Clinical trial NCT02910102
Conditions: Alzheimer's Disease Dementia With Lewy Bodies Parkinson's Disease Dementia
Keywords: RVT-101 intepirdine Alzheimer's disease Dementia with Lewy bodies Lewy body dementia Parkinson's Disease Dementia
Sponsor: Axovant Sciences Ltd.
Start date: 2016-10-01; Completion date: 2017-11-01
Enrollment: 38 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study seeks to evaluate the effect of intepirdine (RVT-101) on gait and balance in patients with Alzheimer's Disease, Dementia with Lewy Bodies or Parkinson's Disease Dementia.

Detailed description:
To assess the effect of intepirdine (RVT-101) versus placebo on quantitative and qualitative gait and balance parameters.

Each subject will be randomized 1:1 to one of the following sequences:

Sequence 1: AB = RVT-101 35 mg during the early treatment period and Placebo during the late treatment period

Sequence 2: BA = Placebo during the early treatment period and RVT-101 35 mg during the late treatment period

Treatment A = RVT-101 35 mg once daily.

Treatment B = Placebo once daily.

Arms: arm 1: RVT-101 35 mg in Period II and Placebo in Period IV arm 2: Placebo in Period II and RVT-101 35 mg in Period IV
Interventions: intervention 1: RVT-101 35 mg intervention 2: Placebo
Intervention descriptions: intervention 1: RVT-101 once daily, oral, 35-mg tablets intervention 2: Placebo once daily, oral

Protocol documents:
Prot_000.pdf: 
Axovant Sciences Ltd.
CONFIDENTIAL
Protocol RVT-101-2003 v3.0
07 Feb 2017
1
CLINICAL STUDY PROTOCOL
Title:
A Phase 2, double-blind, randomized, placebo-controlled crossover 
study evaluating the effect of RVT-101 on gait and balance in 
subjects with Alzheimer’s Disease, Dementia with Lewy Bodies, or 
Parkinson’s Disease Dementia
Sponsor
Axovant Sciences Ltd.
Compound Name:
RVT-101
Protocol Number
RVT-101-2003
Indications
Alzheimer’s Disease, Dementia with Lewy Bodies, Parkinson’s 
Disease Dementia
Development Phase
Phase 2
IND #
78,094
Version/
Date:
3.0
07 Feb 2017
Study Director
Name:
Harald Murck, MD PhD
Telephone:
201-294-1195
Email:
Harald.murck@axovant.com
Medical Monitor
Name:
Sue Frederick, MD
Telephone:
919-614-5103
Email:
Sue.Frederick@innoclinical.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The information contained in this document, particularly unpublished data, is the property or under 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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Protocol RVT-101-2003 v3.0
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SPONSOR SIGNATURE PAGE
Study title:
A Phase 2, double-blind, randomized, placebo-controlled crossover study 
evaluating the effect of RVT-101 on gait and balance in subjects with 
Alzheimer’s Disease, Dementia with Lewy Bodies, or Parkinson’s Disease 
Dementia
Protocol Number:
RVT-101-2003
This protocol has been approved by Axovant Sciences Ltd. The following signatures document 
this approval.
Marianne L. Romeo
Authorized Signatory, Axovant Sciences Ltd.
Date
Harald Murck MD, PhD
Vice President, Clinical Research, Axovant Sciences, Inc.
Date
Shari Coslett 
Senior Director, Clinical Operations, Axovant Sciences, Inc.
Date
Aaron Yarlas, PhD
Statistician
Date
Esin Kosal, PhD
Vice President, Global Regulatory Affairs, Axovant Sciences, 
Inc.
Date
Ilise Lombardo, MD
Senior Vice President, Clinical Research, Axovant Sciences, 
Inc.
Date


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MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/Serious Adverse Event Contact Information:
Name
Contact Information
Medical Monitor
Sue Frederick
Phone: 
919-614-5103
Email:
Sue.Frederick@innoclinical.com
SAE and 
Pregnancy 
Reporting Contact 
Information
n/a
Fax: 
1-866-408-1318
Email: 
SAE-101Gait@innoclinical.com
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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Protocol RVT-101-2003 v3.0
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INVESTIGATOR STATEMENT
I agree to conduct the study in compliance with the protocol.
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 fulfill 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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Protocol RVT-101-2003 v3.0
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TABLE OF CONTENTS
PAGE
CLINICAL STUDY PROTOCOL ............................................................................................................... 1 
SPONSOR SIGNATURE PAGE.................................................................................................................. 2 
MEDICAL MONITOR/SPONSOR INFORMATION PAGE ..................................................................... 3 
INVESTIGATOR STATEMENT................................................................................................................. 4 
TABLE OF CONTENTS.............................................................................................................................. 5 
LIST OF TABLES........................................................................................................................................ 8 
1. 
ABBREVIATIONS............................................................................................................................... 9 
2. 
PROTOCOL SUMMARY.................................................................................................................. 11 
3. 
INTRODUCTION .............................................................................................................................. 14 
3.1. 
Background............................................................................................................................ 14 
3.1.1. 
Disease State.......................................................................................................... 14 
3.1.2. 
Investigational Product.......................................................................................... 15 
3.2 
Study Rationale..................................................................................................................... 15 
3.3 
Dose Rationale...................................................................................................................... 16 
4. 
OBJECTIVES AND ENDPOINTS .................................................................................................... 17 
5. 
STUDY DESIGN................................................................................................................................ 18 
5.1. 
Overall Design ....................................................................................................................... 18 
5.2. 
Study Schematic..................................................................................................................... 18 
6. 
SUBJECT POPULATION.................................................................................................................. 19 
6.1.
Type and Number of Subjects................................................................................................ 19 
6.2. 
Inclusion Criteria.................................................................................................................... 19 
6.3. 
Exclusion Criteria .................................................................................................................. 21 
6.4. 
Other Eligibility Criteria Considerations ............................................................................... 23 
6.5. 
Screening Failures.................................................................................................................. 23 
6.6. 
Withdrawal Criteria................................................................................................................ 24 
6.6.1. 
Reasons for Withdrawal ........................................................................................ 24 
6.6.2. 
Subject Withdrawal Procedures ............................................................................ 25 
7. 
STUDY TREATMENT ...................................................................................................................... 26 
7.1. 
Investigational Product and Other Study Treatment.............................................................. 26 
7.2. 
Randomization/Treatment Assignment.................................................................................. 27 
7.3. 
Blinding.................................................................................................................................. 28 
7.4. 
Packaging and Labeling......................................................................................................... 28 
7.5. 
Preparation/Handling/Storage/Accountability ....................................................................... 29 
7.6. 
Compliance with Investigational Product Administration..................................................... 29 
7.7. 
Treatment of Investigational Product Overdose..................................................................... 30 
7.8. 
Treatment after the End of the Study..................................................................................... 31 


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7.9. 
Concomitant Medications and Non-Drug Therapies ............................................................. 31 
7.9.1. 
Permitted Medications and Non-Drug Therapies.................................................. 31 
7.9.2. 
Prohibited Medications and Non-Drug Therapies................................................. 31 
7.10. 
Lifestyle and/or Dietary Restrictions ..................................................................................... 34 
8. 
STUDY ASSESSMENTS AND PROCEDURES .............................................................................. 35 
8.1.
Time and Events..................................................................................................................... 35
8.2. 
Critical Screening and/or Baseline Assessments ................................................................... 39 
University of Pennsylvania Smell Identification Test (UPSIT)............................ 40 
8.3. 
Study Assessments and Procedures ....................................................................................... 41 
8.3.1. 
Efficacy Assessments............................................................................................ 41 
8.3.1.1. 
Mini Balance Evaluation Systems Test (Mini-BESTest) .................. 41 
8.3.1.2. 
Electronic Walkway Assessment....................................................... 41 
8.3.1.3. 
Freezing of Gait (FOG) Assessment ................................................. 42 
8.3.1.4. 
Movement Disorder Society-Unified Parkinson’s Disease Rating 
Scale (MDS-UPDRS) Parts II and III................................................ 42 
8.3.1.5. 
University of Pennsylvania Smell Identification Test (UPSIT) ........ 42 
8.3.2. 
Safety and Screening Assessments........................................................................ 42 
8.3.2.1. 
Adverse Events.................................................................................. 42 
8.3.2.2. 
Physical and Neurological Examinations.......................................... 47 
8.3.2.3. 
Vital Signs ......................................................................................... 48
8.3.2.4. 
Electrocardiogram ............................................................................. 48 
8.3.2.5. 
Clinical Safety Laboratory Assessments ........................................... 48 
8.3.2.6. 
Assessment of Suicidality.................................................................. 50 
8.3.2.7. 
Pregnancy .......................................................................................... 50 
9. 
DATA MANAGEMENT.................................................................................................................... 51 
10. STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................................... 52 
10.1. 
Hypotheses............................................................................................................................. 52 
10.2. 
Sample Size Considerations................................................................................................... 52 
10.3. 
Data Analysis Considerations ................................................................................................ 52 
10.3.1. 
Analysis Populations............................................................................................. 52 
10.3.2. 
Interim Analysis .................................................................................................... 52 
10.4. 
Key Elements of Analysis Plan.............................................................................................. 52 
10.4.1. 
Safety Analyses..................................................................................................... 52 
10.4.1.1. 
Adverse Events.................................................................................. 53 
10.4.1.2. 
Clinical Laboratory Tests .................................................................. 53 
10.4.1.3. 
Vital Signs, Electrocardiograms, Physical Findings, and Other 
Safety Evaluations............................................................................. 53 
10.4.2. 
Efficacy Analyses.................................................................................................. 53 
10.4.3. 
Other Analyses ...................................................................................................... 54 
11. RESPONSIBILITIES.......................................................................................................................... 55 
11.1. 
Investigator Responsibilities.................................................................................................. 55 
11.1.1. 
Good Clinical Practice........................................................................................... 55 


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11.1.2. 
Institutional Review Board/Independent Ethics Committee Approval ................. 55 
11.1.3. 
Informed Consent.................................................................................................. 55 
11.1.4. 
Confidentiality....................................................................................................... 56 
11.1.5. 
Study Files and Retention of Records ................................................................... 56 
11.1.6. 
Case Report Forms ................................................................................................ 57 
11.1.7. 
Drug Accountability.............................................................................................. 57 
11.1.8. 
Inspections............................................................................................................. 58 
11.1.9. 
Protocol Compliance............................................................................................. 58 
11.2. 
Sponsor Responsibilities........................................................................................................ 58 
11.2.1. 
Protocol Modifications.......................................................................................... 58 
11.2.2. 
Study Report and Publications .............................................................................. 58 
11.2.3. 
Posting of Information on Publicly Available Clinical Trial Registers................. 59 
11.3. 
Joint Investigator/Sponsor Responsibilities........................................................................... 59 
11.3.1. 
Access to Information for Monitoring................................................................... 59 
11.3.2. 
Access to Information for Auditing or Inspections ............................................... 59 
11.3.3. 
Study Discontinuation ........................................................................................... 59 
12. REFERENCES.................................................................................................................................... 60 


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LIST OF TABLES
PAGE
Table 1. 
List of Prohibited and Conditional Concomitant Medications and Non-Drug 
Therapies........................................................................................................................... 32 
Table 2. 
Time and Events Schedule................................................................................................ 38 
Table 3. 
Protocol-Required Screening and Safety Laboratory Assessments.................................. 49 


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1.
ABBREVIATIONS
Abbreviation
Definition
5-HT6
5-hydroxytryptamine sub-type 6
AD
Alzheimer’s disease
ADAS-Cog
Alzheimer’s Disease Assessment Scale – Cognitive Subscale
ADCS-ADL
Alzheimer’s Disease Cooperative Study - Activities of Daily Living
AE
Adverse event
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
BUN
Blood urea nitrogen
CFR
Code of Federal Regulations
CNS
Central nervous system
C-SSRS
Columbia Suicide Severity Rating Scale
CT
Computed tomography
DLB
Dementia with Lewy bodies
ECG
Electrocardiogram
ET
Early termination
FDA
Food and Drug Administration
FSH
Follicle stimulating hormone
GGT
Gamma glutamyltransferase
HBsAg
Hepatitis B surface antigen
hCG
Human chorionic gonadotropin
ICF
Informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IP
Investigational Product
IRB
Institutional Review Board
LBD
Lewy body dementia
MCH
Mean corpuscular hemoglobin
MCV
Mean corpuscular volume
MDS-UPDRS
Movement Disorder Society - Unified Parkinson’s Disease Rating 
Scale 
MedDRA
Medical Dictionary for Regulatory Activities


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Abbreviation
Definition
Mini-BESTest
Mini Balance Evaluation Systems Test
MMSE
Mini Mental State Examination
MRI
Magnetic resonance imaging
PD
Parkinson’s disease
PDD
Parkinson’s disease dementia
PIGD
Postural Instability and Gait Difficulty
PK
Pharmacokinetic(s)
QTc
Corrected QT (interval)
RBC
Red blood cell
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SD
Standard deviation
TSH
Thyroid stimulating hormone
ULN
Upper limit of normal
UPSIT
University of Pennsylvania Smell Identification Test
WBC
White blood cell


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2.
PROTOCOL SUMMARY
Study Title
A Phase 2, double-blind, randomized, placebo-controlled crossover 
study evaluating the effect of RVT-101 on gait and balance in 
subjects with Alzheimer’s disease, dementia with Lewy bodies, or 
Parkinson’s disease dementia
Objectives
Primary
To assess the effect of RVT-101 versus placebo on gait speed, a
quantitative measure of functional mobility, on an electronic 
walkway system after 2 weeks of treatment
Secondary
To assess the safety and tolerability of RVT-101
Exploratory
To assess the effect of RVT-101 versus placebo on gait variability
on an electronic walkway system after 2 weeks of treatment
To assess the effect of RVT-101 versus placebo on gait and 
balance, as measured by the Mini Balance Evaluation Systems  
Test (mini-BESTest) battery total score and individual subscores,
after 2 weeks of treatment
To assess the effect of RVT-101 versus placebo on gait and 
balance, as measured by individual item scores calculated by 
Opal APDM sensors during performance of the mini-BESTest 
battery, after 2 weeks of treatment at sites where the technology 
and capability is available 
To assess the effect of RVT-101 versus placebo on freezing of 
gait (FOG), as measured by clinical and quantitative scores, after 
2 weeks of treatment
To assess the effect of RVT-101 versus placebo on movement 
and balance, as measured by the Movement Disorder Society -
Unified Parkinson’s Disease Rating Scale (UPDRS) Parts II and
III and Postural Instability and Gait Difficulty (PIGD) subscore,
after 2 weeks of treatment
To assess the effect of RVT-101 versus placebo on smell, a proxy 
for cholinergic function, as measured by the University of 
Pennsylvania Smell Identification Test (UPSIT), after 2 weeks of 
treatment
Study Phase
Phase 2
Target Population
Adult subjects aged 50 to 89, inclusive, with Alzheimer’s disease, 
dementia with Lewy bodies, or Parkinson’s disease dementia, and gait 
impairment. Subjects included in the study must have received a
stable dose of cholinesterase inhibitor therapy for at least 6 weeks
prior to screening.


