Clinical trial NCT02585934
Conditions: Alzheimer's Disease
Keywords: Alzheimer's disease RVT-101 donepezil intepirdine dementia
Sponsor: Axovant Sciences Ltd.
Start date: 2015-10-01; Completion date: 2017-09-01
Enrollment: 1315 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study seeks to confirm a demonstrated treatment effect of intepirdine (RVT-101) as an adjunctive therapy to donepezil for the treatment of subjects with Alzheimer's disease.

Detailed description:
This Phase 3 study seeks to confirm a demonstrated treatment effect of intepirdine (RVT-101) on both cognition and activities of daily living when added to stable donepezil treatment in subjects with mild-to-moderate Alzheimer's disease after 24 weeks of double-blind treatment. This study will also provide further information on the safety and tolerability of the 35-mg dose of intepirdine (RVT-101) when used in combination with donepezil compared to donepezil alone. This study is being conducted under the agreement of a Special Protocol Assessment by FDA. Subjects completing this study will be eligible to enroll in a 12 month open-label study of RVT-101 (RVT-101-3002) in which concomitant medications for the treatment of Alzheimer's disease including memantine will be allowed.

Arms: arm 1: RVT-101 adjunct to 5 mg or 10 mg donepezil arm 2: Placebo adjunct to 5 mg or 10 mg donepezil
Interventions: intervention 1: RVT-101 intervention 2: Placebo
Intervention descriptions: intervention 1: once daily, oral, 35 mg tablets intervention 2: once daily, oral, pill manufactured to match RVT-101 35 mg tablet

Protocol documents:
SAP_002.pdf: 
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Statistical Analysis Plan for Protocol RVT-101-3001 
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ADDENDUM TO  
STATISTICAL ANALYSIS PLAN 
 
 
Title: 
Statistical Analytical Plan for RVT-101-3001: A Phase 3, double 
blind, randomized study of RVT-101 versus placebo when added to 
existing stable donepezil treatment in subjects with mild to moderate 
 
Sponsor 
Axovant Sciences Ltd. 
Compound Name: 
Intepirdine 
Protocol Number 
RVT-101-3001 
Indication 
stable therapy with donepezil 
Development Phase 
3 
IND # 
78,094 
Version 
Final SAP, Version:  August 9, 2017 
Addendum to SAP, Version:  September 19, 2017 
Axovant Sciences 
Study Director 
Ilise Lombardo, MD 
Telephone:  646-495-8197 
Email:  ilise.lombardo@axovant.com 
 
This study is being conducted in compliance with good clinical practice, including the archiving 
of essential documents. 
 
 


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SIGNATURE PAGE 
 
 
Lawrence Friedhoff, MD, PhD 
Chief Development Officer 
 
 
 
 
 
 
Signature 
 
Date 
 
Ilise Lombardo, MD 
Senior Vice President 
Clinical Research 
 
 
 
 
 
 
Signature 
 
Date 
 
 
Divakar Sharma, PhD 
Vice President, Biometrics 
 
 
 
 
 
 
Signature 
 
Date 
 
 


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TABLE OF CONTENTS 
1. 
INTRODUCTION ........................................................................................................5 
2. 
SUMMARY OF EMA SCIENTIFIC ADVICE ...........................................................6 
2.1. 
Summary of Additions to Statistical Analysis Plan in Response to Scientific 
Advice ...........................................................................................................................7 
3. 
TARGET OF ESTIMATION .......................................................................................9 
3.1. 
ICH E9 Addendum .......................................................................................................9 
3.2. 
Estimand for Protocol RVT-101-3001 .......................................................................10 
3.2.1. 
Population targeted by the scientific question ............................................................10 
3.2.2. 
Variable (or endpoint), to be obtained for each patient, that is required to 
address the scientific question ....................................................................................10 
3.2.3. 
The specification of how to account for intercurrent events to reflect the 
scientific question of interest ......................................................................................10 
3.2.4. 
The population-level summary for the variable which provides, as required, 
a basis for a comparison between treatment conditions .............................................16 
4. 
ANALYSIS POPULATIONS ....................................................................................17 
5. 
DESCRIPTIONS OF ADDITIONAL STATISTICAL ANALYSES ........................18 
5.1. 
Sensitivity Analyses of the Primary Efficacy Results ................................................18 
5.2. 
Responder Analyses ....................................................................................................19 
6. 
REFERENCES ...........................................................................................................21 
APPENDIX 1. ICH E9 (R1) ADDENDUM ON ESTIMANDS AND SENSITIVITY5 
ANALYSIS IN CLINICAL TRIALS TO THE GUIDELINE ON 
STATISTICAL 6 PRINCIPLES FOR CLINICAL TRIALS .....................................22 
 


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LIST OF TABLES 
Table 1: 
Examples of Patterns of Missingness (Study RVT-101-3001) ...................................10 
 


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1. 
INTRODUCTION 
Axovant Sciences, Inc., provided a request (June 12, 2017) to obtain European Medicines 
Agency (EMA) guidance regarding the ongoing Phase 3 (RVT-101-3001) study in patients with 
.  The Phase 3 clinical trial will conclude in late September 2017. The 
purpose of the request was to reach agreement with EMA on the statistical and data analysis 
plans prior to study unblinding.   
The Committee for Medicinal Products for Human Use (CHMP) has provided a response 
(Scientific Advice) to that June 12, 2017 request.  That Scientific Advice, dated September 14, 
2017, included specific input regarding analyses of the primary efficacy endpoints as well as 
other aspects of the statistical assessment.   
The purpose of this addendum to the final statistical analysis plan (SAP), dated August 9, 2017, 
is to describe the additional analyses that will be performed in response to the Scientific Advice 
received from the EMA. 


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2. 
SUMMARY OF EMA SCIENTIFIC ADVICE 
The focus of this addendum to the SAP is to respond 
 response to Question 1 of the 
June 12, 2017 request.  This section provides a summary of the Scientific Advice to that 
question. 
Question 1 
Does EMA concur with the statistical methodological approach to analyze Study RVT-101- 
3001? Specifically, our plan for the analysis of the primary endpoints, the hierarchical 
analysis of the key secondary endpoints, and the included plans for responder analyses? 
{Following a summary of the study design, CHMP advised the following.} 
The Applicant presents analysis methods for the co-primary and secondary endpoints that are 
comprehensively described in the protocol and the Statistical Analysis Plan. However, the target 
of estimation or scientific question addressed with the trial is not appropriately defined and 
discussed. 
The Applicant proposes that inferences from treatment differences for the changes from baseline 
derived from a mixed model for repeated measures (MMRM) at Week 24 in the defined ITT 
population are appropriate, using all observed data for patients until the primary analysis time 
point and implicit imputations by the MMRM analysis for patients that withdraw from the study 
before the primary analysis time point. While this target of estimation would address a specific 
research question and estimate a treatment effect as if all patients adhered to treatment until the 
primary analysis time point, CHMP is of the opinion that this hypothetical target of estimation 
would provide a too optimistic estimate of an attainable treatment effect if a relevant number of 
patients withdraws from the study and the Missing At Random assumption would not be 
fulfilled. A considerable number of drop-outs has to be expected, withdrawal patterns could be 
different between treatment arms and the assumption of data only missing at random is not 
reasonable. 
A more appropriate primary target of estimation could make use of information observed after a 
patient withdrew from randomized treatment. Patients starting a new medication or have their 
background medication changed after withdrawal should also be followed and included in the 
analysis, as a comparison of treatment policies would also be of interest. Additionally, multiple 
imputation methods would be an acceptable option if no observed data after treatment 
withdrawal are available. For imputation of missing data, information from patients receiving 
placebo should be considered to avoid a potential overestimation of the treatment effect. Reason 
for drop-out could be used and imputations for patients withdrawing due to lack of efficacy or 
adverse events could be treated differently. 
An appropriate primary analysis should be accompanied with sensitivity analysis to test 
assumptions on properties of methods and data. It is noted that the set of analyses defined in the 
SAP partly address a different target of estimation (alternative analysis methods termed 
2. on observed cases). 
analysis that makes use of multiple imputation methods uses the complete trial population to 


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make covariate based predictions for imputation. While multiple imputation methods are 
considered appropriate, the dataset used to generate imputations would have to be justified. 
From the EU Marketing Authorization Application perspective, an appropriate primary analysis 
demonstrating a relevant treatment effect will have to be defined and pre-specified in the 
Statistical Analysis Plan before unblinding the trial. 
It is further noted that study 3001 uses a single-blind placebo run-in period after screening to 
select patients for randomization who do not improve by more than 3 points on the MMSE score 
after placebo treatment. Consequently, the target of estimation estimates a treatment effect in a 
selected subgroup of all patients eligible for treatment with the new product and it will have to be 
justified how the results from this specific trial design can be generalized for the whole 
population. 
With regard to the definition of the ITT population, it is considered that the Intention-To-Treat 
population, as the definition already suggests, should consist of all patients randomized and the 
Applicant will have to justify that their definition (all randomized who took medication with one 
post-baseline assessment) will lead to the same conclusions on treatment effects. 
Use of the proposed co-primary endpoints is acceptable and the strategy to control the type I 
error for the primary (both must be successful) and secondary endpoints with a hierarchical 
approach is considered adequate. 
Methods for the (key) secondary and other secondary endpoints are acceptable. The defined 
responder analyses should not only be based on observed cases with assessments at week 24. 
Imputations should be used and an approach with missing data imputed as failures should be 
included. A responder criterion of 4 on the ADAS-Cog 11 should be generally implemented in 
addition to improvement of at least 3 points. 
The assumptions for the sample size estimations for the co-primary endpoints and use of the 
treatment difference of 1.6 points on the ADAS-cog 11 and 2 points for the ADCS-ADL scales 
between active treatment and placebo are comprehensible appear technically adequate. 
Sub-group analysis based on gender, region, race, MMSE severity, Donepezil dose is endorsed. 
2.1. 
Summary of Additions to Statistical Analysis Plan in Response to 
Scientific Advice 
The following is a summary of the additions to the SAP as well as explanation of the estimand 
and assumptions on missing data to the SAP. 
1. A description of the estimand (based on ICH E9 R1 Addendum) is provided.  A detailed 
description of intercurrent events is included (see Section 3.2.3). 
2. A description of the estimated proportion of missing data due to overall dropout, due to 
missing at random and missing not at random reasons is provided (see Section 3.2.3.1). 
In response to other comments in the CHMP scientific advice, the following additional analyses 
have been added. 
1. Addition of a new imputation of missing data, using missing imputation methods as 
suggested by CHMP, is included.  This new analysis will include: 


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a. The data will be imputed assuming missing not at random data.  This imputation 
method will use information from patients receiving placebo (but not from 
patients receiving Intepirdine) in order to avoid a potential overestimation of the 
treatment effect.  See Section 3.2.3.2. 
b. For patients who discontinued due to adverse event or due to lack of efficacy, 
imputation is treated differently.  Specifically, a scalar adjustment to the imputed 
values will be performed in order to assign an unfavourable outcome.  See 
Section 3.2.3.3. 
2. These imputed datasets will be used to run additional analyses using the MMRM and 
Wilcoxon tests for the ADAS-Cog and ADCS-ADL endpoints at Week 24.  The analysis 
of these endpoints (and the responder outcomes) will also be performed on the 
Randomized population (in addition to the already-planned ITT population), and a 
comparison of the outcomes between the ITT population and Randomized population 
outcomes will be performed.  See Section 4, Section 5. 
Further, for clarification, the responder analysis as was originally in the SAP is re-iterated to 
address the comment from CHMP regarding treating missing data as failures. 
1. The responder analysis (as is included in the final SAP) is confirmed to be performed 
with missing data imputed as failure (as well as being performed with observed cases 
only).  See Section 5.2. 
The following sections describe the additions to the SAP per the scientific advice.   


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3. 
TARGET OF ESTIMATION 
CHMP provided the following advice on this topic: 
The Applicant presents analysis methods for the co-primary and secondary endpoints that 
are comprehensively described in the protocol and the Statistical Analysis Plan. However, 
the target of estimation or scientific question addressed with the trial is not appropriately 
defined and discussed. 
The Applicant proposes that inferences from treatment differences for the changes from 
baseline derived from a mixed model for repeated measures (MMRM) at Week 24 in the 
defined ITT population are appropriate, using all observed data for patients until the 
primary analysis time point and implicit imputations by the MMRM analysis for patients 
that withdraw from the study before the primary analysis time point. While this target of 
estimation would address a specific research question and estimate a treatment effect as if 
all patients adhered to treatment until the primary analysis time point, CHMP is of the 
opinion that this hypothetical target of estimation would provide a too optimistic estimate 
of an attainable treatment effect if a relevant number of patients withdraws from the 
study and the Missing At Random assumption would not be fulfilled. A considerable 
number of drop-outs has to be expected, withdrawal patterns could be different between 
treatment arms and the assumption of data only missing at random is not reasonable. 
A more appropriate primary target of estimation could make use of information observed 
after a patient withdrew from randomized treatment. Patients starting a new medication 
or have their background medication changed after withdrawal should also be followed 
and included in the analysis, as a comparison of treatment policies would also be of 
interest. Additionally, multiple imputation methods would be an acceptable option if no 
observed data after treatment withdrawal are available. For imputation of missing data, 
information from patients receiving placebo should be considered to avoid a potential 
overestimation of the treatment effect. Reason for drop-out could be used and 
imputations for patients withdrawing due to lack of efficacy or adverse events could be 
treated differently. 
3.1. 
ICH E9 Addendum 
ICH E9 (R1) addendum on estimands and sensitivity analysis in clinical trials to the 
guideline on statistical principles for clinical trials (ICH E9 Addendum), see Appendix 1, is 
currently open for consultation and comments.  However, the principles outlined in that 
document form the basis for our response to that aspect of the CHMP advice.   
The ICH E9 Addendum indicates that an estimand defines in detail what needs to be estimated to 
address a specific scientific question of interest. A description of an estimand includes four 
attributes: 
A. the population, that is, the patients targeted by the scientific question. 
B. the variable (or endpoint), to be obtained for each patient, that is required to address the 
scientific question. 
C. the specification of how to account for intercurrent events to reflect the scientific 
question of interest.  


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D. the population-level summary for the variable which provides, as required, a basis for a 
comparison between treatment conditions. 
Together these attributes describe the estimand, defining the treatment effect of interest. 
3.2. 
Estimand for Protocol RVT-101-3001 
Consistent with the ICH E9 Addendum, definition of the attributes of the estimand (target of 
estimation) is provided in this section. 
3.2.1. 
Population targeted by the scientific question 
The population targeted by the scientific question is defined via the inclusion and exclusion 
criteria as part of the original protocol.  Patients may be male or female, and must have a clinical 
diagnosis of AD in accordance with the recommendations from the National Institute on Aging-
n workgroups on diagnostic guidelines for AD. 
A key aspect of eligibility is that subjects must have an MMSE score 12 to 24 inclusive at 
Screening and a Baseline MMSE score 10 to 26 inclusive.  The difference between the Screening 
and Baseline MMSE score must be less than or equal to 3 points.   
3.2.2. 
Variable (or endpoint), to be obtained for each patient, that is required to 
address the scientific question 
The co-primary endpoints to be obtained for each patient in this study to address the scientific 
question are ADAS-Cog-11 score at Week 24 and ADCS-ADL score at Week 24. 
3.2.3. 
The specification of how to account for intercurrent events to reflect the 
scientific question of interest 
Premature discontinuation from the study is the primary potential intercurrent event that could 
occur.  The following are the possible reasons for premature discontinuation that could be related 
to study treatment and that require an adjustment to the imputation strategy: 
 Adverse Event 
 Lack of efficacy 
3.2.3.1. 
Basis for Use of the Multiple Imputation Strategy 
The patterns of missing data for each primary efficacy endpoint will be presented, with the 
number (%) of patients in each treatment group with each pattern of missingness, as 
demonstrated in Table 1.  These data will be examined in order to determine if there was any 
general difference in the pattern of missing data between the treatment groups, as well as to 
explore the assumption of missingness at random. 
Table 1: 
Examples of Patterns of Missingness (Study RVT-101-3001) 
Pattern
Treatment 
Group 
Number (%) of 
Patients 
Baseline
Week 
3 
Week 
6 
Week 
12 
Week 
18 
Week 
24 
1 
Intepirdine 
xx (xx.x%) 
X 
X 
X 
X 
X 
. 
 
Placebo 
xx (xx.x%) 
X 
X 
X 
X 
X 
. 


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Pattern
Treatment 
Group 
Number (%) of 
Patients 
Baseline
Week 
3 
Week 
6 
Week 
12 
Week 
18 
Week 
24 
2 
Intepirdine 
xx (xx.x%) 
X 
X 
X 
X 
. 
. 
 
Placebo 
xx (xx.x%) 
X 
X 
X 
X 
. 
. 
Etc. 
 
 
 
 
 
 
 
 
In addition, a comparison of dropout due to AE will be performed between the treatment groups, 
along with a graphical display of the time to discontinuation due to AE by treatment group. 
A concern indicated by CHMP was relating to considerable dropout.  However, the actual 
dropout in this study is estimated to be no higher than 11%.  An examination of the patterns of 
missing data for the co-primary endpoints demonstrates that missing data are rare, and that 
collection of the endpoints was, in general, thorough, and that over 87% of patients had at least 
one of their Week 24 co-primary efficacy endpoints collected.  Further, dropout (discontinuation) 
due to adverse event is estimated to be less than 4%, and dropout due to lack of efficacy less than 
1%.  Therefore, the overwhelming majority (~95%) of Week 24 values will either be collected or 
will be attributed to MAR.  These outcomes reflect a high level of study oversight and 
management of patient visits as well as patient retention to minimize the effects of missing 
values on the primary targets of estimation. Further, the methods proposed for the primary 
analysis (MMRM) are recognized as robust under these assumptions. 
Data collection beyond premature (early) discontinuation was not performed in this study, while 
the number of patients with missing values at Week 24 is low, patients discontinuing early did 
not have their later efficacy data collected.  Relating to this, CHMP indicated: 
 
A more appropriate primary target of estimation could make use of information 
observed after a patient withdrew from randomized treatment. Patients starting a new 
medication or have their background medication changed after withdrawal should 
also be followed and included in the analysis, as a comparison of treatment policies 
would also be of interest.    
As collection of post-drop data was not performed, the alternative option to address these 
missing values will be pursued. To address this situation, CHMP suggested:  
 
dditionally, multiple imputation methods would be an acceptable option if no 
observed data after treatment withdrawal are available. For imputation of missing 
data, information from patients receiving placebo should be considered to avoid a 
potential overestimation of the treatment effect. Reason for drop-out could be used 
and imputations for patients withdrawing due to lack of efficacy or adverse events 
could be treated differently.    
Therefore, to account for the intercurrent events described above, an additional analysis via 
multiple imputation of those missing data for those patients experiencing certain intercurrent 
events (discontinuation due to AE or due to lack of efficacy) is planned.  The ICH E9 Addendum 
indicates: 
 
for a numerical variable, experiencing an intercurrent event might be ascribed an 
extreme unfavourable value and a suitable summary measure se
 


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Details of the details of this additional multiple imputation strategy are provided in the following 
section.  This analysis will be performed IN ADDITION to the final SAP. 
3.2.3.2. 
Description of Additional Multiple Imputation Strategy 
Missing on-treatment data for the primary endpoints will be imputed utilizing multiple 
imputation methods.  Multiple imputation provides a useful strategy for analyzing data sets with 
Rubin 1976, 
Rubin 1987] multiple imputation strategy replaces each missing value with a set of plausible 
values that represent the uncertainty about the correct value to impute.  Once a monotonic 
missing data pattern is established, the imputation method will specifically impute data at each 
time point based on the distribution data only from the placebo-treated patients.  Thus, all 
Week 24 values will be imputed using only the placebo-based distribution. 
To examine the primary endpoint with a multiple imputation method that does not require the 
MAR assumption, a pattern-mixture approach will be utilized for the imputation.  The first step 
will be to apply a Markov chain Monte Carlo (MCMC) method [Schafer 1997] that assumes 
multivariate normality will be used to impute all missing values to make the imputed (resulting) 
data sets have strictly monotone missing patterns.  The resulting monotone missing pattern will 
then, in a second imputation step, be used to impute the remaining missing values; specifically, a 
regression-based pattern-mixture method for continuous variables will be applied. 
The SAS software system will be used to perform this imputation.  Because the imputation of 
missing data is a key aspect to the analysis of the data, explicit details regarding this imputation 
are provided via sample SAS code that is intended to demonstrate the application of these 
strategies.  Variable definitions are: 
 TRT=treatment group (1=Intepirdine, 0=Placebo) 
 Eff1 is the first time-point for the variable score 
 Eff2 is the second time-point for the variable score 
 Eff_last is the last time point for the variable score. Additional variable scores 
(between Eff1 and Eff_last) would be included in this model according to the time 
points for collection. 
The first step will be to impute partially to obtain a monotone missing data pattern.  This 
imputation will be done independent of treatment.  
proc mi data=DATAIN out=DATAIN_MONO nimpute=100 seed=123;  
 
mcmc chain=multiple impute=monotone;  
run; 
The second step will be to impute the remaining (monotone) missing data that is MAR for each 
of the 100 imputed datasets from the first step.  This step will assume that the distribution of 
missing values are based on the distribution of placebo outcomes ONLY (and thus reduces the 
risk of overestimating the treatment effect). 


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Ratitch 2011) describe an implementation of the pattern-mixture model 
approach that uses a control-based pattern imputation. That is, an imputation model for the 
missing observations in the treatment group is constructed not from the observed data in the 
treatment group but rather from the observed data in the control group. This model is also the 
imputation model that is used to impute missing observations in the control group.  
Following the imputation of the data to create a monotone missing pattern, missing values for the 
earliest missing value (visitnum1) are imputed BY VISIT.  The first visit to be imputed would be 
the Week 3 time-point, then the Week 6, Week 12, Week 18, and finally Week 24.  The Week 24 
time-point is the key timepoint of interest. 
The process is repeated sequentially, ie, by visit, until the monotone missing data pattern is 
completely filled in (imputed), and thus there may be up to 5 calls to the PROC MI procedure to 
generate the final imputed dataset.  
The following sample SAS code demonstrates the general methodology for imputing the first 
visit (Week 3), second visit (Week 6) data, and third visit (Week 12).  Note that the output 
dataset from the first imputation is used as the input dataset for the second imputation, and the 
output dataset from the second imputation is used as the input dataset for the third imputation.  
Note that minor alterations to the SAS code may be performed. 


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**First procedure imputes missing values for the first visit (Week 3); 
proc mi data=DATAIN_MONO out=DATAREG1 seed=465 nimpute=1;  
class trt;  
monotone regression(eff1);  
mnar model (eff1 / 
));  **indicates only observations 
for the outcomes;  
var eff1; 
run; 
  ** Second procedure imputes missing values for the second visit (Week 6) 
proc mi data=DATAREG1 out=DATAREG2 seed=465 nimpute=1;  
class trt;  
monotone regression(eff2);  
mnar model (eff1 eff2 / 
  **indicates only 
imputation model for the outcomes;  
var eff1 eff2; 
run; 
** Third procedure imputes missing values for the Third visit (Week 12) 
proc mi data=DATAREG2 out=DATAREG3 seed=465 nimpute=1;  
class trt;  
monotone regression(eff3);  
mnar model (eff1 eff2 eff3 / 
  **indicates only 
imputation model for the outcomes;  
var eff1 eff2 eff3; 
run; 
This process is continued for all visits through Week 24. 
Note that the regressions do not include the subset of observations from the Intepirdine treatment 
arm.  The imputed data at each time point will be based on the distribution data only from 
the placebo-treated patients, and thus information only from patients receiving placebo are 
considered to avoid potential overestimation of the treatment effect. This is consistent with the 
CHMP advice: 
 
after treatment withdrawal are available. For imputation of missing data, information 
from patients receiving placebo should be considered to avoid a potential 
overestimation of the treatment effect. Reason for drop-out could be used and 
imputations for patients withdrawing due to lack of efficacy or adverse events could 
be treated differently
 


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However, as suggested by CHMP, for those patients discontinuing due to either AE or to lack of 
efficacy, imputation is treated differently.  This is also specifically suggested in the ICH E9 
Addendum, 
for a numerical variable, experiencing an intercurrent event might be ascribed an 
extreme unfavourable value and a suitable summary measure selected.   This will be 
accomplished with an additional imputation step, as described in the following section. 
3.2.3.3. 
Imputation for Intercurrent Events of Discontinuation due to AE or Lack of 
Efficacy 
For patients with intercurrent events of discontinuation due to adverse event OR due to lack of 
efficacy, imputation will follow the same strategy as above, with the difference that the imputed 
Week 24 values (after following the steps in the section above) will be adjusted and therefore 
ascribed an extreme unfavourable value.   
Specifically, for these patients who discontinued due to adverse event or due to lack of efficacy 
at Week 24, the missing values will be scaled to worse as compared to patients with MAR 
Week 24 data.  Ie, a scalar value of 10% worsening, using a patient s baseline to define the 10% 
scalar value, will be added to the patients Week 24 imputed value 
outcome.   
The scalar will be determined as follows.  Patients are expected to have an average ADAS Cog 
11 score of ~25, and thus a 10% worsening would average approximately 2.5 points.  Worsening 
of 2.5 points in the ADAS-Cog 11 was similar for the placebo arms in those clinical trials for 
many approved drugs (eg, donepezil, rivastigmine, memantine), and thus 10% of a 
 
baseline value is a clinically relevant and meaningful adjustment (worsening) to the patients who 
discontinued due to adverse event or due to lack of efficacy. 
For example, assume a patient discontinues prematurely due to an adverse event and the patient 
is therefore missing the Week 24 ADAS Cog 11 value.  Imputation of missing values for this 
patient will be performed as follows: 
 The patients missing values after discontinuation will FIRST be imputed accorded to 
the same procedures as for all patients with missing values.   
 Then, the Week 24 imputed value will be FURTHER scaled (worsened) as follows: 
 The patients baseline value for the variable will be identified (eg, assume the 
patient has an ADAS Cog 11 score of 27 at baseline).  And note that increases in 
the ADAS Cog-11 indicate a worsening of function, and thus increases from 
baseline would indicate a poor treatment outcome. 
 The baseline score will be multiplied by 10%, eg, 27 * 0.1 = 2.7.  This 2.7 would 
be this individual patients  scalar adjustment to the Week 24 ADAS Cog 11 score. 
 Therefore, the imputed Week 24 score for that patient will be increased 
(worsened) by 2.7.  Thus, if, for example, the patients Week 24 value is imputed 
by the primary imputation methods to be 25, a further scalar increase of 2.7 will 
be attributed for that patient, ie, the resulting imputed score for analysis for that 
patient will be 25+2.7 = 27.7. 


