
• Blood sample collection for pharmacodynamic biomarkers 
• Blood sample for APOE4 genetic test (Treatment Period 1 only; for ongoing subjects who 
have completed visits beyond Treatment Period 1, Day 1, the test may be done at any time 
during the study) 
• PK samples:  
1. Prior to dosing 
2. 4 hours (±10 minutes) post dose 
• Pharmacodynamic sample collection prior to dosing 
• EEG (SART to be completed during EEG session at select sites): 
1.  Prior to dosing 
2. 3 hours (±15 minutes) after dosing 
• CANTAB tests and verbal fluency test (alphabet & category): 
1. Prior to dosing 
2. 4 hours (±30 minutes) post dose 
• PLR tests (twice for each eye): 
1. Prior to dosing 
2. After the post dose CANTAB  
• DCFS  
• GDS  
• ESS  
• FOG-Q  
• BioStamp dispensed – to be worn daily throughout each Treatment Period and removed on 
Day 14 
• Administer study medication  
• Provision of subject dosing diary 
• Assessment of AEs 
• Schedule Day 7 Visit 
 
Day 7 (±1), Treatment Periods 1 and 2 
The following procedures will be performed, and assessments/measurements recorded: 
• Assessment of concomitant medications 
• Assessment of AEs 
• Administer study medication and conduct a dosing compliance check 
• Vital signs (BP, HR, respiration rate, and oral/tympanic temperature); BP and HR 
measurements obtained 3 times (separated by approximately 1 minute) after the subject is 
supine for 5 minutes: 
o 1 hour (±30 minutes) after dosing  
• C-SSRS 
• CANTAB and verbal fluency test (alphabet & category): 


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o Up to 4 hours after dosing 
• PLR test (twice for each eye), after the post dose CANTAB 
• GDS 
• ESS 
 
Day 14 (±1), Treatment Periods 1 and 2 / Early Withdrawal (EW) 
The following procedures will be performed, and assessments/measurements recorded: 
• Assessment of concomitant medications 
• Assessment of AEs  
• Collection of subject dosing diary 
• Administer study medication and collect bottles for accountability 
• Vital signs (BP, HR, respiration rate, and oral/tympanic temperature); BP and HR 
measurements obtained 3 times (separated by approximately 1 minute) after the subject is 
supine for 5 minutes: 
o 1 hour (±30) minutes dosing  
• 12-lead ECG, obtained after subject has rested in supine position for at least 5 minutes: 
o 1 hour (±30 minutes) after dosing 
o 4 hours (±30 minutes) after dosing 
• C-SSRS 
• Laboratory tests – subjects should be fasting for 8 hours prior to the safety labs 
o Hematology, chemistry, and urinalysis 
o Serum or urine pregnancy test (per standard site practice) for females of childbearing 
potential; positive urine pregnancy result to be confirmed by serum test 
• PK samples: 
o Prior to dosing 
o 4 hours (±10 minutes) post dose 
• Pharmacodynamic sample collection at 4 hours (±10 minutes) post dose 
• BioStamp collected 
• EEG (SART to be completed during EEG session at select sites) 
• CANTAB and verbal fluency test (alphabet & category) 
o Up to 4 hours after dosing 
• PLR test (twice for each eye), after the post dose CANTAB 
• DCFS 
• GDS 
• ESS 
• FOG-Q 
• Schedule Follow-Up Visit 
 
Follow-Up – 14 (±3) 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); BP and HR 
measurements obtained 3 times (separated by approximately 1 minute) after the subject is 
supine for 5 minutes 


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• 12-lead ECG, obtained after subject has rested in supine position for at least 5 minutes  
• Symptom-driven physical examination 
• C-SSRS 
• Laboratory tests – subjects should be fasting for 8 hours prior to the safety labs 
o Hematology, chemistry, and urinalysis 
o Serum or urine pregnancy test (per standard site practice) for females of 
childbearing potential; positive urine pregnancy result to be confirmed by serum 
test 
• Assessment of concomitant medications 
• Assessment of AEs  
• Register visit in IWRS 
• Neuromelanin scan (optional depending on imaging capabilities) if not performed at 
Screening or any other time during the study. 
 
The Follow-Up Visit should be conducted in the clinic. However, should there be factors and/or 
conditions which would make the Follow-Up 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. 
Assessment of vital signs will include BP, HR, respiration rate, and oral/tympanic temperature. 
All routine measures of BP and HR should be made in triplicate (separated by 1 minute) while 
the subject rests in supine position. 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, 


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abdomen, skin, nails, hair, musculoskeletal, and neurological. A symptom-driven physical exam 
based on subject complaints will be conducted at the Follow-Up Visit. 
5.3.2. 
12-Lead ECG 
A 12-lead ECG will be collected 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. ECGs 
will be reviewed by the Investigator or qualified study staff. 
5.3.3. 
Clinical Laboratory Analysis 
The following clinical safety laboratory assessments will be performed at timepoints detailed in 
the Schedule of Events: 
Safety Labs: 
• 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, 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 done at 
Screening only. 
Serologies for HIV, hepatitis B, and hepatitis C: HIV Ab, HbsAg, HbsAb, and HCV Ab 
(Screening only).  If these results are positive, the PI must refer the subject for counselling and 
treatment as per institution policy and procedures. 
SARS-CoV-2: According to current local COVID management procedures. 
Thyroid-stimulating hormone (TSH): To be done at Screening only. 
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. 
Urine Drug Screen: Tests for drugs of abuse.  
Alcohol test: Urine or breath test per site’s standard practice. 
APOE4: Genetic test to be done on Day 1 of Treatment Period 1 only. For ongoing subjects who 
have completed visits beyond Treatment Period 1, Day 1, the test may be done at any time 
during the study. 


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CST-103 and CST-107 PK samples: Blood samples will be collected for PK analysis on Day 1 
and Day 14 of each treatment period. 
Pharmacodynamic samples: Blood samples will be collected on Day 1 and Day 14 of each 
treatment period. 
Instruction on urine, 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, or for bioanalytical sample analysis if in accordance with the bioanalytical test site SOPs. 
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.  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.  
 
Digit Symbol Substitution Test (DSST) - MCI Subjects  
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). 
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 120-second time limit.  The maximum attainable score is 135, with higher scores 
indicating better performance. Test scores can be benchmarked against published normative data 


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by age group, and education level (2008 NCS Pearson, Inc., Gaertner 2018) as a means of 
evaluating test performance.   
 
Dementia Cognitive Fluctuation Scale (DCFS) – DLB and PDD Subjects 
The DCFS is a 17-item informant completed questionnaire that queries confusion (3 questions), 
differences in functioning through the day (1 question), sleep patterns and problems 
(6 questions), varying levels of alertness (4 questions) and clarity of thought/communication 
(3 questions). Five of the items proved discriminatory between Lewy body dementias, PD and 
AD (items 4, 10,11,12, and 14; range of function differences during the day; REM sleep 
disorder; daytime sleeping; daytime lethargy/drowsiness despite adequate sleep; level of 
consciousness throughout the day). The reduced scale comprised of the 5 items that are sensitive 
and specific to the reliable identification of cognitive fluctuations in Lewy body dementias 
(Lee 2014).  
 
Modified Hoehn and Yahr Scale (MHYS) – RBD+PD, DLB and PDD Subjects  
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. 
 
Hospital Anxiety and Depression Scale (HADS) – MCI and RBD+PD Subjects  
HADS is a 14-item questionnaire with subscales for anxiety and depression. It was originally 
developed to screen for depression and anxiety in a hospital setting but was later validated for 
use in a general population. The subjects are given 14 questions in multiple‐choice format, seven 
about depressive symptoms (HADS‐D) and seven about anxiety symptoms (HADS‐A) and are 
asked to give a score from 0 to 3 where 0 is the least depressed/anxiety option and 3 the most. A  
total score ≥ 12 suggests depression, whereas sub‐scores of ≥ 8 suggest anxiety or depression 
(Bjelland  2002; Kjaergaard 2014).    
 
REM Sleep Behavior Disorder Single-Question Screen (RBD1Q) - RBD+PD 
Subjects Only 
The RBD1Q is a single “yes-no” question that queries the classic dream-enactment behavior of 
RBD (Postuma 2012). 


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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.)?” 
 
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.   
 
Epworth Sleepiness Scale (ESS)  
The ESS is an 8-item, self-administered questionnaire in which subjects are asked to rate, on a 
4-point scale (0-3), their usual chances of dozing off or falling asleep while engaged in 
8 different activities. The total score is the sum of the 8 item scores, with scores ranging from 0 
(no daytime sleepiness) to 24 (high sleep propensity in daily life). 
 
Geriatric Depression Scale (GDS) 
The GDS is a 30-item self-administered yes/no question test constructed for brief screening of 
depression in elderly persons (Yesavage 1982-1983). Scores greater than 9 are considered 
suspect for depression. 
 
Sustained Attention to Response Task (SART) -- DLB and PDD Subjects at 
Select Sites Only 
The Sustained Attention to Response Task (SART) is a computer-based go/no-go task that 
requires participants to withhold behavioral response to a single, infrequent target (often the digit 
3) presented amongst a background of frequent non-targets. There is evidence supporting the role 
of the SART as a measure of working memory, sustained attention, and impulse/inhibitory 
control. In this task, the participant is asked to respond (e.g., button press) to the non-target and 
to inhibit their response to the target. To perform well, individuals must remain sufficiently 
attentive to their responses, such that, at the appearance of a target, they can override the 
dominant pre-potent motor response and substitute the directly antagonistic response (i.e., 
withhold button press) (Phillips 2020).  
 Freezing of Gait Questionnaire — RBD+PD, DLB and PDD Subjects Only 
Freezing of Gait (FOG) is one of the most frequent and disabling symptoms in Parkinson’s 
disease (PD) affecting about half of all patients, especially in the advanced stages of disease. The 
Freezing of Gait Questionnaire (FOG-Q) is considered a valid and reliable tool for the 
assessment of FOG severity. The FOG-Q consists of six items borrowed from the Gait and Falls 
Questionnaire (Giladi 2000). 
 Verbal Fluency Test 
Verbal fluency tests are widely used for assessing executive function and require the generation 
of words from initial letters (phonological verbal fluency) or belonging to a specific category 
(semantic fluency), under a time constraint.  


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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) (Harrison 2000). 
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.  
5.3.7. 
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 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 Rapid Visual Information Processing (RVP) task is a sensitive measure of sustained 
attention, outputting measures of response accuracy, target sensitivity and reaction times.  
For the RVP task single digits appear in a pseudo-random order at a rate of 100 digits per 
minute in box in the center of the screen. Subjects must detect a series of 3-digit target 
sequences (3-5-7; 2-4-6; 4-6-8) and respond by touching the button at the bottom of the 
screen when they see the final number of the sequence. Nine target sequences appear 
every minute. 
• 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). 


