Clinical trial NCT03688685
Conditions: Essential Tremor
Keywords: ET Essential Tremor
Sponsor: Cadent Therapeutics
Start date: 2019-01-23; Completion date: 2019-09-24
Enrollment: 25 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an open-label study designed to evaluate the safety, tolerability and efficacy of CAD-1883, a positive allosteric modulator of the SK channel, administered twice daily orally to adult patients with ET. Patients with the diagnosis of ET based on the Movement Disorder Society (MDS) criteria with a documented severity of tremor based on the clinician-administered TETRAS Performance Subscale are eligible to be enrolled in the study.

Detailed description:
This is an open-label study designed to evaluate the safety, tolerability and efficacy of CAD-1883, a positive allosteric modulator (PAM) of the SK channel, administered twice daily orally to adult subjects with ET. Positive modulation of the small-conductance calcium-activated potassium channels (SK) present in different regions of the brain aims to increase the channel sensitivity to calcium resulting in reduction in neuronal firing rate. In patients with ET, improving the regularity of firing of action potentials in the olivo-cerebellar network can lead to improvement in motor function.

During the Screening period, each subject will undergo full assessment including medical and treatment history for ET, physical examination and other screening assessments. Patients with the diagnosis of ET based on the Movement Disorder Society (MDS) criteria with a documented severity of tremor based on the clinician-administered TETRAS Performance Subscale are eligible to be enrolled in the study. The study consists of treatment groups receiving twice daily oral dosing of CAD-1883 for a treatment period of 14 days.

This study is designed to enable the assessment of safety and tolerability of CAD-1883 in patients with ET as well as the 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, 12-lead ECG, urinalysis, hematology, clinical chemistry, and CAD-1883 plasma concentration level on Days 1, 7, 14 and 21.

Efficacy will be evaluated using the clinician-administered TETRAS Performance Subscale as well as the use of a wearable sensor in the clinic and at home.

Arms: arm 1: Open-label study designed to evaluate the safety, tolerability, and efficacy of CAD-1883 administered twice daily orally to adult subjects with ET
Interventions: intervention 1: CAD-1883
Intervention descriptions: intervention 1: Treatment groups receiving twice-daily oral dosing of CAD-1883 for a treatment period of 14 days.

Protocol documents:
Prot_000.pdf: 
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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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 
withdrawing early), the “since last visit” version will be administered. 


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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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Version Amendment 3.0,  09 July 2019 
71 
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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Version Amendment 3.0,  09 July 2019 
72 
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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SAP_001.pdf: 
Statistical Analysis Plan 
Sponsor 
Cadent Therapeutics, Inc. 
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-I) 
Protocol Number: 
CAD 1883-20 I Protocol Amendment 3 / NCT03688685 
Document Version: 
Final 1.0 
Document Date: 
04-Mar-2020
Approvals 
Role 
Signatures 
Date (DDMMMYYYY) 
I 
Confidential 
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Protocol Number CAD1883-201 
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Document History 
Document 
version 
Date of 
availability 
Note 
1.0 
04-Mar-2020
Final Version 


Statistical Analysis Plan,  
Cadent Therapeutics, Inc.  
Protocol Number CAD1883-201 
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Table of Contents 
Approvals ........................................................................................................................................ 1 
Document History ........................................................................................................................... 2 
Table of Contents ............................................................................................................................ 3 
List of Tables .................................................................................................................................. 5 
List of Figures ................................................................................................................................. 5 
1.
Overview ............................................................................................................................. 6 
2.
Study Objectives and Endpoints ......................................................................................... 6 
2.1. 
Study Objectives ........................................................................................................... 6 
2.1.1. Primary Objective ......................................................................................................... 6 
2.1.2. Secondary Objectives.................................................................................................... 6 
2.2. 
Study Endpoints ............................................................................................................ 7 
2.2.1. Safety Endpoints ........................................................................................................... 7 
2.2.2. Efficacy Endpoints ........................................................................................................ 7 
3.
Overall Study Design and Plan ........................................................................................... 8 
3.1. 
Overall Design .............................................................................................................. 8 
3.2. 
Sample Size and Power ................................................................................................. 8 
3.3. 
Study Population ........................................................................................................... 8 
3.4. 
Treatments Administered .............................................................................................. 8 
3.5. 
Method of Assigning Subjects to Treatment Groups .................................................... 8 
3.6. 
Blinding and Unblinding............................................................................................... 8 
3.7. 
Schedule of Events ........................................................................................................ 9 
4.
Statistical Analysis and Reporting .................................................................................... 15 
4.1. 
Introduction ................................................................................................................. 15 
4.2. 
Interim Analysis and Data Monitoring ....................................................................... 15 
5.
Analysis Populations ......................................................................................................... 15 
6.
General Considerations for Statistical Analysis ............................................................... 16 
6.1. 
Statistical Definitions and Algorithms ........................................................................ 16 
6.1.1. Baseline ....................................................................................................................... 16 
6.1.2. Categorization of Subjects .......................................................................................... 16 
6.1.4. Multiple Comparisons ................................................................................................. 17 
6.1.5. Handling of Dropouts or Missing Data ....................................................................... 17 
6.1.6. Analysis Visit Windows ............................................................................................. 17 
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6.1.7. Pooling of Sites ........................................................................................................... 17 
6.1.8. Derived Variables ....................................................................................................... 17 
6.1.9. Data Adjustments/Handling/Conventions .................................................................. 19 
7.
Study Subjects and Demographics.................................................................................... 21 
7.1. 
Disposition of Subjects and Withdrawals ................................................................... 21 
7.2. 
Protocol Violations and Deviations ............................................................................ 21 
7.3. 
Demographics and Other Baseline Characteristics ..................................................... 21 
7.4. 
Exposure and Compliance .......................................................................................... 21 
8.
Efficacy Analysis .............................................................................................................. 21 
8.1. 
Primary Efficacy Analysis .......................................................................................... 22 
8.2. 
Secondary Efficacy Analysis ...................................................................................... 22 
8.2.1. TETRAS Performance Subscale Scores ..................................................................... 22 
8.2.2. TETRAS Upper Limb Subscale Score ....................................................................... 23 
8.2.3. TETRAS-PS Upper Limb Tremor (Item 4) Total Score ............................................ 24 
8.2.9. Wearable Sensor (Kinesia) ......................................................................................... 26 
9.
Safety and Tolerability Analysis ....................................................................................... 28 
9.1. 
Adverse Events ........................................................................................................... 28 
9.1.1. Adverse Events Leading to Withdrawal ..................................................................... 29 
9.1.2. Deaths and Serious Adverse Events ........................................................................... 29 
9.2. 
Clinical Laboratory Evaluations ................................................................................. 29 
9.3. 
Vital Signs ................................................................................................................... 30 
9.4. 
Electrocardiograms ..................................................................................................... 31 
9.5. 
Further Safety Evaluations .......................................................................................... 31 
9.5.1. Physical Examination.................................................................................................. 31 
9.5.2. Neurological Examination .......................................................................................... 31 
9.5.3. Columbia Suicide Severity Rating Scale .................................................................... 31 
9.7 
Kidney safety Composite Measure Biomarker ........................................................... 32 
10.
Changes from the Protocol-Planned Analysis .................................................................. 33 
11.
Other Planned Analysis..................................................................................................... 33 
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12.
References ......................................................................................................................... 33 
13.
Tables, Listings, and Figures ............................................................................................ 34 
13.1. Planned Table Descriptions ........................................................................................ 35 
13.2. Efficacy Data .............................................................................................................. 35 
13.3. Safety Data .................................................................................................................. 36 
13.5. Planned Listing Descriptions ...................................................................................... 38 
13.6. Planned Figure Descriptions ....................................................................................... 41 
14.
Tables, Listings, and Listing Shells .................................................................................. 42 
14.1. Standard Layout for all Tables, Listings, and Figures ................................................ 42 
14.2. Planned Table Shells ................................................................................................... 44 
14.3. Planned Listing Shells............................................................................................... 105 
14.4. Planned Figure Shells ............................................................................................... 141 
Appendix 1: List of Abbreviations ............................................................................................. 149 
List of Tables 
Table 1: Schedule of Events ......................................................................................................... 10 
Table 2: Analysis Visit Windows ................................................................................................. 17 
Table 3: Kinesia and TETRAS-PS Score Mappingss ................................................................... 28 
Table 4: Demographic Data Summary Tables and Figures .......................................................... 35 
Table 5: Efficacy Data .................................................................................................................. 35 
Table 6: Safety Data...................................................................................................................... 36 
List of Figures 
Figure 1: Standardized Layout ...................................................................................................... 43 
Figure 2: Planned Table Shells ..................................................................................................... 45 
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Statistical Analysis Plan,  
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1.
Overview
This statistical analysis plan (SAP) describes the planned analysis and reporting for Cadent 
Therapeutics, Inc. protocol number CAD1883-201 (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]), dated 09-Jul-2019 Amendment 3. Reference materials for this SAP 
include the protocol and the accompanying sample data collection documents. Operational 
aspects related to data collection and timing of planned clinical assessments are not repeated in 
this SAP unless relevant to the planned analysis. 
The structure and content of this SAP provides sufficient detail to meet the requirements 
identified by the Food and Drug Administration (FDA), European Medicines Agency (EMA), 
and International Conference on Harmonization (ICH) of Technical Requirements for 
Registration of Pharmaceuticals for Human Use: Guidance on Statistical Principles in Clinical 
Trials1. All work planned and reported for this SAP will follow internationally accepted 
guidelines, published by the American Statistical Association2 and the Royal Statistical Society3, 
for statistical practice. 
The planned analyses identified in this SAP may be included in clinical study reports (CSRs), 
regulatory submissions, or future manuscripts.
2.
Study Objectives and Endpoints
2.1. 
Study Objectives 
2.1.1. Primary Objective 
The primary objective is to evaluate the safety and tolerability of twice-daily oral dosing of 
CAD-1883 over 14 days of treatment in adult subjects with Essential Tremor (ET). 
2.1.2. Secondary Objectives 
The secondary objectives 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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2.2. 
Study Endpoints 
2.2.1. Safety Endpoints 
The primary safety endpoint of the study is the occurrence and severity of treatment emergent 
AEs (TEAEs). 
2.2.2. Efficacy Endpoints 
2.2.2.1. 
Primary Efficacy Endpoint 
Not applicable.  The primary endpoint of this study is safety and tolerability. 
2.2.2.2. 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints of this study are: 
•
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
•
Change from Baseline in mean frequency of tremor in arm on table posture, measured in
the clinic using a wearable sensor
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3.
Overall Study Design and Plan
3.1. 
Overall 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. The diagnosis of ET must 
be established by the Principal Investigator at Screening based on the Movement Disorder 
Society (MDS) criteria with a documented severity of tremor based on the clinician-administered 
TETRAS-PS.
 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
 medications, to allow the effects of 
previous medication(s)
 to be eliminated. 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]). 
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. 
subjects will have the option to complete at-home 
assessments of tremor using the wearable sensor 
3.2. 
Sample Size and Power 
Up to 30 subjects will be enrolled. No formal statistical power analysis was conducted. 
3.3. 
Study Population 
This study includes subjects between 18 and 75 years old, inclusive, with a history of tremor for 
at least 3 years. 
3.4. 
Treatments Administered 
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. Dose intervals on Days 1, 7 and 14 are 
changed from the protocol amendment 1 through 3. Subjects enrolled under the protocol 
amendment 1 take the first dose of CAD-1883 300 mg (3 capsules of 100 mg each) at the site, 
2nd dose are taken 8 hours (±2 hours) after the first dose. On Days 7 and 14, the subjects are 
instructed to ingest the first daily dose of CAD-1883 of 300 mg at home. The second daily dose 
are taken in the clinic 8 hours (±2 hours) after the first daily dose. For subjects enrolled under 
the protocol amendment 2 and 3 the first dose on Day 1 is taken in clinic and the second dose is 
taken 4 to 5 hours later. On Days 7 and 14, the first daily dose is taken at home and the second 
daily dose is taken in the clinic 4 to 5 hours later. 
3.5. 
Method of Assigning Subjects to Treatment Groups 
There is 1 treatment group. Eligible subjects are enrolled sequentially.  There was no 
randomization, blinding, or stratification employed in this study. 
3.6. 
Blinding and Unblinding 
This is an open-label study with no blinding. 
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3.7. 
Schedule of Events 
A detailed schedule of events for the study is provided in Table 1. 


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Table 1: Schedule of Events 
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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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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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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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. 
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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 
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  (Protocol Amendment 3) 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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4.
Statistical Analysis and Reporting
4.1. 
Introduction 
Data processing, tabulation of descriptive statistics, calculation of inferential statistics, and 
graphical representations will be performed primarily using SAS (release 9.4 or higher). 
If the use of other 
software is warranted, the final statistical methodology report will detail what software was used 
for what purposes. 
Continuous (quantitative) variable summaries will include the number of subjects (n) with 
non-missing values, mean, standard deviation (SD), median, minimum, and maximum. 
Categorical (qualitative) variable summaries will include the frequency and percentage of 
subjects who are in the particular category for each possible value. In general, the denominator 
for the percentage calculation will be based upon the total number of subjects in the study 
population, unless otherwise specified. The denominator for by-visit displays will be the number 
of subjects in the relevant study population with non-missing data at each visit. If there is any 
missing value for a categorical analysis, a “Missing” category will be displayed as the last 
category in the table for the variable. 
For weight, height, 
 one decimal place will be used for all summary 
statistics.  For all other summaries, the minimum and maximum will be reported with the same 
degree of precision (i.e., the same number of decimal places) as the observed data. Measures of 
location (mean and median) and confidence interval boundaries will be reported to 1 degree of 
precision more than the observed data, up to 3 decimal places. Measures of spread (SD) will be 
reported to 2 degrees of precision more than the observed data, up to 3 decimal places. 
Percentages will be presented to 1 decimal place, unless otherwise specified. Percentages 
equaling 0 or 100 will be displayed with no decimal places or percentage symbols. 
Fractional numeric values will be presented with a zero to the left of the decimal point (for 
example, 0.12 – 0.30). 
Unless otherwise indicated, all statistical tests will be conducted at the 0.05 significance level 
using 2-tailed tests, and P values will be reported. Corresponding 95% confidence intervals (CIs) 
will be presented for statistical tests, where applicable. 
4.2. 
Interim Analysis and Data Monitoring 
There will be no interim analyses in this study. 
5.
Analysis Populations
The following analysis populations are planned for this study: 
•
Safety Population: The Safety population includes all subjects who took at least 1 dose
of study drug, regardless of the Protocol Amendment under which subjects were enrolled.
This population will be used to summarize all safety data.
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•
Full Analysis Set (FAS): The FAS consists of subjects in the Safety Population at least
one TETRAS-PS assessment Total Score at Day 7, Day 14 or early termination visit. The
FAS will be used to summarize all efficacy data.
•
Per-Protocol Population: The Per-Protocol Population includes all subjects in the FAS
who did not have any major protocol deviation and follow the study protocol for
TRETRAS-PS assessment at Day 14 or ET visit.
6.
General Considerations for Statistical Analysis
6.1. 
Statistical Definitions and Algorithms 
6.1.1. Baseline 
The last non-missing observed value recorded on or before the date of the first dose of treatment 
at the Pre-dose visit will be used as the baseline observation for all calculations of change from 
baseline.  
Wearable sensor measurements of upper limb tremor will be captured at 2 different times during 
the Pre-dose visit (Visit 2); the average of the 2 assessments will be used as the baseline 
observation for all calculations of change from baseline in wearable sensor assessments.  
During the Pre-dose visit, baseline orthostatic vital signs will include 3 separate measurements, 
and the average of the 3 (or fewer if missing data occur) baseline orthostatic vital signs 
measurements will be used as baseline for comparison to all post-treatment measurements. 
6.1.2. Categorization of Subjects 
All subjects will be categorized into the following 2 groups based on under which protocol 
amendment they were enrolled: 
•
Cohort-1: Subjects enrolled under Protocol Amendment 1.0
•
Cohort-2: Subjects enrolled under Protocol Amendment 2.0 or 3.0
All analyses will be presented overall and by cohort. 
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6.1.4. Multiple Comparisons 
6.1.5. Handling of Dropouts or Missing Data 
There was no replacement for subjects who had withdrawn from the study or were lost to follow 
up. Individual items of TETRAS-PS,
, and Kinesia scores will not be imputed as 
described in Section 6.1.8. 
6.1.6. Analysis Visit Windows 
Visits will be analyzed as scheduled. Unscheduled and/or repeated measurements will only be 
included if a scheduled measurement is not available and the unscheduled/repeated measurement 
falls within the analysis visit windows as described in Table 2. The windows follow the Schedule 
of Events in Table 1. Unscheduled/repeated measurements will be listed. Study day is defined in 
Section 6.1.8. 
Table 2: Analysis Visit Windows 
Visit Name 
Visit Number Target Start Day Lower Limit Upper Limit 
Screening 
1 
-35
-14
Baseline Pre-dose 
2 
-14
-3
Day 1 
3 
1 
1 
1 
Day 7 
4 
7 
6 
8 
Day 14 
5 
14 
13 
15 
Day 21 
6 
21 
20 
22 
6.1.7. Pooling of Sites 
Not applicable. 
6.1.8. Derived Variables 
•
TETRAS-PS Total score = sum of the 16 individual item scores (only the maximum of
the item 5 lower limb tremor scores will be counted), with a maximum total score of 64.
There will be no missing value imputation performed.
•
TETRAS-PS Upper Limb Subscale score = sum of the item 4, item 6, item 7 and item
8 scores (forward outstretched postural tremor, lateral “wing beating” postural tremor,
kinetic tremor, Archimedes spirals, and dot approximation task from both sides of the
body, as well as handwriting), with a maximum total score of 44. There will be no
missing value imputation performed.
•
TETRAS-PS Upper Limb Tremor (Item 4) Total score = sum of the 6 individual
scores under item 4 scores (forward outstretched postural tremor, lateral “wing beating”
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postural tremor, and kinetic tremor scores for left and right hand, respectively) from both 
sides of the body, with a maximum total score of 24. There will be no missing value 
imputation performed. 
•
Kinesia Upper Limb Tremor score = sum of the scores from the extended arms posture,
wing-beating posture, and kinetic “finger-to-chin” wearable sensor maneuvers from both
sides of the body, with a maximum total score of 24. There will be no missing value
imputation performed.
•
Change from baseline = value at current time point – value at baseline.
• For calculation of change from baseline to Day 14 for discontinued subjects their
assessment value at the early termination (ET) visit should be used
•
Percent change from baseline = (change from baseline / baseline) * 100. If both
baseline and change from baseline are 0 then percent change from baseline will be set to
0.
•
Study day = number of days relative to the first dose date of study drug and will be
calculated using the following formulas:
For pre-dose: study day= Start Date/ Stop Date – first dose date;
For post-dose: study day= Start Date/ Stop Date – first dose date + 1.
•
TEAE (treatment-emergent AE) = any AE with an onset date/time after the first dose
of treatment. If an AE was present at baseline and worsened on or after the first dose of
treatment it will be considered a TEAE.
•
Orthostatic hypotension is 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.
•
Time since first ET symptom = Day 1 (Visit 3) date - Date of first ET symptom as
recorded on the Disease History case report form (CRF) + 1
•
Time since ET diagnosis = Day 1 (Visit 3) date - Date of ET diagnosis as recorded on
the Disease History case report form (CRF) + 1
•
Study drug compliance (capsule count) = total number of capsules taken / total number
of expected doses from the first dose date to the last dose date, inclusive * 100%.
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•
Number of expected doses for subjects who completed study treatment = number of
capsules taken at the clinic + number of capsules dispensed for self-administration at
home = [Day 14 (Visit 5) date – Day 1 (Visit 3) date + 1] x 6 capsules/day
Expected doses are summed up to the point of discontinuation (eg, if a subject
discontinued, only planned doses up to that discontinuation day are counted in the
denominator).
•
Number of capsules taken =  number of expected doses - number of capsules lost -
number of unused capsules returned at next clinic visit, as collected in the case report
form (CRF).
For subjects who discontinued and did not return remaining capsules, the number of
capsules taken will include all doses up to the last dose the subject reported, or the
discontinuation date (the second dose on that day will be excluded in this calculation).
For treatment completers with additional treatment (for example the subject received
study treatments for 15 days) their number of expected doses remains 84. Thus, the
resulting compliance rate will likely be over 100%.
6.1.9. Data Adjustments/Handling/Conventions 
All collected data will be presented in listings. Data not subject to analysis according to this plan 
will not appear in any tables or graphs but will be included in the data listings. 
All P values will be displayed in three decimals and rounded using standard scientific notation (eg, 
0.XXX). If a P value less than 0.001 occurs, it will be shown in tables as <0.001.
Adverse events and medical histories will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) version 21.1 thesaurus or higher. Concomitant medications will be coded 
using WHO Global B3 September 1, 2018. 
A treatment-related AE is any AE with a relationship to the study drug of possibly, probably, or 
definitely related. 
If partial AE or medication dates occur, the convention for replacing missing dates for the 
purpose of statistical analysis is as follows:  
For partial AE and medication start dates: 
•
If the year is unknown, then do not impute the date but assign a missing value.
•
If the year is known, but the month or month and day is unknown, then:
o
If the year matches the year of first dose date and the end date (if present) is after
first dose date, then impute as the month and day of the first dose date.
o
Otherwise, assign 01 January.