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Thus, in this manner, patients who discontinue due to adverse event or due to lack of efficacy 
will, as a group, have a worse distributional outcome for each co-primary endpoint than other 
patients with missing values at random.  A 10% worsening in the co-primary endpoints is 
considered sufficient to ensure that these patients who discontinued due to adverse event or due 
to lack of efficacy are treated accordingly with unfavorable outcomes.  
3.2.4. 
The population-level summary for the variable which provides, as required, a 
basis for a comparison between treatment conditions 
The population-level summary for the co-primary variables in this study are ADAS-Cog-11 
score change from baseline to Week 24 and ADCS-ADL score change from baseline to Week 
24.  The basis for the comparison will be made using the Randomized population and the 
outcomes to those patients with an intercurrent event of dropout due to either adverse event or 
lack of efficacy. 


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4. 
ANALYSIS POPULATIONS 
The Intent-to-Treat (ITT) Population was defined as: 
 All subjects randomized to treatment who have taken at least one dose of double-
blind investigational product and who have at least one baseline (and one post 
baseline) primary efficacy assessment for at least one of either the ADAS-Cog-11 or 
the ADCS-ADL.  This will be the primary population used for the efficacy analysis. 
 assessment was added to the original 
definition.   
The Randomized Population was defined as all patients who are randomized.  
CHMP advice suggested the following: 
 
With regard to the definition of the ITT population, it is considered that the 
Intention-To-Treat population, as the definition already suggests, should consist of all 
patients randomized and the Applicant will have to justify that their definition (all 
randomized who took medication with one post-baseline assessment) will lead to the 
same conclusions on treatment effects.  
Therefore, an analysis of the Randomized Population will be performed for the co-primary 
endpoints using the multiple imputation strategy as indicated above, and the responder analyses 
as described for those outcomes.   
A comparison of the conclusions regarding treatment effect between the Randomized Population 
and the ITT population will be performed.  This analysis comparison will allow for justification 
as to whether the ITT population (as defined) leads to the same conclusions from the 
Randomized population. 


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5. 
DESCRIPTIONS OF ADDITIONAL STATISTICAL ANALYSES 
The key analysis method of these additional imputed data (as described in the previous sections) 
will be using the mixed model repeated measures (MMRM) approach.  A summary of this 
method is described below. 
Treatment comparisons between the intepirdine and placebo groups in ADAS-Cog-11 and 
ADCS-ADL change from baseline to Week 24 will be analyzed for the dataset using a mixed 
model for repeated measures with restricted maximum likelihood estimation, an unstructured 
covariance matrix, and the Kenward-Roger approximation for denominator degrees of freedom.  
The same procedures for analysis of the imputed data (as were proposed in the original SAP) 
would then be performed, as follows: 
 Each of the 100 imputed datasets will be analyzed using the MMRM model.  The 
statistical model will be fitted with terms for treatment group, visit, treatment by visit 
interaction, baseline score, baseline MMSE, baseline score by visit interaction, and 
Region.  In this way, the test of the efficacy endpoint at Week 24 will be obtained 
once for each of the 100 imputed datasets. 
 The 100 resulting treatment effect parameters and standard errors from these will be 
combined to provide a distribution of parameters (and standard errors) upon which 
the sensitivity analysis will be concluded.  PROC MIANALYZE will be used for this 
summary of the analysis. 
Inferences will be drawn from treatment differences for the changes from baseline derived from 
the MMRM models at Week 24.  As additional supportive information, treatment differences for 
each post baseline visit will also be derived.  
intepirdine 
35mg  
sis together 
with the 95% confidence interval and the associated p-value. 
Least Squares Means for each visit will also be presented with the standard error and the number 
of subjects contributing to the Least Squares Means. Least Squares Means and estimated 
treatment differences for each visit and the associated 95% confidence interval will be displayed 
graphically. 
Note that while the primary determination of the effects of treatment will remain based on the 
indicated analyses in the final SAP (August 9, 2017), comparison of those outcomes to the 
additional analyses above will be made to assess the robustness of the outcomes. 
5.1. 
Sensitivity Analyses of the Primary Efficacy Results 
CHMP as the following advice: 
 
An appropriate primary analysis should be accompanied with sensitivity analysis to 
test assumptions on properties of methods and data. It is noted that the set of analyses 
defined in the SAP partly address a different target of estimation (alternative analysis 
8.3.2.4.) would not be acceptable and the outlined analysis that makes use of multiple 


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imputation methods uses the complete trial population to make covariate based 
predictions for imputation. While multiple imputation methods are considered 
appropriate, the dataset used to generate imputations would have to be justified  
In response to this advice, the following sensitivity analysis will be performed for the co-primary 
efficacy endpoints using the 100 imputed datasets: 
 Analysis using a non-parametric (distribution-free) Wilcoxon Rank Sum Test of the 
treatment differences will be run for the Week 24 data, and conclusions will be based 
on the combined outcomes from the 100 imputed datasets. Sample SAS code is as 
follows.  The actual SAS code may be modified as appropriate. 
Proc npar1way data=dat; 
  Class treat; 
  Var outcome; 
  ods select WilcoxonScores; 
  Run; 
5.2. 
Responder Analyses 
CHMP had the following advice: 
 
The defined responder analyses should not only be based on observed cases with 
assessments at week 24. Imputations should be used and an approach with missing 
data imputed as failures should be included. A responder criterion of 4 on the ADAS-
Cog 11 should be generally implemented in addition to improvement of at least 3 
points.  
The analyses of responder (defined below) are consistent with that advice, as shown below.   
The responder analyses will be performed based on the observed data (subjects with Week 24 
assessment for the endpoint of interest), as well as analyzed assuming all subjects with missing 
Week 24 are treatment failures (non-responder). 
The following responder definitions will be defined and each will be analyzed using a logistic 
regression model as described above as well as a CMH test.  The percentage of responders and 
the difference in proportions compared to placebo will be presented.  This analysis is planned for 
both the ITT population as currently defined as well as the Randomized population. 
1. ADAS-Cog-11 Improvement by at least 3 points at Week 24  
a. Repeated for by at least 4 points at Week 24 
b. 
 
 
2. ADCS-ADL No change/improvement vs worsening at Week 24 
3. CIBIC+ No change/improvement vs worsening at Week 24 
4. ADAS-Cog-11/CIBIC+/ADCS-ADL composite, simultaneously meeting the criteria for: 
a. ADAS-Cog-11 Improvement of at least 3 points at Week 24 
b. CIBIC+ No change/improvement at Week 24 


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c. ADCS-ADL No change/improvement at Week 24 
5. ADAS-Cog-11/ADCS-ADL composite, simultaneously meeting the criteria for:   
a. ADAS-Cog-11 Improvement by at least 3 points at Week 24 
b. ADCS-ADL No change/improvement at Week 24 
6. ADAS-Cog-11/CIBIC+/ADCS-ADL composite, simultaneously meeting the criteria for: 
a. ADAS-Cog-11 Improvement of at least 4 points at Week 24 
b. CIBIC+ No change/improvement at Week 24 
c. ADCS-ADL No change/improvement at Week 24 
7. ADAS-Cog-11/ADCS-ADL composite, simultaneously meeting the criteria for:   
a. ADAS-Cog-11 Improvement by at least 4 points at Week 24 
b. ADCS-ADL No change/improvement at Week 24 


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6. 
REFERENCES 
-Mixture Models Using Standard 
SAS/STAT 
Users Group), SP04, Nashville. 


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APPENDIX 1. ICH E9 (R1) ADDENDUM ON ESTIMANDS AND 
SENSITIVITY5 ANALYSIS IN CLINICAL TRIALS TO THE 
GUIDELINE ON STATISTICAL 6 PRINCIPLES FOR CLINICAL 
TRIALS 
 

Prot_000.pdf: 
CLINICAL STUDY PROTOCOL
Title:
A Phase 3, double-blind, randomized study of RVT-101 versus 
placebo when added to existing stable donepezil treatment in 
subjects with mild to moderate Alzheimer’s disease
Sponsor
Axovant Sciences Ltd.
Compound Name:
RVT-101
Protocol Number
RVT-101-3001
Indication
Treatment of mild to moderate Alzheimer’s disease in patients on 
stable therapy with donepezil
Development Phase
3
IND #
78,094
Version/
Date:
3.0
13 April 2016
Axovant Sciences 
Study Director
Ilise Lombardo, MD
Telephone: 646-495-8197
Email: ilise.lombardo@axovant.com
Medical Monitor
Meera Jessani, MD
Telephone:  610-964-2012
Mobile:  310-728-5684
Email: Meera.jessani@wwctrials.com
Confidentiality Statement
The information contained in this document, particularly unpublished data, is the property or 
under control of Axovant Sciences Ltd., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Institutional 
Review Board or Independent Ethics Committee. The information is only to be used by you in 
connection with authorized clinical studies of the investigational product described in the 
protocol. You will not disclose any of the information to others without written authorization 
from Axovant Sciences Ltd., except to the extent necessary to obtain informed consent from 
those persons to whom the investigational product may be administered.




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RVT-101-3001 Protocol v3.0 
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MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/Serious Adverse Event Contact Information:
Role and 
Region
Name
Daytime Phone Number and 
Email Address
After-Hours 
Phone/Cell/
Pager Number
Fax Number
WCT Site 
Address
Primary Medical Monitor
Americas
Meera 
Jessani, 
MD
+1 610 964 2012 
Meerra.jessani@wwctrials.com
+1 310 728 5684
+1 610 225 0050
1000 
Continental 
Drive, King 
of Prussia, PA 
19406, USA
Secondary Medical Monitors
Western and 
Central 
Europe
Manolo 
Beelke, 
MD, PhD
+49 (0) 89 8905 8422 
manolo.beelke@wwctrials.com
+49 (0) 17 3618 9707
+49 (0) 89 8905 8423
Landsberger 
Str.
63A, 82110 
Germering, 
Germany
Eastern 
Europe and 
Asia Pacific
Olga 
Kolotilina, 
MD
+7 384 245 46 70 
olga.kolotilina@wwctrials.com
+7 906 925 18 12
+7 384 245 46 73
536, 12, N. 
Ostrovskogo 
Str., 
Kemerovo, 
650000, 
Russia
SAE 
Contact
Information
Contact Medical Monitor as shown above.
For SAE reporting information, see Study Reference Manual.


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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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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 fulfil their obligations. Mechanisms are in place to ensure 
that site staff receives the appropriate information throughout the study.
______________________________________
__________________________________
Principal Investigator Name (Printed)
Signature
______________________________________
__________________________________
Date
Site


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TABLE OF CONTENTS
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LIST OF TABLES
PAGE
 
 
 
 
 
 
 
 
 
 


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LIST OF FIGURES
PAGE
 
 
 
 
 
 
 
 


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1.
ABBREVIATIONS
Abbreviation
Definition
5HT6
5-hydroxytryptamine sub-type 6
ACh
acetylcholine
AChE
acetylcholinesterase
AChEI
acetylcholinesterase inhibitor
AD
Alzheimer’s disease
ADAS-Cog
Alzheimer’s Disease Assessment Scale – Cognitive Subscale
ADAS-Cog-11
Alzheimer’s Disease Assessment Scale – Cognitive Subscale-
11 items
ADAS-Cog-13
Alzheimer’s Disease Assessment Scale – Cognitive Subscale-
13 items (ADAS-Cog-11 plus delayed word recall and total
digit cancellation tests)
ADCS-ADL
Alzheimer’s Disease Cooperative Study – Activities of Daily 
Living
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical
AUC
area under the concentration-time curve at steady state
BUN
blood urea nitrogen
CDR-SB
Clinical Dementia Rating – Sum of Boxes
CFR
Code of Federal Regulations
CI
confidence interval
CIBIC+
Clinician’s Interview-Based Impression of Change – plus 
caregiver interview
CIBIS
Clinician’s Interview-Based Impression of Severity
Cmax
peak concentration
Cmax-ss
peak concentration at steady state
Cmin
minimum (trough) concentration
Cmin-ss
minimum (trough) concentration at steady state
CNS
central nervous system
C-SSRS
Columbia Suicide Severity Rating Scale
CT
computed tomography
DS
Dependence Scale
ECG
electrocardiogram
eCRF
electronic case report form
EQ-5D
EuroQOL 5 dimensions questionnaire
EQ-VAS
EuroQOL visual analogue scale
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GGT
gamma glutamyltransferase
HBsAg
hepatitis B surface antigen


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Abbreviation
Definition
hCG
human chorionic gonadotropin
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ITT
intent-to-treat
IVRS
interactive voice response system
IWRS
interactive web response system
MAO
monoamine oxidase 
MCH
mean corpuscular hemoglobin
MCV
mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
mixed model for repeated measures
MMSE
Mini Mental State Examination
MRI
magnetic resonance imaging
NMDA
N-methyl-D-aspartate
NPI
Neuropsychiatric Inventory
Pgp
permeability glycoprotein
PK
pharmacokinetic(s)
PP
per protocol
PSA-NCAM
polysialylated form of the neural cell adhesion molecule
QTc
corrected QT (interval)
RBANS
Repeatable Battery for the Assessment of Neuropsychological 
Status
RBC
red blood cell
RUD Lite
Resource Utilization in Dementia Lite
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
standard deviation
SMC
Safety Monitoring Committee
SOC
System Organ Class
TEAE
treatment-emergent adverse event
TSH
thyroid stimulating hormone
ULN
upper limit of normal
WBC
white blood cell
WCT
Worldwide Clinical Trials
WHO
World Health Organization


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2.
PROTOCOL SUMMARY
Study Title
A Phase 3, double-blind, randomized study of RVT-101 versus 
placebo when added to existing stable donepezil treatment in subjects 
with mild to moderate Alzheimer’s disease
Objectives
Primary
To assess the effects of RVT-101 versus placebo as adjuncts to 
stable donepezil therapy on cognitive function as measured by the 
Alzheimer’s Disease Assessment Scale – Cognitive Subscale 11 
items (ADAS-Cog-11) after 24 weeks of treatment
To assess the effects of RVT-101 versus placebo as adjuncts to 
stable donepezil therapy on activities of daily living as measured 
by the Alzheimer’s Disease Cooperative Study - Activities of 
Daily Living (ADCS-ADL) scale after 24 weeks of treatment
Secondary
To assess the effects of RVT-101 versus placebo as adjuncts to 
stable donepezil therapy on cognition as measured by the 
ADAS-Cog-13 (ADAS-Cog-11 plus delayed word recall and total 
digit cancellation tests) after 24 weeks of treatment
To assess the effects of RVT-101 versus placebo as adjuncts to 
stable donepezil therapy on global clinical assessment of change 
as measured by Clinician’s Interview-Based Impression of 
Change – plus caregiver interview (CIBIC+) after 24 weeks of 
treatment
To assess how baseline Mini Mental State Examination (MMSE)
score severity affects efficacy outcome measures after 24 weeks 
of treatment.
To assess the effects of RVT-101 versus placebo as adjuncts to 
stable donepezil therapy on neuropsychiatric symptoms as
measured by the Neuropsychiatric Inventory (NPI) after 24 weeks 
of treatment
To assess the effects of RVT-101 versus placebo as adjuncts to 
stable donepezil therapy on an analysis of responders based on 
prespecified efficacy evaluations
To assess the effects of RVT-101 versus placebo as adjuncts to 
stable donepezil therapy on subject dependency as measured by 
the Dependence Scale (DS) 
To measure RVT-101 plasma concentrations and donepezil 
plasma concentrations in study subjects
To estimate the pharmacokinetic (PK) parameters of RVT-101
and donepezil and explore relationships to efficacy or safety 
endpoints, as appropriate
To assess the safety and tolerability of RVT-101 as an adjunct 
therapy to stable donepezil treatment
Tertiary
To assess the effects of RVT-101 versus placebo as adjuncts to 


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stable donepezil therapy on healthcare utilization as measured by 
the Resource Utilization in Dementia Lite (RUD Lite)
To assess the effects of RVT-101 versus placebo as adjuncts to 
stable donepezil therapy on quality of life as measured by the 
EuroQOL 5 dimensions questionnaire (EQ-5D)
Study Phase
Phase 3
Target Population
Adult subjects aged 50 to 85, inclusive, with mild to moderate 
Alzheimer’s disease (AD). Subjects will be stratified by baseline 
MMSE score into 3 groups by severity.
Number of Subjects 
Planned
Approximately 1150 randomized subjects:
RVT-101: 575 subjects
Placebo:  575 subjects
Number of Study 
Centers Planned
Approximately 185
Study Design
This is a multicenter, double-blind, randomized, placebo-controlled, 
parallel-group study in patients with mild to moderate AD who are on 
stable donepezil therapy.  The efficacy and safety of RVT-101 at a 
dose of 35 mg daily when used as an adjunct treatment to stable 
donepezil therapy will be evaluated over a 24-week treatment period.
All subjects will remain on stable doses of donepezil for the duration 
of the study.  The randomization ratio will be 1:1 (RVT-101:placebo) 
and will be stratified by baseline MMSE score into 3 groups of 
severity.
Duration of Treatment
Study participation will last approximately 33 weeks:  0 to 28 days
for Screening, a 3-week Single-Blind Run-In Period to evaluate 
baseline status, a 24-week randomized Double-Blind Treatment 
Period, and a 2-week Follow-Up Period (for subjects who do not 
enter the open-label extension study RVT-101-3002).
Criteria for Evaluation
Primary efficacy measures: The primary efficacy response will be an 
assessment of change at 24 weeks from baseline in cognition and 
activities of daily living.  Cognition will be measured by the 
ADAS-Cog-11 and activities of daily living will be measured by the 
ADCS-ADL.
Secondary efficacy measures: An additional measure of cognition 
will be the ADAS-Cog-13. Global assessment of change will be 
measured by the CIBIC+. Neuropsychiatric symptoms and 
psychopathology will be measured by the NPI. Subject dependency 
will be measured by the DS.
Tertiary efficacy measures: Healthcare resource utilization, and 
quality of life will be assessed by the RUD Lite, and the EQ-5D.
Pharmacokinetic evaluation: Plasma levels of RVT-101 and 
donepezil will be measured, and standard population PK parameters 
will be calculated for RVT-101.
Safety evaluation: Safety will be based on adverse events (AEs),
changes in physical examinations, vital signs, electrocardiograms 


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(ECGs), suicidality (via the Columbia Suicide Severity Rating Scale 
[C-SSRS]) and routine clinical laboratory assessments.
Statistical Methods
Efficacy:  Treatment comparisons between the RVT-101 and placebo 
groups in ADAS-Cog-11 and ADCS-ADL scores change from 
baseline at Week 24 will be analyzed using a mixed model for 
repeated measures (MMRM) with restricted maximum likelihood 
estimation.
Additional analyses for the change from baseline at Week 24 
endpoints including ADAS-Cog-13, CIBIC+, NPI, and DS will be
analyzed using the same method as that for the primary endpoints.
The CIBIC+ will also be analyzed using the 
Cochran-Mantel-Haenszel test.
Treatment comparisons between the RVT-101 and placebo groups for 
the responder endpoints will be analyzed using logistic regression and 
compared using the Cochran–Mantel–Haenszel test.
The RUD Lite, and the EQ-5D will be summarized descriptively by 
treatment. Treatment comparisons between RVT-101 and placebo 
will be analyzed using an analysis of covariance (ANCOVA) model.
Pharmacokinetic: Plasma concentrations for RVT-101 and donepezil 
will be measured.  RVT-101 PK parameters (area under the 
concentration-time curve at steady state [AUC ], peak concentration 
at steady state [Cmax-ss], and minimum (trough) concentration at steady 
state [Cmin-ss]) for each subject will be estimated via a population PK 
model using nonlinear mixed effect analysis.
Safety:  Safety will be assessed by summarizing and analyzing AEs, 
laboratory analytes, vital signs, physical examination, C-SSRS, and 
ECG parameters.


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3.
INTRODUCTION
3.1.
Background
3.1.1.
Alzheimer’s Disease
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by 
deterioration of memory and other aspects of cognition, progressive impairment of activities of 
daily living, and a variety of behavioral disturbances (Cummings, 2004). An estimated 
5.2 million American’s have AD (Alzheimer’s Association, 2013). In 2010, approximately
503,400 deaths in Americans aged 75 years and older were attributable to AD dementia
(James et al, 2014), and the incidence is increasing as the global population ages 
(Cummings et al, 2014). Between 2000 and 2010, the proportion of deaths resulting from heart 
disease, stroke, and prostate cancer decreased 16%, 23%, and 8%, respectively, whereas the 
proportion of deaths resulting from AD increased 68% (Alzheimer’s Association, 2013).
The first drug specifically approved for the treatment of AD was tacrine, an acetylcholinesterase 
inhibitor (AChEI).  AChEIs increase levels of acetylcholine (ACh), a key neurotransmitter for 
cognitive processes.  Although approved in many countries, tacrine was not widely used, most 
likely because it is associated with liver toxicity and because of an inconvenient dosing regimen.  
Soon after the approval of tacrine, donepezil, another AChEI, was approved and became the 
most widely used drug to treat AD, likely due to its lack of liver toxicity and once-daily dose 
regimen (Aricept® [donepezil] Package Insert, 2013).  Two other AChEIs were approved 
subsequently, resulting in a total of 4 marketed drugs of this class.  Memantine, the only other 
drug approved for the treatment of AD, is an N-methyl-D-aspartate (NMDA) receptor antagonist
and is only approved to treat moderate to severe AD.
Although the approved agents produce a modest improvement in cognition in the short term,
they do not prevent progression of the disease, and patients continue to show decline in cognitive 
performance and inexorable progressive loss of function despite currently available treatments.
There is a lack of treatment options available for patients once the initial effectiveness of the 
AChEI starts to wane, and there are no treatments currently approved for adjunct therapy to 
AChEIs in subjects with mild to moderate AD. No new chemical entities for AD have been 
approved in more than 10 years.  Thus, there is an urgent need to identify new drugs for the 
treatment of AD.
5-Hydroxytryptamine sub-type 6 (5HT6) receptors are widely distributed in regions of the brain 
that are associated with cognition. 5HT6 receptor antagonists have a modulatory effect on 
cholinergic, and other neurotransmitter systems, a profile that is clearly distinct from that of the 
AChEIs (Mitchell and Neumaier, 2005). In addition, 5HT6 receptor antagonists have been 
reported to cause increases in the polysialylated form of the neural cell adhesion molecule 
(PSA-NCAM) in the hippocampal and medial temporal regions of the brain during a learning 
task (Seki and Arai, 1993; Kiss et al, 2001). PSA-NCAM increases have been correlated with 
increases in synaptic plasticity in areas such as the hypothalamus, olfactory bulb, and 
hippocampus of the adult nervous system (Seki and Arai, 1993; Kiss et al, 2001).


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3.1.2.
RVT-101
RVT-101, previously known as SB742457, is a potent and selective 5HT6 receptor antagonist, 
which is being developed as an oral treatment for subjects with mild to moderate AD.
Pharmacology predicts central nervous system (CNS) effects on ACh for both donepezil and 
RVT-101. However, the mechanisms by which this is achieved by each treatment are clearly 
distinct. Donepezil exerts its effect by inhibiting acetylcholinesterase (AChE), thus inhibiting 
the hydrolysis of ACh, which results in increased ACh levels. This can be associated with 
systemic cholinergic side effects, principally gastrointestinal in nature, but these events can be 
mitigated by slow titration. RVT-101 causes a release of neurotransmitters primarily localized in 
the CNS through its antagonism at the 5HT6 receptor. The potential increase in ACh following 
the addition of RVT-101 is expected to augment that already achieved with donepezil, and thus 
may result in an adjunctive treatment benefit (Benhamu et al, 2014).
RVT-101 has previously been investigated as monotherapy in subjects with mild to moderate 
AD in 3 multinational Phase 2 studies, Study AZ3100603, Study AZ3106242, and 
Study AZ3110865. Studies AZ100603 and Study AZ3110865 compared the efficacy of 
RVT-101 to placebo or donepezil on the co-primary endpoints of cognition (Alzheimer’s Disease 
Assessment Scale – Cognitive Subscale [ADAS-Cog]) and global function (Clinician’s
Interview-Based Impression of Change – plus caregiver interview [CIBIC+]) after 24 weeks of 
treatment. Study AZ3100603 demonstrated dose-related effects of RVT-101 on cognition
(ADAS-Cog) with a 1.28-point treatment difference from placebo (p=0.135) at a dose of 35 mg 
and a statistically significant benefit on global function (CIBIC+) (p=0.047). Of note, there was 
no evidence of a placebo decline in this study. Study AZ3110865 did not show a statistically 
significant effect of either donepezil or RVT-101 on ADAS-Cog or CIBIC+.  This study also 
failed to show a decline in the placebo arm.
A third monotherapy study, AZ3106242, was initiated with the aim of investigating whether the 
historical efficacy of donepezil (i.e., approximately 3-point difference from a declining placebo 
group on ADAS-Cog after 24 weeks), could be repeated against non-declining placebo groups,
such as those seen in Studies AZ3100603 and AZ3110865. It has become increasingly common 
in recent trials of potential agents for the treatment of AD to be unable to show the same 3-point 
difference from placebo on ADAS-Cog that was observed in these early studies with AChEIs 
(Panisset, 2002). In addition, the study allowed the effect of RVT-101 to be benchmarked 
against a current, rather than historical, donepezil effect. This exploratory study was not 
powered for formal statistical comparison of RVT-101 and donepezil. For ADAS-Cog and 
CIBIC+, neither RVT-101 nor donepezil showed a statistically significant difference from 
placebo. A post-hoc analysis estimated that the effect of both treatments was larger among 
subjects with moderate AD (Mini Mental State Exam [MMSE] less than or equal to 18) than 
among mild subjects, with ADAS-Cog treatment effects of -2.9 (90% confidence interval [CI]: -
5.5, -0.2) and -4.5 (90% CI: -7.1, -1.9) for the RVT-101 and donepezil groups, respectively.
Study AZ3110866 was a 48-week, Phase 2b study that randomized 684 subjects in a 1:1:1 ratio 
to receive placebo, 15 mg RVT-101, or 35 mg RVT-101 as an adjunct to stable donepezil 
treatment.  The study utilized co-primary cognitive endpoints at Week 24 (ADAS-Cog and 


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Clinical Dementia Rating – Sum of Boxes [CDR-SB]). The Alzheimer’s Disease Cooperative 
Study – Activities of Daily Living (ADCS-ADL) was also included as a secondary endpoint to 
assess the activities of daily living.  When compared to placebo, a statistically significant 
difference of 1.5 points in ADAS-Cog was observed for the 35-mg RVT-101 group versus the 
placebo group at Week 24 (p=0.012). Statistically significant benefit versus placebo was also 
demonstrated at Week 12 (-1.3, p=0.006) and at Week 48 (-1.64, p=0.024).  There was a strong 
trend for statistically significant benefit at Week 36 (-1.21, p=0.057) versus placebo.  The change 
from baseline for the CDR-SB for the 35-mg group was numerically superior to placebo at all 
post-baseline visits.  This difference was statistically significant at Week 12. There were no 
statistically significant differences between the 15-mg group and placebo for either co-primary 
endpoint although the 15-mg group was generally numerically superior to placebo. The 
ADSC-ADL also showed a statistically significant effect for 35 mg RVT-101 compared to 
placebo at Weeks 12 (1.72, p=0.019), 24 (2.0, p=0.024), and 36 (1.93, p=0.038), with a 
continued trend at Week 48 (1.94, p=0.088).  Additional secondary endpoints included the
Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and MMSE.  
There was no statistically significant effect of RVT-101 on RBANS for either dose over placebo, 
but some degree of separation did appear at later visits for the 35-mg group.  No statistically 
significant difference for either group was seen on the MMSE at Weeks 24 or 48.
Details of all 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
The effects of RVT-101 on cognition and activities of daily living observed in the AZ3110866 
study provide a strong rationale for the continued development of RVT-101 as an adjunctive 
therapy to donepezil for the treatment of patients with AD.  This Phase 3 study seeks to confirm 
the previous study results that demonstrated a treatment effect of RVT-101 on both cognition and 
activities of daily living when added to stable donepezil treatment when compared to treatment 
with donepezil alone.  This study will also provide further information on the safety and 
tolerability of the 35-mg dose of RVT-101 when used in combination with donepezil. The 
primary objective of this study is to assess the effects of a 35-mg dose of RVT-101 compared 
with placebo when added to stable treatment with donepezil on the co-primary endpoints of 
cognition as measured by ADAS-Cog 11 item subscale (ADAS-Cog-11; Rosen et al, 1984) and 
activities of daily living as measured by ADCS-ADL (Galasko et al, 1997) after 24 weeks of 
double-blind treatment.  The ADAS-Cog is a widely recognized scale for the assessment of 
cognition in clinical trials with subjects with AD, and the ADCS-ADL is similarly widely used 
for the assessment of function and activities of daily living.  Both scales have established 
psychometric properties and have been employed in previous AD studies, supporting their 
inclusion as primary endpoints in this study.
3.3.
Dose Rationale
A daily dose of 35 mg RVT-101 was selected for use in this study based on the results of the 
AZ3110866 study.  This dose, administered in addition to donepezil, was shown to be well 
tolerated and when added to stable donepezil treatment demonstrated efficacy on measures of 


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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.