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5.3.8. 
Pupillary Light Reflex (PLR) Test 
The pupillometry measurements (PLR) will be completed in a room where ambient noise and 
lighting will be controlled and uniform. After resting for 5 min, and before and after receiving 
the study drug on Day 1 of Treatment Periods 1 and 2, the pupillometry measurements (repeated 
once) will be taken from each eye using a pupilometer with an opaque rubber cup covering one 
eye. Each pupillometry session measuring both eyes is about 1 minute. There is no need for a 
break between measurements. 
On Day 7 and Day 14 of Treatment Periods 1 and 2, additional PLR tests will be performed, as 
per Schedule of Events.  
Effects of treatment on pupillary light reflex include one or more of the following measures: 
pupil area, baseline pupil diameter (BPD), maximum constriction velocity (MCV), absolute 
constriction amplitude (ACA), maximum dilation velocity (MDV), time to reach 75 % of initial 
resting diameter during pupillary dilation (T¾), and dilation velocity at T¾ (DV¾). 
5.3.9. 
Neuromelanin MRI Scan  
Neuromelanin MRI will be measured to evaluate its suitability as a biomarker of noradrenergic 
regions in the brain such as the LC. The neuromelanin MRI scan will be performed once, and 
may be done at any time during the study. The procedure is optional since it is dependent upon 
on imaging center access and the capabilities of the MRI facility. 
Neuromelanin is a dark insoluble complex that is synthesized as an oxidative byproduct of 
dopamine and noradrenaline in regions of high catecholamine activity such as the substantia 
nigra and LC (Wakamatsu 2015). It sequesters potentially toxic organic chemical, exogenous and 
endogenous metals such as iron. When bound to metals such as iron and copper, neuromelanin is 
highly paramagnetic, leading to T1-shortening and hyperintense signal on T1-weighted turbo 
spin-echo MRI sequences. As a result, neuromelanin can be detected by non-invasive MRI 
methodology.   
The neuromelanin MRI will require the subject to lie in the MRI scanner for about 30 minutes. 
 
5.3.10. 
Electroencephalogram (EEG) – DLB and PDD Subjects 
EEG data will be collected in subjects at resting state with eyes open and eyes closed and during 
the administration of the SART (at selected site(s)) using a Stat X24 EEG system. Stat X24 
offers 20 channels of high-quality EEG.  Channels include sites: Fz, Fp1, Fp2, F3, F4, F7, F8, 
Cz, C3, C4, Pz, P3, P4, POz, T3, T4, T5, T6, O1, O2. Referencing is acquired through linked 
mastoids. Each EEG acquisition will be approximately 5 minutes in length for a total of 10 
minutes. For eyes open data collection, the subject will be instructed to focus on a cross on the 
screen while seated and relaxed. For eyes closed, the subject will be instructed to sit, relaxed 
with eyes closed but do not fall asleep. The absolute and relative power spectral densities (PSDs) 
will be calculated for each 1 second epoch (1-59 Hz bins), and also grouped into the standard 
EEG bandwidths: delta, theta, alpha, beta, and gamma. Additionally, the PSD variables will be 
averaged across brain regions of interest, including frontal, central, parietal, temporal, and 


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occipital. Previous data suggests EEG slowing was correlated with CFs, measured by the 
clinician assessment of fluctuations (CAF) scale (Stylianou 2018).  
5.3.11. 
Facial Expression Recognition Task (FERT) – MCI and RBD+PD Subjects 
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 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. 
5.3.12. 
BioStamp nPoint Data Collection 
The BioStamp nPoint device is a wireless remote monitoring system intended for use by 
researchers and healthcare professional for continuous collection of physiological, activity and 
sleep data in home and professional healthcare and home settings. These data include heart rate, 
heart rate variability, respiration rate, activity (including step count and activity classification), 
and posture (body position relative to gravity). Data are transmitted wirelessly from the Sensors 
for storage and analysis. Four key measures of interest will be evaluated: 
• Activity and posture classifications, durations, and temporal patterns  
• Sleep (duration, posture transitions, and activity counts) 
• Autonomic function – heart rate variability (HRV) 
• Temporal pedometry (daily step count, and gait cadence)  
Once all screening visit procedures are completed and the subject meets all eligibility criteria, the 
BioStamp nPoint device will be dispensed to the subject, who will be instructed to wear it for 7 
days during the Lead-In Period. The BioStamp device will be re-dispensed at 2 other timepoints 
(at each of the Day 1 Visits in Treatment Periods 1 and 2), worn for 14 days and removed on 
Day 14 in each period.  
The BioStamp nPoint device will include the BioStamp sensors, Link Hub, Link App mobile 
phone, adhesive stickers, and applicator guide. At the time of dispensing the BioStamp nPoint 
device, written instructions and training videos will be provided to the subject.  
5.4. 
Concomitant Medications  
Subjects who required routine medication to manage and treat concurrent conditions (e.g., 
hyperlipidemia, diabetes, hypertension) must be on stable doses 3 months prior to Screening. 
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 


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notified in advance of (or as soon as possible after) any instances in which prohibited therapies 
are administered. 
Prohibited concomitant medications include the following: 
• Paracetamol >2 g per day 
• PD medication changes within 3 months prior to Screening (applicable to RBD+PD, 
DLB and PDD subjects) 
• Vitamin E >400 IU daily 
• Aspirin >300 mg daily 
• Cannabis and products containing THC and/or CBD 
• Melatonin or hypnotics, such as Zolpidem or Zopiclone, within 48 hours prior to a study 
visit involving cognitive testing 
• Levodopa >1.5 g daily 
• Changes in clonazepam and monoamine oxidase inhibitor (MAOI) dosing within 4 weeks 
before Screening. 
• Use of St. John’s Wort or Ginkgo Biloba within 48 hours prior to study enrollment 
(defined as the Lead-in Period). 
• Use of benzodiazepine (except clonazepam) is prohibited from Screening throughout the 
study. 
• Use of gabapentinoids, phenylephrine and pseudoephedrine are prohibited from Screening 
throughout the study. 
• Prior treatment with any β-AR agonists or β-AR blockers (includes oral medications, eye 
drops with adrenergic agents such as timolol or atenolol, IV, or inhaled), or any meds 
that impact adrenergic signaling within the last month prior to Screening will exclude a 
subject from study enrollment. Use of β-AR agonists or β-AR blockers is not allowed 
during the study. 
• 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 Follow-Up Visit. 
• Opioid use is prohibited within 1 month prior to Screening and during the study. 
5.5. 
Escape/Rescue Medications  
Since CST-103 is being co-administered with the nonselective β-AR antagonist nadolol (CST-
107), the typical β-AR agonist effects such as HR increases, and hypokalemia are unlikely to 
occur. However, if there are intolerable HR/BP increases subjects may be administered the 
lowest commercially available dose of nadolol or equivalent β-AR antagonist. Nadolol has been 
successfully used at low doses (5 mg or less) in previous CuraSen studies to block the peripheral 
effects of CST-103 and other β-AR agonists. The blood pressure and heart rate increase at which 
treatment is given will be based on clinical judgment of the study physician and the PI. If 


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hypokalemia is detected, subjects should be managed based on clinical needs and presentation as 
appropriate per the Investigator’s discretion. 
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 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 
Follow-Up Visit.  
Female subjects of childbearing potential who have a male partner must agree to contraception 
from 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 a reliable method of birth control, including hormonal prescription oral 
contraceptives, contraceptive injections, contraceptive patch, contraceptive implant, 
contraceptive ring, intrauterine device, intrauterine hormone-releasing system, 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. 


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6. 
ASSESSMENT OF SAFETY 
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 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 first dose will 
be documented on the AE CRF. Concurrent illnesses, which existed prior to first dose into 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 


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utilized for rating the intensity of the event (see below); both AEs and SAEs will be assessed 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 Follow-Up 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. 
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 
that occurs after final visit but is felt to be related to the study medication by the Investigator 
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 


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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 
Any clinically significant ECG abnormality will require evaluation by 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-103 is provided as 40 µg capsules and matching placebo. CST-107 is provided as 1 mg 
capsules and matching placebo. Additional details on the study medication can be found in the 
Investigator Brochure.   
7.2. 
Study Medication Dosing and Administration 
Study treatments are: 
• CST-103/CST-107 PO taken in the morning after the first meal of the day  during 
each Treatment Period:  
o 80 µg CST-103, administered as two 40 µg capsules QD Day 1 – Day 14 


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o 1 mg CST-107, administered as one 1 mg capsule QD Day 1 – Day 14 
• Matching placebo taken daily during each Treatment Period 
7.2.1. 
Randomization 
The designated Interactive Response System (IRT) will be used to randomize subjects into the 
study on the first day of the Lead-In Period. Eligible subjects will be randomly assigned in a 1:1 
ratio to one of the following two treatment sequences (CST-103/CST-107 to placebo or placebo 
to CST-103/CST-107).  The IWRS will provide the randomization number. 
Randomization will be stratified by the following factors: 
• Disease criteria:  
o Cohort A: RBD+PD or MCI  
o Cohort B: DLB or PDD 
• Sex (Male vs Female) 
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, IRT system 
administration, and drug supply management team. Limited CuraSen staff or designees who are 
not otherwise involved in study conduct may be unblinded during study to evaluate accruing 
data.    
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-103 40 µg-matched placebo and CST-107 1 mg-matched placebo will be packaged and 
color-, size-, and shape-matched to be indistinguishable from CST-103 40 ug and CST-107 1 
mg. 
7.2.3. 
Packaging and Labeling 
All study medication to be used in this study will be packaged in bottles of 30 capsules each. The 
clinical label will identify the product by name, lot number, Sponsor, storage conditions and 
expiration dating period. The products are limited 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. 


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Study medications will be stored and handled at the clinical site in accordance with instructions 
in the Pharmacy Manual. Study medications will be stored at controlled room temperature 
(15-25°C) with excursions up to 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. 
7.2.5. 
Accountability and Disposition of Study Medication 
The Investigator is responsible for maintaining accurate study medication accountability records 
throughout the clinical trial. The site will be provided with study medication Accountability Logs 
on which the designated site staff, will record the receipt, dates, quantity, dispensing and return 
of study medication, as well as any destruction of study medication or return to the Sponsor. 
Where more than one secure area is being used for storage at a site, all movement of study 
medication through the Chain of Custody must be recorded in accountability records such that 
full reconciliation may be completed at the end of the study. The site may use its own study 
medication Accountability Logs and standard operating procedures, provided the information 
outlined above is collected. 
After completion of the clinical trial, the Investigator is responsible for the disposal or return to 
the Sponsor or designee. 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.  
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 40 subjects is planned in this crossover study, with approximately 20 
subjects with RBD+PD or MCI in Cohort A, and approximately 20 subjects with LDB or PDD in 
Cohort B.  The sample size for the study parts are based on practical considerations. No formal 
hypothesis testing is planned. 
The crossover design allows for an increased level of precision in estimates as compared to a 
parallel design with the same number of subjects. For primary and cognition related secondary 
endpoints, a sample size of 20 subjects in each cohort provides at least 80% power in this cross-


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over design to detect a treatment difference of 0.79*SD (active versus placebo) or larger for each 
endpoint of interest, where SD represents the standard deviation for the endpoint of interest. 
For cognition related secondary endpoints, a sample size of 40 subjects overall (both cohorts 
combined) provides at least 80% power in this cross-over design to detect a treatment difference 
of 0.54*SD (active versus placebo) or larger for each endpoint of interest. Sample size 
assumptions were based on a 2-sided t-test with a Type 1 error rate of 5%, equal (or no) 
carryover effects, and a correlation of at least 0.3 between study periods. No adjustments were 
made for dropouts or multiplicity.  
 