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•
If the year and month are known, but the day is unknown, then:
o
If the month and year match the month and year of the first dose date, then impute
as the day of the first dose date.
o
Otherwise, assign 01.
For partial AE and medication end dates: 
•
If the year is unknown, then do not impute the date but assign as missing value.
•
If the year is known, but the month or month and day is unknown, then:
o
If the year matches the year of the last date of the study (date of last contact if
subject lost to follow-up; date of completion or early termination otherwise), then
impute as the month and day of the last date of the study.
o
Otherwise, assign 31 December.
•
If the year and month are known, but the day is unknown, then:
o
If the month and year match the month and year of the last date of the study, then
impute as the day of the last date of the study.
o
Otherwise, assign the last day of the month.
If partial times occur, the convention is as follows: 
•
if the missing time occurs on the day of the first dose and both the hour and minute are
missing then the time assigned is the time of the first dose, otherwise if both the hour and
minute are missing and the date is not the date of first dose the time assigned is 12:00;
•
if the date is the same as the date of the first dose and
o
only hour is missing the hour assigned is 12 or the hour of first dose, whichever is
later;
o
only the minute is missing the minute assigned is 30 or the minute of first dose,
whichever is later;
•
Otherwise if the date is not the same as the date of first dose, the hour assigned is 12 if
the hour is missing and the minute assigned is 30 if the minute is missing.
Partial dates of first ET symptom and partial dates of ET diagnosis will be imputed similar to the 
rules outlined for AE start dates mentioned above. 


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7.
Study Subjects and Demographics
7.1. 
Disposition of Subjects and Withdrawals 
Disposition will include tabulations of the number of subjects who received treatment, reasons 
for discontinuation from the study, and number of subjects in each analysis population. This 
summary will be based on all subjects enrolled. 
All disposition information will be included in a listing. 
7.2. 
Protocol Violations and Deviations 
Protocol deviations will be listed. 
7.3. 
Demographics and Other Baseline Characteristics 
Summary statistics for age, gender, race, ethnicity, height, weight, 
will be presented. 
Medical history will be listed, and the number and percentage of subjects reporting various 
medical histories grouped by MedDRA System Organ Class (SOC) and Preferred Term (PT) will 
be tabulated. 
Time since first ET symptom, time since ET diagnosis, treatment type, trigger type, and 
frequency of triggers will be summarized descriptively. The number of subjects who report that 
alcohol reduces tremor severity and the number of subjects with a first or second-degree blood 
relative with ET will also be summarized.   
Disease history, including prior treatments for ET, ET triggers, and family history of ET, will 
also be listed. 
These analyses will be conducted for the Safety population. 
7.4. 
Exposure and Compliance 
All subjects were expected to receive treatment twice daily for 14 consecutive days for a total of 
28 doses. Total number of doses taken, number of missed doses, and compliance (%) will be 
summarized and listed for the Safety Population. Compliance via capsule count is defined in 
Section 6.1.8 as the rate of actual number of doses taken compared to the intended number of 
doses taken during the 2-week treatment period. Treatment compliance (rounded to the whole 
number) will also be categorized as <70%, ≥70 to 79%, ≥80 to 89%, ≥90% to 100%, and >100%. 
8.
Efficacy Analysis
All efficacy data (including change from baseline) will be summarized and presented in tabular 
format and in data listings.  
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Efficacy variables include TETRAS-PS score, TETRAS-PS upper limb subscale score, 
TETRAS-PS upper limb tremor item 4 total score, Kinesia Upper Limb Tremor score,  
 Analyses of these data will be conducted on both the FAS and Per-Protocol 
Population within the same output for tables; figures will only be presented on the FAS. 
8.1. 
Primary Efficacy Analysis 
Not applicable. The primary analysis for this study is safety.  
8.2. 
Secondary Efficacy Analysis 
Normality assumptions of efficacy endpoints will be tested using the Anderson-Darling method. 
If the P value for the normality test is >0.05 the data will be considered normally distributed and 
will be analyzed as specified in subsequent sections. Otherwise, if the P value is ≤0.05 the data 
will be considered non-normal and the Wilcoxon signed rank test will be used to assess the 
within-subject changes. The estimates, CIs and P values will be displayed.  
8.2.1. TETRAS Performance Subscale Scores 
The TETRAS-PS Subscale (Version 3.1) score includes the following 9 items: head tremor, face 
(including jaw) tremor, voice tremor, upper limb tremor (left/right), lower limb tremor, 
Archimedes spirals, handwriting, dot approximation task, and standing tremor. Scores for each 
item range from 0 to 4 in increments of 0.5. Derivation for the TETRAS-PS Total score is 
described in Section 6.1.8. For lower limb tremor, only the maximum of the item 5 scores will be 
used. The TETRAS-PS assessments will be administered by a certified rater (referred to as a 
local rater hereafter) at Screening, Pre-dose, Day 1, Day 7, Day 14, and Day 21. The TETRAS-
PS assessments will also be recorded using videography for centralized evaluation and rating by 
independent blinded central raters (neurologists) with expertise in the assessment of ET. All 
scores (item scores and total scores) by both local and central raters will be analyzed in the same 
way as described below for central rater data. 
Observed values and change from baseline in each item score and in TETRAS-PS total score by 
central rater will be summarized overall, by cohort (see Section 6.1.2), and by study visit using 
descriptive statistics. 
Additionally, tests of hypotheses comparing mean and median TETRAS-PS total scores between 
baseline and subsequent study visits will be conducted using a 2-sided paired t-test or Wilcoxon 
signed rank test. The null hypothesis is that the change from baseline in TETRAS-PS total score 
to subsequent visit is 0 with a 2-sided alternative considering a difference not 0 (significant 
changes in tremor). 
As a supportive analysis, change from Screening to Baseline and change from Day 14 to Day 21 
in each item score and in TETRAS-PS total score will be summarized overall and by cohort (see 
Section 6.1.2) using descriptive statistics. 
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8.2.2. TETRAS Upper Limb Subscale Score 
Upper limb tremor is assessed during the following maneuvers: forward outstretched posture, 
lateral “wing beating” posture, kinetic (finger-chin-finger) testing, Archimedes spirals, 
handwriting, and dot approximation task. Each side of the body (right and left) is assessed and 
scored individually for all maneuvers except handwriting. The individual item question scores 
for each side of the body range from 0 to 4, with higher scores indicating more tremors. 
Derivation for the upper limb subscale score is described in Section 6.1.8. 
Assessments will be administered at Screening, Pre-dose, Day 1, Day 7, Day 14, and Day 21. 
Assessment results (scores) by local and central rater will be analyzed in the same way as 
described below for central rater score data. Observed values and change from baseline to all 
subsequent study visits in the upper limb subscale score will be summarized overall, by cohort 
(see Section 6.1.2), and by study visit using descriptive statistics.  
Additionally, tests of hypotheses comparing mean and median TETRAS-PS upper limb subscale 
scores between baseline and subsequent study visits will be conducted using a 2-sided paired t-
test and a Wilcoxon signed rank test, respectively. The null hypothesis is that the change from 
baseline in TETRAS-PS upper limb subscale score to subsequent visit is 0 with a 2-sided 
alternative considering a difference in either direction (i.e., change from baseline not equal to 0, 
representing significant change in tremor). 
As a supportive analysis, change from Screening to Baseline and change from Day 14 to Day 21 
in each item score and in TETRAS-PS upper limb subscale score will be summarized overall and 
by cohort (see Section 6.1.2) using descriptive statistics. 
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8.2.3. TETRAS-PS Upper Limb Tremor (Item 4) Total Score 
Item 4 of the TETRAS-PS represents upper limb tremor. Upper limb tremor is assessed during 
three maneuvers: forward outstretched posture, lateral “wing beating” posture, and kinetic 
(finger-chin-finger) testing. Each side of the body (right and left) is assessed and scored 
individually. The upper limb individual item score for each side of the body ranges from 0 to 4, 
with higher scores indicating more tremors. Derivation for the TETRAS-PS Upper Limb Tremor 
(Item 4) Total score is described in Section 6.1.8. 
Assessments will be administered at Screening, Pre-dose, Day 1, Day 7, Day 14, and Day 21. 
Assessment results (scores) by local and central rater will be analyzed in the same way as 
described below for central rater score data. Observed values and change from baseline to all 
subsequent study visits in the upper limb subscale score will be summarized overall, by cohort 
(see Section 6.1.2), and by study visit using descriptive statistics.  
Additionally, tests of hypotheses comparing mean and median TETRAS-PS Upper Limb Tremor 
(Item 4) Total scores between baseline and subsequent study visits will be conducted using a 2-
sided paired t-test and a Wilcoxon signed rank test, respectively. The null hypothesis is that the 
change from baseline in TETRAS-PS Upper Limb Tremor (Item 4) Total score to subsequent 
visit is 0 with a 2-sided alternative considering a difference in either direction (i.e., change from 
baseline not equal to 0, representing significant change in tremor).  
As a supportive analysis, change from Screening to Baseline and change from Day 14 to Day 21 
in each item score and in TETRAS-PS Upper Limb Tremor (Item 4) Total score will be 
summarized overall and by cohort (see Section 6.1.2) using descriptive statistics. 
A waterfall plot presenting mean change from baseline and 95% CI in TETRAS-PS Upper Limb 
Tremor (Item 4) Total Score by study visit will also be displayed. Additionally, a line graph of 
mean change from baseline and percent change from baseline will be displayed by study visit. 
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8.2.9. Wearable Sensor (Kinesia) 
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 (right and left index fingers). These 
assessments will be conducted during the clinic visits and optionally at-home. The motion sensor 
uses three orthogonal accelerometers and three orthogonal gyroscopes to monitor three-
dimensional motion. Data are then transmitted from the sensor to a computer using Bluetooth 
technology. These measures of three-dimensional motion for each maneuver are then converted 
to Kinesia scores. Each Kinesia score ranges from 0.0 to 4.0; higher scores indicate more severe 
tremor. 
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 Pre-dose 
clinic visit. During the clinic visit on Days 1, 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 
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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.
Two measurements at Pre-dose will be averaged and the means of 2 sets of measurements (mean 
of Kinesia score, mean amplitude, and mean frequency) will be used to represent Pre-dose 
values. 
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.  
Observed values and change from baseline in the in-clinic wearable sensor measures of upper 
limb tremor severity, mean amplitude, and mean frequency will be summarized overall, by 
cohort (see Section 6.1.2), 
 and study visit using 
descriptive statistics. 
As a supportive analysis, change from Screening to Baseline and change from Day 14 to Day 21 
in the in-clinic wearable sensor measures of upper limb tremor severity, mean amplitude, and 
mean frequency for the above maneuvers will also be summarized. 
A waterfall plot presenting mean change from baseline and 95% CI in Wearable Sensor (Kinesia, 
in-clinic) measures by study visit will also be displayed.  
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9.
Safety and Tolerability Analysis
The primary endpoint of the study is the occurrence and severity of TEAEs. 
Safety will be evaluated from reported AEs, serious AEs (SAEs), changes in clinical laboratory 
values, changes in vital signs, changes in orthostatic vital signs, 12-lead electrocardiograms 
(ECG), Columbia-Suicide Severity Rating Scale (C-SSRS), and physical and neurological 
examination results. 
All safety analyses will be performed on the Safety population. 
9.1. 
Adverse Events 
Any AE occurring after the date/time of informed consent signature but prior to the first dose of 
study medication (ie, occurring during the Screening and Baseline periods) will be listed. All 
AEs that occur after the first dose of study drug will be considered TEAEs. This includes any 
AEs that started or worsened (if present at baseline, increased in frequency or severity) after 
taking the first dose of the study drug. For AEs occurring on the date of first dose, if the time of 
onset is missing, the AE will be assumed to be treatment emergent. 
All AEs will be coded using the MedDRA Version 21.1 or higher coding dictionary. 
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The causal relationship of the AE to the study drug is determined by the investigator as Not 
Related, Unlikely Related, Possibly Related, Probably Related, and Definitely Related. These 
will be mapped to Unrelated (Not Related or Unlikely Related) and Related (Possibly Related, 
Probably Related, and Definitely Related).  
Adverse events severity grades are reported as mild, moderate, or severe. 
Summaries of incidence rates (frequencies and percentages) of individual TEAEs will be 
presented by SOC, PT, and cohort. Such summaries will be displayed for all TEAEs, TEAEs by 
maximum severity, and TEAEs by relationship.  
Each subject will be counted only once within each summation level (SOC and PT). If a subject 
experiences more than 1 TEAE within each summation level only the TEAE with the strongest 
relationship or the maximum severity, as appropriate, will be included in the summaries by 
subject for relationship and severity, respectively. If a particular event is missing the severity 
and/or relationship, then the strongest possible severity or relationship will be assumed for 
analysis (severity=severe, relationship = definitely related). 
Incidences will be presented by descending frequency of SOC and PT within SOC, and then 
alphabetically within PT where the incidence is the same. 
Missing and partially missing AE start and/or stop dates will be imputed, for the purpose of 
statistical analysis, according to the specifications described in Section 6.1.9. 
Numbers of AEs will also be presented in these AE summary tables. 
In the AE data listings, all AEs will be displayed. AEs that are treatment emergent will be 
flagged. 
9.1.1. Adverse Events Leading to Withdrawal 
A summary of incidence rates (frequencies and percentages) of TEAEs leading to withdrawal of 
study drug or study discontinuation, by SOC, PT, and cohort will be prepared for the Safety 
population.  
A data listing of AEs leading to withdrawal of study drug or study discontinuation will also be 
provided, displaying details of the event(s) captured on the CRF. 
9.1.2. Deaths and Serious Adverse Events 
Any deaths that occur during the study will be listed. 
SAEs will be listed and also tabulated by SOC, PT, and cohort. 
9.2. 
Clinical Laboratory Evaluations 
Screening and safety laboratory tests will be performed at Screening, Pre-dose, Day 1, Day 7, 
Day 14, and at follow-up on Day 21. All laboratory test results will be summarized descriptively 
by study visit for the Safety Population overall and by cohort as both observed values and change 
from baseline values for each parameter. Categorical urinalysis results will be summarized using 
frequencies by study visit and cohort. Levels of composite biomarker panel for renal tubular 
injury will also be summarized by study visit and listed. 


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Shifts from baseline for clinical laboratory values below, within, or above the normal range will 
be provided for hematology and chemistry results by study visit. See Section 6.1.1 for the 
definition of baseline. Clinically significant abnormal findings will be reported as AEs. 
Abnormal laboratory results will be listed. 
Pregnancy test results will be listed. 
9.3. 
Vital Signs 
Descriptive summaries of observed values and changes from baseline will be calculated for 
supine systolic blood pressure (SBP), standing SBP, supine diastolic blood pressure (DBP), 
standing DBP, supine heart rate (HR), standing HR, respiration rate, and oral temperature by 
study visit for the Safety Population overall and by cohort. Shifts from baseline for SBP, DBP, 
and HR values below, within, or above the normal range will be provided by study visit for the 
Safety Population overall and by cohort.  Vital sign parameters outside the normal range will be 
flagged in the listings. The mean change from baseline in each parameter will also be plotted by 
study visit. Abnormal vital signs are as follows: 
•
SBP >140 mmHg
•
SBP <90 mmHg
•
DBP >90 mmHg
•
DBP <60 mmHg
•
HR >100 bpm
•
HR <60 bpm
•
Respiration rate >20 breaths/min
•
Respiration rate <12 breaths/min
•
Oral temperature >99.1 ºF/37.2 ºC
•
Oral temperature <97.8 ºF/36.5 ºC
Orthostatic vital signs (blood pressure and heart rate) will also be summarized by position and 
study visit and by cohort. During the Pre-dose visit, baseline orthostatic vital signs will include 3 
separate measurements and the average of the 3 baseline orthostatic vital signs measurements 
will be used for comparison to all post-treatment measurements. The average HR, SBP, and DBP 
will be presented in the pre-dose baseline summaries and each of the individual measurements 
will be listed for that study visit.  
Orthostatic hypotension will be defined as a reduction in systolic blood pressure of 20 mmHg or 
more and/or a reduction in diastolic blood pressure of 10 mmHg or more, for the standing 
measurement compared to the supine or semi-supine measurement. The frequency and 
percentage of subjects with orthostatic hypotension will also be presented by cohort. Any 
confirmed orthostatic hypotension or clinically significant measurements that are associated with 
clinical symptoms will be recorded as AEs. Orthostatic vital signs parameters outside the ranges 
specified above will be flagged in the listings.  
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9.4. 
Electrocardiograms 
12-lead ECGs will be obtained at Screening, Pre-dose, Day 1, Day 7, Day 14, and Day 21.
Descriptive summaries will be presented for ECG measures of PR interval, RR interval, mean 
heart rate, QRS interval, QT interval, and QTcF interval. Corrected QTc intervals will be 
calculated using Fridericia’s correction formula. These summaries will be presented by study 
visit for the Safety Population overall and by cohort. The mean change from baseline (pre-dose) 
for each parameter will be plotted by study visit. Values outside the normal range will be flagged 
in the listings. 
The number and percentage of subjects with normal, abnormal but not clinically significant, and 
abnormal and clinically significant ECG results will be summarized for the Safety population by 
study visit. 
Additionally, QTcF data will be summarized by the following categories by study visit: 
•
QTcF > 450 msec to ≤ 480 msec
•
QTcF > 480 msec
•
QTcF > 500 msec
•
Change from baseline > 30 msec to ≤ 60 msec
•
Change from baseline > 60 msec
9.5. 
Further Safety Evaluations
9.5.1. Physical Examination 
A complete physical examination (PE) will include general observations; head, eyes, ears, nose, 
throat, and musculoskeletal. Physical examinations will be conducted at screening, Pre-dose, 
Day 1, Day 7, Day 14, and Day 21. All physical examination results will be listed. 
9.5.2. Neurological Examination 
Neurological examinations will include assessment of mental status, cranial nerves, motor, 
sensory, reflexes, coordination, and gait. Neurological examinations will be conducted at 
screening, Pre-dose, Day 7, Day 14, and Day 21. All results will be listed. 
9.5.3. Columbia Suicide Severity Rating Scale 
The C-SSRS is a questionnaire that prospectively assesses Suicidal Ideation and Suicidal 
Behavior. At the 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 
the past 12 months. At the Day 14 and Day 21 visits (and the Early Termination visit for subjects 
withdrawing early), the “since last visit” version will be administered. 
Suicidality data collected on the C-SSRS will be listed for all subjects in the Safety Population. 
Tables will include results from the Suicidal Ideation and Suicidal Behavior sections of the C-
SSRS. Frequencies and percentages of subjects with a response of “Yes” at any point on the 