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4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
To assess the effects of RVT-101 versus 
placebo as adjuncts to stable donepezil therapy 
on cognitive function as measured by the
ADAS-Cog-11 after 24 weeks of treatment
ADAS-Cog-11 score change from baseline to 
Week 24
To assess the effects of RVT-101 versus 
placebo as adjuncts to stable donepezil therapy 
on activities of daily living as measured by 
ADCS-ADL scale after 24 weeks of treatment
ADCS-ADL score change from baseline to 
Week 24
Secondary
To assess the effects of RVT-101 versus 
placebo as adjuncts to stable donepezil therapy
on cognition as measured by the ADAS-Cog-13
(ADAS-Cog-11 plus delayed recall and total 
digit cancellation) after 24 weeks of treatment
ADAS-Cog-13 score change from baseline to 
Week 24
To assess the effects of RVT-101 versus 
placebo as adjuncts to stable donepezil therapy 
on global clinical assessment of change as 
measured by CIBIC+ after 24 weeks of
treatment
CIBIC+ score at Week 24
To assess how baseline MMSE score affects 
efficacy outcome measures after 24 weeks of 
treatment
ADAS-Cog score change from baseline;
ADCS-ADL score change from baseline;
CIBIC+ score; all assessed by MMSE baseline 
score
To assess the effects of RVT-101 versus 
placebo as adjuncts to stable donepezil therapy 
on neuropsychiatric symptoms as measured by 
the Neuropsychiatric Inventory (NPI) after 24 
weeks of treatment
NPI score change from baseline to Week 24
To assess the effects of RVT-101 versus 
placebo as adjuncts to stable donepezil therapy 
on an analysis of responders based on 
prespecified efficacy evaluations
Analysis of responders defined as improvement 
of at least 3 points on ADAS-Cog-11 from 
baseline AND at least no worsening on
ADCS-ADL from baseline AND no worsening 
on CIBIC+ at 24 weeks


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To assess the effects of RVT-101 versus 
placebo as adjuncts to stable donepezil therapy
on subject dependency as measured by the 
Dependence Scale (DS)
DS score change from baseline to Week 24
To measure RVT-101 plasma concentrations 
and donepezil plasma concentrations in study 
subjects
Measurement of concentrations of RVT-101
and donepezil in plasma
To estimate the PK parameters of RVT-101 and 
explore relationships to efficacy or safety 
endpoints, as appropriate
Steady state area under the concentration-time 
curve (AUC ), peak concentration (Cmax-ss), 
and minimum concentration (Cmin-ss) of RVT-
101 in plasma
To assess the safety and tolerability of RVT-
101 as an adjunct therapy to stable donepezil 
treatment
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)
Tertiary
To assess the effects of RVT-101 versus 
placebo as adjuncts to stable donepezil therapy
on healthcare utilization as measured by the 
Resource Utilization in Dementia Lite (RUD 
Lite)
RUD Lite score change from baseline to 
Week 24
To assess the effects of RVT-101 versus 
placebo as adjuncts to stable donepezil therapy
on quality of life as measured by the EuroQOL 
5 dimensions questionnaire (EQ-5D)
EQ-5D score change from baseline to Week 24


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5.
STUDY DESIGN
5.1.
Overall Design
This is a multicenter, double-blind, randomized, placebo-controlled, parallel-group study in 
patients with mild to moderate AD who are on stable donepezil therapy.  The efficacy and safety 
of RVT-101 at a dose of 35 mg will be evaluated over a 24-week treatment period.
Approximately 1150 subjects will be enrolled.  The randomization ratio will be 1:1 
(RVT-101:placebo) and will be stratified by baseline MMSE score.  The primary endpoints will 
be measured after 24 weeks of treatment.  Study participation will last approximately 33 weeks:  
0 to 4 weeks for Screening, a 3-week Single-Blind Run-In Period to evaluate baseline status, a 
24-week randomized Double-Blind Treatment Period, and a 2-week Follow-Up Period (for 
subjects who do not enter the open-label extension study RVT-101-3002).
5.2.
Study Schematic
The design of the study is illustrated in Figure 1.
Figure 1
Study Design
Abbreviations:  qd = daily; V = visit; WK = week.
1. If a greater than 3 point difference between the Screening and Baseline MMSE score is in the opinion of the 
investigator due to recent changes in AD medication, the Run-In period may be extended for an additional 3 
weeks after discussion with the Medical Monitor, during which time MMSE stability defined as less than or 
equal to 3 point change over 3 weeks must be observed.


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6.
SUBJECT POPULATION
6.1.
Type and Number of Subjects
Approximately 1150 subjects with mild to moderate AD who are on stable donepezil therapy 
will be enrolled.
In order to manage the total study enrollment, Axovant Sciences may suspend screening and/or 
enrollment at any site or study-wide at any time.
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 AD in accordance with the 
recommendations from the National Institute on Aging-Alzheimer’s Association 
workgroups on diagnostic guidelines for AD (McKhann et al, 2011).
2.
Subject has a documented history of at least 4 months of ongoing donepezil therapy for AD,
with stable dosing of 5 or 10 mg/day for at least the last 2 months and with no intent to 
change for the duration of the study.
3.
Subject has an MMSE score 12 to 24 inclusive at Screening and a Baseline MMSE score 
10 to 26 inclusive. The difference between the Screening and Baseline MMSE score is less 
than or equal to 3 points. If a greater than 3-point difference between the Screening and 
Baseline MMSE score is in the opinion of the investigator due to recent changes in AD 
medication, the Run-In period may be extended for an additional 3 weeks after discussion 
with the Medical Monitor, during which time MMSE stability, defined as less than or equal 
to 3-point change over 3 weeks, must be observed.
4.
Subject has a Hachinski Ischaemia score less than or equal to 4 at Screening.
5.
Magnetic resonance imaging (MRI) or computed tomography (CT) scan performed within
12 months before screening with findings consistent with the diagnosis of dementia due to 
AD without any other clinically significant pathologies.  If an MRI (preferred) or CT scan is 
unavailable or was performed longer than 12 months prior to Screening, one must be 
performed during the Screening Period (prior to Run-In).
6.
Age greater than or equal to 50 years to less than or equal to 85 years at the time of 
Screening.
7.
If female, subject must be:
a. Of non-childbearing potential (i.e., any female who is post-menopausal [greater than
1 year without menstrual period in the absence of hormone replacement therapy]) or 
surgically sterile; or,
b. If pre-menopausal or menopausal for 1 year or less, must have a negative pregnancy test 
and must not be lactating at the Screening and Baseline Visits. Female subjects of 


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childbearing potential and who are sexually active are required to practice adequate 
methods of birth control. Female subjects for whom menopausal status is in doubt in the 
opinion of the investigator will be required to use an adequate form of birth control.
Acceptable, adequate form of birth control is defined as consistent use of combined 
effective methods of contraception including at least 1 barrier method.
Male subjects who are sexually active will also be required to use an adequate form of birth 
control as described above.
8.
Subject has the ability to comply with procedures for cognitive and other testing in the 
opinion of the investigator.
9.
Subject must be able to ingest pills (in tablet form) whole. 
10. Subject lives with (or has substantial periods of contact with) a regular caregiver who is 
willing to attend visits, oversee the subject’s compliance with protocol-specified procedures 
and study medication, and report on subject’s status, and who has substantial contact with 
the subject. If the caregiver does not cohabitate with the subject, he/she ideally should have 
a minimum of 10 hours total and at least 3 days contact with the subject per week.  Prior to 
randomization, study representatives will review eligibility of non-cohabitating caregivers.
Every effort should be made to have the same caregiver throughout the study.
11. 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.
12. Caregiver has provided full written informed consent on his/her own behalf prior to the 
performance of any protocol-specified procedure.
13. General health status is acceptable for participation in a 24-week study.
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.
Diagnosis of possible, probable, or definite vascular dementia in accordance with National 
Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche 
l’Enseignement en Neurosciences criteria.
2.
History and/or evidence (including CT or MRI scan performed within the past 12 months or 
at Screening) 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; or Parkinson’s disease.


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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.
Focal findings on the neurological exam (excluding changes attributable to peripheral 
injury) that are inconsistent with a primary diagnosis of AD.
5.
History of existing negative amyloid positron emission tomography scan or similar brain 
amyloid imaging, or Screen Failure from research trial due to negative amyloid imaging
within 5 years. Note: amyloid scan is not required for participation in this study.
6.
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 including, but not 
limited to, frontotemporal dementia, Lewy body dementia, or others.
Confounding Medical Conditions
7.
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.
8.
Significant suicide risk as defined by (1) suicidal ideation as endorsed on items 4 or 5 on the 
C-SSRS within the past year, at Screening or at Baseline, or; (2) suicidal behaviors within 
the past year, or; (3) clinical assessment of significant suicidal risk during subject interview.
9.
Current psychosis that in the opinion of the investigator would interfere with the subject’s 
ability to participate in this study.
10. 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.
11. 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.
12. 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 
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.
13. 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.
14. History of Down syndrome or Intellectual Development Disorder.
Concomitant Medications
15. Participation in another investigational drug or device study in AD during the 60 days prior 
to the Screening Visit (Visit 1), or within 5 half-lives of use of the investigational drug prior 


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to the Screening Visit, whichever is longer.  In addition, subjects who were previously 
screened for another study in AD 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. However, Screen Failures due to negative amyloid imaging 
within 5 years will not be eligible for enrollment (see exclusion criterion 5).
16. Treatment with any concomitant medications as detailed in Table 1. Memantine and other 
treatments for dementia including AChEIs other than donepezil must have been
discontinued 30 days prior to entry into the Single-Blind Run-In Period.  Other 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. Subjects taking memantine or other agents to treat cognitive impairment 
associated with AD at the time of Screening will be considered Screen Failures.  However, 
subjects with recent discontinuation prior to Screening of memantine or other agents to treat 
cognitive impairment who will have been discontinued for 30 days prior to the Single-Blind 
Run-In Period may continue.  Subjects who screen fail may be rescreened once (see 
Section 6.5).
Unacceptable Test/Laboratory Values
17. Postural hypotension (fall in systolic blood pressure of greater than 30 mmHg or fall in 
diastolic blood pressure of greater than 20 mmHg on standing compared to sitting) at the 
time of screening. Subjects who present at the time of screening with postural hypotension 
yet have no known history of postural hypotension, nor underlying medical condition related 
to hypotension, may be rescreened.
18. Persistent or recurrent liver enzyme elevations, alanine transaminase (ALT) and/or aspartate 
aminotransferase (AST) greater than or equal to 2.0 times upper limit of normal (ULN).
19. Total bilirubin over 1.5 x ULN except due to documented Gilbert’s disease.
20. Calculated creatinine clearance less than 40 mL/min (Cockroft-Gault formula) at Screening:
Adult males: [(140 – age in years) × (weight in kg)] ÷ 72 × serum creatinine*
Adult females: 0.85 × [((140 – age in years) × (weight in kg)) ÷ 72 × serum creatinine*]
* in mg/dL
21. Positive hepatitis B surface antigen or hepatitis C antibody test.
22. 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. 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.


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Other
23. Previous exposure to RVT-101 or SB742457.
24. Subject is unable to take study medication 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 medication or procedures.
25. 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.
26. Subject was prescribed cognitive tasks for cognitive rehabilitation performed under medical 
supervision in the 3 months prior to Screening or plans to participate in cognitive 
rehabilitation during the study.
27. Subject has participated in a program of neurostimulation in the past 3 months or plans to 
participate in a program of neurostimulation during the course of the study.
6.4.
Other Eligibility Criteria Considerations
To assess any potential impact on subject eligibility with regard to safety, the investigator must 
refer to the following document(s) for detailed information regarding warnings, precautions, 
contraindications, AEs, and other significant data pertaining to the investigational product(s) 
being used in this study:
RVT-101 Investigator’s Brochure
Package insert/label for donepezil hydrochloride.
6.5.
Screening Failures
Screen Failures are defined as subjects who sign an informed consent form (ICF) for 
RVT-101-3001 but are never subsequently randomized and who do not enter the Single-Blind 
Run-In Phase. A minimal set of screen failure information is required including demography,
screen failure details, eligibility criteria, and any serious adverse events (SAEs).
Subjects who are Screen Failures may be rescreened once only after approval by the study 
Medical Monitor.
6.6.
Withdrawal Criteria
6.6.1.
Reasons for Withdrawal
A withdrawal from the study is defined as withdrawing any time after entering the Single-Blind 
Run-In Phase and before completion of the Week 24 Visit (Visit 8).  Subjects who permanently 
discontinue use of investigational product will be considered to be withdrawn from the study.  
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 appropriate section of the electronic 
case report form (eCRF). Information related to AEs will continue to be collected as per usual 


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procedures on subjects who have discontinued investigational product. 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
Subject requests to discontinue for any reason; it is important to determine whether the 
withdrawal of consent is primarily due to an AE, lack of efficacy, or other reason
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 or subject. Subjects may 
discontinue from treatment with study investigational product but may agree to continue to be 
followed for additional safety evaluation.
If a subject meets discontinuation criteria during treatment, an Early Termination Visit will be 
required (Section 6.6.2).
6.6.2.
Subject Withdrawal Procedures
If a subject is prematurely discontinued from treatment with the investigational product, the 
investigator must make every effort to perform the evaluations scheduled for the Early 
Termination Visit (Table 2).  In the case where the subject permanently discontinues study 
medication between scheduled clinic visits, he/she should be recalled to the clinic as soon as 
possible and preferably within 7 days of stopping study medication for the Early Termination 
Visit.
Lost to follow-up: If a subject is lost to follow-up, every effort must be made by study center 
personnel to contact the subject, inquire about the reason for discontinuation/withdrawal, and 
follow up with any unresolved AEs/SAEs.  A minimum of 3 attempts at contact should be made 
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
Investigational product in this study is defined as RVT-101 tablets and its matching placebo, and
will be provided by Axovant Sciences.  RVT-101 and placebo tablets will be indistinguishable 
from each other.
Investigational product for the Single-Blind Run-In Period (Weeks -3 to 0) will be supplied as 
single individual bottles, each bottle containing 50 tablets which is sufficient medication for 
3 weeks plus 29 days overage.  Investigational product for the Double-Blind Treatment Period 
(Weeks 0 to 24) will be supplied at Visits 3, 5, 6, and 7 as a single individual bottle containing 
50 tablets, which is sufficient for 6 weeks plus 8 days overage. A new bottle of investigational 
product will be dispensed at each visit except at Visit 4, where no drug is dispensed.  In the event 
that the Single-Blind Run-In period is extended to repeat the MMSE, no new investigational 
product will be dispensed.  Drug accountability will be checked, and subjects will be redispensed 
the study medication bottles they received at Visit 2.
Subjects enrolled in this study will have been on donepezil for at least 4 months and on a stable 
dose of 5 or 10 mg/day for at least 2 months prior to enrollment and will continue this regimen 
unchanged for the duration of the study.  Axovant Sciences will supply donepezil tablets in this 
study at the stable clinical dose for each subject.  Study-dispensed donepezil will start in the 
Single-Blind Run-In Period. Subjects should be clearly instructed to take only study-dispensed 
donepezil during the duration of this study until V8, and to discontinue their clinical supply of 
donepezil provided by their personal physician. Subjects should be instructed to take their study-
supplied donepezil exactly as they had been taking their clinically prescribed donepezil during 
the previous 2 months, including at the same time of day.  Compliance with study-dispensed 
donepezil should be assessed at each visit. Confirmation of discontinuation of clinically supplied 
donepezil from subject and caregiver should be obtained at Visit 4 (Week 3) and re-confirmed 
thereafter as needed. Subjects will need to re-start their clinical supply of donepezil (clinically 
prescribed by the Investigator or treating physician) after V8; subjects not entering the open-
label extension study RVT-101-3002 will remain at the same stable dose until V9.
Study-supplied donepezil will be supplied throughout the study as single individual bottles that 
contain 90 tablets.  This is sufficient to cover all visit intervals plus windows as allowed by the 
protocol.  A new bottle of donepezil will be dispensed according to the Time and Events 
Schedule in Table 2. In the event that the Single-Blind Run-In period is extended to repeat the 
MMSE subjects will be redispensed the medication they received at Visit 2.


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Characteristic
Investigational Product
Product name:
RVT-101
Placebo
Formulation description:
Pink film-coated round 
tablets
Pink film-coated round 
tablets
Dosage form:
35-mg tablet
Placebo tablet
Unit dose strength(s)/
Dosage level(s):
35 mg
(1 tablet per dose)
N/A
(1 tablet per dose)
Route of administration:
Duration (Run-in Period):
Duration (Treatment 
Period):
Oral 
N/A
24 weeks
Oral
3 weeks
24 weeks
Dosing instructions:
Take 1 tablet orally each 
morning without regard to 
food
Take 1 tablet orally each 
morning without regard to 
food
Clinical Supplier
Catalent Pharma Solutions, 
Kansas City, MO USA
Catalent Pharma Solutions, 
Kansas City, MO USA
Characteristic
Study-Dispensed Donepezil
Product name:
Donepezil hydrochloride 
(5 mg and 10 mg tablets)
Formulation description:
5 mg tablets:  white to off white film-coated, round tablets 
debossed with ML89 on one side
10 mg tablets:  yellow film-coated round tablets debossed 
with ML88 on one side
Dosage form:
Tablet
Unit dose strength(s)/
Dosage level(s):
5 mg (1 tablet per dose) and 10 mg (1 tablet per dose)
Route of administration:
Duration (Run-in Period):
Duration (Treatment 
Period):
Oral
3 weeks
24 weeks
Dosing instructions:
Take 1 tablet orally as prescribed
Clinical Supplier
Catalent Pharma Solutions, Kansas City, MO USA


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7.2.
Randomization/Treatment Assignment
Subjects will be assigned to receive RVT-101 or placebo as adjunct therapy to existing stable 
donepezil therapy in accordance with the randomization schedule, prior to the start of the 
Double-Blind Treatment Period, using validated software.
Following confirmation of eligibility at Visit 3 (end of Single-Blind Run-In Period), subjects will 
be randomized to placebo or RVT-101 in a 1:1 ratio. Randomization will be stratified according 
to subjects’ baseline MMSE scores, so as not to exceed the limits described in Section 10.2.
7.3.
Blinding
This will be a double-blind study. The study will include a 3-week Single-Blind Run-In Period 
during which investigators will know that the subject is taking placebo but the subject and 
caregiver will not.  This will be followed by a 24-week Double-Blind Treatment Period when 
neither subjects nor their caregivers nor investigators will know which of the 2 treatments the 
subject is receiving.  Subjects will be informed that they will receive placebo at some point 
during the study but they will not know when this will be.  Subjects will not be informed of 
transition from the Single-Blind Run-In Period to the Double-Blind Treatment Period. RVT-101
and placebo will be provided as tablets that are indistinguishable in appearance, smell, and taste.  
Donepezil will be supplied at the start of the Run-In Period and will be clearly marked 
throughout the study in an unblinded fashion.
The following will apply:
The investigator or treating physician may unblind a subject’s treatment assignment. Such a 
measure should be taken only in the case of an emergency OR in the event of a serious 
medical condition when knowledge of the 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 contact the Medical Monitor to discuss the 
potential need for unblinding.  Unblinding will be done through the interactive voice 
response system (IVRS)/interactive web response system (IWRS).  The procedure of 
unblinding for a specific subject is provided in the Study Reference Manual.
If, for safety reasons, the investigator determines that the subject’s treatment must be 
immediately unblinded to provide adequate medical treatment, 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 to reveal a subject’s treatment identity must be requested of, and 
approved by, Axovant Sciences.


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A subject will be withdrawn from the study if his or her treatment code is unblinded by the 
investigator or treating physician. The date, time, and reason for the unblinding must be 
fully documented in the eCRF.
Axovant Sciences or their designee may unblind the treatment assignment for any subject if this 
is required to fulfill regulatory reporting obligations, such as expedited SAE reporting.
7.4.
Packaging and Labeling
RVT-101 35-mg tablets and matching placebo tablets will be packaged in high-density 
polyethylene bottles.  Labels for RVT-101 and placebo bottles will meet all applicable 
requirements of the US Food and Drug Administration (FDA) and Annex 13 of Good 
Manufacturing Practices: Manufacture of investigational medicinal products (July 2010) and/or 
other local regulations as applicable.
A sample of the information included in the label for investigational product is provided in
Figure 2 and for study-supplied donepezil in Figure 3 (5 mg tablets) and Figure 4
(10 mg tablets).
Figure 2
RVT-101 35 mg or placebo
Protocol RVT-101-3001                                                       Subject Number:
Lot number: #####/#####                                                 
Bottle ID No: xxxxx
                                                          
                               
Contains RVT-101 35 mg tablets or Placebo tablets
Quantity: 50 Tablets/Bottle
Dosing Directions: Take one tablet orally each morning with or without food. Do not cut or crush.
Store at room temperature (59-86 F; 15-30 C).  Protect from light.
Caution: New Drug—Limited by Federal law to investigational use.
Keep out of reach of children.
Sponsor: Axovant Sciences Ltd.  
Phone # +1 (646) 495-8197


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RVT-101-3001 v3.0
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Figure 3
Donepezil Hydrochloride 5 mg
Protocol RVT-101-3001
Subject Number:                              
Lot number: #####                                      
Bottle ID No: xxxxx
                     Expiry date: MMMYYYY
Contains: Donepezil Hydrochloride 5 mg 
Quantity: 90 Tablets/Bottle
Dosing Directions:  Take one tablet orally as prescribed.
Store at room temperature (59-86 F; 15-30 C).  Protect from light.
For Clinical Trial Use only. Keep out of reach of children.
Sponsor: Axovant Sciences Ltd.
Phone # +1 (646) 495-8197
Figure 4
Donepezil Hydrochloride 10 mg
Protocol RVT-101-3001
Subject Number:
Lot number: #####                                      
Bottle ID No: xxxxx
                     Expiry date: MMMYYYY
Contains: Donepezil Hydrochloride 10 mg 
Quantity: 90 Tablets/Bottle
Dosing Directions:  Take one tablet orally as prescribed.
Store at room temperature (59-86 F; 15-30 C).  Protect from light.
For Clinical Trial Use only. Keep out of reach of children.
Sponsor: Axovant Sciences Ltd.
Phone # +1 (646) 495-8197


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7.5.
Preparation/Handling/Storage/Accountability
No special preparation of investigational product is required. Investigational product will be 
stored at up to 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 investigational product.  All investigational product 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 investigational product accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records).
Site staff will record the subject number on the packaging label for both investigational 
product and study-supplied donepezil for each bottle dispensed. 
Further guidance and information for final disposition of unused investigational product 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 study monitor, Medical Monitor, and/or the Axovant
Sciences study contact.
A Material Safety Data Sheet/equivalent document describing occupational hazards and 
recommended handling precautions either will be provided to the investigator, where this is 
required by local laws, or is available upon request from Axovant Sciences.
7.6.
Compliance with Investigational Product and Study-Supplied 
Donepezil Administration
When subjects are dosed at the site, they will receive investigational product 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 investigational 
product and study subject identification will be confirmed at the time of dosing by a member of 
the study site staff other than the person administering the investigational product.
Every effort should be made to encourage subject compliance with the dosage regimen as per 
protocol for both investigational product and continued treatment with study-supplied donepezil.
The investigator is responsible for discussing methods to ensure high treatment compliance with 
subjects and caregivers before randomization.  All subjects and their caregivers should be 
instructed to return medication bottles with any unused drug at each visit to the investigator. A
record of the supplies dispensed, taken, and returned at each visit will be made in the eCRF. 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.