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Number of Subjects 
Planned
Approximately 30-40 randomized subjects (approximately 15-20
subjects with Alzheimer’s disease and approximately 15-20 subjects 
with Lewy body dementia – including either dementia with Lewy 
bodies or Parkinson’s Disease Dementia)
Number of Study 
Centers Planned
7-10
Study Design
This is a multicenter, double-blind, randomized, placebo-controlled 
crossover study in patients with Alzheimer’s disease (AD), dementia 
with Lewy bodies (DLB), or Parkinson’s disease dementia (PDD), 
and gait impairment. The efficacy and safety of RVT-101 at a dose of 
35 mg daily will be evaluated in this study. All subjects included in 
the study must be on stable background cholinesterase inhibitor
therapy for at least 6 weeks prior to screening. Subjects who are on 
stable doses of other background therapies for cognitive impairment, 
behavioral disturbances, or motor problems will continue those 
regimens for the duration of the study. All subjects must refrain from 
starting additional treatments for dementia, behavioral disturbances, 
or motor problems during the course of the study.
Following an initial screening period, eligible subjects will enter a 
two-week single-blind placebo run-in period (Period I). At the end of 
this period, all subjects who continue to meet the eligibility criteria 
will enter the first two-week double-blind treatment period (Period 
II). Following the completion of Period II, subjects will undergo a 
washout period (Period III) of two weeks during which subjects will 
receive placebo. After the two-week washout, subjects will enter the 
second two-week double-blind treatment period (Period IV). A safety 
follow-up telephone call will be conducted approximately 2 weeks 
after completion of Period IV.
Each subject will be randomized 1:1 to one of the following 
sequences:
Sequence 1: AB = RVT-101 in Period II and Placebo in Period IV
Sequence 2: BA = Placebo in Period II and RVT-101 in Period IV
Treatment A = RVT-101 35 mg once daily
Treatment B = Placebo
The study design is outlined in Figure 1.
Randomization will be stratified according to Mini Mental State 
Examination (MMSE) score in the groups of 14-19 points and 20-26
points. Randomization will also be stratified according to whether 


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patients have AD or Lewy body dementia (LBD – an umbrella term 
that includes both DLB and PDD)
Duration of Treatment
Study participation will last approximately 14 weeks: 0 to 28 days for 
Screening, a 2-week Single-Blind Placebo Run-In Period, 4 weeks of 
Double-Blind Treatment, a 2-week Washout Period and a 2-week 
Safety Follow-up Period.
Criteria for Evaluation
Primary efficacy measures: The primary efficacy measure will be the 
change in gait speed from baseline, defined as the start of each two-
week double-blind treatment period, to the end of each two-week
double-blind treatment period. 
Exploratory efficacy measures: Measures for exploratory endpoints 
are described above in Objectives.
Safety evaluation: Safety will be evaluated based on adverse events 
(AEs), physical examinations, vital signs, electrocardiograms (ECGs), 
suicidality (Columbia Suicide Severity Rating Scale, or C-SSRS), and 
clinical laboratory assessments.
Figure 1


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3.
INTRODUCTION
3.1.
Background
3.1.1.
Disease State
Falls are a significant issue in the elderly population: up to half of people over the age of 65 
experience a fall each year (Soriano et al., 2007), and approximately 20% of patients who fall 
require medical attention (Kannus et al., 2005). Falls also impose a significant economic burden 
on the healthcare system in addition to the serious morbidity and mortality with which they are 
associated: the total cost of falls is estimated to be well over $20 billion in the U.S. alone (Davis 
et al., 2010).
Patients with dementia are particularly prone to falls due to impaired cognition, gait, and balance.
In a 12-month prospective cohort study, patients with dementia had an eight-fold increased 
likelihood of experiencing a fall compared to age-matched controls (Allan et al., 2009). It has also
been estimated that up to 80% of patients with dementia experience a fall annually (Shaw et al., 
2003). Patients with dementia commonly suffer from gait and balance impairments, including 
slowing of gait and increased gait variability (Montero-Odasso et al., 2015). The cholinergic 
system plays a critical role in locomotion, and cholinergic deficits in the cortex and brainstem
contribute to gait and balance impairment in patients with dementia. Anticholinergic medications 
are known to increase the risk of falls in the elderly (Aizenberg et al., 2002), while drugs that 
increase the concentration of acetylcholine in the brain have been shown to improve gait and 
balance and reduce the incidence of falls. In a Phase 2 clinical trial (n=43) evaluating the effect of 
donepezil on gait parameters in patients with mild Alzheimer’s disease (AD), subjects treated with 
donepezil experienced statistically significant improvements (p=0.010) in gait velocity after four 
months of treatment (Montero-Odasso et al., 2015). In a 32-week randomized, double-blind, 
placebo-controlled study of rivastigmine in Parkinson’s disease patients (n=130) with a history of 
at least one fall in the past year, patients treated with rivastigmine had a statistically significant 
improvement in gait speed and step time variability under normal walking conditions and when 
given a simple cognitive task while walking (gait speed: p=0.003 and p=0.037, respectively; gait 
variability: p=0.002 and p=0.045, respectively). Rivastigmine-treated patients in the study also 
experienced a mean of 1.4 falls per month, compared to 2.4 falls per month among patients treated 
with placebo (p = 0.002) (Henderson et al., 2016). In summary, drugs that increase the 
concentration of acetylcholine in the brain may present promising therapeutic potential to improve 
gait and balance parameters and reduce the risk of falls in patients with neurodegenerative 
disorders.
5-HT6 antagonists, which promote the release of acetylcholine in the brain, have demonstrated 
reductions in the incidence of falls in patients with AD when administered as adjunctive therapy
to stable background treatment with donepezil. In a 48-week, double-blind, placebo-controlled, 
randomized study in subjects with mild-to-moderate AD, 2% of subjects who received RVT-101 
in combination with donepezil experienced falls, as compared to 6% of subjects who received 
donepezil alone (Maher-Edwards et al., 2015). In addition, in a Phase 2 double-blind placebo-
controlled randomized study of idalopirdine in subjects with moderate AD, 2% of subjects who 
received idalopirdine in combination with donepezil experienced falls, compared to 6% of subjects 


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who received donepezil alone (Wilkinson et al., 2014). Based on its mechanism of action as a 5-
HT6 antagonist that promotes the release of acetylcholine within the brain, RVT-101 may have a 
direct positive effect on improving gait and balance parameters and reducing the risk of falls in 
patients with dementia.
3.1.2.
Investigational Product
RVT-101, previously known as SB742457, is a potent antagonist of the 5-HT6 receptor that 
promotes the release of acetylcholine in the brain. As of 31 July 2016, RVT-101 has been 
previously investigated in fourteen Phase 1 studies in healthy subjects, as monotherapy in three
Phase 2 studies in subjects with mild to moderate Alzheimer’s Disease (AD) (Study AZ3100603, 
Study AZ3106242, 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).
In the study in which RVT-101 was tested as an adjunctive therapy to donepezil (study 
AZ3110866), a statistically significant difference of 1.5 points in Alzheimer’s Disease 
Assessment Scale – Cognitive Subscale (ADAS-Cog) was observed for the 35-mg RVT-101
group versus the placebo group at Week 24 (p=0.012). The Alzheimer’s Disease Cooperative 
Study – Activities of Daily Living (ADCS-ADL) also showed a statistically significant effect of 
2.0 points difference for 35 mg RVT-101 compared to placebo at Week 24 (p=0.024). The CDR-
SB showed a statistically significant effect of 35 mg RVT-101 compared to placebo at Week 12 
but not at Week 24. In this study, 2% of subjects who received RVT-101 on top of donepezil 
experienced falls, as compared to 6% of subjects who received placebo on top of donepezil.
RVT-101 is being investigated in an ongoing Phase 3, double-blind, randomized, placebo-
controlled study as an adjunct to stable donepezil therapy in subjects with mild-to-moderate AD 
(Study RVT-101-3001: MINDSET study). In addition, RVT-101 is being investigated in an 
ongoing Phase 2b, double-blind, randomized, placebo-controlled study in subjects with dementia 
with Lewy bodies, or DLB (Study RVT-101-2001: HEADWAY-DLB study). 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 2 study seeks to evaluate the effect of RVT-101 on gait and balance in dementia 
patients with gait impairment. The study will capture quantitative measures of gait and balance
that are clinically-relevant predictors of fall risk. Justification for evaluating RVT-101 as a 
potential treatment of gait and balance impairment in AD, DLB, and Parkinson’s disease 
dementia (PDD) patients is provided by the following: (1) Parkinson’s disease (PD) patients with 
cognitive impairment suffer from prominent cholinergic deficits and impaired gait (Bohnen et 
al., 2013; Bohnen et al., 2006); (2) cholinesterase inhibitors increase acetylcholine levels in the 
brain, reduce the incidence of falls (Chung et al., 2010; Dubois et al., 2012; Li et al., 2015), and 
improve gait speed and reduce gait variability (Henderson et al., 2016; Montero-Odasso et al., 
2015); (3) 5-HT6 antagonists increase the concentration of acetylcholine in the brain; and (4) 5-


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HT6 antagonists have been shown to reduce the incidence of falls in patients with Alzheimer’s 
disease (Maher-Edwards et al., 2015; Wilkinson et al., 2014).
The primary objective of this study is to assess the effect of 35 mg RVT-101 compared to
placebo on gait speed after 2 weeks of double-blind treatment in a crossover design study. Gait 
speed has previously been examined in published studies evaluating the effect of cholinesterase 
inhibitors on balance, gait and falls in AD and PD patients. In a Phase 2 clinical trial evaluating
the effect of donepezil on gait in patients with mild AD, subjects treated with donepezil 
experienced statistically significant improvements (p=0.010) in gait velocity (Montero-Odasso et 
al., 2015). In a 32-week placebo-controlled study of rivastigmine in PD patients, rivastigmine
demonstrated a statistically significant improvement in gait speed under normal walking 
conditions and under challenge with simple and complex cognitive tasks (p=0.003, p=0.037, and 
p=0.048, respectively). Rivastigmine-treated patients also experienced statistically significant 
improvements in step time variability and fewer falls per month on average compared to patients 
treated with placebo. The current study will explore many of the same parameters assessed in 
these prior studies of cholinesterase inhibitors in AD and PD patients.
Exploratory objectives of this study include assessment of the effect of 35 mg of RVT-101
compared to placebo on gait variability, balance, and freezing of gait.
3.3
Dose Rationale
A daily dose of 35 mg RVT-101 was selected for this study based on the results of the 
AZ3110866 study. This dose, administered in addition to donepezil, was shown to be well 
tolerated and demonstrated efficacy on measures of cognition and activities of daily living that 
were statistically significant when compared to placebo treatment. Additional receptor 
occupancy and pharmacokinetic (PK) studies further support the dose selection. This dose is 
currently being evaluated in an ongoing confirmatory Phase 3 study in mild-to-moderate AD, 
and is also being evaluated in an ongoing Phase 2b study in patients with DLB (along with a 70 
mg dose of RVT-101). This dose has been well-tolerated across studies completed to date. 


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4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
To assess the effect of RVT-101 versus placebo 
on gait speed after 2 weeks of treatment
Change from baseline in gait speed measured 
on an electronic walkway system at the end of 
each treatment period
Secondary
To assess the safety and tolerability of RVT-
101
Collection of adverse events and changes over 
time in vital signs, electrocardiogram, clinical 
safety laboratory assessments, and assessments 
of suicidality. 
Exploratory
To assess the effect of RVT-101 versus placebo 
on gait variability after 2 weeks of treatment
Change from baseline in step time variability 
measured on an electronic walkway system at 
the end of each treatment period
To assess the effect of RVT-101 versus placebo 
on gait and balance, as measured by the mini-
BESTest battery, after 2 weeks of treatment
Change from baseline in the mini-BESTest total 
score and individual subscores at the end of 
each treatment period
To assess the effect of RVT-101 versus placebo 
on gait and balance, as measured by individual 
item scores calculated by Opal APDM sensors 
during performance of the mini-BESTest 
battery, after 2 weeks of treatment at sites 
where the technology and capability is available
Change from baseline in individual item scores 
calculated by Opal APDM sensors during 
performance of the mini-BESTest battery at the 
end of each treatment period
To assess the effect of RVT-101 versus placebo 
on freezing of gait (FOG) after 2 weeks of 
treatment
Change from baseline in the FOG score and 
freezing ratio, incorporating input from Opal 
APDM sensors during turning conditions, at the 
end of each treatment period
To assess the effect of RVT-101 versus placebo 
on movement and balance, as measured by the 
Movement Disorder Society - Unified 
Parkinson’s Disease Rating Scale (MDS-
UPDRS), after 2 weeks of treatment
Change from baseline in MDS-UPDRS Part II 
and III subscores and PIGD subscore at the end 
of each treatment period
To assess the effect of RVT-101 versus placebo 
on smell, a proxy for cholinergic function, as 
measured by the University of Pennsylvania 
Smell Identification Test (UPSIT), after 2 
weeks of treatment
Change from baseline in UPSIT score at the end 
of each treatment period


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5.
STUDY DESIGN
5.1.
Overall Design
This is a multi-center, double-blind, randomized, placebo-controlled, crossover study in 
dementia patients with gait impairment. The primary objective of the study will be to evaluate 
the effect of RVT-101 on gait speed. The secondary objective is to assess the safety and 
tolerability of RVT-101. Exploratory objectives of the study include the evaluation of the effects 
of RVT-101 on other quantitative and qualitative measures of gait and balance.
Following an initial screening period, eligible subjects will enter a two-week single-blind 
placebo run-in period (Period I). At the end of this period, all subjects who continue to meet the 
eligibility criteria will enter the first two-week double-blind treatment period (Period II). 
Following the completion of Period II, subjects will undergo a washout period (Period III) of two 
weeks during which subjects will receive placebo. After the two-week washout, subjects will 
enter the second two-week double-blind treatment period (Period IV). A safety follow-up
telephone call will be conducted approximately 2 weeks after completion of Period IV.
Each subject will be randomized 1:1 to one of the following sequences:
Sequence 1: AB = RVT-101 in Period II and Placebo in Period IV
Sequence 2: BA = Placebo in Period II and RVT-101 in Period IV
5.2.
Study Schematic
The design of the study is illustrated in the figure below.
Figure 2.
Study Design


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6.
SUBJECT POPULATION
6.1.
Type and Number of Subjects
Approximately 30-40 patients with dementia (AD, DLB, or PDD) and gait impairment will be 
enrolled. Subjects must be on a stable regimen of a cholinesterase inhibitor for at least two 
months prior to screening, and must have received a cholinesterase inhibitor for at least four
months. Subjects may be on certain other background therapies if on a stable regimen prior to 
screening. These allowed background therapies and stability requirements are listed in Table 1.
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 probable Alzheimer’s disease (AD),
probable dementia with Lewy bodies (DLB), or probable Parkinson’s disease dementia 
(PDD). The diagnosis of probable AD must be in accordance with the recommendations 
from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic 
guidelines for AD (McKhann et al., 2011). The diagnosis of probable DLB must be in 
accordance with Consensus criteria for DLB diagnosis (McKeith et al., 2005). The diagnosis 
of probable PDD must be in accordance with the Movement Disorder Society (MDS) 
criteria for PDD (Emre et al., 2007).
2.
Subject has an MMSE score of 14 to 26 inclusive and able to follow instructions at the 
Screening Visit.
3.
Subject must have experienced at least one fall within the past two years as assessed by 
history and defined by the judgment of the clinical investigator at the time of the Screening 
Visit.
4.
Clinically relevant risk of fall. For example, patients have an average gait speed of less than 
100 cm/s on an electronic walkway evaluation at Visit 1, Visit 2 and Visit 3 or abnormal gait 
and balance on the miniBEST assessment with a score < 16 at Visit 1-3. In case these 
criteria are not met, a justification for the clinically determined fall risk should be 
documented and discussed with the medical monitor. Other documented risks of fall or gait 
impairment may be acceptable with approval from the medical monitor. Mandatory need for 
a walking aid could for example be considered as such a condition.
5.
Subject has a Hachinski Ischemia score less than or equal to 4 at Screening.
6.
Subject has a documented history of at least 6 weeks of stable cholinesterase inhibitor
therapy prior to screening, with no intent to change for the duration of the study.
7.
Age 50 to 89 years, inclusive, at the time of the Screening Visit.
8.
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,


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b. If pre-menopausal or menopausal for 1 year or less, must have a negative pregnancy test 
and must not be lactating at the Screening and Baseline Visits.  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 and until the completion 
of the follow-up visit.  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:
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
9.
Male subjects who are sexually active will be required to use an adequate form of birth 
control including at least 1 barrier method. 
10. Subject has the ability to comply with procedures for evaluating gait, balance, and other 
testing in the opinion of the investigator. Subject should be without physical limitations that 
would significantly impact the gait, balance and other testing in the opinion of the 
investigator.
11. Subject must be able to ingest pills (in tablet form) whole.
12. 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 drug, and report on subject's status, and who has substantial contact with the 
subject. Every effort should be made to have the same caregiver/healthcare provider 
throughout the study.
13. 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 has provided full 
written informed consent on behalf of the subject.
14. Caregiver has provided full written informed consent on his/her own behalf prior to the 
performance of any protocol-specified procedure.
15. General health status is acceptable for participation for the entire duration of the study.


