A Phase 2a Open-Label Study to Evaluate the Safety, Tolerability and Efficacy of CAD-1883 Oral Treatment in Adults With Essential Tremor
Phase: PHASE2
Conditions: Essential Tremor
Sponsor: Cadent Therapeutics

CLINICAL STUDY PROTOCOL 
A Phase 2a Open-Label Study to Evaluate the Safety,  
Tolerability and Efficacy of CAD-1883 Oral Treatment 
in Adults with Essential Tremor (CADENCE-1) 
Investigational Product: CAD-1883 
Protocol Number: CAD1883-201 (CADENCE-1)  / NCT03688685
IND Number: 140185 
EudraCT Number:  2017-004223-70 
Sponsor: 
Cadent Therapeutics, Inc.  
Version Number: Amendment 3.0 
Date: 09 July 2019 
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the written consent of 
Cadent Therapeutics, Inc. except to the extent that disclosure would be required by law and for the 
purpose of evaluating and/or conducting a clinical study for Cadent Therapeutics, Inc. You are allowed to 
disclose the contents of this document only to your Institutional Review Board or Independent Ethics 
Committee and study personnel directly involved with conducting this protocol. Persons to whom the 
information is disclosed must be informed that the information is confidential and proprietary to 
Cadent Therapeutics, Inc and that it may not be further disclosed to third parties. 
Personal Protected Data

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INVESTIGATOR AGREEMENT 
By signing below, I agree that: 
I have read this protocol. I approve this document and I agree that it contains all necessary details 
for carrying out the study as described. I will conduct this study in accordance with the design 
and specific provision of this protocol and will make a reasonable effort to complete the study 
within the time designated. I will provide copies of this protocol and access to all information 
furnished by Cadent Therapeutics, Inc to study personnel under my supervision. I will discuss 
this material with them to ensure they are fully informed about the study product and study 
procedures. I will let them know that this information is confidential and proprietary to 
Cadent Therapeutics, Inc and that it may not be further disclosed to third parties. I understand 
that the study may be terminated, or enrollment suspended at any time by 
Cadent Therapeutics, Inc, with or without cause, or by me if it becomes necessary to protect the 
best interests of the study subjects. 
I agree to conduct this study in full accordance with Food and Drug Administration (FDA) 
Regulations, Institutional Review Board (IRB)/Ethic Committee Regulations and International 
Council for Harmonization (ICH) Guidelines for Good Clinical Practices. 
______________________________________________ 
____________________ 
Investigator’s Signature 
Date 
______________________________________________ 
Investigator’s Printed Name 

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SYNOPSIS 
Sponsor 
Cadent Therapeutics, Inc. 
Investigational 
Product  
CAD-1883 
Protocol Number 
CAD1883-201 
Protocol Title 
A Phase 2a Open-Label Study to Evaluate the Safety, Tolerability and 
Efficacy of CAD-1883 Oral Treatment in Adults with Essential Tremor 
(CADENCE-1) 
Study Phase 
2a 
Study Rationale 
CAD-1883 is an investigational product being developed as a new treatment 
for Essential Tremor (ET), a movement disorder characterized by dysfunction 
of the cerebellum and its associated motor control circuit (Haubenberger 
et al, 2018). Tremor is defined as a rhythmic and oscillatory movement of a 
body part with a relatively constant frequency and variable amplitude. It is 
caused by alternating contractions of antagonistic muscles. Tremor is the 
most common of all movement disorders, and ET is the most common 
neurologic cause of tremor. The usual course of ET is one of gradual 
progression. Patients with persistent disability from ET need continuous 
symptomatic drug therapy. Available drug treatments are not effective in all 
patients, often provide inadequate symptomatic relief, and the symptomatic 
benefit of chronic administration often declines over time and is frequently 
associated with intolerable side effects. Therapy options for ET patients who 
do not benefit from pharmacologic treatment include deep brain stimulation 
(DBS) requiring surgery for placement of brain stimulator(s), magnetic 
resonance image (MRI)-guided thalamotomy via focused ultrasound (to treat 
persistently disabling unilateral limb tremor), or botulinum toxin injections 
(to treat persistently disabling hand, head, or vocal cord tremor). The efficacy 
of these invasive, non-pharmacologic therapies may also wane over time, and 
may be associated with intolerable side effects. Therefore, to address these 
important unmet medical needs, efforts are required to develop new 
treatments for ET targeting the cerebellar dysregulation responsible for the 
movement disorder. 
The cerebellum is required for coordinated motion, including movements of 
the hands, limbs, trunk, and eyes, and the synchrony of speech, all of which 
are disrupted in ET. The cerebellar cortex, together with the inferior olivary 
nucleus and deep cerebellar nuclei, comprises the olivocerebellar circuit. 
Cerebellar output critically depends on the precise timing of action potentials 
in the principal neurons of the olivocerebellar circuit, especially cerebellar 
Purkinje neurons (Llinas, 2014). 
Small conductance calcium-activated potassium (SK) channels are a family 
of potassium channels gated by intracellular calcium (Kshatri, 2018). In 
neurons, SK channels are gated by calcium that passes through voltage-gated 
calcium channels, which are activated by each action potential. SK channels 