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Subjects should be withdrawn from the study where there has been a failure to take blinded 
investigational product or donepezil for a period exceeding 7 consecutive days.  While 
interruptions in investigational product administration should be avoided wherever possible, 
short-term interruptions (less than or equal to 7 days) due to forgetfulness; caregiver illness or 
absence; a pause in investigational product administration required during an intervention, 
hospitalization, or while a subject considers the study continuation; or for any other reason are 
not grounds for automatic withdrawal but should be assessed by the investigator.
Other major protocol violations as well as use of prohibited drugs (see Section 7.9.2) may be 
cause for discontinuation of investigational product or withdrawal from the study.
7.7.
Treatment of Investigational Product Overdose
Any dose of RVT-101 greater than 100 mg within a 24-hour time period will be considered an 
overdose.
No data are available with regard to overdose of RVT-101 in humans.  There is no specific 
treatment to be used in the event of overdose with RVT-101.  Investigators should use their 
clinical judgment in treating cases of overdose as dictated by the subject’s clinical status.
In the event of an overdose the investigator or treating physician should:
Contact the Medical Monitor immediately,
Closely monitor the subject for AEs/SAEs and laboratory abnormalities and ensure 
appropriate clinical management. Overdose in the absence of other AEs will not be reported 
as an AE in its own right.
Obtain a plasma sample for PK analysis within 2 days of the overdose of investigational 
product, if requested by the Medical Monitor (determined on a case-by-case basis), and
Document the quantity of the excess dose as well as the time of administration of the 
overdose in the eCRF.
It is not necessarily required that the investigator unblind a subject who has taken an overdose.  
As noted in Section 7.3, unblinding should only be done in the case of an emergency OR in the 
event of a serious medical condition when knowledge of the investigational product is essential 
for the appropriate clinical management or welfare of the subject, as judged by the investigator.
Decisions regarding dose interruptions will be made by the investigator in consultation with the 
Medical Monitor based on the clinical evaluation of the subject.
7.8.
Treatment after the End of the Study
The investigator is responsible for ensuring that consideration has been given to the post-study 
care of the subject’s medical condition.


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After completion of Visit 8, the subject may be considered for enrollment in the open-label 
extension study RVT-101-3002. Only subjects who do not enroll in the extension study will 
complete the Follow-up Visit (Visit 9).
7.9.
Concomitant Medications and Non-Drug Therapies
7.9.1.
Permitted Medications and Non-Drug Therapies
All current concomitant medications and those taken within the 6 months prior to Screening,
including over-the-counter and herbal remedies, will be recorded in the eCRF. Non-medication 
therapies related to the subject’s AD (neurostimulation, cognitive rehabilitation) that have 
occurred in the 12 months prior to Screening must also be recorded.  The name of the drug, the 
dose, indication and route of administration as well as the dates administered should be 
documented; the minimum requirement is to record the drug name and dates of administration.  
Any medication not specified in the list of prohibited and conditional medications provided in 
Table 1 is permitted during the study.
7.9.2.
Prohibited Medications and Non-Drug Therapies
Subjects who begin treatment during the study with any prohibited medication, or begin 
cognitive tasks for cognitive rehabilitation performed under medical supervision or 
neurostimulation should be withdrawn from the study.  However, where such treatment has been 
for less than or equal to 7 days, termination of the prohibited medication or treatment and 
continuation in the study may be considered by the investigator in discussion with the Medical 
Monitor, based on subject safety and the perceived need for the prohibited treatment.  If
treatment with a conditional medication is initiated during the study and will be prescribed 
chronically, the investigator should discuss this with the Medical Monitor before determining 
whether to continue the subject in the study.  Use of prohibited and conditional medications and 
treatments must be documented in the Concomitant Medications section of the eCRF. Prohibited
and conditional medications are listed in Table 1.


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Table 1.
List of Prohibited and Conditional Medications
Prohibited Medications:
Not allowed during the 
study or within 5 half-lives 
prior to Screening
Prohibited Medications:
Not allowed during the 
study or within 30 days 
prior to Single-Blind Run-
In Period
Conditional Medications:
Not allowed unless 
prescribed at a stable dose 
for at least 2 months prior 
to Screening; dose during 
the study should be stable, 
if possible
Selegiline
Butyrophenones, 
phenothiazines, and other 
“conventional” 
antipsychotics
Barbiturates
MAO inhibitors
Any investigational drug
Substrates of CYP2C91
with narrow therapeutic 
indices: warfarin, 
phenytoin and 
(R)-acenocoumarol
(active component of 
some non-warfarin 
anticoagulants)
Potent CYP3A42
inhibitors/inducers such 
as ketoconazole, 
itraconazole, 
erythromycin, rifampicin, 
phenytoin and 
carbamazepine
Known potent Pgp 
inhibitors3 (itraconazole, 
ketoconazole, 
cyclosporin, diltiazem, 
verapamil, quinidine, and 
carvedilol)
Acetylcholinesterase 
inhibitors other than 
donepezil 
(i.e., galantamine, 
rivastigmine, tacrine)
Memantine
Axona® (caprylidene)
Antidepressants (other 
than MAO inhibitors)
Thyroid hormones
Atypical antipsychotics 
(e.g., risperidone)
Benzodiazepines and 
other sedatives/hypnotics 
Note: Benzodiazepines 
or other 
sedatives/hypnotics 
(including antihistamines) 
with half-life less than 
6 hours can be taken on 
an as-needed basis but 
must not be taken within 
5 half-lives prior to 
cognitive testing.
Abbreviations:  CNS = central nervous system; MAO = monoamine oxidase; Pgp = permeability glycoprotein. 
Notes: 
1 RVT-101 affects CYP2C9 substrates.
2 CYP3A4 is a major enzyme involved with the metabolism of RVT-101.
3 Pgp inhibition may affect CNS levels of RVT-101.


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7.10.
Lifestyle and/or Dietary Restrictions
7.10.1.
Meals and 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, including those specified 
in the Time and Events Table, 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. All raters will be 
trained and certified to perform the specific rating scales in this study.
For Visit 2 there is a visit window of + 5 days.  In the event the Single-Blind Run-In period is 
extended to repeat the MMSE, the new Visit 2 window will be + 3 days.  For Visits 4 and 5 there 
is a visit window of ± 3 days; for all other post-randomization visits, there is a visit window of 
± 5 days. It is important that all visits should be scheduled relative to the baseline visit, except 
for Visit 9 which should be scheduled relative to the last dose of IP. If the visit window is used, 
the subsequent visit should remain according to the planned visit schedule (i.e., the subsequent 
visit date should not be re-calculated from the date of the previous visit but should remain 
relative to baseline).
Information will be recorded in the source documents and, where appropriate, the eCRF.
Every effort should be made to administer the ADAS-Cog within ±1 hour of the time of day of 
the baseline administration on subsequent visits for each subject due to the potential for circadian 
fluctuation in scores.
The order of rating scales should, when possible, be held constant, with the ADAS-Cog given to 
the subject first at each visit. The ADCS-ADL should be the first rating scale given to caregivers
when possible at each visit.
If medical assessments are scheduled for the same nominal time, then the assessments should be 
given after the cognitive testing and occur in the following order whenever possible:
12-lead ECG
Vital signs
Blood draws
Screening Period (up to 28 days before Visit 2): Subjects will be screened for eligibility 
during the Screening Period. Subjects who do not qualify for the study during this period will be 
considered Screen Failures. An ICF will be signed by each subject, if he or she is able, or by the 
caregiver with subject assent.  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 


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14 days if needed to complete assessment activities after approval by the study Medical Monitor.
Subjects who are Screen Failures during the Screening Period may be rescreened after discussion 
with the Medical Monitor. Note: Subjects who are Screen Failures may be rescreened only 
once.
Single-Blind Run-In Period (21 + 5 days before Visit 3): At Visit 2, subjects who meet all 
study screening criteria will enter a Single-Blind Run-In Period.  Investigational product will be 
dispensed.  Subjects will be instructed to take the investigational product once daily in the 
morning.  Subjects will be instructed to take the first Single-Blind Run-In investigational product
(single-blind placebo) during the study visit.  Study-supplied donepezil matching the subject’s 
stable clinical dose will also be dispensed.  Subjects and caregivers should be instructed that 
subjects are to take study-supplied donepezil throughout the course of the study and to 
discontinue any clinically dispensed donepezil prescribed by subjects’ personal physician.  
Visit 2 assessments will be performed according to Table 2 below.  To qualify for randomization 
at Baseline (Visit 3) subjects must return unused study medication, be considered capable of 
completing study assessments, remain within study-specified criteria for MMSE, and meet all 
other eligibility requirements.
The Single-Blind Run-In Period may be extended for 3 weeks after discussion with the Medical 
Monitor for subjects who do not meet MMSE stability criterion for randomization in the event 
that the change in MMSE is seen in the setting of recent change in AD therapy. Subjects who 
require this run-in extension period will have a new baseline visit window of no more than 21 to 
24 days after the originally intended baseline. This subsequent visit will then serve as the 
subject’s baseline if randomization criteria are met.  No new investigational product or 
study-supplied donepezil will be dispensed for the additional run-in period; subjects should be 
instructed to continue taking blinded investigational product and study-supplied donepezil 
dispensed at Visit 2.
The ADAS-Cog assessment should be the first assessment performed, followed by the MMSE.  
If the MMSE score does not meet the stability criterion for randomization, no other assessments 
should be performed.  If after discussion with the Medical Monitor it is determined that the 
Single-Blind Run-In Period may be extended by 3 weeks per the criterion above, the subject 
should be scheduled to return to the clinic in 3 weeks’ time (+ 3 days), and all baseline 
assessments should be performed at this repeat visit.
Baseline (Visit 3) and Double-blind Treatment (Visit 4 through Visit 8): At Visit 3
(Baseline), prior to ingestion of double-blind investigational product, Baseline assessments will 
be performed to determine subject eligibility.  Eligible subjects will be randomized to 1 of 2 
groups, RVT-101 or placebo, for the 24 weeks of double-blind treatment assessment.  
Double-blind investigational product and study-supplied donepezil will be dispensed at Visits 3,
5, 6, and 7.  At the Baseline visit, subjects will ingest the first dose of investigational product in 
the clinic in the presence of study center personnel; this may cause dosing to not occur in the 
morning on this visit according to the timing of the subject’s visit schedule.  All additional doses 
will be ingested as outpatients, except for the Visit 6 dose, which should occur in the clinic after 
the PK sample collection. At each visit, subjects will be reminded to take 1 tablet of blinded 
investigational product each morning, and to take study-provided donepezil in accordance with


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their previously prescribed treatment regimen. Discontinuation of donepezil prescribed by 
subjects’ personal physician should be confirmed at Visit 3 (Baseline + 5 days). As needed, 
subjects should be reminded to maintain discontinuation of clinically prescribed donepezil while 
taking study-supplied donepezil. Note: no investigational product or study-supplied donepezil 
will be dispensed at Visit 4 (Week 3); subjects will be redispensed the medication that they 
received at Visit 3 after drug accountability has been performed. Compliance with 
investigational product and study-supplied donepezil should be assessed at Visit 4, and study 
bottles returned to subjects to continue until Visit 5 (Day 42 ± 3 days) when the next bottles will 
be dispensed.
Throughout the Baseline and Double-Blind Treatment Periods, all clinic visits will be scheduled 
according to specified visit windows, and all specified assessments will be completed (Table 2).
The administration of the ADAS-Cog should be kept within a ± 1-hour window of the time of 
day of the Baseline assessment for each subject to diminish the potential impact of circadian 
fluctuations in cognition.  This should be taken into consideration when scheduling and 
performing baseline ADAS-Cog assessments.
The order of assessments should remain consistent during the Double-Blind Treatment Period,
and when possible, the ADAS-Cog should be given to the subject first, followed by the other 
efficacy endpoint scales.  If possible, other assessments, including ECG, vital signs, and blood 
draws, should be performed after cognitive testing and other endpoint scales. When possible 
ADCS-ADL should be given as the first assessment to the caregiver followed by other endpoint 
scales.
Although caregiver and subject visits are recommended to be on the same day, this is not 
required so long as they are each kept within the specified visit window. However, every effort 
should be made to have the same caregiver throughout the study.
Subjects who prematurely discontinue double-blind investigational product should be 
encouraged to return to the clinic for an Early Termination Visit, and the early termination 
procedures should be performed as indicated in the time and events schedule.
Safety Follow-Up: All subjects who complete the Double-Blind Treatment Period and do not 
enter the open-label extension study RVT-101-3002 will be required to attend a Safety Follow-
Up clinic visit (Visit 9) 14 to 19 days after the last day of treatment.  


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Table 2.
Time and Events Schedule
Study Period: Screening 
Run-in
Baseline
Treatment
Follow-
up11
ET
Study Visit Number:
V1
V2
V31
V4
V5
V6
V7
V8
V9
ET
Study Week:
W(-7)
W(-3)
W0
W3
W6
W12
W18
W24
W26
Study Day:
relative to Baseline 
unless specified
Up to 28
days before 
V2
21 + 5
days1,2
before V3
0
21 ± 3
42 ± 3
84 ± 5
126 ± 5
168 ± 5
14 to 19 
days after 
last dose of 
IP
Informed consent
X
Inclusion and exclusion criteria
X
X
Demography
X
Medical history
X
Concomitant medications review
X
X
X
X
X
X
X
X
X
X
Urine drug screen
X
C-SSRS
X
X
X
X
X
X
X
X
X
Randomization
X
Dispense investigational product3
X
X
X
X
X
Dispense study-supplied donepezil3
X
X
X
X
X
Assess investigational product and 
study-supplied donepezil compliance
X
X
X
X
X
X
X
Physical exam/
current medical conditions 4
X
X
X
X
X
X
X
X
X
X
Complete neurological exam
X
X
X
X
MRI or CT 5
X
12-lead ECG
X
X
X
X
X
X
X
X
X
X
Vital signs 6
X
X
X
X
X
X
X
X
X
X
Review adverse events
X
X
X
X
X
X
X
X
X
Serum OR urine pregnancy test 7
X
X
X
Hep B, and Hep C screen 8
X
TSH, vitamin B12, syphilis serology 9
X
Serum chemistry
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
X
Blood alcohol content
X
X
X
X
X
X
X
X
RVT-101 level 10
X
X
X
X
Donepezil level 10
X
X
X


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Study Period: Screening 
Run-in
Baseline
Treatment
Follow-
up11
ET
Study Visit Number:
V1
V2
V31
V4
V5
V6
V7
V8
V9
ET
Study Week:
W(-7)
W(-3)
W0
W3
W6
W12
W18
W24
W26
Study Day:
relative to Baseline 
unless specified
Up to 28
days before 
V2
21 + 5
days1,2
before V3
0
21 ± 3
42 ± 3
84 ± 5
126 ± 5
168 ± 5
14 to 19 
days after 
last dose of 
IP
Hachinski Ischaemia Scale
X
ADAS-Cog
X
X
X
X
X
X
X
MMSE
X
X
ADCS-ADL
X
X
X
X
X
X
X
CIBIS
X
CIBIC+
X
X
X
NPI
X
X
X
X
DS
X
X
RUD Lite
X
X
EQ-5D
X
X


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Abbreviations:  ADAS-Cog = Alzheimer’s Disease Assessment Scale – cognitive subscale; ADCS-ADL = Alzheimer’s Disease Cooperative Study Group –
Activities of Daily Living Inventory; CIBIC+ = Clinician’s Interview-Based Impression of Change Plus caregiver Interview; CIBIS = Clinician’s 
Interview-Based Impression of Severity; C-SSRS = Columbia Suicide Severity Rating Scale; CT = computed tomography; DS = Dependence Scale; ECG = 
electrocardiogram; ET = early termination; EQ-5D = EuroQOL 5 dimensions questionnaire; Hep = hepatitis; MMSE = mini-mental state examination; MRI =
magnetic resonance imaging; NPI = Neuropsychiatric Inventory; RUD Lite = Resource Utilization in Dementia Lite; TSH = thyroid stimulating hormone; V = 
visit; W = week.
Notes: 
1.
The Single-Blind Run-In Period may be extended for 3 weeks after discussion with the Medical Monitor for subjects who do not meet MMSE stability 
criterion for randomization in the event that the change in MMSE is seen in the setting of recent change in AD therapy.  Subjects requiring this run-in 
extension period will have a new baseline visit window of no more than 21 to 24 days after the originally intended baseline.  This subsequent visit will then 
serve as the subject’s baseline if randomization criteria are met.  No new study drug or study-supply donepezil will be dispensed for the additional run-in 
period; subjects should be instructed to continue taking blinded investigational product and study supply donepezil dispensed at Visit 2.
2.
The ADAS-Cog assessment will be the first assessment performed, followed by the MMSE.  If the MMSE score does not meet the stability criterion for 
randomization, no other assessments should be performed.  If after discussion with the Medical Monitor it is determined that the Single-Blind Run-In 
Period may be extended by 3 weeks per the criterion above, the subject should be scheduled to return to the clinic in 3 weeks’ time, and all baseline 
assessments should be performed at this repeat visit (refer to footnote 1).
3.
No new drug will be dispensed at V4.  The bottles and pill count should be checked for compliance at V4 , but no new medication will be dispensed at that 
visit.
4.
Physical examinations at Screening and V8 will be full examinations; at all other study visits, an abbreviated physical examination is required.  
5.
MRI or CT scan will be performed between V1 and V2 if no scan has been performed within the previous 12 months.  These scan findings must be 
consistent with the diagnosis of dementia due to AD without any other clinically significant pathologies.
6.
Vital signs will include systolic blood pressure, diastolic blood pressure, heart rate, respiratory rate, temperature, and body weight at each visit and height 
at screening. Postural changes in blood pressure will be assessed at screening.
7.
Required only for women of child bearing potential.
8.
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.
9.
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.
10. All PK blood samples should be taken after cognitive testing, ECG, and vital signs measurements have been performed except for the Week 12 (V6) 
sample, which should be taken prior to dosing in the clinic.
11. Required only for subjects who do not enter the open-label extension study RVT-101-3002.


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8.2.
Critical Baseline Assessments
Those subjects whose MMSE at Baseline (Visit 3) has changed significantly (more than 3 points) 
from Screening (Visit 1) and/or those subjects whose MMSE at Baseline changes such that it 
falls outside the range 10-26 will not be randomized. The purpose of this is to exclude subjects 
whose baseline is so variable that any drug effect may not be clearly observable and also to 
exclude subjects whose baseline improves under placebo to the level of very mild, or whose 
baseline worsens to borderline severe, making effects of treatment intervention difficult to 
observe with the assessments included in this study. If a greater than 3-point difference between 
the Screening and Baseline MMSE score is in the setting of recent changes in AD medication, 
Single-Blind Run-In may be extended for an additional 3 weeks after discussion with the 
Medical Monitor, during which time MMSE stability defined as less than or equal to 3-point 
change over 3 weeks must be observed.
8.3.
Study Assessments and Procedures
8.3.1.
Efficacy Assessments
All study assessments should be conducted by the investigator, and/or a suitably qualified 
designee, all of whom will be trained and certified to administer these measures for this study.
Every effort should be made for the same person to conduct specific assessments on each 
individual subject at each study visit. Assessments will be monitored for quality. Screening 
assessments along with accompanying data will be reviewed to insure that subjects meet the 
inclusion criteria.  Other assessments will be monitored by using data collected. Additional 
information regarding the method of quality monitoring of efficacy assessments is provided in 
the Study Reference Manual.
8.3.1.1.
Mini-Mental State Examination (MMSE)
The MMSE (Folstein et al, 1975) consists of 11 tests of orientation, memory (recent and 
immediate), concentration, language, and praxis.  Scores range from 0 to 30, with lower scores 
indicating greater cognitive impairment.  It is based on the performance of the subject and takes 
approximately 5 to 10 minutes to administer.
8.3.1.2.
Alzheimer’s Disease Assessment Scale – Cognitive Subscale (ADAS-Cog)
The 11-item and 13-item ADAS-Cog (Rosen et al, 1984; Mohs et al, 1997) assesses a range of 
cognitive abilities including memory, comprehension, orientation in time and place, and 
spontaneous speech.  Most items are evaluated by tests, but some are dependent on clinician 
ratings on a 5-point scale.  The ADAS-Cog-11 total score range is from 0 to 70, with a higher 
score indicating more severe cognitive impairment.  The ADAS-Cog-13 is the ADAS-Cog-11
with 2 additional items: delayed word recall and total digit cancellation.  Scores for the ADAS-
Cog-13 range from 0 to 85 with higher scores indicating greater dysfunction.  The scale takes 
approximately 30 to 40 minutes to administer.  During the study visits where the ADAS-Cog is 
performed, the full ADAS-Cog-13 test items will be collected.  The primary analysis will be of 
the ADAS-Cog-11 subset of tests from that battery and the full ADAS-Cog-13 will be analyzed
as a secondary endpoint.  When possible, the ADAS-Cog should always be the first assessment 


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conducted and should be administered, if possible, within ±1 hour of the time of baseline 
administration at all subsequent visits to control for potential impact of circadian variation in 
performance.
8.3.1.3.
Alzheimer’s Disease Cooperative Study - Activities of Daily Living
(ADCS-ADL)
The ADCS-ADL scale (Galasko et al, 1997) measures functional impairment in terms of 
activities of daily living. The ADCS-ADL is an interviewer-administered, informant-based scale 
where the informant (caregiver) responds to 23 activities of daily living questions about the 
subject.  The questions range from basic to instrumental activities of daily living and take 
approximately 20 minutes to complete.  The score ranges from 0 to 78; the lower the score, the 
greater the impairment.
8.3.1.4.
Clinician’s Interview-Based Impression of Change Plus Caregiver Interview
(CIBIC+)
The CIBIC+ assessment (Schneider et al, 1997) measures the global functioning of the subject 
through structured interviews by an investigator with both the subject and caregiver.  The CIBIS 
(Clinician’s Interview-Based Impression of Severity) will be administered at Baseline and the 
CIBIC+ will be administered at subsequent study visits.  The change from baseline is recorded 
on a 7-point scale with a score of 4 indicating no change, scores above 4 indicating worsening, 
and scores below 4 indicating improvement. This scale will be administered by a rater 
independent of the ADAS-Cog, who will be trained and certified for this study.
8.3.1.5.
Neuropsychiatric Inventory (NPI)
The NPI (Cummings et al, 1994) is a behavior rating scale composed of a 12-item structured 
interview of the caregiver that is scored from 0 to 144 (the higher the score, the greater the 
psychiatric disturbance).  It assesses 12 behavioral disturbances occurring in dementia patients: 
delusions, hallucinations, agitation, dysphoria, anxiety, apathy, irritability, euphoria, 
disinhibition, aberrant motor activity, night-time behavior disturbances, and eating disturbances.
Both the frequency and the severity of each behavior are determined.  
8.3.1.6.
Resource Utilization in Dementia Lite (RUD Lite)
The RUD scale (Wimo et al, 1998) is designed to assess caregiver burden and provide 
pharmacoeconomic data related to AD.  The RUD Lite 3.3 includes both baseline and follow-up
questions.  Caregiver-related questions include a description of the caregiver for demographic 
information and time spent caring for the subject and changes in work status.  Subject-related 
questions include residential status and healthcare resource utilization.  In the event that a subject
changes caregiver during the course of the study, the new caregiver must complete a baseline 
questionnaire at the earliest possible visit.


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8.3.1.7.
Dependence Scale
The DS measures the amount of assistance patients with dementia require in performing daily 
activities (Brickman et al, 2002).  The caregiver answers questions about the dependency of the 
subject.  The scale consists of 13 items, representing a range of severity from mild to severe
levels of dependency. The score range is from 0 to 15 with higher scores indicating greater 
dependency.
8.3.1.8.
EuroQol-5D
The EQ-5D is a standardized measure of health status that provides a measure of health-related 
quality of life that is widely used in clinical trials (Rabin and deCharro, 2001).  For this study the 
EQ-5D will be a caregiver proxy assessment.  The assessment will be completed by the caregiver 
and will assess the caregiver’s impressions of how the subject would rate his/her own quality of 
life.  The EQ-5D questionnaire consists of 2 components: the EQ-5D descriptive system and the 
EQ visual analogue scale (EQ-VAS).  The EQ-5D descriptive system includes 5 dimensions: 
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.  The EQ-VAS 
records overall health status on a 20-cm vertical line with a score of 0 (worst health one can 
imagine) to 100 (best health one can imagine).
8.3.2.
Safety and Screening Assessments
8.3.2.1.
Adverse Events
The investigator or site staff is responsible for detecting, documenting, and reporting events that 
meet the definition of an AE or SAE.
8.3.2.1.1.
Definition of Adverse Events
An AE is any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug related.  Therefore an AE can be ANY unfavorable and unintended sign 
(including an abnormal laboratory finding or vital sign measurement), symptom, or disease 
temporally associated with the use of a medicinal product, without any judgment about causality.
AEs are recorded from the time that informed consent is signed, including those that occur 
during the Single-Blind Run-in Period.  Treatment emergent adverse events are defined as those 
that occur on or after the date of the first dose of double-blind investigational product.
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.


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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 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.
8.3.2.1.2.
Definition of Serious Adverse Event
An AE is considered serious if, in the view of either investigator or sponsor, it results in any of 
the following outcomes:
Death,
A life-threatening AE,
An AE is considered “life-threatening” if, in the view of either the investigator or 
sponsor, its occurrence places the patient or subject at immediate risk of death.  It does 
not include an AE that, had it occurred in a more severe form, might have caused death.  
The determination of whether an AE is life-threatening can be based on the opinion of 
either the investigator or sponsor.  Thus, if either believes that it meets the definition of 
life-threatening, it must be considered life-threatening for reporting purposes.


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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 contact. SAEs that are spontaneously reported by the subject or 
subject representative or discovered by the investigator or designee after the follow-up visit and 
up to 30 days after the last dose of investigational product must be collected and reported.
All SAEs will be recorded and reported to Worldwide Clinical Trials or Axovant Sciences within 
24 hours of the investigator becoming aware of the SAE.
Investigators are not obligated to actively seek AEs or SAEs in former study subjects. However, 
if the investigator learns of any SAE, including a death, at any time after a subject has been 
discharged from the study, and he/she considers the event reasonably related to the 
investigational product or study participation, the investigator must promptly notify the sponsor 
or sponsor representative.