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 (CST103/CST107 or 
placebo). Subjects will be reported based on treatment and dose received. The Safety Set will be 
used for reporting of safety analyses.  
 
Full Analysis Set (FAS): All randomized subjects who have taken at least 1 dose of blinded 
study drug (CST-103/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 
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-103 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. 
Safety Reviews 
Cumulative, blinded safety data from the raw database will be reviewed by the SRM throughout 
the study when 25%, 50%, and 75% of the subjects are completed. During the review at 50% of 
subjects completed, primary endpoint data and selected secondary endpoint may be assessed. 


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8.3.2. 
Interim Analysis and Accruing Data Review 
No formal interim analysis is planned.  Accruing data will be evaluated informally on an ongoing 
basis. 
8.3.3. 
Final Analysis  
The final analysis will be performed after the last participant completes their follow-up 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 9.3 or higher. Continuous data will display 
number of subjects, means, standard deviations, median, minimum, and maximum. Categorical 
data will display frequency counts and percentages. As this study is descriptive in nature, no 
formal hypothesis testing will be performed. 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 cohort (A or B), disease 
criteria within cohort (RBD+PD or MCI for Cohort A, and PDD or DLB for Cohort B), 
treatment sequence and overall.  Summaries of safety, pharmacodynamics, and PK will be 
presented by disease criteria, treatment (CST103/CST107 versus placebo) and overall.  A limited 
subset of summaries may be presented by treatment sequence and/or period and overall.   
For analysis purposes, Baseline will be defined as either the pre-dose measurement taken within 
each of the study periods, or as the last measurement 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 cohort, disease criteria, 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 cohort, disease criteria, 
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.  


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8.7. 
Analysis of Primary Endpoints 
Primary endpoint data will be summarized by cohort, disease criteria, treatment, and overall 
across disease criteria (i.e., Overall CST103/CST107 and Overall Placebo) using the FAS. 
Selected summaries may be repeated in the PPS. All data will be listed. 
 
Informal differences between CST103/CST107 and placebo may be assessed for primary 
endpoints. For continuous endpoints, the difference is defined as CST107/CST107 minus 
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. 
  
Additional analyses may be performed and will be described in the SAP. 
8.7.1. 
Cohort A: Negative Emotional Bias 
Negative Emotional Bias, measured in the Facial Expression Recognition Task (FERT) and 
collected before dose on Day 1 and after dose on Days 7 and 14 for Cohort A subjects, will be 
summarized by disease criteria and treatment. Observed values and change from baseline will be 
summarized. 
8.7.2. 
Cohort B: Cognitive Fluctuations 
Cognitive fluctuations among Cohort B subjects are measured by spectral analysis of waking 
EEG, activity tracking, pupillometry, and DCFS. The observed values and change from baseline 
in overall values (spectral analysis, activity tracking, and pupillometry) or scales (DCFS) will be 
summarized by disease criteria and treatment. 
8.8. 
Analysis of Secondary Endpoints 
Secondary endpoints related to cognition, physiological symptoms, pupillary data, mood and 
sleep will be summarized by disease criteria, treatment and overall using the FAS. Select 
summaries may be repeated in the PPS. Comparisons between treatments will be performed 
similar to the analysis of primary endpoints. All data will be listed. 
8.8.1. 
Cognition, Mood, and Physiological Symptoms 
The absolute values and change (when applicable) from baseline in overall scores and sub-
domain scores where applicable will be summarized for Verbal Fluency (alphabet & category), 
CANTAB, BioStamp, GDS and HADS. 
8.8.2. 
Pupillary-Related Endpoints 
Pupillary parameters measured using the pupillary light reflex test including pupil area, baseline 
pupil diameter (BPD), maximum constriction velocity (MCV), absolute constriction amplitude 
(ACA), maximum dilation velocity (MDV), time to reach 75 % of initial resting diameter during 
pupillary dilation (T¾), and average dilation velocity will be summarized by disease criteria, 
treatment and overall using the FAS. 


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8.8.3. 
Epworth Sleepiness Scale 
The absolute values and change from baseline in overall scores will be summarized for ESS. 
8.8.4. 
Analysis of Safety  
Safety endpoints will be summarized by disease criteria, treatment and overall using the Safety 
Set. Additional summaries may be performed by treatment sequence and/or period.  A limited set 
of endpoints may also be summarized using other analysis populations.   
8.8.5. 
Adverse Events 
All reported AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Adverse event collection will begin during the Lead-In period 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 (CST103/CST107 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 to the first dose in Treatment Period 2, the AE will be 
attributed to the treatment received in Period 2.  
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.  Treatment-emergent AEs, SAEs, and treatment-related AEs will be 
further summarized by MedDRA system organ class and preferred term and reported by 
treatment group.  
The number and percentage of subjects with adverse events reported during the Lead-In period 
will also be summarized separately. 
All AEs will be listed.  Separate listings may be prepared for SAEs, AEs leading to study drug 
termination, and treatment-related AEs. 
8.8.6. 
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. 
8.8.7. 
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. 
8.8.8. 
Clinical Laboratory Results, Vital Signs, and ECGs 
Absolute values and changes from baseline will be summarized by cohort, disease criteria, 
treatment and overall. In addition, clinical laboratory results and ECG shift tables may be 
generated.  


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All results will be listed.  Laboratory values outside of normal ranges and clinically significant 
ECG abnormalities will be flagged.  
8.8.9. 
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-103 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-103 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-103 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 
Absolute values and changes from baseline in inflammatory and neurodegenerative 
inflammatory biomarkers will be summarized by treatment and overall using the FAS.  
Brain imaging signals in the locus coeruleus complex using neuromelanin-sensitive MRI 
sequence will be summarized. 
Correlations between clinical and biomarker data, as well as other additional analyses, may be 
performed and will be defined further in the SAP. 
All exploratory endpoints will be listed. 
8.10. 
Analysis of Other Endpoints  
Medical history, physical examination, C-SSRS, protocol deviations, screening clinical & 
cognitive scales (i.e., DSST, MHYS, MoCA, HADS, FOG-Q, and RBD1Q) 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. 


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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. 
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, Regulatory 
authorities, Ethics Committees (ECs), 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.  


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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 Investigator Brochure, 
copies of all clinical trial documentation, and all correspondence to and from the EC 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 
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 
consent forms 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 
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 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. 


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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 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, access to which is limited, to prevent theft or diversion of the substances 
into illegal channels of distribution. 
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.   
9.9.3. 
Premature Termination of the Clinical Trial 
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.  
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. 


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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-103 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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SAP_001.pdf: 
 
 
A PHASE II, RANDOMIZED, PLACEBO-CONTROLLED, 
DOUBLE-BLIND, CROSSOVER STUDY OF THE 
PHARMACODYNAMIC EFFECTS OF CST-103 CO-
ADMINISTERED WITH CST-107 ON THE CENTRAL 
NERVOUS SYSTEM IN SUBJECTS WITH 
NEURODEGENERATIVE DISORDERS 
 
 
Statistical Analysis Plan 
 
 
 
PROTOCOL NUMBER: 
CST103/CST107-CLIN-011 
 
 EUDRACT NUMBER: 
2020-006067-28 
 
VERSION / DATE OF PLAN: 
v1.0 /24May2022 
 
 
STUDY DRUG:  
CST-103 and CST-107 
 
 
PREPARED FOR: 
CuraSen Therapeutics, Inc. 


Sponsor: CuraSen Therapeutics, Inc. 
Protocol Number: CST103/CST107-CLIN-011 
Version and Date: 
v1.0 / 24May2022 
 
SAP Approval Signature Page 
 
Array Biostatistics, LLC 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
CuraSen Therapeutics, Inc. 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 


Sponsor: CuraSen Therapeutics, Inc. 
Protocol Number: CST103/CST107-CLIN-011 
Version and Date: 
 v1.0 / 24May2022 
 
Contents 
1. 
Abbreviations .......................................................................................................................... 5 
2. 
Introduction ............................................................................................................................. 7 
2.1. 
Changes from the Protocol ............................................................................................... 7 
3. 
Study Objectives and Endpoints ............................................................................................. 7 
4. 
Study Design ......................................................................................................................... 10 
4.1. 
Study Design and Population ......................................................................................... 10 
4.2. 
Randomization and Blinding .......................................................................................... 11 
4.3. 
Sample Size Considerations ........................................................................................... 12 
4.4. 
Safety Review Meeting Committee ............................................................................... 12 
4.5. 
Interim Analysis ............................................................................................................. 13 
4.6. 
Timing of Analyses ........................................................................................................ 13 
5. 
Data Analysis Considerations ............................................................................................... 13 
5.1. 
Stratification and Covariates .......................................................................................... 14 
5.2. 
Evaluation of Subgroups ................................................................................................ 14 
5.3. 
Multiple Comparisons and Multiplicity ......................................................................... 14 
6. 
General Data Handling Conventions .................................................................................... 14 
6.1. 
Reference Dates.............................................................................................................. 14 
6.2. 
Study Day and Duration Variables................................................................................. 14 
6.3. 
Baseline and Post-Baseline Changes.............................................................................. 15 
6.4. 
Missing Data and Data Imputation Rules ...................................................................... 15 
6.5. 
Multiple Assessments and Visit Windows ..................................................................... 15 
7. 
Study Subject Data ................................................................................................................ 15 
7.1. 
Analysis Populations ...................................................................................................... 15 
7.2. 
Subject Disposition ........................................................................................................ 16 
7.3. 
Protocol Deviations ........................................................................................................ 17 
7.4. 
Demographic and Baseline Characteristics .................................................................... 17 
7.5. 
Medical History .............................................................................................................. 18 
7.6. 
Prior and Concomitant Medication ................................................................................ 18 
7.7. 
Study Drug Exposure and Compliance .......................................................................... 18 
8. 
Endpoint analyses ................................................................................................................. 19 
8.1. 
Primary Endpoint and Analyses ..................................................................................... 19 
8.2. 
Secondary Endpoints and Analyses ............................................................................... 20 


Sponsor: CuraSen Therapeutics, Inc. 
Protocol Number: CST103/CST107-CLIN-011 
Version and Date: 
 v1.0 / 24May2022 
 