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regulate action potential timing by generating hyperpolarizing potassium 
currents between action potentials. In principle neurons of the olivocerebellar 
circuit, including cerebellar Purkinje neurons and their major afferent 
neurons of the inferior olivary nucleus, SK2 and SK3 channel-mediated after-
hyperpolarizing currents represent a molecular pace-making mechanism 
centrally implicated in the coordination of movement. 
CAD-1883 is a small molecule positive allosteric modulator (PAM) of SK 
channels 
CAD-1883 represents the first selective SK channel PAM 
candidate suitable for entering clinical development in patients with ET. 
CAD-1883 is anticipated to be used for the treatment of ET throughout the 
course of the patient’s disease. This study offers the opportunity to 
understand the safety, tolerability, and efficacy of CAD-1883 in the ET 
patient population. 
Study Population 
Subjects will be aged between 18 and 75 years old, inclusive, with a history 
of tremor for at least 3 years. 
Duration of Subject 
Involvement 
Individual subject participation could be up to 56 days. 
Study Objectives 
Primary Objectives 
To evaluate the safety and tolerability of twice-daily oral dosing of 
CAD-1883 over 14 days of treatment in adult subjects with ET. 
Secondary Objectives 
To evaluate the efficacy of twice-daily oral dosing of CAD-1883 over 14 
days of treatment as measured by: 
•
The Essential Tremor Rating Assessment Scale (TETRAS)-
performance subscale (PS) total score change from Baseline to Day 14
•
TETRAS-PS upper limb subscale score change from Baseline to Day
14
•
Change from Baseline to Day 14 in upper limb tremor severity, mean
amplitude, and mean frequency, measured in the clinic using a wearable
sensor
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Study Design 
This is an open-label study designed to evaluate the safety, tolerability, and 
efficacy of CAD-1883 administered twice daily orally to adult subjects with 
ET. Subjects will undergo a screening period of a minimum of 14 days up to 
a maximum of 35 days in which the subject will washout from prior 
, to allow the effects of previous 
medication(s)
 to be eliminated. During the Screening period, each 
subject will undergo full assessment including medical and treatment history 
for ET, physical and neurological examination, in addition to laboratory 
testing, 12-lead electrocardiogram (ECG), and other screening assessments. 
The diagnosis of ET must be established by the Investigator at Screening 
based on the Movement Disorder Society (MDS) criteria (Bhatia, 2018) with 
a documented severity of tremor based on the clinician-administered 
TETRAS-PS (Elble, 2012). 
Per the Investigator’s discretion, re-testing of any laboratory abnormality at 
the central lab or at a local lab is permissible, with prior approval from the 
Medical Monitor. 
Subjects who previously failed screening can be invited to rescreen up to two 
additional times, with recommendation by the Investigator and with approval 
by the Sponsor. 
The study will be open label consisting of 1 treatment group receiving 
300 mg twice daily oral dosing of CAD-1883 for a treatment period of 
14 days. 
The selected dose is anticipated to be well-tolerated by subjects with ET for 
the duration of the treatment period. A 14-day treatment period represents an 
adequate time period to permit the initial assessment of safety and tolerability 
of CAD-1883 as well as a determination of early treatment effect on reducing 
the magnitude and severity of tremor while limiting the potential risk 
associated with a novel investigational drug. 
Safety and tolerability will be monitored throughout the study duration 
including in-clinic assessments of adverse events (AEs), serious adverse 
events (SAEs), vital signs including orthostatic vital signs, 12-lead ECG, 
urinalysis, hematology, clinical chemistry, composite biomarker panel for 
renal tubular injury, and CAD-1883 plasma concentration level on Days 1, 7, 
14, and 21. 
Efficacy will be evaluated as follows: 
•
TETRAS-PS total score change from Baseline to Day 14
•
TETRAS-PS upper limb subscale score change from Baseline to Day
14
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•
Change from Baseline to Day 14 in upper limb tremor severity, mean
amplitude, and mean frequency, measured in the clinic using a wearable
sensor
• 
The TETRAS-PS will be recorded via videography for centralized evaluation 
and rating by an independent blinded panel of experts.  
At the Baseline/Pre-dose visit (which is the last day of the Screening period), 
subjects will undergo all required procedures including confirmation that all 
eligibility criteria are met. 
The Day 1 visit can occur up to 3 business days following the Baseline/Pre-
dose visit. Analysis of the pre-dose laboratory assessments (chemistry, 
hematology, urinalysis) should be conducted by the Central Laboratory, with 
the results available and reviewed by the Principal Investigator, or designee, 
prior to dosing the subject with CAD-1883 (Day 1 visit). On Day 1, subjects 
will be dosed in the clinic with the first dose of CAD-1883 300 mg 
(3 capsules of 100 mg each) and will be monitored in the clinic prior to 
ingesting the second dose of CAD-1883 300 mg (3 capsules of 100 mg each) 
in the clinic, 4 to 5 hours later.  Additional safety and all efficacy assessments 
will be completed after the 2nd in clinic dose on Day 1 as indicated in the 
SOA (Appendix A, Table 2). 
Subjects will be dispensed study drug for continued twice-daily oral self-
administration at home. After Day 1, subjects are instructed to ingest the first 
daily dose of CAD-1883 of 300 mg (3 capsules of 100 mg each) at home 
upon awakening in the morning. The second daily dose of 300 mg (3 
capsules of 100 mg each) will be taken 8 hours (±2 hours) after the first daily 
dose. Each subject is provided with a medication diary to denote the date and 
time of at-home study drug dosing. 
The pre-dose laboratory assessments (chemistry, hematology, urinalysis) 
should be sent to the Central Laboratory for analysis. Under exceptional 
circumstances, the pre-dose laboratory assessments (chemistry, hematology, 
urinalysis) can be sent for expedited analysis at the local laboratory, along 
with duplicate samples sent to the Central Laboratory. The results of all 
laboratory assessments should be available and reviewed by the Principal 
Investigator, or designee, prior to dosing the subject. 
Subjects will return to the site for further assessments on Day 7 (-1 day) and 
Day 14 (±1 day). On these two site visit days, the subjects are instructed to 
ingest the first daily dose of CAD-1883 of 300 mg (3 capsules of 100 mg 
each) 4 to 5 hours prior to the scheduled and/or anticipated dosing of the 
second daily dose of CAD-1883 in the clinic. The second daily dose of CAD-
1883 300 mg (3 capsules of 100 mg each) will be taken in the clinic, under 
the supervision of study staff, 4 to 5 hours after the first daily dose. 
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Subjects will return to the clinic for a Follow-up visit (Day 21 [±1 day]). 
On Days 1, 7, 14, and 21, subjects will undergo safety monitoring consisting 
of reporting of AEs or SAEs, collection of vital signs including orthostatic 
vital signs, undergo a 12-lead ECG, and collection of urine for urinalysis and 
for kidney injury biomarkers assessment, and blood for hematology, clinical 
chemistry, and plasma drug level. Assessment of rating scales and upper limb 
wearable sensor measurements will also be performed. 
subjects will have the option to 
complete at-home assessments of tremor using the wearable sensor. 
Upon completion of the 14-day treatment period, subjects will return to the 
site for the Day 21 Follow-up visit, approximately 7 days (-1 day) after the 
last dose of study drug was administered. 
Study Endpoints 
Primary Endpoint (Safety) 
Safety: 
The primary endpoint of the study is to evaluate the occurrence and severity 
of treatment emergent AEs.  
Secondary Endpoints (Efficacy) 
Secondary efficacy endpoints will be measured by: 
•
TETRAS-PS total score change from Baseline to Day 14
•
TETRAS-PS upper limb subscale score change from Baseline to
Day 14
•
Change from Baseline to Day 14 in upper limb tremor severity, mean
amplitude, and mean frequency, measured in the clinic using a wearable
sensor
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• 
Efficacy Assessments: 
Rating Scales 
The treatment effect will be evaluated by means of the TETRAS-PS, which is 
a validated scale that has been used in recently conducted clinical trials in 
subjects with ET (Elble, 2012). It provides an accurate reflection of the 
clinical response to treatment on the amplitude of tremor over multiple bodily 
locations and over time. 
The TETRAS assessments at Screening, Baseline/Pre-dose, Days 1, 7, 14, 
and Follow-up visit (Day 21) will be administered by a certified rater. 
TETRAS raters at each site must demonstrate expertise in the administration 
of the TETRAS according to criteria preset by independent central rating 
experts. The TETRAS raters at each site can be the Principal Investigator or a 
staff member delegated as a rater by the Principal Investigator. Each site must 
make every effort, to the extent that is possible, to ensure availability of a 
primary rater and a backup rater to perform all TETRAS assessments on the 
same subjects throughout the study duration. 
The TETRAS-PS assessments at the Screening visit, Baseline/Pre-dose, Day 
1, Day 7, Day 14, and Day 21 clinic visits will be recorded using 
videography for centralized evaluation and rating by independent blinded 
central raters (neurologists) with expertise in the assessment of ET. 
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On Day 1: the TETRAS-PS will be administered 2 to 4 hours following the 
second in-clinic dose. 
On Day 7: the TETRAS-PS, 
will be performed 2 to 4 hours following the in-clinic dose. 
On Day 14: the TETRAS-PS, 
will be performed 2 to 4 hours following the in-clinic dose. 
At Follow up visit (Day 21): the TETRAS-PS,
are performed once any time during the visit. 
Efficacy Assessments: 
Wearable Sensor 
In addition to the assessment of efficacy via rating scales, treatment effect 
will be evaluated by measuring tremor with a sensor worn on the upper limb 
(index finger). These assessments will be conducted during the clinic visits 
and optionally at-home. 
In-Clinic Assessment: 
The wearable sensor measurements of upper limb tremor will be completed 
in the clinic once at any time during the Screening visit and at two different 
times during the Baseline/Pre-dose site visit. 
During the clinic visits on Day 1, the wearable sensor measurements of upper 
limb tremor will be captured once, 2 to 4 hours following the second in-clinic 
dose. 
During the site visits on Days 7 and 14, the wearable sensor measurements of 
upper limb tremor will be captured once, 2 to 4 hours following the in-clinic 
dose. 
During the Follow-up visit (Day 21), the wearable sensor measurements of 
upper limb tremor will be completed once, at any time during the visit. 
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In-clinic assessments will be obtained during the performance of 4 
maneuvers: 
1.
extended arms posture,
2.
wing-beating posture,
3.
kinetic “finger-to-chin” movement, and
4.
arm on table posture.
These assessments will be performed with the sensor on the left index finger 
and with the sensor on the right index finger. 
In addition, the subject will wear the sensor on the index finger of each hand 
while performing 3 activities of daily living:  
1.
pouring from a cup,
2.
drinking from a cup, and
3.
eating with a spoon.
Sample Size 
Approximately 30 subjects will be enrolled into the study. 
Treatment Groups 
One open-label treatment group with all subjects being assigned CAD-1883 
300 mg twice daily.  
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Safety Assessments 
Safety will be assessed via  reported AEs (including observed or volunteered 
problems, complaints, or symptoms), scheduled in clinic safety examinations, 
and changes in vital signs including orthostatic vital signs, weight, laboratory 
values, and ECGs.  
Recommendations to alter study conduct due to safety concerns will be based 
solely on safety risk assessment by the Medical Monitor, without regard to 
any effect on the final efficacy analysis. 
Inclusion Criteria 
1.
Adult subjects between 18 and 75 years of age, inclusive, with history of
tremor that fulfills the diagnostic criteria of ET according to Movement
Disorder Society (MDS) Consensus Statement on the classification of
tremors from the task force on tremor of the International Parkinson and
Movement Disorder Society (Bhatia, 2018).
2.
Duration of ET illness since the first symptoms were noticeable of at
least 3 years or more prior to screening, based on the subject’s self-
report, with onset prior to age 65 years old, per the Principal
Investigator’s assessment during screening.
3. 
4. 
5. 
6.
Except for ET, subjects must be otherwise healthy as determined by the
Investigator, based upon a medical evaluation including medical history,
physical examination, laboratory tests, and 12-lead ECG.
7.
Subjects are able to understand study activities required, can give written
informed consent, and are willing to comply with the requirements and
restrictions of the study.
8.
Women of childbearing potential must undertake a pregnancy test with
documented negative serum pregnancy test at Screening and negative
urine pregnancy test result at Baseline/Pre-dose, Days 7 and 14 before
administration of the study drug, and then at the Follow-up visit
(Day 21).
9.
Postmenopausal women must have had ≥365 days of spontaneous
amenorrhea, with documented follicle-stimulating hormone (FSH)
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≥38 IU/mL, prior to screening. If needed, per Investigator’s judgment, 
FSH level can be performed at Screening. 
10. Surgically sterile women must have documentation of a hysterectomy,
bilateral ovariectomy, or bilateral tubal ligation.
11. Female subjects with reproductive potential and male subjects with
reproductive potential or who have female partners of reproductive
potential, must agree to use two effective methods of contraception from
signing informed consent until 90 days after the last dose of study drug.
Acceptable forms of contraception include double barrier (i.e., condom
with spermicide); surgically sterilized partner (180-day minimum); or
abstinence.
12. 
13. 
Exclusion Criteria 
1.
Prior or ongoing medical condition or any abnormal finding on the
Screening visit physical exam, ECG, laboratory testing that, in the
Investigator’s opinion, could adversely affect the safety of the subject or
the conduct of the study assessments.
2.
Any neurological abnormality other than ET upon neurological exam,
including dystonia, ataxia, or any other neurodegenerative disease,
including multiple sclerosis or Parkinson’s disease.
3. 
4.
Significant cognitive impairment or dementia that, in the opinion of the
Investigator, would interfere with participation in the study.
5. 
. 
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6. 
7.
An unstable thyroid condition that, per the Investigator’s judgment based
on medically significant abnormality of thyroid function testing at
Screening. Note: an abnormal TSH level at Screening can be followed by
reflex testing of thyroid hormones (T3, T4), if needed, per the
Investigator’s judgment.
8.
History of, or evidence of psychogenic tremor at Screening.
9. 
10. 
11. History of anaphylaxis or hypersensitivity reactions to any of CAD-1883
excipients
12. Alkaline phosphatase, aspartate aminotransferase (AST), and/or alanine
aminotransferase (ALT) level >2.5 x upper limit of normal (ULN) at
Screening and/or at Baseline/Pre-dose.
13. Serum creatinine >120 μmol/L and/or creatinine clearance <60 mL/min
(according to Cockcroft-Gault formula) at Screening and/or at
Baseline/Pre-dose.
14. Total bilirubin >2.0 x ULN at Screening and/or at Baseline/Pre-dose.
Note: isolated bilirubin >2.0 x ULN is acceptable if bilirubin is
fractionated and direct bilirubin is <35%.
15. Exclusionary ECG abnormalities:
1) History of Long QT syndrome and/or QTcF (Fridericia’s
correction) interval >450 msec (males) or >470 msec (females)
per 12-lead ECG done at Screening.
16.
17. History of Alcohol Use Disorder per Diagnostic Statistical Manual of
Mental Disorders, Fifth Edition (DSM-V) criteria.
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18. History of human immunodeficiency virus (HIV) infection or positive
screening result for: HIV 1 or 2 antibodies, hepatitis B surface antigen
(HBsAg), or hepatitis C virus antibody (HCVAb).
19. Has a diagnosis of epilepsy or any history of seizure as an adult, head
trauma, stroke, transient ischemic attack within 1 year prior to Screening,
unexplained loss of consciousness within 1 year prior to Screening, or
any lifetime history of asymptomatic or symptomatic orthostatic
hypotension (e.g., postural syncope).
20. History of unstable angina, myocardial infarction, chronic heart failure
(New York Heart Association Class 3 or 4), or clinically significant
conduction abnormalities (e.g., unstable atrial fibrillation) within 1 year
prior to screening.
21. 
22. 
23. 
24. 
. 
25. Any major psychiatric disorder that is uncontrolled (for the past 90 days)
that, per the Investigator’s judgment, can interfere with any of the study
procedures.
26. Subject has cancer, except for the following: basal cell carcinoma or
successfully treated squamous cell carcinoma of the skin; cervical
carcinoma in situ; prostatic carcinoma in situ; or other malignancies
curatively treated and with no evidence of disease recurrence for at least
3 years.
27.
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28. 
29.
30. Subjects with scheduled surgeries during the study period.
Statistical Analysis 
Statistical Analysis of Primary Safety Endpoint Data: 
•
Vital sign parameters outside the normal range will be listed and flagged
for review.
•
Orthostatic vital signs parameters for blood pressure outside specified
ranges will be listed and flagged for review.
•
Descriptive statistics of absolute and change from Baseline (pre-dose)
SBP, DBP, pulse rate, respiratory rate, and oral temperature at each
timepoint, will be tabulated. The mean change from Baseline data will
also be plotted across time.
•
Twelve-lead ECG parameters will be listed with any values outside the
normal range flagged. Descriptive statistics of absolute and change from
Baseline (pre-dose) heart rate, PR interval, QRS interval, QT interval and
QTcF interval at each timepoint, will be tabulated. The mean change
from Baseline data will also be plotted across time.
•
In addition, frequencies of QTcF data will be calculated according to the
following categories:
For absolute values
− 
QTcF >450 msec (males) and >470 msec (females) 
− 
QTcF >480 msec 
− 
QTcF >500 msec 
For change from Baseline 
− 
QTcF increase >30 msec 
− 
QTcF increase >60 msec 
Statistical Analysis of Key Secondary Efficacy Data: 
•
Mean TETRAS-PS total score change from Baseline over 14 days.
•
Mean TETRAS-PS upper limb subscale change from Baseline over
14 days.
•
Mean in-clinic wearable sensor measures of upper-limb tremor change
from Baseline severity, mean amplitude, and mean frequency.
•
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• 
Analyses of additional secondary efficacy data 
will be described in 
further detail in the protocol and Statistical Analysis Plan. 
Location of sites 
The study will be conducted at up to 15 clinical research sites. 
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TABLE OF CONTENTS 
Signature Page ................................................................................................................................ 2 
Investigator Agreement ................................................................................................................... 3 
Synopsis .......................................................................................................................................... 4 
Table of Contents .......................................................................................................................... 18 
List of Tables ................................................................................................................................ 22 
List of Abbreviations and Definition of Terms............................................................................. 23 
1 
Introduction and Background Information ............................................................................. 25 
1.1 
Rationale and Risk Benefit ............................................................................................ 26 
2 Study Objectives ..................................................................................................................... 27 
2.1 
Primary Objective(s) ..................................................................................................... 27 
2.2 
Secondary Objectives .................................................................................................... 27 
3 Study Design ........................................................................................................................... 28 
3.1 
Summary of Study Design ............................................................................................ 28 
3.2 
Study Indication ............................................................................................................ 30 
3.3 
Study Endpoints ............................................................................................................ 30 
3.3.1 Primary Endpoints ............................................................................................. 30 
3.3.2 Secondary Endpoints ......................................................................................... 30 
3.3.3 Exploratory Endpoints ....................................................................................... 30 
4 Selection and Withdrawal of subjects ..................................................................................... 32 
4.1 
Inclusion Criteria ........................................................................................................... 32 
4.2 
Exclusion Criteria .......................................................................................................... 33 
4.3 
Diet, Activities, and Other Restrictions......................................................................... 35 
4.3.1 Concomitant Medication .................................................................................... 35 
4.3.2 Caffeine .............................................................................................................. 36 
4.3.4 Physical Activities ............................................................................................. 36 
4.3.5 Dietary Aspects .................................................................................................. 37 
4.3.6 Smoking ............................................................................................................. 37 
4.4 
Withdrawal Criteria ....................................................................................................... 37 
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4.5 
Lost to Follow up .......................................................................................................... 37 
5 Study Treatments .................................................................................................................... 39 
5.1 
Treatment Groups .......................................................................................................... 39 
5.2 
Rationale for Dosing ..................................................................................................... 39 
5.3 
Randomization and Blinding ......................................................................................... 39 
5.4 
Breaking the Blind ........................................................................................................ 39 
5.5 
Drug Supplies ................................................................................................................ 39 
5.5.1 Formulation and Packaging ............................................................................... 39 
5.5.2 Study Drug Preparation and Dispensing ............................................................ 39 
5.5.3 Study Drug Administration ................................................................................ 39 
5.5.4 Treatment Compliance ....................................................................................... 39 
5.5.5 Storage and Accountability ................................................................................ 40 
6 Study Procedures .................................................................................................................... 41 
6.1 
Study Visits ................................................................................................................... 41 
6.1.1 Screening Period ................................................................................................ 41 
6.1.2 Pre-dose (Baseline) Visit ................................................................................... 42 
6.1.3 Day 1 Visit (First In-Clinic Dosing) .................................................................. 42 
6.1.4 In-clinic Treatment Period Study Visits ............................................................ 42 
6.1.5 Intervals Between Site Visits ............................................................................. 42 
6.1.6 Follow-up Visit .................................................................................................. 43 
6.2 
Early Termination Visit and Withdrawal Procedures ................................................... 43 
6.3 
Informed Consent .......................................................................................................... 43 
6.4 
Study Assessments and Procedures ............................................................................... 43 
7 Safety Assessments ................................................................................................................. 44 
7.1 
Adverse Events .............................................................................................................. 44 
7.1.1 Assessment of Adverse Events by the Investigator ........................................... 45 
7.2 
Serious Adverse Events ................................................................................................. 46 
7.3 
Serious Adverse Event Reporting − Procedures for Investigators ................................ 46 
7.4 
Pregnancy Reporting ..................................................................................................... 47 
7.5 
Expedited Reporting ...................................................................................................... 47 
7.6 
Special Situation Reports .............................................................................................. 48 
7.7 
Physical and Neurological Examinations ...................................................................... 48 