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Suicidal Ideation and Suicidal Behavior items will be summarized for the Safety Population 
(overall and by cohort).  
9.7 
Kidney safety Composite Measure Biomarker 
The following 6 kidney safety composite measure biomarkers were tested using urine sample: 
uCreatine (uCr), uClusterin (uCLU) , uCystatin-C (uCysC), uKidney Injury Molecule-1 (uKIM-
1), u N-Acetyl-beta-D-Glucosaminidase (uNAG), Neutrophil Gelatinase-Associated Lipocalin 
(uNGAL) and uOsteopontin (uOPN). Measured concentration is first normalized by dividing it 
by the concentration of uCR at the same timepoint. The fold change from baseline at a given 
timepoint is then calculated using the normalized concentration at a time point divided by the 
normalized concentration at baseline. For example, the normalized uCysC concentration at a 
given timepoint is calculated as the concentration of CysC at that timepoint divided by the 
concentration of uCr at the same timepoint. The uCysC fold change from baseline at a given 
timepoint is calculated as the normalized CysC concentration at a given timepoint divided by the 
normalized uCysC concentration at baseline. Similar calculations apply to other composite 
measures. 
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10.
Changes from the Protocol-Planned Analysis
TETRAS scores from both the central rater and local raters will be summarized. all rating scores 
will be listed. 
11.
Other Planned Analysis
12.
References
1. US Federal Register. (1998) International Conference on Harmonization; Guidance on
Statistical Principles for Clinical Trials. Department of Health and Human Services: Food
and Drug Administration [Docket No. 97D-0174]. Federal Register Volume 63, Number 179,
pages 49583-49598. September 16, 1998.
2. ASA. (2016) Ethical Guidelines for Statistical Practice. Prepared by the Committee on
Professional Ethics, April 2016. http://www.amstat.org/about/ethicalguidelines.cfm
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3. RSS. (2014) The Royal Statistical Society: Code of Conduct, 2014.
http://www.rss.org.uk/Images/PDF/join-us/RSS-Code-of-Conduct-2014.pdf.
4. FNIH and Critical Path Institute. (2019) User’s Guide Kidney Safety Composite Measure
Biomarker for Use in Clinical Development, Version 1. January 11, 2019.
13.
Tables, Listings, and Figures
All listings, tables, and figures (TLFs) will have a header showing the sponsor company name 
and protocol on the left (Cadent Therapeutics, CAD1883-201) and Page x of y on the right, and a 
footer showing the version of SAS, the file name and path, and the source of the data (CRF page 
or listing number) on the left and production run date in DDMMMYYY HH:MM on the right. 
Summary statistics will be presented to the following degree of precision unless otherwise 
specified: 
Statistics 
Degree of Precision 
Mean, Median, Quartiles, Confidence 
limit boundaries 
One more than the raw data, up to 3 decimal places. 
Standard deviation, Standard error 
One more than the mean, up to 3 decimal places. 
Minimum, Maximum 
The same as the raw data. 
p-value
Rounded to 3 decimal places and therefore 
presented as 0.xxx; p-values smaller than 0.001 as 
”<0.001”; p-values greater than 0.999 as ”>0.999”. 
Percentage 
One decimal place. A percentage of 100% will be 
reported as 100%. Percentages of zero will be 
reported as 0. 
For weight, height, 
 one decimal place will be used for all summary 
statistics. Fractional numeric values will be presented with a zero to the left of the decimal point 
(for example, 0.12 – 0.30).  
For summary tables when there are no subjects in a given treatment group/time point, display 0 
in the ”n” row and leave the statistics blank. 
For the AEs by SOC and PT, sort the SOC by alphabetical order and sort the PT under SOC by 
decreasing frequency in the cohort, unless specified otherwise. 
If there is a missing value for any categorical analysis, add a “Missing” category as the last one 
for the variable. 
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13.1. 
Planned Table Descriptions 
The following are planned summary tables for protocol number CAD1883-201. The table 
numbers and page numbers are place holders only and will be determined when the tables are 
produced. 
Table 4: Demographic Data Summary Tables and Figures 
Number 
Population 
Title 
Table 14.1.1 
All Enrolled Subjects 
Subject Disposition 
Table 14.1.2.1 
Safety 
Demographics and Baseline Characteristics 
Table 14.1.2.2 
Safety 
Disease History 
Table 14.1.3 
Safety 
Summary of Medical History by SOC and PT 
Table 14.1.5.1 
Safety 
Summary of Treatment Exposure and Compliance via Capsule Counts 
13.2. 
Efficacy Data 
Table 5: Efficacy Data 
Number 
Population 
Title 
Table 14.2.1.1.1 
FAS/Exposed 
Summary of Central Rater TETRAS-PS Scores by Study Visit 
Table 14.2.1.1.3 
FAS/Exposed 
Summary of Central Rater Categorical TETRAS-PS Item Scores by Study 
Visit 
Table 14.2.1.1.5 
FAS/Exposed 
Summary of Local Rater TETRAS-PS Scores by Study Visit 
Table 14.2.1.2.1 
FAS/Exposed 
Summary of Central Rater TETRAS-PS Upper Limb Subscale Scores by 
Study Visit 
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Number 
Population 
Title 
Table 14.2.1.2.4 
FAS/Exposed 
Summary of Local Rater TETRAS-PS Upper Limb Subscale Scores by 
Study Visit 
Table 14.2.1.3.1 
FAS/Exposed 
Summary of Central Rater TETRAS-PS Upper Limb Tremor (Item 4) Total 
Scores by Study Visit 
Table 14.2.1.3.3 
FAS/Exposed 
Summary of Local Rater TETRAS-PS Upper Limb Tremor (Item 4) Total 
Scores by Study Visit 
13.3. 
Safety Data 
Table 6: Safety Data 
Number 
Population 
Title 
Table 
14.3.1.1 
Safety 
Summary of Adverse Events 
Table 
14.3.1.2 
Safety 
Incidence of Treatment Emergent Adverse Events by SOC and PT 
Table 
14.3.1.3 
Safety 
Incidence of Treatment Emergent Adverse Events by SOC, and PT, and Maximum 
Severity  
 
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Number 
Population 
Title 
Table 
14.3.1.4 
Safety 
Incidence of Treatment Emergent Adverse Events by SOC, PT, and Relationship 
Table 
14.3.2.1 
Safety 
Incidence of TEAEs Leading to Withdrawal of Study Drug by SOC and PT 
Table 
14.3.2.2 
Safety 
Incidence of Serious Adverse Events by SOC and PT 
Table 
14.3.3.1 
Safety 
Listing of Adverse Events Leading to Study Drug Discontinuation 
Table 
14.3.3.2 
Safety 
Listing of Serious Adverse Events 
Table 
14.3.3.3 
Safety 
Listing of Deaths 
Table 
14.3.4.1 
Safety 
Abnormal Laboratory Results 
Table 
14.3.5.1.1 
Safety 
Summary of Hematology Laboratory Results by Study Visit 
Table 
14.3.5.1.2 
Safety 
Shift from Baseline in Hematology Laboratory Results by Study Visit 
Table 
14.3.5.2.1 
Safety 
Summary of Serum Chemistry Laboratory Results by Study Visit 
Table 
14.3.5.2.2 
Safety 
Shift from Baseline in Serum Chemistry Laboratory Results by Study Visit 
Table 
14.3.5.3.1 
Safety 
Summary of Quantitative Urinalysis Laboratory Results by Study Visit 
Table 
14.3.5.3.2 
Safety 
Shift from Baseline in Quantitative Urinalysis Laboratory Results by Study Visit 
Table 
14.3.5.3.3 
Safety 
Summary of Qualitative Urinalysis Laboratory Results by Study Visit 
Table 
14.3.5.4.1 
Safety 
Summary of Quantitative Biomarker Panel for Renal Injury Results by Study Visit 
Table 
14.3.5.4.2 
Safety 
Geometric Mean (GM) Composite Measure (CM) on Quantitative Biomarker Panel 
for Renal Tubular Injury Results by Study Visit 
Table 
14.3.6.1.1 
Safety 
Summary of Vital Signs by Study Visit 
Table 
14.3.6.1.2 
Safety 
Shift from Baseline in Vital Signs by Study Visit 
Table 
14.3.6.1.3 
Safety 
Summary of Orthostatic Vital Signs by Study Visit 
Table 
14.3.6.1.4 
Safety 
Shift from Baseline in Orthostatic Vital Signs by Study Visit 


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Number 
Population 
Title 
Table 
14.3.6.1.5 
Safety 
Summary of Orthostatic Vital Signs Shift from Baseline Categories by Study Visit 
Table 
14.3.6.1.6 
Safety 
Summary of Orthostatic Hypotension by Study Visit 
Table 
14.3.6.2.1 
Safety 
Summary of 12-Lead Electrocardiogram by Study Visit 
Table 
14.3.6.2.2 
Safety 
Summary of 12-Lead Electrocardiogram Interpretation by Study Visit 
Table 
14.3.6.2.3 
Safety 
Summary of QTcF Values by Study Visit 
Table 
14.3.6.4 
Safety 
Summary of Columbia-Suicide Severity Rating Scale (C-SSRS) 
13.5. 
Planned Listing Descriptions 
The following are planned data and subject data listings for protocol number CAD1883-201. 
In general, one listing will be produced per CRF domain. All listings will be sorted by treatment, 
site, and subject number unless otherwise specified. All calculated variables will be included in 
the listings. 
In all listings a blank line will be placed between each subject. Within a data listing, if an item 
appears line after line (eg, repetition of subject number), then only the first occurrence will be 
displayed. 
In data listings, the information for one subject will be kept on one page if at all possible, rather 
than splitting a subject’s information across pages. If a subject's data are displayed on extended 
to another page, the subject number will be displayed again at the top of any subsequent pages 
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Table 6: Planned Listings 
Number 
Population 
Title 
Listing 
16.2.1.1 
All Subjects 
Subject Disposition 
Listing 
16.2.1.2 
All Subjects 
Visit Status 
Listing 
16.2.2.1 
All Subjects 
Descriptions of Protocol Defined Inclusion and 
Exclusion Criteria 
Listing 
16.2.2.2 
All Subjects 
Inclusion and Exclusion Criteria Met/Not Met 
Listing 
16.2.2.3 
All Subjects 
Protocol Deviations 
Listing 
16.2.3 
All Subjects 
Analysis Populations 
Listing 
16.2.4.1 
All Subjects 
Demographics and Baseline Characteristics 
Listing 
16.2.4.2 
All Subjects 
Medical History 
Listing 
16.2.4.3 
All Subjects 
Disease History 
Listing 
16.2.5.1 
All Subjects 
Study Drug Administration 
Listing 
16.2.5.2 
All Subjects 
Drug Accountability 
Listing 
16.2.5.3 
All Subjects 
Missed Doses 
Listing 
16.2.6.1.1 
All Subjects 
Local TETRAS Performance Subscale and Upper Limb 
Subscale Scores 
Listing 
16.2.6.1.2 
All Subjects 
Central TETRAS Performance Subscale and Upper 
Limb Subscale Scores 
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Number 
Population 
Title 
Listing 
16.2.6.6 
All Subjects 
Wearable Sensor (Kinesia) Scores 
Listing 
16.2.7 
All Subjects 
Adverse Events 
Listing 
16.2.8.1.1 
All Subjects 
Clinical Laboratory Data: Hematology 
Listing 
16.2.8.1.2 
All Subjects 
Clinical Laboratory Data: Serum Chemistry 
Listing 
16.2.8.1.3 
All Subjects 
Clinical Laboratory Data: Urinalysis 
Listing 
16.2.8.1.4 
All Subjects 
Clinical Laboratory Data: Biomarker Panel for Renal 
Tubular Injury  
Listing 
16.2.8.1.5 
All Subjects 
Clinical Laboratory Data: Urine Pregnancy Test 
Listing 
16.2.8.1.7 
Safety Population 
Clinical Laboratory Data: Biomarker Panel for Renal 
Tubular Injury 
Listing 
16.2.8.2.1 
All Subjects 
Physical Examination 
Listing 
16.2.8.2.2 
All Subjects 
Neurological Examination 
Listing 
16.2.8.3.1 
All Subjects 
Vital Signs 
Listing 
16.2.8.3.2 
All Subjects 
Blood Pressure and Orthostatic Vital Signs 
Listing 
16.2.8.4.1 
All Subjects 
Qualitative 12-Lead Electrocardiogram (ECG) 
Investigator Results 
Listing 
16.2.8.4.2 
All Subjects 
12-Lead Electrocardiogram (ECG) Central Results
Listing 
16.2.8.6 
All Subjects 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
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13.6. 
Planned Figure Descriptions 
The following are planned summary figures for protocol number CAD1883-201. The figure 
numbers and page numbers are place holders only and will be determined when the figures are 
produced. 
Table 7: Planned Figures 
Number 
Population Title 
Figure 
14.2.1.1.4 
FAS 
Central and Local TETRAS-PS Total Scores by Study Visit 
Figure 
14.2.1.2.3 
FAS 
Central and Local TETRAS-PS Upper Limb Subscale Scores by Study Visit 
Figure 
14.2.1.3.2 
FAS 
Central and Local TETRAS-PS Upper Limb Tremor (Item 4) Scores by Study Visit 
Figure 
14.2.6.1 
FAS 
TETRAS-PS and Wearable Sensor (Kinesia) Upper Limb Tremor Scores by Study 
Visit 
Figure 14.5 
Safety 
Geometric Mean (GM) Composite Measure (CM) of Kidney Injury Biomarkers by 
Study Visit  
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14.
Tables, Listings, and Listing Shells
14.1. 
Standard Layout for all Tables, Listings, and Figures 
The following standard layout will be applied to all TLFs in support of this study. Note that programming notes may be added if 
appropriate after each TLF shell.  


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Figure 1: Standardized Layout 
Cadent Therapeutics, Inc. 
Page xx of xx 
Protocol: CAD1883-201 
Version  
<Table, Listing, Figure> xx.x.x 
<Title of Table Listing or Figure> 
<Study Population and if applicable subgroup Description> 
Body of Table, Listing or Figure 
<Note: If directly Applicable> 
Footnote 1 <if applicable>  Recommendation is to keep footnotes to a minimum 
Footnote 2 <if applicable> 
Footnote n <if applicable> 
Footnote n+1 <pgm path and name>,  <date> 


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Note: 
•
"Page x of x" should be aligned to the right. Page x of y is for individual TLF only, not for the entire table sets. For example
there are 2 pages for T14.1.1, then it will be Page 1 of 2 and Page 2 of 2 respectively.
•
Keep one space line only between TLF title and page headers
•
Keep "program path and name" on the left while align "Run Date: ..." to the right
•
Keep one more decimal place for SD than for mean
•
Add "Missing" category where missing value is available
•
keep under TLF abbreviations in alphabetical order
•
keep different footnotes separately in different lines.
•
For any conditions coded by SOC and PT, please sort the SOC by alphabetical order, and sort the PT under SOC by decreasing
frequency in the overall column, unless specified otherwise.
14.2. 
Planned Table Shells 
See Figure 2 below. 


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Figure 2: Planned Table Shells 
Table 14.1.1 
Subject Disposition 
All Enrolled Subjects 
Category 
Cohort-1 
(N=XX) 
Cohort-2 
 (N=XX) 
Overall 
 (N=XX) 
Enrolled 
XX 
XX 
XX 
Analysis Populations: 
   Safety Population [1] 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   FAS Population [2] 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Per-Protocol Population [4] 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Completed Study  
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Prematurely Discontinued from Study 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Reason for Discontinuation: 
 Adverse Event 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 Death 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 Lack of Efficacy 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 Lost to Follow-Up 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 Newly Emerged Exclusion Criteria During Study 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 Non-Compliance with Study Drug 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 Physician Decision 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 Pregnancy 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 Protocol Violation 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 Study Terminated by Sponsor 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 Withdrawal by Subject 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 Other 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Abbreviations: ADL = activities of daily living; FAS = full analysis set; ICF = informed consent form; 
; PS = performance subscale; TETRAS = Tremor Research Group 
Essential Tremor Rating Assessment Scale. 
Note: Cohort-1 is composed of subjects enrolled under the Protocol Amendment 1. Protocol Amendment 1 was finalized on 03 Dec 2018 with dosing interval of 8±2 hours during entire 
treatment period (Day 1-14). Cohort-2 is composed of subjects enrolled under Amentment 2 or 3. Amendment 2 was finalized on 09 May 2019 and Amendment 3 on 09 July 2019. Dosing 
interval was changed to 4-5 hours on Days 1, 7 and 14 in both Amendments 2 and 3. 
Percentages are n/Number of subjects in the enrolled*100. 
[1] The Safety population includes all subjects who took at least 1 dose of study drug.
[2] The FAS consists of subjects in the Safety Population at least one TETRAS-PS assessment Total Score at Day 7, Day 14 or early termination visit. The FAS will be used to summarize
all efficacy data.
[3]
[4] The Per-Protocol Population includes all subjects in the FAS who did not have any major protocol deviation and follow the study protocol for TRETRAS-PS assessment.
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Source: Listing 16.2.1.1 
Table 14.1.2.1 
Demographics and Baseline Characteristics 
Safety Population 
Variable 
Cohort-1 
Cohort-2 
Overall 
   Statistic or Category 
(N=XX) 
(N=XX) 
(N=XX) 
Age (years) 
   N 
XX 
XX 
XX 
   Mean (SD) 
XX.X (XX.X)
XX.X (XX.X)
XX.X (XX.X)
   Median 
XX.X
XX.X
XX.X
   Min, Max 
XX, XX
XX, XX
XX, XX
Sex 
   Male 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Female 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Child-Bearing Potential? [1] 
   Yes 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   No 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Ethnicity 
   Hispanic or Latino 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Not Hispanic or Latino 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Race 
   American Indian or Alaska Native 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Asian 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Black or African-American 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Native Hawaiian or Other Pacific Islander 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   White 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Unknown 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   More than One Race 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Note: Percentages are n/Number of subjects in the Safety Population*100. 
[1] Only captured for female subjects; percentages are based on the number of female subjects in the Safety Population.
SOURCE: Listing 16.2.4.1


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Table 14.1.2.1 (cont.) 
Demographics and Baseline Characteristics 
Safety Population 
Variable 
Cohort-1 
Cohort-2 
Overall 
   Statistic or Category 
(N=XX) 
(N=XX) 
(N=XX) 
Height (cm) 
   N 
XX 
XX 
XX 
   Mean (SD) 
XX.X (XX.X)
XX.X (XX.X)
XX.X (XX.X)
   Median 
XX.X
XX.X
XX.X
   Min, Max 
XX, XX
XX, XX
XX, XX
Weight (kg) 
   N 
XX 
XX 
XX 
   Mean (SD) 
XX.X (XX.X)
XX.X (XX.X)
XX.X (XX.X)
   Median 
XX.X
XX.X
XX.X
   Min, Max 
XX, XX
XX, XX
XX, XX
Note: Percentages are n/Number of subjects in the Safety Population*100. 
[1] Only captured for female subjects; percentages are based on the number of female subjects in the Safety Population.
SOURCE: Listing 16.2.4.1
Programming note: keep one decimal place for HT, WT 
 statistics except n. 
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Table 14.1.2.2 
Disease History 
Safety Population 
Variable 
Cohort-1 
Cohort-2 
Overall 
   Statistic or Category 
(N=XX) 
(N=XX) 
(N=XX) 
Time Since First ET Symptom (days) 
   N 
XX 
XX 
XX 
   Mean (SD) 
XX.X (XX.X)
XX.X (XX.X)
XX.X (XX.X)
   Median 
XX.X
XX.X
XX.X
   Min, Max 
XX, XX
XX, XX
XX, XX
Time Since ET Diagnosis (days) 
   N 
XX 
XX 
XX 
   Mean (SD) 
XX.X (XX.X)
XX.X (XX.X)
XX.X (XX.X)
   Median 
XX.X
XX.X
XX.X
   Min, Max 
XX, XX
XX, XX
XX, XX
Treatment Type 
   Medication 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Herbal Remedy 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Exercise 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Biofeedback 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Deep Brain Stimulator 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Ultrasound Thalamotomy 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Other 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Response Type 
   Adequate Relief 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Some Relief (Partial Response) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   No Relief 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Abbreviation: ET = Essential Tremor, Max=Maximum, Min=Minimum, SD=Standard Deviation. 
Note: Percentages are n/Number of subjects in the Safety Population*100. Partial dates of first ET symptom or dates of ET diagnosis will be derived according to Section 6.1.9 of 
the statistical analysis plan. 
SOURCE: Listing 16.2.4.3 


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Table 14.1.2.2 (cont.) 
Disease History 
Safety Population 
Variable 
Cohort-1 
Cohort-2 
Overall 
   Statistic or Category 
(N=XX) 
(N=XX) 
(N=XX) 
Trigger Type 
   Stress 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Food 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Diurnal Fluctuation 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Season 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Travel 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Other 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Frequency of Trigger 
   Rarely 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Occasionally 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Often 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Daily 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Other 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Did Alcohol Use Reduce Tremor Severity? 
   Yes 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   No 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Not Applicable 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
First or Second Degree Blood Relative Diagnosed with ET? 
   Yes 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   No 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Abbreviation: ET = essential tremor. 
Note: Percentages are n/Number of subjects in the Safety Population*100. 
SOURCE: Listing 16.2.4.3 


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Table 14.1.3 
Summary of Medical History by SOC and PT 
 Safety Population 
System Organ Class 
Cohort-1 
Cohort-2 
Overall 
   Preferred Term 
(N=XX) 
(N=XX) 
(N=XX) 
Subjects with at least 1 Recorded Medical History 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
System Organ Class 1 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Preferred Term 1 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Preferred Term 2 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Preferred Term 3 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
System Organ Class 2 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Preferred Term 1 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Preferred Term 2 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Preferred Term 3 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Abbreviations: PT = preferred term; SOC = system organ class.  
Note: Percentages are n/Number of subjects in the Safety Population*100. 
Medical histories were coded using MedDRA version 21.1. 
Subjects were counted once for each SOC and once for each PT. 
Medical history terms are displayed by alphabetical order of SOC, then by decreasing frequency of PT within SOC, and then alphabetically by PT. 
SOURCE: Listing 16.2.4.2 
Programming note: ATC & PT text should be in title case in table, as shown in the shell. Ensure proper MedDRA version is printed in footnote. 