8.3. 
Exploratory Endpoints and Analyses ............................................................................. 26 
9. 
Pharmacokinetics .................................................................................................................. 27 
10. 
Safety ................................................................................................................................. 27 
10.1. Adverse Events ............................................................................................................... 27 
10.2. Clinical Laboratory Evaluations..................................................................................... 28 
10.3. Vital Signs ...................................................................................................................... 29 
10.4. Electrocardiogram (ECG) .............................................................................................. 29 
10.5. Physical Examinations ................................................................................................... 30 
10.6. Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................... 30 
11. 
References .......................................................................................................................... 32 
12. 
APPENDICES ................................................................................................................... 33 
12.1. APPENDIX 1: Partial Date Conventions ....................................................................... 33 
12.2. APPENDIX 2: Protocol Schedule of Events.................................................................. 35 
AUS and NZ Subjects: Schedule of Events for Each Treatment Period .............................. 36 
UK/Belgium Subjects: Schedule of Events for Each Treatment Period ............................... 42 
 
 
 
 


Sponsor: CuraSen Therapeutics, Inc. 
Protocol Number: CST103/CST107-CLIN-011 
Version and Date: 
 v1.0 / 24May2022 
 
1. ABBREVIATIONS 
Aβ  
amyloid‐β  
α-syn  
α-synuclein  
β-AR  
Beta-adrenoceptor  
β-hCG  
Beta human chorionic gonadotropin  
AD  
Alzheimer’s Disease  
AE  
Adverse event  
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  
CANTAB  
Cambridge Neuropsychological Test Automated Battery  
CBF  
Cerebral blood flow  
CF  
Cognitive fluctuations  
cGCP  
Current Good Clinical Practice  
CLIN-001  
CST101/CST107-CLIN-001  
CLIN-002  
CST103/CST107/CST109-CLIN-002  
CLIN-003  
CST101/CST103/CST109-CLIN-003  
Cmax  
Maximum concentration  
CNS  
Central nervous system  
CRF  
Case report form  
CK  
Creatinine kinase  
C-SSRS  
CST-103  
Columbia-Suicide Severity Rating Scale  
Clenbuterol HCl 
CST-107  
Nadolol  
CV  
Coefficients of variation  
DCFS  
Dementia Cognitive Fluctuation Scale  
DLB  
Dementia with Lewy Bodies  
DSST  
Digital Symbol Substitution Test  
EC  
Ethics Committee  
eCRF  
Electronic case report form  
ECG  
Electrocardiogram  
EEG  
Electroencephalogram  
ERP  
Event Related Potential  
ESS  
Epworth Sleepiness Scale  
EW  
Early withdrawal  
FAS  
Full analysis set  
FERT  
Facial Expression Recognition Task  
FOG  
FOG-Q  
FSH  
Freezing of Gait  
Freezing of Gait Questionnaire  
Follicle-stimulating hormone  
GDS  
Geriatric Depression Scale  
HADS  
Hospital Anxiety and Depression Scale  
HR  
Heart rate  
HbsAb  
Hepatitis B surface antibody  
HbsAg  
Hepatitis B surface antigen  


Sponsor: CuraSen Therapeutics, Inc. 
Protocol Number: CST103/CST107-CLIN-011 
Version and Date: 
 v1.0 / 24May2022 
 
HCV Ab  
Hepatitis C antibody  
HIV  
Human immunodeficiency virus  
HRV  
Heart rate variability  
IB  
Investigator Brochure  
ICF  
Informed consent form  
ICH  
International Council for Harmonisation  
IRT  
Interactive response technology  
ITT  
Intent to treat  
IV  
Intravenous  
MCI  
Mild cognitive impairment  
MedDRA  
Medical Dictionary for Regulatory Activities  
MHYS  
Modified Hoehn & Yahr Scale  
MoCA  
MRI  
Montreal Cognitive Assessment  
Magnetic resonance imaging  
NDD  
Neurodegenerative disease  
PAL  
Paired Associates Learning  
PD  
Parkinson’s Disease  
PDD  
Parkinson’s Disease Dementia  
PI  
Principal Investigator  
PK  
Pharmacokinetic  
PKS  
PK set  
PLR  
Pupillary Light Reflex  
PO  
By mouth/oral administration  
PPS  
Per protocol set  
QD  
Once daily  
RBD1Q  
REM Sleep Behavior Disorder Single-Question Screen  
RBD+PD  
REM Sleep Behavior Disorder positive Parkinson’s Disease  
RTI  
Reaction Time Index  
RVP  
Rapid Visual information Processing  
SAE  
Serious adverse event  
SAP  
Statistical analysis plan  
SARS-CoV-2  
Severe acute respiratory syndrome coronavirus 2  
SART  
SOC  
Sustained attention response task  
System organ class  
SOP  
Standard operating procedure  
SRM  
Safety review meeting  
t1/2  
Time to maximum observed drug concentration  
TEAE  
Treatment emergent adverse event  
tmax  
Time of maximum concentration  
TP  
Treatment Period  
TSH  
Thyroid-stimulating hormone  
VRM  
Verbal Recognition Memory  
WAIS-IV  
Wechsler Adult Intelligence Scale, Fourth Edition  
 




Sponsor: CuraSen Therapeutics, Inc. 
Protocol Number: CST103/CST107-CLIN-011 
Version and Date: 
 v1.0 / 24May2022 
 
2. Parkinson’s Disease Dementia (PDD) 
with Cognitive Fluctuations 
These pharmacodynamic assessments will 
compare the effect of CST-103 co-
administered with CST-107 with that of 
placebo on the following: 
 
Cohort A: 
• Emotional Facial Processing 
Cohort B: 
• Cognitive fluctuations  
Secondary 
The secondary objectives for all subjects 
include the comparison of the effect of CST-
103 co-administered with CST-107 with that 
of placebo on the following: 
1. Cognition 
2. AUS/NZ Subjects only: Movement 
and time spent sitting, standing and 
sleeping 
3. Sleep 
4. Pupillary reactivity 
5. Mood Assessment 
6. Safety and tolerability of CST-103 co-
administered with CST-107 
7. The pharmacokinetic (PK) profiles of 
CST-103 and CST-107 
The secondary endpoints will compare the 
effect of CST-103 co-administered with CST-
107 with that of placebo on the following: 
1. Verbal fluency test (alphabet & 
category)  
2. CANTAB cognitive assessments, with 
include the following: 
• Reaction Time (RTI) 
• Rapid Visual Information 
Processing (RVP) 
• Verbal Recognition Memory 
(VRM) Phase I 
• Adaptive Tracking Task (ATT) 
• Paired Associated Learning 
Task (PAL) 
• Stop Signal Task (SST) 
• Delayed Verbal Recall 
3. AUS/NZ Subjects Only: Digital 
wearable device (BioStamp) data, 
which includes four key measures of 
interest: 
a) Activity and posture 
classifications, durations, and 
temporal patterns 
b) Sleep (duration, posture 
transitions, and activity counts) 
c) Autonomic function – heart 
rate variability (HRV) 
d) Temporal pedometry (daily 
step count, and gait cadence) 


Sponsor: CuraSen Therapeutics, Inc. 
Protocol Number: CST103/CST107-CLIN-011 
Version and Date: 
 v1.0 / 24May2022 
 
4. Assessment of sleep using the digital 
device and Epworth Sleepiness Scale 
(ESS) 
5. Change in pupillary diameter as 
measured using the pupillary light 
reflex test 
6. Geriatric Depression Scale (GDS), 
Hospital Anxiety and Depression 
Scale (HADS) 
7. Adverse events (AE), 
electrocardiograms (ECGs), vital 
signs, laboratory safety tests 
(hematology, chemistry, and 
urinalysis) 
8. Plasma PK parameters of CST-103 
and CST-107 (including Cmax, tmax, 
AUCt. AUCinf, t1/2) 
Exploratory 
The exploratory objectives are: 
1. To characterize the effect of CST-103 
co-administered with CST-107 on 
inflammatory biomarkers in blood, 
such as C-reactive protein and 
cytokine levels. 
2. To characterize the effect of CST-103 
co-administered with CST-107 on 
neurodegenerative biomarkers in the 
blood study as neurofilament light 
chain, total and phosphorylated tau 
protein, and amyloid-β (Aβ) peptides 
may also be measured 
3. To characterize the effect of CST-103 
co-administered with CST-107 on 
performance of a sustained attention 
task in subjects in Cohort B 
4. To characterize the effect of CST-103 
co-administered with CST-107 on 
Freezing of Gait (FOG) (for subjects 
with RBD+PD, PDD, and DLB). 
5. To characterize the locus coeruleus 
volume and contract ratio (this is an 
optional objective based on imaging 
capabilities) 
The exploratory endpoints are:  
1.   Changes in inflammatory 
biomarkers, such as C-reactive 
protein and cytokine levels, as 
measured prior to and after CST-103 
co-administered with CST-107 may 
be determined.  
2.   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 CST-103 co-administered with 
CST-107 may be evaluated.  
3.   AUS/NZ Subjects Only: 
Performance on the Sustained 
Attention Response Task (SART) as 
measured prior to and after CST-103 
co-administered with CST-107.  
4.   Assessment of FOG using the FOG-
Q (for subjects with PBD+PD, PDD, 
and DLB). 
5.   The characterization of the brain 
imaging signal in the locus 
coeruleus complex using 
neuromelanin-sensitive MRI 
sequence. This is an optional 




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Study Schema – Cohort A in RBD+PD or MCI Subjects*
 
Study Schema – Cohort B in DLB or PDD Subjects*
 
*Biostamp devices will only be used for the Australia/New Zealand subjects but not for the UK 
or Belgian subjects. 
4.2. Randomization and Blinding 
 
The designated Interactive Response System (IRT) will be used to randomize subjects into the 
study on the first day of the Lead-In Period. Eligible subjects will be randomly assigned in a 1:1 
ratio to one of the following two treatment sequences (CST-103/CST-107 to placebo or placebo 
to CST-103/CST-107). The IRT will provide the randomization number. 
Randomization will be stratified by the following factors: 
• Disease Criteria: 


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o Cohort A: PBD+PD or MCI 
o Cohort B: DLB or PDD 
• Sex (Male vs Female) 
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, IRT system 
administration, and drug supply management team. Limited CuraSen staff or designees who are 
not otherwise involved in study conduct may be unblinded during study to evaluate accruing 
data. 
CST-103 40 µg-matched placebo and CST-107 1 mg-matched placebo will be packaged and 
color-, size- and shape-matched to be indistinguishable from CST-103 40 µg and CST-107 1 mg. 
4.3. Sample Size Considerations 
 
A total of approximately 40 subjects is planned in this crossover study. The sample size for the 
study parts are based on practical considerations. No formal hypothesis testing is planned. 
The crossover design allows for an increased level of precision in estimates as compared to a 
parallel design with the same number of subjects. For primary and cognition related secondary 
endpoints, a sample size of 20 subjects in each cohort provides at least 80% power in this cross-
over design to detect a treatment difference of 0.79*SD (active versus placebo) or larger for each 
endpoint of interest, where SD represents the standard deviation for the endpoint of interest. 
For cognition related secondary endpoints, a sample size of 40 subjects overall (both cohorts 
combined) provides at least 80% power in this cross-over design to detect a treatment difference 
of 0.54*SD (active versus placebo) or larger for each endpoint of interest. Sample size 
assumptions were based on a 2-sided t-test with a Type I error rate of 5%, equal (or no) 
carryover effects, and a correlation of at least 0.3 between study periods. No adjustments were 
made for dropouts or multiplicity. 
4.4. Safety Review Meeting Committee 
 