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7.8 
Electrocardiograms ........................................................................................................ 49 
7.9 
Vital Signs ..................................................................................................................... 49 
7.10 Orthostatic Vital Signs .................................................................................................. 49 
7.11 Clinical Laboratory Evaluations .................................................................................... 51 
7.12 Columbia Suicide Severity Rating Scale (C-SSRS) ..................................................... 51 
8 Efficacy Assessments.............................................................................................................. 53 
8.1 
Rating Scales ................................................................................................................. 53 
8.2 
Wearable Sensor ............................................................................................................ 54 
8.2.1 In-Clinic Assessment ......................................................................................... 54 
11 Statistics .................................................................................................................................. 58 
11.1 Analysis Populations ..................................................................................................... 58 
11.2 Statistical Methods ........................................................................................................ 58 
11.2.1 Analysis of Primary (Safety) Endpoint Data ..................................................... 58 
11.2.2 Analysis of Secondary Efficacy Endpoints........................................................ 59 
11.2.4 Sample Size Determination................................................................................ 59 
12 Data Management and Record Keeping ................................................................................. 60 
12.1 Data Management ......................................................................................................... 60 
12.1.1 Data Handling .................................................................................................... 60 
12.1.2 Computer Systems ............................................................................................. 60 
12.1.3 Data Entry .......................................................................................................... 60 
12.1.4 Medical Information Coding.............................................................................. 60 
12.1.5 Data Validation .................................................................................................. 60 
12.2 Record Keeping ............................................................................................................. 61 
12.3 End of Study .................................................................................................................. 61 
13 Investigator Requirements and Quality Control ..................................................................... 62 
13.1 Ethical Conduct of the Study ........................................................................................ 62 
13.2 Institutional Review Board/Independent Ethics Committee ......................................... 62 
13.3 Informed Consent .......................................................................................................... 62 
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13.4 Study Monitoring Requirements ................................................................................... 62 
13.5 Disclosure of Data ......................................................................................................... 63 
13.6 Retention of Records ..................................................................................................... 63 
13.7 Publication Policy ......................................................................................................... 63 
13.8 Financial Disclosure ...................................................................................................... 64 
14 Study Administrative Information .......................................................................................... 65 
14.1 Protocol Amendments ................................................................................................... 65 
15 References ............................................................................................................................... 66 
Appendix A:  Schedule of Assessments ....................................................................................... 67 
Appendix B:  Clinical Laboratory Analytes ................................................................................. 72 