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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.
Instructions for assessing causality are provided in the Study Reference Manual.
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 
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 


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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, basic 
information such as the protocol number, subject’s date of birth, subject identification number, 
period of investigational product intake, event term, nature of the event, the seriousness criteria,
and the investigator’s attribution regarding relatedness to investigational product.  In addition, 
the initial SAE report should include all pertinent known information about the SAE and the 
affected subject. In addition, the investigator should provide a narrative to describe the course of 
events including any treatments or relevant procedures.  Follow-up information, which may 
include copies of relevant subject records and other documents not available at the initial SAE 
report must be sent to Worldwide Clinical Trials as soon as available.  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 (those 
not listed in the Investigator Brochure) according to local regulatory requirements and Axovant
Sciences policy and are forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE(s) or other specific 
safety information (e.g., summary or listing of SAEs) from Axovant Sciences will file it with the 
Investigator Brochure and will notify the IRB/IEC, if appropriate according to local 
requirements.
8.3.2.2.
Safety Monitoring Committee
An independent Safety Monitoring Committee (SMC) will be established by the sponsor to 
review accumulating study data to monitor the safety of all subjects enrolled in RVT-101-3001


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on an ongoing basis.  Members of the committee will include clinicians and a biostatistician who 
are experienced in the conduct and monitoring of clinical studies.  No Axovant Sciences 
employee or investigator involved in the RVT-101-3001 study will be a member of the SMC or 
participate in closed SMC sessions.  However, representatives from Axovant Sciences may 
attend open meeting sessions and will be available to provide additional information to the SMC
as requested.
The SMC will evaluate potential safety and tolerability issues during periodic scheduled reviews 
of the safety data accrued during the conduct of the study.  The content and format of the safety 
data provided will be in agreement with requests by the SMC members and will contain blinded 
interim safety data.  However, the SMC will be provided unblinded treatment codes for these 
studies if a significant safety concern is identified.  Ad hoc SMC meetings may be held as 
necessary.
After reviewing the interim safety data from RVT-101-3001, the SMC may make a 
recommendation to Axovant Sciences to continue the study with or without modification or to 
terminate the study. All SMC meetings will be properly documented in a SMC report to the 
sponsor.
SMC membership and responsibilities will be further outlined in the SMC Charter, which will be 
maintained separately from the protocol.
8.3.2.3.
Physical 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. Neurological examinations will include assessment 
of gait, balance, coordination, cranial nerves and motor and sensory systems.  A brief,
symptoms-directed physical examination will include, at a minimum, assessments of the lungs, 
cardiovascular system, and abdomen (liver and spleen). Physical examinations at Screening and 
Visit 8 will be full examinations; at all other study visits, an abbreviated physical examination is 
required.
8.3.2.4.
Vital Signs
Vital signs will be measured after the subject has been in the seated position for 5 minutes and 
will include temperature, systolic and diastolic blood pressures, pulse rate, and respiratory rate.
Postural changes will be measured within 3 minutes of appropriate body position change.  Body 
weight will also be recorded at each visit and height will be recorded at Screening.
8.3.2.5.
Electrocardiogram (ECG)
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. The investigator or designated qualified physician at the site 
will evaluate the Screening ECG for any abnormalities that should exclude the subject from the 


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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.
8.3.2.6.
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 Study 
Reference Manual. Reference ranges for all safety parameters will be provided to the site by the 
laboratory responsible for the assessments.
Abnormal laboratory tests that are clinically significant should also be recorded as AEs on the 
eCRF. Clinically significant means that the confirmed abnormal test result has an impact on
patient management, including additional monitoring or diagnostic tests, or changes in treatment.
The same standard applies to additional non-protocol specified laboratory assessments that are 
performed at the institution’s local laboratory and result in a change in subject management (i.e.,
monitoring, diagnostic tests, or any alteration in treatment).
Refer to the Study Reference 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.


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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
Every Visit
through the 
End of 
Double-Blind 
Treatment
Blood alcohol content
Routine 
Urinalysis
Specific gravity
pH, glucose, protein, blood, and ketones by dipstick
Microscopic examination (if blood or protein is abnormal)
Screening
Tests Only
HBsAg
Hepatitis C antibody
TSH
Vitamin B12
Syphilis serology
Serum or urine hCG pregnancy test (as needed for women of child 
bearing potential, including at follow-up/early termination)
Drug screen
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; 
GGT = gamma glutamyltransferase; HBsAg = hepatitis B surface antigen; hCG = human chorionic 
gonadotropin; MCH = mean corpuscular hemoglobin; MCV = mean corpuscular volume; RBC = red blood cell;
TSH = thyroid stimulating hormone; WBC = white blood cell.


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All laboratory tests with values that are considered clinically significantly abnormal during 
participation in the study or at the follow-up visit should be repeated until the values return to 
normal or baseline or until the value stabilizes.  If such values do not return to normal within a 
period judged reasonable by the investigator, the etiology should be identified and the Medical 
Monitor notified.
8.3.2.7.
Assessment of Suicidality
Subjects will be assessed for suicidality before and during the study using the Columbia Suicide 
Severity Rating Scale (C-SSRS).  Subjects considered to be at significant risk will be excluded 
from the study.  The C-SSRS is a brief measure which is designed to assess severity and change 
of suicidality by integrating both behavior and ideation.  It assesses intensity of ideation (a 
potentially important marker of severity), specifically asking about frequency, duration, 
controllability, deterrents, and reasons for the ideation which was most severe during the 
respectively assessed timeframe.  Suicidal behavior is also assessed by asking further questions 
to categorize the behaviors into actual, interrupted, or aborted attempts; as well as preparatory 
and non-suicidal self-injurious behavior. The C-SSRS will be completed by a rater trained and 
certified to administer this scale.  Any change in C-SSRS score indicating the presence of 
suicidality should be evaluated by the investigator for clinical significance to determine 
continued study eligibility (Section 6.3) and appropriate clinical actions (including but not 
limited to a referral to a mental health professional).
Clinically meaningful suicidal ideation, suicidal behavior and completed suicide should be 
recorded as AEs.
8.3.2.8.
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. If a pregnancy is reported, then the 
investigator should inform the Medical Monitor within 24 hours of learning 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 the 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.


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8.3.3.
Pharmacokinetics
Blood samples for PK analysis of RVT-101 and donepezil will be collected in a subset of 
patients at selected sites during the study visits indicated in Section 8.1.  The actual date and time 
of each blood sample collection will be recorded, as well as the date and time of the previous 
dose of double-blind IP and/or donepezil administration. The timing of PK samples may be 
altered and/or PK samples may be obtained at additional time points to ensure thorough PK 
monitoring.
Five PK samples per subject will be taken for the purpose of assessing plasma concentrations of 
RVT-101 and donepezil at the following specific time points:
At Baseline (Visit 3), the PK blood sample should be taken after cognitive testing, ECG, 
and vital signs measurements have been performed, and the date and time of the previous
dose of donepezil will be recorded.  The actual date and time of sample collection will be 
recorded.
At Visit 5 (Week 6), the PK blood sample should be taken after cognitive testing, ECG, 
and vital signs measurements have been performed, and the time of the last dose of 
double-blind IP will be recorded.  The actual date and time of sample collection will be 
recorded.
At Visit 6 (Week 12) subjects will be instructed not to take their dose of double-blind IP
in the morning but wait until in the clinic, after 1 PK sample is collected (before dosing,
but after cognitive testing, ECG, and vital signs measurements have been performed). 
Donepezil can be taken on the regular schedule. The date and time of the previous 
double-blind IP and donepezil doses will be recorded along with the actual date and time 
of the pre-dose sample collection at Visit 6.
At Visit 7 (Week 18), the PK blood sample should be taken after cognitive testing, ECG,
and vital signs measurements have been performed, and the time of the last dose of 
double-blind IP will be recorded.  The actual date and time of sample collection will be 
recorded.
At Visit 8 (Week 24), 1 PK blood sample will be collected after cognitive testing, ECG, 
and vital signs measurements have been performed. The date and time of the previous 
donepezil and double-blind IP doses will be recorded along with the actual date and time 
of sample collection.
Unscheduled PK samples may be requested by Axovant Sciences or the Medical Monitor 
after discussion with investigators (e.g., in cases of suspected drug reactions).
The samples will be centrifuged and the resulting plasma stored.  Further details with regard to 
shipping, collection, and processing of samples are provided in the Study Reference Manual.
Plasma analysis will be performed under the control of Axovant Sciences, the details of which 
will be included in the Study Reference Manual. Concentrations of RVT-101, RVT-101
metabolites, and donepezil will be determined in plasma samples using the currently approved 


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bioanalytical methodology. Raw data will be archived at the bioanalytical site (detailed in the 
Study Reference Manual).
Once the plasma has been analyzed for RVT-101 and/or donepezil, any remaining plasma may 
be analyzed for other compound-related metabolites and the results reported under a separate 
protocol.


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9.
DATA MANAGEMENT
For this study, subject data will be entered into Axovant Sciences defined eCRFs, transmitted 
electronically to Axovant Sciences or designee, and combined with data provided from other 
sources in a validated data system.
Management of clinical data will be performed in accordance with applicable Axovant Sciences
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 WCT coding conventions.
Concomitant medications will be coded using the World Health Organization (WHO)
Anatomical Therapeutic Chemical (ATC) classification 
(http://www.whocc.no/filearchive/publications/1_2013guidelines.pdf).
The eCRFs (including queries and audit trails) will be retained by Axovant Sciences, and copies 
will be sent to the investigator to maintain as the investigator copy.  


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10.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES
10.1.
Hypotheses
The primary statistical framework will be to demonstrate superiority of RVT-101 over placebo 
based on the ADAS-Cog-11 and ADCS-ADL change from baseline to Week 24.
The first null hypothesis is that there is no difference between RVT-101 and placebo, when 
added to stable donepezil, in the change from baseline in total ADAS-Cog-11 score at Week 24
in the Intent-to-Treat (ITT) Population. The first alternative hypothesis is that there is a 
difference between RVT-101 and placebo, when added to stable donepezil, in the change from 
baseline to Week 24 total ADAS-Cog-11 score in the ITT Population.
The second null hypothesis is that that there is no difference between RVT-101 and placebo, 
when added to stable donepezil, in the change from baseline in total ADCS-ADL score at 
Week 24 in the ITT Population. The second alternative hypothesis is that there is a difference 
between RVT-101 and placebo, when added to stable donepezil, in the change from baseline to 
Week 24 of ADCS-ADL score in the ITT Population.
The primary comparisons of interest will be performed at the 5% level of significance. All 
hypothesis tests will be 2-sided, with no correction for multiple comparisons.
10.2.
Sample Size Considerations
The primary comparisons of interest are to compare RVT-101 to placebo at Week 24 for change 
from baseline in both ADAS-Cog-11 and ADCS-ADL. A sample size of 435 subjects per 
treatment group will allow a difference of 1.6 points between placebo and active treatment in the 
change from baseline in ADAS-Cog score to be detected with 95% power and a 0.05 
significance level assuming an underlying standard deviation (SD) of 6.5.
This sample size will also allow a difference of 2 points between placebo and active treatment in 
the change from baseline in ADCS-ADL score to be detected with 90% power and a 0.05 
significance level assuming an underlying SD of 9. Sample size estimates were based on data 
from study AZ3110866. 
Both endpoints need to achieve a significance level of 0.05 to maintain an overall 5% 
significance level. Hence, the multiplicity issue associated with the trial having 2 primary 
endpoints is addressed as efficacy will only be concluded if both endpoints are significant.
Assuming a drop-out and missing data rate of approximately 25% up to Week 24, a total of 
approximately 1150 subjects will be randomized in a 1:1 ratio to RVT-101 or placebo.
The impact of baseline severity and possible sub-populations of milder and more moderate 
subjects is an important consideration of this study. Hence, a stratified randomization will be 
used to enroll subjects according to their baseline MMSE score in the groupings of 10-15 points, 
16-20 points, and 21-26 points.


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Two subgroups using MMSE score at baseline will be examined: moderate 10-20 and mild 16-26. 
The thresholds for randomization presented in Table 4 will be enforced.
Table 4.
Baseline Mini Mental State Examination Stratification
Baseline MMSE Score
10-15
16-20
21-26
Target for recruited population
;
20%
;
40%
;
20%
The purpose of this ratio is to ensure that approximately 70% of the recruited population will 
contribute data to a data-defined subgroup analysis of either milder or more moderate subjects on 
ADAS-Cog-11 and/or ADCS-ADL. It is estimated that a difference from placebo of 1.6 points 
in ADAS-Cog-11 and 2.0 points in ADCS-ADL will be observable with approximately 80% 
power in a subgroup, which includes approximately 70% of subjects.
10.2.1.
Sample Size Sensitivity
Based on study AZ3110866, the observed range of standard deviations for ADAS-Cog changes 
from baseline score was 6.13 to 6.37, and the range of observed standard deviations for 
ADCS-ADL changes from baseline was 8.84 to 9.36.  The sample size calculation for this study 
used the SD of 6.5 for the ADCS-Cog endpoint and SD of 9 for the ADCS-ADL endpoint.
The robustness of the sample size calculations have been considered in order to assess the impact 
on the power of the study. Table 5 below shows the sensitivity of the required sample size to the 
assumptions used in the sample size calculation.
Table 5.
Sample Size Estimates with Varying Expected Treatment Differences and
Standard Deviations
Expected 
Difference 
(RVT-101 vs. 
Placebo)
SD
Sample Size to 
have at least 
90% Power
Sample Size to 
have at least 
80% Power
Power with
N=435
ADAS-Cog-11
1.6
6
297
222
97.5
1.6
6.5
348
261
95.2
1.6
7
403
302
92.1
ADCS-ADL
1.8
8.5
469
351
87.7
1.8
9
526
393
83.9
1.8
9.5
586
438
79.8
2
8.5
380
285
93.4
2
9
426
318
90.6
2
9.5
475
355
87.4
Abbreviations:  ADAS-Cog-11 = Alzheimer’s Disease Assessment Scale – Cognitive Subscale-11;
ADCS-ADL = Alzheimer’s Disease Cooperative Study - activities of daily living; SD = standard deviation.


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10.2.2.
Sample Size Re-estimation or Adjustment
No sample size re-estimation is planned.
10.3.
Data Analysis Considerations
10.3.1.
Analysis Populations
The ITT Population will consist of all subjects randomized to treatment who have taken at least 1
dose of investigational product and who have at least 1 post-baseline assessment.  This will be 
the primary population used for the efficacy analysis.
The Per-Protocol (PP) Population will consist of those members of the ITT Population who have 
no major protocol violations.  The PP Population will not be analyzed if this population 
comprises more than 95% or less than 50% of the ITT Population.  This population will be used 
for confirmatory analysis of the 2 primary efficacy variables and other cognitive and functioning 
endpoints. The PP Population will be identified prior to breaking the study blind.
The primary population for safety analyses will be the Safety Population, which will consist of 
all subjects who were randomized and took at least 1 dose of investigational product.
10.3.2.
Interim Analysis
No interim efficacy analyses are planned.
10.4.
Key Elements of Analysis Plan
All hypothesis tests and confidence intervals will be 2-sided at an alpha level of 5%.
For statistical analysis, center information will be pooled by geographical region or size. The 
method of grouping by center will be agreed upon prior to unblinding the study and outlined in 
the Statistical Analysis Plan (SAP).
All efficacy and safety measures over the course of the study will be presented. Continuous data 
will be summarized by means, SDs, medians, maximum, minimum, and number of subjects. 
Categorical data will be summarized by counts and percentages.
10.4.1.
Primary Efficacy Analyses
The primary analyses will be based on the ITT Population.  In addition, analyses of the PP 
Population will be used to support the primary efficacy analysis.
Treatment comparisons between the RVT-101 and placebo groups in ADAS-Cog-11 and 
ADCS-ADL scores change from baseline at Week 24 will be analyzed using a mixed model for 


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repeated measures (MMRM) with restricted maximum likelihood estimation.  This model 
corrects for dropout and accounts for the fact that measurements taken on the same subject over 
time tend to be correlated, by using all available information on subjects within the same 
covariate set to come up with an estimate of the treatment effect for a dropout-free population.  
No imputation of the missing values will be made or required and the data used in the analysis 
will be the actual observed responses at each visit. The statistical model will be fitted with terms 
for treatment group, visit, treatment by visit interaction, baseline score, baseline MMSE, and 
pooled center. 
The interaction terms of baseline MMSE by visit will be evaluated and will be included in the 
model if appropriate.  Details will be provided in the RVT-101 3001 SAP.
Primary inferences will be drawn from treatment differences for the changes from baseline 
derived from the MMRM models at Week 24. As additional supportive information, treatment 
differences for each post baseline visit will also be derived using the MMRM models. The 
estimated treatment difference for at each visit will be displayed in the summary of statistical 
analysis together with the 95% confidence interval and the associated p-value.
The nature of missing data will be explored and the extent of missing data will be summarized.  
Sensitivity analysis will be conducted to support the MMRM analysis.  This will include analysis 
based on completer, and analyses based on complete datasets for Week 24 derived via 
imputation techniques using analysis of covariance (ANCOVA). Details on covariates for 
ANCOVA and missing data imputations will be provided in the SAP.
The relationship between ADAS-Cog-11, ADCS-ADL, and baseline severity will be
investigated.
The primary comparisons will be performed separately by moderate (Baseline MMSE 10-20) 
and mild (Baseline MMSE 16-26) using the same MMRM model.  Additional subgroups 
including gender, demographic, and other baseline characteristics may be performed.  Further 
details will be given in the SAP.
10.4.2.
Secondary Efficacy Analyses
Cognition and other efficacy endpoints:
ADAS-Cog-13 scores change from baseline at Week 24
CIBIC+ scores at Week 24
NPI scores change from baseline at Week 24
The DS change from baseline at Week 24
Comparison of RVT-101 versus placebo for the above endpoints will be performed using 
a mixed model for repeated measures or analysis of covariance (ANCOVA), similar to 
the models described for the primary endpoint.
The relationship between endpoints and demographics/baseline characteristics will be 
investigated.  The comparisons may be repeated by selected subgroups of interest, i.e., gender, 


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baseline severity based on MMSE score, and other baseline characteristics.  Further details will 
be given in the SAP.
In addition, the between treatment comparisons on CIBIC+ based on the Week 24 Observed 
Case (OC) and Week 24 LOCF datasets using Cochran-Mantel-Haenszel test will be performed.  
The number and percentage of subjects in each category of CIBIC+ will also be summarized by 
visit for each treatment group.
10.4.3.
Tertiary Efficacy Measures
The RUD Lite and the EQ-5D will be summarized descriptively by treatment. Treatment 
comparisons between RVT-101 and placebo will be analyzed using an analysis of covariance 
(ANCOVA) model. Details will be provided in the SAP.
10.4.4.
Responder Analysis
In this trial the following responder definitions will be presented:
1. ADAS-Cog-11: Improvement by at least 3 points from baseline at Week 24
2. ADCS-ADL: No change or improvement from baseline at Week 24
3. CIBIC+: No change or improvement at Week 24
4. ADAS-Cog-11 composite: Simultaneously meeting the criteria for ADAS-Cog-11,
CIBIC+, and ADCS-ADL
Alternative composite endpoints and definitions of responders may be explored.  The percentage of 
responders and the difference in proportions compared to placebo will be presented. This data will 
be analyzed using logistic regression or Cochran–Mantel–Haenszel test. Further details will be 
given in the SAP.
10.4.5.
Pharmacokinetic Analyses
Plasma concentrations will be listed and summarized by study visit and treatment group.
Pharmacokinetic parameters for RVT-101 (AUC
, Cmax-ss and Cmin-ss) for each subject will be 
estimated via nonlinear mixed effect modeling using a population PK model based on data from 
previous studies.
No population PK analysis is planned for donepezil. Donepezil concentrations will be visually 
compared to literature steady state values (mean ± SD) (Tiseo et al, 1998):
5 mg Cmin = 21.4 ± 3.8 and Cmax = 34.1 ± 7.3 ng/mL
10 mg Cmin = 38.5 ± 8.6 and Cmax = 60.5 ± 10.0 ng/mL,
where Cmin is the minimum (trough) concentration and Cmax is the peak concentration


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10.4.6.
Pharmacokinetic / Pharmacodynamic Analyses
Relationships between RVT-101 PK parameters and measures of safety and efficacy will be 
explored.
10.4.7.
Safety Analyses
The safety analyses will be based on the Safety Population.
Safety will be assessed by summarizing and analyzing AEs, laboratory analytes, vital signs, ECG 
parameters, physical examination findings, C-SSRS scores, and concomitant medications.
10.4.7.1.
Adverse Events
AEs will be considered treatment-emergent (TEAEs) if they start or worsen after first dose of the 
double-blinded treatment.  If an AE begins or worsens on the first day of investigational product
administration, a CRF and source data note will be provided to clarify whether it occurred prior 
to or after investigational product administration.  TEAEs, SAEs including deaths, AEs that lead 
to discontinuation of investigational product, and AEs by maximum severity and relationship to 
investigational product will be summarized by MedDRA system organ class (SOC) and preferred 
term.  TEAEs will also be summarized by preferred term, sorted by decreasing frequency within 
SOC.  AEs will be summarized separately for the Single-Blind Run-In Period, the Double-Blind 
Treatment Period, and the Follow-up Period.
10.4.7.2.
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.
10.4.7.3.
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.


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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.
10.4.7.4.
Suicidality
A subject data listing of all answers of the C-SSRS questionnaire will be presented. The number 
and percentage of subjects reporting suicidal ideation and behavior will be summarized. 
Additional summaries may be provided if data warrant. Details will be provided in the SAP.
10.4.8.
Subgroup Analyses
The efficacy analyses will be performed for the following subgroups:
Milder Population (Baseline MMSE 16-26)
Moderate Population (Baseline MMSE 10-20)
Female
Male
Analyses of additional subgroups based on demographics and baseline characteristics will be 
described in the SAP.
10.4.9.
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 the country in which the research is conducted, whichever affords the greater 
protection to the study subject. The investigator will ensure that the basic principles of “Good 
Clinical Practice,” as outlined in 21 Code of Federal Regulations (CFR) 312, subpart D, 
“Responsibilities of Sponsors and Investigators,” 21 CFR, part 50, 1998, and 21 CFR, part 56, 
1998, are adhered to. These standards are consistent with the requirements of the European 
Community Directive 2001/20/EC, which shall be adhered to.
Since this is a “covered” clinical trial, the investigator will ensure that 21 CFR, Part 54, 1998, is 
adhered to; a “covered” clinical trial is any “study of a drug or device in humans submitted in a 
marketing application or reclassification petition subject to this part that the applicant or FDA 
relies on to establish that the product is effective (including studies that show equivalence to an 
effective product) or that make a significant contribution to the demonstration of safety.” This 
requires that investigators and all sub-investigators must provide documentation of their financial 
interest or arrangements with Axovant Sciences, or proprietary interests in the drug being 
studied. This documentation must be provided before participation of the investigator and any 
sub-investigator. The investigator and sub-investigator agree to notify Axovant Sciences of any 
change reportable interests during the study and for 1 year following completion of the study. 
Study completion is defined as the date that the last subject has completed the protocol defined 
activities.
This study is also subject to and will be conducted in accordance with 21 CFR, part 320, 1993, 
“Retention of Bioavailability and Bioequivalence Testing Samples.”
11.1.2.
Institutional Review Board/Independent Ethics Committee Approval
This protocol and any accompanying material to be provided to the subject and caregiver (such 
as advertisements, subject information sheets, or descriptions of the study used to obtain
informed consent) will be submitted by the investigator to an IRB or IEC. Approval from the
IRB or IEC must be obtained before starting the study and should be documented in a letter to 
the investigator specifying the protocol number, protocol version, protocol date, documents 
reviewed, and date on which the committee met and granted the approval.
Any modifications made to the protocol or other documents described in the above paragraph 
after receipt of IRB or IEC approval must also be submitted to the IRB or IEC for approval 
before implementation.


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11.1.3.
Informed Consent
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and
potential hazards of the study and before undertaking any study-related procedures. The
investigator must utilize an IRB- or IEC-approved consent form for documenting written
informed consent. Each informed consent will be appropriately signed and dated by the subject
or the subject’s legally authorized representative and the person obtaining consent. Consent 
from both the caregiver representative and subject will 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 initials, date of birth, and an 
identification code (i.e., not names) should be recorded, if permitted by national regulation, 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, including but not
limited to the Investigator’s Brochure, this protocol, eCRFs, the investigational new drug, and
any other study information, remain the sole and exclusive property of Axovant Sciences during 
the conduct of the study and thereafter. This information is not to be disclosed to any third party 
(except employees or agents directly involved in the conduct of the study or as required by law) 
without prior written consent from Axovant Sciences. The investigator further agrees to take all 
reasonable precautions to prevent the disclosure by any employee or agent of the study site to 
any third party or otherwise into the public domain.
11.1.5.
Study Files and Retention of Records
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following 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 are listed in the Source Data Verification Plan, and should include 
sequential notes containing at least the following information for each subject:
Documentation that subject meets eligibility criteria, i.e., history, physical examination,
and confirmation of diagnosis (to support inclusion and exclusion criteria);
Participation in trial (including trial number);


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Trial discussed and date of informed consent;
Dates of all visits;
Documentation that protocol specific procedures were performed;
Results of efficacy parameters, as required by the protocol;
Start and end date (including dose regimen) of trial medication (preferably drug 
dispensing and return should be documented as well);
Record of all AEs and other safety parameters (start and end date, and preferably
including causality and intensity);
Concomitant medication (including start and end date, dose if relevant, 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 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.
Biological samples at the conclusion of this study may be retained in storage by the sponsor for a 
period up to 15 years for purposes of this study.
11.1.6.
Electronic Case Report Forms
For each subject enrolled, an eCRF must be completed and signed by the principal investigator 
or sub-investigator (as appropriate) within a reasonable time period after data collection. This 
also applies to records for those subjects who fail to complete the study (even during a 
pre-randomization screening period if an eCRF was initiated). If a subject withdraws from the 
study, the reason must be noted on the eCRF. If a subject is withdrawn from the study because 
of a treatment-limiting AE, thorough efforts should be made to clearly document the outcome.


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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 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, in accordance with national regulation.
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 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 or its representatives, to IRBs or 
IECs, or to regulatory authority or health authority inspectors.
11.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
11.2.
Sponsor Responsibilities
11.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Axovant Sciences. All protocol modifications must be submitted to the IRB or 
IEC in accordance with local requirements. Approval 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 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.


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After conclusion of the study and without prior written approval from Axovant Sciences, 
investigators in this study may communicate, orally present, or publish in scientific journals or 
other scholarly media only after the following conditions have been met:
the results of the study in their entirety have been publicly disclosed by or with the
consent of Axovant Sciences in an abstract, manuscript, or presentation form; or
the study has been completed at all study sites for at least 5 years.
No such communication, presentation, or publication will include Axovant Sciences’ 
confidential information (see Section 11.1.3).
The investigator will submit any proposed publication or presentation along with the respective 
scientific journal or presentation forum at least 30 days before submission of the publication or 
presentation. The investigator will comply with Axovant Sciences’ request to delete references
to its confidential information (other than the study results) in any paper or presentation and 
agrees to withhold publication or presentation for an additional 60 days in order to obtain patent 
protection if deemed necessary.
11.2.3.
Posting of Information on Publicly Available Clinical Trial Registers
Study information from this protocol will be posted on publicly available clinical trial registers 
before enrollment of subjects begins. Results will be posted as required.
11.3.
Joint Investigator/Sponsor Responsibilities
11.3.1.
Access to Information for Monitoring
In accordance with ICH Good Clinical Practice (ICH GCP) guidelines, the study monitor must 
have direct access to the investigator’s source documentation in order to verify the data recorded 
in the eCRFs for consistency.
The monitor is responsible for routine review of the eCRFs at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them. The monitor should have access to any subject records needed to 
verify the entries on the eCRFs. The investigator agrees to cooperate with the study monitors to 
ensure that any problems detected in the course of these monitoring visits are resolved.
11.3.2.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Axovant Sciences may conduct inspections or 
audits of the clinical study. If the investigator is notified of an inspection by a regulatory
authority the investigator agrees to notify the Axovant Sciences Medical Monitor immediately.
The investigator agrees to provide to representatives of a regulatory agency or Axovant Sciences 
access to records, facilities, and personnel for the effective conduct of any inspection or audit.


