Conditions: Dementia With Lewy Bodies
Keywords: Dementia with Lewy bodies Lewy bodies intepirdine RVT-101 dementia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 484
Healthy volunteers: no

Brief summary:
This study seeks to evaluate the efficacy and safety of intepirdine (RVT-101) in patients with dementia with Lewy bodies.

Detailed description:
The efficacy and safety of RVT-101 at doses of 70 mg and 35 mg daily will be evaluated over a 24-week double-blind treatment period in patients with dementia with Lewy bodies.

The randomization ratio will be 1:1:1 (70 mg RVT-101: 35 mg RVT-101: placebo).

Subjects completing this study will be eligible to enroll in an extension study of RVT-101 (Study RVT-101-2002).

Arms:
arm 1: RVT-101 35 mg once daily arm 2: RVT-101 70 mg once daily arm 3: Placebo

Interventions: intervention 1: RVT-101 35 mg intervention 2: RVT-101 70 mg intervention 3: Placebo
Intervention descriptions: intervention 1: once daily, oral, 35-mg tablets intervention 2: once daily, oral, 35-mg tablets intervention 3: once daily, oral, matching tablets

Protocol document:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL
Title:
A Phase 2b, double-blind, randomized, placebo-controlled study of 
RVT-101 in subjects with dementia with Lewy bodies (DLB) 
Sponsor
Axovant Sciences Ltd.
Compound Name:
RVT-101
Protocol Number
RVT-101-2001
Indication
Dementia with Lewy bodies (DLB)
Development Phase
2b
IND #
127,379
Version/
Effective Date:
4.0
15 November 2017
Axovant Sciences 
Study Director
Ilise Lombardo, MD
Telephone:  646-495-8197
Email:  ilise.lombardo@axovant.com
Medical Monitor
Name: Julie Adams, MD, MPH
Telephone:  1-800-201-8725
Email:  wilsafety@ppdi.com
Confidentiality Statement
The information contained in this document, particularly unpublished data, is the property or 
under control of Axovant Sciences Ltd., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Institutional 
Review Board or Independent Ethics Committee. The information is only to be used by you in 
connection with authorized clinical studies of the investigational product described in the 
protocol. You will not disclose any of the information to others without written authorization 
from Axovant Sciences Ltd., except to the extent necessary to obtain informed consent from 
those persons to whom the investigational product may be administered.


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RVT-101-2001 v4.0
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SPONSOR SIGNATURE PAGE
Study title:
A Phase 2b, double-blind, randomized, placebo-controlled study of RVT-
101 in subjects with dementia with Lewy bodies (DLB)
Protocol Number:
RVT-101-2001
Version:
4.0
Date:
15 November 2017
This protocol has been approved by Axovant Sciences, Inc., and approved by Axovant Sciences 
Ltd. The following signatures document this approval.
Marianne L. Romeo
Authorized Signatory
Axovant Sciences Ltd.
Date
Ilise Lombardo, MD
Senior Vice President, Clinical Research
Axovant Sciences, Inc.
Date
Shari Coslett
Vice President, Clinical Operations
Axovant Sciences, Inc.
Date
Divakar Sharma
Vice President, Biometrics
Date
Eric Floyd,  MS, MBA, PhD
Senior Vice President, Regulatory Affairs 
Axovant Sciences, Inc.
Date


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MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/Serious Adverse Event Contact Information:
Role and 
Region
Name
Daytime Phone 
Number and Email 
Address
After-Hours 
Phone/Cell/
Pager Number
Fax Number
Primary Medical Monitor
Americas 
Julie Adams, 
MD, MPH
1-800-201-8725
wilsafety@ppdi.com
1-800-201-8725
1-888-488-9667
Secondary Medical Monitors
Europe
Yoanna 
Dokova-
Aleksandrova,
MD
+44 1223 374 240
wilsafety@ppdi.com
+44 1223 374 240
+44 1223 374 102
SAE 
Contact 
Information
North America
Phone: 800-201-8725
Fax: 888-488-9697
Europe
Phone: +44 1223374 240 
Fax: +44 1223 374 102
Study Sponsor
This study is sponsored by Axovant Sciences Ltd.
Axovant Sciences Ltd. Registered Address:
Clarendon House
2 Church Street
Hamilton HM11
Bermuda
US Agent and Regulatory Contact:
Axovant Sciences Inc.
320 West 37th Street, 5th Floor
New York, NY  10018
USA


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RVT-101-2001 v4.0
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INVESTIGATOR STATEMENT
I agree to conduct the study in compliance with this protocol (RVT-101-2001, version 4.0,
dated 15 November 2017).
I acknowledge that I am responsible for overall study conduct. I agree to personally conduct 
or supervise the described study.
I agree to ensure that all associates, colleagues, and employees assisting in the conduct of 
the study are informed about and fulfil their obligations. Mechanisms are in place to ensure 
that site staff receives the appropriate information throughout the study.
______________________________________
__________________________________
Principal Investigator Name (Printed)
Signature
______________________________________
__________________________________
Date
Site


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TABLE OF CONTENTS
PAGE
CLINICAL STUDY PROTOCOL......................................................................................1 
SPONSOR SIGNATURE PAGE .....................................................................................2 
MEDICAL MONITOR/SPONSOR INFORMATION PAGE ...............................................3 
TABLE OF CONTENTS..................................................................................................5 
LIST OF TABLES............................................................................................................8 
LIST OF FIGURES .........................................................................................................9 
1. 
ABBREVIATIONS ..................................................................................................10 
2. 
PROTOCOL SUMMARY........................................................................................13 
3. 
INTRODUCTION ...................................................................................................19 
3.1. 
Background ................................................................................................19 
3.1.1. 
Dementia with Lewy Bodies.........................................................19 
3.1.2. 
RVT-101......................................................................................20 
3.2. 
Study Rationale ..........................................................................................21 
3.3. 
Dose Rationale...........................................................................................22 
4. 
OBJECTIVES AND ENDPOINTS........................................................................... 24 
5. 
STUDY DESIGN....................................................................................................26 
5.1. 
Overall Design............................................................................................26 
5.2. 
Study Schematic.........................................................................................27 
6. 
SUBJECT POPULATION.......................................................................................28 
6.1. 
Type and Number of Subjects ....................................................................28 
6.2. 
Inclusion Criteria.........................................................................................28
6.3. 
Exclusion Criteria........................................................................................30
6.4. 
Other Eligibility Criteria ............................................................................... 33
6.5. 
Screening Failures......................................................................................33 
6.6. 
Withdrawal Criteria .....................................................................................33 
6.6.1. 
Reasons for Withdrawal............................................................... 33 
6.6.2. 
Subject Withdrawal Procedures................................................... 34 
7. 
STUDY TREATMENT............................................................................................35 
7.1. 
Investigational Product and Other Study Treatment.................................... 35 
7.2. 
Randomization/Treatment Assignment....................................................... 36 
7.3. 
Blinding ......................................................................................................36 
7.4. 
Packaging and Labeling .............................................................................37 
7.5. 
Preparation/Handling/Storage/Accountability.............................................. 37 
7.6. 
Compliance with Investigational Product Administration ............................. 38 
7.7. 
Treatment of Investigational Product Overdose.......................................... 39 
7.8. 
Treatment after the End of the Study.......................................................... 39 
7.9. 
Concomitant Medications and Non-Drug Therapies.................................... 40 
7.9.1. 
Permitted Medications and Non-Drug Therapies ......................... 40 
7.9.2. 
Prohibited Medications and Non-Drug Therapies......................... 40 
7.10. 
Lifestyle and/or Dietary Restrictions............................................................ 41 
8. 
STUDY ASSESSMENTS AND PROCEDURES..................................................... 42 


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8.1.
Time and Events.........................................................................................42
8.2. 
Critical Baseline Assessments....................................................................49 
8.3. 
Study Assessments and Procedures ..........................................................49 
8.3.1. 
Efficacy Assessments..................................................................49 
8.3.1.1. 
Mini-Mental State Evaluation (MMSE)........................ 49 
8.3.1.2. 
Unified Parkinson’s Disease Rating Scale – Part III 
(UPDRS-III)................................................................50 
8.3.1.3. 
Alzheimer’s Disease Assessment Scale – Cognitive 
Subscale (ADAS-Cog)................................................ 50 
8.3.1.4. 
Clinician’s Interview-Based Impression of Severity 
(CIBIS) and Clinician’s Interview-Based Impression of 
Change Plus Caregiver Interview (CIBIC+) ................ 50 
8.3.1.5. 
Cognitive Drug Research (CDR) Computerized 
Assessment System...................................................51 
8.3.1.6. 
Controlled Oral Word Association Test (COWAT) ...... 54 
8.3.1.7. 
Alzheimer’s Disease Cooperative Study - Activities of 
Daily Living (ADCS-ADL) ........................................... 54 
8.3.1.8. 
Clinician Assessment of Fluctuation (CAF)................. 54 
8.3.1.9. 
North East Visual Hallucinations Inventory (NEVHI)... 55 
8.3.1.10. Neuropsychiatric Inventory......................................... 55 
8.3.1.11. EuroQol Five Dimensions Questionnaire, Five Level 
Version (EQ-5D-5L).................................................... 55 
8.3.1.12. Dependence Scale (DS)............................................. 55 
8.3.1.13. Modified Circadian Sleep Inventory – (CSI)................ 56 
8.3.2. 
Safety and Screening Assessments ............................................ 56 
8.3.2.1. 
Adverse Events.......................................................... 56 
8.3.2.2. 
Safety Monitoring Committee (SMC) .......................... 61 
8.3.2.3. 
Physical and Neurological Examinations.................... 62 
8.3.2.4. 
Vital Signs..................................................................62 
8.3.2.5. 
Electrocardiogram (ECG) ........................................... 62 
8.3.2.6. 
Clinical Safety Laboratory Assessments..................... 63 
8.3.2.7. 
Assessment of Suicidality........................................... 64 
8.3.2.8. 
Questionnaire for Symptoms Potentially Associated 
with Orthostasis.......................................................... 65 
8.3.2.9. 
Pregnancy..................................................................65 
8.3.2.10. Lewy Body Composite Risk Score (LBCRS) .............. 66 
8.3.2.11. CT scan or MRI.......................................................... 66 
8.3.2.12. PET or SPECT...........................................................66 
8.3.3. 
Pharmacokinetics ........................................................................ 66 
9. 
DATA MANAGEMENT...........................................................................................68 
10. STATISTICAL CONSIDERATIONS AND DATA ANALYSES ................................. 69 
10.1. 
Hypotheses ................................................................................................69 
10.2. 
Sample Size Considerations....................................................................... 69 
10.3. 
Data Analysis Considerations..................................................................... 70 
10.3.1. 
Analysis Populations ................................................................... 70 


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10.3.2.
Interim Analysis ........................................................................... 71
10.4. 
Key Elements of Analysis Plan ...................................................................71 
10.4.1. 
Primary Efficacy Analyses ........................................................... 71 
10.4.2. 
Secondary Efficacy Analyses....................................................... 72 
10.4.3. 
Tertiary Efficacy Analyses ........................................................... 72 
10.4.4. 
Exploratory Efficacy Measures ....................................................73 
10.4.5. 
Safety Analyses...........................................................................74 
10.4.5.1. Adverse Events.......................................................... 74 
10.4.5.2. Clinical Laboratory Tests............................................ 74 
10.4.5.3. Vital Signs, Electrocardiograms, Physical Findings, 
and Other Safety Evaluations..................................... 74 
10.4.5.4. Suicidality...................................................................75 
10.4.5.5. Questionnaire for Signs of Potential Orthostasis ........ 75 
10.4.6. 
Other Analyses............................................................................75 
10.4.7. 
PK Analyses................................................................................ 75 
10.4.8. 
PK / PD .......................................................................................75 
11. RESPONSIBILITIES ..............................................................................................76 
11.1. 
Investigator Responsibilities ....................................................................... 76 
11.1.1. 
Good Clinical Practice ................................................................. 76 
11.1.2. 
Institutional Review Board/Independent Ethics Committee 
Approval ......................................................................................76 
11.1.3. 
Informed Consent........................................................................ 77 
11.1.4. 
Confidentiality.............................................................................. 77 
11.1.5. 
Study Files and Retention of Records.......................................... 77 
11.1.6. 
Electronic Case Report Forms.....................................................79 
11.1.7. 
Drug Accountability......................................................................79 
11.1.8. 
Inspections ..................................................................................79 
11.1.9. 
Protocol Compliance ...................................................................79 
11.2. 
Sponsor Responsibilities ............................................................................ 79 
11.2.1. 
Protocol Modifications ................................................................. 79 
11.2.2. 
Study Report and Publications..................................................... 80 
11.2.3. 
Posting of Information on Publicly Available Clinical Trial 
Registers .....................................................................................80 
11.3. 
Joint Investigator/Sponsor Responsibilities................................................. 80 
11.3.1. 
Access to Information for Monitoring............................................ 80 
11.3.2. 
Access to Information for Auditing or Inspections ........................ 81 
11.3.3. 
Study Discontinuation..................................................................81 
12. REFERENCES ......................................................................................................82 


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LIST OF TABLES
PAGE
Table 1 
Prohibited Concomitant Medications...................................................... 41 
Table 2 
Time and Events Schedule .................................................................... 46 
Table 3 
CDR Computerized Assessment System Variables ............................... 52 
Table 4 
Calculation of CDR Computerized Assessment System Domain Scores53 
Table 5. 
Protocol-Required Screening and Safety Laboratory Assessments ....... 64 


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LIST OF FIGURES
PAGE
Figure 1 
Study schematic ....................................................................................27 


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1.
ABBREVIATIONS
Abbreviation
Definition
5HT6
5-hydroxytryptamine sub-type 6
ACh
Acetylcholine
AChE
Acetylcholinesterase
AChEI
acetylcholinesterase inhibitor
AD
Alzheimer’s disease
ADAS-Cog
Alzheimer’s Disease Assessment Scale – Cognitive Subscale
ADAS-Cog-13
Alzheimer’s Disease Assessment Scale – Cognitive Subscale-
13 items
ADCS-ADL
Alzheimer’s Disease Cooperative Study – Activities of Daily 
Living
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
AUC
area under the concentration-time curve at steady state
BP
blood pressure
BUN
blood urea nitrogen
C
Celsius
CAF
Clinician Assessment of Fluctuation
CDR
Cognitive Drug Research
CDR System
Cognitive Drug Research computerized assessment system
CFR
Code of Federal Regulations
CIBIC+
Clinician’s Interview-Based Impression of Change – plus 
caregiver interview
CIBIS
Clinician’s Interview-Based Impression of Severity
Cmax
peak concentration
Cmax-ss
peak concentration at steady state
Cmin
minimum (trough) concentration
Cmin-ss
minimum (trough) concentration at steady state
CMH
Cochran Mantel Haenszel
CNS
central nervous system
COWAT
Controlled Word Association Test
CSI
Circadian Sleep Inventory
C-SSRS
Columbia Suicide Severity Rating Scale
CT
computed tomography
DLB
dementia with Lewy bodies
DS
Dependence Scale
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition
ECG
electrocardiogram
eCRF
electronic case report form


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Abbreviation
Definition
EQ-5D-5L
EuroQOL five dimensions questionnaire, five level version
ET
early termination
FDA
Food and Drug Administration
FSH
follicle stimulating hormone
GGT
gamma glutamyltransferase
HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
HR
heart rate
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IP
investigational product
IRB
Institutional Review Board
ITT
intent-to-treat
IVRS
interactive voice response system
IWRS
Interactive web response system
kg
kilogram
LAR
legally authorized representative
LBCRS
Lewy Body Composite Risk Score
LOCF
last observation carried forward
MCH
mean corpuscular hemoglobin
MCV
mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
mg
milligram
mmHg
millimeters of mercury
MMRM
mixed model for repeated measures
MMSE
Mini Mental State Examination
MRI
magnetic resonance imaging
NEVHI
North East Visual Hallucinations Inventory
NCDLB
Neurocognitive Disorder with Lewy bodies
NMDA
N-methyl-D-aspartate
NPI
Neuropsychiatric Inventory
PET
Positron emission tomography
PK
pharmacokinetic(s)
PoA
Power of Attention
PP
per protocol
PSA-NCAM
polysialylated form of the neural cell adhesion molecule
qd
once a day
QRS
QRS complex
QT
QT interval
QTc
corrected QT (interval)
PET
positron emission tomography


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Abbreviation
Definition
RBANS
Repeatable Battery for the Assessment of Neuropsychological 
Status
RBC
red blood cell
RBD
REM behavior disorder
REM
rapid eye movement
RUD Lite
Resource Utilization in Dementia Lite
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
standard deviation
SMC
Safety Monitoring Committee
SOC
System Organ Class
SPECT
Single-photon emission computerized tomography
TEAE
treatment-emergent adverse event
TSH
thyroid stimulating hormone
ULN
upper limit of normal
UPDRS-III
Unified Parkinson’s Disease Rating Scale – Part III
WBC
white blood cell


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2.
PROTOCOL SUMMARY
Study Title
A Phase 2b, double-blind, randomized, placebo-controlled study of 
RVT-101 in subjects with dementia with Lewy bodies (DLB)
Objectives
Efficacy
Primary
To assess the effects of RVT-101 versus placebo on the Unified 
Parkinson’s Disease Rating Scale – Part III (UPDRS-III) after 24
weeks of treatment
Secondary
To assess the effects of RVT-101 versus placebo on cognition, as
measured by the ADAS-Cog 11 after 24 weeks of treatment
To assess the effects of RVT-101 versus placebo on global 
function as measured by the CIBIC+ after 24 weeks of treatment
Tertiary
To assess the effects of RVT-101 versus placebo on activities of 
daily living as measured by the Alzheimer’s Disease Cooperative 
Study – Activities of Daily Living (ADCS-ADL) scale after 24 
weeks of treatment
To assess the effects of RVT-101 versus placebo on the Basic and 
Instrumental subscores of the ADCS-ADL scale after 24 weeks of 
treatment
To assess the effects of RVT-101 versus placebo on the Unified 
Parkinson’s Disease Rating Scale – Part III, 5-item subscale 
(UPDRS-5) after 24 weeks of treatment
To assess the effects of RVT-101 versus placebo on cognition as 
measured by the composite z-score of the 7-domains of the CDR 
computerized assessment system after 24 weeks of treatment 
(CDR System domains include Power of Attention, Continuity of 
Attention, Quality of Working Memory, Quality of Episodic 
Memory, Speed of Memory, Cognitive Reaction Time and 
Reaction Time Variability)
To assess the effects of RVT-101 versus placebo on executive 
function as assessed by the Controlled Oral Word Association
Test (COWAT) after 24 weeks of treatment
To assess the effects of RVT-101 versus placebo on cognitive 
function as measured by a composite z-score combining the 7 
domains for the CDR System and the COWAT after 24 weeks of 
treatment
To assess the effects of RVT-101 versus placebo on 
hallucinations and delusions as measured by a 2-item subscore on 
the Neuropsychiatric Inventory (NPI), which is the sum of the 
scores for the hallucinations and delusions domains (Parts A and 


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B), after 24 weeks of treatment
To assess the effects of RVT-101 versus placebo on visual 
hallucinations as measured by the total severity score and distress 
score of the North-East Visual Hallucinations Interview (NEVHI)
after 24 weeks of treatment
To assess the effects of RVT-101 versus placebo on fluctuations 
in cognition using the Clinician Assessment of Fluctuation (CAF) 
after 24 weeks of treatment
To assess the effects of RVT-101 versus placebo on subject 
dependence with the dependence scale (DS) after 24 weeks of 
treatment
Exploratory
To assess the effects of RVT-101 versus placebo on quality of life 
as measured by the EuroQual-5D-5L (EQ-5D-5L) after 24 weeks 
of treatment
To assess the effects of RVT-101 versus placebo on sleep-related  
behaviors as measured by the modified Circadian Sleep Inventory 
(CSI)
To assess the effects of RVT-101 versus placebo on each domain 
of the CDR computerized assessment system after 24 weeks of 
treatment
To assess the effects of RVT-101 versus placebo on depression 
and anxiety as measured by a 2-item subscore on the NPI, which 
is the sum of the scores for the depression/dysphoria and anxiety
domains (Parts D & E) after 24 weeks of treatment
To estimate the pharmacokinetic (PK) parameters of RVT-101
and explore relationships to efficacy or safety endpoints, as 
appropriate
Safety
To assess the effects of Intepirdine versus placebo on safety and 
tolerability of RVT-101 via:
Adverse Events
Clinical laboratories
Vital signs
Physical examinations
ECG parameters
Questionnaire for the occurrence of symptoms potentially 
associated with orthostasis
Suicidality
Study Phase
Phase 2b