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LIST OF TABLES 
Table 2: 
Schedule of Assessments ............................................................................................ 67 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
AE 
ALT 
Adverse event 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
CFR 
Code of Federal Regulations 
CRO 
Clinical Research Organization 
C-SSRS
Columbia Suicide Severity Rating Scale 
DBP
Diastolic blood pressure 
DBS
Deep brain stimulation 
DSM-V 
Disorder per Diagnostic Statistical Manual of Mental Disorders, Fifth 
Edition 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EOS 
End of Study 
ET 
Essential Tremor 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HBsAg 
Hepatitis B surface antigen 
HCVAb 
Hepatitis C virus antibody 
HEENT 
Head, eyes, ears, nose, and throat 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization 
IRB 
Institutional Review Board 
MDS 
Movement Disorder Society 
MRI 
Magnetic resonance imaging 
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Abbreviation 
Definition 
PAM 
Positive allosteric modulator 
PCR 
Polymerase chain reaction 
PE 
Physical exam 
PS 
Performance subscale 
PV 
Pharmacovigilance 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic blood pressure 
SK 
Small conductance calcium-activated potassium 
SOA 
Schedule of Assessments 
SUSAR 
Suspected unexpected serious adverse reaction 
TETRAS 
The Essential Tremor Rating Assessment Scale 
TSH 
Thyroid stimulating hormone 
ULN 
VS 
Upper limit of normal 
Vital Signs 
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1 
INTRODUCTION AND BACKGROUND INFORMATION 
CAD-1883 is an investigational product being developed as a new treatment for Essential 
Tremor (ET), a movement disorder characterized by dysfunction of the cerebellum and its 
associated motor control circuit (Haubenberger et al, 2018). Tremor is defined as a rhythmic and 
oscillatory movement of a body part with a relatively constant frequency and variable amplitude. 
It is caused by alternating contractions of antagonistic muscles. Tremor is the most common of 
all movement disorders, and ET is the most common neurologic cause of tremor. The usual 
course of ET is one of gradual progression. Patients with persistent disability from ET need 
continuous symptomatic drug therapy. Available drug treatments are not effective in all patients, 
often provide inadequate symptomatic relief, and the symptomatic benefit of chronic 
administration often declines over time and is frequently associated with intolerable side effects. 
Therapy options for ET patients who do not benefit from pharmacologic treatment include deep 
brain stimulation (DBS) requiring surgery for placement of brain stimulator(s), magnetic 
resonance image (MRI)-guided thalamotomy via focused ultrasound (to treat persistently 
disabling unilateral limb tremor), or botulinum toxin injections (to treat persistently disabling 
hand, head, or vocal cord tremor). The efficacy of these invasive, non-pharmacologic therapies 
may also wane over time, and may be associated with intolerable side effects. Therefore, to 
address these important unmet medical needs, efforts are required to develop new treatments for 
ET targeting the cerebellar dysregulation responsible for the movement disorder. 
The cerebellum is required for coordinated motion, including movements of the hands, limbs, 
trunk, and eyes, and the synchrony of speech, all of which are disrupted in ET. The cerebellar 
cortex, together with the inferior olivary nucleus and deep cerebellar nuclei, comprises the 
olivocerebellar circuit. Cerebellar output critically depends on the precise timing of action 
potentials in the principal neurons of the olivocerebellar circuit, especially cerebellar Purkinje 
neurons (Llinas, 2014). 
Small conductance calcium-activated potassium (SK) channels are a family of potassium 
channels gated by intracellular calcium (Kshatri, 2018) In neurons, SK channels are gated by 
calcium that passes through voltage-gated calcium channels, which are activated by each action 
potential. SK channels regulate action potential timing by generating hyperpolarizing potassium 
currents between action potentials. In principle neurons of the olivocerebellar circuit, including 
cerebellar Purkinje neurons and their major afferent neurons of the inferior olivary nucleus, SK2 
and SK3 channel-mediated after-hyperpolarizing currents represent a molecular pace-making 
mechanism centrally implicated in the coordination of movement. 
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CAD-1883 is anticipated to be used for the treatment of ET throughout the course of the patient’s 
disease. This study offers the opportunity to understand the safety, tolerability, and efficacy of 
CAD-1883 in the ET patient population. 
1.1 
Rationale and Risk Benefit 
The study will be open-label consisting of 1 treatment group receiving twice-daily oral dosing of 
CAD-1883 for a treatment period of 14 days. 
The selected dose is anticipated to be well-tolerated by subjects with ET for the duration of the 
treatment period. A 14-day treatment period represents an adequate time period to permit the 
initial assessment of safety and tolerability of CAD-1883 as well as a determination of early 
treatment effect on reducing the magnitude and severity of tremor while limiting the potential 
risk associated with a novel investigational drug. 
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2 
STUDY OBJECTIVES 
2.1 
Primary Objective(s) 
The primary objective of this study is to evaluate the safety and tolerability of twice-daily oral 
dosing of CAD-1883 over 14 days of treatment in adult patients with ET. 
2.2 
Secondary Objectives 
The secondary objectives of this study are to evaluate the efficacy of twice-daily oral dosing of 
CAD-1883 over 14 days of treatment as measured by: 
•
The Essential Tremor Rating Assessment Scale (TETRAS)-performance subscale (PS)
total score change from Baseline to Day 14
•
TETRAS-PS upper limb subscale score change from Baseline to Day 14
•
Change from Baseline to Day 14 in upper limb tremor severity, mean amplitude, and
mean frequency, measured in the clinic using a wearable sensor
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3 
STUDY DESIGN 
3.1 
Summary of Study Design 
This is an open-label study designed to evaluate the safety, tolerability, and efficacy of CAD-1883 
administered twice daily orally to adult subjects with ET. 
Subjects will undergo a screening period of a minimum of 14 days up to a maximum 
of 35 days in which the subject will “wash-out” from prior tremorgenic and anti-tremor 
medications, to allow the effects of previous medication(s) on tremor to be eliminated. During 
the Screening period, each subject will undergo full assessment including medical and treatment 
history for ET, physical and neurological examination, in addition to laboratory testing, 12-lead 
electrocardiogram (ECG), and other screening assessments. The diagnosis of ET must be 
established by the Principal Investigator at Screening based on the Movement Disorder Society 
(MDS) criteria (Bhatia, 2018) with a documented severity of tremor based on the clinician-
administered TETRAS-PS (Elble, 2012).
Safety and tolerability will be monitored throughout the study duration including in-clinic 
assessments of adverse events (AEs), serious adverse events (SAEs), vital signs including 
orthostatic vital signs, 12-lead ECG, urinalysis, hematology, clinical chemistry, and CAD-1883 
plasma concentration level on Days 1, 7, 14, and 21. 
Efficacy will be evaluated as follows: 
•
TETRAS-PS total score change from Baseline to Day 14
•
TETRAS-PS upper limb subscale score change from Baseline to Day 14
•
Change from Baseline to Day 14 in upper limb tremor severity, mean amplitude, and
mean frequency, measured in the clinic using a wearable sensor
The TETRAS-PS will be recorded via videography for centralized evaluation and rating by an 
independent blinded panel of expert(s).  
At the Baseline/Pre-dose visit, subjects will undergo all required procedures including 
confirmation that all eligibility criteria are met. 
The Day 1 visit can occur up to 3 business days following the Baseline/Pre-dose visit. Analysis 
of the pre-dose laboratory assessments (chemistry, hematology, urinalysis) should be conducted 
by the Central Laboratory, with the results available and reviewed by the Principal Investigator, 
or designee, prior to dosing the subject with CAD-1883 (Day 1 visit). On Day 1, subjects will be 
dosed in the clinic with the first dose of CAD-1883 300 mg (3 capsules of 100 mg each) and will 
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be monitored in the clinic prior to ingesting the second dose of CAD-1883 300 mg (3 capsules of 
100 mg each), 4 to 5 hours later.  Additional safety and all efficacy assessments will be 
completed after the 2nd in clinic dose on Day 1 as specified in the SOA (Appendix A, Table 2). 
Subjects will be dispensed study drug for continued twice-daily oral self-administration at home. 
After Day 1, subjects are instructed to ingest the first daily dose of CAD-1883 of 300 mg (3 
capsules of 100 mg each). The second daily dose of CAD-1883 300 mg (3 capsules of 100 mg 
each) will be taken 8 hours (±2 hours) after the first daily dose. Each subject is provided with a 
medication diary to denote the date and time of at-home study drug dosing.  
The pre-dose laboratory assessments (chemistry, hematology, urinalysis) should be sent to the 
Central Laboratory for analysis. Under exceptional circumstances, the pre-dose laboratory 
assessments (chemistry, hematology, urinalysis) can be sent for expedited analysis at the local 
laboratory, along with duplicate samples sent to the Central Laboratory. The results of laboratory 
assessments should be available and reviewed by the Principal Investigator, or designee, prior to 
dosing the subject. 
Additionally, a urine sample will be collected for determination of baseline levels of composite 
biomarker panel for renal tubular injury, which is not part of eligibility determination. 
Subjects will return to the site for further assessments on Day 7 (-1 day) and Day 14 (±1 day) 
and the Follow-up visit (Day 21 [±1 day]). 
On Days 1, 7, 14, and 21, subjects will undergo safety monitoring consisting of reporting of AEs 
or SAEs, collection of vital signs including orthostatic vital signs, undergo a 12-lead ECG, and 
collection of urine for urinalysis and a composite biomarker panel for renal tubular injury, and 
blood for hematology, clinical chemistry, and plasma drug level. On Day 1, 7 and 14, all urine 
and blood collections should take place after the TETRAS-PS assessment.  Assessment of rating 
scales and upper limb wearable sensor measurements will also be performed. 
On Day 7 and Day 14, the subjects are instructed to ingest the first daily dose of CAD-1883 of 
300 mg (3 capsules of 100 mg each) at home 4 to 5 hours prior to the scheduled and/or 
anticipated dosing of the second daily dose of CAD-1883. The second daily dose of CAD-1883 
300 mg (3 capsules of 100 mg each) will be taken in the clinic, under the supervision of study 
staff, 4 to 5 hours after the first daily dose. 
 subjects will have the option to complete at-home assessments of tremor using 
the wearable sensor. 
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Upon completion of the 14-day treatment period, subjects will return to the site for the Day 21 
Follow-up visit, approximately 7 days (±1 day) after the last dose of study drug was 
administered. 
3.2 
Study Indication 
CAD-1883 is an investigational product being developed as a new treatment for ET, a movement 
disorder characterized by dysfunction of the cerebellum and its associated motor control circuit 
(Haubenberger et al, 2018).  
3.3 
Study Endpoints 
3.3.1 
Primary Endpoints 
•
The occurrence and severity of treatment emergent AEs.
3.3.2 
Secondary Endpoints 
•
TETRAS-PS total score change from Baseline to Day 14
•
TETRAS-PS upper limb subscale score change from Baseline to Day 14
•
Change from Baseline to Day 14 in upper limb tremor severity, mean amplitude, and
mean frequency, measured in the clinic using a wearable sensor
3.3.3 
Exploratory Endpoints 
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4 
SELECTION AND WITHDRAWAL OF SUBJECTS 
4.1 
Inclusion Criteria 
Subjects who meet all of the following criteria will be eligible to participate in the study: 
1. Adult subjects between 18 and 75 years of age, inclusive, with history of tremor that fulfills
the diagnostic criteria of ET according to Movement Disorder Society (MDS) Consensus
Statement on the classification of tremors from the task force on tremor of the International
Parkinson and Movement Disorder Society (Bhatia, 2018).
2. Duration of ET illness since the first symptoms were noticeable of at least 3 years or more
prior to screening, based on the subject’s self-report, with onset prior to age 65 years old, per
the Principal Investigator’s assessment during screening.
3. 
4. 
5. 
6. Except for ET, subjects must be otherwise healthy as determined by the Investigator, based
upon a medical evaluation including medical history, physical examination, laboratory tests,
and 12-lead ECG.
7. Subjects are able to understand study activities required, can give written informed consent,
and are willing to comply with the requirements and restrictions of the study.
8. Women of childbearing potential must undertake a pregnancy test with documented negative
serum pregnancy test at Screening and negative urine pregnancy test result at Baseline/Pre-
dose, Days 7 and 14 before administration of the study drug, and then at the Follow-up visit
(Day 21).
9. Postmenopausal women must have had ≥365 days of spontaneous amenorrhea, with
documented follicle-stimulating hormone (FSH) ≥38 IU/mL, prior to screening. If needed,
per Investigator’s judgment, FSH level can be performed at Screening.
10. Surgically sterile women must have documentation of a hysterectomy, bilateral ovariectomy,
or bilateral tubal ligation.
11. Female subjects with reproductive potential and male subjects with reproductive potential or
who have female partners of reproductive potential, must agree to use two effective methods
of contraception from signing informed consent until 90 days after the last dose of study
drug. Acceptable forms of contraception include double barrier (i.e., condom with
spermicide); surgically sterilized partner (180-day minimum); or abstinence.
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12. 
13. 
4.2 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from participation in the study: 
1. Prior or ongoing medical condition or any abnormal finding on the Screening visit physical
exam, ECG, laboratory testing that, in the Investigator’s opinion, could adversely affect the
safety of the subject or the conduct of the study assessments.
2. Any neurological abnormality other than ET upon neurological exam, including dystonia,
ataxia, or any other neurodegenerative disease, including multiple sclerosis or Parkinson’s
disease.
3. 
4. Significant cognitive impairment or dementia that, in the opinion of the Investigator, would
interfere with participation in the study.
5. 
6. 
7. An unstable thyroid condition that, per the Investigator’s judgment based on medically
significant abnormality of thyroid function testing at Screening. Note: an abnormal TSH
level at Screening can be followed by reflex testing of thyroid hormones (T3, T4), if needed,
per the Investigator’s judgment.
8. History of, or evidence of psychogenic tremor at Screening.
9. 
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10.  
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11. History of anaphylaxis or hypersensitivity reactions to any of CAD-1883 excipients.
12. Alkaline phosphatase, aspartate aminotransferase (AST), and/or alanine aminotransferase
(ALT) level >2.5 x upper limit of normal (ULN) at Screening and/or at Baseline/Pre-dose.
13. Serum creatinine >120 μmol/L and/or creatinine clearance <60 mL/min (according to
Cockcroft-Gault formula) at Screening and/or at Baseline/Pre-dose.
14. Total bilirubin >2.0 x ULN at Screening and/or at Baseline/Pre-dose. Note: isolated bilirubin
>2.0 x ULN is acceptable if bilirubin is fractionated and direct bilirubin is <35%.
15. Exclusionary ECG abnormalities:
a.
History of Long QT syndrome and/or QTcF (Fridericia’s correction) interval
>450 msec (males) or >470 msec (females) per 12-lead ECG done at Screening.
16. 
17. History of Alcohol Use Disorder per Diagnostic Statistical Manual of Mental Disorders, Fifth
Edition (DSM-V) criteria.
18. History of human immunodeficiency virus (HIV) infection or positive screening result for:
HIV 1 or 2 antibodies, hepatitis B surface antigen (HBsAg), or hepatitis C virus antibody
(HCVAb).
19. Has a diagnosis of epilepsy or any history of seizure as an adult, head trauma, stroke,
transient ischemic attack within 1 year prior to Screening, unexplained loss of consciousness
within 1 year prior to Screening, or any lifetime history of asymptomatic or symptomatic
orthostatic hypotension (e.g., postural syncope).
20. History of unstable angina, myocardial infarction, chronic heart failure (New York Heart
Association Class 3 or 4), or clinically significant conduction abnormalities (e.g., unstable
atrial fibrillation) within 1 year prior to screening.
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21. 
22. 
23.
24. 
25. Any major psychiatric disorder that is uncontrolled (for the past 90 days) that, per the
Investigator’s judgment, can interfere with any of the study procedures.
26. Subject has cancer, except for the following: basal cell carcinoma or successfully treated
squamous cell carcinoma of the skin; cervical carcinoma in situ; prostatic carcinoma in situ;
or other malignancies curatively treated and with no evidence of disease recurrence for at
least 3 years.
27. 
28. 
29. 
30. Subjects with scheduled surgeries during the study period.
4.3 
Diet, Activities, and Other Restrictions 
4.3.1 
Concomitant Medication 
Occasional use of paracetamol will be allowed up to a maximum 
of 4 grams per 24 hours where required, but not on a regular basis. If a concomitant 
medication is needed during the study, this medication must be recorded on the electronic 
case report form (eCRF), stating its generic name, time of administration, dose, route and 
duration, as well as the reason for administration. 
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4.3.2 
Caffeine 
Consumption of caffeine- or xanthine- containing products (e.g., coffee, tea, cola drinks and 
chocolate) must be maintained without a change from well-established habit from 48 hours 
prior to the Baseline/Pre-dose visit until the Day 21 visit.  
4.3.4 
Physical Activities 
From Screening until the EOS examination, the subjects should refrain from excessive 
physical exercise and strenuous sports activities (endurance sports). 
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4.3.5 
Dietary Aspects 
No restrictions. 
4.3.6 
Smoking 
No restrictions. 
4.4 
Withdrawal Criteria 
Participation of a subject in this clinical study may be discontinued for any of the following 
reasons: 
•
The subject withdraws consent or requests discontinuation from the study for any reason
•
Occurrence of any medical condition or circumstance that exposes the subject to
substantial risk and/or does not allow the subject to adhere to the requirements of the
protocol
•
Any SAE, clinically significant AE, severe laboratory abnormality, intercurrent illness, or
other medical condition which indicates to the Investigator that continued participation is
not in the best interest of the subject
•
Pregnancy
•
Subject failure to comply with protocol requirements or study-related procedures
•
Termination of the study by the Sponsor or the regulatory authority
If a subject withdraws prematurely from the study due to the above criteria or any other reason, 
study staff should make every effort to complete the full panel of assessments scheduled for the 
Early Termination visit (Day 14). The reason for subject withdrawal must be documented in the 
eCRF. 
Withdrawn subjects may be replaced per the Sponsor’s discretion. 
4.5 
Lost to Follow up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 
The following actions must be taken if a subject fails to return to the clinic for a required study 
visit: 
•
The site must attempt to contact the subject and reschedule the missed visit as soon as
possible and counsel the subject on the importance of maintaining the assigned visit
schedule and ascertain whether or not the subject wishes to and/or should continue in the
study.
•
Before a subject is deemed lost to follow up, the Investigator or designee must make
every effort to regain contact with the subject (where possible, 3 telephone calls and, if
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necessary, a certified letter to the subject’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the subject’s medical record. 
•
Should the subject continue to be unreachable, he/she will be considered to have
withdrawn from the study.

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5 
STUDY TREATMENTS 
5.1 
Treatment Groups 
There will be 1 treatment group. 
5.2 
Rationale for Dosing 
The dose level of CAD-1883 is 300 mg (3 capsules of 100 mg each) twice daily, with the first 
dose for Day 1 taken in clinic, and the second daily dose taken 4 to 5 hours later on clinic visit 
Days 1, 7 and 14 only. The second daily dose for all other (at home) days will be taken 8 hours 
later (±2 hours). 
5.3 
Randomization and Blinding 
This will be an open label study with no blinding. 
5.4 
Breaking the Blind 
Not applicable. 
5.5 
Drug Supplies 
5.5.1 
Formulation and Packaging 
Cadent Therapeutics, Inc. will provide CAD-1883 as capsules (Coni-Snap Gelatin, Size 4, 
Swedish Orange) of 100 mg dosage strength in 60-cc wide-mouth round white HDPE unit bottles 
with 33-mm SecuRx® Closures. Additional information on formulation and packaging can be 
found in the Pharmacy Manual. A detailed description of the chemistry, manufacturing, and 
quality controls of CAD-1883 100 mg capsules is provided in the Investigator’s Brochure (IB). 
5.5.2 
Study Drug Preparation and Dispensing 
All study drugs will be dispensed by the Investigator or a person under the Investigator’s 
supervision. 
5.5.3 
Study Drug Administration 
CAD-1883 is administered orally at the dose of 300 mg (3 capsules of 100 mg each) twice daily, 
with the first dose for Day 1 taken in clinic, and the second daily dose to be taken 4 to 5 hours 
later on clinic visit Days 1, 7 and 14 only. The second daily dose for all other (at home) days will 
be taken 8 hours later (±2 hours). Each subject is provided with a medication diary to denote the 
date and time of at-home study drug dosing. Dosing instructions for medication intake are 
provided in the pharmacy manual. 
5.5.4 
Treatment Compliance 
The subject must return the bottle containing unused capsules (if any) to the study site for a 
compliance check at the visits specified in the SOA (Appendix A, Table 2).  
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5.5.5 
Storage and Accountability 
The subject kits will be stored at controlled room temperature between +15°C and +25°C in each 
study site pharmacy, which will be locked with restricted access. No additional procedures are 
required for the safe handling of the capsules. 
Recommendations for subjects: the capsules should be kept in the original packaging (bottles). 
The bottles should be stored in the subject’s home at room temperature and out of reach of 
children and away from direct sunlight. The study drug must not be given to other persons. 