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Table 14.1.5.1 
Summary of Treatment Exposure and Compliance via Capsule Count 
 Safety Population 
Variable 
   Statistic 
Cohort-1 
(N=XX) 
Cohort-2 
(N=XX) 
Overall 
(N=XX) 
Number of Doses Taken 
n 
XX 
XX 
XX 
Mean (SD) 
XX.X (XX.X)
XX.X (XX.X)
XX.X (XX.X)
Median 
XX.X
XX.X
XX.X
Min, Max 
XX, XX
XX, XX
XX, XX
Number of Missed Doses 
   n 
XX 
XX 
XX 
   Mean (SD) 
XX.X (XX.X)
XX.X (XX.X)
XX.X (XX.X)
   Median 
XX.X
XX.X
XX.X
   Min, Max 
XX, XX
XX, XX
XX, XX
Compliance (%) 
n 
XX 
XX 
XX 
Mean (SD) 
XX.X (XX.X)
XX.X (XX.X)
XX.X (XX.X)
Median 
XX.X
XX.X
XX.X
Min, Max 
XX, XX
XX, XX
XX, XX
Compliance Category 
< 70% 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
≥ 70% to 79% 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
≥ 80% to 89% 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
≥ 90% to 100% 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
> 100%
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Note: Percentages are n/Number of subjects in the Safety Population*100. Subjects were to receive treatment twice daily for 14 consecutive days for a total of 28 doses. Compliance 
is number of doses taken / number of expected doses * 100%. Number of doses taken is calculated as the number of expected doses (number of capsules dispensed) minus total 
number of pills not taken minus number of unused capsules returned, as collected in the case report form. Expected doses are summed up to the point of discontinuation (eg, if a 
subject discontinues early, only planned doses up to that discontinuation day are counted in the denominator). 
SOURCE: Listings 16.2.5.1, 16.2.5.2, and 16.2.5.3 
Table 14.1.5.2 


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Table 14.2.1.1.1 
Summary of Central Rater TETRAS-PS Scores by Study Visit 
FAS and Per-Protocol Population 
Parameter: TETRAS-PS Total Score 
Study Visit 
   Statistic 
Full Analysis Set 
Per-Protocol Population 
Cohort-1 
(N=XX) 
Cohort-2 
(N=XX) 
Overall 
(N=XX) 
Cohort-1 
(N=XX) 
Cohort-2 
(N=XX) 
Overall 
(N=XX) 
Screening 
   n 
XX 
XX 
XX 
XX 
XX 
XX 
   Mean (SD) 
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
   Median 
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
   Min, Max 
XX, XX
XX, XX
XX, XX
XX, XX
XX, XX
XX, XX
Baseline [1] 
   n 
XX 
XX 
XX 
XX 
XX 
XX 
   Mean (SD) 
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
   Median 
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
   Min, Max 
XX, XX
XX, XX
XX, XX
XX, XX
XX, XX
XX, XX
  Change from Screening 
  n 
XX 
XX 
XX 
XX 
XX 
XX 
  Mean (SD) 
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
  Median 
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
  Min, Max 
XX, XX
XX, XX
XX, XX
XX, XX
XX, XX
XX, XX
   Mean Change from Screening (SE) [2] 
XX.X (X.XX)
XX.X (X.XX)
XX.X (X.XX)
XX.X (X.XX)
XX.X (X.XX)
XX.X (X.XX)
   (95% CI for Mean Change from  
   Screening) 
(XX.X, XX.X)
(XX.X, XX.X)
(XX.X, XX.X)
(XX.X, XX.X)
(XX.X, XX.X)
(XX.X, XX.X)
   P value for Mean Change from  
   Screening [3] 
X.XXX
X.XXX
X.XXX
X.XXX
X.XXX
X.XXX
   P value for Median Change from  
   Screening [4] 
X.XXX
X.XXX
X.XXX
X.XXX
X.XXX
X.XXX
Abbreviations: CI = confidence interval; TETRAS-PS = Tremor Research Group Essential Tremor Rating Assessment Scale (TETRAS)-performance subscale (PS); SE = standard 
error. 
Note: TETRAS-PS Total score is derived as the sum of all of the individual item scores, with the exception of item 5, only the maximum of the lower limb tremor scores will be counted. 
Each individual item question score ranges from 0 to 4, where higher scores indicate worse performance. A negative change indicates improvement. 
[1] The baseline value is the last observation recorded prior to the first dose of treatment.
[2] Estimates for mean change from screening/baseline and accompanying 95% CIs and P values are from a paired t-test
[3] P‐value for testing mean change from screening/baseline is based on a paired t-test with null hypothesis that the change in TETRAS-PS total score to subsequent visit is 0 with a 2-
sided alternative considering a difference not equal to 0 (change in tremor).
[4] P-value for testing median change from screening/baseline is based on a Wilcoxon signed-rank test with null hypothesis that the change in TETRAS-PS total score to subsequent
visit is 0 with a 2-sided alternative considering a difference not equal to 0 (change in tremor).
SOURCE: Listing 16.2.6.1.1
Table 14.2.1.1.1 (cont.) 


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Summary of Central Rater TETRAS-PS Scores by Study Visit 
FAS and Per-Protocol Population 
Parameter: TETRAS-PS Total Score 
Study Visit 
   Statistic 
Full Analysis Set 
Per-Protocol Population 
Cohort-1 
(N=XX) 
Cohort-2 
(N=XX) 
Overall 
(N=XX) 
Cohort-1 
(N=XX) 
Cohort-2 
(N=XX) 
Overall 
(N=XX) 
  % Change from Screening 
  n 
XX 
XX 
XX 
XX 
XX 
XX 
  Mean (SD) 
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
  Median 
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
  Min, Max 
XX, XX
XX, XX
XX, XX
XX, XX
XX, XX
XX, XX
Day 1, Post-dose 
   n 
XX 
XX 
XX 
XX 
XX 
XX 
   Mean (SD) 
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
   Median 
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
   Min, Max 
XX, XX
XX, XX
XX, XX
XX, XX
XX, XX
XX, XX
  Change from Baseline 
  n 
XX 
XX 
XX 
XX 
XX 
XX 
  Mean (SD) 
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
  Median 
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
  Min, Max 
XX, XX
XX, XX
XX, XX
XX, XX
XX, XX
XX, XX
Abbreviations: CFB = change from baseline; ET = essential tremor; TETRAS-PS = Tremor Research Group Essential Tremor Rating Assessment Scale (TETRAS)-performance 
subscale (PS); SE = standard error. 
Note: TETRAS-PS Total score is derived as the sum of all of the individual item scores, with the exception of item 5, only the maximum of the lower limb tremor scores will be counted. 
Each individual item question score ranges from 0 to 4, where higher scores indicate worse quality of life. A negative change indicates improvement. 
[1] The baseline value is the last observation recorded prior to the first dose of treatment.
[2] Estimates for mean change from screening/baseline and accompanying 95% CIs and P values are from a paired t-test
[3] P‐value for testing mean change from screening/baseline is based on a paired t-test with null hypothesis that the change in TETRAS-PS total score to subsequent visit is 0 with a 2-
sided alternative considering a difference not equal to 0 (change in tremor).
[4] P-value for testing median change from screening/baseline is based on a Wilcoxon signed-rank test with null hypothesis that the change in TETRAS-PS total score to subsequent
visit is 0 with a 2-sided alternative considering a difference not equal to 0 (change in tremor).
SOURCE: Listing 16.2.6.1.1


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Table 14.2.1.1.1 (cont.) 
Summary of Central Rater TETRAS-PS Scores by Study Visit 
FAS and Per-Protocol Population 
Parameter: TETRAS-PS Total Score 
Study Visit 
   Statistic 
Full Analysis Set 
Per-Protocol Population 
Cohort-1 
(N=XX) 
Cohort-2 
(N=XX) 
Overall 
(N=XX) 
Cohort-1 
(N=XX) 
Cohort-2 
(N=XX) 
Overall 
(N=XX) 
   Mean Change from Baseline (SE) [2] 
XX.X (X.XX)
XX.X (X.XX)
XX.X (X.XX)
XX.X (X.XX)
XX.X (X.XX)
XX.X (X.XX)
   (95% CI for Mean Change from 
Baseline) 
(XX.X, XX.X)
(XX.X, XX.X)
(XX.X, XX.X)
(XX.X, XX.X)
(XX.X, XX.X)
(XX.X, XX.X)
   P value for Mean Change from 
Baseline [3] 
X.XXX
X.XXX
X.XXX
X.XXX
X.XXX
X.XXX
   P value for Median Change from 
Baseline [4] 
X.XXX
X.XXX
X.XXX
X.XXX
X.XXX
X.XXX
  % Change from Baseline 
  n 
XX 
XX 
XX 
XX 
XX 
XX 
  Mean (SD) 
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
  Median 
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
  Min, Max 
XX, XX
XX, XX
XX, XX
XX, XX
XX, XX
XX, XX
Continue for Days 7 and 14,. 
Day 21 
   n 
XX 
XX 
XX 
XX 
XX 
XX 
   Mean (SD) 
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
   Median 
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
   Min, Max 
XX, XX 
XX, XX 
XX, XX 
XX, XX 
XX, XX 
XX, XX 
Abbreviations: CFB = change from baseline; ET = essential tremor; TETRAS-PS = Tremor Research Group Essential Tremor Rating Assessment Scale (TETRAS)-performance 
subscale (PS); SE = standard error. 
Note: TETRAS-PS Total score is derived as the sum of all of the individual item scores, with the exception of item 5, only the maximum of the lower limb tremor scores will be counted. 
Each individual item question score ranges from 0 to 4, where higher scores indicate worse quality of life. A negative change indicates improvement. 
[1] The baseline value is the last observation recorded prior to the first dose of treatment.
[2] Estimates for mean change from screening/baseline and accompanying 95% CIs and P values are from a paired t-test
[3] P‐value for testing mean change from screening/baseline is based on a paired t-test with null hypothesis that the change in TETRAS-PS total score to subsequent visit is 0 with a 2-
sided alternative considering a difference not equal to 0 (change in tremor).
[4] P-value for testing median change from screening/baseline is based on a Wilcoxon signed-rank test with null hypothesis that the change in TETRAS-PS total score to subsequent
visit is 0 with a 2-sided alternative considering a difference not equal to 0 (change in tremor).
SOURCE: Listing 16.2.6.1.1


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Table 14.2.1.1.1 (cont.) 
Summary of Central Rater TETRAS-PS Scores by Study Visit 
FAS and Per-Protocol Population 
Parameter: TETRAS-PS Total Score 
Study Visit 
   Statistic 
Full Analysis Set 
Per-Protocol Population 
Cohort-1 
(N=XX) 
Cohort-2 
(N=XX) 
Overall 
(N=XX) 
Cohort-1 
(N=XX) 
Cohort-2 
(N=XX) 
Overall 
(N=XX) 
  Change from Baseline 
  n 
XX 
XX 
XX 
XX 
XX 
XX 
  Mean (SD) 
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
  Median 
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
  Min, Max 
XX, XX
XX, XX
XX, XX
XX, XX
XX, XX
XX, XX
   Mean Change from Baseline (SE) [2] 
XX.X (X.XX)
XX.X (X.XX)
XX.X (X.XX)
XX.X (X.XX)
XX.X (X.XX)
XX.X (X.XX)
   (95% CI for Mean Change from 
Baseline) 
(XX.X, XX.X)
(XX.X, XX.X)
(XX.X, XX.X)
(XX.X, XX.X)
(XX.X, XX.X)
(XX.X, XX.X)
   P value for Mean Change from 
Baseline [3] 
X.XXX
X.XXX
X.XXX
X.XXX
X.XXX
X.XXX
   P value for Median Change from 
Baseline [4] 
X.XXX
X.XXX
X.XXX
X.XXX
X.XXX
X.XXX
  % Change from Baseline 
  n 
XX 
XX 
XX 
XX 
XX 
XX 
  Mean (SD) 
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
  Median 
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
  Min, Max 
XX, XX
XX, XX
XX, XX
XX, XX
XX, XX
XX, XX
Abbreviations: CFB = change from baseline; ET = essential tremor; TETRAS-PS = Tremor Research Group Essential Tremor Rating Assessment Scale (TETRAS)-performance 
subscale (PS); SE = standard error. 
Note: TETRAS-PS Total score is derived as the sum of all of the individual item scores, with the exception of item 5, only the maximum of the lower limb tremor scores will be counted. 
Each individual item question score ranges from 0 to 4, where higher scores indicate worse quality of life. A negative change indicates improvement. 
[1] The baseline value is the last observation recorded prior to the first dose of treatment.
[2] Estimates for mean change from screening/baseline and accompanying 95% CIs and P values are from a paired t-test
[3] P‐value for testing mean change from screening/baseline is based on a paired t-test with null hypothesis that the change in TETRAS-PS total score to subsequent visit is 0 with a 2-
sided alternative considering a difference not equal to 0 (change in tremor).
[4] P-value for testing median change from screening/baseline is based on a Wilcoxon signed-rank test with null hypothesis that the change in TETRAS-PS total score to subsequent
visit is 0 with a 2-sided alternative considering a difference not equal to 0 (change in tremor).
SOURCE: Listing 16.2.6.1.1


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Table 14.2.1.1.1 (cont.) 
Summary of Central Rater TETRAS-PS Scores by Study Visit 
FAS and Per-Protocol Population 
Parameter: TETRAS-PS Total Score 
Study Visit 
   Statistic 
Full Analysis Set 
Per-Protocol Population 
Cohort-1 
(N=XX) 
Cohort-2 
(N=XX) 
Overall 
(N=XX) 
Cohort-1 
(N=XX) 
Cohort-2 
(N=XX) 
Overall 
(N=XX) 
  Change from Day 14 
  n 
XX 
XX 
XX 
XX 
XX 
XX 
  Mean (SD) 
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
  Median 
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
  Min, Max 
XX, XX
XX, XX
XX, XX
XX, XX
XX, XX
XX, XX
   Mean Change from Day 14  (SE) [2] 
XX.X (X.XX)
XX.X (X.XX)
XX.X (X.XX)
XX.X (X.XX)
XX.X (X.XX)
XX.X (X.XX)
   (95% CI for Mean Change from Day 
14) 
(XX.X, XX.X)
(XX.X, XX.X)
(XX.X, XX.X)
(XX.X, XX.X)
(XX.X, XX.X)
(XX.X, XX.X)
   P value for Mean Change from Day 
14 [3] 
X.XXX
X.XXX
X.XXX
X.XXX
X.XXX
X.XXX
   P value for Median Change from Day 
14 [4] 
X.XXX
X.XXX
X.XXX
X.XXX
X.XXX
X.XXX
  % Change from Day 14 
  n 
XX 
XX 
XX 
XX 
XX 
XX 
  Mean (SD) 
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
  Median 
XX.X
XX.X
XX.X
XX.X
XX.X
XX.X
  Min, Max 
XX, XX
XX, XX
XX, XX
XX, XX
XX, XX
XX, XX
Abbreviations: CFB = change from baseline; ET = essential tremor; TETRAS-PS = Tremor Research Group Essential Tremor Rating Assessment Scale (TETRAS)-performance 
subscale (PS); SE = standard error. 
Note: TETRAS-PS Total score is derived as the sum of all of the individual item scores, with the exception of item 5, only the maximum of the lower limb tremor scores will be counted. 
Each individual item question score ranges from 0 to 4, where higher scores indicate worse quality of life. A negative change indicates improvement. 
[1] The baseline value is the last observation recorded prior to the first dose of treatment.
[2] Estimates for mean change from screening/baseline and accompanying 95% CIs and P values are from a paired t-test
[3] P‐value for testing mean change from screening/baseline is based on a paired t-test with null hypothesis that the change in TETRAS-PS total score to subsequent visit is 0 with a 2-
sided alternative considering a difference not equal to 0 (change in tremor).
[4] P-value for testing median change from screening/baseline is based on a Wilcoxon signed-rank test with null hypothesis that the change in TETRAS-PS total score to subsequent
visit is 0 with a 2-sided alternative considering a difference not equal to 0 (change in tremor).
SOURCE: Listing 16.2.6.1.1
Programming Note:  Continue for all parameters. Parameters include: Head Tremor, Face (including jaw) Tremor, Voice Tremor, Upper Limb Tremor: Forward Outstretched Postural 
Tremor-Right, Upper Limb Tremor: Forward Outstretched Postural Tremor-Left, Upper Limb Tremor: Lateral Wing Beating Postural Tremor-Right, Upper Limb Tremor: Lateral Wing 
Beating Postural Tremor-Left, Upper Limb Tremor: Kinetic Tremor-Right, Upper Limb Tremor: Kinetic Tremor-Left, Lower Limb Tremor: Extended-Right, Lower Limb Tremor: 
Extended-Left, Lower Limb Tremor: Heel-Shin-Right, Lower Limb Tremor: Heel-Shin-Left, Archimedes Spirals-Right, Archimedes Spirals-Left, Handwriting, Dot Approximation Task-
Right, Dot Approximation Task-Left, and Standing Tremor. Change from Screening should only be presented after the baseline visit.  
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Table 14.2.1.1.3 
Summary of Central Rater Categorical TETRAS-PS Item Scores by Study Visit 
FAS and Per-Protocol Population 
Protocol Amendment: 1.0 
Item 
   Score 
Full Analysis Set 
Per-Protocol Population 
Baseline [1] 
Day 7 
Day 14 
Day 21 
Baseline [1] 
Day 7 
Day 14 
Day 21 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
Head Tremor 
   0 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   0.5 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   1 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   1.5 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   2 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   2.5 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   3 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   3.5 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   4 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Face (including jaw) 
Tremor 
   0 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   0.5 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   1 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   1.5 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   2 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   2.5 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   3 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   3.5 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   4 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Abbreviations: TETRAS-PS = Tremor Research Group Essential Tremor Rating Assessment Scale (TETRAS)-performance subscale (PS). 
Note: Percentages are n/Number of subjects in the respective population and cohort at each visit*100. TETRAS-PS Total score is derived as the sum of all of the individual item 
scores, with the exception of item 5, only the maximum of the lower limb tremor scores will be counted. Each individual item question score ranges from 0 to 4, where higher scores 
indicate worse quality of life.  
[1] The baseline value is the last observation recorded prior to the first dose of treatment.
SOURCE: Listing 16.2.6.1.1
Programming note: Continue for Cohort-2  and Overall. Items include: Head Tremor, Face (including jaw) Tremor, Voice Tremor, Upper Limb Tremor: Forward Outstretched Postural 
Tremor-Right, Upper Limb Tremor: Forward Outstretched Postural Tremor-Left, Upper Limb Tremor: Lateral Wing Beating Postural Tremor-Right, Upper Limb Tremor: Lateral Wing 
Beating Postural Tremor-Left, Upper Limb Tremor: Kinetic Tremor-Right, Upper Limb Tremor: Kinetic Tremor-Left, Lower Limb Tremor: Extended-Right, Lower Limb Tremor: 
Extended-Left, Lower Limb Tremor: Heel-Shin-Right, Lower Limb Tremor: Heel-Shin-Left, Archimedes Spirals-Right, Archimedes Spirals-Left, Handwriting, Dot Approximation Task-
Right, Dot Approximation Task-Left, and Standing Tremor. 
Table 14.2.1.1.4 


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Correlation between Central and Local TETRAS-PS Scores by Study Visit 
FAS and Per-Protocol Population 
Parameter: TETRAS-PS Total Score 
Study Visit 
   Statistic 
Full Analysis Set 
Per-Protocol Population 
Cohort-1 
Cohort-2 
Overall 
Cohort-1 
Cohort-2 
Overall 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
Screening 
   Correlation [1] 
X.XXXX
X.XXXX
X.XXXX
X.XXXX
X.XXXX
X.XXXX
P-Value [2]
X.XXXX
X.XXXX
X.XXXX
X.XXXX
X.XXXX
X.XXXX
Baseline [3] 
   Correlation 
X.XXXX
X.XXXX
X.XXXX
X.XXXX
X.XXXX
X.XXXX
P-Value
X.XXXX
X.XXXX
X.XXXX
X.XXXX
X.XXXX
X.XXXX
Day 1, Post-dose 
   Correlation 
X.XXXX
X.XXXX
X.XXXX
X.XXXX
X.XXXX
X.XXXX
P-Value
X.XXXX
X.XXXX 
X.XXXX 
 
X.XXXX
X.XXXX
X.XXXX
Continue for Days 7, 14, and 21 and all parameters.
Abbreviations: TETRAS-PS = Tremor Research Group Essential Tremor Rating Assessment Scale (TETRAS)-performance subscale (PS). 
Note: TETRAS-PS Total score is derived as the sum of all of the individual item scores, with the exception of item 5, only the maximum of the lower limb tremor scores will be 
counted. Each individual item question score ranges from 0 to 4, where higher scores indicate worse quality of life.  
[1] Pearson correlation coefficient is presented for all study visits.
[2] P-value for testing the correlation is 0.
[3] The baseline value is the last observation recorded prior to the first dose of treatment.
SOURCE: Listings 16.2.6.1.1, 16.2.6.1.2
Programming Note: Check Section 8.3.2 of SAP.  If Spearman correlation coefficient is used, update footnote [1] accordingly. 


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Table 14.2.1.1.5 
Summary of Local Rater TETRAS-PS Scores by Study Visit 
FAS and Per-Protocol Population 
Same shell as Table 14.2.1.1.1 
Programming Note:  Continue for all parameters. Parameters include: Head Tremor, Face (including jaw) Tremor, Voice Tremor, Upper Limb Tremor: Forward Outstretched Postural 
Tremor-Right, Upper Limb Tremor: Forward Outstretched Postural Tremor-Left, Upper Limb Tremor: Lateral Wing Beating Postural Tremor-Right, Upper Limb Tremor: Lateral Wing 
Beating Postural Tremor-Left, Upper Limb Tremor: Kinetic Tremor-Right, Upper Limb Tremor: Kinetic Tremor-Left, Lower Limb Tremor: Extended-Right, Lower Limb Tremor: 
Extended-Left, Lower Limb Tremor: Heel-Shin-Right, Lower Limb Tremor: Heel-Shin-Left, Archimedes Spirals-Right, Archimedes Spirals-Left, Handwriting, Dot Approximation Task-
Right, Dot Approximation Task-Left, and Standing Tremor. Change from Screening should only be presented after the baseline visit.  