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6.3.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria apply:
Other Causes for Dementia
1.
History and/or evidence of any other CNS disorder that could be interpreted as a cause of 
dementia (in the opinion of the investigator), e.g., cerebrovascular disease (transient 
ischemic attack, stroke, hemorrhage); structural or developmental abnormality; epilepsy; 
infectious, degenerative, or inflammatory/demyelinating CNS conditions.
2.
A CT or MRI scan performed within the past five years and since the time of diagnosis of 
dementia 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, or Wernicke’s encephalopathy.
4.
Atypical clinical features or clinical course of dementia that would lead the investigator to 
conclude symptoms are more likely due to an alternate dementia diagnosis other than AD, 
DLB, or PDD.
Confounding Medical Conditions
5.
History of significant psychiatric illness such as schizophrenia or bipolar affective disorder 
or any other significant psychiatric illness that in the opinion of the investigator would 
interfere with participation in the study; history of major depressive disorder in the past year, 
or current major depressive episode.
6.
Significant suicide risk as defined by (1) suicidal ideation as endorsed on items 4 or 5 on the
Columbia Suicide Severity Rating Scale (C-SSRS) within the past year, at Screening or 
since last visit at Baseline; (2) suicidal behaviors within the past year; or (3) clinical 
assessment of significant suicidal risk during subject interview.
7.
Current psychosis that in the opinion of the investigator would interfere with the subject’s 
ability to participate in this study.
8.
History of epilepsy or unexplained seizure in the past 5 years, unexplained recent loss of 
consciousness, or history of significant head trauma with loss of consciousness.
9.
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.
10. Any clinically relevant concomitant disease including progressive liver or kidney 
dysfunction, history of myocardial infarction or unstable angina within 6 months of 
Screening, history of more than 1 myocardial infarction within 5 years of Screening, history 


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of clinically significant stroke, or any other medical or psychiatric condition, which, in the 
opinion of the investigator, makes the subject unsuitable for inclusion in the study.
11. History of alcohol use disorder or other substance abuse disorder (excluding tobacco use), 
according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, criteria 
in the past 10 years.
12. History of Down syndrome or Intellectual Development Disorder.
13. Severe and/or debilitating arthritis or peripheral neuropathy. Peripheral neuropathy should 
be assessed quantitatively with a 128-Hz clanging tuning fork test applied to the hallux of 
both feet. Vibration sensation by the subject for 4 seconds or less will be excluded due to 
severe neuropathy. Any other assessment by the clinician suggesting severe and/or 
debilitating arthritis or peripheral neuropathy can also serve as a basis for exclusion of a 
subject from the study. 
14. Significant tremor which would interfere with recording balance and walking.
15. Uncorrected vision disturbance or vestibular problems that would affect gait and balance.
16. Symptomatic hypotension or symptomatic orthostatic hypotension (e.g. subjective feeling of 
lightheadedness, faintness, dizziness, or fear of collapsing due to these symptoms, reported 
by the patient and/or caregiver on clinical history).
17. Symptomatic bradycardia which in the opinion of the investigator may place the subject at 
risk of syncope.
18. History of frequent and/or unexplained syncopal episodes.
Concomitant Medications
19. Participation in another investigational drug or device study during the 60 days prior to the 
Screening Visit, 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 dementia or movement disturbance 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 review with the Medical Monitor, there is a realistic 
possibility that the subject would be eligible.  
20. Treatment with any concomitant medications or non-drug therapies 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 Test/Laboratory Values
21. History of persistent or recurrent liver enzyme elevations, or alanine transaminase (ALT) 
and/or aspartate aminotransferase (AST) greater than or equal to 2.0 times upper limit of 
normal (ULN) at Screening.


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22. Total bilirubin over 1.5 x ULN at Screening, except due to documented Gilbert’s disease,
when considered clinically significant.
23. Clinically relevant renal dysfunction: plasma creatinine > 1.5 mg/dl, when considered 
clinically significant.
24. Positive hepatitis B surface antigen or hepatitis C antibody test at Screening.
25. 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 a QTc value less than 500 msec may be eligible 
following discussion with the Medical Monitor. Subjects who are unable to have a QTc 
interval reliably measured (e.g. subjects with a pacemaker) may be considered for inclusion 
after discussion with the Medical Monitor.
Other
26. Previous exposure to RVT-101 or SB742457.
27. Subject is unable to take study drug as prescribed throughout the study (with assistance is 
acceptable), has a significant history of non-compliance with prescribed medication, or is at 
risk of non-compliance with study drug or procedures.
28. 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.
6.4.
Other Eligibility Criteria Considerations
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 subjects.
6.5.
Screening Failures
Screen Failures are defined as subjects who sign an informed consent form (ICF) for RVT-101-
2003 but did not enter the Single-Blind Run-In Phase (i.e., did not receive IP). A minimal set of 
screen failure information is required to be recorded in the electronic data capture (EDC) system,
including demography, diagnosis, screen failure details, eligibility criteria, and any adverse 
events (AEs). 
Subjects who are screen failures may be rescreened after approval by the study Medical Monitor.


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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 6 Visit (Visit 6). 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 case 
report form. 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:
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, such as:
o
Subject misses >3 consecutive doses of investigational product or > 5 doses of 
investigational product within one of the 2-week double-blind treatment periods
o
Initiation of new cognitive or motor tasks for cognitive or motor 
rehabilitation/neurostimulation, including occupational rehabilitation and/or physical 
therapy that may impact gait or balance
o
Use of prohibited drugs should be discussed with and approved by the medical 
monitor
Subject or caregiver 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
Investigator unblinding of subject
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.


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If a subject meets discontinuation criteria during treatment, an Early Termination (ET) 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 ET Visit (Table 2). In the case where 
the subject permanently discontinues study drug between scheduled clinic visits he/she should be 
recalled to the clinic as soon as possible and preferably within 7 days of stopping study drug for 
the ET 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 one tablet of IP daily in the morning, with or without food; this will 
consist of either one tablet of 35 mg RVT-101 or one tablet of placebo.
IP for Period I (the Single-Blind Run-In Period, Weeks -2 to 0) will be supplied at Visit 2. 
Subjects will be given 1 bottle of placebo tablets at this visit. Each bottle will contain 50 tablets, 
which is sufficient medication for 2 weeks plus 36 days’ overage. Subjects will be instructed to 
take one tablet of IP daily in the morning with or without food. Subjects will take the first dose 
of investigational product from this bottle in clinic at Visit 2.
IP for the Periods II, III, and IV (Double-Blind Treatment Periods and Washout Period), Weeks 
0 to 6) will be supplied at Visits 3, 4, and 5. At each dispensing visit during the Treatment 
Period, subjects will be given one bottle of IP. Depending on treatment assignment, subjects will 
receive either one bottle of 35 mg RVT-101 tablets or one bottle of placebo tablets. Subjects will 
not know which treatment they are taking. Each bottle will contain 50 tablets, which is sufficient 
for 2 weeks plus 36 days’ overage. Subjects will be instructed to take one tablet of IP daily in 
the morning with or without food. Subjects will take the first dose of investigational product 
from each bottle in clinic at Visits 3, 4 and 5.
New bottles of IP will not be dispensed at Visit 6. Drug accountability will be checked at Visits 
3, 4, 5 and 6.
All subjects and their caregivers should be instructed to return IP bottles, with any unused drug, 
to each visit.
Acetylcholinesterase inhibitor background therapies will not be supplied by the sponsor. 


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Characteristic
Investigational Product
Product Name:
Investigational Product
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
N/A
placebo
Route of Administration:
Duration (Run-in Period):
Duration (Treatment Periods):
Duration (Washout Period):
Oral
N/A
2 weeks
N/A
Oral
2 weeks
2 weeks
2 weeks
Dosing Instructions:
Take in the morning with or 
without food
Take in the morning with or 
without food
Manufacturer/Source of 
Procurement
Catalent Pharma Solutions
Kansas City, MO USA
Catalent Pharma Solutions
Kansas City, MO USA
7.2.
Randomization/Treatment Assignment
During the Screening Period and Period I (single-blind placebo run-in period), subjects will be 
identified by their initials, screening number and date of birth. Subjects who meet all screening 
eligibility criteria at Visit 2 will receive placebo tablets for two weeks during Period I. The tablet 
should be taken once-daily in the morning (at approximately the same time each day). At Visit 3, 
if subjects continue to meet all eligibility criteria, they will be randomized and assigned a 
randomization identification number. Only the screening (subject) number will be used to 
identify the subject on any related study documents. The Investigator will keep a record relating 
the names of the subjects to their identification numbers, to allow easy checking of data in 
subject files, when required. The randomization process is described in further detail in the Study 
Reference Manual.
Eligible subjects will be randomized to receive study treatments according to one of the 
treatment sequences listed in the table below.
Treatment Sequence
First Double-Blind 
Treatment (Period II)
Second Double-Blind
Treatment (Period IV)
AB
RVT-101
Placebo
BA
Placebo
RVT-101
The study drugs used in the trial are RVT-101 35 mg and matching placebo tablets.


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7.3.
Blinding
This will be a double-blind study.  The study will include a 2-week single-blind placebo Run-In 
Period (Period I) during which investigators will know that the subject is taking placebo but the 
subject/caregiver will not.  This will be followed by a 2-week Double-Blind Treatment Period 
(Period II), a 2-week single-blind placebo Washout Period (Period III), and a 2-week Crossover 
Treatment Period (Period IV). During the Double-Blind Treatment Periods, neither subjects nor 
investigators will know which of the two treatments the subject is receiving. Subjects and 
caregivers will not be informed of transition from the Single-Blind Run-In Period or Washout 
Period to the Double-Blind Treatment Periods or vice versa. 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 only 
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.
In the event that a medical emergency or condition requires knowledge of the subject’s 
treatment assignment, the investigator will access the interactive response technology 
(IRT) system to obtain the treatment assignment for that subject. The procedure of 
unblinding for a specific subject is provided in the IRT 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.
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 by the investigator 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 case report form.
Axovant Sciences or its 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 one bottle at each IP dispensing visit. The individual 
IP bottles will be labeled.
Labels for RVT-101 and placebo bottles will meet all applicable requirements of the US Food
and Drug Administration (FDA), EU Commission Directive 2003/94/EC, Eudralex Volume 10 


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ANNEX 13-Good Manufacturing Practice for the 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:
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 investigational product 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.
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 
Study Reference Manual.
Under normal conditions of handling and administration, investigational product is not 
expected to pose significant safety risks to site staff.  In the case of unintentional 
occupational exposure, notify the Medical Monitor.
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 


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confirmed at the time of dosing by a member of the study site staff in addition to the person 
administering the IP.
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 case report 
form 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.
Subjects should be withdrawn from the study where there has been a failure to take double-blind
IP for a period exceeding 3 consecutive days or for more than 5 days in total within one of the 2-
week, double-blind treatment periods. In addition, subjects should not have missed any double-
blind doses of IP within the 2 days before gait testing is performed; subjects who have missed a 
dose of IP within the 2 days before gait testing is performed should have their study visit 
rescheduled to a different day within the visit window. While interruptions in IP administration 
should be avoided wherever possible, short-
days) due to forgetfulness, 
caregiver 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 necessarily grounds for automatic withdrawal but should be assessed by the investigator and 
discussed with the medical monitor.
Other major protocol violations as well as use of prohibited 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. 


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Document the quantity of the excess dose as well as the time of administration of the 
overdose in the case report form. 
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.
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 case report form. Non-medication 
therapies related to the subject’s dementia or movement disorder 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. 
If the subject is receiving one of the conditional medications or non-drug therapies 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 60 days prior to the Screening Visit, and longer for certain 
therapies. In addition, the treatment regimen of these conditional medications or non-drug 
therapies should be kept stable during the study, if possible. If treatment with a conditional 
medication or non-drug therapy 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.
7.9.2.
Prohibited Medications and Non-Drug Therapies
Subjects who receive treatment during the study with any prohibited medication or non-drug 
therapy listed in Table 1 should be withdrawn from the study. However, where such treatment 
has been for less than or equal to 3 days, termination of the prohibited medication or non-drug 
therapy 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.


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Use of prohibited and conditional medications and treatments must be documented in the 
Concomitant Medications section of the case report form. Prohibited and conditional medications 
are listed in Table 1.
Table 1.
List of Prohibited and Conditional Concomitant Medications and Non-Drug 
Therapies
Prohibited Medications and Non-Drug 
Therapies:
Not allowed during the study or within 5 half-
lives prior to Screening
Conditional Medications and Non-Drug 
Therapies:
Stable regimen (drug/therapy, dose and 
dosing frequency) for at least 60 days prior to 
the Screening Visit; dosing or therapy
regimen during the study should be stable, if 
possible
Butyrophenones, phenothiazines, and other 
typical antipsychotics
Barbiturates
Non selective MAO inhibitors.
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)
Anticoagulants
Any investigational drug
Trans-Magnetic Stimulation (TMS)
Marijuana/THC
Acetylcholinesterase inhibitors 
(i.e., donepezil, galantamine, 
rivastigmine, tacrine)
Note: Subjects should have a history of at 
least 4 months of ongoing cholinesterase 
inhibitor therapy prior to screening, with 
stable dosing for at least 60 days prior to
screening and with no intent to change for 
the duration of the study.
Selective MAO-B inhibitors (rasagiline, 
selegiline)
Memantine
Axona® (caprylidene)
Antidepressants (other than non-selective 
MAO inhibitors)
Thyroid hormones
Atypical antipsychotics (e.g., risperidone)
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.
Pimavanserin


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Stable medication with benzodiazepines 
and other sedatives/hypnotics, including 
melatonin and sedating antihistamines
Note: Intermittent (as needed) use of 
benzodiazepines and other 
sedative/hypnotics is discouraged. If 
required, short acting benzodiazepines 
should be used (i.e. a plasma half-life of 
< 6 h) . An interval between the intake 
and the gait testing of at least 12 h should 
be observed. 
Dopaminergic therapies for motor 
impairment
Deep Brain Stimulation (DBS)                
Note: DBS settings, parameters, and 
regimen should be stable if possible for at 
least 60 days prior to the screening visit. 
If a subject has switched between 
multiple DBS settings during the 60 days 
prior to the study, or if it is anticipated 
that the subject may need to switch 
between multiple settings during the 
study, then the subject is not a suitable 
candidate for participation. If a subject 
follows a particular regimen regarding 
use of the DBS (for example, switching 
off the device before sleeping at night), 
then that regimen should have been stable 
if possible for at least 60 days prior to the 
screening visit and should be maintained 
for the duration of the study if possible.
Cognitive or motor tasks for cognitive or 
motor rehabilitation performed under 
medical supervision, including 
occupational rehabilitation and/or 
physical therapy that may impact gait and 
balance
Thrombocyte aggregation inhibitors (low 
dose ASS, clopidogrel)
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.


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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. 
Visit 3 will occur within 14 to 17 days after Visit 2. For Visits 4 through 6, there is a visit 
window of +3 days. If the visit window is used, the subsequent visit should be scheduled
according to the date when the prior study visit actually took place and not according to the 
original visit schedule (i.e., the subsequent visit date should be re-calculated from the date of the 
previous visit).
Information will be recorded in the source documents and, where appropriate, the case report 
form.
If, during the visit, the subject is unable or, in the judgment of the investigator, unlikely to be
able to complete the study 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 should, however, be completed within a single day. In addition, every effort should 
be made to complete all motor assessments on the same day. 
Assessment should occur in the following order whenever possible:
MMSE (Screening only)
Modified Hachinski Ischemia Scale (mHIS) (Screening only)
Motor testing
o
Electronic walkway tests
o
Mini-BESTest
o
FOG assessment
o
Note: for patients with Lewy Body dementia (dementia with Lewy bodies or 
Parkinson’s disease dementia) who are in the “off” state or show motor 
fluctuations, motor testing should be done during the “on” phase
Caregiver FES (Screening only), UPSIT, C-SSRS
MDS-UPDRS
Physical and neurological exam
12-lead ECG


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Vital signs
Blood draws
Study visits for patients on dopaminergic therapies should not be scheduled during “off” periods.
Whenever possible, the following should be done, with priority given in the order presented
below:
1) If a subject is taking levodopa, he/she should be instructed to continue to take this medication 
throughout the study in the same manner and time of day as usual. 
2) Begin motor testing within 2 hours of the subject taking levodopa, for subjects on this 
medication. The time of last ingestion of levodopa and any other dopaminergic therapies by 
the subject should be attempted to be recorded by the study staff.
3) Begin all visits subsequent to the baseline visit (Visit 3) within one hour of the time of day at 
which the baseline visit (Visit 3) began.
Subjects who prematurely discontinue from study should be encouraged to return to the clinic for 
an ET Visit, and ET assessments and procedures will be completed according to Table 2.
For subjects with a DBS device, study staff should attempt to record the settings, parameters, and 
regimen of the device at all study visits, to verify that these are the same at all study visits. 
Screening Period (up to 28 + 14 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 
LAR with subject assent, before any study-specific procedures are performed.  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 
potentially be rescreened after discussion with the Medical Monitor.
At the screening visit, all potential subjects will undergo MMSE assessment, Modified Hachinski 
Ischemia Scale (mHIS), and gait speed evaluation on an electronic walkway system. If possible, 
the MMSE should be the first assessment performed, followed by the mHIS, followed by the 
electronic walkway assessment. If the MMSE score, mHIS score or gait speed do not meet the 
criterion for eligibility at screening, no other assessments should be performed. Subjects will also 
undergo an evaluation of isometric handgrip strength assessed with a hand dynamometer. 
Visit 2 (Start of Period I [Single Blind Run-In Period]): At Visit 2, subjects who meet all 
study eligibility criteria will enter Period I. If possible, the electronic walkway assessment 
should be the first assessment performed at Visit 2. If the subject’s average gait speed is not 
below 89 cm/s the subject should not proceed with other assessments.  The subject should not be 
enrolled at Visit 2 and should not proceed in the study.