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6 
STUDY PROCEDURES 
•
Study procedures and their timing are summarized in the SOA (Appendix A, Table 2).
Protocol waivers or exemptions are not allowed.
•
Immediate safety concerns should be discussed with the Investigator, Medical Monitor,
and Sponsor immediately upon occurrence or awareness to determine if the subject
should continue or discontinue study intervention.
•
Adherence to the study design requirements, including those specified in the SOA
(Appendix A, Table 2), is essential and required for study conduct.
•
All screening evaluations must be completed and reviewed to confirm that potential
subjects meet all eligibility criteria. The Investigator will maintain a screening log to
record details of all subjects screened and to confirm eligibility or record reasons for
screening failure, as applicable. See Section 6.1.1 for information about re-screening
subjects.
6.1 
Study Visits 
The study period consists of Screening, Baseline/Pre-dose visit, treatment period, and Follow-up 
visit for a total study period that could be up to 56 days. Subjects will undergo a screening period 
of a minimum of 14 days up to a maximum of 35 days, a 1-day Baseline/Pre-dose visit, a Day 1 
visit that may occur up to 3 business days post the Baseline/Pre-dose visit, a treatment period for 
14 days (including Day 1), and a Follow-up visit at Day 21. All procedures and assessments will 
occur as indicated in the SOA (Appendix A, Table 2). 
6.1.1 
Screening Period 
Subjects will undergo a screening period of a minimum of 14 days up to a maximum of 35 days 
in which the subject will “wash-out” from prior tremorgenic and anti-tremor medications, to 
allow the effects of previous medication(s) on tremor to be eliminated. During the Screening 
period, each subject will undergo full assessment including medical and treatment history for ET, 
physical and neurological examination (including a focused neurological exam to include full 
assessment of tremor per Movement Disorder Society classification criteria (Bhatia, 2018)), in 
addition to laboratory testing, 12-lead ECG and other screening assessments as indicated in the 
SOA (Appendix A, Table 2). The diagnosis of ET must be established by the Principal 
Investigator at Screening based on the MDS criteria (Bhatia, 2018) with a documented severity 
of tremor based on the clinician-administered TETRAS-PS (Elble, 2012). 
Per the Investigator’s discretion, re-testing of any laboratory abnormality at the central lab or at a 
local lab is permissible, with prior approval from the Medical Monitor. 
Subjects who previously failed screening can be invited to re-screen up to two additional times, 
with recommendation by the Investigator and with approval by the Sponsor. 
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6.1.2 
Pre-dose (Baseline) Visit 
At the Baseline/Pre-dose visit, subjects will undergo all required procedures as indicated in the 
SOA (Appendix A, Table 2) including confirmation that all eligibility criteria are met. Analysis 
of the pre-dose laboratory assessments (chemistry, hematology, urinalysis) should be conducted 
by the Central Laboratory, with the results available and reviewed by the Principal Investigator, 
or designee, prior to dosing the subject with CAD-1883 (Day 1 visit). 
Under exceptional circumstances, the pre-dose laboratory assessments (chemistry, hematology, 
urinalysis) can be sent for expedited analysis at the local laboratory, along with duplicate 
samples sent to the Central Laboratory. The results of the above-referenced laboratory 
assessments should be available and reviewed by the Principal Investigator, or designee, prior to 
dosing the subject. 
Additionally, a urine sample will be collected for determination of baseline levels of composite 
biomarker panel for renal tubular injury, which is not part of eligibility determination. 
6.1.3 
Day 1 Visit (First In-Clinic Dosing) 
The Day 1 visit may occur up to 3 business days following the Baseline/Pre-dose visit. 
Baseline/Pre-dose laboratory assessments should be available and reviewed by Principal 
Investigator, or designee prior to dosing the subject with CAD-1883. 
On Day 1, subjects will be dosed in the clinic with the first dose of CAD-1883 300 mg 
(3 capsules of 100 mg each) and will be monitored in the clinic prior to ingesting the second dose 
of CAD-1883 300 mg (3 capsules of 100 mg each), 4 to 5 hours later. Additional safety and all 
efficacy assessments will be completed after the second in clinic dose on Day 1 as indicated in 
the SOA (Appendix A, Table 2). 
 Subjects will be dispensed study drug for continued twice-daily oral self-administration at home. 
6.1.4 
In-clinic Treatment Period Study Visits 
Subjects will return to the site for further assessments on Day 7 (-1 day) and Day 14 (±1 day) 
and a Follow-up visit (Day 21 [±1 day]). On Days 7 and 14, subjects are instructed to ingest the 
first daily dose of CAD-1883 of 300 mg (3 capsules of 100 mg each) at home 4 to 5 hours prior 
to the scheduled and/or anticipated dosing of the second daily dose of CAD-1883 in the clinic. 
The second daily dose of CAD-1883 300 mg (3 capsules of 100 mg each) will be taken in the 
clinic, under the supervision of study staff, 4 to 5 hours after the first daily dose, as indicated in 
the SOA (Appendix A, Table 2). 
6.1.5 
Intervals Between Site Visits 
Subjects will self-administer CAD-1883 300 mg (3 capsules of 100 mg each) twice-daily. 
Subjects are instructed to ingest the first daily dose of CAD-1883 at home. The second daily 
dose will be taken 8 hours (±2 hours) after the first daily dose. Each subject is provided with a 
medication diary to denote the date and time of at-home study drug dosing, as indicated in the 
SOA (Appendix A, Table 2). 

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6.1.6 
Follow-up Visit 
Upon completion of the 14-day treatment period, subjects will return to the site for the Day 21 
Follow-up visit, approximately 7 days (±1 day) after the last dose of study drug was 
administered. Subjects will complete all study assessments and procedures as indicated in the 
SOA (Appendix A, Table 2). 
6.2 
Early Termination Visit and Withdrawal Procedures 
The end of treatment for subjects completing the study is Follow-up Visit on Day 21 (±1 day). 
For subjects who are withdrawn from the study prior to completion, all Day 14 procedures will 
be performed at an Early Termination visit as indicated in the SOA (Appendix A, Table 2) and 
they will also complete the C-SSRS. Subjects withdrawing from the study early will not receive 
study drug on-site at the Early Termination visit.  
6.3 
Informed Consent 
After adequate explanation of the aims, methods, objectives of the study and potential hazards of 
the study drug, a written informed consent from each individual participating in this study will be 
obtained. 
6.4 
Study Assessments and Procedures 
All study assessments and procedures will be conducted as indicated in the SOA (Appendix A, 
Table 2) and as described in Section 7 for safety assessments, Section 8 for efficacy assessments, 
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7 
SAFETY ASSESSMENTS 
7.1 
Adverse Events 
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a pharmaceutical product, which does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and/or unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of an 
investigational medicinal product, whether or not related to the investigational medicinal 
product. All AEs, including observed or volunteered problems, complaints, or symptoms, are to 
be recorded on the appropriate eCRF. 
AEs, which include clinical laboratory test variables, will be monitored and documented from 
the time the subject signs the informed consent form (ICF) until Follow-up Day 21. Subjects 
should be instructed to report any AE that they experience to the Investigator, whether or not 
they think the event is due to study treatment. Beginning at Screening, the Investigators should 
make an assessment for AEs at each visit and record the event on the appropriate AE eCRF. 
Wherever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms should be identified by the Investigator and recorded on the eCRF. However, if an 
observed or reported sign or symptom is not considered a component of a specific disease or 
syndrome by the Investigator, it should be recorded as a separate AE on the eCRF. Additionally, 
the condition that led to a medical or surgical procedure (e.g., surgery, endoscopy, tooth 
extraction, or transfusion) should be recorded as an AE, not the procedure itself.  
Any medical condition already present at Screening should be recorded as medical history and 
not be reported as an AE unless the medical condition or signs or symptoms present at pre-dose 
change in severity, frequency, or seriousness at any time during the study. In this case, it should 
be reported as an AE. 
Clinically significant abnormal laboratory or other examination (e.g., ECG) findings that are 
detected during the study or are present at Screening and significantly worsen during the study 
should be reported as AEs, as described below. The Investigator will exercise his or her medical 
and scientific judgment in deciding whether an abnormal laboratory finding or other abnormal 
assessment is clinically significant. Clinically significant abnormal laboratory values occurring 
during the clinical study will be followed until repeat tests return to normal, stabilize, or are no 
longer clinically significant. Abnormal test results that are determined to be an error should not 
be reported as an AE. Laboratory abnormalities or other abnormal clinical findings (e.g., ECG 
abnormalities) should be reported as an AE if any of the following are applicable: 
•
If an intervention is required as a result of the abnormality
•
If action is required to be taken with the study drug as a result of the abnormality
•
Based on the clinical judgment of the Investigator