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Table 14.2.1.2.1 
Summary of Central Rater TETRAS-PS Upper Limb Subscale Scores by Study Visit 
FAS and Per-Protocol Population 
Same shell as Table 14.2.1.1.1 
Programming Note: Parameter will be TETRAS-PS Upper Limb Subscale Score, Upper Limb Tremor: Forward Outstretched Postural Tremor-Right, Upper Limb Tremor: Forward 
Outstretched Postural Tremor-Left, Upper Limb Tremor: Lateral Wing Beating Postural Tremor-Right, Upper Limb Tremor: Lateral Wing Beating Postural Tremor-Left, Upper Limb 
Tremor: Kinetic Tremor-Right, Upper Limb Tremor: Kinetic Tremor-Left, Archimedes Spirals-Right, Archimedes Spirals-Left, Handwriting, Dot Approximation Task-Right, and Dot 
Approximation Task-Left. Update footnote to read “The TETRAS Upper limb subscale score is the sum of the item 4, item 6, item 7 and item 8 scores (forward outstretched postural 
tremor, lateral “wing beating” postural tremor, kinetic tremor, Archimedes spirals, and dot approximation task from both sides of the body, as well as handwriting. The upper limb 
individual item question scores for each side of the body range from 0 to 4, with higher scores indicating more tremors. A negative change indicates improvement.” 
Table 14.2.1.2.3 
Correlation between Central and Local TETRAS-PS Upper Limb Subscale Scores by Study Visit 
FAS and Per-Protocol Population 
Same shell as Table 14.2.1.1.4 
Programming Note: Update footnote to read “The TETRAS Upper limb subscale score is the sum of the item 4, item 6, item 7 and item 8 scores (forward outstretched postural 
tremor, lateral “wing beating” postural tremor, kinetic tremor, Archimedes spirals, and dot approximation task from both sides of the body, as well as handwriting. The upper limb 
individual item question scores for each side of the body range from 0 to 4, with higher scores indicating more tremors.” 
Table 14.2.1.2.4 
Summary of Local Rater TETRAS-PS Upper Limb Subscale Scores by Study Visit 
FAS and Per-Protocol Population 
Same shell as Table 14.2.1.1.1 
Programming Note: Parameter will be TETRAS-PS Upper Limb Subscale Score, Upper Limb Tremor: Forward Outstretched Postural Tremor-Right, Upper Limb Tremor: Forward 
Outstretched Postural Tremor-Left, Upper Limb Tremor: Lateral Wing Beating Postural Tremor-Right, Upper Limb Tremor: Lateral Wing Beating Postural Tremor-Left, Upper Limb 
Tremor: Kinetic Tremor-Right, Upper Limb Tremor: Kinetic Tremor-Left, Archimedes Spirals-Right, Archimedes Spirals-Left, Handwriting, Dot Approximation Task-Right, and Dot 
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Approximation Task-Left. Update footnote to read “The TETRAS Upper limb subscale score is the sum of the item 4, item 6, item 7 and item 8 scores (forward outstretched postural 
tremor, lateral “wing beating” postural tremor, kinetic tremor, Archimedes spirals, and dot approximation task from both sides of the body, as well as handwriting. The upper limb 
individual item question scores for each side of the body range from 0 to 4, with higher scores indicating more tremors. A negative change indicates improvement.” 


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Table 14.2.1.3.1 
Summary of Central Rater TETRAS-PS Upper Limb Tremor (Item 4) Scores by Study Visit 
FAS and Per-Protocol Population 
Same shell as Table 14.2.1.1.1 
Programming Note: Parameters will be TETRAS-PS Upper Limb Tremor (Item 4) Score, Upper Limb Tremor: Forward Outstretched Postural Tremor-Right, Upper Limb Tremor: 
Forward Outstretched Postural Tremor-Left, Upper Limb Tremor: Lateral Wing Beating Postural Tremor-Right, Upper Limb Tremor: Lateral Wing Beating Postural Tremor-Left, Upper 
Limb Tremor: Kinetic Tremor-Right, Upper Limb Tremor: Kinetic Tremor-Left. Update footnote to read “The TETRAS-PS Upper Limb Tremor (Item 4) Total score is the sum of the 6 
item 4 scores (forward outstretched postural tremor, lateral “wing beating” postural tremor, and kinetic tremor scores) from both sides of the body, as well as handwriting. The upper 
limb individual item question scores for each side of the body range from 0 to 4, with higher scores indicating more tremors. A negative change indicates improvement.” 
Table 14.2.1.3.2 
Correlation between Central and Local TETRAS-PS Upper Limb Tremor (Item 4) Scores by Study Visit 
FAS and Per-Protocol Population 
Same shell as Table 14.2.1.1.4  
Programming Note: Update footnote to read “The TETRAS-PS Upper Limb Tremor (Item 4) Total score is the sum of the 6 item 4 scores (forward outstretched postural tremor, lateral 
“wing beating” postural tremor, and kinetic tremor scores) from both sides of the body, The upper limb individual item question scores for each side of the body range from 0 to 4, with 
higher scores indicating more tremors.” 
Table 14.2.1.3.3 
Summary of Local Rater TETRAS-PS Upper Limb Tremor (Item 4) Scores by Study Visit 
FAS and Per-Protocol Population 
Same shell as Table 14.2.1.1.1 
Programming Note: Parameters will be TETRAS-PS Upper Limb Tremor (Item 4) Score, Upper Limb Tremor: Forward Outstretched Postural Tremor-Right, Upper Limb Tremor: 
Forward Outstretched Postural Tremor-Left, Upper Limb Tremor: Lateral Wing Beating Postural Tremor-Right, Upper Limb Tremor: Lateral Wing Beating Postural Tremor-Left, Upper 
Limb Tremor: Kinetic Tremor-Right, Upper Limb Tremor: Kinetic Tremor-Left. Update footnote to read “The TETRAS-PS Upper Limb Tremor (Item 4) Total score is the sum of the 6 
item 4 scores (forward outstretched postural tremor, lateral “wing beating” postural tremor, and kinetic tremor scores) from both sides of the body, as well as handwriting. The upper 
limb individual item question scores for each side of the body range from 0 to 4, with higher scores indicating more tremors. A negative change indicates improvement.” 


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Table 14.2.5.1
Summary of In-Clinic Wearable Sensor (Kinesia) by Study Visit 
FAS and Per-Protocol Population 
Same Shell as Table 14.2.1.1.1 
Parameter: Kinesia Score, Side: Right, Task: Extended Arms Posture 
Study Visit 
   Statistic 
Full Analysis Set 
Per-Protocol Population 
Protocol 
Amendment 
1.0 
(N=XX) 
Protocol Amendment 
2.0 or 3.0 
(N=XX) 
Overall 
(N=XX) 
Cohort-1 
(N=XX) 
Protocol 
Amendment 
2.0 or 3.0 
(N=XX) 
Overall 
(N=XX) 
Programming Note:  Remove footnote describing TETRAS-PS. Update SOURCE: to Listing 16.2.6.6.1. Continue for all study days and the following: 
 Parameter: Kinesia Score, Side: Right, Task: Wing-beating posture, 
Parameter: Kinesia Score, Side: Right, Task: Kinetic “finger-to-chin” Movement, 
 Parameter: Kinesia Score, Side: Right, Task: Arm on Table Posture 
Parameter: Kinesia Score, Side: Left, Task: Extended Arms Posture, 
Parameter: Kinesia Score, Side: Left, Task: Wing-beating Posture, 
Parameter: Kinesia Score, Side: Left, Task: Kinetic “finger-to-chin” Movement, 
 Parameter: Kinesia Score, Side: Left, Task: Arm on Table Posture 
Parameter: Tremor Amplitude, Side: Right, Task: Extended Arms Posture, 
Parameter: Tremor Amplitude, Side: Right, Task: Wing-beating Posture, 
Parameter: Tremor Amplitude, Side: Right, Task: Kinetic “finger-to-chin” Movement, 
 Parameter: Tremor Amplitude, Side: Right, Task: Arm on Table Posture 
Parameter: Tremor Amplitude, Side: Left, Task: Extended Arms Posture, 
Parameter: Tremor Amplitude, Side: Left, Task: Wing-beating Posture, 
Parameter: Tremor Amplitude, Side: Left, Task: Kinetic “finger-to-chin” Movement, 
 Parameter: Tremor Amplitude, Side: Left, Task: Arm on Table Posture 
Parameter: Tremor Frequency, Side: Right, Task: Extended Arms Posture, 
Parameter: Tremor Frequency, Side: Right, Task: Wing-beating Posture, 
Parameter: Tremor Frequency, Side: Right, Task: Kinetic “finger-to-chin” Movement, 
 Parameter: Tremor Frequency, Side: Right, Task: Arm on Table Posture 
Parameter: Tremor Frequency, Side: Left, Task: Extended Arms Posture, 
Parameter: Tremor Frequency, Side: Left, Task: Wing-beating Posture, 
Parameter: Tremor Frequency, Side: Left, Task: Kinetic “finger-to-chin” Movement, 
 Parameter: Tremor Frequency, Side: Left, Task: Arm on Table Posture 
Parameter: Finger-Chin-Finger Quality, Side: Right, Task: Extended Arms Posture, 
Parameter: Finger-Chin-Finger Quality, Side: Right, Task: Wing-beating Posture, 
Parameter: Finger-Chin-Finger Quality, Side: Right, Task: Kinetic “finger-to-chin” Movement, 
 Parameter: Finger-Chin-Finger Quality, Side: Right, Task: Arm on Table Posture 
Parameter: Finger-Chin-Finger Quality, Side: Left, Task: Extended Arms Posture, 
Parameter: Finger-Chin-Finger Quality, Side: Left, Task: Wing-beating Posture, 
Parameter: Finger-Chin-Finger Quality, Side: Left, Task: Kinetic “finger-to-chin” Movement, 
 Parameter: Finger-Chin-Finger Quality, Side: Left, Task: Arm on Table Posture 


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Table 14.3.1.1 
Summary of Adverse Events 
Safety Population 
Cohort-1 
(N=XX) 
Cohort-2 
(N=XX) 
Overall 
(N=XX) 
Category 
Subjects 
n (%) 
Events 
Subjects 
n (%) 
Events 
Subjects 
n (%) 
Events 
Subjects with at least 1 TEAE 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
Maximum Severity of TEAE 
 Mild 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
 Moderate 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
 Severe 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
Subjects with a Related TEAE [1] 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
Subjects with a TEAE Leading to 
Discontinuation of Study Drug 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
Subjects with an AE leading to Death 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
Subjects with at least 1 SAE 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
Maximum Severity of SAE 
 Mild 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
 Moderate 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
 Severe 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
Subjects with a Related SAE [1] 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
Subjects with a SAE Leading to 
Discontinuation of Study Drug 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
Subjects with an SAE leading to Death 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
Abbreviations: TEAE = treatment emergent adverse event; SAE = serious adverse event. 
 
Note: Percentages are n/Number of subjects in the Safety Population and respective Protocol Amendment*100. AEs were coded using MedDRA version 21.1. A TEAE is any AE 
that occurs after the time of treatment with the study agent. Events meeting this definition will be those events that are a change from the subject’s baseline conditions, including an 
increase in frequency or severity.  
[1] Related TEAEs are those marked as Possibly Related, Probably Related, or Definitely Related on the case report form.
SOURCE: Listing 16.2.7


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Table 14.3.1.2 
Incidence of Treatment Emergent Adverse Events by SOC and PT 
Safety Population 
System Organ Class 
   Preferred Term 
Cohort-1 
(N=XX) 
Cohort-2 
(N=XX) 
Overall 
(N=XX) 
Subjects 
n (%) 
Events 
Subjects 
n (%) 
Events 
Subjects 
n (%) 
Events 
Subjects with at least 1 TEAE 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
System Organ Class 1 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
   Preferred Term 1 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
   Preferred Term 2 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
   Preferred Term 3 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
System Organ Class 1 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
   Preferred Term 1 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
   Preferred Term 2 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
   Preferred Term 3 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
Abbreviations: PT = preferred term; SOC = system organ class; TEAE = treatment emergent adverse event.  
Note: Percentages are n/Number of subjects in the Safety Population and respective Protocol Amendment * 100.  
AEs were coded using MedDRA version 21.1.  
A TEAE is any AE that occurs after the time of treatment with the study agent. Events meeting this definition will be those events that are a change from the subject’s baseline 
conditions, including an increase in frequency or severity.  
Subjects are counted once for each SOC and once for each PT. AEs are displayed by descending frequency of SOC, then PT within SOC, and then alphabetically by PT.  
SOURCE: Listing 16.2.7 
Programming note: SOC & PT text should be in title case in table, as shown in the shell. Ensure correct MedDRA version is printed in footnote. 


Statistical Analysis Plan 
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Table 14.3.1.3 
Incidence of Treatment Emergent Adverse Events by SOC, PT, and Maximum Severity 
Safety Population 
System Organ Class 
   Preferred Term 
 Maximum Severity 
Cohort-1 
(N=XX) 
Cohort-2 
(N=XX) 
Overall 
(N=XX) 
Subjects 
n (%) 
Events 
Subjects 
n (%) 
Events 
Subjects 
n (%) 
Events 
Subjects with at least 1 TEAE 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
   Any Event (Total) 
 Mild 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
 Moderate 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
 Severe 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
System Organ Class 1 
   Any Event (Total) 
 Mild 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
 Moderate 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
 Severe 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
   Preferred Term 1 
 Mild 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
 Moderate 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
 Severe 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
Abbreviations: PT = preferred term; SOC = system organ class; TEAE = treatment emergent adverse event.  
Note: Percentages are n/Number of subjects in the Safety Population and respective Protocol Amendment *100.  
AEs were coded using MedDRA version 21.1.  
A TEAE is any AE that occurs after the time of treatment with the study agent. Events meeting this definition will be those events that are a change from the subject’s baseline 
conditions, including an increase in frequency or severity.  
Subjects are counted once for each SOC and once for each PT.  
The severity shown is the greatest severity reported for a particular subject (Severe > Moderate > Mild). AEs with a missing severity were counted as Severe.  
AEs are displayed by descending frequency of SOC, then PT within SOC, and then alphabetically by PT.  
SOURCE: Listing 16.2.7 
Programming note: SOC & PT text should be in title case in table, as shown in the shell. Ensure correct MedDRA version is printed in footnote. 


Statistical Analysis Plan 
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Table 14.3.1.4 
Incidence of Treatment Emergent Adverse Events by SOC, PT, and Relationship 
Safety Population 
System Organ Class 
   Preferred Term 
      Relationship 
Cohort-1 
(N=XX) 
Cohort-2 
(N=XX) 
Overall 
(N=XX) 
Subjects 
n (%) 
Events 
Subjects 
n (%) 
Events 
Subjects 
n (%) 
Events 
Subjects with at least 1 TEAE 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Any Event (Total) 
 Related 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
 Not Related 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
System Organ Class 1 
   Any Event (Total) 
 Related 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
 Not Related 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
   Preferred Term 1 
 Related 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
 Not Related 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
XX (XX.X%) 
XX 
Abbreviations: CRF = case report form; PT = preferred term; SOC = system organ class; TEAE = treatment emergent adverse event.  
Note: Percentages are n/Number of subjects in the Safety Population and respective Protocol Amendment *100. 
AEs were coded using MedDRA version 21.1.  
A TEAE is any AE that occurs after the time of treatment with the study agent. Events meeting this definition will be those events that are a change from the subject’s baseline 
conditions, including an increase in frequency or severity.  
Subjects are counted once for each SOC and once for each PT.  
Subjects are classified according to the strongest relationship if the subject reported one or more events. Related TEAEs are those marked as Possibly Related, Probably Related, 
or Definitely Related on the CRF. AEs with a missing relationship will be considered related for this summary.  
AEs are displayed by descending frequency of SOC, then PT within SOC, and then alphabetically by PT.  
SOURCE: Listing 16.2.7 
Programming note: SOC & PT text should be in proper case in table, as shown in the shell. Ensure correct MedDRA version is printed in footnote. 


Statistical Analysis Plan 
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Table 14.3.2.1 
Incidence of TEAEs Leading to Withdrawal of Study Drug by SOC and PT 
Safety Population 
Same shell as Table 14.3.1.2 
Table 14.3.2.2 
Incidence of Serious Adverse Events by SOC and PT 
Safety Population 
Same shell as Table 14.3.1.2 
Programming note: Add SAE to abbreviations. 


Statistical Analysis Plan 
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Table 14.3.3.1 
Listing of Adverse Events Leading to Study Drug Discontinuation 
All Subjects 
Subject ID 
System Organ Class/ 
Preferred Term/ 
Verbatim Term 
Start Date (Study Day) Start Time/ 
End Date  (Study Day) End Time 
Severity/ 
Relationship 
Outcome/ 
Study Drug Action Taken/ 
Other Action Taken 
TEAE?/ 
Serious?/ 
Criteria Met 
XXXXXX 
XXXXXXXXXXXXXXXXX/ 
DDMMMYYYY/HH:MM (XX)/ 
XXXXXXXXX/ 
XXXXXXXXXXXX/ 
XX/ 
   XXXXXXXXXXXXXX/ 
   DDMMMYYYY/HH:MM (XX) 
   XXXXXXXX 
  XXXXXXXXXXXXX/ 
   XXX/ 
      XXXXXXXXXXXXX 
  XXXXXXXXXXXXXXX 
XXXXXXXXX 
XXXXXXXXX/ 
DDMMMYYYY/HH:MM (XX)/ 
XXXXXXXXX/ 
XXXXXXXXXXXXX 
XX/ 
   XXXXXXXXXXXXXXX/ 
   DDMMMYYYY/HH:MM (XX) 
   XXXXXXXX 
  XX 
 XXXXXXXXXXX 
XXXXXXXXX/ 
DDMMMYYYY/HH:MM (XX)/ 
XXXXXXX/ 
XXXXXXXXXXXXXX 
XX/ 
   XXXXXXXXXXXXXX/ 
   DDMMMYYYY/HH:MM (XX) 
   XXXXXXX 
  XX 
 XXXXXXXXXXXXXXXX 
Abbreviation: TEAE = treatment emergent adverse event. 
Note: Study day is calculated relative to the date of first dose. For pre-dose: study day= Start Date/ Stop Date – first dose date; For post-dose: study day= Start Date/ Stop Date – 
first dose date + 1. 
AEs were coded using MedDRA version 21.1.  
A TEAE is any AE that occurs after the time of treatment with the study agent. Events meeting this definition will be those events that are a change from the subject’s baseline 
conditions, including an increase in frequency or severity. 
Programming note: “Other Action Taken” will be either None, Medication Required, Relevant Procedure, or Other; if specify text is needed, concatenate “Relevant Procedure:” or 
“Other:” with the text. If Serious? Is Yes, concatenate all serious criteria marked as Yes with a semicolon. If no events meet the criteria for display, present “No events are reported.” 
SOC & PT text should be in proper case in table, as shown in the shell. Ensure correct MedDRA version is printed in footnote. 


Statistical Analysis Plan 
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Table 14.3.3.2 
Listing of Serious Adverse Events 
Safety Population 
Same shell as Table 14.3.3.1 
Table 14.3.3.3 
Listing of Deaths 
Safety Population 
Same shell as Table 14.3.3.1 


Statistical Analysis Plan 
  
 
 
 
 
 
 
 
 
 
 
 
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Table 14.3.4.1 
Abnormal Laboratory Results 
Safety Population 
 
 
Subject 
ID 
 
Treatment 
Received 
Parameter (unit) 
Study Visit 
Date/Time of Assessment 
(Study Day) 
Standard 
Results 
Change 
from 
Baseline 
[1] 
Reference 
Range [2] 
Reference 
Range Flag 
Lab Panel 
Comments/Reason 
Not Done 
 
 
 
 
 
 
 
 
 
 
 
XXXXXX 
CAD-1883 
Hemoglobin 
(unit) 
XXXXXX 
DDMMMYYYY/HH:MM (X) 
XX 
 
XX – YY 
 
XXXXXXX 
 
 
 
 
XXXXXX 
DDMMMYYYY/HH:MM (X) 
XX 
XX 
XX – YY 
 
XXXXXXX 
 
 
 
 
XXXXXX 
DDMMMYYYY/HH:MM (X) 
XX 
XX 
XX – YY 
 
XXXXXXX 
 
 
 
 
XXXXXX 
DDMMMYYYY/HH:MM (X) 
XX 
XX 
XX – YY 
XXX 
XXXXXXX 
 
 
 
 
XXXXXX 
DDMMMYYYY/HH:MM (X) 
XX 
XX 
XX – YY 
 
XXXXXXX 
 
 
 
 
XXXXXX 
DDMMMYYYY/HH:MM (X) 
XX 
XX 
XX – YY 
 
XXXXXXX 
 
 
 
 
XXXXXX 
DDMMMYYYY/HH:MM (X) 
XX 
XX 
XX – YY 
 
XXXXXXX 
 
 
 
 
XXXXXX 
DDMMMYYYY/HH:MM (X) 
XX 
XX 
XX – YY 
 
XXXXXXX 
 
 
 
 
XXXXXX 
 
ND 
 
 
 
 
XXXXXXX 
 
 
 
XXXXXX 
DDMMMYYYY/HH:MM (X) 
XX 
XX 
XX – YY 
 
XXXXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: AL = abnormal-low; AH = abnormal-high; CS = clinically significant; NCS = not clinically significant; ND = not done. 
Note: Study day is calculated relative to the date of first dose of study drug. For pre-dose: study day= Start Date/ Stop Date – first dose date; For post-dose: study day= Start Date/ Stop Date – first 
dose date + 1. 
If any parameter has an abnormal value, results for all study visits are presented. 
[1] Baseline is the last observation recorded prior to the first dose of treatment. 
[2] Reference range is used to identify potentially clinically significant laboratory values. 
 