Safety Review Meetings (SRMs) will be held to review blinded safety data (such as AEs, vital 
signs, ECGs, and safety labs) and PK (if available) when 25%, 50%, and 75% of the subjects are 
completed. Data to be reviewed may not necessarily be validated and cleaned (data query 
resolution may be pending). Data will be reviewed blinded (treatment assignment will not be 
revealed) unless unblinding is deemed necessary for the SRM committee. 
The SRM members will include the regional Lead Investigator(s) or representative, CuraSen 
Chief Medical Officer, CuraSen Medical Monitor(s), and Clinical Research Study Manager. 
Additional members may be added as needed (e.g., statistician, PK scientist). The SRM 
committee will monitor subject safety and recommend whether to continue with dosing, to 
modify the protocol, to perform additional safety assessments and/or reviews, to delay or 
terminate subject enrollment, or to decrease and/or increase sample size based on emerging 


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safety data from this study or emerging safety, PK, and pharmacodynamics data from other 
ongoing and completed CuraSen studies. 
4.5. Interim Analysis 
 
No formal interim analysis is planned for this study. Accruing data will be evaluated informally 
on an ongoing basis. 
4.6. Timing of Analyses 
 
The full set of analyses summarized in this SAP will be generated upon final study database 
lock. 
5. DATA ANALYSIS CONSIDERATIONS 
 
All analyses will be conducted based on SAS 9.4 or higher. 
All data in the database will be presented in by-subject data listings. 
Unless otherwise stated, all listings will be sorted by cohort, disease type, treatment sequence, 
subject number, and assessment date (and time, if available). 
Unless stated otherwise, continuous data will be summarized by cohort, disease type, treatment 
sequence and overall based on n, mean, median, standard deviation (SD), minimum value, and 
maximum value.  
Unless stated otherwise, categorical data will be summarized by cohort, disease type, treatment 
sequence and overall using n and percentage based on the number of nonmissing values. 
• 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. 
Precision 
• Mean and Median: one additional decimal place to that reported for Minimum and 
Maximum 
• SD: 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 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). 


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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. 
5.1. Stratification and Covariates 
 
There are no formal plans for analysis stratification. 
5.2. Evaluation of Subgroups 
 
There are no formal plans for examining subgroups. 
5.3. 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. 
6. GENERAL DATA HANDLING CONVENTIONS 
 
6.1. Reference Dates 
• Screening date is defined as the eCRF provided date on which a subject was screened for 
trial entry. 
• Treatment start date is defined as the date of first dose of study drug. Each treatment 
period will have a treatment start date (i.e., in order to determine AEs occurring during a 
treatment). 
• 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. 
6.2. 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. 
 


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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. 
6.3. Baseline and Post-Baseline Changes 
 
Unless stated otherwise, baseline and post-baseline change values will be based on the following: 
• 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.  
6.4. 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. 
6.5. 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 subject data listings.  
7. STUDY SUBJECT DATA  
7.1. Analysis 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. 


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Safety Set (SAF): All subjects who received at least 1 dose of study drug (CST-103/CST-107 or 
placebo). Subjects will be reported based on the treatment and dose received. The Safety Set will 
be used for the reporting of safety analyses. 
Full Analysis Set (FAS): All randomized subjects who have taken at least 1 dose of blinded 
study drug (CST-103/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 
pharmacodynamic endpoints, and selected secondary endpoints. 
Per-Protocol Set (PPS): A subset of the Full Analysis Set who sufficiently complied with the 
protocol. The analysis set will only include subjects without protocol deviations classified as 
“major”. The Per Protocol Set may be used for selected safety analyses. 
BioStamp Set (BSS): A subset of the Full Analysis Set who have at least one BioStamp 
measurement during the baseline period each of the post-baseline periods. The BioStamp Set will 
be used for demographics and the BioStamp related endpoints. 
Pharmacokinetic Set (PKS): All subjects in the Safety Set who have at least one valid plasma 
concentration assessment for CST-103 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. 
7.2. Subject 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 study cohort, disease criteria, and sequence. 
Screen failures, analysis populations, and final subject disposition status will be listed. Visit 
dates and reasons for visits not done will also be listed. 


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7.3. Protocol Deviations 
 
Protocol deviations will be recorded and detailed in a data listing. Deviations will be identified as 
major or minor, as evaluated by the monitoring team.  
7.4. Demographic and Baseline Characteristics 
 
Subject demographics using the ITT set will be summarized, and repeated on the BSS.  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, 
country (United Kingdom/Belgium  / Australia/New Zealand), baseline height (cm), baseline 
weight (kg), and BMI (kg/m2).  Data will be presented by study cohort, disease criteria, and 
sequence. 
 
Clinical and Cognitive Scales 
The Montreal Cognitive Assessment (MoCA, for all subjects) 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, for MCI subjects only) 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 RBD+PD, DLB, and PDD 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 5.3.6.3 of the study protocol. 
The REM Sleep Behavior Disorder Single-Question Screen (RBD1Q, for RBD+PD subjects 
only) 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.)?”  
MoCA and DSST, MHYS, and RBD1Q data will be summarized in the demographics and 
baseline characteristics tables and listed by subject. 
Descriptions of the Hospital Anxiety and Depression Scale (HADS) can be found in section 8.2 
below, and descriptions of Neuromelanin-MRIs can be found in section 8.3 below. Baseline 
HADS depression and anxiety subscores and neuromelanin MRI contrast-to-noise (by scanner 
type) will be summarized in the demographics and baseline characteristics table. 
 


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These demographic and baseline data will be listed. Additionally, drugs of abuse and alcohol 
findings and serology data will be listed. 
 
7.5. Medical History 
 
Medical history among the ITT set will be summarized and listed by Medical Dictionary for 
Regulatory Activities (MedDRA 23.1) system organ class (SOC) and preferred term (PT), and 
verbatim term as collected in the study database. 
7.6. Prior and Concomitant Medication  
 
The incidence of medication use will be summarized by WHO Drug Dictionary (B3, 2020-09-
01) anatomic therapeutic chemical classification (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).  Concomitant 
medications are those which have been identified to have been taken at any point after first dose.  
Concomitant medication use will be summarized on the ITT set and presented by study cohort, 
disease type, and sequence, as applicable.  
All prior and concomitant medication data will be listed including the verbatim and preferred 
drug name and ATC Level 2. Procedures and non-med therapies will also be listed. 
7.7. 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 follows: 
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-103 and CST-107 
based on number of tablets/capsules 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-103 or placebo capsules are expected to be taken during each treatment period, 
per protocol (i.e., two capsules once daily). Summaries will be presented by treatment 
(i.e., Placebo and CST-103/CST-107) based on each subjects’ exposure to each 
treatment. 
• 14 CST-107 or placebo capsules are expected to be taken during each treatment period, 
per protocol (i.e., one capsule once daily). Summarized will be presented by treatment 
(i.e., Placebo and CST-103/CST-107) based on each subjects’ exposure to each 
treatment. 


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Drug exposure will be summarized by cohort, 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/capsules dispensed and returned, and compliance will be listed. 
8. 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. 
8.1. Primary Endpoint and Analyses 
 
Cohort A 
Analyses of FERT data will be summarized in a separate analysis plan. 
Cohort B 
Due to the small sample size, all primary endpoint data for Cohort B subjects will be listed only 
using the FAS. 
Waking EEG 
Analyses of waking EEG data will be summarized in a separate analysis plan. 
 
Activity Tracking (AUS/NZ Subjects Only) 
The BioStamp nPoint device will be worn continuously for the 7 days prior to the Treatment 
Period 1 through the Day 1 visit (Baseline period), and re-dispensed at each of the Day 1 Visits 
in both periods, worn for 14 days, and removed on Day 14. During each of the three periods in 
which the subject wears the device, the device calculates 49 cumulative metrics for each day 
worn within the period. The metrics are then aggregated by study period (Baseline period, 
Treatment Period 1, Treatment Period 2).  The 7 metrics related to activity tracking/classification 
are: 
• Percent Wake Time defined as the percentage of sensor wear time spent awake.  All time 
not spent awake is time spent asleep (identified in the raw data as wake_percent). 
• Percent Moving Time defined as the percentage of waking time spent moving (sum of 
walking and other) (identified in the raw data as moving_percent). 
• Percent Moving Other Time defined as the percentage of time spent moving but not 
walking (identified in the raw data as moving_other_percent). 
• Percent Walking Time defined as the percentage of time spent walking 


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• Moving Activity Count defined as the activity counts per hour during moving periods 
(identified in the raw data as activity_moving). 
• Resting Activity Count defined as the activity counts per hour during resting periods 
• Wake Activity Count defined as the activity counts per hour during moving and resting 
periods (identified in the raw data as activity_resting). 
All BioStamp aggregated data will be listed. 
Pupillometry 
The PLR test will be conducted for each eye in duplicate prior to first dose on Day 1 (Baseline), 
and 4 hours post dose on Day 1, Day 7, and Day 14 of each treatment period. Results from the 
duplicate measurements and across eyes will be averaged (i.e., the four pre-dose measurements 
on Day 1 [left eye occasions 1 and 2; right eye occasions 1 and 2] will be averaged). Parameters 
collected include initial pupil diameter (INIT), diameter at end of constriction (END), average 
constriction velocity (ACV), maximum constriction velocity (MCV), averaged dilated velocity 
(ADV) and time to reach 75% of initial resting diameter during pupillary dilation (T75).  
All pupillometry data will be listed. 
Dementia Cognitive Fluctuation Scale (DCFS) 
The DCFS is a questionnaire consisting of 17 items that queries confusion, differences in 
functioning through the day, sleep patterns and problems, varying levels of alertness, and clarity 
of thought/communication. The DCFS will be administered during screening, on Day 1 
(Baseline), and on Day 14 of each treatment period.  
Responses for all 17 items and domain scores will be reported in by-subject listings. 
8.2. 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. 
 
Cohort A and Cohort B 
 
CANTAB 
 
Cognition function is assessed using the following CANTAB tests: 
• Reaction Time (RTI) 
• Verbal Recall Memory (VRM) Phase 1 
• Adaptive Tracking Task (ATT) 
• Paired Associates Learning Task (PAL) 
• Stop Signal Task (SST) 


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• Delayed Verbal Recall 
 
The cognitive assessments measured as part of the CANTAB tests will be administered prior to 
dosing on Day 1 (Baseline), and 4 hours after dosing on Days 1, 7, and 14 of each treatment 
period. Summaries will be presented by cohort, disease type, and treatment sequence. 
 