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7.1.1 
Assessment of Adverse Events by the Investigator 
The Investigator will assess the severity (intensity) of each AE as mild, moderate, or severe, and 
will also categorize each AE as to its potential relationship to study drug using the categories of 
‘yes’ or ‘no’. 
Assessment of severity: 
Mild – An event that is easily tolerated and generally not interfering with normal daily activities. 
Moderate – An event that is sufficiently discomforting to interfere with normal daily activities. 
Severe – An event that is incapacitating with inability to work or perform normal daily activities. 
Causality assessment: 
The relationship of an AE to the administration of the study drug is to be assessed according to 
the following definitions: 
No (unrelated, not related, unlikely to be related) – The time course between the administration 
of study drug and the occurrence or worsening of the AE rules out a causal relationship and 
another cause (concomitant drugs, therapies, complications, etc.) is suspected. 
Yes (possibly, probably, or definitely related) – The time course between the administration of 
study drug and the occurrence or worsening of the AE is consistent with a causal relationship and 
no other cause (concomitant drugs, therapies, complications, etc.) can be identified. 
The definition implies a reasonable possibility of a causal relationship between the event and the 
study drug. This means that there are facts (evidence) or arguments to suggest a causal 
relationship. 
The following factors should also be considered: 
•
The temporal sequence from study drug administration-
The event should occur after the study drug is given. The length of time from study drug 
exposure to event should be evaluated in the clinical context of the event. 
•
Underlying, concomitant, intercurrent diseases-
Each report should be evaluated in the context of the natural history and course of the disease 
being treated and any other disease the subject may have. 
•
Concomitant drug-
The other drugs the subject is taking or the treatment the subject receives should be examined 
to determine whether any of them might be recognized to cause the event in question. 
•
Known response pattern for this class of study drug-
Clinical and/or preclinical data may indicate whether a particular response is likely to be a 
class effect. 
•
Exposure to physical and/or mental stresses-
The exposure to stress might induce adverse changes in the recipient and provide a logical 
and better explanation for the event. 
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7.2 
Serious Adverse Events 
An AE or adverse reaction is considered serious if, in the view of either the Investigator or the 
Sponsor, it results in any of the following outcomes: 
•
Death
•
A life-threatening AE
Note: An AE or adverse reaction is considered “life-threatening” if, in view of either the 
Investigator or the Sponsor, its occurrence places the subject at immediate risk of death. It 
does not include an event that, had it occurred in a more severe form, might have caused 
death. 
•
Requires hospitalization or prolongation of existing hospitalizations
Note: Any hospital admission with at least one overnight stay will be considered an inpatient 
hospitalization. An emergency room or urgent care visit without hospital admission will not 
be recorded as a SAE under this criterion, nor will hospitalization for a procedure scheduled 
or planned before signing of informed consent, or elective treatment of a pre-existing 
condition that did not worsen from Baseline. However, unexpected complications and/or 
prolongation of hospitalization that occur during elective surgery should be recorded as AEs 
and assessed for seriousness. Admission to the hospital for social or situational reasons (i.e., 
no place to stay, live too far away to come for hospital visits, respite care) will not be 
considered inpatient hospitalizations.  
•
A persistent or significant disability/incapacity or substantial disruption of the ability to
conduct normal life functions
•
A congenital anomaly/birth defect
•
An important medical event.
Note: Important medical events that do not meet any of the above criteria may be considered 
an SAE when, based upon appropriate medical judgment, they may jeopardize the subject 
and may require medical or surgical intervention to prevent one of the outcomes listed above. 
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalizations, or the development of drug dependency. 
7.3 
Serious Adverse Event Reporting − Procedures for Investigators 
Initial Reports 
All SAEs occurring from the time the subject signs the informed consent until 30 days following 
the last administration of study drug must be reported to CRO within 24 hours of the knowledge 
of the occurrence. After the 30-day reporting window, any SAE that the Investigator considers 
related to study drug must be reported to CRO or designee. 
To report the SAE, complete the AE form electronically in the eCRF for the study and then the 
paper SAE report form. Send the paper SAE report form via email to the CRO 
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within 24 hours of awareness regardless of the relationship to the study drug. The 
SAE report form should be completed as thoroughly as possible; however, submission of the 
report should not be delayed if information is not available at the time of the initial report.  
Follow-Up Reports 
The Investigator must continue to follow the subject until the SAE has subsided or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment), or the 
subject dies. 
Within 24 hours of receipt of follow-up information, the Investigator must update the paper SAE 
report form and the AE form electronically in the eCRF and submit any supporting 
documentation (e.g., patient discharge summary or autopsy reports) to CRO via fax or email.  
7.4 
Pregnancy Reporting 
If a subject becomes pregnant during the study, the Investigator is to stop dosing with study drug 
immediately and the subject should be withdrawn from the study. Early Termination study visit 
procedures as indicated in the SOA should be implemented at that time.  
A pregnancy is not considered to be an AE or SAE; however, it must be reported to the CRO 
within 24 hours of knowledge of the pregnancy during the study or up to 90 days after the last 
dose of study drug via the Pregnancy Data Collection Form. The Investigator must complete the 
Pregnancy Data Collection Form and fax or email it to the CRO (contact information listed in 
Section 7.6).  
If the female partner of a male subject becomes pregnant while the subject is receiving study 
drug or up to 90 days after the last dose of study drug, the Investigator should notify the CRO as 
described above.  
The pregnancy should be followed until the outcome of the pregnancy, whenever possible. Once 
the outcome of the pregnancy is known, the Pregnancy Data Collection Form should be 
completed and faxed or emailed to the CRO (contact information listed in Section 7.6). If the 
outcome of the pregnancy meets the criteria for immediate classification as an SAE (i.e., 
postpartum complication, spontaneous abortion, stillbirth, neonatal death, or congenital 
anomaly), the Investigator should follow the procedures for reporting an SAE. 
7.5 
Expedited Reporting 
The CRO will report all relevant information about Suspected Unexpected Serious Adverse 
Reactions (SUSAR) that are fatal or life-threatening as soon as possible to the Food and Drug 
Administration (FDA), and in any case no later than 7 days after knowledge by the CRO of such 
a case. Relevant follow-up information will subsequently be communicated within an additional 
8 days.  
All other SUSARs will be reported to the FDA as soon as possible but within a maximum of 
15 days of first knowledge by the CRO.  
The CRO will also report any additional expedited safety reports required in accordance with the 
relevant timelines.  
The CRO will also inform all Investigators as required per local regulation. 
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The requirements above refer to the requirements relating to investigational medicinal product. 
7.6 
Special Situation Reports 
Special situation reports include reports of overdose, misuse, abuse, medication error, and reports 
of adverse reactions associated with product complaints. 
•
Overdose: Refers to the administration of a quantity of a medicinal product given per
administration or cumulatively (accidentally or intentionally), which is above the
maximum recommended dose according to the protocol. Clinical judgement should
always be applied. In cases of a discrepancy in the drug accountability, overdose will be
established only when it is clear that the subject has taken additional dose(s), or the
Investigator has reason to suspect that the subject has taken additional dose(s).
•
Misuse: Refers to situations where the medicinal product is intentionally and
inappropriately used that is not in accordance with the protocol instructions or local
prescribing information and may be accompanied by harmful physical and/or
psychological effects.
•
Abuse: Is defined as persistent or sporadic, intentional excessive use of a medicinal
product, which is accompanied by harmful physical or psychological effects.
•
Medication error: Is any unintentional error in the prescribing, dispensing, or
administration of a medicinal product by a healthcare professional, subject, or consumer,
respectively. The administration or consumption of the unassigned treatment and
administration of an expired product are always reportable as medication errors. Cases of
subjects missing doses of investigational product are not considered reportable as
medication error.
All special situation events as described above must be reported on the Special Situations Report 
form and faxed or emailed to the CRO (contact information listed below) within 24 hours of 
knowledge of the event. All AEs associated with these Special Situation reports should be 
reported as AEs or SAEs as well as recorded on the AE eCRF and/or the paper SAE report form. 
Details of the symptoms and signs, clinical management, and outcome should be provided, when 
available. 
CRO Clinical Safety Contact Information: 
Premier Research Pharmacovigilance (PV) 
7.7 
Physical and Neurological Examinations 
A complete physical examination (PE) will include general observations; head, eyes, ears, nose, 
and throat (HEENT); cardiovascular; respiratory; abdomen; skin; extremities; lymphatic system; 
and musculoskeletal. Height, weight, 
 will also be measured and 
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recorded.  A symptom-based PE will be performed at Baseline/Pre-dose and Day 21 Follow-up 
visits only (includes: general, HEENT, cardiovascular, respiratory, abdomen, skin, extremities). 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
Neurological examinations will include assessment of mental status, cranial nerves, motor, 
sensory, reflexes, coordination, and gait. In addition to the complete neurological exam, a 
focused neurological exam is conducted during the Screening visit to include full assessment of 
tremor per Movement Disorder Society classification criteria (Bhatia, 2018). 
Physical and neurological exams will be conducted at timepoints indicated in the SOA 
(Appendix A, Table 2). 
7.8 
Electrocardiograms 
Triplicate 12-lead ECG will be obtained as indicated in the SOA (Appendix A, Table 2), using an 
ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTcF 
intervals. ECGs are to be assessed prior to vital signs and blood sampling for laboratory tests. 
Triplicate ECG recordings will be taken, after a minimum of 5 minutes of rest in supine position: 
3 consecutive recordings will be made in succession, no more than 2 minutes apart. The full set of 
triplicates should be completed in less than 4 minutes. These ECGs will be read by the Investigator 
to rule out any clinically significant findings. An ECG is to be taken at the Screening, Baseline/Pre-
dose, Day 1, Day 7, Day 14 and Day 21 Follow-up visits. At the Day 1, Day 7 and Day 14 visits, 
ECGs are to be obtained at the following time points: 30min, 60min, and 2 hours following the 
first dose of the day and again 30 min, 60 min, 2 hours and 4 hours after the second dose of study 
drug in the clinic.  On Days 7 and 14, an ECG is to be taken at 30 min, 60 min, 2 hours, and 4 
hours following the dose of study drug in the clinic. There is a +/- 5-minute allowable window for 
these ECGs.  
After a minimum of 5 minutes of rest in supine position, 3 consecutive recordings should be 
made in succession, no more than 2 minutes apart. The full set of triplicates should be completed 
in less than 4 minutes. These ECGs will be read by the Investigator to rule out any clinically 
significant findings. 
7.9 
Vital Signs 
Vital signs (VS) assessments (to be taken before blood collection for laboratory tests) will be 
assessed and include blood pressure (systolic and diastolic), heart rate, respiratory rate and oral 
temperature.  Vital signs are to be taken at the Screening, Baseline/Pre-dose, Day 1, Day 7, Day 
14 and Day 21 Follow-up visits. The vital signs on Day 1 are to be taken at 30min, 60min, and 2 
hours following the first dose of the day and again 30 min, 60 min, 2 hours and 4 hours after the 
second dose of study drug in the clinic.  On Days 7 and 14, the vital signs are to be taken at 30 
min, 60 min, 2 hours, and 4 hours following the dose of study drug in the clinic. There is a +/- 5-
minute allowable window for these vital signs.  
7.10 
Orthostatic Vital Signs 
Orthostatic vital signs will be measured at Screening, Baseline, Day 1, Day 7, Day 14 and during 
the Follow-up visit. 

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During the Screening visit, orthostatic VS measurements will be done once, at any time during 
the visit. 
During the Baseline/Pre-Dose visit, baseline orthostatic VS will include 3 separate measurements 
with each measurement of blood pressure and heart rate separated from the next by at least 
15-20 minutes apart, to minimize the potential impact of biological variability of a single 
baseline measurement. The average of the 3 baseline orthostatic VS measurements will be used 
for comparison to all post-treatment measurements. 
During Day 1, orthostatic VS measurements will be done twice, 2 to 4 hours following each in-
clinic dose. 
During Day 7 and Day 14 visits, orthostatic VS measurements will be done once, 2 to 4 hours 
following the in-clinic dose. 
During the Follow-up visit, orthostatic VS measurements will be done once, at any time during 
the visit. 
Orthostatic VS must be assessed using an appropriate device, and the arm position must be 
standardized for each subject. These measurements are to be taken in the same arm for the 
duration of the study. The position of the cuff on the arm should be in line with the heart with the 
arm lying next to the subject when semi-supine and should be in line with the heart at 
approximately a 45 degrees angle from horizontal for the standing measure. 
In order to obtain orthostatic VS, the subjects will undergo the following procedures in 
sequential order: 
1. The subject will rest in a supine or semi-supine position for at least 5 minutes. 
2. After remaining supine or semi-supine for 5 minutes, one measurement of blood pressure and 
heart rate will be taken. 
3. The subject will then be asked to sit on the edge of the bed/chair with feet on the floor (or 
with feet dangling from the bed/chair depending on the height of the bed/chair) for 
approximately 30 seconds. 
4. The person performing the assessment will then ask the question, “Are you ready to 
stand?” 
• If the subject responds in the affirmative, the subject will proceed to stand and 
then be asked to remain standing for 2 minutes. After standing for 2 minutes, blood pressure and 
heart rate will be recorded. 
• If the subject states that he or she is not ready to stand, the subject will be allowed to sit 
as positioned for one additional minute and will be asked again if they are ready to stand. 
The subject will proceed to stand. After standing for 2 minutes, one measurement will be 
taken for blood pressure and heart rate. 
• If the individual is still unable to stand, vital signs will be measured while the subject is 
in an upright seated position. 

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Orthostatic hypotension will be defined as a reduction in SBP of 20 mmHg or more, and/or a 
reduction in DBP of 10 mmHg or more, for the standing measurement compared to the supine or 
semi-supine measurement. If orthostatic hypotension is suspected, the measurement process may 
be repeated at the Investigator’s discretion. Any confirmed orthostatic hypotension or clinically 
significant measurements that are associated with clinical symptoms will be recorded as adverse 
events. 
If routine VS and orthostatic VS coincide at the same time points, the same values for routine VS 
(blood pressure and heart rate) during the supine or semi-supine position should be recorded in 
the CRFs as the same values of the start of orthostatic VS in the supine or semi-supine position. 
7.11 
Clinical Laboratory Evaluations 
A list of clinical laboratory tests to be performed is in Appendix B. See Table 2, SOA in 
Appendix A for the timing and frequency. 
The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless judged 
by the Investigator to be more severe than expected for the subject’s condition. 
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study or within 30 days after the last dose of study intervention should be repeated until 
the values return to normal or baseline or are no longer considered clinically significant by the 
Investigator or Medical Monitor. 
•
If such values do not return to normal/baseline within a period of time judged reasonable
by the Investigator, the etiology should be identified and the CRO notified.
•
All protocol-required laboratory assessments, as defined in Appendix B, must be
conducted in accordance with the laboratory manual and the SOA (Table 2).
•
If laboratory values from non-protocol specified laboratory assessments performed at the
institution’s local laboratory require a change in the subject’s management or are
considered clinically significant by the Investigator (e.g., SAE or AE or dose
modification), then the results must be recorded as an AE in the eCRF for AEs and also
the paper form if an SAE.
•
On Days 1, 7, 14 all clinical laboratory samples should be collected after the TETRAS-
PS assessment
7.12 
Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a questionnaire that prospectively assesses Suicidal Ideation and Suicidal 
Behavior. The C-SSRS, which uses a semi-structured interview to probe subject responses, will 
be administered by an individual who has received training and certification in its administration. 
At the Baseline/Pre-dose visit, the “baseline” version of the C-SSRS will be administered. This 
version assesses Suicidal Ideation and Suicidal Behavior during the subject’s lifetime and during 