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Target Population
Adult subjects aged 50 to 85, inclusive, with a diagnosis of probable 
dementia with Lewy bodies (DLB), in accordance with Consensus 
criteria (McKeith, 2005).
Subjects included in the study may or may not be receiving other 
treatments (such as cholinesterase inhibitors and/or memantine) for 
DLB. If subjects are taking other treatments for dementia and/or 
hallucinations associated with DLB, the treatment regimen must have 
been at a stable dose for at least 30 days, and be expected to remain 
stable during the study.
Number of Subjects 
Planned
Approximately 240 randomized subjects
RVT-101 70 mg: 80 subjects
RVT-101 35 mg: 80 subjects
Placebo: 80 subjects
Number of Study 
Centers Planned
Approximately 40-50
Study Design
This is a multi-center, double-blind, randomized, placebo-controlled, 
parallel-group study in patients with probable DLB. The efficacy and 
safety of RVT-101 at doses of 70 mg and 35 mg daily will be 
evaluated over a 24-week treatment period in subjects with probable 
DLB with or without existing background DLB therapy. All subjects 
who are on stable doses of other background therapies for dementia 
and/or hallucinations associated with DLB will continue those 
regimens unchanged for the duration of the study. Subjects who are 
not on background DLB therapies at the time of screening will also be 
eligible for participation.  All subjects will refrain from starting 
additional DLB treatments during the course of the study.  The 
randomization ratio will be 1:1:1 (70 mg RVT-101: 35 mg RVT-101: 
placebo).
Randomization will be stratified according to Baseline MMSE score 
in the groupings of 14-17 points, 18-21 points and 22-26 points and 
according to whether subjects are or are not taking a cholinesterase 
inhibitor as a concomitant medication.
During double-blind treatment, there will be weekly clinical 
assessments for the first two weeks of treatment, bi-weekly 
assessments until Week 12 and every six weeks thereafter.  For 
certain visits, subjects may have the option of whether to have 
assessments performed at the clinical study site or by a trained, 
visiting nurse in their own home.
An independent Safety Monitoring Committee (SMC) will review 
interim safety data accumulated after approximately 30 subjects have 


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completed 4 weeks of double-blind treatment and throughout the 
study at points specified in the SMC Charter. The SMC will provide 
their recommendation regarding the acceptability of reducing the visit 
frequency by skipping certain visits for both newly enrolled subjects 
and subjects active in the study at the time of the SMC 
recommendation. Study enrollment will not be stopped or slowed to 
wait for the SMC recommendation and will proceed as planned with 
all visits until the SMC recommendation is made.
Duration of Treatment
Study participation will last approximately 32 weeks: 0 to 28 days for 
Screening, a 2-week Single-Blind Run-In Period to evaluate baseline 
status, a 24-week randomized Treatment Period and a 2-week Safety 
Follow-up Period for subjects who do not enter the extension study.
Criteria for Evaluation
Primary efficacy endpoint: The primary efficacy endpoint will be an 
assessment of motor function at Week 24. Change from Baseline to 
Week 24 in motor function will be measured by the UPDRS-III.
Secondary efficacy endpoints: Cognition will be measured by the 
ADAS-Cog 11 and global function by the CIBIC+ as the secondary 
endpoints.
Safety evaluation: Safety will be evaluated based on adverse events 
(AEs), physical examinations, vital signs (including measurements of 
orthostatic changes in blood pressure [BP] and heart rate [HR]), a 
questionnaire evaluating the occurrence of symptoms potentially 
associated with orthostasis, electrocardiograms (ECGs), the 
Columbia-Suicide Severity Rating Scale (C-SSRS) and routine 
clinical laboratory assessments.
Statistical Methods
The primary statistical framework will be to test the superiority of 
Intepirdine over placebo.  The null hypothesis is as follows, with a 
be rejected.
There is NO statistically significant difference between 
Intepirdine and placebo in the mean change from baseline 
to Week 24 in the UPDRS- III.
There IS a statistically significant difference between 
Intepirdine and placebo in in the mean change from 
baseline to Week 24 in the UPDRS- III.
The individual Intepirdine arms will be tested, as follows:
Intepirdine 70 mg vs placebo
Intepirdine 35 mg vs placebo
All hypothesis tests will be 2-sided, performed at the 5% level of 
significance.  The primary endpoint needs to achieve a significance 
level of 0.05 within an Intepirdine dose to allow for testing of the 


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secondary endpoint, in order to maintain an overall 5% significance 
level within that dose.
Sample Size: 
The sample size is based on assumptions of treatment benefit for one 
primary endpoint, the UPDRS- III total score.  A sample size of 70 
subjects per treatment group will allow a treatment difference of 4 
points between placebo and active treatment in the change from 
baseline in UPDRS- III score to be detected with 88% power and a 
0.05 significance level assuming an underlying standard deviation 
(SD) of 7.5  
There are two secondary endpoints:
ADAS-Cog 11 total score.  A sample size of 80 subjects 
per treatment group will allow a treatment difference of 3 
points between placebo and active treatment in the 
change from baseline in ADAS-Cog-11 score to be 
detected with 88% power and a 0.05 significance level 
assuming an underlying standard deviation (SD) of 6.  
Under the assumptions of a 2.5, 2.0 and 1.5 point 
treatment effect, the power is 74%, 55% and 35%, 
respectively.
CIBIC+.  A sample size of 80 subjects per treatment 
group will allow a treatment difference of 0.5 points 
between placebo and active treatment in the observed 
values in the CIBIC+ to be detected with 91% power and 
a 0.05 significance level assuming an underlying standard 
deviation (SD) of 0.95.  Under the assumptions of a 0.4 
and 0.3 point treatment effect, the power is 75% and 
51%, respectively.
Randomization will be stratified according to Baseline MMSE score 
in the groupings of 14-17 points, 18-21 points and 22-26 points and 
according to whether subjects are or are not taking a cholinesterase 
inhibitor as a concomitant medication.
Efficacy:
The primary efficacy endpoint is the change from Baseline in the 
UPDRS-III total score at Week 24.  Primary treatment comparisons 
between Intepirdine and placebo will be performed on the change 
from Baseline to Week 24 using an MMRM with restricted maximum 
likelihood estimation, an unstructured covariance matrix, and the 
Kenward-Roger approximation for denominator degrees of freedom.  
The model will include terms for treatment, visit, treatment by visit 
interaction, pooled geographic region, baseline MMSE score, and use 
of cholinesterase inhibitor at baseline (Yes/No) as covariates. 


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The secondary efficacy endpoints are the change from baseline in the 
ADAS-Cog 11 score at Week 24 and the CIBIC+ total score at Week 
24. The ADAS-Cog 11 will be analyzed using similar MMRM 
methods as the primary endpoint.  Between-treatment comparisons on 
CIBIC+ based on the week 24 observed data and Week 24 LOCF data 
using Cochran-Mantel-Haenszel (CMH) test will be performed.  The 
number and percentage of subjects in each category of CIBIC+ will 
also be summarized by visit for each treatment group.   
Similar analyses will be performed for the tertiary and exploratory 
endpoints. Treatment comparisons between the RVT-101 and placebo 
groups for the categorical endpoints will be analyzed using the CMH 
test.
Safety:
Safety will be assessed by summarizing and analyzing AEs, 
laboratory analytes, vital signs, physical examination, ECG 
parameters, questionnaire for the occurrence of symptoms potentially 
associated with orthostasis, and C-SSRS.


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3.
INTRODUCTION
3.1.
Background
3.1.1.
Dementia with Lewy Bodies
Dementia with Lewy bodies (DLB), also termed major neurocognitive disorder with Lewy 
bodies (NCDLB) (The Diagnostic and Statistical Manual of Mental Disorders, 5th ed.; [DSM-5]),
is a progressive neurocognitive illness characterized pathologically by the presence of diffuse 
clusters comprised of alpha synuclein and other proteins that aggregate in the brain and disrupt 
cognitive function (McKeith et al., 1996; McKeith et al., 2005; American Psychiatric 
Association [APA], 2013). These pathologic protein clusters were first identified by Friederich 
H. Lewy in the early 1900’s, though DLB has only recently been more fully recognized
(McKeith, 2004). DLB is considered to be the second most prevalent cause of degenerative 
dementia in the elderly population (McKeith, 2004), accounting for up to 15 – 25% of dementia 
presentations (McKeith et al., 2000) and 15 – 20% of all autopsy confirmed dementias in old age
(Mosimann & McKeith, 2003). While few studies of the exact prevalence of DLB have been 
published, the Lewy Body Dementia Association estimates that 1.4 million individuals are 
affected by Lewy body dementia in the US alone.
The clinical course of DLB tends to be more rapid in its decline than Alzheimer’s disease, with a 
mean disease duration of five to six years in DLB (Mosimann & McKeith, 2003) as compared to 
approximately 8.5 years in Alzheimer’s disease (Jost & Grossberg, 1995). Unlike Alzheimer’s 
disease, which is fundamentally an amnestic disorder characterized by memory loss, patients 
with DLB have relatively preserved memory function (Shimomura et al., 1998). Rather, deficits 
and fluctuations in attention and alertness are the most characteristic manifestations of cognitive 
dysfunction in DLB and are core components of the diagnostic criteria. In addition, patients with 
DLB commonly suffer from two key behavioral disturbances: recurrent complex visual 
hallucinations and REM Sleep Behavior Disorder (RBD). Other core features and suggestive 
diagnostic features include Parkinsonism and severe sensitivity to neuroleptic drugs. 
The Consensus criteria for a diagnosis of probable DLB (McKeith et al., 2005) were adopted in 
slightly modified form in the DSM-5 in 2013, in which DLB is referred to as NCDLB (APA, 
2013).  The diagnostic criteria for DLB have a sensitivity of 83% and a specificity of 95% for the 
presence of neocortical Lewy bodies at autopsy (McKeith et al., 2000).
Cholinergic deficits are a prominent feature of the pathophysiology underlying deficits in 
attention and cognition in DLB, and cholinergic neurotransmission is considered to be more 
defective in DLB compared to Alzheimer’s disease (Mori et al., 2012). For this reason, it is not 
surprising that drugs that increase the concentration of acetylcholine in the brain have been 
shown to confer a benefit over placebo on cognition, including specifically attention, in patients 
with DLB. Specifically, cholinesterase inhibitors have demonstrated robust superiority to 
placebo treatment across multiple randomized double-blind placebo-controlled clinical trials, 
including in studies of donepezil (Mori et al., 2012; Ikeda et al., 2015) and rivastigmine
(McKeith et al., 2000; Wesnes et al., 2002). Some publications have reported that cholinesterase 
inhibitors confer more benefit in patients with DLB than in Alzheimer’s disease patients (Neef & 
Walling, 2006). While cholinesterase inhibitors are widely used in the management of patients 
with DLB, none have been approved by the FDA for the treatment of DLB. One exception to the 
lack of approved DLB treatments worldwide is donepezil, which was approved in Japan as a 


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treatment for DLB. Given its severity and widespread prevalence, DLB represents a significant 
unmet medical need.
3.1.2.
RVT-101
RVT-101, previously known as SB742457, is a potent antagonist of the 5-HT6 receptor that 
promotes the release of acetylcholine in the brain. Given the benefits reported for the 
cholinesterase inhibitors as DLB treatments, it is logical to hypothesize that RVT-101, which 
also increases synaptic acetylcholine concentrations, may also confer some benefit as a treatment 
for DLB. RVT-101 also has antagonist activity against the 5-HT2a receptor, which may be a 
useful target for the treatment of motor symptoms.
RVT-101 has been administered in 18 Phase 1 studies, as monotherapy in 3 Phase 2 studies in 
subjects with mild to moderate Alzheimer’s Disease (AD) (Study AZ3100603, Study Z3106242,
and Study AZ3110865) and as an adjunct to stable donepezil treatment in subjects with mild to 
moderate Alzheimer’s Disease (AD) in one Phase 2 study (Study AZ3110866) and one Phase 3 
study (Study RVT-101-3001).
Study AZ3100603 demonstrated dose-related effects of RVT-101 on cognition (ADAS-Cog) 
with a 1.28-point treatment difference from placebo (p=0.135) at a dose of 35 mg and a 
statistically significant benefit on global function (CIBIC+; p=0.047). In Study AZ3110865,
neither dose of RVT-101 demonstrated statistically significant efficacy over placebo on either of 
the co-primary endpoints.  Donepezil also failed to demonstrate statistically significant efficacy 
over placebo for ADAS-Cog in Study AZ3110865; however, a treatment effect was observed on
CIBIC+ (p=0.049) for donepezil. This study also failed to show a decline in the placebo arm. In
Study AZ3106242, which was not powered for formal statistical comparison of RVT-101 and 
donepezil, neither RVT-101 nor donepezil showed a statistically significant difference from 
placebo on the ADAS-Cog and CIBIC+. In Study AZ3110866, a statistically significant 
difference of 1.5 points in ADAS-Cog was observed for the 35-mg RVT-101 group versus the 
placebo group at Week 24 (p=0.012). The ADCS-ADL also showed a statistically significant 
effect for 35 mg RVT-101 compared to placebo at Week 24 (2.0, p=0.024). A numeric 
advantage, but not statistical significance was seen for 35 mg RVT-101 on the Clinical Dementia 
Rating – Sum of Boxes (CDR-SB) compared to placebo at Week 24.
Study RVT-101-3001 was a 24-week, Phase 3 study that randomized 1315 subjects in a 1:1 ratio 
to receive placebo or 35 mg RVT-101 as an adjunct to stable donepezil treatment. The study 
utilized co-primary cognitive and functional endpoints at Week 24 (ADAS-Cog and ADCS-
ADL) and a key secondary endpoint of global functioning at Week 24 (CIBIC+). When 
compared to placebo, a numerically superior difference of 0.36 points in ADAS-Cog was 
observed for the 35-mg RVT-101 group at Week 24, although it is not statistically significant 
(p= 0.2249). The functional endpoint of ADCS-ADL at Week 24 did not show much treatment 
difference (-0.09, p=0.8260). For the key secondary endpoint of CIBIC+ at Week 24, statistically 
significant benefit versus placebo was demonstrated at Week 24 (-0.12, p=0.0234). The 
treatment difference between 35 mg RVT-101 and placebo in CIBIC+ at Week 24 was largely 
consistent among subgroups of MMSE, age, sex, geographic region, and donepezil dose. In 


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addition, completer analysis, per protocol analysis and various sensitivity analyses using various 
statistical methods also showed statistical significance for CIBIC+ at Week 24.
RVT-101 is also being investigated in an ongoing, Phase 3, open-label, long-term extension to 
Study RVT-101-3001 (Study RVT-101-3002) and an ongoing, Phase 2b, long-term extension to 
this study RVT-101-2001 (Study RVT-101-2002). In addition, Axovant has assessed the 
tolerability and pharmacokinetics of multiple oral doses of 70 mg RVT-101 in a Phase 1 study 
(Study RVT-101-1001) and found the dose to be well-tolerated in elderly healthy subjects.
Details of all of the preclinical and clinical investigations with RVT-101 are contained in the 
current version of the RVT-101 Investigator’s Brochure.
3.2.
Study Rationale
This Phase 2b study seeks to demonstrate an effect of RVT-101 on motor function, cognition and 
global function in subjects with DLB. This study will also provide further information on the
safety and tolerability of 35 mg and 70 mg RVT-101 in subjects with DLB. 
Justification for testing RVT-101 as a treatment of DLB is warranted by the following: (1) 
animal studies that show administration of RVT-101 is associated with increases of acetylcholine 
concentrations in the brain; (2) marked and prominent cholinergic deficits in patients with DLB 
that are associated with deficits in attention (Mori et al., 2012); (3) evidence that cholinesterase 
inhibitors, which work by increasing the concentrations of acetylcholine in the brain, are 
effective in the treatment of patients with DLB (McKeith et al., 2000) (Wesnes et al., 2002; Mori
et al., 2012; Ikeda et al., 2015); (4) evidence of the efficacy of RVT-101 as an adjunct to 
donepezil in a Study AZ3110866 in mild-to-moderate Alzheimer’s disease (Maher-Edwards,
2015); (5) an acceptable safety and tolerability profile of RVT-101 based on preclinical and 
clinical studies to date.
In addition to its 5-HT6 receptor antagonism, RVT-101 also has antagonist activities against the 
5-HT2a receptor. In Study AZ3103943, PET analysis showed that intepirdine demonstrated dose-
dependent receptor occupancy at the frontal cortex, presumed to reflect 5-HT2a receptor binding. 
The relationship between plasma intepirdine concentration and 5-HT2a receptor occupancy at 
steady state was described by a sigmoid Emax model where the IC50 (95% CI) = 69 (55, 90) 
ng/mL. The Cmax at steady-state with a 70 mg dose is approximately 500 ng/ml based on Study 
RVT-101-1001. This concentration would result in > 80% receptor occupancy of 5-HT2a
receptors based on this relationship.
Clinical studies have suggested that 5-HT2a serotonin receptor antagonists may be useful in the 
treatment of the motor symptoms of Parkinson’s Disease. Ritanserin, a mixed 5-HT2a/c receptor 
antagonist, has been shown to reduce bradykinesia and improve gait in PD patients (Henderson 
et al., 1992), as well as ameliorate neuroleptic-induced parkinsonism (Bersani et al., 1990). This 
premise is further supported by the results of a recent interim analysis of the pre-specified 
primary endpoint of the first 11 completers of a cross-over study of nelotenserin, a 5-HT2a
receptor inverse agonist in patients with DLB. The mean change from baseline in the UPDRS 
Parts II + III exhibited statistically significant improvements (p-value < 0.05) for nelotanserin 
relative to placebo at 4 weeks (Press Release: Nelotanserin Interim Analysis).


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The primary objective of this study is to assess the effects of 35-mg and 70-mg doses of RVT-
101 compared with placebo on the primary endpoint of motor function as measured by the 
Unified Parkinson’s Disease Rating Scale – Part III (UPDRS-III). The UPDRS-III is a gold 
standard measurement for capturing pharmacologic effects on parkinsonian motor symptoms. 
The secondary objectives are to assess the effects of RVT-101 compared to placebo on cognition 
as measured by the ADAS-Cog 11 and global function as measured by the CIBIC+.
3.3.
Dose Rationale
Two doses of RVT-101 will be evaluated in the proposed Phase 2 clinical study: 35 mg and 70 
mg. The 35 mg dose of RVT-101 has been evaluated in multiple clinical studies in healthy 
volunteers and Alzheimer’s disease patients. This dose has been safe and well-tolerated in all 
clinical studies to date. 
The rationale for evaluating a 70 mg dose of RVT-101 is based on its modest antagonist activity 
against the 5-HT2a receptor which has been estimated to be 1/40th as potent as its primary activity 
against the 5-HT6 receptor. The 5-HT2a receptor has been implicated in the pathophysiology 
underlying visual hallucinations in Lewy body diseases, with preservation of 5-HT2 receptors in 
the temporal cortex differentiating hallucinating and non-hallucinating DLB cases (Cheng et al., 
1991). Given that RVT-101 has a lower affinity for the 5-HT2a receptor than the 5-HT6 receptor, 
it is reasonable to evaluate higher doses in a population that could benefit from 5-HT2a receptor 
antagonism. In addition, it is possible that greater benefit from the effect on the 5-HT6 receptor 
could also be observed since the efficacy of doses higher than 35 mg has not been previously 
assessed. 
RVT-101 has been administered in 18 completed Phase 1 studies. In these studies, a total of 398
subjects received RVT-101, with a further 64 subjects receiving either placebo alone or another
treatment. Single doses up to 175 mg have been administered to healthy adult subjects. Multiple
doses up to 70 mg daily for 10 days in healthy elderly subjects (ages 60 to 77) and up to 50 mg
daily for 13 days in younger subjects (ages 22 to 45) have been administered. Approximately 213
subjects received doses greater than 35 mg as single or repeat doses. Four Phase 2 studies in 
mild to moderate Alzheimer’s disease have been completed. These include 3 monotherapy 
studies (Studies AZ3100603, AZ3106242, and AZ3110865) and 1 adjunctive therapy study in 
subjects on background donepezil (Study AZ3110866). In addition, one Phase 3 study has been 
completed; a double-blind, placebo controlled study in subjects with mild or moderate 
Alzheimer’s disease (RVT-101-3001).  A 12-month open-label extension study to RVT-101-
3001 is ongoing (RVT-101-3002).
In completed Phase 2 clinical studies to investigate the efficacy and safety of RVT-101 as
monotherapy in subjects with mild to moderate Alzheimer's disease, 591 subjects have received 
RVT-101.  In the completed Phase 2b and Phase 3 clinical studies to investigate the efficacy and
safety of RVT-101 as adjunctive therapy to stable donepezil therapy in subjects with mild to 
moderate Alzheimer's disease, 1113 subjects received RVT-101.
The data from completed studies suggest that the compound is well tolerated and there were no
safety issues or trends identified that would preclude further studies with RVT-101.