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If the patient meets eligibility criteria, investigational product will be dispensed.  Subjects will be 
instructed to take the investigational product once daily in the morning.  Subjects will ingest the 
first dose of investigational product during the study visit in the clinic in the presence of study 
personnel.
Visit 3 (Start of Period II [Double-blind Treatment]): At Visit 3, assessments will be 
performed to determine subject eligibility. To qualify for randomization at Visit 3, subjects must 
return unused study drug, be considered capable of completing study assessments, continue to 
meet criteria for having slow gait as described in the protocol (i.e. average gait speed below 89 
cm/s), and meet all other eligibility requirements.  
The electronic walkway assessment should be the first assessment performed at Visit 3. If the 
gait speed does not meet the criterion for randomization at Visit 3, no other assessments should 
be performed and the subject should not be randomized.  
Eligible subjects will be randomized 1:1 to one of the following treatment sequences:
1. AB = RVT-101 in Period II and Placebo in Period IV
2. BA = Placebo in Period II and RVT-101 in Period IV
Investigational product will be dispensed at Visit 3. Subjects will ingest the first dose of 
investigational product from the Visit 3 bottle during the study visit in the clinic in the presence 
of study personnel. 
Visit 4 (Start of Period III [Washout Period]): Investigational product will be dispensed at 
Visit 4. Subjects will ingest the first dose of investigational product from the Visit 4 bottle during 
the study visit in the clinic in the presence of study personnel.
Visit 5 (Start of Period IV [Double-blind Treatment]): Investigational product will be 
dispensed at Visit 5. Subjects will ingest the first dose of investigational product from the Visit 5 
bottle during the study visit in the clinic in the presence of study personnel.
Visit 6 (End of Study Visit): Subjects who complete Visit 6 will be considered completers, 
since Visit 6 is the final on-treatment visit. 
Visit 7 (Follow-up Visit): All subjects will be contacted by phone 14 to 19 days after the last 
dose of IP is taken to assess for any new AEs and follow-up on any open AEs. The Investigator 
may choose to conduct this visit in the clinic and may perform additional assessments if deemed 
necessary (e.g., if results of any of the Visit 6 evaluations are considered clinically significant).


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Table 2.
Time and Events Schedule
Visit Description
Screening
Beginning 
of Period I
Randomization
/ Beginning of 
period II
Beginning 
of Period 
III
Beginning 
of Period 
IV
End of 
Study
Follow-
up
Visit
ET1
Study Visit Number
V1
V2
V3
V4
V5
V6
V7
n/a
Study Week
W (-6)
W (-2)
W0
W2
W4
W6
W8
n/a
Study Day2
Up to 28
+ 14 days 
before V2
14 +3 days 
before V3
0
14 ± 3
28 ± 3
42 ± 3
56 + 5
n/a
Informed consent
X
Inclusion/Exclusion criteria
X
X
X
Demography
X
Medical History
X
Concomitant medications
X
X
X
X
X
X
X
Blood alcohol and urine drug screen
X
X
C-SSRS, Screening version
X
C-SSRS, Since Last Visit version
X
X
X
X
X
X
Randomization
X
Dispense IP
X
X
X
X
Assess IP compliance
X
X
X
X
X
Physical exam
X3
X4
X4
X4
X4
X3
X3
Complete neurological exam5
X
X
X
X
X
X
X
MRI or CT6
X
12-Lead ECG
X
X
X
X
X
X
X
Vital signs7
X
X
X
X
X
X
X
Review Adverse Events
X
X
X
X
X
X
X
X
Serum OR urine pregnancy test8
X
X
X
Urine pregnancy test8
X
Hep B and Hep C screen9
X
TSH, vitamin B12, syphilis 
serology10
X
Serum chemistry
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
MMSE
X
UPSIT
X
X
X
X
X
Primary Gait Screen: assessment of 
gait speed 11,12
X
X
X
Single and dual task gait 
assessments11
X
X
X
X
X
X
Mini BESTest assessment11
X
X
X
X
X
X
Freezing of gait evaluation11
X
X
X
X
X
MDS-UPDRS Parts II and III11
X
X
X
X
X
Caregiver-adapted Falls Efficacy 
Scale - International
X
Handgrip strength evaluation
X
Hachinski Ischemia Scale
X


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Abbreviations: ECG = electrocardiogram; Hep = hepatitis; IP = investigational product; mini-BESTest = mini Balance Evaluation Systems Test; 
MMSE = mini-mental state examination; TSH = thyroid stimulating hormone; MDS-UPDRS = Movement Disorder Society - Unified 
Parkinson’s Disease Rating Scale; UPSIT = University of Pennsylvania Smell Identification Test
1.
Early Termination visit should be performed within 7 days of stopping study drug if permanently discontinued between scheduled 
clinic visits.
2.
If the visit window is used, the subsequent visit should be scheduled according to the date when the prior study visit actually took 
place and not according to the original visit schedule (i.e., the subsequent visit date should be re-calculated from the date of the 
previous visit).
3.
Complete physical exam will be performed at Screening, V6, and ET visit and include, at a minimum, assessment of the 
cardiovascular, respiratory, gastrointestinal, and neurological systems.  In addition, the following body systems should be assessed, if 
possible: skin, head, eyes, ears, nose, neck/throat, endocrine/metabolic, genitourinary, blood/lymphatic, musculoskeletal, and abdomen 
(liver and spleen).
4.
Brief, symptoms-directed physical examination will be performed at V2, V3, V4, and V5 and include, at a minimum, assessments of 
the head, eyes, ears, nose, neck/throat, lungs, cardiovascular system, and abdomen (liver and spleen) lungs, cardiovascular system, and 
abdomen (liver and spleen).
5.
Neurological examinations will include assessment of gait, balance, coordination, cranial nerves and motor and sensory systems, 
including assessment of peripheral neuropathy.
6.
MRI or CT will be performed between V1 and V2 if no CT or MRI scan has been performed within the previous five years since 
diagnosis. These scan findings must be consistent with the diagnosis of AD, DLB, or PDD without any other clinically significant 
pathologies.   
7.
Vital signs will include systolic blood pressure, diastolic blood pressure, heart rate, respiratory rate, and temperature and body weight 
at each visit and height at screening. Postural changes in blood pressure and heart rate will also be assessed at every visit. 
8.
Required only for women of child bearing potential. Either a serum or urine pregnancy test is to be performed at V1, V3, and Early 
Termination. A urine pregnancy test is to be performed at Visit 6. If a urine pregnancy test result is positive, an unscheduled serum 
pregnancy test must be performed to confirm the results.
9.
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.
10.
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.
11.
Note: for patients with Lewy body dementia (dementia with Lewy bodies or Parkinson’s disease dementia) who show motor
fluctuations, motor testing should be done during the “on” phase.
12.
Patients who require assistive devices and meet the criteria for clinically relevant risk of falls may not perform the PGS.
8.2.
Critical Screening and/or Baseline Assessments
All baseline and efficacy assessments should be performed following the methodology included 
in the Study Reference Manual. All study assessments should be conducted by the investigator, 
and/or a suitably qualified designee.  Every effort should be made for the same person to conduct 
specific assessments on each individual subject at each study visit. Assessments may 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. 
Mini-Mental State Evaluation (MMSE)
The MMSE (Folstein et al., 1975) is a clinician-administered performance measure that 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. The 
MMSE for patients included in the study must be between 14 and 26 inclusive at the screening 
visit in order to qualify for randomization into the study. 
Electronic Walkway Assessment
Electronic walkway systems, such as the GAITRite and Zeno Walkway system, are 
computerized assessment tools that utilize an electronic mat consisting of pressure-sensitive pads 


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that can calculate spatiotemporal gait parameters including gait velocity, cadence, step time, step 
length, stride length, stride time, swing time, stance time, and double support time (Buesing et 
al., 2015). Parameters such as gait velocity and cadence on the electronic walkway system are 
highly correlated with manually timed tests in PD patients (ICC = 0.96, p<0.0005) (Bryant et al., 
2013). Gait variability, specifically step length and step time, predict falls (Hausdorff, 2005)
(Bryant et al., 2013). Stride length has been highly correlated with the Postural Instability and 
Gait Difficulty (PIGD) UPDRS subscore (r=-0.90, p<0.0001) (Salarian et al., 2004). Further, 
electronic walkway systems are highly sensitive to demonstrating the effects of medications used 
to treat PD. The GAITRite system is able to detect gait changes with dopaminergic medications 
only 45 minutes after administration (Bryant et al., 2013).  Recently, evidence has shown that 
cholinesterase inhibitors are also able to improve gait parameters in AD and PD (Henderson et 
al., 2016). Hence, the parameters measured by an electronic walkway system correlate well with 
established clinical scoring methods of gait, and these parameters are reliable and sensitive to 
capturing the effects of pharmacologic treatment.
Subjects included in the study must have an average gait speed of less than 100 cm/s, (Cesari et 
al, 2005) or other clinically relevant risk of falls at Visits 1, 2 and 3. Subjects without assistive 
devices will undergo the Primary Gait Screen assessment (PGS) at Visits 1, 2 and 3, and all 
subjects will complete additional gait assessments under single and dual task conditions at all 
study visits. The specific procedures for the PGS and single and dual task gait assessments, 
including the calculation to determine study eligibility, are described in the Study Reference 
Manual. 
University of Pennsylvania Smell Identification Test (UPSIT)
The olfactory system is a cholinergic rich area of the brain that degenerates early in PD (Doty, 
2012; Mancini and Horak, 2010). Approximately 90% of patients with early stage PD have 
olfactory dysfunction, and olfactory dysfunction correlates with loss of cholinergic neurons in 
structures such as the nucleus basalis of Meynert (nBM). The UPSIT is a 40 item ‘scratch-and-
sniff’ test that takes about 15 minutes to administer and is a reliable measure of olfactory 
function. The materials for the test will be provided to the sites, and the procedure for 
administering the test are described in the Study Reference Manual. 
Caregiver-Adapted Version of the Falls Efficacy Scale – International
This scale will be rated by the caregiver and will capture his/her degree of concern about the 
likelihood of a patient falling while under a variety of different circumstances and performing 
different activities. The scale is adapted from the Falls Efficacy Scale – International, which is a 
16-item self-reported scale in which individuals rate their degree of concern regarding the 
likelihood of their falling during different activities. The degree of concern is reflected in a 1-4
rating for each item, with “1” indicating that the individual is “not at all concerned” and “4”
indicating that the individuals is “very concerned.” The scale has been reported to have strong 
internal validity (Cronbach’s alpha = 0.96) and test-retest reliability (ICC = 0.96) (Yardley et al., 
2005). A caregiver-adapted version of this scale will be used in this study and administered only 
at the screening visit.  
Handgrip Strength Assessment


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Low handgrip strength is a clinically relevant indicator of poor mobility ((Cruz-Jentoft et al., 
2010). Moreover, baseline handgrip strength has been shown to have a linear relationship with 
risk of incident disability of activities of daily living (Al Snih et al., 2004). In this study, 
handgrip strength will be captured at screening. Handgrip strength will be assessed by a baseline 
hand dynamometer embedded with a strain gauge, as described on the Study Reference Manual. 
Modified Hachinski Ischemia Scale (mHIS) 
This scale asks about the presence or absence of 8 clinical symptoms. It is being used in this 
study at Screening to identify and exclude subjects with vascular dementia.
8.3.
Study Assessments and Procedures
8.3.1.
Efficacy Assessments
8.3.1.1.
Mini Balance Evaluation Systems Test (Mini-BESTest)
The Mini-BESTest is a short, validated 14 item assessment of dynamic balance, specifically 
anticipatory postural transitions, postural responses, and dynamic gait (King et al., 2012). Each 
item is scored from (0-2) with a score of 2 being normal. The total score is out of 28. This test 
has excellent test-retest reliability (ICC= 0.96) and interrater reliability (ICC= 0.96) (Godi et al., 
2013). The test takes about 10 minutes to administer (Mancini and Horak, 2010). The Mini-
BESTest assessment will be performed with subjects wearing the Opal APDM sensors if 
available at the site, which will collect quantitative measures of dynamic gait and balance. 
8.3.1.2.
Electronic Walkway Assessment
Electronic walkway systems, such as the GAITRite and Zeno Walkway system, are 
computerized assessment tools that utilize an electronic mat consisting of pressure-sensitive pads 
that can calculate spatiotemporal gait parameters including gait velocity, cadence, step time, step 
length, stride length, stride time, swing time, stance time, and double support time (Buesing et 
al., 2015). Parameters such as gait velocity and cadence on the electronic walkway system are 
highly correlated with manually timed tests in PD patients (ICC = 0.96, p<0.0005) (Bryant et al., 
2013). Gait variability, specifically step length and step time, predict falls (Hausdorff, 2005)
(Bryant et al., 2013). Stride length has been highly correlated with the Postural Instability and 
Gait Difficulty (PIGD) UPDRS subscore (r=-0.90, p<0.0001) (Salarian et al., 2004). Further, 
electronic walkway systems are highly sensitive to demonstrating the effects of medications used 
to treat PD. The GAITRite system is able to detect gait changes with dopaminergic medications 
only 45 minutes after administration (Bryant et al., 2013).  Recently, evidence has shown that 
cholinesterase inhibitors are also able to improve gait parameters in AD and PD (Henderson et 
al., 2016). Hence, the parameters measured by an electronic walkway system correlate well with 
established clinical scoring methods of gait, and these parameters are reliable and sensitive to 
capturing the effects of pharmacologic treatment.
Subjects without assistive devices will undergo the Primary Gait Screen assessment (PGS) at 
Visits 1, 2 and 3, as well as additional gait assessments under single and dual task conditions at 
all study visits. The specific procedures for the PGS and single and dual task gait assessments are 
described in the Study Reference Manual. 