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a predefined period. At the Day 21 visit (and the Early Termination visit for subjects 
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8 
EFFICACY ASSESSMENTS 
8.1 
Rating Scales 
The treatment effect will be evaluated by means of the TETRAS-PS (Version 3.1), which is a 
validated scale that has been used in recently conducted clinical trials in subjects with ET (Elble, 
2012). It provides an accurate reflection of the clinical response to treatment on the amplitude of 
tremor over multiple bodily locations and over time. 
The TETRAS assessments at Screening, Baseline/Pre-dose, Days 1, 7, 14, and Follow-up visit 
(Day 21) will be administered by a certified rater. TETRAS raters at each site must demonstrate 
expertise in the administration of the TETRAS according to criteria preset by independent 
central rating experts. The TETRAS raters at each site can be the Principal Investigator or a staff 
member delegated as a rater by the Principal Investigator. Each site must make every effort, to 
the extent that is possible, to ensure availability of a primary rater and a backup rater to perform 
all TETRAS assessments on the same subjects throughout the study duration. 
The TETRAS-PS assessments at the Screening visit, Baseline/Pre-dose, Days 1, 7, 14, and 21 
clinic visits will be recorded using videography for centralized evaluation and rating by 
independent blinded central raters (neurologists) with expertise in the assessment of ET. 
On Screening and Baseline/Pre-dose visits: TETRAS-PS, 
are performed. 
On Day 1: The TETRAS-PS will be administered 2 to 4 hours following the second in-clinic 
dose.  
On Day 7: the TETRAS-PS, 
will be performed 
2 to 4 hours following the in-clinic dose. 
On Day 14: the TETRAS-PS, 
 will be performed 
2 to 4 hours following the in-clinic dose. 
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At Follow up visit (Day 21): the TETRAS-PS, 
 are 
performed once any time during the visit. 
8.2 
Wearable Sensor 
In addition to the assessment of efficacy via rating scales, treatment effect will be evaluated by 
measuring tremor with a sensor worn on the upper limb (index finger). These assessments will be 
conducted during the clinic visits and optionally at-home. 
8.2.1 
In-Clinic Assessment 
The wearable sensor measurements of upper limb tremor assessments will be completed in the 
clinic once at any time during the Screening visit and at two different times during the 
Baseline/Pre-dose site visit. 
During the site visit on Day 1 the wearable sensor measurements of upper limb tremor will be 
captured once, 2 to 4 hours following the second in-clinic dose. 
During the site visit on Days 7 and 14, the wearable sensor measurements of upper limb tremor 
will be captured once, 2 to 4 hours following the in-clinic dose. 
During the Follow-up visit (Day 21), the wearable sensor measurements of upper limb tremor 
will be completed at any time during the visit. 
In-clinic assessments will be obtained during the performance of 4 maneuvers: 
1. extended arms posture,
2. wing-beating posture,
3. kinetic “finger-to-chin” movement, and
4. arm on table posture.
These assessments will be performed twice, once with the sensor on the left index finger and 
once with the sensor on the right index finger.  
In addition, the subject will wear the sensor on the index finger of each hand while performing 
3 activities of daily living:  
1. pouring from a cup,
2. drinking from a cup, and
3.
eating with a spoon
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11 
STATISTICS 
11.1 
Analysis Populations 
For purposes of analysis, the following populations are defined: 
Safety population: All enrolled subjects who take at least 1 dose of study intervention. 
•
Full Analysis Set (FAS): FAS consists of subjects in the safety population who had at least
1 post-baseline assessment of both TETRAS-PS 
. FAS will be used to 
summarize all efficacy data. 
•
Exposed Population (EP): The exposed population includes all subjects in the Safety
population who are at least 90% compliant with study treatment
Selected efficacy analyses will be repeated in this population if this population differs from 
FAS. 
11.2 
Statistical Methods 
The statistical analysis plan (SAP) will be developed and finalized before database lock and will 
describe the subject populations to be included in the analyses, and procedures for accounting for 
missing, unused, and spurious data. This section is a summary of the planned statistical analyses 
of the primary and secondary endpoints. 
11.2.1 
Analysis of Primary (Safety) Endpoint Data 
•
Vital sign parameters outside the normal range will be listed and flagged for review.
•
Orthostatic vital signs parameters for blood pressure outside the ranges specified in
Section 7.10 below will be listed and flagged for review.
•
Descriptive statistics of absolute and change from Baseline (pre-dose) SBP, DBP, pulse rate,
respiratory rate, and oral temperature at each timepoint, will be tabulated. The mean change
from Baseline data will also be plotted across time.
•
Twelve-lead ECG parameters will be listed with any values outside the normal range flagged.
Descriptive statistics of absolute and change from Baseline (pre-dose) heart rate, PR, QRS,
QT, and QTcF intervals at each timepoint, will be tabulated. The mean change from Baseline
data will also be plotted across time.
•
In addition, frequencies of QTcF data will be calculated according to the following
categories:
For absolute values
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•
QTcF >450 msec (males) and >470 msec (females)
•
QTcF >480 msec
•
QTcF >500 msec
For change from Baseline 
•
QTcF increase >30 msec
•
QTcF increase >60 msec
11.2.2 
Analysis of Secondary Efficacy Endpoints 
•
Mean TETRAS-PS total score change from Baseline over 14 days.
•
Mean TETRAS-PS upper limb subscale score change from Baseline over 14 days.
•
Mean in-clinic wearable sensor measures of upper-limb tremor change from Baseline
severity, mean amplitude, and mean frequency over 14 days.
11.2.4 
Sample Size Determination 
Approximately 30 subjects will be enrolled. No formal statistical power analysis was conducted. 
Each subject will be assessed for change from their own Baseline. 
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12 
DATA MANAGEMENT AND RECORD KEEPING 
12.1 
Data Management 
12.1.1 
Data Handling 
Data will be recorded at the site on eCRFs and reviewed during monitoring visits. Selected data 
recorded in the eCRF system will be verified with source documents. All corrections or changes 
made to any study data must be appropriately tracked in an audit trail in the EDC system. An 
eCRF will be considered complete when all missing, incorrect, and/or inconsistent data has been 
accounted for. 
12.1.2 
Computer Systems 
Data will be processed using a validated computer system conforming to regulatory 
requirements. 
12.1.3 
Data Entry 
Data must be recorded using the EDC system as the study is in progress. All site personnel must 
log into the system using their secure username and password in order to enter, review, or correct 
study data. These procedures must comply with Title 21 of the Code of Federal Regulations (21 
CFR Part 11) and other appropriate international regulations. All passwords will be strictly 
confidential. 
12.1.4 
Medical Information Coding 
For medical information, the following thesauri will be used: 
•
Medical Dictionary for Regulatory Activities (latest) for medical history and AEs
•
World Health Organization Drug Dictionary
 and concomitant medications 
12.1.5 
Data Validation 
Validation checks programmed within the EDC system, as well as supplemental validation 
performed via review of the downloaded data, will be applied to the data in order to ensure 
accurate, consistent, and reliable data. Data identified as erroneous, or data that are missing, will 
be referred to the investigative site for resolution through data queries. 
The eCRFs must be reviewed and electronically signed by the Investigator. 
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12.2 
Record Keeping 
Records of subjects, source documents, monitoring visit logs, eCRFs, inventory of study product, 
regulatory documents, and other Sponsor correspondence pertaining to the study must be kept in 
the appropriate study files at the site. Source data is defined as all information in original records 
and certified copies of original records of clinical findings, observations, or other activities in a 
clinical study necessary for the evaluation and reconstruction of the clinical study. Source data 
are contained in source documents (original records or certified copies). These records will be 
retained in a secure file for the period as set forth in the Clinical Study Agreement. Prior to 
transfer or destruction of these records, the Sponsor must be notified in writing and be given the 
opportunity to further store such records.  
12.3 
End of Study 
The EOS (“study completion”) is defined as the date of the last protocol-specified 
visit/assessment (including telephone contact) for the last subject in the study.  

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13 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL 
13.1 
Ethical Conduct of the Study 
Good Clinical Practice (GCP) is an international ethical and scientific quality standard for 
designing, conducting, recording, and reporting studies that involve human subjects. Compliance 
with this standard provides public assurance that the rights, safety, and wellbeing of study 
subjects are protected, consistent with the principles that have their origin in the Declaration of 
Helsinki, and that the clinical study data are credible. 
13.2 
Institutional Review Board/Independent Ethics Committee 
The Institutional Review Board (IRB) will review all appropriate study documentation in order 
to safeguard the rights, safety, and well-being of subjects. The study will only be conducted at 
sites where IRB approval has been obtained. The protocol, Investigator’s Brochure, ICF, 
advertisements (if applicable), written information given to the subjects, safety updates, annual 
progress reports, and any revisions to these documents will be provided to the IRB by the 
Investigator. 
Federal regulations and International Council for Harmonization (ICH) Guidelines require that 
approval be obtained from an IRB prior to participation of subjects in research studies. Prior to 
study onset, the protocol, any protocol amendments, ICFs, advertisements to be used for subject 
recruitment, and any other written information regarding this study to be provided to a subject or 
subject’s legal guardian must be approved by the IRB. 
No drug will be released to the site for dosing until written IRB authorization has been received 
by the Sponsor or designee. 
13.3 
Informed Consent 
The ICF and any changes to the ICF made during the course of the study must be agreed to by 
the Sponsor or designee and the IRB prior to its use and must be in compliance with all ICH 
GCP, local regulatory requirements, and legal requirements.   
The Investigator must ensure that each study subject is fully informed about the nature and 
objectives of the study and possible risks associated with participation and must ensure that the 
subject has been informed of his/her rights to privacy. The Investigator or designee will obtain 
written informed consent from each subject before any study-specific activity is performed and 
should document in the source documentation that consent was obtained prior to enrollment in 
the study. The original signed copy of the ICF must be maintained by the Investigator and is 
subject to inspection by a representative of the Sponsor, their representatives, auditors, the IRB 
and/or regulatory agencies. A copy of the signed ICF will be given to the subject. 
13.4 
Study Monitoring Requirements 
It is the responsibility of the Investigator to ensure that the study is conducted in accordance with 
the protocol, Declaration of Helsinki, ICH GCP, and applicable regulatory requirements, and that 
valid data are entered into the eCRFs. 
To achieve this objective, the monitor’s duties are to aid the Investigator and, at the same time 
the Sponsor in the maintenance of complete, legible, well organized and easily retrievable data. 
Before the enrollment of any subject in this study, the Sponsor or their designee will review with 

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the Investigator and site personnel the following documents: protocol, Investigator’s Brochure, 
eCRFs and procedures for their completion, informed consent process, and the procedure for 
reporting SAEs. 
The Investigator will permit the Sponsor or their designee to monitor the study as frequently as 
deemed necessary to determine that data recording and protocol adherence are satisfactory. 
During the monitoring visits, information recorded on the eCRFs will be verified against source 
documents and requests for clarification or correction may be made. After the eCRF data is 
entered by the site, the monitor will review the data for safety information, completeness, 
accuracy, and logical consistency. Computer programs that identify data inconsistencies may be 
used to help monitor the clinical study. If necessary, requests for clarification or correction will 
be sent to Investigators. The Investigator and his/her staff will be expected to cooperate with the 
monitor and provide any missing information, whenever possible. 
All monitoring activities will be reported and archived. In addition, monitoring visits will be 
documented at the investigational site by signature and date on the study-specific monitoring log. 
13.5 
Disclosure of Data 
Data generated by this study must be available for inspection by the FDA, the Sponsor or their 
designee, applicable foreign health authorities, and the IRB as appropriate. Subjects or their legal 
representatives may request their medical information be given to their personal physician or 
other appropriate medical personnel responsible for their welfare. 
Subject medical information obtained during the study is confidential and disclosure to third 
parties other than those noted above is prohibited. 
13.6 
Retention of Records 
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator 
will keep records, including the identity of all participating subjects (sufficient information to 
link records, e.g., eCRFs and hospital records), all original signed ICFs, copies of all eCRFs, 
SAE forms, source documents, and detailed records of treatment disposition. The records should 
be retained by the Investigator according to specifications in the ICH guidelines, local 
regulations, or as specified in the Clinical Study Agreement, whichever is longer. The 
Investigator must obtain written permission from the Sponsor before disposing of any records, 
even if retention requirements have been met. 
If the Investigator relocates, retires, or for any reason withdraws from the study, the Sponsor 
should be prospectively notified. The study records must be transferred to an acceptable 
designee, such as another Investigator or another institution. 
13.7 
Publication Policy 
Following completion of the study, the data may be considered for publication in a scientific 
journal or for reporting at a scientific meeting. Each Investigator is obligated to keep data 
pertaining to the study confidential. The Investigator must consult with the Sponsor before any 
study data are submitted for publication. The Sponsor reserves the right to deny publication 
rights until mutual agreement on the content, format, interpretation of data in the manuscript, and 
journal selected for publication are achieved. 

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13.8 
Financial Disclosure 
Investigators are required to provide financial disclosure information to the Sponsor to permit the 
Sponsor to fulfill its obligations under 21 CFR Part 54. In addition, Investigators must commit to 
promptly updating this information if any relevant changes occur during the study and for a 
period of 1 year after the completion of the study. 

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14 
STUDY ADMINISTRATIVE INFORMATION 
14.1 
Protocol Amendments 
Any amendments to the study protocol will be communicated to the Investigators by the Sponsor 
or designee. All protocol amendments will undergo the same review and approval process as the 
original protocol. A protocol amendment may be implemented after it has been approved by the 
IRB, unless immediate implementation of the change is necessary for subject safety. In this case, 
the situation must be documented and reported to the IRB within 5 business days. 

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15 
REFERENCES 
 
1. Bhatia KP, Bain P, Bajaj N, Elble RJ, Hallett M, Louis ED et al. Consensus statement on 
the classification of tremors from the task force on tremor of the International Parkinson 
and Movement Disorder Society. Mov Disord. 2018 Jan;33(1):75-87. 
doi: 10.1002/mds.27121. Epub 2017 Nov 30. 
2. Elble R, Comella C, Fahn S, Hallett M, Jankovic J, Juncos JL, et al. Reliability of a new 
scale for essential tremor. Mov Disord. 2012 Oct;27(12):1567-9. 
doi: 10.1002/mds.25162. Epub 2012 Oct 2. 
3. Haubenberger D, Hallett M. Essential Tremor. N Engl J Med. 2018 
May 10;378(19):1802-10. 
4. Kshatri AS, Gonzalez-Hernandez A, Giraldez T. Physiological roles and therapeutic 
potential of Ca2+ activated potassium channels in the nervous system. Front Mol 
Neurosci. 2018;11:258. doi: 10.3389/fnmol.2018.00258 
5. Llinás RR. The olivo-cerebellar system: a key to understanding the functional 
significance of intrinsic oscillatory brain properties. Front Neural Circuits. 2014 
Jan 28;7:96. doi: 10.3389/fncir.2013.00096. eCollection 2013. 
 