Absolute values of each key measure at each assessment and changes from baseline will be 
summarized using descriptive statistics on the FAS. There are sixteen 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 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 


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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. 
• 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. 
• 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 SSTSRT. 
• 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. 
 
In addition to the descriptive statistic summaries for the above, 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: 4 hrs post-dose, Day 7: 4 hrs post-dose, Day 14: 4 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 


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corresponding p-value for this LS mean difference will be provided. All inferential analyses are 
exploratory in nature given that this study was not powered based on any statistical assumptions.  
 
Line plots detailing individual subject results of the ATT parameters will be produced. 
 
All CANTAB data, which includes 80 total measurements, will be listed on the FAS. 
 
Verbal Fluency Test 
 
The ‘ALPHABET’ and ‘CATEGORY’ tests from the Brief and Simple Index of Cognition 
(BASIC) tests are used in this study. For the ALPHABET task, subjects are given one 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. 
 
Similar to the CANTAB data, descriptive summaries for the ALPHABET and CATEGORY total 
scores (identified in the raw data as AAACCPT and CAACCPT, respectively) and change from 
baseline will be provided at each collection timepoint (i.e, Day 1: 4 hrs post-dose, Day 7: 4 hrs 
post-dose, Day 14: 4 hrs post-dose), and a mixed effects model with change from baseline as the 
dependent variable, baseline as a covariate, treatment sequence, period, timepoint, disease type, 
and treatment as fixed effects, and subject as a random effect. The LS mean, LS mean difference, 
and p-value for the difference will be reported. 
 
Verbal fluency data will be listed on the FAS. 
 
BioStamp (AUS/NZ Subjects Only) 
 
In addition to activity tracking/classification, the BioStamp nPoint device will continuously track 
posture (classifications, durations, and temporal patterns), sleeping patterns (duration, posture, 
transitions, and activity counts), autonomic function (heart rate variability (HRV)), and temporal 
pedometry via daily step count and gait cadence. There are 29 daily metrics calculated by the 
BioStamp device related to posture, sleeping patterns, autonomic function, and temporal 
pedometry. These metrics are then aggregated by study period (Baseline period, Treatment 
Period 1, Treatment Period 2).   
• Posture: 
o Percent Resting Time defined as the percentage of waking time spent resting (sum 
of lying, sitting, and standing) (identified in the raw data as resting_percent). 
o Percent Lying Time defined as the percentage of waking time spent lying 
(identified in the raw data as resting_lying_percent). 
o Percent Sitting Time defined as the percentage of waking time spent sitting 
(identified in the raw data as resting_sitting_percent). 
o Percent Standing Time defined as the percentage of waking time spent standing 
(identified in the raw data as resting_standing_percent). 


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o Percent Upright Posture defined as the percentage of resting time when the 
patient’s posture was classified as upright. All time not classified as upright is 
classified as leaning (identified in the raw data as upright_posture_percent). 
• Sleeping patterns: 
o Average Sleep Duration as defined by average hours of sleep for days that include 
sleep periods (identified in the raw data as avg_sleep_duration). 
o Average Sleep Posture Transitions as defined by the average number of sleeping 
posture transitions that occur per hour during sleep (identified in the raw data as 
sleeping_posture_transitions_rate). 
o Sleeping Activity Counts as defined by activity counts per hour during sleeping 
periods (identified in the raw data as activity_sleeping). 
• Autonomic function: 
Heart Rate Variability (HRV) is computed for each activity period using two methods, 
LF/HF which is a ratio of low frequency to high frequency and RMSSD which is the root 
mean square of the successive differences.  For each of the 8 metrics below, a set of 
descriptive statistics is computed (coefficient of variation, minimum, maximum, mean, 
5th , 25th, 75th, 95th percentiles, standard deviation), and the mean of each parameter will 
be assessed using the mixed modeling described later on: 
o Sleeping HRV LF_HF (identified in the raw data as hrv_lfhf_sleeping). 
o Sleeping HRV RMSSD (identified in the raw data as hrv_rmssd_sleeping). 
o Resting HRV LF_HF (identified in the raw data as hrv_lfhf_resting). 
o Resting HRV RMSSD (identified in the raw data as hrv_rmssd_resting). 
o Moving HRV LF_HF (identified in the raw data as hrv_lfhf_moving). 
o Moving HRV RMSSD (identified in the raw data as hrv_rmssd_moving). 
o Waking HRV LF_HF (identified in the raw data as hrv_lfhf_wake). 
o Walking HRV RMSSD (identified in the raw data as hrv_rmssd_wake). 
 
• Temporal pedometry: 
o Average Gait Cadence as defined as steps per minute during walking (identified 
in the raw data as avg_gate_cadence). 
o Step Count Rate as defined as step counts per hour during periods classified as 
walking (identified in the raw data as step_count_rate). 
 
If a subject has at least 5 days of sensor wear within each period, the metrics will be aggregated 
for each period to obtain a single value. Descriptive statistics of the 17 metrics noted above, as 
well as the 7 activity metrics noted in Section 8.1 above, and change from baseline will be 
reported for both Cohort A and Cohort B subjects. A mixed model with change from baseline 
period as the dependent variable, baseline period value as a covariate, treatment sequence, post-
baseline period (i.e., 1, 2), disease type, and treatment as fixed effects, and subject as a random 
effect will be analyzed for these posture, sleep, autonomic function, activity tracking, and 
temporal pedometry parameters for all subjects and LS means, LS mean differences, and p-
values will be presented. 
 
Epworth Sleepiness Scale (ESS) 
 


Sponsor: CuraSen Therapeutics, Inc. 
Protocol Number: CST103/CST107-CLIN-011 
Version and Date: 
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The ESS is an 8-item, self-administered questionnaire in which subjects are asked to rate, on a 4-
point scale (0-3), their usual chances of dozing off or falling asleep while engaged in 8 different 
activities. The total score is the sum of the 8 item scores, with scores ranging from 0 (no daytime 
sleepiness) to 24 (high sleep propensity in daily life). The ESS will be administered on Day 1 
(Baseline), Day 7, and Day 14 of each treatment period. Descriptive statistics of total scores and 
change from baseline will be reported. Additionally, a mixed model will be used to evaluate the 
treatment effect. The model will include change from baseline as the dependent variable, fixed 
effects for baseline, treatment sequence, period, timepoint (i.e., Day 7, Day 14), disease type, and 
treatment, and a random subject effect. LS mean, LS mean difference, and LS mean difference p-
value will be reported. 
 
ESS data, including responses to individual questions, will be provided in a listing. 
 
Pupillary Diameter 
 
Summary statistics of the observed values (averages by occasion) and change from baseline for 
the parameters listed in Section 8.1 (INIT, END, ACV, MCV, ADV, T75) will be reported. In 
addition, to assess the treatment difference between CST-103/CST-107 and placebo, a mixed 
model with baseline, treatment sequence, period, timepoint (i.e., Day 1: 4 hrs post-dose, Day 7: 4 
hrs post-dose, Day 14: 4 hrs post-dose), disease type, and treatment as fixed effects, and a 
random subject effect, will be analyzed, with the LS mean, LS mean difference, and p-value for 
the LS mean difference will be reported for each pupillometry parameter noted above. 
 
Geriatric Depression Scale (GDS) 
 
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 7, 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 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. 
 
All GDS data, included responses to individual questions, will be listed. 
 
Hospital Anxiety and Depression Scale (HADS) 
 
HADS is a 14-item questionnaire with subscales for anxiety and depression. Subjects are given 
14 questions in multiple-choice format, seven about depressive symptoms and seven about 
anxiety symptoms and are asked to give a score from 0 to 3 where 0 is the least 
depressed/anxiety option and 3 the most. Depression and Anxiety sub-scores are recorded in the 
electronic database and are calculated as the sum of responses to the 7 questions within the 


Sponsor: CuraSen Therapeutics, Inc. 
Protocol Number: CST103/CST107-CLIN-011 
Version and Date: 
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category. HADS will be administered on Day 1 (Baseline) and Day 14 of each treatment period. 
Summary statistics of sub-scores and changes from baseline will be reported. A mixed model to 
assess the treatment effect, including fixed effects baseline, treatment sequence, period, 
timepoint (i.e., Day 14), disease type, and treatment, and random subject effect will be analyzed, 
and LS means, LS mean differences, and associated p-value will be presented. 
 
HADS data will be listed. 
8.3. Exploratory Endpoints and Analyses 
 
The FAS will be used for all exploratory endpoint analyses unless stated otherwise. 
 
Cohort A and Cohort B 
 
Inflammatory Biomarkers 
 
Inflammatory biomarkers include C-reactive protein and cytokine levels and will be collected at 
Day 1 (Baseline) and Day 14 of each treatment period. Descriptive statistics of observed values 
and change from baseline will be presented for both biomarkers. Inflammatory biomarker data 
will also be listed. 
 
Neurodegenerative Biomarkers 
 
Neurodegenerative biomarkers including neurofilament light chain, total and phosphorylated tau 
protein, and amyloid-β (Aβ) peptides will also be collected at Day 1 (Baseline) and Day 14 of 
each treatment period. Similar to inflammatory biomarker data, descriptive statistics of the 
neurodegenerative biomarkers and change from baseline to Day 14 will be summarized. All 
neurodegenerative biomarker data will be listed. 
 
Sustained Attention to Response Task (SART, Cohort B AUS Subjects from Site 502 only) 
 
SART is a computer-based go/no-go task that requires participants to withhold behavioral 
response to a single, infrequent target presented among a background of frequent non-targets. 
The subject is asked to respond to the non-target and inhibit their response to the target. 
Parameters collected include error rate and reaction time. The SART will be administered prior 
to dosing on Day 1 (Baseline) and 3 hours post-dose on Days 1 and 14 of each treatment period. 
SART data will be reported in by-subject listings. 
 
Freezing of Gait Questionnaire (FOG-Q, RBD+PD, DLB, and PDD Subjects Only) 
 
The FOG-Q assesses Freezing of Gait (FOG) and consists of six items borrowed from the Gait 
and Falls Questionnaire. Each question ranges from 0 to 4, with higher scores indicating 
worsening gait. FOG-Q will be administered on Day 1 (Baseline) and Day 14 of each treatment 


Sponsor: CuraSen Therapeutics, Inc. 
Protocol Number: CST103/CST107-CLIN-011 
Version and Date: 
 v1.0 / 24May2022 
 
period. Summary statistics of responses to each of the six question and change from baseline will 
be reported. FOG-Q data will additionally be listed. 
 
Neuromelanin MRI Scan 
 
The neuromelanin-sensitive MRI sequence is optional depending on the imaging facility’s 
capabilities, and can be performed at Screening. If not performed at Screening, it may be 
performed at the Follow-up visit or at any other convenient time during the study. Neuromelanin 
will be measured to evaluate its suitability as a biomarker of locus coeruleus integrity. 
 
MRI data will be listed. 
 