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The Phase 1 study (RVT-101-1001) investigated the PK and safety of RVT-101 in healthy elderly 
subjects at doses of 35 mg and 70 mg once daily for 7 days (Part 1) and the food effect on 35 mg 
(Part 2).  Data from Part 1 in subjects receiving the 70 mg dose show that this dose was well-
tolerated; there were no Grade 2-4 AEs, SAEs, or withdrawals due to AEs. One minor (Grade 1) 
adverse event was reported (dry mouth) which was considered related to study drug by the 
investigator and which resolved without any interruption of treatment.  There were no clinically 
significant changes in vital signs, laboratory values, or ECGs. This supports the use of 70 mg in 
the current study in subjects with DLB.


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4.
OBJECTIVES AND ENDPOINTS
Objective
Endpoint
Primary Efficacy 
To assess the effects of RVT-101 versus 
placebo on motor function as measured by the 
Unified Parkinson’s Disease Rating Scale – Part 
III (UPDRS-III) after 24 weeks of treatment
Change from baseline in the UPDRS-III total 
score at Week 24
Secondary Efficacy
To assess the effects of RVT-101 versus 
placebo on cognition as measured by the 
ADAS-Cog 11 after 24 weeks of treatment
Change from Baseline on ADAS-Cog 11 at 
Week 24
To assess the effects of RVT-101 versus 
placebo on global function as measured by the 
CIBIC+ after 24 weeks of treatment
Total score of the CIBIC+ at Week 24
Tertiary Efficacy
To assess the effects of RVT-101 versus 
placebo on activities of daily living as measured 
by the ADCS-ADL scale after 24 weeks of 
treatment
Change from Baseline in the ADCS-ADL at 
Week 24
To assess the effects of RVT-101 versus placeo 
on the Basic and Instrumental subscores of the 
ADCS-ADL scale after 24 weeks of treatment.
Change from Baseline in the Basic and 
Instrumental subscores of the ADCS-ADL at 
Week 24
To assess the effects of Intepirdine versus 
placebo on the Unified Parkinson’s Disease 
Rating Scale – Part III, 5-item subscale 
(UPDRS-5) after 24 weeks of treatment
Change from baseline in the UPDRS-5 total 
score at Week 24
To assess the effects of RVT-101 versus 
placebo on cognition as measured by the 
composite z-score of the 7-domains of the CDR 
computerized assessment system after 24 weeks 
of treatment (CDR System domains include 
Power of Attention, Continuity of Attention, 
Quality of Working Memory, Quality of 
Episodic Memory, Speed of Memory, Cognitive 
Reaction Time and Reaction Time Variability)
Change from Baseline in the composite z-score 
combining the 7 domains of the CDR 
computerized assessment system at Week 24
To assess the effects of RVT-101 versus 
placebo on working memory as a measure of 
executive function as assessed by the COWAT 
after 24 weeks of treatment
Change from Baseline in COWAT score at 
Week 24
To assess the effects of RVT-101 versus 
placebo on cognitive function as measured by a 
composite z-score combining the 7 domains for 
the CDR computerized assessment system and 
the COWAT after 24 weeks of treatment
Change from Baseline in composite z-score 
combining the 7 CDR System domains plus the 
COWAT at Week 24


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To assess the effects of RVT-101 versus 
placebo on hallucinations and delusions as 
measured by a 2-item subscore on the NPI 
which is the sum of the scores for the 
hallucinations and delusions domains (Parts A 
and B) after 24 weeks of treatment
Change from Baseline in the sum of Parts A and 
B of the NPI at Week 24
To assess the effects of RVT-101 versus 
placebo on visual hallucinations as measured by 
the NEVHI after 24 weeks of treatment
Change from Baseline on the total severity 
score and distress score of the NEVHI score at 
Week 24 for subjects with visual hallucinations
To assess the effects of RVT-101 versus 
placebo on fluctuations in cognition using the 
CAF after 24 weeks of treatment
Change from Baseline in CAF severity score at 
Week 24 for subjects with cognitive fluctuations
To assess the effects of RVT-101 versus 
placebo on subject dependence using the DS 
after 24 weeks of treatment
Change from Baseline on DS at Week 24
Safety
To assess the safety and tolerability of RVT-101
after 24 weeks of treatment
AEs, physical examinations, vital signs 
(including orthostatic changes in BP and HR), 
ECGs, routine clinical laboratory assessments, 
questionnaire for symptoms potentially 
associated with orthostasis, and C-SSRS.
Exploratory 
To assess the effects of RVT-101 versus 
placebo on quality of life as measured by the 
EQ-5D-5L after 24 weeks of treatment
Change from Baseline on EQ-5D-5L at Week 
24
To assess the effects of RVT-101 versus 
placebo on sleep-related behaviors as measured 
by the modified CSI
Change from Baseline on CSI scores (Part I, 
Part II) at Week 24
To assess the effects of RVT-101 versus 
placebo on each domain of the CDR 
Computerized Assessment System after 24 
weeks of treatment
Change from Baseline on each domain of the 
CDR computerized assessment system at Week 
24
To assess the effects of RVT-101 versus 
placebo on depression and anxiety as measured 
by a 2-item subscore on the NPI, which is the 
sum of the scores for the depression/dysphoria 
and anxiety domains (Parts D and E) after 24 
weeks of treatment
Change from Baseline in sum of Parts D and E 
of the NPI at Week 24
To estimate the pharmacokinetic (PK) 
parameters of RVT-101 and explore 
relationships to efficacy or safety endpoints, as 
appropriate
Plasma concentrations and PK parameters 
(AUC , Cmax-ss and Cmin-ss) for each subject


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5.
STUDY DESIGN
5.1.
Overall Design
This is a multi-center, double-blind, randomized, placebo-controlled, parallel-group study in 
patients with probable DLB who are either not receiving therapy for DLB or are receiving a 
stable regimen of standard therapy for DLB. The efficacy and safety of RVT-101 at doses of 70 
mg and 35 mg daily will be evaluated over a 24-week treatment period. All subjects who are on 
stable doses of other therapies to treat cognitive deficits and/or hallucinations associated with 
DLB will continue to remain on them for the duration of the study. Approximately 240 subjects 
will be randomized. The randomization ratio will be 1:1:1 (70 mg RVT-101: 35 mg RVT-101: 
placebo). The primary endpoint will be measured after 24 weeks of treatment. Study 
participation will last approximately 32 weeks: 0 to 4 weeks for Screening, a 2-week Single-
Blind Run-In Period to evaluate baseline status, a 24-week randomized, double-blind, placebo-
controlled Treatment Period and a 2-week Safety Follow-up Period for subjects who do not enter 
the extension study RVT-101-2002.
There will be weekly clinical assessments for the first two weeks of double-blind treatment, bi-
weekly assessments thereafter until 12 weeks post-randomization and every six weeks thereafter.  
For certain visits (Visits 5, 7 and 9), subjects may have the option of whether to have 
assessments performed at the clinical study site or by a trained, visiting nurse in their own home.
An independent Safety Monitoring Committee (SMC) will review interim safety data 
accumulated after approximately 30 subjects have completed 4 weeks of double-blind treatment
and throughout the study at points specified in the SMC Charter. The SMC will provide their 
recommendation regarding the acceptability of reducing the visit frequency by omitting certain 
visits (Visits 5, 7 and 9) for both newly enrolled subjects and subjects active in the study at the 
time of the recommendation. Study enrollment will not be stopped or slowed to wait for SMC’s 
recommendation and will proceed as planned with all visits until the SMC recommendation is 
made. Site will be formally notified of the SMC’s recommendation regarding whether or not 
Visits 5, 7 and 9 can be omitted.
After completion of Visit 12, the subject may be considered for enrollment in the extension study
RVT-101-2002. If the subject does not enter the extension study, he/she will return for the Safety 
Follow-up Visit (Visit 13). Subjects who enter the extension study will not be required to 
complete Visit 13.


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5.2.
Study Schematic
The design of the study is illustrated in Figure 1.
Figure 1
Study schematic


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6.
SUBJECT POPULATION
6.1.
Type and Number of Subjects
Approximately 240 subjects with probable DLB who are either not receiving therapy for DLB or 
who are taking a stable regimen of therapy(ies) for DLB will be enrolled.
In order to manage the total study enrollment, Axovant Sciences, may suspend screening and/or 
enrollment at any site or study-wide at any time.
With the exception of the determination required in inclusion criterion #1, all study assessments 
and determinations may be delegated by the investigator to a suitably qualified designee
approved and documented for this study. Medical decisions must be made by a qualified 
physician. If the investigator is not a physician, he/she must delegate medical decisions to a 
qualified physician and consult a physician for medical issues related to eligibility. 
6.2.
Inclusion Criteria
Subjects eligible for enrollment in the study must meet all of the following criteria:
1)
Male or female subject with a clinical diagnosis of DLB established for a minimum of 2
months prior to Visit 1 and who currently meet Consensus criteria (McKeith et al., 2005) for 
probable DLB as determined by the principal investigator by virtue of having dementia,
defined as progressive cognitive decline of sufficient magnitude to interfere with normal 
social or occupational function, and either a) or b) below:
a) At least two of the following three Core features:
i)
Fluctuating cognition with pronounced variations in attention and alertness,
ii) Recurrent visual hallucinations that are typically well-formed and detailed, or
iii) Spontaneous features of parkinsonism with a date of onset no greater than one year 
before the onset of the cognitive decline.
b) One of the Core features above and at least one of the following three Suggestive
features:
i)
REM sleep behavior disorder,
ii) Severe neuroleptic sensitivity, or 
iii) Low dopamine transporter uptake in basal ganglia demonstrated by single photon 
emission computed tomography (SPECT) or positron emission tomography (PET) 
scan as determined by the investigator
2)
Subject has an MMSE score of 14 to 26, inclusive, at Screening.
Note: Subject must also have an MMSE score of less than or equal to 26 at Visit 2 and an 
MMSE score of 14 to 26, inclusive, at the Baseline visit. Subjects not meeting these MMSE 
criteria at Visit 2 and the Baseline visit will be discontinued from the study.


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In addition, the MMSE score at Baseline (Visit 3) must not have declined by 4 points or 
more from the Visit 2 MMSE score. For subjects with an MMSE score at Baseline (Visit 3)
of 4 or more points lower than their Visit 2 MMSE score or an MMSE <14 at Visit 3, the 
Run-In period may be extended for 1 to 10 days. If, after the first extension to the Run-In 
Period, the subject still does not meet the MMSE stability criterion, the Run-In period may 
again be extended for an additional 1 to 10 days. No more than 2 extensions to the Run-In 
Period will be allowed. If this MMSE stability requirement is not met after 2 extensions of 
the Run-In Period, the subject will be discontinued from the study (see also Section 8.1).
3)
If the subject is currently receiving any of the following medications, the treatment regimen 
has been stable (i.e., no changes in the type of drug, dose or frequency of dosing) for at least 
30 days prior to the Screening Visit and there is no intent to change this treatment regimen 
for the duration of the study. 
Acetylcholinesterase inhibitors (i.e., donepezil, galantamine, rivastigmine, tacrine)
Memantine
Axona® (caprylidene)
Antidepressants (other than MAO inhibitors)
Thyroid hormones
Atypical antipsychotics (e.g., quetiapine); Note: Clozapine is allowed, but must be stable 
for at least 5 months prior to Screening. In addition, the subject must not have had any 
episodes of neutropenia or severe infections since starting clozapine as confirnmed by the 
clozapine-prescribing physician and must follow the clozapine prescribing information 
with regards to monitoring of white blood cell count.
Benzodiazepines and other sedatives/hypnotics 
Note: Intermittent (as needed) use of benzodiazepines and other sedative/hypnotics is 
allowed only if the drug has a half-life of less than 6 hours and it is not taken within 
5 half-lives prior to cognitive testing.
4)
Subject is 50 to 85 years of age, inclusive, at the time of the Screening Visit.
5)
Female subjects must be:
a) Of non-childbearing potential (i.e., any female who is post-menopausal [greater than 1
year without menstrual period in the absence of hormone replacement therapy]) or 
surgically sterile; or,
b) If pre-menopausal or menopausal for 1 year or less, must have a negative pregnancy test 
and must not be lactating at Screening. Female subjects of childbearing potential and 
who are sexually active are required to practice highly effective methods of birth control
during the course of the study. Female subjects for whom menopausal status is in doubt,
in the opinion of the investigator, will be required to use a highly effective form of birth 
control. Highly effective forms of birth control are defined as methods that have a failure 
rate of less than 1% per year when used correctly and consistently and include:.


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combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation; oral, intravaginal, or transdermal
progestogen-only hormonal contraception associated with inhibition of ovulation; 
oral, injectable, or implantable
intrauterine device (IUD) 
intrauterine hormone-releasing system ( IUS) 
bilateral tubal occlusion 
vasectomised partner 
sexual abstinence
double barrier method: condom and an occlusive cap (diaphragm or cervical/vault 
caps) with a vaginal spermicidal agent (foam/gel/film/cream/suppository)
c) Subjects who have a positive pregnancy test during the study or become pregnant during 
the study will be discontinued.
Note: Male subjects who are sexually active and whose partner is of child-bearing 
potential are also required to use an adequate form of birth control including at least 1 
barrier method.
6)
Subject has the ability to comply with procedures for cognitive and other testing in the 
opinion of the investigator.
7)
Subject must be able to ingest pills (in tablet form) whole.
8)
Subject lives with (or has substantial periods of contact with) a regular caregiver who is 
willing to attend visits, oversee the subject's compliance with protocol-specified procedures 
and study medication, and report on subject's status, and who has substantial contact with 
the subject. If the caregiver does not cohabitate with the subject, he/she ideally should have 
a minimum of 10 hours total and at least 3 days contact with the subject per week. Prior to 
randomization, study staff will review eligibility of non-cohabitating caregivers. Every 
effort should be made to have the same caregiver throughout the study.
9)
Subject has provided full written informed consent prior to the performance of any 
protocol-specified procedure; or if unable to provide informed consent due to cognitive 
status, subject has provided assent and a legally acceptable representative (LAR) has 
provided full written informed consent on behalf of the subject.
10) Caregiver has provided full written informed consent on his/her own behalf prior to the 
performance of any protocol-specified procedure.
11) The subject’s general health status is acceptable for participation in a 24-week study in the 
opinion of the investigator.
6.3.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria apply:


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Other Causes for Dementia:
1)
Atypical clinical features or clinical course of dementia that would lead the investigator to
conclude primary symptoms are more likely explained by an alternate dementia diagnosis 
including, but not limited to, Parkinson’s disease dementia, vascular dementia, 
frontotemporal dementia, or Alzheimer’s disease dementia.
2)
A CT or MRI scan performed within the past 12 months or at Screening that is indicative of 
any other CNS disorder that, in the opinion of the investigator, could be interpreted as the 
primary cause of dementia (e.g., cerebrovascular disease [transient ischemic attack, stroke, 
hemorrhage]; structural or developmental abnormality; epilepsy; infectious, or degenerative 
or inflammatory/demyelinating CNS conditions) or any other history and/or evidence to 
suggest the same.
3)
Evidence of the following disorders where this is thought to be the cause of, or to contribute 
to the severity of, the subject’s dementia: current vitamin B12 deficiency, hypothyroidism, 
neurosyphilis, HIV dementia, or Korsakoff’s encephalopathy.
4)
Focal findings on the neurological exam (excluding changes attributable to peripheral 
injury) that are inconsistent with a primary diagnosis of DLB.
Confounding Medical Conditions
5)
History of schizophrenia, major depressive episode in the past 6 months, or any other 
significant psychiatric condition such as bipolar affective disorder that in the opinion of the 
investigator would interfere with participation in the study or could affect performance on 
outcome measures.
6)
Significant suicide risk as defined by (1) suicidal ideation as endorsed on items 4 or 5 on the 
C-SSRS within the past year, at Screening or since the last visit at Baseline or; (2) suicidal 
behaviors within the past year or; (3) clinical assessment of significant suicidal risk during 
subject interview.
7)
History of epilepsy or unexplained seizure in the past 5 years or history of significant head 
trauma with loss of consciousness in the past 5 years.
8)
History of malignancy during the 5 years before Screening. History of basal cell carcinoma 
and melanoma in situ are permitted. History of other cancers currently in a non-active state 
may be acceptable after review with the Medical Monitor.
9)
Any clinically relevant concomitant disease including unregulated diabetes, progressive 
liver or kidney dysfunction, history of myocardial infarction or unstable angina within 6 
months of Screening, history of more than one myocardial infarction within 5 years of 
Screening, history of clinically significant stroke, history or evidence of HIV infection, or 
any other medical or psychiatric condition, which, in the opinion of the investigator, makes 
the subject unsuitable for inclusion in the study.
10) History of alcohol use disorder or other substance abuse disorder (excluding tobacco use),
according to the DSM-5 in the past 10 years.


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Concomitant Medications
11) Participation in another investigational drug or device study during the 30 days prior to the 
Screening Visit (Visit 1), or within 5 half-lives of use of the investigational drug prior to the 
Screening Visit, whichever is longer.  In addition, subjects who were previously screened 
for another study in DLB but failed the entry criteria for that study may be screened with no 
time delay prior to the Screening Visit, provided that, in the opinion of the investigator, and
after consultation with the Medical Monitor as needed, there is a realistic possibility that the 
subject would be eligible.
12) Treatment with any concomitant medications as detailed in Table 1. Prohibited medications 
as outlined in Table 1 unless otherwise specified, need to have been discontinued for 5 half-
lives prior to screening and assessed as no longer clinically necessary for the subject.
Unacceptable Tests/Laboratory Values
13) Alanine transaminase 
of normal (ULN) at Screening.
14) Total bilirubin over 1.5 x ULN at Screening except due to documented Gilbert’s disease or 
evidence of Gilbert’s disease on Screening laboratory assessments.
15) Calculated creatinine clearance <40 mL/min (Cockroft-Gault formula) at Screening:
Adult Males:  [(140 – age in years) x (weight in kg)] ÷ 72 x serum creatinine in mg/dL]
Adult Females:  0.85 x [((140 – age in years) x (weight in kg)) ÷ 72 x serum creatinine in ng/dL]
16) Positive hepatitis B surface antigen or hepatitis C antibody test at Screening.
17) Confirmed corrected QT interval (QTc) value greater than or equal to 450 msec for males or 
greater than or equal to 470 msec for females at Screening. Subjects with a QRS value 
greater than 120 msec and subjects with QTc value less than 500 msec may be eligible 
following discussion with the Medical Monitor.
Other
18) Previous exposure to RVT-101 (SB742457).
19) Subject is unable to take study medication as prescribed throughout the study (with 
assistance is acceptable) or is at risk of non-compliance with study medication or procedures
as determined by the investigator.
20) Subject is unable to complete the CDR computerized assessment system during the 
Screening period (repeat assessments allowed) or, in the investigator’s opinion, the subject
will not be able to consistently complete the CDR computerized assessment system
throughout the course of the study. Subjects who are unable to complete the CDR 
computerized assessment system during the Run-In or Baseline visits will not be randomized.  
If a subject is unable to complete the CDR computerized assessment system testing during 
one of the study visits, testing may be rescheduled within the Visit window.