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8.3.1.3.
Freezing of Gait (FOG) Assessment
FOG is a symptom where patients experience a paroxysmal inability to either continue or initiate 
gait (Shine et al., 2011). FOG is an independent risk factor for future falls in PD (Latt et al., 
2009). Though dopaminergic pathways account for some of the pathophysiology, FOG is closely 
associated with gait disturbance, impaired executive function and attention, and diminished 
neocortical cholinergic innervation (Bohnen et al., 2014; Peterson et al., 2015; Shine et al., 
2011). In this study, freezing of gait will be assessed while subjects perform a procedure 
involving multiple turns. Subjects will wear Opal APDM sensors while performing this 
procedure, which will provide quantitative data related to freezing of gait. This procedure is 
described in more detail in the Study Reference Manual.
8.3.1.4.
Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-
UPDRS) Parts II and III
The MDS-UPDRS is considered the ‘gold standard’ clinical scale for PD (Song et al., 2009). The 
MDS-UPDRS is a revision of the original UPDRS (Goetz et al., 2008) made by the Movement 
Disorder Society. Part II of the MDS-UPDRS is a questionnaire that focuses on motor aspects of 
experiences of daily living and Part III is a motor examination. Each item on the MDS-UPDRS 
is rated on a zero to four scale, where four represents the worst disability and zero represents no 
disability. The PIGD subscale focuses on items related to postural instability and gait difficulty 
and correlates highly with fall risk (Rudzinska et al., 2007) and deficits of executive function 
(Xu et al., 2014).
8.3.1.5.
University of Pennsylvania Smell Identification Test (UPSIT)
The olfactory system is a cholinergic rich area of the brain that degenerates early in PD (Doty, 
2012; Mancini and Horak, 2010). Approximately 90% of patients with early stage PD have 
olfactory dysfunction and olfactory dysfunction correlates with loss of cholinergic neurons in 
structures such as the nucleus basalis of Meynert (nBM). The UPSIT is a 40 item ‘scratch-and-
sniff’ test that takes about 15 minutes to administer and is a reliable measure of olfactory 
function. The materials for the test will be provided to the sites, and the procedure for
administering the test are described in the Study Reference Manual. 
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 


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(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.
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 the 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.
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:


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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
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 
continues until the follow-up phone call (Visit 7) as shown in the Time and Events Schedule 
(Section 8.1). SAEs that are spontaneously reported by the subject or subject representative or 
discovered by the investigator or designee after the follow-up phone call (Visit 7) and up to 30 
days after the last dose of IP must be collected and reported.
All SAEs will be recorded and reported to the sponsor or sponsor’s representatives within 
24 hours of the investigator becoming aware of the SAE according to Section 8.3.2.1.7.
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 


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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
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 plausible (pharmacologically, pathologically) 
o
Event definitive pharmacologically or phenomenologically (ie, an objective and 
specific medical disorder or a recognized pharmacological phenomenon) 
o
Rechallenge 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 clinically reasonable 
o
Rechallenge 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 


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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 
o
Disease or other drugs provide definitive explanations 
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 to the study sponsor or sponsor’s representatives
indicated on page 3 of this protocol and in the Study Reference Manual within 24 hours of the 
investigators first knowledge of the event using the sponsor-supplied Serious Adverse Event 
Form regardless of relationship to the study procedures or investigational product. All deaths 
must be reported within 24 hours of the investigator’s first knowledge of the event. It is 
recognized that complete information may not be available at the time of the initial SAE report.  
Additional information should be supplied on subsequent Serious Adverse Event Forms as it 
becomes available.
For the initial SAE notification report, the investigator must provide, at minimum if available,
basic information such as the protocol number, subject’s date of birth, subject identification 
number, period of investigational product intake, event term, and 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 


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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.  Follow-up
information, which may include copies of relevant subject records and other documents not 
available at the initial SAE report must be sent as soon as available to the sponsor or sponsor’s 
representatives. Follow-up SAE reports may describe the evolution of the reported event and any 
new assessment of outcome and/or relationship to investigational product. 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.
Additional instructions regarding SAE reporting are provided in the Study Reference Manual. 
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 
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.
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, 
gastrointestinal, and neurological systems. In addition, the following body systems should be 
assessed, if possible: skin, head, eyes, ears, nose, neck/throat, endocrine/metabolic, 
genitourinary, blood/lymphatic, musculoskeletal, and abdomen (liver and spleen). A brief, 
symptoms-directed physical examination will include, at a minimum, assessments of the head, 
eyes, ears, nose, neck/throat, lungs, cardiovascular system, and abdomen (liver and spleen).  
Physical examinations at Screening, Visit 6, and ET will be full examinations; at all other study 
visits, an abbreviated physical examination is required.
Complete neurological examinations will include assessment of gait, balance, coordination, 
cranial nerves and motor and sensory systems. Complete neurological exams will be performed 
at all visits.


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8.3.2.3.
Vital Signs
Height will be measured at the screening visit only.  Body weight will be measured at each visit. 
Vital signs will be measured after the subject has been in the supine position for 5 minutes and 
will include temperature, systolic blood pressure, diastolic blood pressure, heart rate, respiratory 
rate, and temperature. For subjects who are unable to lie down, the vital signs can be measured 
after the subject has been in the seated position for 5 minutes.
Postural changes in systolic blood pressure, diastolic blood pressure, and heart rate will be 
measured again approximately 3 minutes after standing. 
Abnormal vital signs that are clinically significant according to the investigator or designee 
should be recorded as Medical History (if found during Visit 1) or an AE (if found during any 
visit after Visit 1).
The equipment used (scale, blood pressure monitor, etc.) should remain consistent across the 
study for a given subject.
8.3.2.4.
Electrocardiogram
Single 12-lead ECGs will be obtained at each time point during the study 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 
physician 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 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. If the QTc interval is 
site staff should 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, the ECG should be repeated. Subjects who are unable to 
have a QTc interval reliably measured (e.g. subjects with a pacemaker) may be considered for 
inclusion after discussion with the Medical Monitor.
8.3.2.5.
Clinical Safety Laboratory Assessments
All protocol-required laboratory assessments, as defined in Table 3, must be conducted in 
accordance with the Study Reference 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 be recorded as AEs on the case 
report form. Clinically significant means that the confirmed abnormal test result has an impact 


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on subject management, including additional monitoring 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 3.
Table 3.
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 by dipstick
Microscopic examination (if blood or protein is abnormal)
Other Tests
Drugs and alcohol screen
HBsAg
Hepatitis C antibody
TSH
Vitamin B12
Syphilis serology
Serum or urine hCG pregnancy test ( for women of child bearing potential)
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen;
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 at the follow-up phone call (Visit 7) should be repeated until the 
values return to normal or baseline or until the value stabilizes.  If such values do not return to 


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normal within a period judged reasonable by the investigator, the etiology should be identified 
and the Medical Monitor notified.
8.3.2.6.
Assessment of Suicidality
Subjects will be assessed for suicidality before and during the study using the 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, 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. 
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 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.
8.3.2.7.
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 investigational product. Pregnancies are to be reported by the 
Investigator to the Medical Monitor within 24 hours of the site’s awareness of the pregnancy.
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.
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 the sponsor’s representative as described above. 
The 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 sponsor or the 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.
Additional instructions regarding pregnancy reporting are provided in the Study Reference 
Manual.  


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9.
DATA MANAGEMENT
For this study subject data will be entered into Axovant Sciences defined case report forms,
transmitted to Axovant Sciences or designee, and combined with data provided from other data 
sources.
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 case report forms (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 evaluate the efficacy of RVT-101 as compared to 
placebo in improving gait speed and other quantitative balance and gait parameters following 
treatment for two weeks.
10.2.
Sample Size Considerations
The primary comparison of interest is to compare the efficacy of RVT-101 to placebo after a two 
week treatment period in patients with AD or LBD. A sample size of approximately 30-40
patients (comprised of approximately 15-20 AD patients and approximately 15-20 LBD patients) 
will be included in this study.
10.3.
Data Analysis Considerations
10.3.1.
Analysis Populations
The primary population for safety analyses will be the Safety Population, which will consist of 
all subjects who were randomized and took at least one dose of investigational product.
The efficacy analysis population will consist of all randomized subjects who have taken at least 
one dose of investigational product and who have at least one post-baseline efficacy assessment.  
This will be the primary population used for the efficacy analysis.
10.3.2.
Interim Analysis
Interim analyses may be conducted during the course of the study and will be fully outlined in 
the SAP prior to undertaking.
10.4.
Key Elements of Analysis Plan
The primary objective of this study is to evaluate the efficacy of RVT-101 versus placebo in 
improving gait speed in patients with AD or LBD. Secondary objectives of the study include the 
evaluation of the efficacy of RVT-101 versus placebo in improving other gait and balance 
parameters in patients with AD or LBD. 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 number of subjects.  Categorical data will be summarized by counts 
and percentages.
Listings will be sorted by sequence subject, period and time. Summaries will be presented by 
treatment and time. Further details of analyses to be performed will be provided in the statistical 
analysis plan.
10.4.1.
Safety Analyses
The safety analyses will be based on the Safety Population.


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Safety will be assessed by summarizing and analyzing AEs, laboratory analytes, vital signs, ECG 
parameters, physical examination findings, the C-SSRS, and concomitant medications.
10.4.1.1.
Adverse Events
AE verbatim text will be coded and classified by body system and preferred (coded) term using 
the Medical Dictionary for Regulatory Activities (MedDRA). AEs will be assigned to the 
treatment based on the last dose received. All AEs will be listed. AEs, Drug related AEs, SAEs, 
AEs that lead to discontinuation of investigational product will be summarized by treatment 
group.  AEs will be summarized separately for the Single-Blind Run-In Period, the Double-Blind 
cross-over Treatment Period and the Follow-up Period.
10.4.1.2.
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 worst value will be used for the data summaries.
Laboratory values that fall outside of the reference range will be flagged as H=High or L=low.  
A lab shift table may be provided to show the baseline to the worst post value.  Laboratory 
values that do not meet the laboratory abnormalities will be assigned N=normal in the shift table.
10.4.1.3.
Vital Signs, Electrocardiograms, Physical Findings, and Other Safety 
Evaluations
Descriptive summaries of medical history, vital signs, weight, and ECG parameters will be 
presented separately for each study visit and treatment group.  Clinically significant abnormal 
morphological ECG findings will be summarized by study visit.
Abnormal physical examination findings will be summarized to include the number and 
percentage of subjects experiencing each treatment-emergent abnormal physical finding.
Concomitant medications will be coded using the WHO ATC classification 
(http://www.whocc.no/filearchive/publications/1_2013guidelines.pdf).
These data will be summarized by treatment group.
10.4.2.
Efficacy Analyses
Efficacy data will be summarized and listed by treatment and assessment time by period and 
overall. The between treatment differences for the efficacy endpoints of interest will be estimated 
using a mixed effect model. Baseline and stratification parameters may be included as covariates 
of interest. The least squares means, treatment difference and 95% CIs, and P-values will be 
estimated for efficacy endpoints, which may include but are not limited to the following:


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Change in gait speed as measured on an electronic walkway system from the start to the 
end of each treatment period with RVT-101
Change in step time variability as measured on an electronic walkway system from the 
start to the end of each treatment period with RVT-101
Change in step length variability as measured on an electronic walkway system from the 
start to the end of each treatment period with RVT-101
Change in the mini-BESTest total score and change from baseline in measures of 
dynamic gait and balance assessed with Opal APDM sensors during the mini-BESTest 
evaluation from the start to the end of each treatment period with RVT-101
Change in freezing of gait score and freezing ratio using Opal APDM sensors while 
turning, from the start to the end of each treatment period with RVT-101
Change in MDS-UPDRS Parts II and III and PIGD sub-scores from the start to the end of 
each treatment period with RVT-101
Change from baseline in UPSIT score from the start to the end of each treatment period 
with RVT-101
The baseline for the efficacy analysis is defined as the start of each individual treatment period.
Carry over effect will be tested and evaluated based on the baseline in each treatment period. 
The between treatment comparisons may also be performed using an analysis of covariance 
model based on Period B data. 
10.4.3.
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.


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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 that 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 Ltd., 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 Ltd. 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.
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


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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 legally authorized representative and the person obtaining consent. Consent 
from both the caregiver representative and subject, or subject’s LAR, should be obtained.
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 date of birth, and an 
identification code (i.e., not names) should be recorded on any form or biological sample 
submitted to the sponsor, 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.
The investigator agrees that all information received from Axovant Sciences Ltd., including but 
not limited to the Investigator’s Brochure, this protocol, case report forms, the investigational 
new drug, and any other study information, remain the sole and exclusive property of Axovant 
Sciences Ltd. 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 Ltd. 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 2 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.
The required source data 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;


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Results of safety parameters, as required by the protocol;
Start and end date of investigational product (including dose regimen, dispensing and 
return);
Record of all AEs (start and end date, causality and intensity);
Concomitant medication (including start and end dates, dose, and dose changes;
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 writing 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.
11.1.6.
Case Report Forms
For each subject enrolled, a case report form 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 a case report form was initiated). If a subject 
withdraws from the study, the reason must be noted on the case report form. 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 investigational product. This includes acknowledgment of receipt of each 
shipment of investigational product (quantity and condition), subject dispensing records, and 
returned or destroyed investigational product. Dispensing records will document quantities 
received from Axovant Sciences Ltd. and quantities dispensed to subjects, including lot number, 
date dispensed, subject identifier number, subject initials, and the initials of the person 
dispensing the investigational product.


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The investigator or his/her designee will be responsible for maintaining accurate records of 
investigational product dispensing and collection and for returning all unused investigational 
product to Axovant Sciences Ltd. or its designee at the end of the study.  Detailed instructions 
for return of investigational product will be provided in the Study Reference 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 Ltd. 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 Ltd. All protocol modifications must be submitted to the IRB or 
IEC in accordance with local requirements. Approval must be obtained before changes can be 
implemented.
11.2.2.
Study Report and Publications
A clinical study report will be prepared and provided to the regulatory agency(ies). Axovant 
Sciences Ltd. 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 Ltd.,
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 Ltd. 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 Ltd.
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 Ltd. request to delete 
references to its confidential information (other than the study results) in any paper or


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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 case report forms for consistency.
The monitor is responsible for routine review of the case report forms 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 case report forms. The investigator agrees to 
cooperate with the study monitors to ensure that any problems detected in the course of these 
monitoring visits are resolved.
11.3.2.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Axovant Sciences Ltd. 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 Ltd. medical monitor 
immediately. The investigator agrees to provide to representatives of a regulatory agency or
Axovant Sciences Ltd. access to records, facilities, and personnel for the effective conduct of any
inspection or audit.
11.3.3.
Study Discontinuation
The sponsor 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 Ltd. 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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SAP_001.pdf: 
Axovant Sciences, Inc.                              RVT-101 (Intepirdine)                                    
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STATISTICAL ANALYSIS PLAN
Study Title:
A Phase 2, double-blind, randomized, placebo-
controlled crossover study evaluating the effect of 
RVT-101 on gait and balance in subjects with 
Alzheimer’s Disease, Dementia with Lewy Bodies, or 
Parkinson’s Disease Dementia
Protocol Number:
RVT-101-2003
Development Phase:
Phase 2
Investigational Product:
RVT-101 (Intepirdine)
Indications:
Alzheimer’s Disease, Dementia with Lewy Bodies,
Parkinson’s Disease Dementia
Sponsor Study Director:
Ilise Lombardo, MD
Axovant Sciences, Inc.
11 Times Square, 33rd Floor
New York, NY 10036
Telephone: +1 (646) 822-8626
Email: ilise.lombardo@axovant.com
Preparer:
Rui (Rachel) Li, PhD
Version:
Final v1.0
Based on Protocol Version:
v3.0 – 07FEB2017
Confidentiality Statement
The information contained in this document is confidential and the property of Axovant Sciences Ltd. 
and may not be disclosed to others without the consent of Axovant Sciences Ltd.


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November 29, 2017 – v1.0 FINAL                  Confidential                                                               Page 2 of 33
FINAL STATISTICAL ANALYSIS PLAN APPROVAL
A Phase 2, double-blind, randomized, placebo-controlled crossover study evaluating the 
effect of RVT-101 on gait and balance in subjects with Alzheimer’s Disease, Dementia with 
Lewy Bodies, or Parkinson’s Disease Dementia
Rachel Li, PhD
Director, Biostatistics
Date
Divakar Sharma, PhD
Vice President, Biometrics
Date
Ilise Lombardo, MD
Senior Vice President, Clinical Research
Date
Eric Floyd, PhD
Senior Vice President, Regulatory Affairs
Date


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DOCUMENT HISTORY
Draft 
Version
Date
Comments and Changes
v1.0
16 Oct 2017
Circulate for core team review
v1.1
10 Nov 2017
Circulate for extended team review
v1.2
21 Nov 2017
Update MDS-UPDRS, baseline per team comments
v1.2
28 Nov 2017
Add sensitivity analyses


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November 29, 2017 – v1.0 FINAL                  Confidential                                                               Page 4 of 33
TABLE OF CONTENTS
DOCUMENT HISTORY.....................................................................................................................................3
LIST OF TABLES................................................................................................................................................5
LIST OF FIGURES..............................................................................................................................................5
ABBREVIATIONS...............................................................................................................................................6
1
INTRODUCTION ..........................................................................................................................................7
1.1 Study Design............................................................................................................................................7
1.2 Study Objectives ......................................................................................................................................8
1.3 Sample Size Considerations.....................................................................................................................8
1.4 Randomization and Stratification.............................................................................................................9
1.5 Nomenclature...........................................................................................................................................9
2
STUDY ENDPOINTS ....................................................................................................................................9
2.1 Co-Primary Endpoints..............................................................................................................................9
2.2 Secondary Endpoints................................................................................................................................9
2.3 Exploratory Endpoints .............................................................................................................................9
2.4 Description of Efficacy Endpoints .........................................................................................................10
3
ANALYSIS POPULATIONS ......................................................................................................................12
4
GENERAL CONSIDERATIONS AND HANDLING OF MISSING DATA..........................................13
4.1 Definitions..............................................................................................................................................13
4.2 Standard Reporting Conventions............................................................................................................18
4.3 Handling of Missing Data ......................................................................................................................18
4.4 Subgroups...............................................................................................................................................21
5
BASELINE AND OTHER SUMMARIES AND ANALYSES..................................................................21
5.1 Subjects Disposition...............................................................................................................................21
5.2 Screen Failures.......................................................................................................................................21
5.3 Protocol Deviations................................................................................................................................22
5.4 Demographic and Baseline Characteristics............................................................................................22
5.5
Subject Inclusion and Exclusion Criteria ...............................................................................................22
5.6 Medical History and Medical Conditions Present at Entry....................................................................22
5.7
Prior and Concomitant Medications.......................................................................................................22
5.8 Extent of Treatment Exposure................................................................................................................23
5.9 Treatment Compliance...........................................................................................................................23
5.10 Overdose ................................................................................................................................................24
6
EFFICACY SUMMARIES AND ANALYSES ..........................................................................................24
6.1 General Considerations ..........................................................................................................................24
6.2 Statement of the Null and Alternate Hypothesis ....................................................................................24
6.3 Analyses of the Primary Efficacy Endpoints..........................................................................................25
6.4 Analysis of the Exploratory Efficacy Endpoints ....................................................................................26
7
SAFETY SUMMARIES AND ANALYSES...............................................................................................27
7.1 Adverse Events.......................................................................................................................................27
7.2 Clinical Laboratory ................................................................................................................................28
7.3 Vital Signs..............................................................................................................................................29
7.4 ECGs 30 
7.5 Physical Examination.............................................................................................................................30