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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 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.
REFERENCES
Alzheimer’s Association. 2013 Alzheimer’s disease facts and figures. Alzheimers Dement.
2013;9(2):208-245.
Aricept (donepezil hydrochloride) Package Insert. Woodcliff Lake, NJ: Eisai Inc.; 2013.
Benhamu B, Martin-Fontecha M, Vazquez-Villa H, et al. Serotonin 5-HT6 receptor antagonists 
for the treatment of cognitive deficiency in Alzheimer’s disease. J Med Chem.
2014;57(17):7160-7181.
Brickman AM, Riba A, Bell K, et al.. Longitudinal assessment of patient dependence in 
Alzheimer disease. Arch Neurol. 2002;59(8):1304-1308.
Cummings JL. Alzheimer’s Disease. N Engl J Med. 2004;351:56-67.
Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, et al. The Neuropsychiatric 
Inventory: comprehensive assessment of psychopathology in dementia. Neurology.
1994;44:2308-2314.
Cummings JL, Morstorf T, Zhong K. Alzheimer’s disease drug-development pipeline: few 
candidates, frequent failures. Alzheimers Res Ther. 2014;6:37.
Folstein MF, Folstein SE, McHugh PR. “Mini-Mental State”: A practical method for grading the 
cognitive state of patients for the clinician. J Psychiatry Res. 1975;12:189-198.
Galasko D, Bennett D, Sano M, et al. An inventory to assess activities of daily living for clinical 
trials in Alzheimer’s disease. Alzheimer Dis Assoc Disord. 1997;Suppl 2:S33-39.
James BD, Leurgans SE, Hebert LE, et al. Contribution of Alzheimer disease to mortality in the 
United States. Neurology. 2014;82:1045-50.
Kiss JZ, Tonsoco E, Djebbara Z, et al. The role of neural cell adhesion molecules in plasticity 
and repair. Brain Res Brain Res Rev. 2001;36:175-184.
McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer’s 
disease: recommendations from the National Institute on Aging- Alzheimer’s Association 
workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement.
2011;7(3):263-269.
Mitchell ES, Neumaier JF. 5-HT6 receptors: a novel target for cognitive enhancement. 
Pharmacol Ther. 2005;108:320-333.
Mohs RC, Knopman D, Petersen RC, et al. Development of cognitive instruments for use in 
clinical trials of antidementia drugs: additions to the Alzheimer's Disease Assessment Scale that 


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broaden its scope. The Alzheimer's Disease Cooperative Study. Alzheimer Dis Assoc 
Disord. 1997;11(Suppl 2):S13–21.
Panisset M, Gauthier S, Moessler H, Windisch M, The Cerebrolysin Study Group. Cerebrolysin 
in Alzheimer’s disease: a randomized, double-blind, placebo-controlled trial with a neurotropic 
agent. J Neural Transm. 2002;109:1089-1104.
Rabin R, deCharro F. EQ-5D: a measure of health status from the EuroQol Group. Ann Med.
2001;33(5):337-343.
Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer’s disease. Am J Psychiatry.
1984;141:1356-1364.
Schneider L, Olin J, Doody R, et al. and the ADCS. Validity and reliability of the Alzheimer’s 
disease cooperative study-clinical global impression of change. Alzheimer Dis Assoc Disord.
1997;11(2):S22-S32.
Seki T, Arai Y. Distribution and possible roles of the polysialylated neural cell adhesion 
molecule (NCAM-H) in the developing and adult central nervous system. Neurosci Res.
1993;17:265-290.
Tiseo PJ, Rogers SL, Friedhoff LT. Pharmacokinetic and pharmacodynamics profile of donepezil 
HCl following evening administration. Br J Clin Pharm. 1998;46:Suppl 1:13-18.
Wimo A, Wetterholm AL, Mastey V, Winblad B. Evaluation of the resource utilization and 
caregiver time in Anti-dementia drug trials - a quantitative battery. In: Wimo A, Jonsson B, 
Karlsson G, Winblad B, editors. The Health Economics of dementia. London: John Wiley & 
Sons; 1998. Pp1. 465-499.

SAP_001.pdf: 
Axovant Sciences Ltd. 
 
Statistical Analysis Plan for Protocol RVT-101-3001 
Version:  August 9, 2017 
 
1 
 
 
  
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
Title: 
Statistical Analytical Plan for RVT-101-3001: A Phase 3, double 
blind, randomized study of RVT-101 versus placebo when added to 
existing stable donepezil treatment in subjects with mild to moderate 
Alzheimer’s disease 
Sponsor 
Axovant Sciences Ltd. 
Compound Name: 
Intepirdine 
Protocol Number 
RVT-101-3001 
Indication 
Treatment of mild to moderate Alzheimer’s disease in patients on 
stable therapy with donepezil 
Development Phase 
3 
IND # 
78,094 
Version 
Version:  August 9, 2017 
Axovant Sciences 
Study Director 
Ilise Lombardo, MD 
Telephone:  646-495-8197 
Email:  ilise.lombardo@axovant.com 
 
This study is being conducted in compliance with good clinical practice, including the archiving 
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TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS.......................................................................................7 
2. 
INTRODUCTION ........................................................................................................8 
2.1. 
Nomenclature ................................................................................................................8 
3. 
STUDY OBJECTIVES AND ENDPOINTS ................................................................9 
3.1. 
Study Objectives ...........................................................................................................9 
3.1.1. 
Primary Objective .........................................................................................................9 
3.1.2. 
Secondary Objectives ...................................................................................................9 
3.1.3. 
Tertiary Objectives .....................................................................................................10 
3.2. 
Study Endpoints ..........................................................................................................10 
3.2.1. 
Primary Endpoints ......................................................................................................10 
3.2.2. 
Secondary Endpoints ..................................................................................................10 
3.2.3. 
Tertiary Endpoints ......................................................................................................11 
3.3. 
Descriptions and Scoring of Efficacy Endpoints ........................................................12 
3.3.1. 
Mini-Mental State Evaluation (MMSE) .....................................................................12 
3.3.2. 
Alzheimer’s Disease Assessment Scale – Cognitive Subscale (ADAS-Cog) ............12 
3.3.3. 
Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-
ADL) ...........................................................................................................................13 
3.3.4. 
Dependence Scale (DS) ..............................................................................................16 
3.3.5. 
Clinician’s Interview Based Impression of Change Plus Care Giver 
Interview (CIBIC+) ....................................................................................................16 
3.3.6. 
Neuropsychiatric Inventory (NPI) ..............................................................................16 
3.3.7. 
EuroQol-5D (EQ-5D) .................................................................................................18 
4. 
STUDY DESIGN .......................................................................................................20 
4.1. 
Summary of Study Design ..........................................................................................20 
4.2. 
Definition of Study Drugs ..........................................................................................20 
4.3. 
Sample Size Considerations .......................................................................................21 
4.3.1. 
Sample Size Justifications ..........................................................................................21 
4.3.2. 
Sample Size Re-estimation .........................................................................................21 
4.4. 
Randomization/Stratification ......................................................................................21 
4.5. 
Clinical Assessments ..................................................................................................21 
5. 
ANALYSES ...............................................................................................................24 
5.1. 
Interim Analyses .........................................................................................................24 


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5.2. 
Final Analyses ............................................................................................................24 
6. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING ...............................................................................................................25 
6.1. 
General Table and Individual Subject Data Listing Considerations ..........................25 
6.2. 
Analysis Populations ..................................................................................................25 
6.2.1. 
Screening Population ..................................................................................................26 
6.2.2. 
Placebo Run-In ...........................................................................................................26 
6.2.3. 
Randomized Population ..............................................................................................26 
6.2.4. 
Safety Population ........................................................................................................26 
6.2.5. 
ITT Population ............................................................................................................26 
6.2.6. 
Per-Protocol (PP) Population ......................................................................................26 
6.2.7. 
Completers (CS) Population .......................................................................................27 
6.2.8. 
Pharmacokinetics (PK) Population .............................................................................27 
6.3. 
Multiple Comparisons and Multiplicity......................................................................27 
6.4. 
Baseline Definition .....................................................................................................28 
6.5. 
Derived and Transformed Data ..................................................................................28 
6.5.1. 
Baseline Age ...............................................................................................................28 
6.5.2. 
Study Day ...................................................................................................................28 
6.5.3. 
Handling of Incomplete Dates ....................................................................................28 
6.5.4. 
Visit Windows ............................................................................................................28 
6.5.5. 
Missing Start and Stop Dates for Prior and Concomitant Medication and 
Adverse Events ...........................................................................................................30 
6.6. 
Subgroups ...................................................................................................................31 
7. 
STUDY POPULATION .............................................................................................33 
7.1. 
Subjects Disposition ...................................................................................................33 
7.2. 
Screen Failures ............................................................................................................33 
7.3. 
By-Center ....................................................................................................................33 
7.4. 
Protocol Deviations ....................................................................................................33 
7.5. 
Demographic and Baseline Characteristics ................................................................34 
7.6. 
Subject Inclusion and Exclusion Criteria ...................................................................34 
7.7. 
Medical History and Medical Conditions Present at Entry ........................................34 
7.8. 
Prior and Concomitant Medications ...........................................................................34 
7.9. 
Extent of Exposure .....................................................................................................35 


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7.10. 
Treatment Compliance ................................................................................................35 
7.11. 
Overdose .....................................................................................................................36 
8. 
EFFICACY .................................................................................................................37 
8.1. 
General Considerations ...............................................................................................37 
8.2. 
Statement of the Null and Alternate Hypothesis ........................................................37 
8.3. 
Analysis of the Primary Efficacy Endpoint ................................................................37 
8.3.1. 
Primary Endpoints ......................................................................................................37 
8.3.2. 
Primary Efficacy Analysis ..........................................................................................37 
8.4. 
Analysis of the Secondary Efficacy Endpoints ..........................................................43 
8.4.1. 
Key Secondary Endpoints ...........................................................................................43 
8.4.2. 
Other Secondary Endpoints ........................................................................................44 
8.4.3. 
Responder Analyses ....................................................................................................45 
9. 
SAFETY AND TOLERABILITY ..............................................................................47 
9.1. 
Adverse Events ...........................................................................................................47 
9.2. 
Clinical Laboratory .....................................................................................................49 
9.3. 
Vital Signs ..................................................................................................................50 
9.4. 
Physical Examination .................................................................................................51 
9.5. 
ECGs ...........................................................................................................................51 
9.6. 
Pregnancy ...................................................................................................................51 
9.7. 
Suicidality ...................................................................................................................52 
10. 
PHARMACOKINETIC /PHARMACODYNAMIC ANALYSES ............................54 
10.1. 
Exposure-Efficacy Analyses .......................................................................................54 
10.2. 
Exposure-Safety Analyses ..........................................................................................54 
11. 
CHANGES FROM THE PROTOCOL TO THIS SAP ..............................................55 
12. 
REFERENCES ...........................................................................................................56 
APPENDIX 1. CENTRAL LABORATORY REFERENCE RANGES ....................................57 
 
 


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LIST OF TABLES 
Table 1: 
List of Abbreviations ....................................................................................................7 
Table 2: 
Calculation of Imputed ADAS-Cog-11 Total Score (Study RVT-101-3001) ............13 
Table 3: 
Calculation of Imputed ADAS-Cog-13 Total Score (Study RVT-101-3001) ............13 
Table 4: 
Calculation of Imputed ADCS-ADL Instrumental Score (Study RVT-101-
3001) ...........................................................................................................................14 
Table 5: 
Scores for NPI Individual Questions (Study RVT-101-3001) ...................................17 
Table 6: 
RUD-Lite Domains (Study RVT-101-3001) ..............................................................19 
Table 7: 
MMSE Stratification Levels (Study RVT-101-3001) ................................................21 
Table 8: 
Schedule of Events (Study RVT-101-3001) ...............................................................22 
Table 9: 
Windows for Slotting Visits (Study RVT-101-3001) .................................................29 
Table 10: Imputation Rules for Pre-Treatment (Baseline) Total Scores for ADAS-Cog-
11 and ADCS-ADL (Study RVT-101-3001) ..............................................................37 
Table 11: Examples of Patterns of Missingness (Study RVT-101-3001) ...................................40 
Table 12: NPI Total Score Progressors Analysis (Study RVT-101-3001) .................................44 
Table 13: Serum Chemistry Potentially Clinically Significant Criteria (Study RVT-
101-3001) ....................................................................................................................50 
Table 14: Haematology and Differentials Potentially Clinically Significant Criteria 
(Study RVT-101-3001) ...............................................................................................50 
Table 15: List of Potentially Clinically Significant Ranges for Vital Sign Parameters 
(Study RVT-101-3001) ...............................................................................................50 
Table 16: List of Potentially Clinically Significant Ranges for ECG Parameters (Study 
RVT-101-3001) ..........................................................................................................51 
Table 17: Sample Table Demonstrating How C-SSRS Outcomes will be Presented 
(Study RVT-101-3001) ...............................................................................................53 
 


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1. 
LIST OF ABBREVIATIONS 
Table 1: 
List of Abbreviations 
Abbreviation 
Term 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ANOVA 
Analysis of Variance 
CMH 
Cochran Mantel-Haenszel 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
DOB 
Date of Birth 
ITT 
Intent-to-Treat Population 
LLN 
Lower Limit of Normal 
MedDRA 
Medical Dictionary for Regulatory Activities Terminology 
MMRM  
Mixed model for repeated measures 
N 
Total Sample Size 
OC 
Observed Cases 
PCS 
Potential Clinical Significance 
PP 
Per-Protocol Population 
SD 
Standard Deviation 
SAE 
Serious Adverse Event 
SAS 
Statistical Analysis System  
ULN 
Upper Limit of Normal 
 


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2. 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the analyses to be performed 
following the completion of Study RVT-101-3001, a Phase 3, double blind, randomized study of 
RVT-101 versus placebo when added to existing stable donepezil treatment in subjects with mild 
to moderate Alzheimer’s disease. 
Study measurements and assessments, planned statistical methods, and derived variables are 
summarized in this plan.  Planned tables, figures, and listings are specified.  The SAP was 
finalized prior to locking the study database and the blind being broken (unblinding the study). 
2.1. 
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. 


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3. 
STUDY OBJECTIVES AND ENDPOINTS 
3.1. 
Study Objectives 
3.1.1. 
Primary Objective 
The primary objective of this study is: 
• To assess the effects of intepirdine versus placebo as adjuncts to stable donepezil 
therapy on cognitive function as measured by the Alzheimer’s Disease Assessment 
Scale – Cognitive Subscale 11 items (ADAS-Cog-11) after 24 weeks of treatment. 
• To assess the effects of intepirdine versus placebo as adjuncts to stable donepezil 
therapy on activities of daily living as measured by the Alzheimer’s Disease 
Cooperative Study - Activities of Daily Living (ADCS-ADL) scale after 24 weeks of 
treatment 
3.1.2. 
Secondary Objectives 
Key secondary objectives include: 
• To assess the effects of intepirdine versus placebo as adjuncts to stable donepezil 
therapy on global clinical assessment of change as measured by Clinician’s 
Interview-Based Impression of Change – plus caregiver interview (CIBIC+) after 24 
weeks of treatment 
• To assess the effects of intepirdine versus placebo as adjuncts to stable donepezil 
therapy on subject dependency as measured by the Dependence Scale (DS) total score 
after 24 weeks of treatment 
Other secondary objectives include: 
• To assess the effects of intepirdine versus placebo as adjuncts to stable donepezil 
therapy on neuropsychiatric symptoms as measured by the Neuropsychiatric 
Inventory (NPI) total score after 24 weeks of treatment 
• To assess the effects of intepirdine versus placebo as adjuncts to stable donepezil 
therapy on the incidence of falls during 24 weeks of treatment 
• To assess the effect of intepirdine versus placebo as an adjunct to stable donepezil 
therapy on different domains of neuropsychiatric symptoms as measured by the NPI 
after 24 weeks of treatment 
• To assess the effects of intepirdine versus placebo as an adjunct to stable donepezil 
therapy on an analysis of responders based on prespecified efficacy evaluations 
• To measure intepirdine plasma concentrations and donepezil plasma concentrations in 
study subjects 
• To assess the effects of intepirdine versus placebo as adjuncts to stable donepezil 
therapy on cognition as measured by the ADAS Cog-13 (ADAS-Cog-11 plus delayed 
recall and digit cancellation count tests) after 24 weeks of treatment   


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• To assess how baseline Mini Mental State Examination (MMSE) score severity 
affects efficacy outcome measures after 24 weeks of treatment 
• To estimate the pharmacokinetic (PK) parameters of intepirdine and explore 
relationships to efficacy or safety endpoints, as appropriate 
• To assess the safety and tolerability of intepirdine as an adjunct therapy to stable 
donepezil treatment 
3.1.3. 
Tertiary Objectives 
Tertiary objectives of this study are: 
• To assess the effects of intepirdine versus placebo as adjuncts to stable donepezil 
therapy on healthcare utilization as measured by the Resource Utilization in Dementia 
Lite (RUD Lite) 
• To assess the effects of intepirdine versus placebo as adjuncts to stable donepezil 
therapy on quality of life as measured by the EuroQOL five dimensions questionnaire 
(EQ-5D)  
3.2. 
Study Endpoints 
3.2.1. 
Primary Endpoints 
The co-primary endpoints in this study are: 
• ADAS-Cog-11 score change from baseline to Week 24 
• ADCS-ADL score change from baseline to Week 24 
3.2.2. 
Secondary Endpoints 
Key secondary endpoints will be tested in a sequential manner as follows: 
• CIBIC+ score at Week 24 
• DS Total Score changes from baseline to Week 24 
Other secondary endpoints include: 
• NPI total score change from baseline to Week 24, analyzed as 'No Change/ 
Improvement' versus 'Worsening (ie, Progressors)' 
• Incidence of falls through Week 24 (as collected through adverse event reporting) 
• ADAS-cog score change from baseline; ADCS-ADL score change from baseline; 
CIBIC+ score; all assessed by MMSE baseline score 
• ADCS-ADL Basic, Instrumental, and Independence score changes from baseline to 
Week 24 
− Communication and Engagement Factor and Outside Activities Factor changes 
from baseline to Week 24 


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• NPI total, caregiver distress, Psychosis domain score changes from baseline to Week 
24 and Progressors analyses of the Psychosis Domain and each of the 12 NPI domain 
scores 
• Responders, using the following definitions: 
1. ADAS-Cog-11 Improvement by at least 3 points at Week 24  
a. Repeated for by at least 4 points at Week 24 
b. Repeated for ‘no change or improvement’ vs ‘worsening’ 
2. ADCS-ADL No change/improvement vs worsening at Week 24 
3. CIBIC+ No change/improvement vs worsening at Week 24 
4. ADAS-Cog-11/CIBIC+/ADCS-ADL composite, simultaneously meeting the 
criteria for: 
a. ADAS-Cog-11 Improvement of at least 3 points at Week 24 
b. CIBIC+ No change/improvement at Week 24 
c. ADCS-ADL No change/improvement at Week 24 
5. ADAS-Cog-11/ADCS-ADL composite, simultaneously meeting the criteria for:   
a. ADAS-Cog-11 Improvement by at least 3 points at Week 24 
b. ADCS-ADL No change/improvement at Week 24 
• Progressors in Dependence Level, defined as patients worsening from baseline,  
• ADAS-Cog-13 (ADAS-Cog-11 plus delayed recall and total digit cancellation) score 
change from baseline to Week 24 
• ADAS-Cog-11 and ADCS-ADL Time to progression, defined as a worsening (from 
baseline) by 1 point (or more).  
• Measurement of concentrations of intepirdine and donepezil in plasma 
• Steady state area under the concentration-time curve (AUCτss), peak concentration 
(Cmax-ss), and minimum concentration (Cmin-ss) of intepirdine in plasma 
• 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)  
3.2.3. 
Tertiary Endpoints 
The tertiary endpoints in this study are: 
• RUD Lite score change from baseline to Week 24 
• EQ-5D score change from baseline to Week 24 


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3.3. 
Descriptions and Scoring of Efficacy Endpoints 
3.3.1. 
Mini-Mental State Evaluation (MMSE) 
While the MMSE is not specifically an endpoint, it is used to measure baseline disease severity, 
and therefore is included in the descriptions in this section. 
The MMSE [Folstein 1975] consists of 11 tests of orientation, memory (recent and immediate), 
concentration, language and praxis.  Scores range from 0 to 30, with lower scores indicating 
greater cognitive impairment. The MMSE score is the sum of the 11 items; if any item is missing 
then the total score will be set to missing. 
3.3.2. 
Alzheimer’s Disease Assessment Scale – Cognitive Subscale (ADAS-Cog) 
The 11-item and 13-item ADAS-Cog [Rosen 1984; Mohs 1997] assesses a range of cognitive 
abilities including memory, comprehension, orientation in time and place, and spontaneous 
speech.  Most items are evaluated by tests, but some are dependent on clinician ratings on a 5-
point scale. 
• The ADAS-Cog 11 total score range is from 0 to 70, with a higher score indicating 
more severe cognitive impairment. 
• The ADAS-Cog 13 is the ADAS-Cog 11 with two additional items: 
− Delayed Word Recall and Number Cancellation. 
− Scores for the ADAS-Cog-13 range from 0 to 85 with higher scores indicating 
greater dysfunction. 
If a question was not completed for cognitive reasons, the worst possible score will be assigned 
for the question. 
In order to calculate the ADAS-Cog-11 total, the following scores are first computed: 
1. The score for Word Recall is calculated as the mean number of words not recalled over 
the three trials (Trial 1, 2 and 3). Note that if data is available for only two of the trials 
then the calculated score for Word Recall will be the average of the two trials, and if a 
score for only one trial is recorded then this will be set to be the score for Word Recall.  
The score for Word Recall will be set to missing only if data is missing for all three trials. 
2. The results from Naming Objects and Fingers are scored as follows: 
0 = 0 – 2 items named incorrectly 
1 = 3 – 5 items named incorrectly 
2 = 6 – 8 items named incorrectly 
3 = 9 – 11 items named incorrectly 
4 = 12 – 14 items named incorrectly 
5 = 15 – 17 items named incorrectly 
The ADAS-Cog-11 total score is the sum of the calculated scores for the following items: 
1. Word Recall 
2. Commands 


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3. Constructional Praxis 
4. Naming Objects and Fingers 
5. Ideational Praxis 
6. Orientation 
7. Word Recognition 
8. Remembering Test Instructions 
9. Comprehension 
10. Word Finding Difficulty 
11. Spoken Language Ability 
Most items are evaluated by tests, but some are dependent on clinician ratings. The total score 
ranges from 0-70 with higher scores indicating greater dysfunction. 
When a score is missing due to non-cognitive reasons for one of the questions, the total score 
will be calculated as a weighted average of the scores provided for the remaining ten questions as 
follows (and see Table 2):  
• Imputed Total= Observed Total Score * (1+ Maximum Score of the missing value / 
Sum of the Maximum Score of the non - missing values) 
Table 2: 
Calculation of Imputed ADAS-Cog-11 Total Score (Study RVT-101-3001) 
Missing Question 
Imputed Total formula 
Word Recall  
Observed Total*(1+10/60) 
Orientation 
Observed total*(1+8/62) 
Word Recognition 
Observed total*(1+12/58) 
All other questions 
Observed total*(1+5/65) 
In cases where 2 or more questions are missing, the total score will not be imputed and will be 
set to missing. 
ADAS-COG-13 will be sum of all the ADAS-COG-11 item scores plus the item scores of 
Delayed Word Recall and Number Cancellation. The imputed total score of ADAS-Cog-13 when 
there is only one item is missing due to non-cognitive reasons is presented in Table 3. 
Table 3: 
Calculation of Imputed ADAS-Cog-13 Total Score (Study RVT-101-3001) 
Missing Question 
Imputed Total formula 
Word Recall  
Observed Total*(1+10/75) 
Orientation 
Observed total*(1+8/77) 
Word Recognition 
Observed total*(1+12/73) 
Delayed Word Recall  
Observed Total*(1+10/75) 
All other questions 
Observed total*(1+5/80) 
3.3.3. 
Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) 
The ADCS-ADL (Alzheimer's Disease Cooperative Society - Activities of Daily Living) scale 
[Galasko 1997] measures functional impairment in terms of activities of daily living. The ADCS-


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ADL is an interviewer-administered informant-based scale where the informant (caregiver) 
responds to 23 activities of daily living questions about the subject.  There are 4 scores derived:  
the Total score, Basic score, Instrumental score, and the Independence Score. 
The questions range from basic to instrumental activities of daily living and take approximately 
20 minutes to complete. The Total score ranges from 0-78 and a higher score signifies greater 
functional ability; the lower the score the greater (worse) the impairment. 
The questionnaire is split into two types of questions, an initial question relating to whether a 
subject has completed a particular activity and then a follow-on question which scores how much 
assistance the subject has required if they have performed that particular activity.  
• The Total score is calculated by adding up the responses for each of the individual 
activities. Note if a caregiver responds to the question relating to whether the subject 
performed a particular activity as no or don’t know this will contribute a zero to the 
Total score. 
• The Basic score will also be calculated as the sum of questions 1-6b and ranges from 
0-22 (activities included in the basic score are: eating, walking, using the toilet, 
bathing, grooming and dressing) 
• The Instrumental score in the, sum of questions 7-23, ranges from 0-56 (the 
Instrumental score includes: using the telephone, watching television, conversations, 
clearing dishes, personal belongings, making drinks, making snacks, taking rubbish 
out, getting out and about, shopping, keeping appointments, being left alone, current 
events, reading, writing, pastimes/hobbies, household chores). 
• The Independence Score is calculated by re-scoring all 23 individual questions for 
each activity, such that a given question is given a ‘1’ if the MAXIMUM (best) score 
is observed, and a ‘0’ otherwise.  Thus, each question contributes a maximum of 1 
unit to the total, with a total range for the Independence Score ranging from 0 (worst) 
to 23 (best). 
If there are any missing scores within the Basic activities questions, the Basic total score will not 
be imputed and therefore will be set to missing. 
If there is only one missing score within the Instrumental activities questions, the Instrumental 
score will be calculated as a weighted average of the scores provided for the remaining 16 
activities as follows (and see Table 4): 
• Imputed Total = Observed Total Score x (1+ Maximum Score of the missing value/ 
Sum of the Maximum Score of the non -missing values) 
Table 4: 
Calculation of Imputed ADCS-ADL Instrumental Score (Study RVT-101-
3001) 
Missing Question 
Imputed Instrumental formula 
8a, 8b, 8c, 16b, 18a,18b, 18c,19a,19b,19c, 20a, 20b Observed total*(1+1/55) 
9, 10, 11, 12, 14, 16a, 17, 21, 22b 
Observed total*(1+3/53) 
13, 15, 23b  
Observed total*(1+4/52) 
7 
Observed total*(1+5/51)   