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21) Subject or caregiver is an immediate family member or employee of the participating 
investigator, any of the participating site staff, or of the sponsor study staff.
22) Subject was prescribed and initiated cognitive tasks for cognitive rehabilitation under 
medical supervision in the 2 months prior to Screening or plans to initiate a program of 
cognitive rehabilitation during the course of the study. Subjects who are treated with stable 
programs of cognitive rehabilitation for at least 2 months prior to Screening with no plan to 
change or discontinue the cognitive rehabilitation for the duration of the study are acceptable.
23) Subject has initiated a program of neurostimulation in the past 2 months or plans to initiate a
program of neurostimulation during the course of the study. Subjects who are treated with 
stable programs of neurostimulation for at least 2 months prior to Screening with no plans to 
change or discontinue the neurostimulation for the duration of the study are acceptable.
6.4.
Other Eligibility Criteria 
To assess any potential impact on subject eligibility with regard to safety, the investigator must 
refer to the RVT-101 Investigator Brochure for detailed information regarding warnings,
precautions, contraindications, AEs, and other significant data pertaining to the investigational 
product(s) being used in this study.
Eligibility review by Axovant or its representative(s) may be undertaken for select subjects.
6.5.
Screening Failures
Screen Failures are defined as subjects who sign an informed consent form (ICF) for 
RVT-101-2001 but are never subsequently randomized and who do not enter the Single-Blind 
Run-In Phase. A minimal set of screen failure information is required including demography,
screen failure details, eligibility criteria, and any serious adverse events (SAEs).
Subjects who are screen failures may be rescreened only after approval by the study Medical 
Monitor.
6.6.
Withdrawal Criteria
6.6.1.
Reasons for Withdrawal
A withdrawal from the study is defined as withdrawing any time after entering the Single-Blind 
Run-In Phase and before completion of the Week 24 Visit (Visit 12). Subjects who permanently 
discontinue use of investigational product (IP) will be considered to be withdrawn from the study
and will not be allowed to rescreen. Subjects may withdraw from the study at any time and for 
any reason.  The investigator (or designee) must document the reason for withdrawal in the 
electronic case report form (eCRF). Information related to AEs will continue to be collected as 
per usual procedures on subjects who have discontinued IP. Withdrawn subjects will not be 
replaced.  The reasons for subject withdrawal will be recorded and may include, but are not 
limited to:


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Any clinical AE, laboratory abnormality, or other medical condition or situation occurs such 
that continued participation in the study would not be in the best interest of the subject in the 
opinion of the investigator.
Pregnancy of female subject (discontinuation of treatment, but will be followed until the 
outcome of pregnancy is known)
Significant protocol violation
Subject requests to discontinue for any reason; it is important to determine whether the 
withdrawal of consent is primarily due to an AE, lack of efficacy, or other reason.
Sponsor decision to withdraw the subject or terminate the study, if it is considered in the best 
interest of the subject or study.
The above reasons do not automatically lead to withdrawal from the study in all cases. The final 
decision will be based on consultation between the principal investigator and the study Medical 
Monitor, with the ultimate decision by the principal investigator, subject or caregiver, except in 
cases where the Sponsor decides to terminate the study or withdraw the subject from the study.
If a subject meets discontinuation criteria during treatment, an Early Termination Visit will be 
required (Section 6.6.2).
6.6.2.
Subject Withdrawal Procedures
If a subject is prematurely discontinued from treatment with the IP, the investigator must make 
every effort to perform the evaluations scheduled for the Early Termination Visit (Table 2).  In 
the case where the subject permanently discontinues study medication between scheduled clinic 
visits he/she should be recalled to the clinic as soon as possible and preferably within 7 days of 
stopping study medication for the Early Termination Visit.
Lost to follow-up: If a subject is lost to follow-up, every effort must be made by study center 
personnel to contact the subject, inquire about the reason for discontinuation/withdrawal, and 
follow up with any unresolved AEs/serious adverse events (SAEs).  A minimum of 3 attempts at 
contact should be made and recorded in the subject’s source documentation, with 1 contact being 
by certified letter.  All measures taken to contact the subject and information received during 
those attempts must be documented.


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7.
STUDY TREATMENT
7.1.
Investigational Product and Other Study Treatment
IP in this study is defined as 35 mg RVT-101 tablets and their matching placebo, and will be 
provided by Axovant Sciences. RVT-101 and placebo tablets will be indistinguishable from each 
other. All subjects will take two tablets of IP daily at bedtime, one from each supplied bottle,
with or without food; this will consist of either two tablets of 35 mg RVT-101, one tablet of 35 
mg RVT-101 and one tablet of placebo, or two tablets of placebo.
IP for the Single-Blind Run-In Period (Weeks -2 to 0) will be supplied at Visit 2. Subjects will 
be given an IP kit containing 2 bottles of placebo tablets. Each bottle will contain 50 tablets, 
which is sufficient medication for 2 weeks plus 36 days overage. Subjects will be instructed to 
take two tablets of IP daily at bedtime with or without food; this will consist of one tablet from 
each of the two bottles supplied. In the event that the Single-Blind Run-In period is extended to 
repeat the MMSE, no new IP will be dispensed. Drug accountability will be checked, and 
subjects will be re-dispensed study medication kit and bottles they received at Visit 2.
IP for the Double-Blind Treatment Period (Weeks 0 to 24) will be supplied at Visits 3, 6, 8, 10,
and 11. At each dispensing visit during the Treatment Period, subjects will be given an IP kit 
containing 2 bottles of IP. Depending on treatment assignment, subjects will receive either two 
bottles of 35 mg RVT-101 tablets, one bottle of 35 mg RVT-101 tablets and one bottle of 
placebo tablets, or two bottles of placebo tablets. Each bottle will contain 50 tablets, which is 
sufficient for 4 weeks plus 22 days overage (V3, V6, V8) and for 6 weeks plus 8 days overage
(V10 and V12). Subjects will be instructed to take two tablets of IP daily at bedtime with or 
Product name:
RVT-101
Placebo
Formulation description:
pink, film-coated, round tablets
pink, film-coated, round tablets
Dosage form:
35 mg Tablet
Placebo Tablet
Unit dose strength(s)/
Dosage level(s):
35 mg
35 mg or 70 mg
N/A
placebo
Route of Administration:
Duration (Run-in Period):
Duration (Treatment Period):
Oral 
N/A
24 weeks
Oral
2 weeks
24 weeks
Dosing instructions:
Take before bedtime with or 
without food
Take before bedtime with or 
without food
Manufacturer/Source of 
Procurement
Metrics Contract Services
Greenville, NC
or
Catalent Pharma Solutions
Kansas City, MO
Metrics Contract Services 
Greenville, NC
or
Catalent Pharma Solutions
Kansas City, MO


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without food; this will consist of one tablet from each of the two bottles in the kit. New bottles 
of IP will not be dispensed at Visits 4, 5, 7, and 9, however, drug accountability will be checked, 
and subjects will be re-dispensed the IP bottles they received at the previous dispensing visit. All 
subjects and their caregivers should be instructed to bring IP bottles, with any unused drug, to 
each visit. It is important that drug accountability is checked individually for each of the two 
dispensed bottles.
7.2.
Randomization/Treatment Assignment
Subjects will be assigned to receive 35 mg RVT-101, 70 mg RVT-101, or placebo in accordance 
with the randomization schedule, prior to the start of the Double-Blind Treatment Period, using 
validated software.
Following confirmation of eligibility at the end of Single-Blind Run-In Period, subjects will be 
randomized to placebo or 35 mg RVT-101, 70 mg RVT-101 in a 1:1:1 ratio. Randomization will 
be stratified according to Baseline MMSE score in the groupings of 14-17 points, 18-21 points 
and 22-26 points and according to whether subjects are or are not taking a cholinesterase 
inhibitor as a concomitant medication.
7.3.
Blinding
This will be a double-blind study. The study will include a 2-week Single-Blind Run-In Period 
during which investigators will know that the subject is taking placebo but the subject/caregiver
will not.  This will be followed by a 24-week Double-Blind Treatment Period when neither 
subjects nor investigators will know which of the three treatments the subject is receiving.  
Subjects will be informed that they will receive placebo at some point during the study but they 
will not know when this will be.  Subjects will not be informed of transition from the Single-
Blind Run-In Period to the Double-Blind Treatment Period. RVT-101 and placebo will be 
provided as tablets that are indistinguishable in appearance, smell, and taste.
The following will apply:
The investigator or treating physician may unblind a subject’s treatment assignment. Such a 
measure should be taken only in the case of an emergency OR in the event of a serious 
medical condition when knowledge of the IP is essential for the appropriate clinical 
management or welfare of the subject as judged by the investigator.
In the event that a medical emergency or condition requires knowledge of the subject’s 
treatment assignment, the investigator will access the interactive voice response system 
(IVRS)/interactive web response system (IWRS) to obtain the treatment assignment for that
subject. The procedure of unblinding for a specific subject is provided in the IVRS/IWRS 
manual.
The investigator must inform the Medical Monitor about the unblinding as soon as possible,
but without revealing the treatment assignment of the unblinded subject.


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The sponsor will be informed without delay of the decision to unblind any subject and will 
determine whether any additional measures need to be taken for the safety of subjects 
currently in the study.
Any other requests to reveal a subject's treatment identity must be requested of, and approved 
by, Axovant Sciences.
A subject will be withdrawn from the study if his or her treatment code is unblinded by the 
investigator or treating physician.  The date and reason for the unblinding must be fully
documented in the eCRF.
Axovant Sciences or their designee may unblind the treatment assignment for any subject if this 
is required to fulfill regulatory reporting obligations such as expedited SAE reporting.
7.4.
Packaging and Labeling
RVT-101 35 mg tablets and matching placebo tablets will be packaged in high-density 
polyethylene bottles. Subjects will receive an IP kit consisting of two bottles at each IP 
dispensing visit. The IP kit and the individual bottles will be labeled.
Labels for IP kits and for RVT-101 and placebo bottles will meet all applicable requirements of 
the US Food and Drug Administration (FDA) and Annex 13 of Good Manufacturing Practices: 
Manufacture of investigational medicinal products (July 2010) and/or other local regulations as 
applicable.
The label for the IP will contain at a minimum the following information for the US (additional 
items will be added as required for other study countries):
Protocol number
Lot number
Kit or bottle identification number
Quantity
Dosing directions
“Caution: New Drug – Limited by Federal law to investigational use”
7.5.
Preparation/Handling/Storage/Accountability
No special preparation of IP is required. IP will be stored at room temperature (15 - 30°C) and
protected from light.
Only subjects enrolled in the study may receive IP and only authorized site staff may supply 
or administer IP.  All IP must be stored in a secure, environmentally controlled and 
monitored (manual or automated) area in accordance with the labelled storage conditions,
with access limited to the investigator and authorized site staff.


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The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for IP accountability, reconciliation, and record maintenance (i.e., receipt, 
reconciliation, and final disposition records).
Site staff will record the subject number on the packaging labels for the kit and each bottle 
dispensed.
Further guidance and information for final disposition of unused IP are provided in the 
pharmacy manual.
Under normal conditions of handling and administration, IP is not expected to pose 
significant safety risks to site staff.  In the case of unintentional occupational exposure, notify 
the monitor, Medical Monitor, and/or the Axovant Sciences study contact.
A Material Safety Data Sheet/equivalent document describing occupational hazards and 
recommended handling precautions either will be provided to the investigator, where this is 
required by local laws, or is available upon request from Axovant Sciences.
7.6.
Compliance with Investigational Product Administration
When subjects are dosed at the site, they will receive IP directly from the investigator or 
designee, under medical supervision. The date and time of each dose administered in the clinic 
will be recorded in the source documents. The dose of IP and study subject identification will be 
confirmed at the time of dosing by a member of the study site staff other than the person 
administering the IP.
Subjects and caregivers should be instructed that subjects are to take one tablet of IP from each 
bottle before bedtime.  Subjects and caregivers must be made aware that subjects are not to take 
two tablets from the same bottle, and are not to combine pills from the two bottles into a single 
storage bottle.  The contents of each bottle must remain distinct.  Product administration 
instructions should be reinforced at each visit.
Every effort should be made to encourage subject compliance with the dosage regimen as per 
protocol for IP. The investigator is responsible for discussing methods to ensure high treatment 
compliance with patients and caregivers before randomization.  All subjects and their caregivers 
should be instructed to return IP bottles with any unused drug at each visit to the investigator or 
designee. A record of the supplies dispensed, taken, and returned will be made in the eCRF at 
each visit. The investigator or designee is responsible for reconciling the number of tablets 
returned with the expected number of tablets to be taken by a study subject and accounting for 
any discrepancies for each of the two bottles.
Subjects should be withdrawn from the study where there has been a failure to take blinded IP
for a period exceeding 7 consecutive days.  While interruptions in IP administration should be 
avoided wherever possible, short-term interruptions ( 7 days) due to forgetfulness, caregiver 


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illness or absence, a pause in IP administration required during an intervention, hospitalization, 
or while a subject considers the study continuation, or for any other reason are not grounds for 
automatic withdrawal but should be assessed by the investigator.
Other major protocol violations as well as use of excluded drugs (see Section 7.9.2) may be 
cause for discontinuation of IP or withdrawal from the study.
7.7.
Treatment of Investigational Product Overdose
Any dose of RVT-101 greater than 105 mg within a 24-hour time period will be considered an 
overdose.
No data are available with regard to overdose of RVT-101 in humans.  There is no specific 
treatment to be used in the event of overdose with RVT-101.  Investigators should use their 
clinical judgment in treating cases of overdose as dictated by the subject’s clinical status.
In the event of an overdose the investigator or treating physician should:
Contact the Medical Monitor immediately,
Closely monitor the subject for AEs/SAEs and laboratory abnormalities and ensure 
appropriate clinical management. Overdose in the absence of other AEs will not be reported 
as an AE in its own right.
Obtain a plasma sample for PK analysis within 2 days of the overdose of IP, if requested by 
the Medical Monitor (determined on a case-by-case basis), and
Document the quantity of the excess dose as well as the time of administration of the 
overdose in the eCRF.
It is not necessarily required that the investigator unblind a subject who has taken an overdose.  
As noted in Section 7.3, unblinding should only be done in the case of an emergency OR in the 
event of a serious medical condition when knowledge of the investigational product is essential 
for the appropriate clinical management or welfare of the subject, as judged by the investigator.
Decisions regarding dose interruptions will be made by the investigator in consultation with the 
Medical Monitor based on the clinical evaluation of the subject.
7.8.
Treatment after the End of the Study
The investigator is responsible for ensuring that consideration has been given to the post-study 
care of the subject’s medical condition.
After completion of Visit 12, the subject may be considered for enrollment in the extension study 
RVT-101-2002. Only subjects who do not enroll in the extension study will complete the 
Follow-up Visit (Visit 13).


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7.9.
Concomitant Medications and Non-Drug Therapies
7.9.1.
Permitted Medications and Non-Drug Therapies
All concomitant medications and those taken within 6 months prior to Screening, including over-
the-counter and herbal remedies, will be recorded in the eCRF.  Non-medication therapies 
related to the subject’s DLB (e.g. neurostimulation, cognitive rehabilitation) that have occurred 
in the 12 months prior to Screening must also be recorded. The name of the drug, the dose,
indication and route of administration as well as the dates administered should be documented; 
the minimum requirement is to record the drug name and dates of administration.  Any 
medication not specified in the list of prohibited and conditional medications provided in Table 1
is permitted during the study.
7.9.2.
Prohibited Medications and Non-Drug Therapies
Subjects who begin treatment during the study with any prohibited medication, or begin 
cognitive tasks for cognitive rehabilitation performed under medical supervision or 
neurostimulation should be withdrawn from the study.  However, where such treatment has been 
for less than or equal to 7 days, termination of the prohibited medication or treatment and 
continuation in the study may be considered by the investigator in discussion with the Medical 
Monitor, based on subject safety and the perceived need for the prohibited treatment. 
If the subject is receiving one of the conditional medications listed in Table 1, the treatment 
regimen must have been stable (i.e., no changes in the type of drug, dose or frequency of dosing) 
for at least 30 days prior to the Screening Visit. In addition, the treatment regimen of these 
conditional medications should be kept stable during the study, if possible. If treatment with a 
conditional medication is initiated during the study and will be prescribed chronically, the 
investigator should discuss this with the Medical Monitor before determining whether to 
continue the subject in the study.
Use of prohibited and conditional medications and treatments must be documented in the 
Concomitant Medications section of the eCRF. Prohibited and conditional medications are listed 
in Table 1.


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Table 1
Prohibited Concomitant Medications
PROHIBITED MEDICATIONS:
Not allowed during the study or within 5 half-
lives prior to the Screening Visit
CONDITIONAL MEDICATIONS:
Stable regimen (drug, dose and dosing 
frequency) for at least 30 days prior to the 
Screening Visit; dosing regimen during the 
study should be stable, if possible
Butyrophenones, phenothiazines, and other 
“conventional” antipsychotics
Barbiturates
MAO inhibitors, including selegiline 
(Exception: selective MAO-B inhibitors such 
as rasagiline are allowed)
Any investigational drug
Substrates of CYP2C91 with narrow 
therapeutic indices: warfarin, phenytoin and 
(R)-acenocoumarol (active component of 
some non-warfarin anticoagulants)
Potent CYP3A42 inhibitors/inducers such as 
ketoconazole, itraconazole, erythromycin, 
rifampicin, phenytoin and carbamazepine
Known potent Pgp inhibitors3 (itraconazole, 
ketoconazole, cyclosporin, diltiazem, 
verapamil, quinidine, and carvedilol)
Acetylcholinesterase inhibitors (i.e., donepezil,
galantamine, rivastigmine, tacrine)
Memantine
Axona® (caprylidene)
Antidepressants (other than MAO inhibitors)
Thyroid hormones
Atypical antipsychotics (e.g., quetiapine)
Note: Clozapine is allowed, but must be stable 
for at least 5 months prior to Screening. In 
addition, the subject must not have had any 
episodes of neutropenia or severe infections 
since starting clozapine as confirmed by the 
clozapine-prescribing physician and must 
follow the clozapine prescribing information 
with regards to monitoring of white blood cell 
count.Benzodiazepines and other 
sedatives/hypnotics, including melatonin and 
sedating antihistamines
Note: Intermittent (as needed) use of 
benzodiazepines and other sedative/hypnotics
is allowed only if the drug has a half-life of 
less than six hours and it is not taken within 
5 half-lives prior to cognitive testing.
Abbreviations:  CNS = central nervous system; MAO = monoamine oxidase; Pgp = permeability glycoprotein. 
Notes: 
1 RVT-101 affects CYP2C9 substrates.
2 CYP3A4 is a major enzyme involved with the metabolism of RVT-101.
3 Pgp inhibition may affect CNS levels of RVT-101.
7.10.
Lifestyle and/or Dietary Restrictions
Subjects should refrain from consumption of grapefruit or grapefruit juice due to the potential to
raise RVT-101 concentrations.