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7.6
Suicidality ..............................................................................................................................................30
7.7
Pregnancy...............................................................................................................................................31
8
INTERIM AND FINAL ANALYSES .........................................................................................................31
9
CHANGES FROM THE PROTOCOL TO THIS SAP.............................................................................32
10 REFERENCES .............................................................................................................................................33
LIST OF TABLES
Table 1:
Schedule of Events ........................................................................................................................15
Table 2:
Serum Chemistry Potentially Clinically Significant Criteria.........................................................28
Table 3:
Hematology and Differentials Potentially Clinically Significant Criteria .....................................29
Table 4:
List of Potentially Clinically Significant Ranges for Vital Sign Parameters .................................29
Table 5:
List of Potentially Clinically Significant Ranges for ECG Parameters .........................................30
LIST OF FIGURES
Figure 1.
Study Design ...................................................................................................................................7


Axovant Sciences, Inc.                              RVT-101 (Intepirdine)                                    
November 29, 2017 – v1.0 FINAL                  Confidential                                                               Page 6 of 33
ABBREVIATIONS
Abbreviation
Term
AD
Alzheimer’s Disease
AE
Adverse Event
ATC
Anatomic Therapeutic Chemical
CRF
Case Report Form
CS
Population of those who Completed the Study
CSR
Clinical Study Report
C-SSRS
Columbia Suicide Severity Rating Scale
DLB
Dementia with Lewy Bodies
DOB
Date of Birth
FOG
Freezing of Gait
ECG
Electrocardiograms
ITT
Intent-to-Treat Population
LBD
Lewy Body Dementia
MedDRA
Medical Dictionary for Regulatory Activities Terminology
Mini-BESTest
Mini Balance Evaluation Systems Test
MMSE
Mini Mental State Examination
MDS-UPDRS
Movement Disorder Society Unified Parkinson’s Disease Rating Scale
N
Total Sample Size
OC
Observed Cases
TEAE
Treatment-Emergent AE
PCS
Potential Clinical Significance
PDD
Parkinson’s Disease Dementia
PGS
Primary Gait Screen assessment
PIGD
Postural Instability and Gait Difficulty
PP
Per-Protocol Population
SD
Standard Deviation
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SAS
Statistical Analysis System
SOC
System Organ Class
ULN
Upper Limit of Normal
UPSIT
University of Pennsylvania Smell Identification Test
WHO-DD
World Health Organization’s Drug Dictionary


Axovant Sciences, Inc.                              RVT-101 (Intepirdine)                                    
November 29, 2017 – v1.0 FINAL                  Confidential                                                               Page 7 of 33
1
INTRODUCTION
The purpose of this Statistical Analysis Plan (SAP) is to describe the detailed methodology 
for summary and statistical analyses to be performed following the completion of Study 
RVT-101-2003, a Phase 2, double-blind, randomized, placebo-controlled crossover study 
evaluating the effect of RVT-101 on gait and balance in subjects with Alzheimer’s Disease, 
Dementia with Lewy Bodies, or Parkinson’s Disease Dementia.
Study measurements and assessments, planned statistical methods, and derived variables are
summarized in this plan.  Planned tables, figures, and listings are specified in a separate 
spreadsheet.  All decisions regarding final analyses, as defined in this SAP document, have 
been made prior to locking the database.
1.1
Study Design
This is a multi-center, double-blind, randomized, placebo-controlled, crossover study in 
dementia subjects with gait impairment. The primary objective of the study will be to 
evaluate the effect of intepirdine on gait speed. The secondary objective is to assess the 
safety and tolerability of intepirdine. Exploratory objectives of the study include the 
evaluation of the effects of RVT-101 on other quantitative and qualitative measures of gait 
and balance.
Following an initial screening period, eligible subjects will enter a two-week single-blind 
placebo run-in period (Period I). At the end of this period, all subjects who continue to meet 
the eligibility criteria will enter the first two-week double-blind treatment period (Period II). 
Following the completion of Period II, subjects will undergo a washout period (Period III) of 
two weeks during which subjects will receive placebo. After the two-week washout, subjects 
will enter the second two-week double-blind treatment period (Period IV). A safety follow-
up telephone call will be conducted approximately 2 weeks after completion of Period IV.
Figure 1 provides a study scheme demonstrating the key design elements and scheduled 
study visits.
Figure 1. Study Design


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1.2
Study Objectives
1.2.1
Primary Objective
The primary objective of this study is to assess the effect of intepirdine versus placebo on 
gait speed, a quantitative measure of functional mobility, on an electronic walkway system 
after 2 weeks of treatment.
1.2.2
Secondary Objective
Secondary objective is to assess the safety and tolerability of intepirdine.
1.2.3
Exploratory Objectives
Exploratory objectives of this study are:
To assess the effect of intepirdine versus placebo on gait variability on an electronic 
walkway system after 2 weeks of treatment
To assess the effect of intepirdine versus placebo on gait and balance, as measured by the 
Mini Balance Evaluation Systems Test (mini-BESTest) battery total score and individual 
subscores, after 2 weeks of treatment
To assess the effect of intepirdine versus placebo on gait and balance, as measured by 
individual item scores calculated by Opal APDM sensors during performance of the 
mini-BESTest battery, after 2 weeks of treatment at sites where the technology and 
capability is available 
To assess the effect of intepirdine versus placebo on freezing of gait (FOG), as measured 
by clinical and quantitative scores, after 2 weeks of treatment
To assess the effect of intepirdine versus placebo on movement and balance, as measured 
by the Movement Disorder Society - Unified Parkinson’s Disease Rating Scale (MDS-
UPDRS) Parts II and III, Postural Instability and Gait Difficulty (PIGD), and MDS-
UPDRS 7-Item subscore, after 2 weeks of treatment
To assess the effect of intepirdine versus placebo on smell, a proxy for cholinergic 
function, as measured by the University of Pennsylvania Smell Identification Test 
(UPSIT), after 2 weeks of treatment
1.3
Sample Size Considerations
The primary comparison of interest is to compare the efficacy of intepirdine to placebo after 
a two-week treatment period in subjects with Alzheimer’s Disease (AD) or Lewy body 
dementia (LBD). LBD is an umbrella term that includes both Dementia with Lewy Bodies
(DLB) and Parkinson’s Disease Dementia (PDD).  A sample size of approximately 30-40
subjects (comprised of approximately 15-20 AD subjects and approximately 15-20 LBD 
subjects) will be included in this study. No formal power calculations were performed.


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1.4
Randomization and Stratification
Each subject will be randomized 1:1 to one of the following sequences:
Sequence 1: AB = Intepirdine in Period II and Placebo in Period IV
Sequence 2: BA = Placebo in Period II and Intepirdine in Period IV
Randomization will be stratified according to Mini Mental State Examination (MMSE) score 
in the groups of 14-19 points and 20-26 points. Randomization will also be stratified 
according to whether subjects have AD or LBD.
1.5
Nomenclature
For purposes of this SAP, as well as in the analysis tables, figures, and listings, the study 
drug is referred to as “intepirdine”.  The study drug is also referred to (eg, in the protocol) as 
RVT-101.
2
STUDY ENDPOINTS
2.1
Co-Primary Endpoints
The co-primary endpoints in this study are:
Change from baseline in gait speed measured on an electronic walkway system under 
single task trial condition at the end of each two-week treatment period
Change from baseline in gait speed measured on an electronic walkway system under 
dual task trial condition at the end of each two-week treatment period
2.2
Secondary Endpoints
Secondary endpoints include occurrence of adverse events (AEs) and changes in physical 
examinations, vital signs measurements, electrocardiograms (ECGs), routine laboratory 
assessments, and Columbia Suicide Severity Rating Scale (C-SSRS).
Secondary endpoints are discussed in the Safety Analysis section of this SAP.
2.3
Exploratory Endpoints
The exploratory endpoints in this study are:
Change from baseline in step time variability and step length variability measured on an 
electronic walkway system at the end of each treatment period
Change from baseline in the mini-BESTest total score and individual subscores at the end 
of each treatment period
Change from baseline in individual item scores calculated by Opal APDM sensors during 
performance of the mini-BESTest battery at the end of each treatment period 


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Change from baseline in the FOG score and freezing ratio, incorporating input from Opal 
APDM sensors during turning conditions, at the end of each treatment period
Change from baseline in MDS-UPDRS Parts II and III subscores, PIGD, and MDS-
UPDRS 7-Item subscore at the end of each treatment period
Change from baseline in UPSIT score at the end of each treatment period
2.4
Description of Efficacy Endpoints
2.4.1
Gait Speed
Electronic walkway systems, such as the GAITRite and Zeno Walkway system, are 
computerized assessment tools that utilize an electronic mat consisting of pressure-sensitive 
pads that can calculate spatiotemporal gait parameters which include gait speed (Buesing et 
al., 2015) as the primary efficacy endpoint.
Subjects will undergo the gait assessments under single and dual task conditions, each with 3 
trials, at all study visits. All assessments will be done on the Zero Walkway system. The 
PKMAS software will be utilized to capture and process gait data in the study. The average 
of the 3 measurements will be used in the statistical analysis.
Each co-primary outcome measures (ie, gait speed assessed under single and dual task 
conditions) in this study will be tested at two-sided 5% level of significance.
2.4.2
Step Time and Length Variability
Step time variability and step length variability, similarly to gait speed are calculated during 
the electronic walkway system assessment. The calculated endpoints will be directly obtained 
from the electronic walkway system and will be utilized in statistical analysis separately by 
single and dual task conditions.
Change in step time variability as measured on an electronic walkway system from the 
start to the end of each treatment period with intepirdine
Change in step length variability as measured on an electronic walkway system from the 
start to the end of each treatment period with intepirdine
2.4.3
Mini Balance Evaluation Systems Test (Mini-BESTest)
The Mini-BESTest is a short, validated 14-item assessment of dynamic balance, specifically 
anticipatory postural transitions, postural responses, and dynamic gait (King et al., 2012). 
Each item is scored from 0-2 with a score of 2 being normal. The total score is out of 28. The 
analysis will be performed on the total score and individual subscores. The subscales are:
Anticipatory: the total subscore is out of 6
Reactive postural control: the total subscore is out of 6
Sensory orientation: the total subscore is out of 6


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Dynamic gait: the total subscore is out of 10
2.4.4
Mini Balance Evaluation Systems Test (Mini-BESTest) Analyzed by OPAL 
Sensors
The Mini-BESTest assessment will be performed with subjects wearing the Opal APDM 
sensors if available at the site, which will collect quantitative measures of dynamic gait and 
balance as captured by the Mobility Lab Software. The following measurements calculated 
by Opal APDM sensors during performance of the mini-BESTest battery will be utilized in 
statistical analysis.
MiniBest Item 1: Sit to stand
MiniBest Item 3: Stand on one leg
MiniBest Item 7: Stance (feet together)
MiniBest Item 8: Stance (feet apart on foam surface)
MiniBest Item 9: Stance (feet apart on firm surface)
2.4.5
Freezing of Gait (FOG) Assessment
FOG is a symptom where subjects experience a paroxysmal inability to either continue or 
initiate gait (Shine et al., 2011). FOG is an independent risk factor for future falls in PD (Latt 
et al., 2009). 
In this study, freezing of gait will be assessed while subjects perform a procedure 
involving multiple turns. Subjects will wear Opal APDM sensors while performing this 
procedure, which will provide quantitative data related to freezing of gait. The calculated 
FOG ratio is evaluable only if duration of turn is at least 50 seconds (Martina Mancini, 
personal communication, November 21, 2017).
Additionally, the freezing of gait assessment will be done by a rater. This freezing 
severity will be on a 0 to 4 scale: 0, Absent (no freezing episodes); 1, Mild (hesitation or 
episodic slowing); 2, Moderate (at least arrest); 3, Severe (multiple arrests); 4, Unable 
(required assistance).
2.4.6
Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-
UPDRS) Parts II and III 
The MDS-UPDRS is considered the ‘gold standard’ clinical scale for PD (Song et al., 2009). 
The MDS-UPDRS is a revision of the original UPDRS (Goetz et al., 2008) made by the 
Movement Disorder Society. Part II of the MDS-UPDRS is a questionnaire that focuses on 
motor aspects of experiences of daily living (13 items, score range: 0 to 52) and Part III (18 
items, 33 ratings, score range: 0 to 132) is a motor examination. Each item on the MDS-
UPDRS is rated on a 0 to 4 scale, where 4 represents the worst disability and 0 represents no 
disability. Part II and Part III totals will be analyzed separately and then combined.


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The PIGD 4-item subscale of MDS-UPDRS Part III (ie, posture, gait, postural stability, 
arising from chair) focuses on items related to postural instability and gait difficulty which 
are highly correlated with fall risk (Rudzinska et al., 2007) and deficits of executive function 
(Xu et al., 2014). The scale measurement range is 0 to 16.
The MDS-UPDRS 7-item subscale of MDS-UPDRS Part III (ie, facial expression, rigidity, 
global spontaneity of movement, postural tremor of hands [right, left], kinetic tremor of 
hands [right, left], rest tremor amplitude, constancy of rest tremor) was found to have high 
specificity and sensitivity for cognitively impaired patients with extrapyramidal features 
(Ballard et al., 1997) and can be computed as the sum of numeric responses to MDS-UPDRS 
Part III items 2, 3 (5 ratings), 14, 15 (2 ratings), 16 (2 ratings), 17 (5 ratings) and 18, with 
subscale scores ranging from 0 to 68 (inclusive).
2.4.7
University of Pennsylvania Smell Identification Test (UPSIT)
Approximately 90% of subjects with early stage PD have olfactory dysfunction, and 
olfactory dysfunction correlates with loss of cholinergic neurons in structures such as the 
nucleus basalis of Meynert (nBM) (Doty, 2012; Mancini and Horak, 2010). The UPSIT is a 
40-item ‘scratch-and-sniff’ test that takes about 15 minutes to administer and is a reliable 
measure of olfactory function. The result of the test is the number of items correctly 
identified.
3
ANALYSIS POPULATIONS
It is intended that a complete accounting of subjects for the analysis populations will be 
provided, from the Screened Population through the Completers Population.
3.1.1
Screened Population
All subjects who have signed an informed consent and completed the screening phase will be 
included in the Screened Population.
3.1.2
Run-In Population
All subjects entering the Placebo Run-in will be included in the Run-In population.  This 
population will be used to provide an accounting of the disposition of subjects during this 
phase of the study.
3.1.3
Randomized Population
The Randomized Population will include all subjects who are randomized.
3.1.4
Safety Population
The Safety Population will consist of all subjects who were randomized and took at least one 
dose of double-blind investigational product.


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3.1.5
ITT Population
The Intent-to-Treat (ITT) Population will consist of all subjects randomized to treatment who 
have taken at least one dose of double-blind investigational product and have an evaluable 
baseline assessment and a valid post baseline primary efficacy assessment during double-
blind treatment period.  This will be the primary population used for the efficacy analysis.
3.1.6
Per-Protocol (PP) Population
The Per-Protocol (PP) Population will be defined on the sponsor’s protocol deviation 
guidance. The PP Population will consist of those members of the ITT Population who have 
no major protocol violations deemed to have a potential impact on the primary efficacy 
analysis.
3.1.7
Completers (CS) Population
The Study Completers (CS) Population will consist of those members of the ITT Population 
who have completed the entire sequence (Period II and Period IV).  This population will be 
used for supportive analysis of the primary efficacy variable and other efficacy endpoints.
4
GENERAL CONSIDERATIONS AND HANDLING OF MISSING DATA
4.1
Definitions
4.1.1
Study Drugs
There are two study drugs being given:
Intepirdine 35mg (Test therapy)
Placebo (Reference)
4.1.2
Baseline
For both safety and efficacy evaluations, baseline for Period II is the pre-dose assessment at 
Visit 3 and baseline for Period IV is the pre-dose assessment at Visit 5.
4.1.3
Age
Age in years will be determined using the date of informed consent as recorded in the Case 
Report Form (CRF).
Some birth dates may be incomplete.  If the month and the day are missing, we will impute 
January 1; if the day is missing, we will impute the 1st of the month.