Programming note: update abbreviations to reflect actual data. If test was not done, set results to ND; make sure last column is populated accordingly. Do not display serum HCG 
results in this listing. For reference range flag, concatenate AL or AH with clinical significance like “XX-YY” (eg, AL-CS). 
 
 


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Table 14.3.5.1.1 
Summary of Hematology Laboratory Results by Study Visit 
Safety Population 
Programming Note: Continue all parameters for Day 7, Day 14, and Day 21. Sort alphabetically by parameter. 
Parameter: XXXXXXXXXXXX 
Study Visit 
   Statistic 
Cohort-1 
(N=XX) 
Cohort-2 
(N=XX) 
Overall 
(N=XX) 
Screening 
   n 
XX 
XX 
XX 
   Mean (SD) 
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
   Median 
XX.X
XX.X
XX.X
   Min, Max 
XX, XX
XX, XX
XX, XX
Baseline [1] 
   n 
XX 
XX 
XX 
   Mean (SD) 
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
   Median 
XX.X
XX.X
XX.X
   Min, Max 
XX, XX
XX, XX
XX, XX
Day 1 
   n 
XX 
XX 
XX 
   Mean (SD) 
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
   Median 
XX.X
XX.X
XX.X
   Min, Max 
XX, XX
XX, XX
XX, XX
  Change from Baseline 
  n 
XX 
XX 
XX 
  Mean (SD) 
XX.X (XX.XX)
XX.X (XX.XX)
XX.X (XX.XX)
  Median 
XX.X
XX.X
XX.X
  Min, Max 
XX, XX
XX, XX
XX, XX
[1] The baseline value for each variable is the last observation recorded prior to the first dose of treatment.
SOURCE: Listing 16.2.8.1.1


Statistical Analysis Plan 
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Table 14.3.5.1.2 
Shift from Baseline in Hematology Laboratory Results by Study Visit and Treatment 
Safety Population 
Parameter: XXXXXXX 
Baseline [1] 
Cohort-1 (N=XX) 
Study Visit 
Low 
Normal 
High 
Abnormal 
Missing 
   Category 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Day 7 
   Low 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Normal 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   High 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Abnormal 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Missing 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Day 14 
   Low 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Normal 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   High 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Abnormal 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Missing 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Day 21 
   Low 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Normal 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   High 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Abnormal 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Missing 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Note: Percentages are n/Number of subjects in the Safety Population and respective Protocol Amendment*100. 
[1] The baseline value for each variable is the last observation recorded prior to the first dose of treatment.
SOURCE: Listing 16.2.8.1.1
Programming Note: Continue all parameters, for Protocol Version: 2.0 or 3.0 and Overall as well as for Day 7, Day 14, and Day 21. Sort alphabetically by parameter. 


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Table 14.3.5.2.1 
Summary of Serum Chemistry Laboratory Results by Study Visit 
Safety Population
Same shell as Table 14.3.5.1.1 
Programming note: Update footnote to SOURCE: Listing 16.2.8.1.2 
Table 14.3.5.2.2 
Shift from Baseline in Serum Chemistry Laboratory Results by Study Visit 
Safety Population 
Same shell as Table 14.5.1.2 
Programming note: Update footnote to SOURCE: Listing 16.2.8.1.2 
Table 14.3.5.3.1 
Summary of Quantitative Urinalysis Laboratory Results by Study Visit 
Safety Population 
Same shell as Table 14.3.5.1.1  
Programming note: Update footnote to SOURCE: Listing 16.2.8.1.3 
Table 14.3.5.3.2 
Shift from Baseline in Quantitative Urinalysis Laboratory Results by Study Visit 
Safety Population 
Same shell as Table 14.3.5.1.2 
Programming note: Update footnote to SOURCE: Listing 16.2.8.1.3 


Statistical Analysis Plan 
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Table 14.3.5.3.3 
Summary of Qualitative Urinalysis Laboratory Results by Study Visit 
Safety Population 
Parameter: XXXXXXXX 
Cohort-1 
Cohort-2 
Overall 
Study Visit 
(N=XX) 
(N=XX) 
(N=XX) 
   Category 
n (%) 
n (%) 
n (%) 
Screening 
   Category 1 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Category 2 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Category 3 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Baseline [1] 
   Category 1 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Category 2 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Category 3 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Day 1 
   Category 1 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Category 2 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Category 3 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Day 7 
   Category 1 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Category 2 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Category 3 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Day 14 
   Category 1 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Category 2 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Category 3 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Day 21 
   Category 1 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Category 2 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Category 3 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Note: Percentages are n/Number of subjects in the Safety Population and respective Protocol Amendment*100. 
[1] The baseline value for each variable is the last observation recorded prior to the first dose of treatment.
SOURCE: Listing 16.2.8.1.3
Programming Note: Continue all parameters. Sort alphabetically by parameter. 


Statistical Analysis Plan 
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Table 14.3.5.4.1 
Summary of Quantitative Biomarker Panel for Renal Tubular Injury Results by Study Visit 
Safety Population 
Parameter: uCreatine (uCr); CAD-1883 Treatment 300mg BID 
Cohort-1 
(N=XX) 
Cohort-2 
(N=XX) 
Overall 
(N=XX) 
Study Visit 
 Statistic 
Results 
(Measured) 
ng/mL 
Results 
(Measured) 
ng/mL 
Results 
(Normalized) 
ng/mg Cr 
Results 
(Normalized) 
ng/mg Cr 
Results 
(Normalized) 
ng/mg Cr 
Results 
(Normalized) 
ng/mg Cr 
Baseline [1] 
   n 
xx 
xx 
xx 
xx 
xx 
xx 
   Mean (SD) 
xxx.x (xxx.xx)
xxx.x (xxx.xx)
xxx.x (xxx.xx)
xxx.x (xxx.xx)
xxx.x (xxx.xx)
xxx.x (xxx.xx)
   Median 
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
   Min, Max 
x, xxx
x, xxx
x, xxx
x, xxx
x, xxx
x, xxx
Day 1 
   n 
xx 
xx 
xx 
xx 
xx 
xx 
   Mean (SD) 
xxx.x (xxx.xx)
xxx.x (xxx.xx)
xxx.x (xxx.xx)
xxx.x (xxx.xx)
xxx.x (xxx.xx)
xxx.x (xxx.xx)
   Median 
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
   Min, Max 
x, xxx
x, xxx
x, xxx
x, xxx
x, xxx
x, xxx
Fold Change from Baseline to Day 1 
   n 
- 
- 
xx 
xx 
xx 
xx 
   Mean (SD) 
- 
- 
xx.xxx (xx.xxxx) 
xx.xxx (xx.xxxx)
xx.xxx (xx.xxxx)
xx.xxx (xx.xxxx)
   Median 
- 
- 
x.xxx 
x.xxx
x.xxx
x.xxx
   Min, Max 
- 
- 
x.xx, xx.xx 
x.xx, xx.xx
x.xx, xx.xx
x.xx, xx.xx
BID=Twice a day, SD=Standard Deviation, Min=Minimum, Max=Maximum. 
Note: The normalized concentration at a given time point is calculated as the concentration at that time point divided by the concentration of uCreatinine (mg/dL) at the 
same time point.  Fold Change from Baseline at a given time point is calculated as the normalized concentration at the time point divided by the normalized 
concentration at baseline. 
[1] The baseline value for each measure is the last observation recorded prior to the first dose of treatment.
SOURCE: Listing 16.2.8.1.4.
Table 14.3.5.4.2 
Programming note:  
Parameters are uCreatine (uCr)), uClusterin (uCLU) , uCystatin-C (uCysC), uKidney Injury Molecule-1 (uKIM-1), u N-Acetyl-beta-D-Glucosaminidase (uNAG), Neutrophil 
Gelatinase-Associated Lipocalin (uNGAL) and uOsteopontin (uOPN). 
Keep the decimal places as exactly the same as what is shown in this table shells 
Exten the table for visits Day 7, 14 and 21. 
Commercially Confidential Information


Statistical Analysis Plan 
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Geometric Mean (GM) Composite Measure (CM) on Quantitative Biomarker Panel for Renal Tubular Injury Results by Study Visit 
Safety Population 
Visit 
Number of Subjects (N=xx) 
GM CM 
Baseline 
xx 
x.xx
Day 1 
xx 
x.xx
Day 7 
xx 
x.xx
Day 14 
xx 
x.xx
Day 21 
xx 
x.xx
GM CM = Geometric Mean (GM) Composite Measure (CM) 
Programming note: Update footnote to SOURCE: Listing 16.2.8.1.4 


Statistical Analysis Plan 
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Table 14.3.6.1.1 
Summary of Vital Signs by Study Visit 
Safety Population 
Same shell as Table 14.3.5.1.1 
Programming note: Visits include Screening, Baseline, Day 1, Day 7 Pre-Dose,  Day 7 Post-Dose, Day 14 Pre-Dose, Day 14 Post-Dose, and Day 21; parameters include 
Temperature (C), Respiration Rate (breaths per min), Systolic Blood Pressure (mmHg), Heart Rate (bpm), Diastolic Blood Pressure (mmHg), and Weight (kg); SOURCE: Listing 
16.2.8.3.1, Listing 16.2.8.3.2. 
Table 14.3.6.1.2 
Shift from Baseline in Vital Signs by Study Visit 
Safety Population 
Same shell as Table 14.3.5.1.2 
Programming note: Visits include Screening, Baseline, Day 1, Day 7 Pre-Dose, Day 7 Post-Dose, Day 14 Pre-Dose, Day 14 Post-Dose, and Day 21; parameters include 
Temperature (C), Respiration Rate (breaths per min), Systolic Blood Pressure (mmHg), Heart Rate (bpm), Diastolic Blood Pressure (mmHg), and Weight (kg); Add the following 
footnote: “Abnormal vital signs are as follows:
 SBP >140 mmHg, SBP <90 mmHg, DBP >90 mmHg, DBP <60 mmHg, HR >100 bpm, HR <60 bpm, 
Respiration rate >20 breaths/min, Respiration rate <12 breaths/min, Oral temperature >99.1 ºF/37.2 ºC, Oral temperature <97.8 ºF/36.5 ºC” Update footnote to SOURCE: Listing 
16.2.8.3.1, Listing 16.2.8.3.2 
Table 14.3.6.1.3 
Summary of Orthostatic Vital Signs by Study Visit 
Safety Population 
Same shell as Table 14.3.5.1.1 
Programming note: Visits include Screening, Baseline, Day 1, Day 7 Post-Dose, Day 14 Post-Dose, and Day 21; parameters include Standing Systolic Blood Pressure (mmHg), 
Supine Systolic Blood Pressure (mmHg), Supine Heart Rate (bpm), Standing Heart Rate (bpm), Standing Diastolic Blood Pressure (mmHg), and Supine Diastolic Blood Pressure 
(mmHg); SOURCE: Listing 16.2.8.3.1, Listing 16.2.8.3.2.  
Table 14.3.6.1.4 
Shift from Baseline in Orthostatic Vital Signs by Study Visit 
Safety Population 
Same shell as Table 14.3.5.1.2 
Programming note: Visits include Screening, Baseline, Day 1, Day 7 Post-Dose, Day 14 Post-Dose, and Day 21; parameters include Standing Systolic Blood Pressure (mmHg), 
Supine Systolic Blood Pressure (mmHg), Supine Heart Rate (bpm), Standing Heart Rate (bpm), Standing Diastolic Blood Pressure (mmHg), and Supine Diastolic Blood Pressure 
(mmHg); Update footnote to SOURCE: Listing 16.2.8.3.1, Listing 16.2.8.3.2 
CCI


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Table 14.3.6.1.5 
Summary of Orthostatic Vital Signs Shift from Baseline Categories by Study Visit 
Safety Population 
Cohort-1 
Cohort-2 
Study Visit 
SBP [1] 
(N=XX) 
DBP [1] 
(N=XX) 
HR [1] 
(N=XX) 
SBP [1] 
(N=XX) 
DBP [1] 
(N=XX) 
HR [1] 
(N=XX) 
   Shift Category 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Day 7 
   Shifted 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Unshifted 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Missing 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Day 14 
   Shifted 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Unshifted 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Missing 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Day 21 
   Shifted 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Unshifted 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Missing 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Abbreviations: DBP= diastolic blood pressure (mmHg); HR = heart rate (bpm); SBP = systolic blood pressure (mmHg). 
Note: Percentages are n/Number of subjects in the Safety Population and respective Protocol Amendment * 100. Shift status is defined as a reduction in SBP of 20 mmHg or more, 
and/or a reduction in DBP of 10 mmHg or more, and/or an increase in heart rate >20 beats/min for the standing measurement compared to the supine or semi-supine 
measurement. 
[1] The baseline value for each variable is the last observation recorded prior to the first dose of treatment.
SOURCE: Listing 16.2.8.3.2
Programming note: Repeat table for Overall. 


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Table 14.3.6.1.6 
Summary of Orthostatic Hypotension by Study Visit 
Safety Population 
Cohort-1 
Cohort-2 
Overall 
Study Visit 
(N=XX) 
(N=XX) 
(N=XX) 
   Category 
n (%) 
n (%) 
n (%) 
Baseline [1] 
   Reduction of SBP of 20 mmHg or more 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Reduction of DBP of 10 mmHg or more 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Day 7 Post-Dose 
   Reduction of SBP of 20 mmHg or more 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Reduction of DBP of 10 mmHg or more 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Day 14 Post-Dose 
   Reduction of SBP of 20 mmHg or more 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Reduction of DBP of 10 mmHg or more 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Day 21 
   Reduction of SBP of 20 mmHg or more 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Reduction of DBP of 10 mmHg or more 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Abbreviations: DBP = diastolic blood pressure; SBP= systolic blood pressure. 
Note: Percentages are n/Number of subjects in the Safety Population and respective Protocol Amendment*100.  Orthostatic hypotension is 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. 
[1] The average of the 3 baseline orthostatic vital signs measurements will be used for comparison to all post-treatment measurements.
SOURCE: Listing 16.2.8.3.2


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Table 14.3.6.2.1 
Summary of 12-Lead Electrocardiogram by Study Visit 
Safety Population 
Same shell as Table 14.3.5.1.1 
Programming Note: Visits include Screening, Baseline, Day 1, Day 7 Pre-Dose, Day 7 Post-Dose, Day 14 Pre-Dose, Day 14 Post-Dose, and Day 21; parameters include PR interval 
(msec), RR interval (msec), mean heart rate (beats/min) QRS interval (msec), QT interval (msec), and QTcF interval (msec); SOURCE: Listing 16.2.8.4.2 


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Table 14.3.6.2.2 
Summary of 12-Lead Electrocardiogram Interpretation by Study Visit 
Safety Population 
Cohort-1 
Cohort-2 
Overall 
Study Visit 
(N=XX) 
(N=XX) 
(N=XX) 
   Category 
n (%) 
n (%) 
n (%) 
Screening 
   Normal 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Abnormal, Not Clinically Significant 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Abnormal, Clinically Significant 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Baseline [1] 
   Normal 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Abnormal, Not Clinically Significant 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Abnormal, Clinically Significant 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Day 1 
   Normal 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Abnormal, Not Clinically Significant 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Abnormal, Clinically Significant 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Note: Percentages are n/Number of subjects in the Safety Population and respective Protocol Amendment*100.  
[1] The baseline value for each variable is the last observation recorded prior to the first dose of treatment.
SOURCE: Listing 16.2.8.4.1
Programming note: Continue for Day 7 Pre-Dose, Day 7 Post-Dose, Day 14 Pre-Dose, Day 14 Post-Dose, and Day 21. 


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Table 14.3.6.2.3 
Summary of QTcF Values by Study Visit 
Safety Population 
Cohort-1 
Cohort-2 
Overall 
Study Visit 
(N=XX) 
(N=XX) 
(N=XX) 
   Category 
n (%) 
n (%) 
n (%) 
Screening 
  QTcF Value 
> 450 msec to ≤ 480 msec [1]
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
> 480 msec
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
> 500 msec
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Baseline [3] 
  QTcF Value 
> 450 msec to ≤ 480 msec [1]
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
> 480 msec
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
> 500 msec
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Day 1 
  QTcF Value 
> 450 msec to ≤ 480 msec [1]
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
> 480 msec
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
> 500 msec
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
  QTcF Increase from Baseline [3] 
> 30 msec to ≤60 msec
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
> 60 msec
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Note: Percentages are n/Number of subjects in the Safety Population and respective Protocol Amendment*100. 
[1] Percentages are based on the number of male subjects in the Safety Population.
[2] Percentages are based on the number of female subjects in the Safety Population.
[3] The baseline value for each variable is the last observation recorded prior to the first dose of treatment
SOURCE: Listing 16.2.8.4.2
Programming note: Continue for Day 7 Pre-Dose, Day 7 Post-Dose, Day 14 Pre-Dose, Day 14 Post-Dose, and Day 21. 


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Table 14.3.6.4 
Summary of Columbia-Suicide Severity Rating Scale (C-SSRS) 
Safety Population 
Cohort-1 
(N=XX) 
Cohort-2 
(N=XX) 
Overall 
(N=XX) 
C-SSRS Section
Pre-treatment 
Post-treatment 
Pre-treatment 
Post-treatment 
Pre-treatment 
Post-treatment 
C-SSRS Item
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
Suicidal Ideation 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Wish to be Dead 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Non-Specific Active Suicidal Thoughts 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Active Suicidal Ideation with Any Methods 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Active Suicidal Ideation with Some Intent 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Active Suicidal Ideation with Specific Plan 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Suicidal Behavior 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Actual Attempt 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Subject Engaged in Non-Suicidal Self-Injurious Behavior 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Interrupted Attempt 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Aborted Attempt 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Preparatory Acts or Behavior 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
   Suicidal Behavior 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Note: Percentages are n/Number of subjects in the Safety Population and respective Protocol Amendment*100. The C-SSRS scale consists of a Baseline evaluation that assesses 
the lifetime and more recent experience (past 12 months) of the subject with suicidal ideation and behavior, a baseline evaluation that focuses on suicidality since Screening that 
occurs before first dose of study drug (all of which is summarized under “pre-treatment”), and a post-baseline evaluation (“post-treatment”) administered at either Day 21 visit or 
early termination visit for discontinued subjects, which focuses on suicidality since the last study visit. Subjects are counted once for each C-SSRS section and once for each C-
SSRS item answered “Yes” in pre-treatment and post-treatment. 
SOURCE: Listing 16.2.8.6 


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14.3. 
Planned Listing Shells 
Listing 16.2.1.1 
Subject Disposition 
All Subjects 
Subject ID 
Protocol 
Amendment 
Subject Status 
Date of Last Dose 
(Study Day) 
Date of Discontinuation/Completion 
(Study Day) 
Reason for Discontinuation 
XXXXXX 
1.0 
XXXXXXXX 
DDMMMYYYY (X) 
DDMMMYYYY (X) 
XXXXXX 
2.0 
XXXXXXXX 
DDMMMYYYY (X) 
DDMMMYYYY (X) 
XXXXXX 
2.0 
XXXXXXXX 
DDMMMYYYY (X) 
DDMMMYYYY (X) 
XXXXXX 
3.0 
XXXXXXXX 
DDMMMYYYY (X) 
DDMMMYYYY (X) 
XXXXXXXXXX: XXXXXXXXX 
XXXXXX 
3.0 
XXXXXXXX 
DDMMMYYYY (X) 
DDMMMYYYY (X) 
XXXXXXXXXXXXXXXXXXXXXX 
Note: Study day is calculated relative to the date of first dose of study drug. For pre-dose: study day= Event Date – Date of the first dose of date; For post-dose: study day= Start 
Date/ Stop Date – first dose date + 1. 
Programming note: Concatenate specify text with a colon. If reason for early termination is Other, concatenate the specify text as follows: “Other: XXXXXXXXX”.  If the reason for 
Discontinuation is Death, then concatenate cause of death and date of death as shown above. If lost to follow-up, concatenate with date of last contact and specify text as follows: 
“Lost to follow-up: XXXXXXX; date of last contact: DDMMMYYYY”. 