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8.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed, with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements are essential and 
required for study conduct.
8.1.
Time and Events
The Time and Events Schedule (Table 2) displays each study assessment and procedure along 
with the time of occurrence.  All study assessments should be conducted by the investigator, 
and/or a suitably qualified designee approved and documented for this study. With the exception 
of the determination required in inclusion criterion #1, all study assessments and determinations 
may be delegated by the investigator to a suitably qualified designee approved and documented 
for this study. A qualified physician should be responsible for all study-related medical decisions
and care. If the principal investigator is not a physician, he/she must delegate medical decisions 
and care to a qualified physician. All raters will be trained and certified to perform the specific 
rating scales in this study.
For Visit 3 there is a visit window of +5 days.  For Visits 4 through 12, there is a visit window of 
±5 days (in relation to the Baseline visit). It is important that all visits should be scheduled 
relative to the Baseline visit, except for Visit 13. If the visit window is used, the subsequent visit 
should remain according to the planned visit schedule (i.e., the subsequent visit date should not 
be re-calculated from the date of the previous visit but should remain relative to Baseline).
Information will be recorded in the source documents and, where appropriate, the eCRF.
If, during the visit, the subject is unable or, in the judgment of the investigator, unlikely to be 
able to complete the cognitive assessments, the testing may be rescheduled within the windows 
described previously.  
Subjects may be given breaks during the assessments or may have assessments split across 
different days so long as all assessments are completed within the visit window.  Individual 
assessments or cognitive batteries such as the CDR computerized assessment system should, 
however, be completed within a single day.
Every effort should be made to administer the CDR computerized assessment system within ±1
hour of the time of day of the Baseline administration on subsequent visits for each subject due 
to the potential for circadian fluctuation in scores. This should be taken into consideration when 
scheduling and performing Baseline CDR System assessments.
The order of rating scales should, when possible, be held constant, with the CDR computerized 
assessment system given to the subject first at each visit.


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If medical assessments are scheduled for the same day as cognitive testing, then the medical 
assessments should be conducted after the cognitive testing and occur in the following order
whenever possible:
12-lead ECG
Vital signs
Blood draws
Screening Period (up to 28 days before Visit 2): Subjects will be screened for eligibility 
during the Screening Period. Subjects who do not qualify for the study during this period will be 
considered screen failures. An ICF will be signed by each subject, if they are able, or by the 
subject’s LAR.  An ICF will also be signed by the caregiver before any study-specific procedures 
are performed.  Subjects will be screened according to study inclusion/exclusion criteria.  This 
Screening Period may be extended for up to an additional 14 days if needed to complete 
assessment activities after approval by the study Medical Monitor. Subjects who are screen
failures during the Screening Period may be rescreened after discussion with the Medical 
Monitor.
Single-Blind Run-In Period (14 + 5 days before Visit 3): Subjects must have an MMSE score 
of less than or equal to 26 at Visit 2. Subjects not meeting this MMSE criteria at Visit 2 will be 
discontinued from the study.
At Visit 2, subjects who meet all study screening criteria will enter a Single-Blind Run-In Period. 
IP will be dispensed.  Subjects will be instructed to take the first Single-Blind Run-In IP (single-
blind placebo) during the study visit (two tablets; one from each bottle). Subjects will be 
instructed to take two tablets of IP once daily at bedtime, one tablet from each of 2 bottles,
beginning on the day after the Visit 2. Visit 2 assessments will be performed according to Table 
2 below.  
To qualify for randomization at Baseline subjects must return unused IP, be considered capable 
of completing study assessments, remain within study-specified criteria for MMSE, and meet all 
other eligibility requirements. The CDR computerized assessment should be the first assessment 
performed, followed by the MMSE. If the MMSE score does not meet the criterion for 
randomization, no other assessments should be performed. 
The Single-Blind Run-In Period may be extended for 1 to 10 days for subjects who do not meet 
MMSE stability criterion for randomization at Visit 3. If, after the first extension to the Single-
Blind Run-In Period, the subject still does not meet the MMSE stability criterion for 
randomization, the run-in period may again be extended for an additional 1 to 10 days. No more 
than 2 extensions to the Single-Blind Run-In Period will be allowed. No new IP will be 
dispensed for the extended run-in periods; subject should be instructed to continue taking blinded 
IP dispensed at Visit 2.
Baseline (Visit 3) and Double-blind Treatment (Visit 4 through Visit 12): At Visit 3
(Baseline), assessments will be performed to determine subject eligibility.  Subjects who require 
one extension to the Run-in period will have a new Baseline visit occurring no more than 10 


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days after the originally intended Baseline at Visit 3. Subjects who require two extensions to the 
Run-in period will have a new Baseline visit occurring no more than 20 days after the originally 
intended Baseline at Visit 3. 
Eligible subjects will be randomized to one of 3 groups, 35 mg RVT-101, 70 mg RVT-101, or 
placebo, for the 24 weeks of double-blind treatment assessment. At the Baseline visit, subjects 
will ingest the first dose of double-blind IP in the clinic in the presence of study center personnel
(2 tablets; one from each bottle). Subjects will be instructed to take two tablets of IP once daily 
at bedtime, one tablet from each of 2 bottles, beginning on the day after the Baseline visit.
At each visit, subjects will be reminded to take one tablet of blinded IP from each bottle once 
daily at bedtime. Compliance with IP should be assessed at all visits.
Throughout the Baseline and Double-Blind Treatment Periods, all clinic visits will be scheduled 
according to specified visit windows, and all specified assessments will be completed (Table 2).
There will be weekly clinical assessments for the first two weeks of treatment, bi-weekly 
assessments until Week 12 and every six weeks thereafter.  For Visits 5, 7 and 9, subjects may be 
given the option of whether to have assessments performed at the clinical study site or by a 
trained, visiting nurse in their own home.
An independent SMC will review interim safety data accumulated after approximately 30 
subjects have completed 4 weeks of double-blind treatment, and throughout the study at point 
specified in the SMC Charter. The SMC will provide their recommendation regarding the 
acceptability of skipping Visits 5, 7 and 9 for both newly enrolled subjects and subjects active in 
the study at the time of the recommendation. Study enrollment will not be stopped or slowed to 
wait for this assessment and will proceed as planned with all visits until the SMC
recommendation is made. Formal communication will be made to the study sites regarding the 
SMC’s decision regarding the acceptability of skipping Visits 5, 7 and 9.
Throughout the Baseline and Double-Blind Treatment Periods, the administration of the CDR
computerized assessment System (at applicable visits) should be kept within a ± 1-hour window 
of the time of day of the Baseline assessment for each subject when possible to diminish the 
potential impact of circadian fluctuations in cognition.  This should be taken into consideration 
when scheduling and performing Baseline CDR System assessments.
The order of assessments should remain consistent during the Double-Blind Treatment Period,
and when possible, the CDR System should be given to the subject first, followed by the other 
efficacy endpoint scales.  If possible, other assessments, including ECG, vital signs, and blood 
draws, should be performed after cognitive testing and other endpoint scales. When possible 
CIBS/CIBIC+ should be given as the first assessment to the caregiver followed by other 
endpoint scales. The assessor for each endpoint should be the same person for all study visits if 
at all possible.  This is especially true for the CIBIC+, which is a change from Baseline score.


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Although caregiver and subject visits are recommended to be on the same day, this is not 
required so long as they are each kept within the specified visit window. However, every effort 
should be made to have the same caregiver throughout the study.
Subjects who prematurely discontinue double-blind IP should be encouraged to return to the 
clinic for an Early Termination (ET) Visit, and the ET assessments and procedures should be 
performed as indicated on the time and events schedule.
Safety Follow-Up: All subjects who complete the Double-Blind Treatment Period and who do 
not enter the extension study will be required to attend a Safety Follow-Up clinic visit (Visit 13) 
14 to 19 days after Visit 12.


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Table 2
Time and Events Schedule
Study Period
Screening
Run-in
Baseline
Treatment
Follow-
up3
ET
Study Visit Number
V1
V2
V31
V4
V52
V6
V72
V8
V92
V10
V11
V12
V13
Study Week
W(-6)
W(-2)
W0
W1
W2
W4
W6
W8
W10
W12
W18
W24
W26
Study Day relative to 
Baseline unless specified
Up to 28 
days 
before V2
14 +5 
days 
before 
V3
0
7 ± 5
14 ± 5
28 ± 5
42 ± 5
56 ± 5
70 ± 5
84 ± 5
126 ± 5
168 ± 5
14 to 
19 days 
after 
V12
Informed consent
X
Inclusion/Exclusion criteria
X
Demography
X
Medical History
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood alcohol and urine drug 
screen
X
X
C-SSRS, Screening/Baseline 
version
X
C-SSRS, Since Last Visit 
version
X
X
X
X
X
X
X
X
X
Randomization
X
Dispense IP5
X
X
X
X
X
X
Assess IP compliance
X
X
X
X
X
X
X
X
X
X
X
Physical exam6
X
X
X
X
X
X
X
X
X
X
X
Complete neurological exam
X
X
X
X
X
X
MRI or CT7
X
PET / SPECT13
X
12-Lead ECG
X
X
X
X
X
X
X
X
X
X
X
Vital signs8
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Review Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Questionnaire for symptoms 
of potential orthostasis
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum OR urine pregnancy 
test9
X
X
X
X
X
Hep B and Hep C screen10
X


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Study Period
Screening
Run-in
Baseline
Treatment
Follow-
up3
ET
Study Visit Number
V1
V2
V31
V4
V52
V6
V72
V8
V92
V10
V11
V12
V13
Study Week
W(-6)
W(-2)
W0
W1
W2
W4
W6
W8
W10
W12
W18
W24
W26
Study Day relative to 
Baseline unless specified
Up to 28 
days 
before V2
14 +5 
days 
before 
V3
0
7 ± 5
14 ± 5
28 ± 5
42 ± 5
56 ± 5
70 ± 5
84 ± 5
126 ± 5
168 ± 5
14 to 
19 days 
after 
V12
TSH, vitamin B12, syphilis 
serology11
X
Serum chemistry
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
X
RVT-101 level
X
X
MMSE4
X
X
X
LBCRS
X
ADAS-Cog 134
X
X
X
CIBIS
X
CIBIC+
X
X
X
X
X
CDR System4, 12
X
X
X
X
X
X
X
X
COWAT4
X
X
X
X
X
X
X
X
ADCS-ADL
X
X
X
NPI Parts A, B, D & E
X
X
X
NEVHI
X
X
X
EQ-5D-5L
X
X
DS
X
X
CAF
X
X
X
X
X
UPDRS-III
X
X
X
X
X
CSI
X
X
X
Abbreviations: ADAS-Cog = Alzheimer’s Disease Assessment Scale; ADCS-ADL = Alzheimer’s Disease Cooperative Study – Activities of Daily Living; CAF = Clinician’s Assessment of  
Fluctuation; CDR System= Cognitive Drug Research computerized assessment system; CIBIS = Clinician’s Interview-Based Impression of Severity; CIBIC+ = Clinician’s Interview-Based Impression 
of Change Plus caregiver Interview; COWAT = Controlled Oral Word Association Test;  CSI = Circadian Sleep Inventory; C-SSRS = Columbia-Suicide Severity Rating Scale; CT = computed 
tomography; DS = Dependence Scale; ECG = electrocardiogram; EQ-5D-5L = EuroQual five dimensions questionnaire, five level version; Hep = hepatitis; IP = investigational product; LBCRS = Lewy 
Body Composite Risk Score; MMSE = mini-mental state examination; MRI = Magnetic Resonance Imaging; NEVHI = North East Visual Hallucinations Inventory; NPI = Neuropsychiatric Inventory; 
PET = positron emission tomography; SPECT = single-photon emission computed tomography; TSH = thyroid stimulating hormone; UPDRS-III = Unified Parkinson’s Disease Rating Scale, Part III


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1.
The Single-Blind Run-In Period may be extended for 1 to 10 days for subjects who do not meet MMSE stability criterion for randomization. If, after the first extension to the Single-Blind 
Run-In Period, the subject still does not meet the MMSE stability criterion for randomization, the run-in period may again be extended for an additional 1 to 10 days. No more than 2 
extensions to the Single-Blind Run-In Period will be allowed. Subjects who require one extension to the run-in period will have a new Baseline visit occurring no more than 10 days after the 
originally intended Baseline at Visit 3. Subjects who require two extensions to the run-in period will have a new Baseline visit occurring no more than 20 days after the originally intended 
Baseline at Visit 3. No new IP will be dispensed for the extended run-in periods; subject should be instructed to continue taking blinded IP dispensed at Visit 2.
2.
After the first approximately 30 subjects have completed 4 weeks of treatment and throughout the study at points specified in the SMC Charter, the SMC will meet and determine if a reduced 
visit frequency is acceptable. If and when the SMC approves a reduced visit frequency, Visits 5, 7 and 9 will be skipped. Subjects may have the option of whether to have assessments for 
Visits 5, 7 and 9 performed at the clinical study site or by a trained, visiting nurse in their own home.
3.
The Follow-Up Visit (V13) is required only for subjects who do not enter the extension study.
4.
If, during the visit, the subject is unable or, in the judgment of the investigator, unlikely to be able to complete the cognitive assessments, the testing may be rescheduled within the visit 
windows.
5.
The bottles and pill count should be checked for compliance at V4, V5, V7, and V9, but no new medication will be dispensed at those visits.
6.
Full physical examination at Screening (V1), V3, V10, V12, V13and ET; abbreviated physical examination at V2, V4, V6, V8 and V11.
7.
MRI or CT scan will be performed between V1 and V2 if no scan has been performed within the previous 12 months. These scan findings must be consistent with the diagnosis of DLB 
without any other clinically significant pathologies.
8.
Vital signs will include systolic blood pressure, diastolic blood pressure, heart rate, respiratory rate, temperature and body weight at each visit and height at screening. Postural changes in 
blood pressure, heart rate and respiration rate will also be assessed at every visit.
9.
Required only for women of child bearing potential.
10.
If these tests were performed within 3 months prior to the planned first dose of investigational product, testing is not required. Records must be present in the subject’s source documents.
11.
If these tests were performed within 12 months prior to the planned first dose of investigational product, testing is not required. Records must be present in the subject’s source documents.
12.
The CDR computerized assessment System performed at Visits 1 and 2 will be training sessions.
13.
PET / SPECT imaging is not required. However, it may be performed during Screening for eligibility per inclusion criterion number 1.


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8.2.
Critical Baseline Assessments
Those subjects whose MMSE at Baseline (Visit 3) has declined significantly (decrease of 4 or 
more points) from Visit 2 and/or those subjects whose MMSE at Baseline changes such that it 
falls outside the range 14-26 will not be randomized. The purpose of this is to exclude subjects 
whose baseline is so variable that any drug effect may not be clearly observable with the 
assessments included in this study.
For subjects with an MMSE score at Baseline (Visit 3) of 4 or more points lower than their Visit 
2 MMSE score or those who fall below an MMSE of 14, the Run-In period may be extended for 
1 to 10 days. If, after the first extension to the Run-In Period, the subject still does not meet the 
MMSE stability criterion, the Run-In period may again be extended for an additional 1 to 10 
days. No more than 2 extensions to the Single-Blind Run-In Period will be allowed. If this
MMSE stability requirement is not met after 2 extensions of the Run-In Period, the subject will 
be discontinued from the study (see also Section 8.1).
8.3.
Study Assessments and Procedures
8.3.1.
Efficacy Assessments
All study assessments should be conducted by the investigator, and/or a suitably qualified 
designee, all of whom will be trained and certified to administer these measures for this study.
Every effort should be made for the same person to conduct specific assessments on each 
individual subject at each study visit. Assessments will be monitored for quality. Screening 
assessments along with accompanying data will be reviewed to ensure that subjects meet the 
inclusion criteria.  Other assessments will be monitored by using data collected.
The subject will be audio recorded during portions of the interviews for some of the rating scales
at all visits, except for Visits 4, 5, 7, 9 and 12. The audio recordings will be sent to qualified 
researchers who are representatives of Axovant Sciences for their review. The researchers will 
listen to the recordings and evaluate them to assess quality of the ratings. The recorded interview 
and/or information obtained from them may also be shared with Axovant Sciences, the 
investigator and/or the study site staff.
In addition, information regarding the clarity of the recorded interviews, such as transmission 
issues, equipment problems, and sound quality issues, may be shared with Axovant Sciences.
The recordings will be stored in and transmitted through a secure system, which controls access 
through encryption and password protection.
8.3.1.1.
Mini-Mental State Evaluation (MMSE)
The MMSE (Folstein, 1975) consists of 11 tests of orientation, memory (recent and immediate), 
concentration, language, and praxis.  Scores range from 0 to 30, with lower scores indicating 
greater cognitive impairment.  It is based on the performance of the subject and takes 
approximately 5 to 10 minutes to administer. This scale will be administered by a rater who is
qualified and trained for this study.


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8.3.1.2.
Unified Parkinson’s Disease Rating Scale – Part III (UPDRS-III)
The UPDRS-III is a widely used scale designed to follow the longitudinal course of Parkinson’s 
disease. It is completed by a trained and qualified clinician, based on clinical examination, 
observation and questioning of the subject. The UPDRS is made up of six parts. In this study, 
only Part III of the UPDRS will be used, which is a motor evaluation. The UPDRS-III is the 
primary endpoint in this study. 
UPDRS-III is a motor evaluation, consisting of 27 items each scored on a scale of 0 to 4, with 
higher scores indicating greater severity of the motor symptom. UPDRS-III total is the sum of 
the 27 items, with scores ranging from 0 to 108.
A 5-item subscale of the UPDRS-III (UPDRS-5) will also be calculated. The UPDRS-5
combines scores from 5 items:
rest tremor
action tremor
rigidity
facial expression
bradykinesia.  
Thus, UPDRS-5 is the sum of these items, with scores ranging from 0 to 56, with higher scores 
indicating greater severity of the motor symptoms.
8.3.1.3.
Alzheimer’s Disease Assessment Scale – Cognitive Subscale (ADAS-Cog)
The 11-item and 13-item ADAS-Cog (Rosen et al., 1984) assesses a range of cognitive abilities 
including memory, comprehension, orientation in time and place, and spontaneous speech.  Most 
items are evaluated by tests, but some are dependent on clinician ratings on a 5-point scale.  The 
ADAS-Cog 11 is the secondary endpoint in this study. The ADAS-Cog 11 total score range is 
from 0 to 70, with a higher score indicating more sever cognitive impairment. The ADAS-Cog 
13 is the ADAS-Cog 11 with two additional items. Scores for the ADAS-Cog 13 item range 
from 0 to 85 with higher scores indicating greater dysfunction.  The scale takes approximately 30 
to 40 minutes to administer. This scale will be administered by a rater who is trained and 
certified for this study.
8.3.1.4.
Clinician’s Interview-Based Impression of Severity (CIBIS) and Clinician’s 
Interview-Based Impression of Change Plus Caregiver Interview (CIBIC+)
The CIBIC+ assessment (Schneider et al., 1997) measures the global functioning of the subject 
through structured interviews with both the subject and caregiver.  The Clinician’s Interview-
Based Impression of Severity (CIBIS) will be administered at Baseline and the CIBIC+ will be 
administered at subsequent study visits.  The change from Baseline is recorded on a 7-point scale 
with a score of 4 indicating no change, scores above 4 indicating worsening, and scores below 4 
indicating improvement.  This scale will be administered by a rater who is trained and certified 