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4.1.4
Study Day
Study day will be calculated separately for Period II and Period IV. Day on Treatment will be 
calculated as the first dose date during Period II and Period IV, respectively.
If the assessment date of interest is on or after the first dose date of Period II or Period 
IV, but before or on the last day of Period II or Period IV:
Day on Treatment = assessment date – first dose of Period II (or Period IV) + 1
If Day of Assessment falls in the washout or follow-up periods, the day from the 
beginning of the previous period (Period II for the washout and Period IV for the follow 
up) will be calculated and appropriately flagged to differentiate it from Day on Treatment
If Day of Assessment falls in the run-in or screening:
Day on Treatment = assessment date – first dose of Period II
The study day will be displayed in all relevant data listings.
4.1.5
Visits and Periods
There are 5 study periods during this study:
The Screening Period is defined as the period of time prior to the subject receiving the 
first dose of single-blind placebo run-in medication.
The Single-Blind Placebo Run-In Period (Period I) is defined as the period from the first 
dose of single-blind run-in medication and ends on the last dose date of single-blind run-
in medication. The assessments taken on the date of the first dose of randomized double-
blind investigational product will be assumed to have been completed before the first 
dose of double-blind investigational product and will be slotted to this period.
The First Two-Week Double-Blind Treatment Period (Period II) starts on the date of first 
dose of double-blind investigational product and ends on the last dose date. If the first
dose of randomized investigational product is taken on the same day as Visit 3 
assessments, it will be assumed that the assessments were completed before the first dose 
of double-blind investigational product has been taken.
The Single-Blind Placebo Washout Period (Period III) starts one day after the last dose of 
the double-blind medication has been taken in Period II and lasts until the first dose of the 
double-blind investigational product in Period IV. The assessments taken on the date of 
the first dose of randomized double-blind investigational product will be assumed to have 
been completed before the first dose of double-blind investigational product and will be 
slotted to this period.
The Second Two-Week Double-Blind Treatment Period (Period IV) starts on the date of 
the first dose of double-blind investigational product and ends on the last dose date. If the 
first dose of randomized investigational product is taken on the same day as Visit 5 
assessments, it will be assumed that the assessments were completed before the first dose 
of double-blind investigational product has been taken.


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A safety follow-up telephone call will be conducted approximately 2 weeks after completion 
of Period IV.
Study visits will be determined from the scheduled times as reported on the CRF. As 
indicated in Table 1, Schedule of Assessments visit windows of +/- 3 days are allowed for 
scheduling purposes. For analysis purposes in this crossover study, no visit reassignment will 
be used even if a visit falls before or after the scheduling window.
Table 1:
Schedule of Events


Axovant Sciences, Inc.                              RVT-101 (Intepirdine)
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Visit Description
Screening
Beginning of 
Period I
Randomization /
Beginning of 
period II
Beginning of 
Period III
Beginning of 
Period IV
End of Study
Follow-up
Visit
ET1
Study Visit Number
V1
V2
V3
V4
V5
V6
V7
n/a
Study Week
W (-6)
W (-2)
W0
W2
W4
W6
W8
n/a
Study Day2
Up to 28 + 14 
days before V2
14 +3 days 
before V3
0
14 ± 3
28 ± 3
42 ± 3
56 + 5
n/a
Informed consent
X
Inclusion/Exclusion criteria
X
X
X
Demography
X
Medical History
X
Concomitant medications
X
X
X
X
X
X
X
Blood alcohol and urine drug screen
X
X
C-SSRS, Screening version
X
C-SSRS, Since Last Visit version
X
X
X
X
X
X
Randomization
X
Dispense IP
X
X
X
X
Assess IP compliance
X
X
X
X
X
Physical exam
X3
X4
X4
X4
X4
X3
X3
Complete neurological exam5
X
X
X
X
X
X
X
MRI or CT6
X
12-Lead ECG
X
X
X
X
X
X
X
Vital signs7
X
X
X
X
X
X
X
Review Adverse Events
X
X
X
X
X
X
X
X
Serum OR urine pregnancy test8
X
X
X
Urine pregnancy test8
X
Hep B and Hep C screen9
X
TSH, vitamin B12, syphilis serology10
X
Serum chemistry
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
MMSE
X
UPSIT
X
X
X
X
X
Primary Gait Screen: assessment of gait speed 
X
X
X
Single and dual task gait assessments
X
X
X
X
X
X
Mini BESTest assessment
X
X
X
X
X
Freezing of gait evaluation
X
X
X
X
X
MDS-UPDRS Parts II and III
X
X
X
X
X


Axovant Sciences, Inc.                              RVT-101 (Intepirdine)
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Visit Description
Screening
Beginning of 
Period I
Randomization /
Beginning of 
period II
Beginning of 
Period III
Beginning of 
Period IV
End of Study
Follow-up
Visit
ET1
Study Visit Number
V1
V2
V3
V4
V5
V6
V7
n/a
Study Week
W (-6)
W (-2)
W0
W2
W4
W6
W8
n/a
Study Day2
Up to 28 + 14 
days before V2
14 +3 days 
before V3
0
14 ± 3
28 ± 3
42 ± 3
56 + 5
n/a
Caregiver-adapted Falls Efficacy Scale -
International
X
Handgrip strength evaluation
X
Hachinski Ischemia Scale
X
Abbreviations: ECG = electrocardiogram; Hep = hepatitis; IP = investigational product; mini-BESTest = mini Balance Evaluation Systems Test; MMSE = mini-mental state examination; TSH = thyroid 
stimulating hormone; MDS-UPDRS = Movement Disorder Society - Unified Parkinson’s Disease Rating Scale; UPSIT = University of Pennsylvania Smell Identification Test
1.
Early Termination visit should be performed within 7 days of stopping study drug if permanently discontinued between scheduled clinic visits.
2.
If the visit window is used, the subsequent visit should be scheduled according to the date when the prior study visit actually took place and not according to the original visit schedule 
(ie, the subsequent visit date should be re-calculated from the date of the previous visit).
3.
Full physical exam will be performed at Screening, V6, and ET; abbreviated physical exam will be performed at V2, V3, V4, and V5. 
4.
Brief, symptoms-directed physical examination will be performed at V2, V3, V4, and V5.
5.
Neurological examinations will include assessment of gait, balance, coordination, cranial nerves, and motor and sensory systems, including assessment of peripheral neuropathy.
6.
MRI or CT will be performed between V1 and V2 if no CT or MRI scan has been performed within the previous five years since diagnosis. These scan findings must be consistent with 
the diagnosis of AD, DLB, or PDD without any other clinically significant pathologies.   
7.
Vital signs will include systolic blood pressure, diastolic blood pressure, heart rate, respiratory rate, and temperature and body weight at each visit and height at screening. Postural 
changes in blood pressure and heart rate will also be assessed at every visit. 
8.
Required only for women of childbearing potential. Either a serum or urine pregnancy test is to be performed at V1, V3, and Early Termination. A urine pregnancy test is to be 
performed at Visit 6.  If a urine pregnancy test result is positive, an unscheduled serum pregnancy test must be performed to confirm the results.
9.
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.
10.
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.


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4.2
Standard Reporting Conventions
Tables, listings, and figures will be prepared in accordance with the current International 
Conference on Harmonization Guidelines.  The information and explanatory notes in the 
“footer” or bottom of each table and listing will include the following information:
Date of output generation
SAS® program name, including the path that generates the output
Any other output specific details that require further elaboration
All hypothesis tests and confidence intervals will be two-sided at an alpha level of 5%.
Version 9.1 or higher of the SAS system will be used to analyze the data, as well as to 
generate tables, figures, and listings. 
In general, tables will be formatted with a column displaying findings for all subjects 
combined.  The summary tables will clearly indicate the number of subjects to which the data 
apply and unknown or not performed are distinguished from missing data.
The treatment groups will be referred to in the tables, listings, and figures with the following 
conventions:
Intepirdine 35 mg
Placebo
Data analyses will be performed by, or under the direct supervision of, Axovant Sciences. 
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 number of subjects.  
Categorical data will be summarized by counts and percentages.
Data collected in the CRF, as well as laboratory data, will be provided in data listings, sorted 
(in general) by sequence, subject, period, and date.  For date fields, Day on Treatment will be 
calculated and presented in these listings.
Deviations from the analyses as described in this SAP will be identified in the final Clinical 
Study Report.  When differences exist between the protocol-described analysis and the SAP, 
the SAP will take precedence.
4.3
Handling of Missing Data
Unless otherwise specified, all data will be evaluated as observed, and no imputation method 
for missing values will be used.


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Where necessary for the calculation of derived variables, partial dates will be completed 
using the earliest calendar date based on the partial date provided. This rule is valid for all 
partial dates with the exception of the following:
Start and stop dates of adverse events
Start and stop dates of concomitant medication
Completely missing dates will not be replaced and the corresponding derived variables will 
be set to missing.
4.3.1
Incomplete Dates for Concomitant Medication and Adverse Events
For analyses of AEs and concomitant medication usage, a complete date must be established 
in order to correctly identify the AE or medication as occurring during treatment or not. For 
purposes of imputing missing components of partially-reported start and stop dates for AEs 
and for medication use, the algorithms listed below will be followed. Start and stop dates of 
AEs or concomitant medication will be displayed as reported in the subject data listings (ie, 
no imputed values will be displayed in data listings).
Missing start day, but month and year present:
If the occurrence of the AE/concomitant medication is in the same month and year as is 
the date of first dose of investigational product in Period II (which is the first Two-Week 
Double-Blind Treatment Period), then the start day of the event/concomitant medication 
will be assigned to the day of the first dose of investigational product taken in Period II.
If the occurrence of the AE/concomitant medication is in the same month and year as is 
the date of the first dose of investigational product in period IV (which is the second 
Two-Week Double-Blind Treatment Period), then the start day of the event/concomitant 
medication will be assigned to the day of the first dose of investigational product taken in 
Period IV.
If the dates of first dose of investigational product for Period II and for Period IV fall in 
the same month, then the start date day of the event/concomitant medication will be 
assigned to the day of the first dose of investigational product taken in Period II. 
Otherwise, the start day will be set to the 1st day of the month.
Missing start day and month, but year present:
If the occurrence of the AE/concomitant medication is in the same year as is the date of 
first dose of investigational product in Period II (which is the first Two-Week Double-
Blind Treatment Period), then the start day of the event/concomitant medication will be 
assigned to the day of the first dose of investigational product taken in Period II.
If the occurrence of the AE/concomitant medication is in the same year as is the date of 
the first dose of investigational product in period IV (which is the second Two-Week 


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Double-Blind Treatment Period), then the start day of the event/concomitant medication 
will be assigned to the day of the first dose of investigational product taken in Period IV.
If the dates of first dose of investigational product for Period II and for Period IV fall in 
the same year, then the start date day of the event/concomitant medication will be 
assigned to the day of the first dose of investigational product taken in Period II.
Otherwise the start day and month will be set to January 1st.
Missing end day, but month and year present:
The end day will be set to the last day of the month.
Missing end day and month, but year present:
The end day and month will be set to the maximum of the date of study termination or the 
date equivalent to 30 days after the last dose of the double-blinded medication.
However, if the study termination year and year for the date of the last dose of the 
double-blinded medication +30 days are greater than the event/concomitant medication 
year, the day and month are to be set to December 31st.
4.3.2
Missing Walkway Data
No values will be imputed for missing data. If one of the triplicate measurements for a Gait
parameter are missed, the average of the remaining two measurements can be used in the 
analyses. If two of or all the triplicate measurements are missing at a timepoint for a Gait
parameter, no values will be imputed or calculated for this timepoint.
4.3.3
Missing MDS-UPDRS Data
MDS-UPDRS items with missing responses will be recoded with imputed values. The 
imputation approach used for each missing item within a scale will be mean item 
substitution, such that the missing item response will be recoded as the mean of the subjects’ 
numeric responses to all non-missing items on the same scale (ie, Part II or Part III) at the 
same assessment.
According to a recent report by Goetz et al. (2015), values for missing items within a scale 
will only be imputed at assessments for which the number of missing items on the scale 
and
be computed, then no scale or composite score which includes that item can be calculated.
No separate imputations for missing values will be conducted for items specific to the PIGD 
4-item and MDS-UPDRS 7-item subscales. These subscales will be scored only if values are 
available for all the corresponding Part III items.


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4.3.4
Missing Baseline Data
For efficacy evaluations, the baseline is considered invalid and will be excluded from the 
analysis if an assessment being analyzed is completed after the first dose of double-blind 
investigational product has been taken.
To assess sensitivity to missing data assumptions, the primary analysis of gait speed will be 
repeated with above invalid baseline included or substituting them with the respective non-
missing assessment at Visit 2.
4.4
Subgroups
The efficacy and safety analyses will also be presented by the following subgroups:
Dementia type (AD, LBD)
Baseline MMSE (14-19, 20-26)
Sex (Male, Female) [Note: efficacy analysis only]
5
BASELINE AND OTHER SUMMARIES AND ANALYSES
5.1
Subjects Disposition
The total number of subjects that participated in the study will be summarized, including 
whether they were randomized or not.  A tabulation will be provided for the number of 
subjects screened and screen-failed prior to the Placebo Run-in period.  The denominator for 
those outcomes for this analysis will be based on the number of screened subjects.
The number of subjects entering the Placebo Run-in and the number of subjects not 
completing the Placebo Run-in (and reasons for not completing) will be presented, using the 
subjects entering the Placebo Run-in as the denominator.
The number of subjects randomized, as well as the number of subjects in the analysis 
populations (Safety, ITT, Per Protocol, Completers populations), will be presented for the 
Randomized Population. This will be summarized by sequence.
An overall summary of the number and percentage of subjects who completed or withdrew 
prematurely from the study will be displayed by sequence, for the overall population as well 
as by dementia type (AD versus LBD [DLB and PDD]) strata. Reasons for premature 
withdrawal will be presented in the order they are displayed in the CRF. Subjects who 
withdrew prematurely from the study will be listed by treatment group and subject.
5.2
Screen Failures
Screen failure data will be tabulated by reason subjects were found to not be eligible for the 
study.