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Listing 16.2.1.2 
Visit Status 
All Subjects 
Day 7 Visit Status 
Day 14 Visit Status 
Subject 
ID 
Protocol 
Amendment 
Complete 
Day 7 as 
Scheduled? 
If No, 
Early 
Terminate 
from the 
Study? 
Complete 
the Early 
Termination 
Visit? 
Day 7 Visit 
Date 
(Study Day) 
Complete 
Day 14 as 
Scheduled? 
If No, 
Early 
Terminate 
from the 
Study? 
Complete 
the Early 
Termination 
Visit? 
Day 7 Visit 
Date 
(Study Day) 
Date of Early 
Termination 
(Study Day) 
XXXXXX 
X.X
XXX 
XXX 
XXX 
DDMMMYYYY 
(X) 
XXX 
XXX 
XXX 
DDMMMYYYY 
(X) 
DDMMMYYYY 
(X) 
XXXXXX 
X.X
XXX 
XXX 
XXX 
DDMMMYYYY 
(X) 
XXX 
XXX 
XXX 
DDMMMYYYY 
(X) 
DDMMMYYYY 
(X) 
XXXXXX 
X.X
XXX 
XXX 
XXX 
DDMMMYYYY 
(X) 
XXX 
XXX 
XXX 
DDMMMYYYY 
(X) 
DDMMMYYYY 
(X) 
XXXXXX 
X.X
XXX 
XXX 
XXX 
DDMMMYYYY 
(X) 
XXX 
XXX 
XXX 
DDMMMYYYY 
(X) 
DDMMMYYYY 
(X) 
Note: Study day is calculated relative to the date of first dose of study drug. For pre-dose: study day= Assessment Date – Date of the first dose of date; For post-dose: study day= 
Assessment Date – first dose date + 1. 


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Listing 16.2.2.1 
Descriptions of Protocol Defined Inclusion and Exclusion Criteria 
All Subjects 
Protocol 
Amendment 
Inclusion/Exclusion 
Criterion Number 
Criteria Description 
X.X
Inclusion 
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 
X.X
Inclusion 
2 
XXXXXXXXXXXX 
…
… 
… 
… 
X.X
Exclusion 
1 
XXXXXXXXXXXX 
X.X
Exclusion 
2 
XXXXXXXXXXXX 
Programming note: This listing will be programmed similarly to how SDTM.TI would be created. 


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Listing 16.2.2.2 
Inclusion and Exclusion Criteria Met/Not Met 
All Subjects 
Subject ID 
Protocol Amendment 
Date (Study Day) of: 
Informed Consent 
All Inclusion 
Criteria Met? 
Any Exclusion 
Criteria Met? 
XXXXXX 
X.X
DDMMMYYYY (X) 
Yes 
No 
XXXXXX 
X.X
DDMMMYYYY (X) 
No: 05, 10 
No 
XXXXXX 
X.X
DDMMMYYYY (X) 
No: 05 
No 
XXXXXX 
X.X
DDMMMYYYY (X) 
Yes 
Yes: 04 
XXXXXX 
X.X
DDMMMYYYY (X) 
Yes 
No 
XXXXXX 
X.X
DDMMMYYYY (X) 
Yes 
No 
Note: Study day is calculated relative to the date of first dose of study drug (= ICF Date – Date of the first dose of date) 
Refer to Listing 16.2.2.1 for inclusion and exclusion criteria text. 
Programming note: If more than 1 inclusion or exclusion criterion number exists, concatenate with a comma as shown above. 


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Listing 16.2.2.3 
Protocol Deviations 
All Subjects 
Subject ID 
Protocol Amendment 
Date (DDMMMYYYY) (Study Day) 
Event Type 
Violation 
Level 
Description 
XXXXXX 
X.X
XXXXXXXXXXX 
MAJOR 
XXXXXXX 
XXXXXXXXXXXXXX 
MINOR 
XXXXXXXXXXXXXXX 
XXXXXX 
X.X
XXXXXXXXXXXX 
MINOR 
XXXXXXXXXXXXXXXXXXX 
XXXXXXXXXXXXXXXX 
MINOR 
XXXXXXXXXXX 
XXXXXX 
X.X
XXXXXXXXXXXX 
MAJOR 
XXXXXXXXXXXXXXXXXXXX 
Note: Study day is calculated relative to the date of first dose of study drug. For pre-dose: study day= Event Date – Date of the first dose of date; 
For post-dose: study day= Event Date – first dose date + 1. 
Programming note: the structure of this listing may change depending on the information in the protocol deviations file. 


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Listing 16.2.3 
Analysis Populations 
All Subjects 
Programming note: Concatenate all reasons for exclusion with a semi-colon. 
Subject ID 
Analysis Population 
Primary Reason for Exclusion 
Protocol Amendment 
Safety [1] 
FAS [2] 
Exposed [3] 
XXXXXX 
X.X
Yes 
Yes 
Yes 
XXXXXXXXXXXXXX 
XXXXXX 
X.X
Yes 
No 
Yes 
XXXXXXXXXXXXXX 
XXXXXX 
X.X
Yes 
Yes 
Yes 
XXXXXXXXXXXXXX 
XXXXXX 
X.X
Yes 
Yes 
Yes 
XXXXXXXXXXXXXX 
XXXXXX 
X.X
Yes 
Yes 
No 
XXXXXXXXXXXXXXXXXXX 
Abbreviations: FAS = full analysis set;
; TETRAS-PS = Tremor Research Group Essential Tremor Rating Assessment Scale (TETRAS)-
; TETRAS-PS = Tremor Research Group Essential Tremor Rating Assessment Scale (TETRAS)-performance subscale (PS). 
Note: All subjects received CAD-1883 300 mg BID. [1] The Safety population includes all subjects who take at least 1 dose of study drug. 
[2] The FAS consists of subjects in the Safety population who had at least 1 post-baseline assessment of both TETRAS-PS
. 
[3]
[4]
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Listing 16.2.4.1 
Demographics and Baseline Characteristics 
All Subjects 
Programming Note: If subject has multiple races, concatenate them. 
Subject ID 
Protocol Amendment 
Site 
Sex 
Child-
Bearing 
Potential? 
Date of 
Birth 
Age 
(years) 
Ethnicity 
Race 
XXXXXX 
X.X
XXXXXX 
XXXX 
No 
DDMMMYYY 
XX 
XXXXXXX 
XXXXXXX 
XXXXXX 
X.X
XXXXXX 
XXXXXX 
No 
DDMMMYYY 
XX 
XXXXXXX 
XXXXXX 
XXXXXX 
X.X
XXXXXX 
XXXXXX 
DDMMMYYY 
XX 
XXXXXXX 
XXXXXX 
XXXXXX 
X.X
XXXXXX 
XXXX 
DDMMMYYY 
XX 
XXXXXXX 
XXXXX 
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Listing 16.2.4.2 
Medical History 
All Subjects 
Subject ID 
Protocol Amendment 
System Organ Class/ 
   Preferred Term/ 
 Verbatim Term 
Start Date (Study Day)/ 
   End Date (Study Day)/Ongoing 
XXXXXX 
X.X
XXXXXXXXXXXXXXX/ 
   XXXXXXXXXXXXXX/ 
       XXXXXXXXXXXXX 
DDMMMYYYY (X)/ 
   DDMMMYYYY (X) 
XXXXXXXXXXXXXXX/ 
   XXXXXXXXXXXXXX/ 
       XXXXXXXXXXXXX 
MMMYYYY (X)/ 
   Ongoing 
XXXXXXXXXXXXXXX/ 
   XXXXXXXXXXXXXX/ 
       XXXXXXXXXXXXX 
DDMMMYYYY (X)/ 
   Ongoing 
XXXXXX 
X.X
XXXXXXXXXXXXXXX/ 
   XXXXXXXXXXXXXX/ 
       XXXXXXXXXXXXX 
DDMMMYYYY (X)/ 
   DDMMMYYYY (X) 
Note: Study day is calculated relative to the date of first dose of study drug. For pre-dose: study day= Start Date/ Stop Date – Date of the first dose of date; 
For post-dose: study day= Start Date/ Stop Date – first dose date + 1. 
Medical history was coded using MedDRA version 20.1. Only subjects with medical history recorded are listed. 
[1]
Programming note: SOC & PT text should be in title case in table, as shown in the shell. 
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Listing 16.2.4.3 
Disease History 
All Subjects 
Programming note: Concatenate specify text for Treatment Type, Trigger Type, Frequency Type as shown above if the answer is “OTHER”
Subject ID 
Protocol 
Amendment 
Date of First ET 
Symptom 
(Study Day) 
Date of ET 
Diagnosis 
(Study Day) 
ET Triggers 
Did 
Alcohol 
Use 
Reduce 
Tremor 
Severity? 
First or 
Second- 
Degree 
Blood 
Relative with 
Prior ET 
Diagnosis? 
Trigger Type 
Frequency 
XXXXXX 
X.X
DDMMMYYY 
(XX) 
DDMMMYYY 
(XX) 
XXX 
XXX 
XXX 
XXX 
XXXXXX 
X.X
DDMMMYYY 
(XX) 
DDMMMYYY 
(XX) 
XXX 
XXX 
XXX 
XXX 
XXXXXX 
X.X
DDMMMYYY 
(XX) 
DDMMMYYY 
(XX) 
XX 
XX 
XX 
XX 
XXXXXX 
X.X
DDMMMYYY 
(XX) 
DDMMMYYY 
(XX) 
XX 
XX 
XX 
XX 
Abbreviation: ET = Essential Tremor. 
Note:  Study day is calculated relative to the date of first dose of study drug. For pre-dose: study day= Start Date/ Stop Date – Date of the first dose of date; For post-dose: study 
day= Start Date/ Stop Date – first dose date + 1.
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Listing 16.2.5.1 
Study Drug Administration 
All Subjects 
Subject ID 
Protocol 
Amendment 
Study Visit 
Administered 
Proper Dosage 
of Study Drug? 
Reason Dose 
 Not Administered 
Date/Time of In-Clinic 
Administration 
(Study Day) 
Date/Time of Last Dose Prior to 
Clinic Visit 
(Study Day) 
XXXXXX 
X.X
XXXXXXX 
Yes 
DDMMMYYYY/HH:MM 
DDMMMYYYY/HH:MM 
X.X
XXXXXXX 
Yes 
DDMMMYYYY/HH:MM 
DDMMMYYYY/HH:MM 
X.X
XXXXXXX 
Yes 
DDMMMYYYY/HH:MM 
DDMMMYYYY/HH:MM 
X.X
XXXXXXX 
Yes 
DDMMMYYYY/HH:MM 
DDMMMYYYY/HH:MM 
XXXXXXX 
No 
XXXXXXXXXXXXXX 
XXXXXX 
X.X
XXXXXXX 
Yes 
DDMMMYYYY/HH:MM 
DDMMMYYYY/HH:MM 
X.X
XXXXXXX 
Yes 
DDMMMYYYY/HH:MM 
DDMMMYYYY/HH:MM 
X.X
XXXXXXX 
Yes 
DDMMMYYYY/HH:MM 
DDMMMYYYY/HH:MM 
Note: Study day is calculated relative to the date of first dose of study drug. 
Time for last dose prior to clinic visit is approximate. 


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Listing 16.2.5.2 
Drug Accountability 
All Subjects 
Subject ID 
Protocol 
Amendment 
Total Daily 
Dose 
Bottle 
Date Dispensed 
(Study Day) 
Number of Capsules 
Dispensed 
Was Bottle Returned 
to the Clinic? 
Date Returned 
(Study Day) 
Number of Unused 
Capsules Returned 
XXXXXX 
X.X 
300 mg BID Bottle A 
DDMMMYYYY (X) 
XX 
Yes 
DDMMMYYYY (X) 
XX 
XXXXXX 
X.X 
300 mg BID Bottle A 
DDMMMYYYY (X) 
XX 
Yes 
DDMMMYYYY (X) 
XX 
Note: Study day is calculated relative to the date of first dose of study drug. 
Programming note:  Concatenate specify text with a colon if the Capsules Dispensed is OTHER.


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Listing 16.2.5.3 
Missed Doses 
All Subjects 
Subject ID 
Protocol Amendment 
Were any Doses 
Missed? 
Date of Missed Dose 
(Study Day) 
AM/PM Dose 
Number of 
Pills not Taken 
Reason for 
Missed Dose 
XXXXXX 
X.X
No 
XXXXXX 
X.X
Yes 
DDMMMYYYY (X) 
AM 
XX 
XXXXXXXXXXX 
XXXXXX 
X.X
Yes 
DDMMMYYYY (X) 
PM 
XX 
XXXXXXXXXXX 
Note: Study day is calculated relative to the date of first dose of study drug (= Date of Missed Dose – first dose date + 1). 


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Listing 16.2.6.1.1 
Local TETRAS Performance Subscale and Upper Limb Subscale Scores 
All Subjects 
Subject 
ID 
Protocol 
Amendment 
Study Visit 
CAD-1883 
Administered In-
Clinic? 
Was Assessment 
Completed? 
Date/Time of 
Assessment 
(Study Day) 
Number of 
Minutes 
Assessment 
Started after 
Dosing 
Was the 
Videography 
Uploaded to 
Portal? 
Item 
Result 
XXXXXX 
X.X 
XXXXXX 
XXX 
Yes 
DDMMMYYYY/HH:MM 
(X) 
XX 
Yes 
Head Tremor 
XX 
Face (including 
jaw) Tremor 
XX 
Voice tremor 
XX 
Upper limb 
tremor: Forward 
outstretched 
postural tremor 
– Right
XX 
… 
TETRAS-PS 
Upper Limb 
Subscale Score 
XX 
TETRAS-PS 
Upper Limb 
Tremor (Item 4) 
Score 
XX 
TETRAS-PS 
Total Score 
XX 
Abbreviation: TETRAS-PS = Tremor Research Group Essential Tremor Rating Assessment Scale Performance Subscale. 
Note: Study day is calculated relative to the date of first dose of study drug. For pre-dose: study day= Assessment Date – Date of the first dose of date; For post-dose: study day= 
Assessment Date – first dose date + 1.  
Each individual item question score ranges from 0 to 4, where higher scores indicate worse quality of life. 
TETRAS-PS Total score is derived as the sum of the 16 individual item scores (only the maximum of the item 5, lower limb tremor scores will be counted), with a maximum total 
score of 64.  
TETRAS-PS Upper Limb Subscale score is derived as the sum of the item 4, item 6, item 7 and item 8 scores (forward outstretched postural tremor, lateral “wing beating” postural 
tremor, kinetic tremor, Archimedes spirals, and dot approximation task from both sides of the body, as well as handwriting, with a maximum total score of 44.  
TETRAS-PS Upper Limb Tremor (Item 4) Total score is derived as the sum of the 6 item 4 scores (forward outstretched postural tremor, lateral “wing beating” postural tremor, and 
kinetic tremor scores) from both sides of the body, with a maximum total score of 24. 
Programming Note: If Assessment was not completed or videography was not uploaded to the portal, concatenate reason. CAD-1883 Administered In-Clinic will come from EX CRF, 
if date of in-clinic administration at the corresponding visit is not null. If not administered in clinic, concatenate reason not administered with a semicolon. 


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Listing 16.2.6.1.2 
Central TETRAS Performance Subscale and Upper Limb Subscale Scores 
All Subjects 
Same Shell as Listing 16.2.6.1.1 


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Listing 16.2.6.6 
Wearable Sensor (Kinesia) Scores 
All Subjects 
Subject 
ID 
Protocol 
Amendme
nt 
Study Visit 
Date/Time of 
Assessment 
(Study Day) 
Side 
Task 
Kinesia Score 
Tremor 
Amplitude 
Tremor 
Frequency 
Finger-Chin- 
Finger Quality 
XXXXXX 
X.X 
XXXXXX 
DDMMMYYYY/HH:MM 
(X) 
Left 
Extended 
arms posture 
X 
XX 
XX 
XXXX 
Wing-beating 
posture 
X 
XX 
XX 
XXXX 
Kinetic “finger-
to-chin” 
movement 
X 
XX 
XX 
XXXX 
Arm on table 
posture 
X 
XX 
XX 
XXXX 
Right 
Extended 
arms posture 
X 
XX 
XX 
XXXX 
Wing-beating 
posture 
Kinetic “finger-
to-chin” 
movement 
X 
XX 
XX 
XXXX 
Arm on table 
posture 
X 
XX 
XX 
XXXX 
Both 
Kinesia Upper 
Limb Tremor 
Score 
X 
XX 
XX 
XXXX 
Note: Study day is calculated relative to the date of first dose of study drug. 
Kinesia score ranges from 0 to 4; higher scores indicate more severe tremor. Finger-Chin-Finger quality values of 1 represent good quality and values of 0 represent poor 
quality. Kinesia Upper Limb Tremor score is derived as the sum of the scores from the extended arms posture, wing-beating posture, and kinetic “finger-to-chin” wearable 
sensor maneuvers from both sides of the body, with a maximum total score of 24. 
Programming Note: If assessment was done at home, place ‘NA’ in study visit column and add to abbreviations. 


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Listing 16.2.7 
Adverse Events 
All Subjects 
Subject ID 
Protocol 
Amendment 
TEAE/Disc 
System Organ Class/ 
   Preferred Term/ 
 Verbatim Term 
Start Date/Time (Study Day)/ 
   End Date/Time (Study Day) 
Severity/ 
   Relationship 
Action Taken/ 
   Outcome 
Serious (SAE)?/ 
  Criteria Met 
XXXXX 
X.X
Yes/No 
XXXXXXXXXXXXXX/ 
   XXXXXXXXXXXXXXXXX 
  XXXXXXXXXXXXX 
DDMMMYYYY/HH:MM (X)/ 
   DDMMMYYYY/HH:MM (X) 
XXXXXXXXX/ 
   XXXXXXXXXX 
XXXXXXXXX/ 
   XXXXXXXXXX  
Yes/xxxxxx 
XXXXX 
X.X
No/No 
XXXXXXXXXXXXXX/ 
   XXXXXXXXXXXXXXXXX 
  XXXXXXXXXXXXX 
DDMMMYYYY/HH:MM (X)/ 
   DDMMMYYYY/HH:MM (X) 
XXXXXXXXX/ 
   XXXXXXXXXX 
XXXXXXXXX/ 
   XXXXXXXXXX  
No 
Yes/Yes 
XXXXXXXXXXXXXX/ 
   XXXXXXXXXXXXXXXXX 
      XXXXXXXXXXXXXXXXXXX 
DDMMMYYYY/HH:MM (X))/ 
  DDMMMYYYY/HH:MM (X) 
XXXXXXXXX/ 
   XXXXXXXXXX 
XXXXXXXXX/ 
   XXXXXXXXXX  
DISC = Discontinued, SAE = Serious Adverse Event, TEAE = Treatment Emergent Adverse Event 
Note: Study day is calculated relative to the date of first dose of study drug. For pre-dose: study day= Start/End Date – Date of the first dose of date; For post-dose: study day= 
Start/End Date – first dose date + 1.  
Programming note: If time missing, display “- -:- -”. If Serious? is Yes, concatenate all serious criteria marked as Yes with a semicolon. If no events meet the criteria for display, 
present “No events are reported.” SOC & PT text should be in proper case in table, as shown in the shell. “Other Action Taken” will be either None, Medication Required, Relevant 
Procedure, or Other; if specify text is needed, concatenate “Relevant Procedure:” or “Other:” with the text.


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Listing 16.2.8.1.1 
Clinical Laboratory Data: Hematology 
All Subjects 
Subject ID: XXXXXX, Protocol Amendment: X.X, Sex: M/F, Age: XX, Date of First/Last Dose (Study Day): DDMMMYYYY (X)/ DDMMMYYYY (X) 
Parameter (unit) 
Study Visit 
Date/Time of Assessment 
(Study Day) 
Standard 
Results 
Change 
from 
Baseline 
(%) [1] 
Reference 
Range [2] 
Reference 
Range Flag 
Lab Panel 
Comments/Reason 
Not Done 
Hemoglobin 
(unit) 
XXXXXX 
DDMMMYYYY/HH:MM (X) 
XX 
XX – YY 
XXXXXXX 
XXXXXX 
DDMMMYYYY/HH:MM (X) 
XX 
XX (XX.X) 
XX – YY 
XXXXXXX 
XXXXXX 
DDMMMYYYY/HH:MM (X) 
XX 
XX – YY 
XXXXXXX 
XXXXXX 
DDMMMYYYY/HH:MM (X) 
XX 
XX – YY 
XXX 
XXXXXXX 
XXXXXX 
DDMMMYYYY/HH:MM (X) 
XX 
XX – YY 
XXXXXXX 
XXXXXX 
DDMMMYYYY/HH:MM (X) 
XX 
XX – YY 
XXXXXXX 
XXXXXX 
DDMMMYYYY/HH:MM (X) 
XX 
XX – YY 
XXXXXXX 
XXXXXX 
DDMMMYYYY/HH:MM (X) 
XX 
XX – YY 
XXXXXXX 
XXXXXX 
ND 
XXXXXXX 
XXXXXX 
DDMMMYYYY/HH:MM (X) 
XX 
XX – YY 
XXXXXXX 
Abbreviations: AL = abnormal-low; AH = abnormal-high; CS = clinically significant; NCS = not clinically significant; ND = not done. 
Note: Study day is calculated relative to the date of first dose of study drug. For pre-dose: study day= Assessment Date – Date of the first dose of date; For post-dose: 
study day= Assessment Date – first dose date + 1.  
[1] Baseline is the last observation recorded prior to the first dose of treatment.
[2] Reference range is used to identify potentially clinically significant laboratory values.
Programming note: Update abbreviations to reflect actual data. If test was not done, set results to ND; make sure last column is populated accordingly. Do not display serum HCG 
results in this listing. For reference range flag, concatenate AL or AH with clinical significance like “XX-YY” (eg, AL-CS). Sort by Subject ID, Treatment, Sex, Age, First Dose Date, 
Parameter, Study visit, Date of Assessment. 