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for this study, and who is independent of other cognitive and functional rating scales.  Every 
effort should be made to have the same CIBIS/CIBIC+ rater for each subject for the duration of 
the study.
8.3.1.5.
Cognitive Drug Research (CDR) Computerized Assessment System
The CDR computerized assessment system is a computerized battery of cognitive tests (Simpson 
et al., 1991; Keith et al., 1998).  The CDR computerized assessment system includes tests of 
attention and information processing speed (Simple Reaction Time, Choice Reaction Time, and 
Digit Vigilance), verbal and visuospatial working memory (Numeric and Spatial Working 
Memory) and verbal and visual episodic memory (Immediate and Delayed Word Recall, Word 
Recognition and Picture Recognition). 
The CDR computerized assessment system will be administered at the study sites by trained 
administrators. During the Screening visit (Visit 1) and Visit 2, the CDR computerized 
assessment will be administered as training sessions to overcome test anxiety, ensure the patient 
is able and willing to undergo testing, and overcome initial training effects in order that a stable 
score is subsequently obtained at Baseline (Visit 3). All tasks are computer-controlled. The 
information is presented on the screen of a notebook computer and the responses recorded via a 
response module containing two buttons, one marked 'NO' and the other 'YES'. The test 
administrator sits with the patient throughout testing, explains each test using pre-set 
instructions, initiates each test and ensures the patient performs it appropriately. Patients should 
not smoke or drink caffeine containing drinks for a minimum of 1 hour prior to testing on the 
study days.
When possible, the CDR computerized assessment system should always be the first assessment 
conducted, and should be administered, within ±1 hour of the time of Baseline administration at 
all subsequent visits to control for potential impact of circadian variation in performance.
The tests are administered in the following order:
•
Immediate Word Recall: A list of 12 words is presented on the screen at the rate of 1 
every 2 seconds for the patient to remember.  The patient is then given 1 minute to 
recall as many of the words as possible.
•
Picture Presentation: A series of 14 pictures is presented on the screen at the rate of 1 
every 3 seconds for the patient to remember.
•
Simple Reaction Time: The patient is instructed to press the 'YES' response button as 
quickly as possible every time the word 'YES' is presented on the screen.  Thirty 
stimuli are presented with a varying inter-stimulus interval.
•
Digit Vigilance: A target digit is randomly selected and constantly displayed to the 
right of the screen.  A series of digits is then presented in the center of the screen at 
the rate of 80 per minute and the patient is required to press the 'YES' button as 


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quickly as possible every time the digit in the series matches the target digit. There 
are 15 targets in the series.  The task lasts for 3 minutes.
•
Choice Reaction Time: Either the word 'NO' or the word 'YES' is presented on the 
screen and the patient is instructed to press the corresponding button as quickly as 
possible.  There are 30 trials for which each stimulus word is chosen randomly with 
equal probability and there is a varying inter-stimulus interval.
•
Spatial Working Memory: A picture of a house is presented on the screen with 4 of its 
9 windows lit. The patient has to memorize the position of the lit windows. For each 
of the 36 subsequent presentations of the house, the patient is required to decide 
whether or not the 1 window that was lit was also lit in the original presentation.  The 
patient responds by pressing the ‘YES’ or ’NO’ buttons as appropriate, as quickly as 
possible.
•
Numeric Working Memory: A series of 3 digits is presented for the patient to hold in 
memory.  This is followed by a series of 18 probe digits for each of which the patient 
has to decide whether or not it is in the original series and press the 'YES' or 'NO' 
response button as appropriate, as quickly as possible.
•
Delayed Word Recall: The patient is again given 1 minute to recall as many of the 
words as possible.
•
Word Recognition: The original words plus 12 distracter words are presented one at a 
time in a randomized order. For each word the patient is required to indicate whether 
or not the patient recognizes it as being from the original list of words by pressing the 
'YES' or 'NO' button as appropriate, as quickly as possible.
•
Picture Recognition: The original pictures plus 14 distracter pictures are presented 
one at a time in a randomized order.  For each picture the patient has to indicate 
whether or not the patient recognizes it as being from the original series by pressing 
the 'YES' or 'NO' button as appropriate, as quickly as possible.
Seven domains will be calculated from the CDR computerized assessment system tests (Power 
of Attention, Continuity of Attention, Cognitive Reaction Time, Response Variability, Quality of 
Working Memory, Quality of Episodic Secondary Memory, and Speed of Memory). Table 3 and 
Table 4 provide details on how these 7 domains are calculated. 
Table 3
CDR Computerized Assessment System Variables
Task Name
Variable 
Abbreviation
Unit
Immediate Word Recall
Words Recalled Correctly
IRCL
#
Errors
IRCLERR
#
Simple Reaction Time
Mean Reaction Time 
SRT
ms
Median Reaction Time 
SRTM
ms
Standard Deviation 
SRTSD
ms
Digit Vigilance
Mean Reaction Time
VIGRT
ms


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Task Name
Variable 
Abbreviation
Unit
Accuracy
VIGACC
%
False Alarms
VIGFA
#
Standard Deviation
VIGSD
ms
Choice Reaction Time
Mean Reaction Time
CRT
ms
Median Reaction Time
CRTM
ms
Accuracy
CRTACC
%
Standard Deviation
CRTSD
ms
Spatial Working Memory
Median Reaction Time
SPMRTM
ms
Sensitivity Index
SPMSI
SI
Numeric Working Memory
Median Reaction Time
NWMRTM
ms
Sensitivity Index
NWMSI
SI
Delayed Word Recall
Words Recalled Correctly
DRCL
#
Errors
DRCLERR
#
Word Recognition
Median Reaction Time
DRECRTM
ms
Original Stimuli Accuracy
DRECOACC
%
New Stimuli Accuracy
DRECNACC
%
Picture Recognition
Median Reaction Time
DPICRTM
ms
Original Stimuli Accuracy
DPICOACC
%
New Stimuli Accuracy
DPICNACC
%
Table 4
Calculation of CDR Computerized Assessment System Domain Scores
Name
Abbreviation
Unit
Calculation
Power of Attention
POW_ATT
ms
SRTM+VIGRT+CRTM
Continuity of Attention
CONT_ATT
#
(VIGACC*0.45)+(CRTACC*0.5)-
VIGFA
Cognitive Reaction 
Time
COGRT
ms
CRTM-SRTM
Response Variability
POWATTCV
%
(SRTSD/SRT*100)+(CRTSD/CRT*1
00)+(VIGSD/VIGRT*100)
Quality of Working 
Memory
QL_WORK
SI
SPMSI+NWMSI
Quality of Episodic 
Secondary Memory
QL_EPIS
#
(DRECOACC+DRECNACC–100) 
+(DPICOACC+DPICNACC–100) 
+((IRCL–IRCLERR)*100/12) 
+((DRCL–DRCLERR)*100/12)
Speed of Memory
SPEEDMEM
ms
SPMRTM+NWMRTM+DRECRTM+ 
DPICRTM
Based on the derived domain scores, a standardized z-score will be derived for each CDR system 
domain using the formula below:
Domain z-score = (X2 – X1)/SD1
Where:


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X2 is the domain score for each individual at any study assessment time post 
Baseline 
X1 is the Baseline domain score for that individual
SD1 is the domain standard deviation of the population at Baseline
A composite z-score for the 7 CDR domains will be calculated based on the individual domain 
scores as: 
(Continuity of Attention z-score + Quality of Episodic Secondary Memory z-score - Response 
Variability z-score + Quality of Working Memory z-score - Power of Attention z-score -
Cognitive Reaction Time - Speed of Memory z-score)/7
8.3.1.6.
Controlled Oral Word Association Test (COWAT)
The COWAT, which is subtest of the Multilingual Aphasia Examination (Benton, 1994), is a 
verbal fluency test that measures spontaneous production of words beginning with some 
designated letter. The COWAT uses the three letter set to assess phonemic fluency. Individuals 
are given 1 minute to name as many words as possible beginning with one of the letters. The 
procedures is then repeated for the remaining two letters. The COWAT takes approximately 5 to 
10 minutes to administer. This scale will be administered by a rater who is trained for this study.
8.3.1.7.
Alzheimer’s Disease Cooperative Study - Activities of Daily Living 
(ADCS-ADL)
The ADCS-ADL scale (Galasko et al., 1997) measures functional impairment in terms of 
activities of daily living.  The ADCS-ADL is an interviewer-administered, informant-based scale 
where the informant (caregiver) responds to 23 activities of daily living questions about the 
subject.  The questions range from basic to instrumental activities of daily living and take 
approximately 20 minutes to complete.  The total score ranges from 0 to 78; the lower the score, 
the greater the impairment.  This scale will be administered by a rater who is trained and certified 
for this study.
8.3.1.8.
Clinician Assessment of Fluctuation (CAF)
The CAF assesses fluctuating cognition and impaired consciousness over the previous month 
(Walker, 2000). The CAF is one of the measures of cognitive fluctuation recommended by the 
DLB Consortium when applying the DLB diagnostic criteria (McKeith et al., 2005). The CAF is 
a 2-item questionnaire, with the first item capturing the presence of fluctuating level of 
consciousness and the second item capturing the presence of fluctuating cognitive impairment. 
According to the CAF, fluctuating cognition is considered present if either of the scale’s 2 items 
is marked ‘yes’.  In addition, if fluctuating cognition is present, frequency and duration are 
assessed each on a separate scale. These 2 values (frequency and duration) are multiplied to 


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achieve a severity score (Van Dyk et al., 2015). This scale will be administered by a rater who is
trained for this study.
8.3.1.9.
North East Visual Hallucinations Inventory (NEVHI)
The NEVHI is a semi-structured interview that assesses visual hallucinations in elderly patients 
with visual and/or cognitive impairments (Mosimann, 2008). The NEVHI has 3 sections. It will 
take approximately 3 minutes for subjects without visual symptoms and up to 12 minutes for 
subjects with hallucinations. Section 1 screens for the presence of visual hallucinations and 
assesses hallucination phenomenology. Section 2 assesses the severity of hallucinations by rating 
temporal aspects (frequency and duration) of hallucinations. Section 3 assesses emotion, 
cognition, and behavior associated with the most prominent recurrent visual hallucination during 
the month prior to the assessment. This scale will be administered by a rater who is trained for 
this study.
8.3.1.10.
Neuropsychiatric Inventory
The full NPI (Cummings et al., 1994) is a 12-item behavior rating scale composed of a structured 
interview of the caregiver, which assess psychiatric disturbance. In this study, only Parts A, B, D 
& E of the NPI will be performed, which assess delusions hallucinations, depression/dysphoria 
and anxiety, respectively. Both the frequency and the severity of each behavior are determined. 
Two separate 2-item subscores will be calculated; one for Parts A and B (delusions and 
hallucinations domains) and one for Parts D & E (depression and anxiety domains) of the NPI.
This scale will be administered by a rater who is trained for this study.
8.3.1.11.
EuroQol Five Dimensions Questionnaire, Five Level Version (EQ-5D-5L)
The EQ-5D-5L is a standardized measure of health status that provides a measure of health-
related quality of life that is widely used in clinical trials (Rabin, 2001).  For this study, the EQ-
5D-5L will be a caregiver proxy assessment.  The assessment will be completed by the caregiver 
and will assess the caregiver’s impressions of how the subject would rate his/her own quality of 
life.  The EQ-5D-5L questionnaire consists of 2 components: the EQ-5D-5L descriptive system 
and the EQ visual analogue scale (EQ VAS).  The EQ-5D-5L descriptive system includes 
5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.  The 
EQ VAS records overall health status on a 20-cm vertical line with a score of 0 (worst health one 
can imagine) to 100 (best health one can imagine). This scale will be administered by a rater who 
is trained for this study.
8.3.1.12.
Dependence Scale (DS)
The DS measures the amount of assistance patients with dementia require in performing daily 
activities (Brickman et al., 2002). The caregiver answers questions about the dependency of the 
subject. The scale consists of 13 items, representing a range of severity from mild to severe 
levels of dependency. The score range is from 0 to 15 with higher scores indicating greater 
dependency. This scale will be administered by a rater who is trained for this study.


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8.3.1.13.
Modified Circadian Sleep Inventory – (CSI)
The Circadian Sleep Inventory is a two-part questionnaire that assesses sleep-related problems 
and behaviours. In this study, modifications have been made to remove questions assessing sleep 
apnea and restless leg syndrome. The modified CSI contains 12 questions that are answered by 
the caregiver about the subject’s sleep-related behaviours, and an overall sleep quality rating.
For each question, both the frequency and the severity of each behaviour are determined and are 
multiplied.  The CSI total score will be calculated as the sum of the scores for all questions. This 
scale will be administered by a rater who is trained for this study.
8.3.2.
Safety and Screening Assessments
8.3.2.1.
Adverse Events
The investigator or site staff is responsible for detecting, documenting, and reporting events that 
meet the definition of an AE or SAE.
8.3.2.1.1.
Definition of Adverse Events
An AE is any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug related.  Therefore, an AE can be ANY unfavorable and unintended sign 
(including an abnormal laboratory finding or vital sign measurement), symptom, or disease 
temporally associated with the use of a medicinal product, without any judgment about causality.
Events meeting the definition of an AE include:
Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition.
New conditions detected or diagnosed after investigational product administration even 
though it may have been present prior to the start of the study.
Signs, symptoms, or the clinical sequelae of a suspected drug interaction.
Signs, symptoms, or the clinical sequelae of a suspected overdose of either investigational 
product or a concomitant medication.
Clinically significant abnormal findings (laboratory test results, vital signs, physical 
examination findings, ECGs, radiologic exams or other studies) should be recorded as AEs.
A “clinically significant” finding is one that affects clinical management, including
additional visits, monitoring or referrals, diagnostic tests or alteration of treatment, or that is 
considered clinically significant by the investigator.  A clinically significant finding may be a 
change in a test that has previously been abnormal but now requires additional action.
When a medical or surgical procedure is performed, the condition that leads to the procedure 
should be recorded as the AE unless the condition is part of the subject’s medical history.


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Events that do not meet the definition of an AE include:
Anticipated day-to-day fluctuations or expected progression of pre-existing disease(s) or 
condition(s) present or detected at the start of the study unless judged by investigator to be 
more severe than expected for the subject’s underlying condition.
Abnormal laboratory, ECG, or vital sign measurements that are not labelled clinically 
significant (see definition above).
Situations where an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital).
Overdose in the absence of other AEs will not be reported as an AE in its own right.
Changes in C-SSRS during the course of the study indicating worsening should be evaluated 
by the investigator for clinical significance, and if clinically significant (e.g., alteration in 
medical care or intervention is required), an associated AE should be recorded, if present.  
The AE should be the primary underlying clinical manifestation assessed as clinically 
significant, and not the change in score itself.
Adverse events are recorded from the time that informed consent is signed, including those that
occur during the Single-Blind Run-in Period.  Treatment emergent adverse events are defined as 
those that occur on or after the date of the first dose of double-blind investigational product.
8.3.2.1.2.
Definition of Serious Adverse Event
An AE is considered serious if, in the view of either investigator or sponsor, it results in any of 
the following outcomes:
Death,
A life-threatening AE,
An AE is considered “life-threatening” if, in the view of either the investigator or sponsor, its 
occurrence places the patient or subject at immediate risk of death.  It does not include an AE 
that, had it occurred in a more severe form, might have caused death.  The determination of 
whether an AE is life threatening can be based on the opinion of either the investigator or 
sponsor.  Thus, if either believes that it meets the definition of life-threatening, it must be 
considered life-threatening for reporting purposes.
Inpatient hospitalization or prolongation of existing hospitalization,
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, or


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A congenital anomaly/birth defect.
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition.  Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse.
This definition of an SAE permits either the sponsor or the investigator to decide if an event is 
serious.  Because SAEs are critically important for the identification of significant safety 
problems, FDA believes taking into account both the investigator’s and the sponsor’s assessment 
is important.  For example, the investigator’s perspective may be informed by having actually 
observed the event, and the sponsor is likely to have broader knowledge of the drug and its 
effects to inform its evaluation of the significance of the event.  If either the sponsor or 
investigator believes that the event is serious, the event must be considered serious and evaluated 
by the sponsor for possible expedited reporting.
8.3.2.1.3.
Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information
Collection of AEs and SAEs will begin at the time a subject signs informed consent and continue
until the follow-up visit. SAEs that are spontaneously reported by the subject or subject 
representative or discovered by the investigator or designee after the follow-up visit and up to 30 
days after the last dose of IP must be collected and reported.
All SAEs will be recorded and reported to PPD or Axovant Sciences within 24 hours of the 
investigator becoming aware of the SAE.
Investigators are not obligated to actively seek AEs or SAEs in former study subjects. However, 
if the investigator learns of any SAE, including a death, at any time after a subject has been 
discharged from the study, and he/she considers the event reasonably related to the 
investigational product or study participation, the investigator must promptly notify the sponsor
or sponsor representative.
8.3.2.1.4.
Assessment of Adverse Events
The severity of each AE will be assessed by the investigator, or designee approved and 
documented for this study, as mild, moderate, or severe based on the below definitions:
Mild: Event that is usually transient and may require only minimal treatment or therapeutic 
intervention.  The event does not generally interfere with usual activities of daily living.


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Moderate: Event that is usually alleviated with additional specific therapeutic intervention.  
The event interferes with usual activities of daily living, causing discomfort, but poses no 
significant or permanent risk of harm to the subject.
Severe: Event that interrupts usual activities of daily living or significantly affects clinical 
status, or may require intensive therapeutic intervention.
Note that severity is not the same as “seriousness,” which is defined in Section 8.3.2.1.2.
Outcome will be assessed using the following categories: recovered/resolved, not recovered/not 
resolved, recovered/resolved with sequelae, fatal, or unknown.
Causality with respect to IP will be assessed as follows:
Certain: 
o
An event or laboratory test abnormality, with plausible time relationship to drug 
intake 
o
Cannot be explained by disease or other drugs 
o
Response to withdrawal is plausible (pharmacologically, pathologically) 
o
Event definitive pharmacologically or phenomenologically (i.e., an objective and 
specific medical disorder or a recognized pharmacological phenomenon) 
o
Re-challenge satisfactory, if necessary 
Probable: 
o
An event or laboratory test abnormality, with reasonable time relationship to drug 
intake 
o
Unlikely to be attributed to disease or other drugs 
o
Response to withdrawal is clinically reasonable 
o
Re-challenge not required 
Possible: 
o
An event or laboratory test abnormality, with reasonable time relationship to drug 
intake 
o
Could also be explained by disease or other drugs 
o
Information on drug withdrawal may be lacking or unclear 
Unlikely: 
o
An event or laboratory test abnormality, with a time to drug intake that makes a 
relationship improbable (but not impossible) 
o
Disease or other drugs provide plausible explanations 
Not Related: 
o
An event or laboratory test abnormality, with a time to drug intake that makes a 
relationship impossible
Disease or other drugs provide definitive explanations.


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8.3.2.1.5.
Method of Detecting Adverse Events and Serious Adverse Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning is the preferred method to inquire about AE occurrence.  
Appropriate questions include:
“How are you feeling?”
“Have you had any (other) medical problems since your last visit/contact?”
“Have you taken any new medicines, other than those provided in this study, since your last 
visit/contact?”
8.3.2.1.6.
Follow-up of Adverse Events and Serious Adverse Events
After the initial AE/SAE report, the investigator is required to proactively follow each subject at 
subsequent visits/contacts.  All AEs and SAEs will be followed until resolution, until the 
condition stabilizes, until the event is otherwise explained, or until the subject is lost to 
follow-up.
8.3.2.1.7.
Reporting of Serious Adverse Events
All new SAEs must be reported in English, by the Investigator, within 24 hours of awareness of 
the event, through data entry in the Adverse Event electronic case report form (eCRF) via the 
Medidata RAVE electronic data capture (EDC) system. In the event that the Medidata RAVE 
EDC system is unavailable, the paper Serious Adverse Event Report form should be used and 
faxed to the PPD Pharmacovigilance (PVG) Safety Hotline Fax Number shown below:
Americas: 888-488-9697
Europe: +44 1223 374 102 
For the initial SAE notification report, the investigator must provide, at minimum, basic 
information such as the protocol number, subject identification number, period of IP intake, 
event term, nature of the event, the seriousness criteria and the investigator’s attribution 
regarding relatedness to investigational product.  In addition, the initial SAE report should 
include all pertinent known information about the SAE and the affected subject. In addition, the 
investigator should provide a narrative to describe the course of events including any treatments 
or relevant procedures.  If requested by PPD PVG, any missing or additional relevant 
information concerning the SAE should be entered into the Medidata RAVE EDC system or 
faxed to PPD PVG. Full supporting documentation should be solicited by the investigative site 
even if the SAE occurred at another institution.  Such documentation may include copies of 
relevant medical/hospital records, pathology, or autopsy reports. 