9. 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. 
10. SAFETY  
 
All safety analysis reporting will be based on the Safety Set. All safety summaries except for 
laboratory summaries will be presented by cohort, disease type, and treatment taken at time of 
data collection. Lab summaries will be presented by cohort, disease type, and treatment 
sequence.  
10.1. Adverse Events 
 
Adverse events (AEs) will be recorded from the signing informed consent 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 of first dose 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.  
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. 


Sponsor: CuraSen Therapeutics, Inc. 
Protocol Number: CST103/CST107-CLIN-011 
Version and Date: 
 v1.0 / 24May2022 
 
Adverse events will be coded based on the Medical Dictionary for Regulatory Affairs (MedDRA 
23.1) 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 
10.2. 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, white blood cell (WBC) count with 
differential, and reticulocyte count. 
• Clinical chemistry: albumin, alkaline phosphatase (ALP), alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), BUN, calcium, bicarbonate, serum creatinine, 
creatinine phosphokinase (CPK), glucose, lipase, 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: thyroid-stimulating hormone (TSH) and calculated creatinine clearance 
according to the Cockcroft-Gault equation.  
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]).  
All laboratory results will be provided in subject data listings. The following additional results 
will be included in these listings: 


Sponsor: CuraSen Therapeutics, Inc. 
Protocol Number: CST103/CST107-CLIN-011 
Version and Date: 
 v1.0 / 24May2022 
 
• 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. 
• 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. 
Box plots of observed results or change from baseline at each visit for potassium and glucose 
results for each treatment group may be generated. 
10.3. 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). Any vital signs taken in 
triplicate will be averaged within timepoint. 
Observed values and changes from screening/baseline for vital signs will be summarized at each 
visit and time point.  For parameters collected as triplicate measurements, the average of the non-
missing measurements will be summarized.   
Summaries will be presented by treatment at the time of data collected (i.e., Placebo and CST-
103/CST-107).  
All vital sign data will be listed. 
Box plots of observed results or change from baseline at each visit for heart rate results for each 
treatment group may be generated. 
10.4. Electrocardiogram (ECG) 
ECG parameters include:  Heart rate, PR interval, RR interval, QRS interval, QT interval and 
QTcF. Observed values and changes from baseline for ECG parameters will be summarized at 
each visit and time point.  
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 


Sponsor: CuraSen Therapeutics, Inc. 
Protocol Number: CST103/CST107-CLIN-011 
Version and Date: 
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• 480 msec < QTcF ≤ 500 msec 
• QTcF > 500 msec 
• QTcF change from baseline of ≤ 30 msec 
• QTcF change from baseline of > 30 msec and ≤ 60 msec 
• QTcF change from baseline of > 60 msec 
Box plots of observed results or change from baseline at each visit and timepoint for QTcF 
results for each treatment group may be generated. 
10.5. Physical Examinations 
Physical examinations 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 
10.6. 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. 
 


Sponsor: CuraSen Therapeutics, Inc. 
Protocol Number: CST103/CST107-CLIN-011 
Version and Date: 
 v1.0 / 24May2022 
 
The C-SSRS will be completed at Day 1 (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: 
(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. 


Sponsor: CuraSen Therapeutics, Inc. 
Protocol Number: CST103/CST107-CLIN-011 
Version and Date: 
 v1.0 / 24May2022 
 
11. 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.            
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 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. 
 
 






Sponsor: CuraSen Therapeutics, Inc. 
Protocol Number: CST103/CST107-CLIN-011 
Version and Date: 
v1.0 / 24May2022 
 
12.2. APPENDIX 2: Protocol Schedule of Events 
 
 


Sponsor: CuraSen Therapeutics, Inc. 
Protocol Number: CST103/CST107-CLIN-011 
Version and Date: 
v1.0 / 24May2022 
 
AUS and NZ Subjects: Schedule of Events for Each Treatment Period 
 
Screening 
Lead-In 
Treatment Periods 1 & 21 
Follow-Up 
Day -28 to 
Day -8 
Day -14 to 
Day -1 
Day 1 
Day 72 
(±1) 
Day 14/EW3, 4 
(±1) 
~2 Weeks after 
Last Dose of 
Study Drug or 
EW Visit3 
Outpatient visit 
X 
X 
X 
X 
X 
X 
Informed consent 
X 
Randomization 
X 
Inclusion / Exclusion 
criteria valuation 
X 
X 
X 
Medical history 
X 
Height and weight, BMI 
calculation 
X 
Vital signs5 
X 
X 
X 
X 
X 
ECG6 
X 
X 
X 
X 
X 
Physical exam, complete7 
X 
X 
Safety labs8 
X 
X 
X 
X 
Urine drug screen 
X 
Alcohol test 
X 
X 
Hepatitis and HIV 
serologies 
X 
TSH 
X 
Serum FSH9 
X 
β-hCG pregnancy test9 
X 
 


Sponsor: CuraSen Therapeutics, Inc. 
Protocol Number: CST103/CST107-CLIN-011 
Version and Date: 
 v1.0 / 24May2022 
 
Screening 
Lead-In 
Treatment Periods 1 & 21 
Follow-Up 
Day -28 to 
Day -8 
Day -14 to 
Day -1 
Day 1 
Day 72 
(±1) 
Day 14/EW3, 4 
(±1) 
~2 Weeks 
after Last 
Dose of Study 
Drug or EW 
Serum or urine pregnancy 
test9 
X 
X 
X 
SARS-CoV-2 status 
assessment10 
X 
X 
PK sample11 
X 
X 
Pharmacodynamic sample 
collection 
X 
X 
C-SSRS 
X 
X24 
X 
X 
X 
DSST12, 13 
X 
Dementia Cognitive 
Fluctuation Scale 
(
)12 14
X 
X 
X 
Modified Hoehn & Yahr 
Scale (MHYS)12, 15 
X 
HADS18 
X 
X 
X 
Freezing of Gait 
Questionnaire (FOG-Q)12, 15 
X 
X 
RBD1Q17, 18 
X 
MoCA12 
X 
Epworth Sleepiness Scale 
(ESS)18 
X 
X 
X 
X 
Geriatric Depression Scale 
(GDS)18 
X 
X 
X 
 


Sponsor: CuraSen Therapeutics, Inc. 
Protocol Number: CST103/CST107-CLIN-011 
Version and Date: 
 v1.0 / 24May2022 
 
Screening 
Lead-In 
Treatment Periods 1 & 21 
Follow-Up 
Day -28 to 
Day -8 
Day -14 to 
Day -1 
Day 1 
Day 72 
(±1) 
Day 14/EW3, 4 
(±1) 
~2 Weeks after 
Last Dose of 
Study Drug or 
EW Visit3 
CANTAB19 
 
X 
X 
X 
X 
 
Pupillary Light Reflex 
(PLR) Test20 
 
 
X 
X 
X 
 
EEG21 
 
 
X 
 
X 
 
Sustained Attention to 
Response Task (SART)21 
 
 
X 
 
X 
 
Facial Recognition Task 
(FERT) 16, 22 
 
 
X 
X 
X 
 
BioStamp digital device 23 
 
X 
 
 
 
 
CST-103+CST-107 or 
matching placebo 
administration 
 
 
 
 
 
 
Neuromelanin MRI scan 
X25 
 
 
 
 
X25 
Assessment of AEs 
 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
AE = adverse event; ECG = electrocardiogram; EEG = electroencephalogram; PK = pharmacokinetics 
1 Wash-out period between Treatment Periods 1 & 2 is 14 (+ 5) days. 
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. 
3 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. 
4 Subjects who withdraw from the study prior to completion of dosing should complete Day 14 safety assessments at the time of withdrawal. 
5 Vital signs to include BP, HR, respiration rate, and oral/tympanic temperature; triplicate BP and HR measurements (separated by approximately 1 minute) 
after subject is supine for 5 minutes; vital signs will be obtained at every study visit as follows: 


Sponsor: CuraSen Therapeutics, Inc. 
Protocol Number: CST103/CST107-CLIN-011 
Version and Date: 
 v1.0 / 24May2022 
 
• 
Screening 
• 
Day 1 of each treatment period: 
1. Prior to dosing (within 15 minutes) 
2. 1 hour (±30 mins) after dosing 
• 
Day 7 of each treatment period: 1 hour (±30 mins) after dosing 
• 
Day 14 of each treatment period: 1 hour (±30 mins) after dosing 
• 
Follow-Up Visit 
6 Subjects will be required to rest in a supine position for at least 5 minutes prior to the recording of ECG. ECGs to be obtained at the following timepoints: 
• 
Screening 
• 
Lead-In 
• 
Day 1 of each treatment period: 
1. Prior to dosing (within 15 minutes) 
2. 1 hour (±30 mins) after dosing 
3. 4 hours (±30 mins) after dosing 
• 
Day 14 of each treatment period: 
1. 1 hour (±30 mins) after dosing 
2. 4 hours (±30 mins) after dosing 
• 
Follow-Up Visit 
7 A complete physical examination (PE) (excluding genital, rectal and breast exams) is required at Screening; the Follow-Up PE will be symptom-driven based 
on subject complaints. 
8 Safety labs to include hematology, chemistries, and urinalysis. Subjects should be fasting for 8 hours for the safety labs. 
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 and at the Follow-Up visit. 
10 Subjects to be assessed for current infection per local site standard procedure. 
11 PK sample timepoints (CST-103/CST-107) in each treatment period: 
• 
Day 1: 
1. 
Prior to dosing 
2. 
4 hours (±10 mins) post dose 
• 
Day 14: 
1. 
Prior to dosing 
2. 
4 hours (±10 mins) post dose 
12 The DSST, DCFS, MHYS, FOG-Q, and MoCA to be done by a qualified clinical rater. 
13 MCI subjects only 
14 Cohort B only; DLB and PDD subjects 
15RBD+PD, DLB and PDD subjects only 
16 Cohort A only; MCI and RBD+PD subjects 
17 RBD+PD subjects only 


Sponsor: CuraSen Therapeutics, Inc. 
Protocol Number: CST103/CST107-CLIN-011 
Version and Date: 
v1.0 / 24May2022 
 