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Listing 16.2.8.1.2 
Clinical Laboratory Data: Serum Chemistry 
All Subjects 
Same shell as Listing 16.2.8.1.1 
Listing 16.2.8.1.3 
Clinical Laboratory Data: Urinalysis 
All Subjects 
Same shell as Listing 16.2.8.1.1 
Listing 16.2.8.1.4 
Clinical Laboratory Data: Biomarker Panel for Renal Tubular Injury 
All Subjects 
Same shell as Listing 16.2.8.1.1 


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Listing 16.2.8.1.5 
Clinical Laboratory Data: Urine Pregnancy Test 
All Subjects 
Subject ID 
Protocol 
Amendment 
Age 
(years) 
Sex 
Was Pregnancy Test 
Performed? 
Date Performed (Study 
Day) 
Reason not Performed 
Result 
XXXXX 
X.X
XX 
XXXXXX 
Yes 
DDMMMYYYY (XX) 
XXXXXXXX 
XXXXX 
X.X
XX 
XXXXXX 
Yes 
DDMMMYYYY (XX) 
XXXXXXXXX 
XXXXX 
X.X
XX 
XXXXXX 
No 
XXXXXXXXXXXX 
XXXXXXXXX 
Note: Study day is calculated relative to the date of first dose of study drug. For pre-dose: study day= Assessment Date – Date of the first dose of date; For post-dose: study day= 
Assessment Date – first dose date + 1. 


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Listing 16.2.8.1.7 
Clinical Laboratory Data: Biomarker Panel for Renal Tubular Injury 
Safety Population 
Subject ID: 840002-005, Age=xx years, Sex=F, CAD-1883 Treatment: 300 mg BID, First/Last Dosing Date=25APR2019 (Day 1)/09MAY2019 (Day 15), Subject Status=Completed 
Results 
Parameter 
Study Visit 
Date/Time of  
Assessment (Study Day) 
Measured 
Unit 
Normalized 
Unit 
Fold Change from 
Baseline [1] 
uCreatinine (uCr) 
SCREENING 
01APR2019/14:03 (-24) 
127.1 
mg/dL 
PRE-DOSE 
22APR2019/12:44 (-3) 
116 
mg/dL 
DAY 1 
25APR2019/15:45 (1) 
78.1 
mg/dL 
DAY 7 
02MAY2019/12:50 (8) 
78.8 
mg/dL 
DAY 14 
09MAY2019/12:17 (15) 
93.4 
mg/dL 
DAY 21/FOLLOW UP 
14MAY2019/12:58 (20) 
124.4 
mg/dL 
uClusterin (uCLU) 
PRE-DOSE 
22APR2019/12:44 (-3) 
131 
ng/mL 
 113 
ng/mg Cr 
 1.00 
DAY 1 
25APR2019/15:45 (1) 
12 
ng/mL 
 15 
ng/mg Cr 
 0.13 
DAY 7 
02MAY2019/12:50 (8) 
235 
ng/mL 
 298 
ng/mg Cr 
 2.64 
DAY 14 
09MAY2019/12:17 (15) 
117 
ng/mL 
 125 
ng/mg Cr 
 1.11 
DAY 21/FOLLOW UP 
14MAY2019/12:58 (20) 
85 
ng/mL 
 68 
ng/mg Cr 
 0.60 
Note: The normalized concentration at a given time point is calculated as the concentration at that time point divided by the concentration of uCreatinine (mg/dL) at the same time 
point. 
[1] Fold Change from Baseline at a given time point is calculated as the normalized concentration at the time point divided by the normalized concentration at baseline.
PROGRAM: L_16.2.8.1.4_Biomarker.sas 
Run Date: 28AUG2019 18:09 
Programming note: Parameters include uCreatine (uCr), uClusterin (uCLU) , uCystatin-C (uCysC), uKidney Injury Molecule-1 (uKIM-1), uN-Acetyl-beta-D-Glucosaminidase (uNAG), 
Neutrophil Gelatinase-Associated Lipocalin (uNGAL) and uOsteopontin (uOPN).  
Units are different for different parameters. 


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Listing 16.2.8.2.1 
Physical Examination 
All Subjects 
Subject ID: XXXXXX, Protocol Amendment: X.X, Sex: M/F, Age: XX, Date of First/Last Dose (Study Day): DDMMMYYYY (X)/ DDMMMYYYY (X) 
Study Visit 
Physical Exam 
Performed? 
Any CS Changes since Last 
Visit? 
Exam Date 
(Study Day) 
Body System 
Result 
Abnormal Findings 
Clinically 
Significant? 
XXXXXX 
Yes 
NA 
DDMMMYYYY (XX) 
XXXXXXX 
NORMAL 
DDMMMYYYY (XX) 
XXXXXXX 
NORMAL 
XXXXXX 
Yes 
XX 
DDMMMYYYY (XX) 
XXXXXXX 
ABNORMAL 
XXXXXXXXXXXXXX 
No 
XXXXXX 
No; XXXXXX 
DDMMMYYYY (XX) 
XXXXXXX 
NORMAL 
Abbreviations: CS = clinically significant; NA = not applicable. 
Note: Study day is calculated relative to the date of first dose of study drug. For pre-dose: study day= Exam Date – Date of the first dose of date; For post-dose: study day= Exam 
Date – first dose date + 1. 
Programming Note: If exam was not performed, concatenate reason. Any Clinically Significant Changes since Last Visit? will be NA at the Screening visit. 


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Listing 16.2.8.2.2 
Neurological Examination 
All Subjects 
Subject ID: XXXXXX, Protocol Amendment: X.X, Sex: M/F, Age: XX, Date of First/Last Dose (Study Day): DDMMMYYYY (X)/ DDMMMYYYY (X) 
Study Visit 
Neurological 
Examination 
Performed? 
Any Clinically 
Significant 
Changes since 
Last Visit? 
Exam Date 
(Study Day) 
Body System 
Result 
Abnormal Findings 
Clinically 
Significant? 
XXXXXX 
Yes 
XX 
DDMMMYYYY (XX) 
XXXXXXX 
NORMAL 
XXXXXX 
Yes 
XX 
DDMMMYYYY (XX) 
XXXXXXX 
ABNORMAL 
XXXXXXXXXXXXXX 
No 
XXXXXX 
No 
XX 
DDMMMYYYY (XX) 
XXXXXXX 
NORMAL 
Abbreviations: CS = clinically significant; NA = not applicable. 
Note: Study day is calculated relative to the date of first dose of study drug. For pre-dose: study day= Exam Date – Date of the first dose of date; For post-dose: study day= Exam 
Date – first dose date + 1. 
Programming Note: If exam was not performed, concatenate reason. Any Clinically Significant Changes since Last Visit? will be NA at the Screening visit.


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Listing 16.2.8.3.1 
Vital Signs 
All Subjects 
Subject 
ID 
Protocol 
Amendmen
t 
Study Visit 
Were Vital Signs 
Collected? 
Date/Time 
Collected 
(Study Day) 
Body 
Temperature 
(F) 
Respiration 
Rate 
(breaths/min
) 
Height 
(cm) 
Weight 
(kg) 
Abnormal? 
XXXXXX 
X.X
XXXXXX 
XXX 
DDMMMYYYY/ 
HH:MM (X) 
XX.X
XX 
XX.X
XX.X
XXX 
DDMMMYYYY/ 
HH:MM (X) 
XX.X
XX 
XXX 
XXXXXX 
X.X
XXXXXX 
XXX; XXXXXX 
DDMMMYYYY/ 
HH:MM (X) 
XX.X
XX 
XXX 
DDMMMYYYY/ 
HH:MM (X) 
ND 
ND 
ND 
Abbreviation: 
ND = not done. 
Note: Study day is calculated relative to the date of first dose of study drug. For pre-dose: study day= Assessment Date – Date of the first dose of date; For post-dose: study 
day= Assessment Date – first dose date + 1. 
Abnormal vital signs are as follows: 
 Systolic blood pressure >140 mmHg; Systolic blood pressure <90 mmHg; Diastolic blood pressure >90 
mmHg;  Diastolic blood pressure <60 mmHg; Heart rate >100 bpm; Heart rate <50 bpm; Respiration rate >20 breaths/min; Respiration rate <12 breaths/min; Oral temperature 
>99.5 ºF; Oral temperature <97 ºF.
[1] Treatment is based on treatment received.
Programming Note: If vital signs were not collected, concatenate reason, as shown above. If a measurement is outside the normal range, place an asterisk (*) next to the
value in the cell.
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Listing 16.2.8.3.2 
Blood Pressure and Orthostatic Vital Signs 
All Subjects 
Subject 
ID 
Protocol 
Amendment 
Study Visit/ 
Date/Time Collected 
(Study Day) 
Measurement No. / /Total 
No. Measurements 
Position 
Parameter 
(unit) 
Result 
Change 
from 
Baseline 
Orthostatic 
Hypotension? 
[1] 
XXXXXX 
1 
XXXXXX/ 
DDMMMYYYY/ 
HH:MM (X) 
X / X 
Standing 
SBP 
(mmHg) 
XXX 
XXX 
NA 
2 or 3 
XXXXXX/ 
DDMMMYYYY/ 
HH:MM (X) 
X / X 
Standing 
DBP 
(mmHg) 
XXX 
XXX 
XX 
XXXXXX/ 
DDMMMYYYY/ 
HH:MM (X) 
X / X 
Standing 
HR (bpm) 
XXX 
XXX 
XX 
XXXXXX/ 
DDMMMYYYY/ 
HH:MM (X) 
NA 
Supine 
SBP 
(mmHg) 
ND 
NA 
NA 
XXXXXX/ 
DDMMMYYYY/ 
HH:MM (X) 
X / X 
Supine 
DBP 
(mmHg) 
XXX 
XXX 
XX 
XXXXXX/ 
DDMMMYYYY/ 
HH:MM (X) 
X / X 
Supine 
HR (bpm) 
XXX 
XXX 
XX 
XXXXXX/ 
DDMMMYYYY/ 
HH:MM (X) 
X / X 
Standing-Average 
SBP 
(mmHg) 
XXX 
XXX 
NA 
XXXXXX/ 
DDMMMYYYY/ 
HH:MM (X) 
X / X 
Average 
DBP 
(mmHg) 
XXX 
XXX 
XX 
XXXXXX/ 
DDMMMYYYY/ 
HH:MM (X) 
X / X 
Average 
HR (bpm) 
XXX 
XXX 
XX 
Note: Study day is calculated relative to the date of first dose of study drug. For pre-dose: study day= Assessment Date – Date of the first dose of date; For post-dose: study 
day= Assessment Date – first dose date + 1. 
[1] Orthostatic hypotension is 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.
Programming Note:  If measurements are not orthostatic, put ‘NA’ in the “Measurement Number/Was Measurement Performed?” and “Average” Columns. If a 
measurement is outside the normal range, place an asterisk (*) next to the value in the cell. 
Please use "Standing-Average", "Supine-Average" respectively for averaged values. "Standing-Supine" for difference.


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Listing 16.2.8.4.1 
Qualitative 12-Lead Electrocardiogram (ECG) Investigator Results 
All Subjects  
Subject 
ID 
Protocol 
Amendment 
3 ECGs 
Performed 
Per 
Protocol? 
Time 
Point 
Study Visit/ 
Date of Assessment 
(Study Day) 
Time 
Reason not 
Performed 
Investigator 
Interpretation 
Comments 
1st Reading 
2nd Reading 
3rd Reading 
XXXXXX 
X.X
Yes 
XX 
XXXXX / 
DDMMMYYYY (XX) 
HH:MM 
HH:MM 
HH:MM 
Normal 
XX 
XXXXX / 
DDMMMYYYY (XX) 
HH:MM 
HH:MM 
HH:MM 
Normal 
XX 
XXXXX / 
DDMMMYYYY (XX) 
HH:MM 
HH:MM 
HH:MM 
Abnormal-NCS 
XXXXXXXXXXXXXX 
XX 
XXXXX / 
DDMMMYYYY (XX) 
HH:MM 
HH:MM 
HH:MM 
XX 
XXXXX / 
DDMMMYYYY (XX) 
HH:MM 
HH:MM 
HH:MM 
Normal 
XXXXXX 
X.X
No 
XX 
XXXXXXXXXXX 
Abbreviations: CS = clinically significant; NCS = not clinically significant. 
Note: Study day is calculated relative to the date of first dose of study drug. For pre-dose: study day= Assessment Date  – Date of the first dose of date; For post-dose: study day= 
Assessment Date – first dose date + 1. 
Programming Note: time point will be pre-dose or post-dose. 


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Listing 16.2.8.4.2 
12-Lead Electrocardiogram (ECG) Central Results
All Subjects 
Subject ID 
Protocol 
Amendment 
Study Visit 
Date/Time of 
ECG 
(Study Day) 
Overall 
Interpretation 
PR 
Interval 
(msec) 
QRS 
Interval 
(msec) 
QT 
Interval 
(msec) 
QTcF 
Interval 
(msec) 
XXXXXX 
1 
XXXXX 
DDMMMYYYY/ 
HH:MM (XX) 
XXXXXXX 
XXX 
XXX 
XXX 
XXX 
XXXXX 
DDMMMYYYY/ 
HH:MM (XX) 
XXXXXXXXXXX 
XXX 
XXX 
XXX 
XXX 
XXXXX 
DDMMMYYYY/ 
HH:MM (XX) 
XXXXXXXXX 
XXX 
XXX 
XXX 
XXX 
ND 
XXXXXX 
2 or 3 
XXXXX 
DDMMMYYYY/ 
HH:MM (XX) 
XXXXXXX;XXXXX 
XXX 
XXX 
XXX 
XXX 
XXXXX 
DDMMMYYYY/ 
HH:MM (XX) 
XXXXXXXXXXX 
XXXX 
XXXX 
XXXX 
XXXX 
ECG = electrocardiogram; ND = not done.   
Note: Study day is calculated relative to the date of first dose of study drug. For pre-dose: study day= ECG Date – Date of the first dose of date; For post-
dose: study day= ECG Date – first dose date + 1. 
Programming Note:   If a measurement is outside the normal range, place an asterisk (*) next to the value in the cell.


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Listing 16.2.8.6 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
All Subjects  
Subject 
Protocol 
Date of 
Assessment 
Reference 
Reason not 
ID 
Version 
Study Visit 
(Study Day) 
Period 
Completed 
Category 
Assessment 
Result 
XXXXXX 
X.X
XXXXXX 
DDMMMYYYY 
(XX) 
Baseline/ 
Screening 
Suicidal Ideation 
1. Wish to be dead
XX 
If yes, describe: 
2. Non-Specific Active Suicidal
Thoughts
XX 
If yes, describe:
3. Active Suicidal Ideation with
Any Methods (not Plan) without 
Intent to Act 
XX 
If yes, describe: 
4. Active Suicidal Ideation with
Some Intent to Act, without 
Specific Plan 
XX 
If yes, describe: 
5. Active Suicidal Ideation with
Specific Plan and Intent 
XX 
If yes, describe: 
Intensity of Ideation 
Most Severe Ideation Type # (1-5) 
X 
Description of Ideation 
XXXXXXXXXXX
XXXX 
Frequency 
1 = 1-4 hours/a 
lot of time 
Duration 
1 = Fleeting – 
few seconds or 
minutes 
Controllability 
1 = Easily able to 
control thoughts 
… 
… 
… 
Note: All subjects received CAD-1883 300 mg BID. At the Pre-dose visit, the “baseline” version of the C-SSRS was 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 was administered.  
Study day is calculated relative to the date of the first dose of study drug.


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Figure 14.2.1.1.4 
Central and Local TETRAS-PS Total Scores by Study Visit 
Full Analysis Set  
Study Visit=Screening 
Abbreviation: TETRAS-PS = Tremor Research Group Essential Tremor Rating Assessment Scale (TETRAS)-performance subscale (PS). 
Note: TETRAS-PS Total score is derived as the sum of all of the individual item scores. Each individual item question score ranges from 0 to 4, where higher scores indicate worse 
quality of life. Pearson correlation coefficient and regression lines are presented for all study visits. 
Reference Table: 14.2.1.1.4 
SOURCE: Listings 16.2.6.1.1, 16.2.6.1.2 
Programming Note: Check Section 8.3.2 of SAP. If Spearman correlation coefficient is used, update footnote [1] accordingly. A separate graph will be produced for each 
study visit. 


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Figure 14.2.1.2.3 
Central and Local TETRAS-PS Upper Limb Subscale Scores by Study Visit 
Full Analysis Set  
Same shell as Figure 14.2.1.1.4 
Y-axis: Central Score
X-axis: Local Score
Programming notes: A separate graph will be produced for each study visit. Update footnote to read: TETRAS-PS Upper Limb Subscale score is derived as the sum of the
item 4, item 6, item 7 and item 8 scores (forward outstretched postural tremor, lateral “wing beating” postural tremor, kinetic tremor, Archimedes spirals, and dot
approximation task from both sides of the body, as well as handwriting, with a maximum total score of 44.
Reference Table: 14.2.1.2.3
SOURCE: Listings 16.2.6.1.1, 16.2.6.1.2
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Protocol Number CAD1883-201 
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Figure 14.2.1.3.2 
Central and Local TETRAS-PS Upper Limb Tremor (Item 4) Scores by Study Visit 
Full Analysis Set 
Same shell as Figure 14.2.1.1.4 
Y-axis: Central Score
X-axis: Local Score
Programming notes: A separate graph will be produced for each study visit. Update footnote to read: TETRAS-PS Upper Limb Tremor (Item 4) Total score is derived as the
sum of the 6 item 4 scores (forward outstretched postural tremor, lateral “wing beating” postural tremor, and kinetic tremor scores) from both sides of the body, with a
maximum total score of 24.
Reference Table: 14.2.1.3.2
SOURCE: Listings 16.2.6.1.1 and,16.2.6.1.2
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Statistical Analysis Plan 
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Protocol Number CAD1883-201 
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Figure 14.2.4 
TETRAS-PS and Wearable Sensor (Kinesia) Upper Limb Tremor Scores by Study Visit 
Full Analysis Set 
Same shell as Figure 14.2.1.1.4 
Y-axis: Central Score
X-axis: Local Score
Programming notes: A separate graph will be produced for each study visit. Update the footnote to read: TETRAS-PS Upper Limb Tremor (Item 4) Total score is derived as
the sum of the 6 item 4 scores (forward outstretched postural tremor, lateral “wing beating” postural tremor, and kinetic tremor scores) from both sides of the body, with a
maximum total score of 24. Kinesia Upper Limb Tremor score is derived as the sum of the scores from the extended arms posture, wing-beating posture, and kinetic “finger-
to-chin” wearable sensor maneuvers from both sides of the body, with a maximum total score of 24.
Reference Table: 14.2.6.1
SOURCE: Listings 16.2.6.1.1 and 16.2.6.6.1
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Statistical Analysis Plan 
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Protocol Number CAD1883-201 
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 Page 147 of 151 
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Statistical Analysis Plan 
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Protocol Number CAD1883-201 
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Figure 14.5 
Geometric Mean (GM) Composite Measure (CM) of Kidney Injury Biomarkers by Study Visit 
Safety Population 
Programming note: Remove “GM CM of CAD1883-201 subjects as of Fri, 5/17/2019” from the graph. The threshold values need to be updated per the user guide (Threshold=1.18 with 
n=20).


Statistical Analysis Plan 
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Protocol Number CAD1883-201 
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Appendix 1: List of Abbreviations 
Abbreviation 
Definition 
AE 
adverse event 
ATC 
anatomical therapeutic chemical 
BLQ 
beneath limit of quantification 
CI 
confidence intervals 
CM 
Composite Measure 
CRF 
case report form 
CRO 
contract research organization 
CS 
clinically significant 
CSR 
clinical study report 
DBP 
diastolic blood pressure 
DEA 
drug enforcement administration 
DIA 
drug information association 
DOB 
date of birth 
DSMB 
data safety monitoring board 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
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Protocol Number CAD1883-201 
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Abbreviation 
Definition 
GM 
Geometric Mean 
EMA 
European Medicines Agency 
ET 
Essential Tremor 
FDA 
Food and Drug Administration 
GCP 
good clinical practice 
HEENT 
Head, Ears, Eyes, Nose, Throat 
HR 
heart rate 
IB 
investigator’s brochure 
IC or ICF 
informed consent or informed consent form 
ICH 
International Council for Harmonization 
ID 
identification 
IEC 
independent ethics committee 
IND 
investigational new drug 
IP 
investigational product 
ITT 
intent-to-treat 
MDS 
Movement Disorder Society 
MedDRA 
medical dictionary for regulatory activities 
N 
number 
NA 
not applicable 
NCS 
non-clinically significant 
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Abbreviation 
Definition 
PD 
protocol deviation 
PE 
physical examination 
PS 
Performance subscale 
QOL 
quality of life 
RR 
respiratory rate or relative rate 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS®  
a software system used for data analysis 
SBP 
systolic blood pressure 
SD 
standard deviation 
SOC 
system organ class 
SOP 
standard operating procedure 
TEAE 
treatment-emergent adverse event 
TETRAS 
Tremor Research Group Essential Tremor Rating Assessment Scale 
UTC 
universal coordinated time 
WHO 
World Health Organization 
WHO-DD 
World Health Organization drug dictionary 
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