 

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APPENDIX A:  SCHEDULE OF ASSESSMENTS 
Table 2: 
Schedule of Assessments 
ASSESSMENTS 
SCREENING BASELINE 
TREATMENT 
FOLLOW-UP 
14-35 days
prior to Day 1 
Pre-dose1,2 
(≤ 3 days 
prior to Day 
1) 
(In-clinic) 
Day 12 
(In-
clinic: 
Pre-
Dose 1) 
Day 12 
(In-clinic: 
Dosing & 
Post-Dose 1) 
Day 12 
(In-clinic: 
Dosing & 
Post Dose 2) 
Days 2-6 
(At-
home) 
Day 72 (-1 day) 
(In-clinic) 
Days 8-13 
(At-home) 
Day 142 
(±1 day) / 
Early 
Termination24
(In-clinic) 
Days 15-20 
(At-home) 
Day 212 
(±1 day) 
(In-clinic) 
Eligibility Check 
X 
X 
Informed Consent 
X 
Inclusion/Exclusion 
Criteria 
X 
X 
Demographics 
X 
Medical History 
X 
Neurological Exam 
X3 
X 
X 
X
X 
Physical Exam
X 
X4 
X 
X 
X 
X4 
Height
X
Weight 
X5 
X 
X 
12-lead ECG6
X 
X 
X8 
X8 
(30 min, 60 
min, 2 hours 
post 1st dose) 
X8 
(30 min, 60 
min, 2 & 4 
hours post 
2nd dose 
X8 
(30 min, 60 
min, 2 & 4 
hours post 2nd 
dose 
X8 
(30 min, 60 min, 
2 & 4 hours post 
2nd dose 
X 
Vital Signs7
X 
X 
X8 
X8 
(30 min, 60 
min, 2 hours 
post 1st dose) 
X8 
(30 min, 60 
min, 2 & 4 
hours post 
2nd dose) 
X8 
(30 min, 60 
min, 2 & 4 
hours post 2nd 
dose) 
X8 
(30 min, 60 min, 
2 & 4 hours post 
2nd dose) 
X 
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Table 2: 
Schedule of Assessments 
ASSESSMENTS 
SCREENING BASELINE 
TREATMENT 
FOLLOW-UP 
14-35 days
prior to Day 1 
Pre-dose1,2 
(≤ 3 days 
prior to Day 
1) 
(In-clinic) 
Day 12 
(In-
clinic: 
Pre-
Dose 1) 
Day 12 
(In-clinic: 
Dosing & 
Post-Dose 1) 
Day 12 
(In-clinic: 
Dosing & 
Post Dose 2) 
Days 2-6 
(At-
home) 
Day 72 (-1 day) 
(In-clinic) 
Days 8-13 
(At-home) 
Day 142 
(±1 day) / 
Early 
Termination24
(In-clinic) 
Days 15-20 
(At-home) 
Day 212 
(±1 day) 
(In-clinic) 
Orthostatic VS9 
X 
(3 times, 15-20 
min apart) 
X 
X 
(2-4 hours 
post 1st dose) 
X 
(2-4 hours 
post 2nd 
dose) 
X 
(2-4 hours post 
dose) 
X 
(2-4 hours post 
dose) 
X 
Clinical Chemistry 
X 
X 
X27 
X27 
X27 
X 
Hematology 
X 
X 
X27 
X27 
X27 
X 
Urinalysis10 
X 
X 
X27 
X27 
X27 
X 
Biomarker panel for 
renal tubular injury 
X 
X27 
X27 
X27 
X 
Pregnancy Test 
X11 
X12 
X12 
X12 
X12 
HIV, 
HBsAg, HCVAb 
X 
TSH – FSH (optional 
for females only; if 
needed) 
X 
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Table 2: 
Schedule of Assessments 
ASSESSMENTS 
SCREENING BASELINE 
TREATMENT 
FOLLOW-UP 
14-35 days
prior to Day 1 
Pre-dose1,2 
(≤ 3 days 
prior to Day 
1) 
(In-clinic) 
Day 12 
(In-
clinic: 
Pre-
Dose 1) 
Day 12 
(In-clinic: 
Dosing & 
Post-Dose 1) 
Day 12 
(In-clinic: 
Dosing & 
Post Dose 2) 
Days 2-6 
(At-
home) 
Day 72 (-1 day) 
(In-clinic) 
Days 8-13 
(At-home) 
Day 142 
(±1 day) / 
Early 
Termination24
(In-clinic) 
Days 15-20 
(At-home) 
Day 212 
(±1 day) 
(In-clinic) 
Administer 
CAD-1883 Study 
Drug
X26 
(in clinic) 
X26 
(in clinic 4-5 
hours post 1st 
dose) 
X
X14 
(in clinic 4-5 
hours post 1st 
dose) 
X 
X14 
(in clinic 4-5 
hours post 1st 
dose) 
Dispense Study Drug
X 
X
Medication Diary 
X 
X 
CAD-1883 PK 
Sample 
X15 
X16 
X16 
X17 
(Anytime 
during visit)
TETRAS 
Performance 
Subscale18 
X19 
X 
X20 
X21 
X21 
X 
In-clinic Wearable 
Sensor on Upper 
Limb 
X22 
X23 
X24 
X24 
X24 
X22 
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Table 2: 
Schedule of Assessments 
ASSESSMENTS 
SCREENING BASELINE 
TREATMENT 
FOLLOW-UP 
14-35 days
prior to Day 1 
Pre-dose1,2 
(≤ 3 days 
prior to Day 
1) 
(In-clinic) 
Day 12 
(In-
clinic: 
Pre-
Dose 1) 
Day 12 
(In-clinic: 
Dosing & 
Post-Dose 1) 
Day 12 
(In-clinic: 
Dosing & 
Post Dose 2) 
Days 2-6 
(At-
home) 
Day 72 (-1 day) 
(In-clinic) 
Days 8-13 
(At-home) 
Day 142 
(±1 day) / 
Early 
Termination24
(In-clinic) 
Days 15-20 
(At-home) 
Day 212 
(±1 day) 
(In-clinic) 
C-SSRS25
X 
X 
X 
AEs 
X 
Continuous reporting of adverse events 
* Refer to list of abbreviations
Schedule of Assessment Footnotes:
1 
The Baseline/Pre-dose visit is the last day of the Screening period. The Baseline/Pre-dose visit must be conducted in the afternoon. 
2
. 
3 
In addition to the complete neurological exam, a focused neurological exam is conducted during the Screening visit to include full assessment of tremor per 
Movement Disorder Society classification criteria (Bhatia, 2018). 
4 
Complete PE at Screening, Days 1, 7, and 14 (includes: General; HEENT; Cardiovascular; Respiratory; Abdomen; Skin; Extremities; Lymphatic system and 
Musculoskeletal); symptom-based PE at Baseline/Pre-dose and Day 21 Follow-up visit (includes: General, HEENT, Cardiovascular, Respiratory, Abdomen, Skin, 
Extremities). 
5
6
Triplicate ECG recordings, after a minimum of 5 minutes of rest in supine position: 3 consecutive recordings will be made in succession, no more than 2 minutes 
apart. The full set of triplicates should be completed in less than 4 minutes. These ECGs will be read by the Investigator to rule out any clinically significant 
findings. ECGs are to be performed prior to vital signs and blood sampling. 
7 
Blood pressure (systolic and diastolic), heart rate, respiratory rate and oral temperature. 
8 
Obtained prior to dosing and post dosing at 30min, 60min, 2 hours and 4 hours following the dose of study drug in the clinic. For Day 1, this is to be done 
Baseline/Pre-dose and 30min, 60min, and 2 hours after the first dose in the clinic, and again 30 min, 60 min, 2 hours, and 4 hours after the second dose in the 
clinic. There is a +/- 5-minute allowable time window for these assessments.  ECG to be done before the corresponding vital sign measurements. 
9  For details re: orthostatic vital signs measurements, refer to Section 7.10. 
10  Urinalysis includes: Bilirubin, Blood, Creatinine, Glucose, Ketones, Leukocyte esterase, Microscopy, Nitrite, pH, Protein, Specific gravity, Microalbumin and 
Urobilinogen 
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11   A serum pregnancy test is done at Screening only. 
12  A urine pregnancy test is done at Baseline/Pre-dose, Days 7, 14, and 21. 
13 
14    The subject should be instructed to self-administer their first daily dose of CAD-1883 4 to 5 hours prior to the scheduled and/or anticipated dosing of the second 
daily dose of CAD-1883. The second daily dose of CAD-1883 should be taken in the clinic 4 to 5 hours after the first daily dose. 
15 
16 
17
18  TETRAS Performance Subscale assessments at Screening, Baseline/Pre-dose, Days 1, 7, 14, and 21 will be recorded via videography for central rating. 
19 Screening:
20  Performed between 2-4 hours following the second dose in the clinic. 
21  Performed between 2-4 hours following the second daily dose in the clinic. 
22  Wearable sensor measurement of upper-limb tremor will be captured once at the site, at any time during Screening and Day 21. 
23 Wearable sensor measurements of upper limb tremor will be captured at two different times during the Baseline/Pre-dose visit. 
24  Wearable sensor measurements of upper limb tremor will be captured once, 2 to 4 hours following the in-clinic dose.  For Day 1, this is to be done 2-4 hours after 
the 2nd in-clinic dose. 
25  At the Baseline/Pre-dose visit, the “baseline” version of the C-SSRS will be administered. This version assesses Suicidal Ideation and Suicidal Behavior during the 
subject’s lifetime and during a predefined period. At the Day 21 visit (and the Early Termination visit for subjects withdrawing early), the “since last visit” version 
will be administered. The C-SSRS does not need to be completed at the Day 14 visit if it is not an Early Termination visit. During Early Termination visit, the 
subject will not receive study drug, will undergo all required procedures as well as the C-SSRS. 
26  Both doses of study drug are to be administered in the clinic with the second dose being administered 4-5 hours after the first.  
27  All laboratory collections on Days 1, 7, 14 should be performed after the TETRAS-PS assessment.  
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APPENDIX B:  CLINICAL LABORATORY ANALYTES 
Clinical Chemistry Panel 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Amylase 
Aspartate aminotransferase 
Bicarbonate 
Blood urea nitrogen 
Calcium 
Chloride 
Creatine kinase 
Creatinine 
Estimated glomerular filtration rate 
Glucose 
Gamma-glutamyl transferase 
Inorganic phosphorus 
Lactate dehydrogenase 
Lipase 
Potassium 
Sodium 
Total and direct bilirubin 
Total protein 
Uric acid 
Biomarker panel for renal tubular injury 
Endocrinology 
Follicle-stimulating hormone [1] 
Thyroid-stimulating hormone [2] 
[1] Postmenopausal women must have had ≥365 days of spontaneous amenorrhea, with
documented follicle-stimulating hormone (FSH) ≥38 IU/mL, prior to screening. If needed, per
Investigator’s judgment, FSH level can be performed at Screening.
[2] An abnormal TSH level at Screening can be followed by reflex testing of thyroid hormones
(T3, T4), if needed, per the Investigator’s judgment.
Hematology 
Hematocrit 
Hemoglobin 
Platelets 
Red blood cell count 
White blood cell count with differentials [1]: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Red blood cell indices: 
MCV 
MCH 
%Reticulocytes 
[1] Manual microscopic review is performed only if white blood cell count and/or
differential values are out of reference range.
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Urinalysis 
Bilirubin 
Blood 
Creatinine 
Ketones 
Glucose 
Leukocyte esterase 
Microscopy [1] 
Microalbumin 
Nitrite 
pH 
Protein 
Specific gravity 
Urobilinogen 
[1] Microscopy is performed only as needed based on positive dipstick test results.
Additional Laboratory Tests   
HIV 
HBsAg 
HCVAb [1] 
Pregnancy (urine or serum according to SOA [Appendix A, Table 2]) 
[1] A positive result for HCVAb is acceptable provided that it was effectively treated as
documented by negative results from Reflex Testing for HCV RNA (performed during Screening
at the central lab or at a local or specialized lab) by either the quantitative (viral load) or
qualitative (Real-Time polymerase chain reaction [PCR]) method.
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