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8.3.2.1.8.
Regulatory Reporting Requirements for Serious Adverse Events
Prompt notification by the investigator to the sponsor or sponsor representative of all SAEs and 
non-serious AEs occurring during a clinical trial is essential so that legal obligations and ethical 
responsibilities towards the safety of subjects and the safety of a product under clinical 
investigation are met.
Axovant Sciences has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  Axovant Sciences
will comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee (IEC) and 
investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse reactions (those 
not listed in the Investigator Brochure) according to local regulatory requirements and Axovant
Sciences policy and are forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE(s) or other specific 
safety information (e.g., summary or listing of SAEs) from Axovant Sciences will file it with the 
Investigator Brochure and will notify the IRB/IEC, if appropriate according to local 
requirements.
8.3.2.2.
Safety Monitoring Committee (SMC)
An independent SMC will be established by Axovant Sciences to review accumulating study 
data in order to monitor the safety of all subjects enrolled in RVT-101-2001 on an ongoing basis.  
Members of the committee will include clinicians and a biostatistician who are experienced in 
the conduct and monitoring of clinical studies.  No Axovant Sciences employee or investigator 
involved in the RVT-101-2001 study will be a member of the SMC or participate in closed SMC
sessions. However, representatives from Axovant Sciences may attend open meeting sessions 
and will be available to provide additional information to the SMC as requested.
The SMC will review interim safety data accumulated after approximately 30 subjects have 
completed 4 weeks of double-blind treatment. The SMC will also perform additional, periodic,
scheduled reviews of the safety data accrued during the conduct of the study as specified in the 
SMC Charter. After reviewing the interim safety data from RVT-101-2001, the SMC will 
provide their recommendation regarding the acceptability of reducing the visit frequency by 
skipping certain visits (Visits 5, 7 and 9) for both newly enrolled subjects and subjects active in 
the study at the time of the recommendation. Study enrollment will not be stopped or slowed to 
wait for this assessment and will proceed as planned with all visits until the SMC
recommendation is made.
In addition, the SMC may make a recommendation to Axovant Sciences to continue the study
with or without modification or to terminate the study.  All SMC meetings will be properly 
documented in a SMC report.


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The content and format of the safety data provided to the SMC will be in agreement with 
requests by the SMC members and will contain blinded interim safety data.  However, the SMC
will be provided unblinded treatment codes if a significant safety concern is identified.  Ad hoc 
SMC meetings may be held as necessary. All analyses that are required to support the SMC will 
be performed by an unblinded statistician not otherwise involved in the study.
SMC membership and responsibilities will be further outlined in the SMC Charter, which will be 
maintained separately from the protocol.
8.3.2.3.
Physical and Neurological Examinations
Physical examinations will be performed as indicated in Table 2. A complete physical 
examination will include, at a minimum, assessment of the cardiovascular, respiratory, and 
gastrointestinal, and neurological systems. An abbreviated, symptoms-directed physical 
examination will include, at a minimum, assessments of the lungs, cardiovascular system, and 
abdomen (liver and spleen). Physical examinations at Screening (Visit 1), Visit 3, Visit 10, Visit 
12, Visit 13 and ET will be full examinations; an abbreviated physical examination is required at 
Visit 2, Visit 4, Visit 6, Visit 8 and Visit 11.
Neurological examinations will include assessment of gait, balance, coordination, cranial nerves 
and motor and sensory systems. Abnormal findings on the physical or neurological exams that 
are clinically significant should be recorded as AEs on the eCRF.
8.3.2.4.
Vital Signs
Vital signs will be measured at each visit after the subject has been in the supine position for a
minimum of 5 minutes and will include temperature, systolic and diastolic blood pressures, HR,
and respiratory rate. For subjects who are unable to lie down, the vital signs can be measured 
after the subject has been in a seated position for 5 minutes.
Postural changes in systolic and diastolic blood pressures, HR, and respiratory rate will be 
measured within 3 minutes after standing. For subjects who are unable to stand, the postural 
change in these parameters can be made in the seated position.
Body weight will also be recorded at each visit and height will be recorded only at Screening
(Visit 1). Abnormal vital signs that are clinically significant should be recorded as AEs on the 
eCRF.
8.3.2.5.
Electrocardiogram (ECG)
Single 12-lead ECGs will be obtained at all visits, except Visit 5, Visit 7 and Visit 9 using an 
ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc 
intervals with the subject in the supine position after 5 minutes. The investigator or designated 
qualified individual at the site will evaluate the Screening ECG for any abnormalities that should 
exclude the subject from the study or require acute additional evaluation or intervention.  They 


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should also evaluate the ECG printouts for all subsequent visits for any new abnormalities.  Any 
abnormality should include a determination of clinical significance.  A clinically significant ECG 
finding is one that requires additional medical evaluation or treatment. Abnormal ECG findings 
that are clinically significant should be recorded as AEs on the eCRF. If the QTc interval is 
, ensure the subject was fasting for at least 2 
hours and was in a supine position for at least 5 minutes prior to obtaining the reading, as this 
can influence the QTc interval. If the subject was not fasting for at least 2 hours or was not 
supine for 5 minutes, repeat the ECG.
8.3.2.6.
Clinical Safety Laboratory Assessments
All protocol-required laboratory assessments, as defined in Table 5, must be conducted in 
accordance with the laboratory manual and Protocol Time and Events Schedule (Table 2).
Laboratory requisition forms must be completed and samples must be clearly labelled with the 
subject number, protocol number, site/center number, and visit date. Details for the preparation
and shipment of samples will be provided by the laboratory and are detailed in the laboratory 
manual. Reference ranges for all safety parameters will be provided to the site by the laboratory 
responsible for the assessments.
Abnormal laboratory tests that are clinically significant should also be recorded as AEs on the 
eCRF. Clinically significant means that the confirmed abnormal test result has an impact on
patient management, including additional monitoring or diagnostic tests, or changes in treatment.
The same standard applies to additional non-protocol specified laboratory assessments that are 
performed at the institution’s local laboratory and result in a change in subject management (i.e.,
monitoring, diagnostic tests, or any alteration in treatment).
Refer to the laboratory manual for appropriate processing and handling of samples to avoid 
duplicate and/or additional blood draws.
Hematology, clinical chemistry, urinalysis, and other screening laboratory parameters to be 
tested are listed in Table 5.


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Table 5.
Protocol-Required Screening and Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet count
RBC count
Hemoglobin
Hematocrit
RBC Indices
MCV
MCH
WBC Count with Differential
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Clinical 
Chemistry
BUN
Creatinine
Glucose
Potassium
Sodium
Calcium
Chloride
Bicarbonate
AST
ALT
Alkaline phosphatase
Total and direct bilirubin
Total protein
Albumin
GGT
Routine 
Urinalysis
Specific gravity
pH, glucose, protein, blood, and ketones
Microscopic examination (if blood or protein is abnormal)
Screening Tests
only
Blood alcohol and urine drug screen (done at Screening and Baseline)
HBsAg
Hepatitis C antibody
TSH
Vitamin B12
Syphilis serology
Serum or urine hCG pregnancy test (for women of child bearing potential
including at Baseline, follow-up and early termination visits)
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; 
FSH = follicle stimulating hormone; GGT = gamma glutamyltransferase; HBsAg = hepatitis B surface antigen; 
hCG = human chorionic gonadotropin; MCH = mean corpuscular hemoglobin; MCV = mean corpuscular 
volume; RBC = red blood cell; TSH = thyroid stimulating hormone; WBC = white blood cell.
All laboratory tests with values that are considered clinically significantly abnormal during 
participation in the study or within 7 days after the last dose of IP should be repeated until the 
values return to normal or baseline or until the value stabilizes.  If such values do not return to 
normal within a period judged reasonable by the investigator, the etiology should be identified 
and the Medical Monitor notified.
8.3.2.7.
Assessment of Suicidality
Subjects will be assessed for suicidality before and during the study using the Columbia Suicide 
Severity Rating Scale (C-SSRS).  Subjects considered to be at significant risk will be excluded 
from the study.  The C-SSRS is a brief measure which is designed to assess severity and change 
of suicidality by integrating both behavior and ideation.  It assesses intensity of ideation (a 
potentially important marker of severity), specifically asking about frequency, duration, 


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controllability, deterrents, and reasons for the ideation which was most severe during the 
respectively assessed timeframe.  Suicidal behavior is also assessed by asking further questions 
to categorize the behaviors into actual, interrupted, or aborted attempts; as well as preparatory 
and non-suicidal self-injurious behavior. The C-SSRS will be completed by a rater trained and 
certified to administer this scale.  Any change in C-SSRS score indicating the presence of 
suicidality should be evaluated by the investigator for clinical significance to determine 
continued study eligibility (Section 6.3) and appropriate clinical actions (including but not 
limited to a referral to a mental health professional).
Clinically meaningful suicidal ideation, suicidal behavior and completed suicide should be 
recorded as adverse events.
8.3.2.8.
Questionnaire for Symptoms Potentially Associated with Orthostasis
At all visits, a short questionnaire will be used to assess the occurrence of 
dizziness/lightheadedness, fainting/loss of consciousness and falls. The questionnaire will collect 
the occurrence of symptoms from a pre-defined checklist of terms as well as the frequency and 
severity of the symptoms.
8.3.2.9.
Pregnancy
Details of all pregnancies in female subjects will be collected after the start of dosing and until 
30 days after the last dose of IP.
Pregnancies are not considered AEs but are to be reported by the Investigator within 24 hours of 
the site’s awareness using the paper Pregnancy Report Form, which should be faxed to the PPD 
PVG Safety Hotline Fax Number as shown below:
North America: 888-488-9697
EMEA: +44 1223 374 102 
The pregnancy must be followed up to determine outcome (including premature termination) and 
status of mother and child.  Pregnancy complications and elective terminations for medical 
reasons must be reported as an AE or SAE. Spontaneous abortions must be reported as an SAE.
Follow-up information documenting the pregnancy outcome should be captured in the Follow-up
Pregnancy Report Form, which should be faxed to PPD PVG.
Any SAE occurring in association with a pregnancy brought to the investigator’s attention after 
the subject has completed the study and considered by the investigator as possibly related to the 
investigational product must be promptly reported to the sponsor or the sponsor’s representative.
The investigator must attempt to collect pregnancy information on any female partners of male 
study subjects who become pregnant while the subject is enrolled in the study.  Pregnancy 
information must be reported to the sponsor or sponsor’s representative as described above. The 


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partner will also be followed to determine the outcome of the pregnancy. Information on the 
status of the mother and child will be forwarded to the sponsor or sponsor’s representative.
Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery date. 
Any premature termination of the pregnancy will be reported.
8.3.2.10.
Lewy Body Composite Risk Score (LBCRS)
The LBCRS is a scale that has been shown to help discriminate DLB from other causes of 
dementia, such as Alzheimer’s disease, using a cut-off score of 3 (Galvin, 2015). LBCRS will be 
administered during screening to collect baseline information regarding the clinical presentation 
of DLB symptoms.
8.3.2.11.
CT scan or MRI
An MRI or CT scan will be performed between Visit 1 and Visit 2 if no scan has been performed 
within the 12 months prior to the Screening Visit. These scan findings must be consistent with 
the diagnosis of dementia due to DLB without any other clinically significant pathologies.
8.3.2.12.
PET or SPECT
A PET or SPECT scan PET / SPECT imaging is not required. However, it may be performed 
during Screening for eligibility per inclusion criterion number 1.
8.3.3.
Pharmacokinetics
Blood samples for PK analysis of RVT-101 will be collected during the study visits indicated in 
Section 8.1. The actual date and time of each blood sample collection will be recorded, as well 
as the date and time of the previous dose of IP.  The timing of PK samples may be altered and/
or PK samples may be obtained at additional time points to ensure thorough PK monitoring.
Two PK samples per subject will be taken for the purpose of assessing plasma concentrations of 
RVT-101 at the following specific time points:
At Visit 6 (Week 4), the blood sample should be taken after cognitive testing, ECG, 
questionnaire for dizziness and falls, and vital signs measurements have been performed.
At Visit 8 (Week 8), the blood sample should be taken after cognitive testing, ECG, 
questionnaire for dizziness and falls, and vital signs measurements have been performed.
Unscheduled PK samples may be requested by Axovant Sciences or the Medical Monitor 
after discussion with investigators (e.g., in cases of suspected drug toxicity).
The samples will be centrifuged and the resulting plasma will be shipped to a central laboratory.
Further details with regard to shipping, collection, and processing of samples are provided in the 
laboratory manual.


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Plasma analysis will be performed under the control of Axovant Sciences. Concentrations of 
RVT-101 and RVT-101 metabolites will be determined in plasma samples using the currently 
approved bioanalytical methodology. Raw data will be archived at the bioanalytical site.
Once the plasma has been analyzed for RVT-101, any remaining plasma may be analyzed for 
other compound-related metabolites and the results reported under a separate protocol.


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9.
DATA MANAGEMENT
For this study subject data will be entered into Axovant Sciences defined eCRFs, transmitted 
electronically to Axovant Sciences or designee, and combined with data provided from other 
sources in a validated data system.
Management of clinical data will be performed in accordance with applicable Axovant Sciences’
or its representative’s standards and data cleaning procedures to ensure the integrity of the data, 
e.g., correcting errors and inconsistencies in the data.
AEs and medical history terms will be coded using an agreed version of the Medical Dictionary 
for Regulatory Activities (MedDRA), using Axovant Sciences’ or its representative’s coding 
conventions.
Concomitant medications will be coded using the WHO ATC classification 
(http://www.whocc.no/filearchive/publications/1_2013guidelines.pdf).
The eCRFs (including queries and audit trails) will be retained by Axovant Sciences, and copies 
will be sent to the investigator to maintain as the investigator copy.  


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10.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES
10.1.
Hypotheses
The primary statistical framework will be to demonstrate superiority of RVT-101 over placebo.
The null hypothesis 
hypothesis to be rejected.
There is NO statistically significant difference between Intepirdine and placebo in the 
mean change from baseline to Week 24 in the UPDRS- III.
There IS a statistically significant difference between Intepirdine and placebo in in 
the mean change from baseline to Week 24 in the UPDRS- III.
The individual Intepirdine arms will be tested, as follows:
Intepirdine 70 mg vs placebo
Intepirdine 35 mg vs placebo
All hypothesis tests will be 2-sided, performed at the 5% level of significance. 
The primary endpoint needs to achieve a significance level of 0.05 within an Intepirdine dose to 
allow for testing of the secondary endpoints within that dose.
10.2.
Sample Size Considerations
The sample size is based on assumptions of treatment benefit for one primary endpoint, the 
UPDRS- III total score.  A sample size of 70 subjects per treatment group will allow a treatment 
difference of 4 points between placebo and active treatment in the change from baseline in 
UPDRS- III score to be detected with 88% power and a 0.05 significance level assuming an 
underlying standard deviation (SD) of 7.5
There are two secondary endpoints:
ADAS-Cog 11 total score.  A sample size of 80 subjects per treatment group will 
allow a treatment difference of 3 points between placebo and active treatment in the 
change from baseline in ADAS-Cog-11 score to be detected with 88% power and a 
0.05 significance level assuming an underlying standard deviation (SD) of 6. Under 
the assumptions of a 2.5, 2.0 and 1.5-point treatment effect, the power is 74%, 55% 
and 35%, respectively.
CIBIC+. A sample size of 80 subjects per treatment group will allow a treatment 
difference of 0.5 points between placebo and active treatment in the observed values 
in the CIBIC+ to be detected with 91% power and a 0.05 significance level assuming 
an underlying standard deviation (SD) of 0.95. Under the assumptions of a 0.4 and 
0.3-point treatment effect, the power is 75% and 51%, respectively. Randomization
will be stratified according to Baseline MMSE score in the groupings of 14-17 points, 
18-21 points and 22-26 points and according to whether subjects are or are not taking 
a cholinesterase inhibitor as a concomitant medication.


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Randomization will be stratified according to Baseline MMSE score in the groupings of 14-17
points, 18-21 points and 22-26 points and according to whether subjects are or are not taking a 
cholinesterase inhibitor as a concomitant medication.
10.3.
Data Analysis Considerations
10.3.1.
Analysis Populations
It is intended that a complete accounting of patients for the analysis populations will be provided, 
from the Screening Population through the Per-Protocol Population.
Screening Population:  All patients who are screened (signed an informed consent) 
will be included in the Screening Population.  
Placebo Run-In Population:  All patients who took at least 1 dose of IP in the Placebo 
Run-in will be included in the Placebo Run-In Population.  This population will be 
used to provide an accounting of the disposition of patients during this phase of the 
study.
Randomized Population: The Randomized Population will include all patients who 
are randomized. 
Safety Population: All subjects who were randomized and took at least one dose of 
double-blind investigational product.
Intent-to-Treat (ITT): All subjects randomized to treatment who have taken at least 
one dose of double-blind IP and who have a baseline and at least one post-baseline 
efficacy assessment for the UPDRS-III or for the ADAS-Cog 11.  This will be the 
primary population used for the efficacy analysis of all variables EXCEPT the 
UPDRS Part III and Part 5. In analyses using this population, subjects will be grouped 
according to their randomized treatments.
UPDRS Primary Analysis Population:  This will be the primary population used for 
the UPDRS Part III efficacy analysis, and is comprised of all ITT patients 
EXCLUDING those with no change OR a worsening in UPDRS-III total score prior 
to a dose increase in anti-parkinsonian medications and where there is subsequent
improvement or stabilization of UPDRS-III total score. 
Dose increase in anti-parkinsonian medication is defined as an increase in dose, 
dose frequency or commencement of the medication where the total daily dose of 
the medication at Week 24 is higher than at Baseline.
UPDRS Sensitivity Analysis Population:  All ITT patients EXCLUDING those who 
increase or start an anti-parkinsonian mediation during the double-blind treatment 
period.
Dose increase in an anti-parkinsonian medication is defined as an increase in dose 
or frequency or commencement of the medication where the total daily dose of 
the medication at Week 24 is higher than at Baseline.
Completers (CS) Population:  ITT subjects who have completed the Week 24 visit 
with non-missing endpoints for all three variables, the UPDRS-III, ADAS-Cog 11, 


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and CIBIC+.  This population will be used for supportive analysis of the primary 
efficacy variable and other cognition and efficacy endpoints.
Pharmacokinetics (PK) Population:  All subjects in the Safety Population who 
undergo plasma PK sampling and have at least one post-baseline evaluable PK 
concentration result.
Per-Protocol (PP) Population: Subjects in the ITT Population who have no major 
protocol violations.  The PP Population will not be analyzed if this population 
comprises more than 95% or less than 50% of the ITT Population.  This population 
will be used for confirmatory analysis of the primary efficacy variable and the two 
secondary efficacy variables.  The PP Population will be identified prior to breaking 
the study blind.
10.3.2.
Interim Analysis
No interim analyses are planned.
10.4.
Key Elements of Analysis Plan
All hypothesis tests and confidence intervals will be two-sided at an alpha level of 5%. For 
statistical analysis and use in models, sites will be pooled by geographical region or size.  The 
method of grouping sites will be defined prior to unblinding the study and described in the 
Statistical Analysis Plan (SAP).
All efficacy and safety measures over the course of the study will be presented.  Continuous data 
will be summarized by means, SDs, medians, maximum, minimum, and numbers of subjects.  
Categorical data will be summarized by counts and percentages. Data will be tabulated by 
treatment group.
10.4.1.
Primary Efficacy Analyses
The primary efficacy endpoint is the change from Baseline in the UPDRS-III total score at Week 
24.  The primary method of analysis will be using a mixed model for repeated measures 
(MMRM), with supportive method being the Wilcoxon rank statistic (a nonparametric test).
For the primary efficacy and secondary efficacy variable ONLY, in addition to the primary 
pairwise analyses, a table will be presented that will compare the POOLED data (pooled across 
the 35 mg and 70 mg Intepirdine arms) vs placebo.  This will be done ONLY for the MMRM 
analysis.
Primary treatment comparisons between Intepirdine and placebo will be performed on the 
change from Baseline to Week 24 using an MMRM with restricted maximum likelihood 
estimation, an unstructured covariance matrix, and the Kenward-Roger approximation for 
denominator degrees of freedom. The model will include terms for treatment, visit, treatment by 
visit interaction, pooled geographic region, baseline MMSE score, the baseline value, and the 
baseline value by visit interaction.