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The total ADCS-ADL score will be calculated by adding up the Basic total score and the 
Instrumental imputed total score. 
The Total Independence score will give any missing score from either Basic or Instrumental 
questions a value of zero. 
In cases where 2 or more questions are missing, the total Instrumental score will not be imputed 
(ie, it will be set to missing) except for the following situation: 
The following is the English version of Questions 18a, 18b and 18c: 
18a. Was {P} left AWAY FROM HOME, for 15 minutes or longer, during the day? 
18b. Was {P} left AT HOME, for an hour or longer, during the day? 
18c. Was {P} left AT HOME, for less than 1 hour, during the day? 
In Spain and Korea, because Questions 18b and 18c were incorrectly translated as “left AWAY 
FROM HOME” rather than “left AT HOME”, scores of Questions 18b and 18c are not correct as 
intended when Question 18, “During the past 4 weeks, was {P} ever left on his/her own?”, has 
a response of “Yes”.  Therefore, for all subjects’ visits in Spain and Korea, when Question 
18=Yes, Questions 18b and 18c will be considered missing and the total Instrumental Score will 
be normalized as follows in cases where no other Instrumental ADCS-ADL question is actually 
missing: 
Observed total*(1+2/54) 
Correct scores of Questions 18b and 18c in Spain and Korea will also be collected separately for 
visits that occur after accurate translations are deployed to sites.   
The Independence score will assign a ‘0’ to any question that is missing. 
In addition, two Factor Scores are predefined for this study.  These Factor Scores are specifically 
noted to be of relevance to patients with AD, particularly with progression of the disease. 
• Communication and Engagement Factor Score, defined as the sum of the following 
questions (where all questions are needed to calculate the Factor Score): 
− Watching television (Questions 8a to 8c) 
− Conversation (Question 9) 
− Keeping appointments (Question 17) 
− Current events (Questions 19a to 19c) 
− Reading (Questions 20a and 20b) 
− Writing (Question 21) 
− Hobbies (Question 22). 
• Outside Activities Factor Score, defined as the sum of the following questions (where 
all questions are needed to calculate the Factor Score): 
− Getting out and about (traveling, Question 15) 
− Shopping and paying (Questions 16a and 16b) 


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− Being left alone (Questions 18a to 18c). 
3.3.4. 
Dependence Scale (DS) 
The DS measures the amount of assistance patients with dementia require in performing daily 
activities [Brickman 2002].  The caregiver answers questions about the dependency of the 
subject.  The scale consists of 13 items. A total score will be calculated with a range from 0 to 15 
with higher scores indicating greater dependency. 
In addition, a Dependence Level score ranging from 0 to 5 based on responses to the DS items 
will be analyzed. The Dependence Level score of 0 indicates no dependence, while a score of 5 
indicates complete dependence in self-care activities.  This will be used for a Progressor-type 
analysis, with any score increasing is considered progressing (worsening). 
No imputation for missing values is performed; thus, if an item is missing, the corresponding 
domain is not calculated (ie, is set to missing). 
3.3.5. 
Clinician’s Interview Based Impression of Change Plus Care Giver Interview 
(CIBIC+) 
The CIBIC+ assessment [Schneider 1997] measures the global functioning of the subject through 
structured interviews by an investigator with both the subject and caregiver.  The change from 
baseline is recorded on a 7-point scale with a score of 4 indicating no change, scores above 4 
indicating worsening, and scores below 4 indicating improvement. 
The CIBIC+ scale is a single item instrument, if the CIBIC+ is not done at a visit or the result is 
missing at a visit, the result will be set to missing. 
3.3.6. 
Neuropsychiatric Inventory (NPI) 
The NPI is a behavior rating scale composed of a 12-item structured interview of the caregiver 
that is scored from 0 to 144 (the higher the score, the greater the psychiatric disturbance). It 
assesses 12 behavioral and psychological disturbances (domains) occurring in dementia patients. 
These 12 domains are: 
• Delusions 
• Hallucinations 
• Dysphoria 
• Anxiety 
• agitation/aggression 
• euphoria 
• disinhibition 
• irritability 
• apathy 
• aberrant motor activity 


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• night time behavior disturbance 
• eating abnormalities.   
For each domain there are four scores assigned: 
• Frequency  
• Severity  
• Total (frequency x severity).  
• Caregiver distress  
Scores are assigned to questions as demonstrated in Table 5.  No imputation for missing values is 
performed; thus, if an item is missing, the corresponding domain is not calculated (ie, is set to 
missing). 
Table 5: 
Scores for NPI Individual Questions (Study RVT-101-3001) 
Category 
Numeric values assigned 
Frequency is 
rated as: 
1=Occasionally - less than once per week 
2=Often - about once per week 
3=Frequently - several times per week but less than every day 
4=Very frequently - daily or essentially continuously present 
Severity is rated 
as: 
1=Mild - produces little distress in the patient 
2=Moderate - more disturbing to the patient but can be redirected by the 
caregiver 
3=Severe - very disturbing to the patient and difficult to redirect 
Caregiver 
Distress is rated 
as: 
0=no distress 
1=minimal 
2=mild 
3=moderate 
4=moderately severe 
5=very severe or extreme. 
There are three overall scores that will be analyzed from the NPI: 
• A Psychosis Domain will be defined as the sum of the Delusions total and the 
Hallucinations total.   
− Thus, the Psychosis Domain score can range from 0 to 24.  This will be then 
dichotomized as ‘No Change/ Improvement’ versus ‘Worsening (ie, Progressors)’ 
from baseline for each patient. 
• The NPI Total score will be calculated by adding the total scores of the 12 domain 
scores together (and thus a range of 0 to 144). The caregiver distress score is not 
included in the total NPI score. 
• Caregiver Distress is defined as the sum of the caregiver distress items from the 12 
domains, and thus scores can range from 0 to 60 


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3.3.7. 
EuroQol-5D (EQ-5D) 
The EQ-5D is a standardized measure of health status that provides a measure of health-related 
quality of life that is widely used in clinical trials [Rabin 2001].  For this study the EQ-5D will 
be a caregiver proxy assessment.  The assessment will be completed by the caregiver and will 
assess the caregiver’s impressions of how the subject would rate his/her own quality of life.  
The EQ-5D questionnaire consists of 2 components: the EQ-5D descriptive system and the EQ 
visual analogue scale (EQ-VAS).  The EQ-VAS records overall health status on a 20 cm vertical 
line with a score of 0 (worst health one can imagine) to 100 (best health one can imagine).  
The EQ-5D comprises the following five dimensions:  
• Mobility 
• self-care 
• usual activities 
• pain/discomfort 
• anxiety/depression.  
Each dimension has 5 response levels:  
• no problem 
• slight problems 
• moderate problems 
• severe problems 
• extreme problems.  
The number and percentage by response level will be summarized by visit and treatment for each 
domain.  The response levels will be dichotomized to show number and percentage of subjects 
without problems (reported no problems) and with problems (slight problems, moderate 
problems, severe problems, and extreme problems).   
The index values of EQ-5D-5L Health Status Today and attack EQ-5D-5L will be calculated 
using the crosswalk link function based on the published EQ-5D-5L Crosswalk Index Value set. 
For countries where the index value sets were not yet available, regional values will be selected.  
3.3.7.1. 
RUD-Lite 
The RUD-Lite scale [Wimo 1998] is designed to assess caregiver burden and provide 
pharmacoeconomic data related to AD.  The RUD-Lite (Version 3.3) includes both baseline and 
follow-up questions, and includes two domains: 
• Personal ADL relates to assisting subjects with basic activities of daily living (eg, 
grooming).  
• Instrumental ADL relates to assisting subjects with instrumental activities of daily 
living (eg, driving to store). 


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Table 6 demonstrates how these measures will be calculated for caregiver time spent during the 
last 30 days caring for the subject: 
Table 6: 
RUD-Lite Domains (Study RVT-101-3001) 
Category 
Formula from Questions 
Personal ADL (Activities of Daily Living) 
2A (hours and minutes) x 2B (days) 
Instrumental ADL 
3A (hours and minutes) x 3B (days) 
In addition to the categories above, a Total score will be calculated as follows: 
• Total Score = Personal ADL + Instrumental ADL 


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4. 
STUDY DESIGN 
4.1. 
Summary of Study Design 
This is a multi-center, double-blind, randomized, placebo-controlled, parallel-group study in 
patients with mild to moderate Alzheimer’s disease who are on stable donepezil therapy.  The 
efficacy and safety of intepirdine at a dose of 35 mg will be evaluated over a 24 week treatment 
period.  Approximately 1150 subjects will be enrolled.  The randomization ratio will be 1:1 
(intepirdine:placebo) and enrolled patients will be stratified by baseline MMSE score.  The 
primary endpoints will be measured after 24 weeks of treatment.  Study participation will last 
approximately 33 weeks:  0 to 4 weeks for Screening, a 3 week Single-Blind Placebo Run-In 
Period to evaluate baseline status, a 24 week randomized Double-Blind Treatment Period, and a 
2-week Follow Up (post-treatment) Period. 
Figure 1 provides a study scheme demonstrating the key design elements and scheduled study 
visits. 
Figure 1: 
Study Schema (Study RVT-101-3001) 
 
4.2. 
Definition of Study Drugs 
There are two study drugs being given: 
• Intepirdine (Test therapy):  Intepirdine 35 mg given as an adjunct to a stable regimen 
of donepezil (5 mg or 10 mg) 
• Placebo (Reference):  Matching placebo, also given as an adjunct to a stable regimen 
of donepezil (5 mg or 10 mg) 


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4.3. 
Sample Size Considerations 
4.3.1. 
Sample Size Justifications 
The primary comparisons of interest are to compare intepirdine to placebo at Week 24 for 
change from baseline in both ADAS-Cog-11 and ADCS-ADL. A sample size of 435 subjects per 
treatment group will allow a difference of 1.6 points between placebo and active treatment in the 
change from baseline in ADAS-Cog score to be detected with 95% power and a 0.05 
significance level assuming an underlying standard deviation (SD) of 6.5. This sample size will 
also allow a difference of 2 points between placebo and active treatment in the change from 
baseline in ADCS-ADL score to be detected with 90% power and a 0.05 significance level 
assuming an underlying SD of 9. 
Both endpoints need to achieve a significance level of 0.05 to maintain an overall 5% 
significance level. Hence, the multiplicity issue associated with the trial having two primary 
endpoints is addressed as efficacy will only be concluded if both endpoints are significant. 
Assuming a drop-out and missing data of approximately 25% up to Week 24, a total of 
approximately 1150 subjects will be randomized in a 1:1 ratio to intepirdine or placebo. 
4.3.2. 
Sample Size Re-estimation 
No sample size re-estimation is planned. 
4.4. 
Randomization/Stratification 
Subgroups using MMSE score at baseline will be examined (see Section 6.6).  Stratification 
levels will be defined as presented in Table 7. 
Table 7: 
MMSE Stratification Levels (Study RVT-101-3001) 
Baseline MMSE Score 
10-15 
16-20 
21-26 
Target for recruited population 
≤30%; >20% 
≤60%; >40% 
≤30%; >20% 
4.5. 
Clinical Assessments 
The schedule of clinical assessments is presented in Table 8.  Detailed descriptions of these 
assessments can be found in the study protocol. 


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Table 8: 
Schedule of Events (Study RVT-101-3001) 
Study Period: Screening 
Run-in 
Baseline 
Treatment 
Follow-
up 
ET 
Study Visit Number: 
V1 
V2 
V3
V4 
V5 
V6 
V7 
V8 
V9 
ET 
Study Week: 
W(-7) 
W(-3) 
W0 
W3 
W6 
W12 
W18 
W24 
W26 
Study Day: 
relative to Baseline 
unless specified 
Up to 28 
days 
before V2 
21 + 5 
days 
before V3 
0 
21 ± 3 
42 ± 3 
84 ± 5 
126 ± 5 
168 ± 5 
14 to 19 
days after 
last dose 
of IP 
Informed consent 
X 
Inclusion and exclusion criteria 
X 
X 
Demography 
X 
Medical history 
X 
Concomitant medications review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine drug screen 
X 
C-SSRS
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
X 
Dispense investigational product
X 
X 
X 
X 
X 
Dispense study-supplied donepezil 
X 
X 
X 
X 
X 
Assess investigational product and 
study-supplied donepezil 
compliance 
X 
X 
X 
X 
X 
X 
X 
Physical exam/ 
current medical conditions 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete neurological exam 
X 
X 
X 
X 
MRI or CT 
X 
12-lead ECG
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum OR urine pregnancy test 
X 
X 
X 
Hep B, and Hep C screen 
X 
TSH, vitamin B12, syphilis 
serology 
X 
Serum chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood alcohol content 
X 
X 
X 
X 
X 
X 
X 
X 
intepirdine level 
X 
X 
X 
X 


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Study Period: Screening 
Run-in 
Baseline 
Treatment 
Follow-
up 
ET 
Study Visit Number: 
V1 
V2 
V3
V4 
V5 
V6 
V7 
V8 
V9 
ET 
Study Week: 
W(-7) 
W(-3) 
W0 
W3 
W6 
W12 
W18 
W24 
W26 
Study Day: 
relative to Baseline 
unless specified 
Up to 28 
days 
before V2 
21 + 5 
days 
before V3 
0 
21 ± 3 
42 ± 3 
84 ± 5 
126 ± 5 
168 ± 5 
14 to 19 
days after 
last dose 
of IP 
Donepezil level 
X 
X 
X 
Hachinski Ischaemia Scale 
X 
ADAS-Cog 
X 
X 
X 
X 
X 
X 
X 
MMSE 
X 
X 
ADCS-ADL 
X 
X 
X 
X 
X 
X 
X 
CIBIS 
X 
CIBIC+ 
X 
X 
X 
NPI 
X 
X 
X 
X 
DS 
X 
X 
RUD Lite 
X 
X 
EQ-5D 
X 
X 


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5.
ANALYSES
5.1. 
Interim Analyses 
No unblinded interim efficacy or safety analyses are planned. 
5.2. 
Final Analyses 
There is only one analysis 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 patients excluded from Per Protocol population has been identified.


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6.
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND
HANDLING
6.1. 
General Table and Individual Subject Data Listing Considerations
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” will be distinguished from “missing” values 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.. 
Summaries will be presented by treatment and time. Unless stated otherwise, descriptive 
summaries will include n, mean, standard deviation, coefficient of variation (CV), median, 
minimum, and maximum for continuous variables, and n and percent for categorical variables. 
In addition, the geometric mean with associated 95% CI, between-subject CVs (CVb), and SD of 
the logs based on the geometric mean, will be included for the log-transformed PK parameters. 
The between-subject %CV of the log transformed variable will be calculated as: 
•
%CVb = 100 * √(eSD^2 – 1), with SD of the log-transformed data
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. 
All data collected in the CRF, as well as laboratory data, will be provided in data listings, sorted 
(in general) by patient and chronological date order.  For date fields, Study Day will be 
calculated and presented in these listings. 
6.2. 
Analysis Populations 
It is intended that a complete accounting of patients for the analysis populations will be provided, 
from the Screening Population through the Per-Protocol Population. 


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6.2.1. 
Screening Population 
All patients who are screened (signed an informed consent) will be included in the Screening 
Population.   
6.2.2. 
Placebo Run-In 
All patients entering the Placebo Run-in will be included in the Placebo Run-In population.  This 
population will be used to provide an accounting of the disposition of patients during this phase 
of the study. 
6.2.3. 
Randomized Population 
The Randomized Population will include all patients who are randomized. 
6.2.4. 
Safety Population 
Safety population will consist of all subjects who were randomized and took at least one dose of 
double-blind investigational product.   
6.2.5. 
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 who have at least one 
baseline and one post baseline primary efficacy assessment for at least one of either the ADAS-
Cog-11 or the ADCS-ADL.  This will be the primary population used for the efficacy analysis. 
6.2.6. 
Per-Protocol (PP) Population 
The Per-Protocol (PP) Population will consist of those members of the ITT Population who have 
no major protocol violations.  This population will be used for confirmatory analysis of the two 
primary efficacy variables. 
Major protocol violations will be defined as follows: 
•
Subject had >7 consecutive days interruption in double-blind study medication
•
Subject had >7 consecutive days interruption or change in donepezil dose during the
study
•
Treatment with excluded concomitant medications.
•
Significant study drug administration errors.
•
No documented history of at least 4 months of ongoing donepezil therapy for AD.
•
No documented history of at least 2 months of stable donepezil therapy of 5 or 10 mg
•
Invalid week 0 efficacy assessment.
•
Subject does not have MMSE score 12-24 inclusive at Screening
•
Subject does not have MMSE score 10-26 inclusive at baseline.
•
MMSE score at baseline not within +/- 3 points of the Screening value


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•
Evidence of other causes of dementia.
•
History or presence of significant medical or psychiatric condition.
•
Subject does not live with (or have substantial Periods of contact with) a regular
caregiver.
•
Subject is <80 % compliant or > 120% compliant between Visit 7 (Week 18) and
Visit 8 (Week 24) with either study drug or donepezil.  Patients who fail to return
their bottle (and thus compliance cannot be determined) will be assumed to have been
compliant for purposes of the Per Protocol population.
6.2.7. 
Completers (CS) Population
The study completers (CS) Population will consist of those members of the ITT Population who 
have completed the study.  This population will be used for supportive analysis of the primary 
efficacy variable and other cognition and efficacy endpoints. 
6.2.8. 
Pharmacokinetics (PK) Population 
The PK population will include all subjects in the Safety Population who undergo plasma PK 
sampling and have at least one post-baseline evaluable PK concentration result. 
6.3. 
Multiple Comparisons and Multiplicity 
This is a Phase 3 study in which a number of efficacy endpoints will be assessed.  There are two 
pre-specified co-primary endpoints, the ADAS-Cog-11 and the ADCS-ADL, tested at Week 24.  
Both endpoints need to achieve a significance level of 0.05 to maintain an overall (study-wise) 
5% significance level. Hence, the multiplicity issue associated with the trial having two primary 
endpoints is addressed as efficacy will only be concluded if both endpoints are significant. 
Further, the pre-specified key secondary endpoints will be tested in a sequential manner.  The 
comparisons for the pre-specified key secondary efficacy endpoints will be performed at the 5% 
level of significance using a stepwise gate-keeping testing procedure in which testing will 
proceed to the next ordered tests only if the prior test was found to be significant (p-value ≤ 
0.05).  This method will be used to control the type I error rate for these key secondary 
endpoints. 
Analysis of each key secondary variable will be performed, with the nominal p-values reported.  
The interpretation of those p-values (and conclusions regarding hypothesis testing) will then be 
performed using the sequential testing strategy, as follows: 
1. CIBIC+ score at Week 24. If significant (p-value ≤ 0.05), proceed to next test.
2. Dependence Scale (DS) Total Score changes over time.  The DS is collected at only one
time point post-baseline.  Thus, this analysis will be performed using BOTH, an observed
case and LOCF.   The ANCOVA will have effects for treatment, baseline DS score,
baseline MMSE, and Region (as defined in Section 6.6).  The observed case analysis will
be considered the primary assessment of this variable, with the LOCF analysis
supportive.


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6.4. 
Baseline Definition 
Baseline or pre-dose assessment is the last available assessment prior to time of first dose of 
double-blind treatment, unless otherwise specified.  If assessments fall on the same day as the 
date of first dose, those assessments will be assumed to be baseline assessments.  If there are 
multiple assessments collected on the same date, the average of these assessments will be used.  
6.5. 
Derived and Transformed Data 
6.5.1. 
Baseline Age 
Age (in years) will be determined at the baseline visit (V3) using the date of the baseline visit as 
recorded in the 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. 
6.5.2. 
Study Day 
Study day for the assessment date of interest should be calculated relative to the first dose date of 
double-blind investigational product using the appropriate formula below: 
•
If the assessment date of interest is on or after the first dose date of double-blind
investigational product:
−
Study day = assessment date – first dose date of double-blind investigational
product + 1
•
If the assessment date of interest is before the first dose date of double-blind
investigational product:
−
Study day = assessment date – first dose date of double-blind investigational
product
6.5.3. 
Handling of Incomplete Dates 
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, for which the date is left as missing: 
•
Start and stop dates of adverse events
•
Start and stop dates of concomitant medication
•
Start and stop dates of double-blinded medication
Completely missing dates will not be replaced and the corresponding derived variables will be 
set to missing. 
6.5.4. 
Visit Windows 
Actual times will be used in the listings, individual concentration-time profiles, and in the 
calculation of PK parameters. 


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There are 4 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 (or Placebo) Run-In Period 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 study medication will be assumed to have been completed before the first
dose of study medication and will be slotted to this period.
•
The Double-Blind Treatment Period starts on the date of first dose of randomized
double-blind investigational product and ends on the last dose date +7 days. If the
first dose of randomized investigational product is taken on the same day as the
baseline assessments, it will be assumed that the baseline assessments were
completed before the first dose of investigational product was taken.
•
The Post-Treatment Period.  Assessments are regarded as Follow-Up if the
assessment occurred >7 days after the last dose date of investigational product.
Data collected at assessment visits provide information of the status at that point in time (e.g. 
efficacy measures, vital signs, laboratory parameters, etc.) and may provide biased results if the 
visit is attended early or late, in which case the subject will have received more or less treatment 
than scheduled. For this reason, visits will be slotted with similar investigational product 
exposure. 
Post-baseline assessments from the Double-Blind Treatment Period data will be visit slotted 
according to the time intervals shown based on the days relative to the date of first dose of 
double blind investigational product (Day 1). Early withdrawal data that is assigned to Double-
Blind Treatment Period will be slotted using the assessment windows. 
Data will be phased first. All data that slots into pre-treatment period will be assigned a visit of 
Screening. All data that occurs in Single-Blind Run-In Period will be assigned a visit of Run-in 
or Baseline depending on medication start/stop dates and data that slots into the Follow Up 
Period will be assigned a visit of Follow Up. 
Table 9 provides the windows (relative to start of double-blind treatment) that visit data are to be 
slotted into. 
Table 9: 
Windows for Slotting Visits (Study RVT-101-3001) 
Days relative to start of double-blind 
treatment* 
Target Day 
Visit Slot 
Days 2 - 34 
21 
Week 3 
Days 35 - 69 
42 
Week 6 
Days 70 – 104 
84 
Week 12 
Days 105 - 140 
126 
Week 18 
Days 141 - 196 
168 
Week 24 
*Date of assessment – date of first dose + 1


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For data where two or more assessments are slotted into the same visit interval, the data recorded 
closest to the target visit day will be used for the summary tables and analyses. If two 
assessments are equally close to the target day, the later of the two assessments will be used in 
tabulations and analyses; data from the earlier assessment(s) will be listed only. 
•
Note that for safety data (except blood pressure or heart rate assessments), the closest
assessment is always the assessment used, however, for efficacy, if the closest
assessment is not evaluable, the other assessment would be used. For example, for
ADAS-Cog, if the total score could not be calculated for the closest assessment, the
other assessment would be used.
•
If on one of the dates only one of the sitting or standing blood pressure assessments is
present then the assessments recorded on the other date, which slots to the same visit
interval, will be used in tabulations and analyses. Therefore orthostatic blood pressure
will always be calculated using sitting and standing measurements from the same
date, these assessments however may not be the closest to the target day. A similar
rule applies for Heart rate assessments.
For data where two or more assessments are slotted to follow up (and thus after double-blind 
treatment has ended), then the data recorded closest to target day (14 days after last dose of 
double-blind medication) will be used for summaries. 
6.5.5. 
Missing Start and Stop Dates for Prior and 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 date of the first dose of double–blinded study medication is in the same month
and year as the occurrence of the AE/concomitant medication, the start day of the
event/concomitant medication will be assigned to the day of the first dose of the
double-blinded medication.
•
Otherwise the start day will be set to the 1st day of the month.
Missing start day and month, but year present: 
•
If the first dose of double–blinded study medication in the same year as the
occurrence of the AE/concomitant medication, the start day and month will be
assigned to the date of the first dose of the double-blinded medication.
•
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.


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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.
6.6. 
Subgroups
While this study is not powered for subgroup analyses, select efficacy and safety endpoints will 
be analyzed by defined subgroups.  Additional subgroup may be added as the data dictate.  If the 
total number of subjects in a subgroup is < 10% of the total number of randomized subjects, the 
analysis for that subgroup may not be performed. 
The following subgroups are planned for safety analysis: 
•
Disease Severity based on baseline MMSE
−
10-19 and 20-26
−
Mild (16-26) and Moderate (MMSE of 10-20)
•
Geographic Region
−
US, Non-US English (UK, Canada, Australia), West Europe (Germany, Spain,
Italy, France), East Europe (Czech Republic, Poland, Slovakia, Croatia, Serbia,
Bulgaria), and Other (Rest of World)
•
Age (years)
−
<74 and ≥74
−
<65 and ≥65
•
Gender
−
Female and Male
•
Race
−
White and Non-White
•
Ethnicity
−
Hispanic and Not Hispanic
•
Stable Dose of Donepezil
−
5 mg and 10 mg
The following subgroups are planned for efficacy analysis: 
•
Disease Severity based on baseline MMSE
−
10-19 and 20-26
−
Mild (16-26) and Moderate (MMSE of 10-20)


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•
Geographic Region
−
US, Non-US English (UK, Canada, Australia), West Europe (Germany, Spain,
Italy, France), East Europe (Czech Republic, Poland, Slovakia, Croatia, Serbia,
Bulgaria), and Other (Rest of World)
•
Age
−
<74 and ≥74
•
Gender
−
Female and Male
•
Race
−
White and Non-White
•
Stable Dose of Donepezil
−
5 mg and 10 mg
Analysis of the primary endpoints and the CIBIC+ will be run by these subgroups.  