18 The RBD1Q, ESS, HADS, and GDS are per subject self-report. 
19 First administration of CANTAB is to familiarize the subject with the tests and equipment. The CANTAB should be administered after completion of FERT 
for Cohort A, and after completion of EEG for Cohort B at the following timepoints in each treatment period: 
• 
Cohort A: 
• 
Day 1: 
1. 
Prior to first dose 
2. 
4 hours (±30 mins) after dosing 
• 
Day 7: After dosing (up to 4 hours) 
• 
Day 14: After dosing (up to 4 hours) 
• 
Cohort B: 
1. Day 1: 
1. Prior to first dose 
2. 4 hours (±30 mins) after dosing 
2. Day 7: After dosing (up to 4 hours) 
3. Day 14: After dosing (up to 4 hours) 
20 The PLR test will be conducted after the CANTAB. The PLR test will be performed at the following timepoints in each treatment period: 
4. Day 1: 
1. Prior to first dose 
2. After post dose CANTAB 
5. Day 7: After post dose CANTAB 
6. Day 14: After post dose CANTAB 
21 Cohort B only: First assessment with EEG on Day 1 pre-dose is to obtain a baseline for each period. The EEG will be conducted on Day 14 in clinic (~1 
hour). EEG will be conducted at the following timepoints in each treatment period: 
• 
Day 1: 
• Prior to dosing 
• 3 hours (±15 mins) after dosing 
• 
Day 14: After dosing (up to 3 hours) 
Cohort B (select sites only): First administration of Sustained Attention to Response Task (SART) is to obtain baseline for each period (it will be conducted 
only at a subset of sites). SART will be conducted at the following timepoints in each treatment period: 
• 
Day 1: 
1. 
Prior to dosing 
2. 
3 hours (±15 mins) after dosing such as to occur during the EEG collection period 
• 
Day 14: After dosing (up to 3 hours) such as to occur during the EEG collection period 
22 Cohort A only: FERT will be conducted at the following timepoints in each treatment period: 
• 
Day 1: Prior to dosing 
• 
Day 7: After dosing 


Sponsor: CuraSen Therapeutics, Inc. 
Protocol Number: CST103/CST107-CLIN-011 
Version and Date: 
 v1.0 / 24May2022 
 
• 
Day 14: After dosing 
23 Once all screening visit procedures are completed and the subject meets all eligibility criteria, the BioStamp device will be dispensed to the subject who will 
be instructed to wear for 7 days prior to the Treatment Period 1 – Day 1 Visit. The BioStamp device will be re-dispensed at 2 other timepoints (at each of 
the Day 1 Visits in Treatment Periods 1 and 2), worn for 14 days and removed on Day 14. 
24 C-SSRS not completed on Day 1 during Treatment Period 1. 
25 The neuromelanin sensitive MRI sequence is optional depending on the imaging facility’s capabilities. If not performed at Screening, it may be performed at 
the Follow-up visit or at any other convenient time during the study. 
 
 


Sponsor: CuraSen Therapeutics, Inc. 
Protocol Number: CST103/CST107-CLIN-011 
Version and Date: 
v1.0 / 24May2022 
 
UK/Belgium Subjects: Schedule of Events for Each Treatment Period 
 
Screening 
Lead-In 
Treatment Periods 1 & 21 
Follow-Up 
Day -28 to 
Day -8 
Day -14 to 
Day -1 
Day 1 
Day 72 
(±1) 
Day 14/EW3, 4 
(±1) 
~2 Weeks after 
Last Dose of 
Study Drug or 
EW Visit3 
Outpatient visit 
X 
X 
X 
X 
X 
X 
Informed consent 
X 
Randomization 
X 
Inclusion / Exclusion 
criteria valuation 
X 
X 
X 
Medical history 
X 
Height and weight, BMI 
calculation 
X 
Vital signs5 
X 
X 
X 
X 
X 
ECG6 
X 
X 
X 
X 
X 
Physical exam, complete7 
X 
X 
Safety labs8 
X 
X 
X 
X 
Urine drug screen 
X 
Alcohol test 
X 
X 
Hepatitis and HIV 
serologies 
X 
TSH 
X 
Serum FSH9 
X 
β-hCG pregnancy test9 
X 
 


Sponsor: CuraSen Therapeutics, Inc. 
Protocol Number: CST103/CST107-CLIN-011 
Version and Date: 
v1.0 / 24May2022 
 
 
Screening 
Lead-In 
Treatment Periods 1 & 21 
Follow-Up 
Day -28 to 
Day -8 
Day -14 to 
Day -1 
Day 
1 
Day 72 
(±1) 
Day 14/EW3, 4 
(±1) 
~2 Weeks after 
Last Dose of 
Study Drug or 
EW Visit3 
Serum or urine pregnancy 
test9 
X 
X 
X 
SARS-CoV-2 status 
assessment10 
X 
X 
PK sample11 
X 
X 
Pharmacodynamic sample 
collection 
X 
X 
C-SSRS 
X 
X23 
X 
X 
X 
DSST12, 13 
X 
Dementia Cognitive 
Fluctuation Scale (DCFS)12,14 
X 
X 
X 
Modified Hoehn & Yahr 
Scale (MHYS)12, 15 
X 
HADS18 
X 
X 
X 
Freezing of Gait Questionnaire 
(FOG-Q)12, 15 
X 
X 
RBD1Q17, 18 
X 
MoCA12 
X 
Epworth Sleepiness Scale 
(ESS)18 
X 
X 
X 
X 
Geriatric Depression Scale 
(GDS)18 
X 
X 
X 
 


Sponsor: CuraSen Therapeutics, Inc. 
Protocol Number: CST103/CST107-CLIN-011 
Version and Date: 
 v1.0 / 24May2022 
 
Screening 
Lead-In 
Treatment Periods 1 & 21 
Follow-Up 
Day -28 to 
Day -8 
Day -14 to 
Day -1 
Day 1 
Day 72 
(±1) 
Day 14/EW3, 4 
(±1) 
~2 Weeks after 
Last Dose of 
Study Drug or 
EW Visit3 
CANTAB19 
 
X 
X 
X 
X 
 
Pupillary Light Reflex 
(PLR) Test20 
 
 
X 
X 
X 
 
EEG21 
 
 
X 
 
X 
 
Sustained Attention to 
Response Task (SART)21 
 
 
X 
 
X 
 
Facial Recognition Task 
(FERT) 16, 22 
 
 
X 
X 
X 
 
CST-103+CST-107 or 
matching placebo 
administration 
 
 
 
 
 
 
Neuromelanin MRI scan 
X24 
 
 
 
 
X24 
Assessment of AEs 
 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
AE = adverse event; ECG = electrocardiogram; EEG = electroencephalogram; PK = pharmacokinetics 
1 Wash-out period between Treatment Periods 1 & 2 is 14 (+ 5) days. 
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. 
3 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. 
4 Subjects who withdraw from the study prior to completion of dosing should complete Day 14 safety assessments at the time of withdrawal. 
5 Vital signs to include BP, HR, respiration rate, and oral/tympanic temperature; triplicate BP and HR measurements (separated by approximately 1 minute) 
after subject is supine for 5 minutes; vital signs will be obtained at every study visit as follows: 
• 
Screening 
• 
Day 1 of each treatment period: 


Sponsor: CuraSen Therapeutics, Inc. 
Protocol Number: CST103/CST107-CLIN-011 
Version and Date: 
 v1.0 / 24May2022 
 
1. Prior to dosing (within 15 minutes) 
2. 1 hour (±30 mins) after dosing 
• 
Day 7 of each treatment period: 1 hour (±30 mins) after dosing 
• 
Day 14 of each treatment period: 1 hour (±30 mins) after dosing 
• 
Follow-Up Visit 
6 Subjects will be required to rest in a supine position for at least 5 minutes prior to the recording of ECG. ECGs to be obtained at the following timepoints: 
• 
Screening 
• 
Lead-In 
• 
Day 1 of each treatment period: 
• 
Prior to dosing (within 15 minutes) 
• 
1 hour (±30 mins) after dosing 
• 
4 hours (±30 mins) after dosing 
• 
Day 14 of each treatment period: 
1. 1 hour (±30 mins) after dosing 
2. 4 hours (±30 mins) after dosing 
• 
Follow-Up Visit 
7 A complete physical examination (PE) (excluding genital, rectal and breast exams) is required at Screening; the Follow-Up PE will be symptom-driven based 
on subject complaints. 
8 Safety labs to include hematology, chemistries, and urinalysis. Subjects should be fasting for 8 hours for the safety labs. 
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 and at the Follow-Up visit. 
10 Subjects to be assessed for current infection per local site standard procedure. 
11 PK sample timepoints (CST-103/CST-107) in each treatment period: 
• 
Day 1: 
1. Prior to dosing 
2. 4 hours (±10 mins) post dose 
• 
Day 14: 
1. Prior to dosing 
2. 4 hours (±10 mins) post dose 
12 The DSST, DCFS, MHYS,  FOG-Q, and MoCA to be done by a qualified clinical rater. 
13 MCI subjects only 
14 Cohort B only; DLB and PDD subjects 
15RBD+PD, DLB and PDD subjects only 
16 Cohort A only; MCI and RBD+PD subjects 
17 RBD+PD subjects only 
18 The RBD1Q, ESS, HADS, and GDS are per subject self-report. 
19 First administration of CANTAB is to familiarize the subject with the tests and equipment. The CANTAB should be administered after completion of FERT 
for Cohort A, and after completion of EEG for Cohort B at the following timepoints in each treatment period: 


Sponsor: CuraSen Therapeutics, Inc. 
Protocol Number: CST103/CST107-CLIN-011 
Version and Date: 
 v1.0 / 24May2022 
 
• 
Cohort A: 
o Day 1: 
1. Prior to first dose 
2. 4 hours (±30 mins) after dosing 
• 
Day 7: After dosing (up to 4 hours) 
• 
Day 14: After dosing (up to 4 hours) 
• 
Cohort B: 
• 
Day 1: 
1. Prior to first dose 
2. 4 hours (±30 mins) after dosing 
• 
Day 7: After dosing (up to 4 hours) 
• 
Day 14: After dosing (up to 4 hours) 
20 The PLR test will be conducted after the CANTAB. The PLR test will be performed at the following timepoints in each treatment period: 
• 
Day 1: 
1. Prior to first dose 
2. After post dose CANTAB 
• 
Day 7: After post dose CANTAB 
• 
Day 14: After post dose CANTAB 
21 Cohort B only: First assessment with EEG on Day 1 pre-dose is to obtain a baseline for each period. The EEG will be conducted on Day 14 in clinic (~1 
hour). EEG will be conducted at the following timepoints in each treatment period: 
• 
Day 1: 
1. 
Prior to dosing 
2. 
3 hours (±15 mins) after dosing 
• 
Day 14: After dosing (up to 3 hours) 
Cohort B (select sites only): First administration of Sustained Attention to Response Task (SART) is to obtain baseline for each period (it will be conducted 
only at a subset of sites). SART will be conducted at the following timepoints in each treatment period: 
• 
Day 1: 
1. 
Prior to dosing 
2. 
3 hours (±15 mins) after dosing such as to occur during the EEG collection period 
• 
Day 14: After dosing (up to 3 hours) such as to occur during the EEG collection period 
22 Cohort A only: FERT will be conducted at the following timepoints in each treatment period: 
• 
Day 1: Prior to dosing 
• 
Day 7: After dosing 
• 
Day 14: After dosing 
 
23 C-SSRS not completed on Day 1 during Treatment Period 1. 


Sponsor: CuraSen Therapeutics, Inc. 
Protocol Number: CST103/CST107-CLIN-011 
Version and Date: 
 v1.0 / 24May2022 
 
24 The neuromelanin sensitive MRI sequence is optional depending on the imaging facility’s capabilities. If not performed at Screening, it may be 
performed at the Follow-up visit or at any other convenient time during the study.