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As additional supportive information, treatment differences at each post baseline visit will also 
be derived using the MMRM model; however, primary inferences will be drawn from treatment 
differences derived from the MMRM models at Week 24.
The estimated treatment difference (“Intepirdine 35mg – Placebo” and “Intepirdine 70mg –
Placebo”) at each visit will be displayed in the summary of statistical analysis together with the 
95% confidence interval and the associated p-value.
No imputation of the missing values will be performed for the primary analyses, ie, the data used 
in the analysis will be the actual observed responses at each visit. 
Least Squares Means for each visit will also be presented with the standard error and the number 
of subjects contributing to the Least Squares Means. Least Squares Means and estimated 
treatment differences for each visit and the associated 95% confidence interval will be displayed 
graphically. 
The nature of missing data will be explored and the extent of missing data pattern will be 
summarized. Details will be provided in the SAP.
10.4.2.
Secondary Efficacy Analyses
The secondary efficacy analyses endpoints are the change from baseline in the ADAS-Cog 11
score at Week 24, and the observed scores of the CIBIC+ at Week 24.
This will be analyzed using similar MMRM methods as the primary endpoint (however, for the 
CIBIC+, no baseline value or interaction with visit will be included). A Wilcoxon Rank test will 
also be performed, as will the sensitivity analysis for LOCF to Week 24 and multiple imputation.
The sensitivity analyses as being performed on the primary endpoint (CDF, LOCF, and multiple 
imputation) will be performed for the secondary endpoints.
For the CIBIC+, The number and percentage of subjects in each category of CIBIC+ will also be 
summarized by visit for each treatment group and tested using a CMH RMS test.
10.4.3.
Tertiary Efficacy Analyses
Other cognition and functional efficacy endpoints include:
Change from Baseline on UPDRS-5 at Week 24
Change from Baseline in the ADCS-ADL at Week 24
Change from Baseline in the Basic and Instrumental subscales of the ADCS-ADL at 
Week 24
Change from Baseline in ADAS-Cog-13 at Week 24
Change from Baseline in the Total Composite z-score and in the actual score (NOT the z-
scores) of each individual domain of the CDR computerized assessment system at Week 
24.   Thus, in addition to the Total Composite, this includes the following 7 domains:
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Continuity of Attention
Cognitive Reaction Time
Response Variability
Quality of Working Memory
Quality of Episodic Secondary Memory
Speed of Memory
Change from Baseline in COWAT score at Week 24
Change from Baseline in composite z-score combining the 7 CDR System domains with 
the COWAT
Change from Baseline in the sum of Parts A & B of the NPI at Week 24
Change from Baseline in the total severity score and the distress score on the NEVHI at 
Week 24 for subjects with visual hallucinations
Number (%) of patients with shifts from baseline in the NEVHI Total Severity Score and 
in the Distress Score (ie, 2 separate analyses) at Week 24
Change from Baseline in CAF severity score for each question (there are 2 questions) at 
Week 24
The number (%) of patients with CAF cognition or confusion (ie, a yes on one or the 
other question) at Week 24.
Change from Baseline in DS at Week 24
Comparisons of RVT-101 versus placebo for most of the above endpoints will be performed 
using MMRM similar to the models described for the primary endpoints based on change from 
baseline at Week 24. CMH tests will be used on shifts from baseline in the NEVHI total severity 
score and number (%) of patients with CAF cognition or confusion.
Details and additional sensitivity analyses will be described in the SAP.  
10.4.4.
Exploratory Efficacy Measures
The EQ-5D-5L, Parts D & E of the NPI, and CSI will be summarized descriptively by treatment. 
Treatment comparisons for EQ-5D-5L visual analogue scale between RVT-101 and placebo will 
be analyzed using an ANCOVA model. Comparisons of RVT-101 versus placebo for the change 
from Baseline to Week 24 on each domain and subtest of the CDR and for the CSI score will be 
performed using MMRM or ANCOVA, similar to the models described for the primary 
endpoints.
Details will be provided in the SAP.


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10.4.5.
Safety Analyses
The safety analyses will be based on the Safety Population.
Safety will be assessed by summarizing and analyzing AEs, laboratory analytes, vital signs, ECG 
parameters, physical examination findings, C-SSRS scores, results of the questionnaire of 
symptoms of potential orthostasis, and concomitant medications.
10.4.5.1.
Adverse Events
Adverse events occurring on or after the first dose of double-blind study medication, and within 
7 days of the last dose of double-blind study medication, will be referred to as On-Treatment 
AEs (OTAEs).  If an AE begins or worsens on the first day of investigational product 
administration, a CRF and source data note will be provided to clarify whether it occurred prior 
to or after investigational product administration.  OTAEs, SAEs including deaths, AEs that lead 
to discontinuation of study medication, and AEs by maximum severity and relationship to 
investigational product will be summarized by MedDRA system organ class (SOC) and preferred 
term.  OTAEs will also be summarized by preferred term, sorted by decreasing frequency within 
SOC.  AEs will be summarized separately for the Single-Blind Run-In Period, the Double-Blind 
Treatment Period and the Follow-Up Period.
10.4.5.2.
Clinical Laboratory Tests
Summaries of clinical laboratory data will be provided for subjects in the Safety Population.  No 
inferential statistics will be provided.
Quantitative values and change from Baseline in quantitative values will be summarized by 
planned nominal time and treatment for each quantitative laboratory value.  Listings of all 
laboratory results and reference ranges will be provided.  For multiple lab assessments at the 
same time point, the average of these assessments will be used.
Laboratory values that fall outside of the reference range will be flagged as H=High or L=low.
A lab shift table will summarize the change from the Baseline to the worst post-baseline value.
Laboratory values that do not meet the abnormality criteria will be assigned N=normal in the 
shift table.
10.4.5.3.
Vital Signs, Electrocardiograms, Physical Findings, and Other Safety 
Evaluations
Descriptive summaries of vital signs (including measurements of orthostatic changes in blood 
pressure [BP] and heart rate [HR]), weight, and ECG parameters will be presented separately for 
each study visit and treatment group.  
ECG data will be summarized by treatment, visit, and planned time and listed by subject, visit, 
treatment, planned time and actual date and time.  Change from baseline will also be 
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The incidence of PCS values and overall Investigator interpretation of ECG by visit (shifts from 
baseline) will be presented.
Physical and neurological examination data will be listed by patient and time point..
10.4.5.4.
Suicidality
A subject data listing of all answers of the C-SSRS questionnaire will be presented.  The 
numbers and percentages of subjects reporting suicidal ideation and behavior will be 
summarized.  Additional summaries may be provided if data warrant.  Details will be provided in 
the SAP.
10.4.5.5.
Questionnaire for Signs of Potential Orthostasis
The incidence of dizziness/lightheadedness, fainting/loss of consciousness and falls will be 
analyzed using data collected at each visit in the Treatment Period via the Questionnaire for 
Signs of Potential Orthostasis.
Descriptive summaries of the results from the questionnaire for signs of potential orthostasis will 
be presented separately for each study visit and treatment group.
10.4.6.
Other Analyses
Additional analyses of the data may be conducted as deemed appropriate and will be detailed in 
the SAP.  Further analyses of the data not specified in the SAP may be undertaken as post hoc 
analyses after completion of the study.  Results of all study assessments will be included in an 
appendix to the study report.
10.4.7.
PK Analyses
Plasma concentrations will be listed and summarized by study visit and treatment group.
Pharmacokinetic parameters for RVT-101 (AUC ss, Cmax-ss and Cmin-ss) for each subject may be 
estimated via nonlinear mixed effect modeling using a population PK model based on data from 
previous studies.
10.4.8.
PK / PD
Relationships between RVT-101 PK parameters and measures of safety and efficacy may be 
explored.


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11.
RESPONSIBILITIES
11.1.
Investigator Responsibilities
11.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with the principles of the 
“Declaration of Helsinki” (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and South 
Africa), International Conference on Harmonisation (ICH) guidelines, or with the laws and 
regulations of the country in which the research is conducted, whichever affords the greater 
protection to the study subject. The investigator will ensure that the basic principles of “Good 
Clinical Practice,” as outlined in 21 Code of Federal Regulations (CFR) 312, subpart D, 
“Responsibilities of Sponsors and Investigators,” 21 CFR, part 50, 1998, and 21 CFR, part 56, 
1998, are adhered to. These standards are consistent with the requirements of the European 
Community Directive 2001/20/EC, which shall be adhered to.
Since this is a “covered” clinical trial, the investigator will ensure that 21 CFR, Part 54, 1998, is 
adhered to; a “covered” clinical trial is any “study of a drug or device in humans submitted in a 
marketing application or reclassification petition subject to this part that the applicant or FDA 
relies on to establish that the product is effective (including studies that show equivalence to an 
effective product) or that make a significant contribution to the demonstration of safety.” This
requires that investigators and all sub-investigators must provide documentation of their financial 
interest or arrangements with Axovant Sciences, or proprietary interests in the drug being 
studied. This documentation must be provided before participation of the investigator and any 
sub-investigator. The investigator and sub-investigator agree to notify Axovant Sciences of any 
change reportable interests during the study and for one year following completion of the study. 
Study completion is defined as the date that the last subject has completed the protocol defined 
activities.
This study is also subject to and will be conducted in accordance with 21 CFR, part 320, 1993, 
“Retention of Bioavailability and Bioequivalence Testing Samples.”
11.1.2.
Institutional Review Board/Independent Ethics Committee Approval
This protocol and any accompanying material to be provided to the subject and caregiver (such 
as advertisements, subject information sheets, or descriptions of the study used to obtain
informed consent) will be submitted by the investigator to an IRB or IEC. Approval from the
IRB or IEC must be obtained before starting the study and should be documented in a letter to 
the investigator specifying the protocol number, protocol version, protocol date, documents
reviewed, and date on which the committee met and granted the approval.
Any modifications made to the protocol or other documents described in the above paragraph 
after receipt of IRB or IEC approval must also be submitted to the IRB or IEC for approval 
before implementation.


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11.1.3.
Informed Consent
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and
potential hazards of the study and before undertaking any study-related procedures. The
investigator must utilize an IRB- or IEC-approved consent form for documenting written
informed consent. Each informed consent will be appropriately signed and dated by the subject 
or the subject’s LAR and the person obtaining consent. Consent from both the caregiver and 
subject should be obtained (or subject’s LAR).
11.1.4.
Confidentiality
The investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only subject initials, date of birth, and an 
identification code (i.e., not names) should be recorded on any form or biological sample 
submitted to Axovant Sciences, IRB or IEC, or laboratory. The investigator must keep a
screening log showing codes, names, and addresses for all subjects screened and for all subjects 
enrolled in the trial. In countries where the subjects’ names, initials and/or date of birth cannot be 
used by local regulations, study sites will use dummy initials and or year of birth only.
The investigator agrees that all information received from Axovant Sciences, including but not
limited to the Investigator’s Brochure, this protocol, eCRFs, the investigational new drug, and
any other study information, remain the sole and exclusive property of Axovant Sciences during 
the conduct of the study and thereafter. This information is not to be disclosed to any third party 
(except employees or agents directly involved in the conduct of the study or as required by law) 
without prior written consent from Axovant Sciences. The investigator further agrees to take all 
reasonable precautions to prevent the disclosure by any employee or agent of the study site to 
any third party or otherwise into the public domain.
11.1.5.
Study Files and Retention of Records
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following two categories: (1) investigator’s study file, and 
(2) subject clinical source documents.
The investigator’s study file will contain the protocol/amendments, eCRF and query forms, IRB 
or IEC and governmental approval with correspondence, informed consent, drug records, staff 
curriculum vitae and authorization forms, and other appropriate documents and correspondence.


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The required source data are listed in the Source Data Verification Plan, and should include 
sequential notes containing at least the following information for each subject:
Documentation that subject meets eligibility criteria, i.e., history, physical 
examination, and confirmation of diagnosis (to support inclusion and exclusion 
criteria);
Participation in trial (including trial number);
Trial discussed and date of informed consent;
Dates of all visits;
Documentation that protocol specific procedures were performed;
Results of efficacy parameters, as required by the protocol;
Start and end date (including dose regimen) of trial medication (preferably drug 
dispensing and return should be documented as well);
Record of all AEs and other safety parameters (start and end date, and preferably
including causality and intensity);
Concomitant medication (including start and end date, dose if relevant; dose changes
should be motivated);
Date of trial completion and reason for early discontinuation, if applicable.
All clinical study documents must be retained by the investigator until at least 2 years after the 
last approval of a marketing application in an ICH region (i.e., United States, Europe, or Japan) 
and until there are no pending or contemplated marketing applications in an ICH region; or, if no 
application is filed or if the application is not approved for such indication, until 10 years after 
the investigation is discontinued and regulatory authorities have been notified. Investigators may 
be required to retain documents longer if required by applicable regulatory requirements, by 
local regulations, or by an agreement with Axovant Sciences. The investigator must notify 
Axovant Sciences before destroying any clinical study records.
Should the investigator wish to assign the study records to another party or move them to another 
location, Axovant Sciences must be notified in advance.
If the investigator cannot guarantee this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Axovant
Sciences to store these in sealed containers outside of the site so that they can be returned sealed 
to the investigator in case of a regulatory audit. When source documents are required for the 
continued care of the subject, appropriate copies should be made for storage outside of the site.


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11.1.6.
Electronic Case Report Forms
For each subject enrolled, an eCRF must be completed and signed by the principal investigator 
or sub-investigator (as appropriate) within a reasonable time period after data collection. This 
also applies to records for those subjects who fail to complete the study (even during a 
pre-randomization screening period if an eCRF was initiated). If a subject withdraws from the 
study, the reason must be noted on the eCRF. If a subject is withdrawn from the study because 
of a treatment-limiting AE, thorough efforts should be made to clearly document the outcome.
11.1.7.
Drug Accountability
The investigator or designee (i.e., pharmacist) is responsible for ensuring adequate accountability 
of all used and unused IP. This includes acknowledgment of receipt of each shipment of IP
(quantity and condition), subject dispensing records, and returned or destroyed IP. Dispensing 
records will document quantities received from Axovant Sciences and quantities dispensed to 
subjects, including lot number, date dispensed, subject identifier number, subject initials (where 
allowed by local regulations), and the initials of the person dispensing the IP.
The investigator or his/her designee will be responsible for maintaining accurate records of IP
dispensing and collection and for returning all unused IP to Axovant Sciences or its designee at 
the end of the study.  Detailed instructions for return of IP will be provided in the pharmacy 
manual.
All drug supplies and associated documentation will be periodically reviewed and verified by the 
study monitor over the course of the study.
11.1.8.
Inspections
The investigator should understand that source documents for this trial should be made available 
to appropriately qualified personnel from Axovant Sciences or its representatives, to IRBs or 
IECs, or to regulatory authority or health authority inspectors.
11.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
11.2.
Sponsor Responsibilities
11.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Axovant Sciences. All protocol modifications must be submitted to the IRB or 
IEC in accordance with local requirements. Approval from the IRB or IEC must be obtained 
before changes can be implemented. In the case of substantial protocol amendments, approval 
from the Competent Regulatory Authorities will be sought before implementation.


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11.2.2.
Study Report and Publications
A clinical study report will be prepared and provided to the regulatory agency(ies). Axovant
Sciences will ensure that the report meets the standards set out in the ICH Guideline for Structure 
and Content of Clinical Study Reports (ICH E3). Note that an abbreviated report may be 
prepared in certain cases.
After conclusion of the study and without prior written approval from Axovant Sciences, 
investigators in this study may communicate, orally present, or publish in scientific journals or 
other scholarly media only after the following conditions have been met:
the results of the study in their entirety have been publicly disclosed by or with the
consent of Axovant Sciences in an abstract, manuscript, or presentation form; or
the study has been completed at all study sites for at least 5 years.
No such communication, presentation, or publication will include Axovant Sciences’ 
confidential information (see Section 11.1.3).
The investigator will submit any proposed publication or presentation along with the respective 
scientific journal or presentation forum at least 30 days before submission of the publication or 
presentation. The investigator will comply with Axovant Sciences’ request to delete references 
to its confidential information (other than the study results) in any paper or presentation and 
agrees to withhold publication or presentation for an additional 60 days in order to obtain patent 
protection if deemed necessary.
11.2.3.
Posting of Information on Publicly Available Clinical Trial Registers
Study information from this protocol will be posted on publicly available clinical trial registers 
before enrollment of subjects begins. Results will be posted as required.
11.3.
Joint Investigator/Sponsor Responsibilities
11.3.1.
Access to Information for Monitoring
In accordance with ICH Good Clinical Practice (ICH GCP) guidelines, the study monitor must 
have direct access to the investigator’s source documentation in order to verify the data recorded 
in the eCRFs for consistency.
The monitor is responsible for routine review of the eCRFs at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them. The monitor should have access to any subject records needed to 
verify the entries on the eCRFs. The investigator agrees to cooperate with the study monitors to 
ensure that any problems detected in the course of these monitoring visits are resolved.


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11.3.2.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Axovant Sciences may conduct inspections or 
audits of the clinical study. If the investigator is notified of an inspection by a regulatory
authority the investigator agrees to notify the Axovant Sciences medical monitor immediately.
The investigator agrees to provide to representatives of a regulatory agency or Axovant Sciences 
access to records, facilities, and personnel for the effective conduct of any inspection or audit.
11.3.3.
Study Discontinuation
Axovant Sciences reserves the right to terminate the study at any time. Should this be necessary, 
both parties will arrange discontinuation procedures and notify the appropriate regulatory 
authority(ies), IRBs, and IECs. In terminating the study, Axovant Sciences and the investigator
will assure that adequate consideration is given to the protection of the subjects’ interests. The 
investigator may discontinue participation in the study at any time.  However, the obligations to 
provide study results for completed subjects and reports to ethics committees shall continue as 
required by this protocol and applicable laws and regulations.


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12.
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Maher-Edwards, G., Watson, C., Ascher, J., et al. (2015). Two randomized controlled trials of 
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SAP_001.pdf: 
























X
ADCS-ADL 
 
 
X 
 
 
 
 
 
 
X 
 
X 
Parts A, B, D & E
-5L








































NO
IS




or
subsequent
























NO
IS


each post baseline visit
Sample
ods trace on; 


Proc mixed data=MMRM1 method=reml PLOTS(MAXPOINTS=200000000000); 
  class usubjid trt avisitn region; 
  model chg=trt avisitn trt*avisitn trt*region base basemmsescore 
base*avisitn region /ddfm=kr; 
  repeated avisitn/subject=usubjid type=un r; 
  lsmeans trt*avisitn/pdiff cl ; 
  lsmeans trt*region/pdiff alpha =0.10; 
  ods output lsmeans=_LS diffs=_lsdiff  tests3  =tst; 
run;
ods trace off; 
Sample
Proc npar1way data=dat; 
  By visit; 
  Class treat; 
  Var chg_from_baseline; 
  ods select WilcoxonScores


Sample
Proc Mixed data=dat; 
  Class treat MMSEbase center; 
  Model outcome=treat mmsebase center basescore; 
  Run;


proc mi data=DATAIN out=DATAIN_MONO nimpute=100 seed=123;
var TRT Eff1 Eff2 …. Eff_last; 
mcmc chain=multiple impute=monotone;
run;


**First procedure imputes missing values for the first visit (Week 4); 
proc mi data=DATAIN_MONO out=DATAREG1 seed=465 nimpute=1;
by _Imputation_;
var visitnum1 basescore MMSEbase region previous; 
monotone regression(visitnum1);
run;
  ** Second procedure imputes missing values for the second visit (Week 24) 
proc mi data=DATAREG1 out=DATAREG2 seed=465 nimpute=1;
by _Imputation_;
var visitnum1 visitnum2 basescore MMSEbase region previous; 
monotone regression(visitnum2);
run;




Sample
Proc freq data=dat; 
  Tables MMSEbase*treat*outcome / cmh rms; 
  Run;