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5.3
Protocol Deviations
Protocol deviations will be identified prior to the database lock and unblinding, and the Per-
Protocol Population will be determined based on a review of those deviations.  Protocol 
deviations will be tabulated and listed, indicating major/minor.  In addition, a listing of 
subjects for whom the treatment blind was broken during the study will also be provided, if 
appropriate.
5.4
Demographic and Baseline Characteristics
Demographics and baseline characteristics will be summarized for the Safety Population.
The variables to be included in the summary are age, sex, race, ethnicity, baseline body 
weight, height, body mass index (BMI), history of smoking, baseline MMSE, dementia 
type, fall history, and caregiver-adapted Falls Efficacy Scale – International.
Details of the primary caregiver (relationship to subject, live with the subject) will be 
included in a tabulation.
All demographic data will be tabulated overall and then by sequence.
Other characteristics collected on the CRF will be listed as appropriate.
5.5
Subject Inclusion and Exclusion Criteria
Subjects not meeting specific eligibility criteria questions will be listed.
5.6
Medical History and Medical Conditions Present at Entry
Past and current medical conditions will be collected and coded using the Medical Dictionary 
for Regulatory Activities (MedDRA), using Axovant Sciences coding conventions.
A tabulation displaying medical history will be provided by system organ class (SOC) and 
preferred term for the safety population.
5.7
Prior and Concomitant Medications
Prior and concomitant medication verbatim text will be coded using the World Health 
Organization’s Drug Dictionary (WHO-DD), and will be classified according to the default 
Anatomical Therapeutic Chemical (ATC) classification system code, WHO-DD Drug Name, 
and preferred term.
Medications will be tabulated as:
Prior medications 
Concomitant medications
–
Single-blind run-in and washout periods
–
Double-blind periods


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Medications received prior to the date of first dose of single-blind investigational product are 
considered as prior medications. Medications will be considered as concomitant if the start 
date of the medication is on or after the date of first intake of investigational product or if the 
start date is prior to the first date of investigational product, but the medication is ongoing 
during the treatment period in the study.
Concomitant medications will be further split by concomitant medications taken during the 
Single-Blind Placebo Run-In Periods and concomitant medications taken during the Double-
Blind Treatment Periods. Those will be presented by treatment group. It should be noted that 
a concomitant medication can be counted in more than one period.
Use of non-investigational products will be summarized (number and percentage of subjects) 
by treatment, the highest ATC class level, and preferred term for the safety population.
A listing of non-medication therapy will be provided.
5.8
Extent of Treatment Exposure
Duration of exposure for the Double-Blind Treatment Period (Period II and Period IV) will 
be calculated by treatment group as follows:
Duration of exposure in days = (Double-Blind Treatment Period stop date – Double-
Blind Treatment Period start date) + 1
Duration of exposure will be tabulated descriptively and categorized as:
0 to 1 week
>1 to 2 weeks
>2 weeks
Note: Duration of exposure will exclude any dates with documented dose interruptions.
5.9
Treatment Compliance
Compliance with study drug will be assessed during the run-in and over the Double-Blind 
Treatment Periods (Period II and Period IV) using drug dispensing records. Treatment 
compliance during the double-blind period will be computed by determining the number of 
tablets taken relative to the number of tablets expected.  Subjects are expected to take one 
tablet per day of each.
Treatment compliance based on the drug accountability per subject/period will be calculated 
as follows:
Compliance (%) = (number of tablets taken in the period)/(number of tablets 
expected)*100


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Number of tablets taken = the number of tablets dispensed in the period – the number of 
tablets returned
Number of tablets expected = (date of the last dose-date of the first dose+1 in the period)
Summary of treatment compliance will be presented by treatment group. The number and 
>120%) will also be presented by treatment group.
5.10 Overdose
Any occurrence of overdose will be provided in the data listing in the same section of dose 
administration record.
6
EFFICACY SUMMARIES AND ANALYSES
6.1
General Considerations
Tabulation of the primary and exploratory endpoints will generally be presented for the ITT, 
Per-Protocol, Completers Population (as described in Section 3), and subgroups (as identified 
in Section 4.4).  The primary efficacy assessments will be performed on the ITT dataset.  
Sensitivity analysis will be performed on CS dataset.  The per-protocol analysis (on the PP 
population) will also be conducted. If deemed necessary
6.2
Statement of the Null and Alternate Hypothesis
This study will examine the following primary hypothesis:
Ho:  There is NO difference between treatment with intepirdine and treatment with 
placebo with respect to changes from baseline in gait speed (under single and dual task 
conditions) at the end of two-week double-blind treatment periods (Period II and Period 
IV).
Ha:  There IS a difference between treatment with intepirdine and treatment with placebo 
with respect to changes from baseline in gait speed (under single and dual task 
conditions) at the end of two-week double-blind treatment periods (Period II and Period 
IV).
The primary comparison of interest will be performed at the 5% level of significance. All 
hypothesis tests will be two-sided. The primary objective of the study will be considered met 
only if the primary analyses of both endpoints indicate statistical significance in favor of 
Intepirdine. No correction for multiplicity will be taken.


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6.3
Analyses of the Primary Efficacy Endpoints
6.3.1
Co-Primary Endpoints
The co-primary endpoints in this study are change from baseline in gait speed observed at the 
end of the two-week double-blind treatment period (Period II and Period IV) under either 
single or dual task condition.
6.3.2
Primary Efficacy Analyses
Separately by each trial condition, treatment comparisons between intepirdine and placebo in 
change from baseline in gait speed at the end of the two-week double-blind treatment period 
(Period II and Period IV) will be analyzed for the ITT Population using a mixed model for 
crossover design with restricted maximum likelihood estimation and an unstructured 
covariance matrix. Degrees of freedom will be calculated using Satterthwaite’s method.
This model corrects for dropouts and missing values replacement is not necessary.
Therefore, no imputation of the missing values will be made or required and the data used 
in the analysis will be the actual observed responses.
The statistical model will be fitted initially with sequence, treatment, period, baseline 
value, both stratification factors (ie, MMSE and dementia type), sex, dementia type by 
treatment interaction as fixed effects and with subject within sequence as a random effect.
–
If the effects of sex and/or dementia type by treatment interaction are not statistically 
significant (p > 0.10), they will be removed from the final analysis model.
–
If the sequence effect is statistically significant (p
0.05) in the model described 
above, subjects within a sequence will be fitted separately in the model with 
treatment, baseline value, and both stratification factors (ie, MMSE and dementia 
type).
The estimated treatment difference for “intepirdine – Placebo” will be displayed together 
with the 95% confidence interval and the associated p-value.
Least Squares Means will also be presented with the standard error and the number of 
subjects contributing to the Least Squares Means. 
The model will be fitted using SAS PROC MIXED procedure with restricted maximum 
likelihood estimation and an unstructured covariance matrix. The unstructured covariance is 
the least restrictive and generally performs well with limited number of repeated measures 
per subject and puts no parameters on the data with respect to the covariance structure 
assumptions.
Only in the unlikely circumstance that there are convergence problems with the analysis will 
other covariance structures be examined to resolve the convergence issue (ie, we would 
evaluate other additional variance-covariance structures, including compound symmetry 
(CS), heterogeneous compound symmetry (CSH), and auto-regressive [AR(1)]).  In this 


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eventuality, the Akaike’s Information Criterion (AIC) will be used to determine the optimal 
variance-covariance structure matrix for the primary comparisons.
6.4
Analysis of the Exploratory Efficacy Endpoints
Continuous and ordinal variables will be analyzed in a fashion similar to that of the primary 
endpoints, using the mixed model for crossover design on the ITT dataset.
6.4.1
Exploratory Endpoints
The exploratory endpoints in this study will be analyzed using the same mixed model as for 
the primary endpoints. The exploratory endpoints in this study are:
Change from baseline in step time variability and step length variability measured on an 
electronic walkway system at the end of each treatment period
Change from baseline in the mini-BESTest total score and subscores at the end of each 
treatment period
Change from baseline in quantitative gait and balance measurements calculated by Opal 
APDM sensors during performance of the mini-BESTest battery at the end of each 
treatment period
Change from baseline in the FOG score and freezing ratio, incorporating input from Opal 
APDM sensors during turning conditions, at the end of each treatment period
Change from baseline in the FOG assessment by the rater on 0 to 4 ordinal scale can 
range from -4 to 4 and will also be analyzed using the same mixed model as for the 
primary endpoints
Change from baseline in MDS-UPDRS Parts II and III subscores, PIGD and MDS-
UPDRS 7-Item subscores at the end of each treatment period
Change from baseline in UPSIT score at the end of each treatment period
6.4.2
Responder Analyses
The percentage of subjects with a 1-point, 3-point, and 5-point reduction in the MDS-
UPDRS will be presented graphically overall by treatment, and then by subgroups of 
dementia type, baseline MMSE, and sex. No inferential statistics will be calculated to 
compare differences in proportion of subjects meeting each of these 3 thresholds after 2-
week double-blind treatment period between treatment groups.
6.4.3
Other Analyses
If deemed appropriate, additional sensitivity analyses of the data not specified in the SAP 
may be undertaken and will be described in the clinical study report.


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7
SAFETY SUMMARIES AND ANALYSES
The safety analysis will be descriptive in nature, and will be presented for the Safety 
Population.  All safety data collected and captured in the CRF will be included in data 
listings sorted by domain, sequence, subject, and time point, or as appropriate.  Mean 
changes from pre-treatment to on-treatment (Periods II and IV together) will be tabulated by 
treatment, while the number of subjects with potentially clinically significant values at pre-
treatment and at the end of each double-blind two-week treatment period (Period II and 
Period IV) will be presented.
Generally, safety data will be presented for the Placebo Run-In Period, for the Double-Blind 
Treatment Period by treatment group (Period II and Period IV plus 7 days after the end of 
these periods, for the Washout Period starting at day 8 of the Washout Period, and for the 
post-treatment Follow-up Period starting at day 8 of the Follow-up Period.
All safety data will be summarized overall and then by stratified subgroup: dementia type 
(AD, LBD) and baseline MMSE (14-19 and 20-26).
7.1
Adverse Events
Adverse events will be classified using the MedDRA version 18.1 coding dictionary.  
Tabulations will include an overall incidence of at least one adverse event, incidence within 
system organ class (SOC), and incidence by preferred term.  Each subject may only 
contribute once per treatment group, that is by first occurrence to each of the incidence rates, 
regardless of the number of occurrences, as follows:
Adverse events occurring prior to the first dose of double-blind investigational product 
will be referred to as Treatment-Emergent AEs (TEAEs) and presented as Placebo Run-
In events.
Adverse events occurring on or after the first dose of each double-blind two-week 
treatment period (Period II and period IV), and within 7 days of the last dose of double-
blind investigational product, will be referred to as TEAEs and presented by treatment 
group.
Events occurring 7 days after the last dose of Period II and Period IV and for the post-
treatment Follow-up Period starting at day 8 (up to 14 days post-last-dose) will be 
presented as Post-Treatment Period. These events will only be included in a data listing.
Tabulations of the incidence of AEs will be presented as follows:
Overview of TEAE
TEAE by SOC and preferred term
TEAE by preferred term
TEAE by SOC, preferred term, and relationship to study drug
TEAE by SOC, preferred term, and maximum severity (mild, moderate, and severe)


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All AEs will be listed with its relationship to study drug and severity, flagging those which 
are not events during treatment-emergent period.
A listing of all deaths and serious AEs will be provided. Any TEAE leading to study drug 
temporary and permanent discontinuation will also be listed.
7.2
Clinical Laboratory
Clinical laboratory parameters will be presented using three methods:
1. Tabulations of observed values for the double-blind two-week periods pre-and post-
treatment (Period II: Visit 3 and Visit 4; Period IV: Visit 5 and Visit 6) by treatment 
group.
2. Tabulations of the incidence of potentially clinically significant (PCS) values by 
treatment group.  A focus will be on new-onset PCS values (ie, subjects with pre-existing 
PCS values at pre-treatment will not be considered to have new-onset values on-
treatment).  For purposes of this analysis, the most extreme (highest and lowest) value 
AT ANY TIME during Period II plus 7 days and Period IV plus 7 days for a parameter 
(for a given subject) will be used.  Thus, a subject may contribute to both a low PCS 
value for a parameter as well as a high PCS value for that same parameter.  PCS 
laboratory values are presented for serum chemistry in Table 2 and for hematology in
Table 3.
3. Shifts from baseline to on-treatment, where values are categorized as low, normal, or 
high according to the lab normal values by treatment group.  For purposes of this 
analysis, the most extreme on-treatment values will be used (most extreme low and most 
extreme high).  On-Treatment values are considered values during Period II plus 7 days 
and during Period IV plus 7 days. Shifts from baseline will be based on laboratory normal 
ranges as provided by the central laboratory.
In addition, the incidence of TEAEs relating to hematology and serum chemistry laboratory 
parameters during Period II plus 7 days and Period IV plus 7 days will be presented by 
treatment group.  These laboratory AEs will be identified from a review of the adverse events
and select SOC and preferred terms will be included.
Table 2:
Serum Chemistry Potentially Clinically Significant Criteria
Parameter 
Gender
Low PCS
High PCS
Alanine aminotransferase (U/L)
Male
NA
133
Female
NA
100
Albumin (g/L)
Male/Female
29
NA
Alkaline phosphatase (U/L)
Male
NA
323
Female
NA
246
Aspartate aminotransferase (U/L)
Male
NA
118


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Female
NA
103
Direct bilirubin (umol/L)
Male/Female
NA
7.7
Total bilirubin (umol/L)
Male/Female
NA
30.8
Calcium (mmol/L)
Male/Female
1.99
2.91
Creatinine (umol/L)
Male
NA
174
Female
NA
147
GGT (U/L)
Male
NA
136
Female
NA
93
Creatinine clearance (mL/min)
Male/Female
59
NA
Random glucose (mmol/L)
Male/Female
2.9
NA
Potassium (mmol/L)
Male/Female
3.4
5.6
Sodium (mmol/L)
Male/Female
129
151
Table 3:
Hematology and Differentials Potentially Clinically Significant Criteria
Parameter 
Gender
Low PCS
High PCS
WBC (109/L)
Male/Female
2.9
100.1
Hemoglobin (g/L)
Male
99
196
Female
99
181
Platelets (109/L)
Male/Female
74
NA
Absolute neutrophil count (109/L)
Male/Female
1.4
NA
Calculated absolute neutrophil count (109/L)
Male/Female
1.4
NA
Absolute lymphocyte count (109/L)
Male/Female
0.7
5.1
Calculated absolute lymphocyte count (109/L)
Male/Female
0.7
4.1
7.3
Vital Signs
Vital sign data (blood pressure [BP], pulse, and weight) will be summarized by treatment, 
and listed by subject and sequence.
Change from baseline will also be summarized by treatment group using data from Periods II 
and IV.  The incidence of PCS values will be presented, with a focus on new-onset PCS 
values.  
PCS ranges for these parameters are provided in Table 4.
Table 4:
List of Potentially Clinically Significant Ranges for Vital Sign Parameters
Systolic blood pressure:
High: >140


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Diastolic blood pressure:
Pulse
Weight
7.4
ECGs
ECG data will be listed by sequence, subject, and time point.  Change from baseline will be 
summarized by treatment group using data collected during the double-blind treatment 
periods plus 7 days.
The ECG analysis will include a careful review of QTcF values. As part of this review, a 
summary of the number (percent) of subjects with QTcF values in the following ranges will 
be performed at ANY time during the double-blind treatment periods plus 7 days (where the 
highest QTcF value will be used for that assessment) and presented by treatment group.
The overall Investigator interpretation of ECG by treatment (shifts from baseline) will be 
tabulated. The incidence of PCS values will be presented, with a focus on new-onset PCS 
values in Table 5.
Table 5:
List of Potentially Clinically Significant Ranges for ECG Parameters
QTcF Interval:
7.5
Physical Examination
Physical examination data will be summarized by treatment group and listed by sequence, 
subject, and time point.
7.6
Suicidality
The following outcomes are C-SSRS categories and have binary responses (yes/no). The 
categories have been re-ordered from the actual scale to facilitate the definitions of the 
composite and comparative endpoints, and to enable clarity in the presentation of the results.


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Category 1 – Wish to be Dead
Category 2 – Non-specific Active Suicidal Thoughts
Category 3 – Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act
Category 4 – Active Suicidal Ideation with Some Intent to Act, without Specific Plan
Category 5 – Active Suicidal Ideation with Specific Plan and Intent
Category 6 – Preparatory Acts or Behavior
Category 7 – Aborted Attempt
Category 8 – Interrupted Attempt
Category 9 – Actual Attempt (non-fatal)
Category 10 – Completed Suicide
Self-injurious behavior without suicidal intent is also a C-SSRS outcome (although not 
suicide-related) and has a binary response (yes/no)
Endpoints based on the above categories are defined below.
Suicidal ideation: A “yes” answer at any time during treatment to any one of the five 
suicidal ideation questions (Categories 1-5) on the C-SSRS
Suicidal behavior: A “yes” answer at any time during treatment to any one of the five 
suicidal behavior questions (Categories 6-10) on the C-SSRS
Suicidal ideation or behavior: A “yes” answer at any time during treatment to any one of 
the ten suicidal ideation and behavior questions (Categories 1-10) on the C-SSRS
Self-injurious behavior without suicidal intent:  a binary response (yes/no)
The number and percentage of subjects with any occurring suicidal events (ideation or 
behavior) will be presented by treatment group and time point.
A listing of all C-SSRS data will be provided, while a listing of subjects who demonstrated a 
worsening on any one of the four endpoints will also be provided for pre-and post-treatment 
(V3 vs V4 and V5 vs V6) including the Day on Treatment the C-SSRS was collected.
7.7
Pregnancy
If any female subjects or female partners of male subjects become pregnant during the study, 
a listing will be provided.
8
INTERIM AND FINAL ANALYSES
No unblinded interim efficacy or safety analyses are planned for this study. This final 
analysis will be performed upon completion of the following items:
The database has been locked according to the Study Data Management Plan
The list of subjects excluded from Per-Protocol Population has been identified


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9
CHANGES FROM THE PROTOCOL TO THIS SAP
There are no meaningful changes from the protocol to this SAP.  Additional details and 
specifications have been included in this SAP to allow for better understanding of the 
intended procedures.


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