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7.
STUDY POPULATION
7.1. 
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, 
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 subjects entering the Placebo Run-in, number 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 patients randomized, as well as the number of patients in the analysis populations 
(Safety, ITT, etc.) will be presented for the Randomized Population. 
A second analysis will be performed, using the Safety population as the denominator, of the 
number of patients included in the Safety, ITT, Per Protocol, Completers and pharmacokinetic 
populations; this will be summarized by treatment group. 
•
A tabulation of the number of subjects randomized in each country will be provided.
•
An overall summary of the number and percentage of subjects who completed or
withdrew prematurely from the study will be displayed by treatment group, for the
overall population as well as by MMSE 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.
•
A cumulative distribution plot of the time to early withdrawal will be plotted and will
include both treatment groups in order to allow for a visual inspection of the time to
discontinuation.  A similar plot will be provided for those patients who discontinue
due to adverse event.  The denominator for this plot will be the underlying population
(and thus ‘censoring’ will not be applied).
7.2. 
Screen Failures
Screen failure data will be tabulated by reason patients were found to not be eligible for the 
study.  
7.3. 
By-Center 
A tabulation of the number of patients enrolled by country will be presented.  This tabulation 
will also include the pooled center counts (number of patients in each of the pooled/geographic 
region-based centers).   
7.4. 
Protocol Deviations 
Protocol deviations will be identified prior to unblinding, and the Per Protocol population will be 
determined based on a review of those deviations.  A list of all protocol deviations will be 
tabulated and listed.  In addition, a listing of subjects for whom the treatment blind was broken 
during the study will also be provided, if appropriate.  


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7.5. 
Demographic and Baseline Characteristics 
Demographic data will be summarized for the ITT Population and the Safety Population. 
•
All demographic data [eg, age, gender, race, baseline MMSE, donepezil dose and
duration of donepezil treatment prior to randomization (as captured from concomitant
medications)] will be tabulated, along with the defined subgroups that will be used for
safety or efficacy analyses (as listed in Section 6.6).
•
Alzheimer’s disease diagnosis information will be summarized in a similar fashion.
•
Other characteristics collected on the CRF (eg, significant worsening in the past 6
months) will be summarized by the number and percentage of subjects, or as
appropriate.
•
Baseline values for the primary and secondary efficacy endpoints (eg, ADAS-Cog-11,
ADCS-ADL, DB Total Score) will be included.
•
Details of the primary caregiver (sex, relationship to patient, live with the patient)
will be included in a tabulation.
7.6. 
Subject Inclusion and Exclusion Criteria
Patients not meeting specific eligibility criteria questions will be listed. 
7.7. 
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 and will form the basis for discussion 
regarding the medical history of patients enrolled in this study. 
7.8. 
Prior and Concomitant Medications 
Medication verbatim text will be coded using the WHO ATC classification 
(http://www.whocc.no/filearchive/publications/1_2013guidelines.pdf). 
Medications will be tabulated as: 
•
Prior medications
•
Concomitant medications
−
Single-blind run-in
−
Double-blind period
•
New-onset concomitant medications during the double-blind period
Medications received prior to the date of first dose of single-blind study medication 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. 


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Concomitant medications will be further split by concomitant medications taken during the 
Single-Blind Placebo Run-In Period and concomitant medications taken during the Double-Blind 
Treatment Period. It should be noted that a concomitant medication can be counted in more than 
one period. 
New-onset medications (those starting only after the date of first dose of double-blind study 
medication) will also be presented. 
Note that multiple drug use (by preferred name) will be counted once only per subject in the 
tabulations. No inferential statistics are planned. 
Use of non-study medications will be summarized (number and percentage of subjects) by 
treatment and WHO preferred name.  
A listing of non-medication therapy will be provided. 
7.9. 
Extent of Exposure 
Duration of exposure for the Double-Blind Treatment Period will be calculated as follows: 
•
Duration of exposure in days = (Double-Blind Treatment Period stop date – Double-
Blind Treatment Period start date) + 1
Total dose will be calculated as: 
•
Total Dose = duration of exposure × dose.
Duration of exposure and Total dose will be tabulated descriptively.  Exposure also will be 
categorized as: 
•
0 to 2 weeks
•
>2 to 4 weeks
•
>4 to 8 weeks
•
>8 to 12 weeks
•
>12 to 16 weeks
•
>16 to 24 weeks
•
>24 weeks
7.10. 
Treatment Compliance 
Compliance with study drug and with donepezil (separately) will be assessed over the Double-
Blind Treatment Period 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.  Patients are expected to take one tablet per day of each. 
Treatment compliance based on the drug accountability will be calculated as follows: 
•
compliance (%) = (number of tablets taken)/(number of tablets expected)*100
−
number of tablets taken = the number of tablets dispensed – the number of tablets
returned


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−
number of tablets expected = (date of the last dose-date of the first dose+1)
Summary of treatment compliance will be presented by treatment group, between Week 18 and 
24 as well as overall. The number and percentage for compliance expressed as a categorical 
variable (<80%, ≥80% to ≤120%, and >120%) will be also presented by treatment group, for 
Week 18 to Week 24 as well as overall.  Note that patients missing a bottle (ie, they do not return 
a bottle) will have compliance set to MISSING. 
For each bottle of double-blind medication, 50 tablets are included.  For each bottle of donepezil 
is 90 tablets. 
7.11. 
Overdose 
A listing of any overdose information will be provided.  This will be included in the same section 
of the data listings as the compliance listings. 


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8.
EFFICACY
8.1. 
General Considerations 
Tabulation of the primary and secondary endpoints will generally be presented for the ITT, Per-
Protocol, Completers Population, and subgroups as identified in Section 6.6.  The primary 
efficacy assessments will be performed on the Observed Cases (OC) dataset.  The observed cases 
dataset is the data that is analyzed “as is”, with no imputation for missing values. 
Sensitivity analyses will be performed for the primary efficacy endpoint using a multiple 
imputation approach as described in Section 8.3.2.3. 
For the total scores for ADAS-Cog-11 and ADCS-ADL, if an endpoint has not been completed 
at the baseline visit or has too many missing items to be able to calculate the imputed total score 
or has not been completed at all, the imputation rules as shown in Table 10 will be applied. 
Table 10: 
Imputation Rules for Pre-Treatment (Baseline) Total Scores for ADAS-Cog-
11 and ADCS-ADL (Study RVT-101-3001) 
Week -3 Total Score 
Week 0 Total Score 
Baseline Total Score 
x 
x 
Week 0 
. 
x 
Week 0 
x 
. 
Week -3 
. 
. 
Missing 
8.2. 
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 over 24 weeks in the ADAS-Cog-11 score or in the
ADCS-ADL score in patients with Alzheimer’s disease.
•
Ha:  There IS a difference between treatment with intepirdine and treatment with
placebo with respect to changes over 24 weeks in the ADAS-Cog-11 score and in the
ADCS-ADL score in patients with Alzheimer’s disease.
The primary comparisons of interest will be performed at the 5% level of significance. All 
hypothesis tests will be two-sided. 
8.3. 
Analysis of the Primary Efficacy Endpoint 
8.3.1. 
Primary Endpoints 
The co-primary endpoints in this study are ADAS-Cog-11 score change from baseline to Week 
24 and ADCS-ADL score change from baseline to Week 24. 
8.3.2. 
Primary Efficacy Analysis 
Treatment comparisons between the intepirdine and placebo groups in ADAS-Cog-11 and 
ADCS-ADL change from baseline to Week 24 will be analyzed for the OC dataset using a mixed 
model for repeated measures (MMRM) with restricted maximum likelihood estimation, an 


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unstructured covariance matrix, and the Kenward-Roger approximation for denominator degrees 
of freedom.  
•
This model corrects for dropout and accounts for the fact that measurements taken on
the same subject over time tend to be correlated, by using all available information on
subjects within the same covariate set to come up with an estimate of the treatment
effect for a dropout free population.
•
For this primary analysis, no imputation of the missing values will be made or
required and the data used in the analysis will be the actual observed responses at
each visit.
•
The statistical model will be fitted with terms for treatment group, visit, treatment by
visit interaction, baseline score, baseline MMSE, baseline score by visit interaction,
and Region (as defined in Section 6.6).
The region by treatment interaction term will be evaluated at the 10% level of significance; if the 
interaction term is found to be significant, it will be included in the MMRM model.  Note, this 
applies to ALL MMRM models, EXCEPT the by-region Subgroup analyses, where, because the 
subgroup analyses by Region only include 1 region, the interaction makes no sense.  The same 
MMRM model is also used for subgroups for the efficacy endpoints, as appropriate. 
Primary inferences will be drawn from treatment differences for the changes from baseline 
derived from the MMRM models at Week 24. As additional supportive information, treatment 
differences for each post baseline visit will also be derived using the MMRM models. 
The estimated treatment difference for “intepirdine 35mg – Placebo” at each visit will be 
displayed in the summary of statistical analysis together with the 95% confidence interval and 
the associated p-value. 
Least Squares Means for each visit will also be presented with the standard error and the number 
of subjects contributing to the Least Squares Means. Least Squares Means and estimated 
treatment differences for each visit and the associated 95% confidence interval will be displayed 
graphically. 
8.3.2.1. 
Further Details of the MMRM Analysis 
The mixed model for repeated measures (MMRM) model will be fitted using SAS PROC 
MIXED procedure with restricted maximum likelihood estimation, an unstructured covariance 
matrix, and the Kenward-Roger approximation for denominator degrees of freedom.  The 
unstructured covariance is the least restrictive and generally performs well with limited number 
of repeated measures per patient 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
MMRM 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 eventuality, the Akaike’s Information
Criterion (AIC) will be used to determine the optimal variance-covariance structure
matrix for the primary comparisons.


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8.3.2.2. 
Sensitivity Analyses of the Primary Efficacy Results 
The following sensitivity analyses will be performed for the primary efficacy endpoint: 
•
An ANCOVA model, using observed cases, will be run for the Week 24 data.  SAS
Proc Mixed will be used for this analysis.
•
Repeat the primary MMRM analysis (using the same model as was used for the
primary assessment of ADCS-ADL, ie, excluding or including the region by
treatment interaction as appropriate) for both the co-primary endpoints in the
following two scenarios’ regarding the ADCS-ADL translation errors observed for
Question 18b and 18c, in Spain and Korea:
−
For all subject visits in Spain and Korea, when Question 18 is answered “Yes”,
Questions 18b and 18c will both be considered as zero when calculating total
Instrumental Score in cases where no other Instrumental ADCS-ADL question is
missing.
−
For all subject visits in Spain and Korea, when Question 18 is answered “Yes”,
then assign the total Instrumental Score as missing.
•
Analysis using a Cochran-Mantel-Haenszel test with modified ridit scores to assess
the differences in row mean scores between the treatment groups (CMH-RMS).
Sample SAS code is as follows, where MMSEbase is the MMSE baseline stratum,
treat is the treatment variable, and outcome (change from baseline) is the endpoint.
This analysis will be performed for the Week 24 observed cases data.  The actual
SAS code may be modified as appropriate.
Proc freq data=dat; 
  Tables MMSEbase*treat*outcome / cmh rms; 
  Run; 
•
Analysis using a non-parametric (distribution-free) Wilcoxon Rank Sum Test and
Hodges-Lehmann estimates of the treatment differences. This analysis will be
performed for the Week 24 observed cases data. Confidence intervals based on the
Wilcoxon Rank Sum Test will also be provided.   Sample SAS code is as follows.
The actual SAS code may be modified as appropriate.
Proc npar1way data=dat; 
  Class treat; 
  Var outcome; 
  ods select WilcoxonScores HodgesLehmann 
  Run; 
8.3.2.3. 
Description of Missing Data for the Primary Efficacy Endpoints 
The patterns of missing data for each primary efficacy endpoint will be presented, with the 
number (%) of patients in each treatment group with each pattern of missingness, as 


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demonstrated in Table 11.  These data will be examined in order to determine if there was any 
general difference in the pattern of missing data between the treatment groups, as well as to 
explore the assumption of missingness at random. 
Table 11: 
Examples of Patterns of Missingness (Study RVT-101-3001) 
Pattern 
Treatment 
Group 
Number (%) of 
Patients 
Baseline 
Week 
3 
Week 
6 
Week 
12 
Week 
18 
Week 
24 
1 
Intepirdine 
xx (xx.x%) 
X 
X 
X 
X 
X 
. 
Placebo 
xx (xx.x%) 
X 
X 
X 
X 
X 
. 
2 
Intepirdine 
xx (xx.x%) 
X 
X 
X 
X 
. 
. 
Placebo 
xx (xx.x%) 
X 
X 
X 
X 
. 
. 
Etc. 
8.3.2.4. 
Sensitivity Analysis from Imputation of Missing Efficacy Data for Primary 
Efficacy Endpoints 
8.3.2.4.1. Last Observation Carried Forward 
An ANCOVA model will be run on the Week 24 data for which any missing values at Week 24 
are imputed from last non-missing value carried forward (LOCF) for a given patient.  Sample 
SAS code is as follows (where basescore is the baseline score for the endpoint and center is the 
pooled geographic region variable [US,  non-US English, West Europe, East Europe, and Rest of 
World]). 
Proc Mixed data=dat; 
  Class treat MMSEbase center; 
  Model outcome=treat mmsebase center basescore; 
  Run; 
8.3.2.4.2. Multiple Imputation 
Missing data for the primary endpoints will be imputed utilizing multiple imputation methods.  
Multiple imputation provides a useful strategy for analyzing data sets with missing values. 
Instead of filling in a single value for each missing value, Rubin’s [Rubin 1976, Rubin 1987] 
multiple imputation strategy replaces each missing value with a set of plausible values that 
represent the uncertainty about the correct value to impute. 
The assumption that data are missing at random (MAR) is common to the above analyses.  To 
examine the primary endpoint with an analysis that does not require the MAR assumption, a 
pattern-mixture approach will be utilized for the imputation.  The first step will be to apply a 
Markov chain Monte Carlo (MCMC) method [Schafer 1997] that assumes multivariate normality 
will be used to impute all missing values to make the imputed (resulting) data sets have strictly 
monotone missing patterns.  The resulting monotone missing pattern will then, in a second 
imputation step, be used to impute the remaining missing values; specifically, a regression-based 
pattern-mixture method for continuous variables will be applied. 


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The SAS software system will be used to perform this imputation.  Because the imputation of 
missing data is a key aspect to the analysis of the data, explicit details regarding this imputation 
are provided via sample SAS code that is intended to demonstrate the application of these 
strategies.  Variable definitions are: 
•
TRT=treatment group (1 or 0)
•
Eff1 is the first time point for the variable score
•
Eff2 is the second time point for the variable score
•
Eff_last is the last time point for the variable score. Additional variable scores
(between Eff1 and Eff_last) would be included in this model according to the time
points for collection.
The first step will be to impute partially in order to obtain a monotone missing data pattern. 
proc mi data=DATAIN out=DATAIN_MONO nimpute=100 seed=123; 
var TRT Eff1 Eff2 …. Eff_last; 
mcmc chain=multiple impute=monotone; 
run; 
The second step will be to impute the remaining (monotone) missing data that is MAR for each 
of the 100 imputed datasets from the first step.   
Following the imputation of the data to create a monotone missing pattern, missing values for the 
earliest missing value (visitnum1) are imputed BY VISIT (thus, one imputation at a time), using 
the covariates basescore, MMSEbase, center, time_from_diagnosis (of AD), gender, and 
previous score (ie, the non-missing score from previous visit).   The first visit to be imputed 
would be the Week 3 time point, then the Week 6, Week 12, Week 18, and finally Week 24. 
Thus, the process is repeated sequentially, by visit, until the monotone missing data pattern is 
completely filled in (imputed), and thus there may be up to 5 calls to the PROC MI procedure to 
generate the final imputed dataset.   The following sample SAS code demonstrates the general 
methodology for imputing the first visit (Week 3) and second visit (Week 6) data.  Note that the 
output dataset from the first imputation is used as the input dataset for the second imputation. 


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**First procedure imputes missing values for the first visit (Week 3); 
proc mi data=DATAIN_MONO out=DATAREG1 seed=465 nimpute=1;  
by _Imputation_; 
var visitnum1 basescore MMSEbase center time_from_diagnosis gender 
previous; 
monotone regression(visitnum1); 
run; 
  ** Second procedure imputes missing values for the second visit (Week 6) 
proc mi data=DATAREG1 out=DATAREG2 seed=465 nimpute=1;  
by _Imputation_; 
var visitnum1 visitnum2 basescore MMSEbase center time_from_diagnosis 
gender  previous; 
monotone regression(visitnum2); 
run; 
Note that the regressions do not include the treatment variable, and thus the imputed data at each 
time point will be based on the distribution of all data in the model rather than treatment-group 
specific distributions. 
•
A total of 100 imputed datasets will be created using these imputed data.
•
Each of the 100 imputed datasets will then be analyzed using the MMRM model with
effects for treatment, mmsebase, center, and basescore.  In this way, the test of the
efficacy endpoint at Week 24 will be obtained, once for each of the 100 imputed
datasets.
•
The 100 resulting treatment effect parameters and standard errors from these will be
combined to provide a distribution of parameters (and standard errors) upon which
the sensitivity analysis will be concluded.  PROC MIANALYZE may be used for this
summary of the analysis.
8.3.2.5. 
Additional Analyses of Primary Efficacy Endpoints 
The primary endpoints will be analyzed in the additional manner: 
•
A cumulative distribution plot of changes in scores from baseline to Week 24 will be
provided, with percent of patients on Y-axis and change score on X-axis.
•
Time to progression, defined as a worsening (from baseline) by 1 point (or more).
Worsening must be observed in 2 consecutive visits (eg, Week 6 and 12) in order to
be defined as progression.  Thus, the worsening must be by 1 point or more from
baseline for two consecutive visits.  A log-rank statistic will be provided.
•
For the efficacy subgroup analyses, the same MMRM model will be used as for the
primary analysis of the variable of interest.  Thus, if region by treatment interaction is
not significant (at 0.10) for the primary efficacy endpoint overall, then it will not be
included in the model for the subgroup analyses for that variable.


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−
However, for the REGION subgroups, the region by treatment interaction term
will necessarily be excluded.
8.4. 
Analysis of the Secondary Efficacy Endpoints 
Continuous variables will be analyzed in a fashion similar to that of the primary endpoint, using 
the MMRM methodology on the observed cases dataset.  The MMRM model will include the 
same terms as the analysis of the primary efficacy endpoints.   
For those endpoints that are collected only once on-treatment (DS, RUD Lite, and EQ-5D), as 
there are no repeated measurements, an ANCOVA will be used; however, it is intended that the 
PROC MIXED SAS procedure will be used in all cases to perform the analysis, as it is capable 
of both the ANCOVA and MMRM analyses.  The region by treatment interaction term will be 
evaluated at the 10% level of significance; if the interaction term is found to be significant, it will 
be included in the MMRM model.   
Categorical outcomes will be analyzed using a logistic regression approach to test the effect of 
treatment on the outcomes.  The model will include terms for treatment, baseline score, baseline 
MMSE, and Geographic Region. The odds ratios for each treatment group compared to placebo 
will be displayed with the 95% confidence intervals. 
8.4.1. 
Key Secondary Endpoints 
The key secondary endpoints in this study will be analyzed in the following manner: 
•
CIBIC+
−
Observed values at each time point using MMRM as the primary approach, with
similar subgroups as for the primary endpoints. The statistical model will be fitted
with terms for treatment group, visit, treatment by visit interaction, baseline
MMSE, and Region (as defined in Section 6.6).  The region by treatment
interaction term will be evaluated at the 10% level of significance; if the
interaction term is found to be significant, it will be included in the MMRM
model.  Note, that as no baseline CIBIC+ score was collected, there is no baseline
covariate.
−
Frequency Distribution of CIBIC+ at Week 24 (including tabulation and bar
chart), with percentage of patients on Y-axis and CIBIC+ rating categories
(Markedly Improved through Markedly Worse on the X-axis).
−
Analyzed, for Week 24, using a CMH row means scores (modified ridit scores)
test, a Hodges-Lehmann test, and a Wilcoxon Rank-Sum Test (see Section 8.3.2.2
for sample SAS code that is generally applicable for this analysis).
•
Dependence Scale (DS) Total Score changes over time.  The DS is collected at only
one time point post-baseline.  Thus, this analysis will be performed using BOTH, an
observed case and LOCF.   The ANCOVA will have effects for treatment, baseline
DS score, baseline MMSE, and Region (as defined in Section 6.6).  The region by
treatment interaction term will be evaluated at the 10% level of significance; if the
interaction term is found to be significant, it will be included in the MMRM model.


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8.4.2. 
Other Secondary Endpoints 
The other secondary endpoints in this study will be analyzed in the following manner: 
•
Dependence Scale (DS)
−
Progressors in Dependence Level, defined as patients worsening from baseline,
analyzed as a categorical outcome (using logistic regression)
•
NPI Total score as a shift from baseline, defined as 'No Change/ Improvement' versus
'Worsening (ie, Progressors)' (Table 12).  This variable will be analyzed as a
categorical outcome (using logistic regression stratified by the baseline MMSE).
Table 12: 
NPI Total Score Progressors Analysis (Study RVT-101-3001) 
NPI Total Score Outcome 
Placebo 
Intepirdine 35 mg 
No Change/Improvement 
XX (%) 
XX (%) 
Progressors 
XX (%) 
XX (%) 
• 
• Falls 
−
The incidence of falls will be compared, where MedDRA SOC=Injury, poisoning,
and procedural complications, PT=Fall will be selected.  A logistic regression
model controlling for baseline stratification of MMSE will be used for this
analysis.  In the Phase 2 study AZ3110866, the incidence of falls in the
intepirdine 35 mg treatment group was numerically lower than that in the placebo
group.  The pre-specified analysis of the incidence of falls in RVT-101-3001 is to
assess whether the observed reduction of falls can be replicated in a larger study.
•
ADAS-Cog-11 and ADCS-ADL
−
Time to progression, defined as a worsening (from baseline) by 1 point (or more).
Worsening must be observed in 2 consecutive visits (eg, Week 6 and 12) in order
to be defined as progression.  Thus, the worsening must be by 1 point or more
from baseline for two consecutive visits.  A log-rank statistic will be provided.
•
ADCS-ADL Basic, Instrumental, and Independence subscores
−
Changes over Time
•
ADCS-ADL Communication and Engagement Factor and Outside Activities Factors
−
Changes over Time
•
ADAS-Cog-13
−
Changes over Time
•
The NPI scores will be analyzed as follows:
−
NPI Total score as changes over Time
−
Caregiver distress as changes over Time


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−
NPI Domain score of the following Domains as changes over Time
−
Agitation/aggression
−
Anxiety
−
Apathy
−
Dysphoria
−
Irritability
−
Progressors analysis of the Psychosis Domain score
−
Progressors analysis for each of the 12 NPI domain scores.
•
RUD Lite, the Total, Personal, and Instrumental domains
−
Changes from baseline to end of study
•
EQ-5D
−
Total score changes from baseline to end of study (including EQ-VAS)
−
The number and percentage of patients by each response level will be summarized
by visit and treatment for each of the 5 domains.  This will be analyzed via a
CMH RMS test stratified by baseline MMSE strata levels.
−
The response levels will be dichotomized to show number and percentage of
subjects without problems (reported no problems) and with problems (slight
problems, moderate problems, severe problems, and extreme problems).  This will
be analyzed via a logistic regression model.
8.4.3. 
Responder Analyses 
The following responder definitions will be defined and each will be analyzed using a logistic 
regression model as described above as well as a CMH test.  The percentage of responders and 
the difference in proportions compared to placebo will be presented. The analyses will be 
performed based on the observed data (subjects with Week 24 assessment for the endpoint of 
interest).  
1. ADAS-Cog-11 Improvement by at least 3 points at Week 24
a.
Repeated for by at least 4 points at Week 24
b. Repeated for ‘no change or improvement’ vs ‘worsening’
2. ADCS-ADL No change/improvement vs worsening at Week 24
3. CIBIC+ No change/improvement vs worsening at Week 24
4. ADAS-Cog-11/CIBIC+/ADCS-ADL composite, simultaneously meeting the criteria for:
a.
ADAS-Cog-11 Improvement of at least 3 points at Week 24
b. CIBIC+ No change/improvement at Week 24
c.
ADCS-ADL No change/improvement at Week 24
5. ADAS-Cog-11/ADCS-ADL composite, simultaneously meeting the criteria for:


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a.
ADAS-Cog-11 Improvement by at least 3 points at Week 24
b. ADCS-ADL No change/improvement at Week 24
The analyses will be performed based on the observed data (subjects with Week 24 assessment 
for the endpoint of interest), as well as analyzed assuming that all subjects with missing Week 24 
are treatment failures (non-responder). 


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9.
SAFETY AND TOLERABILITY
The safety analysis will be descriptive in nature, and will be presented for the Safety Population.  
All safety data collected and captured in the eCRF will be included in data listings sorted by 
domain, patient and time point, or as appropriate.  Mean observed values at pre-treatment and 
on-treatment (as well as post-treatment) will generally be tabulated by protocol-specified time 
points, while the number of patients with potentially clinically significant values at pre-treatment 
and at each endpoint will be presented.  The last non-missing baseline value will be used as the 
baseline value for that parameter. 
Adverse events will be classified using the most up-to-date MedDRA coding dictionary.  
Tabulations will include an overall incidence of at least one adverse event, incidence within body 
system, and incidence by preferred term.  Each patient may only contribute once (ie, first 
occurrence) to each of the incidence rates, regardless of the number of occurrences. 
Generally, safety data will be presented for the Placebo Run-In Period, for the Double-Blind 
Treatment Period, and for the post-treatment Follow-up Period.  AEs will be presented for the 
Screening period as well. 
9.1. 
Adverse Events 
Adverse events will be tabulated by MedDRA system organ class (SOC) and preferred term, 
unless otherwise specified.   
•
Adverse events occurring prior to the first dose of single-blind study medication (ie,
prior to the Placebo Run-In period) will be presented as Screening events.
•
Adverse events occurring prior to the first dose of double-blind study medication will
be presented as Placebo Run-In events.
•
Adverse events occurring on or after the first dose of double-blind study medication,
and within 7 days of the last dose of double-blind study medication, will be referred
to as On-Treatment AEs (OTAEs).
•
Events occurring after that will be presented as Post-Treatment.  While the Post-
Treatment period is defined as up to 30 days post-last-dose, it is possible some events
may be reported that start after that 30 day period.  These events will be included in
the analysis.
AEs during the double-blind treatment period will be presented overall as well as by the 
subgroups as defined in Section 6.6 for OTAEs, SAEs, and OTAEs resulting in death. 
Tabulations of the incidence of AEs will be presented as follows: 
•
Screening (using the Screening Population as the denominator).
•
Single-Blind Placebo Run-In (using the Placebo Run-In Population as the
denominator)
−
AEs
−
AEs resulting in discontinuation from study


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−
SAEs.  SAEs will be tabulated (separately) as All SAEs, Non-Fatal SAEs and
Fatal SAEs.
−
Deaths
•
Double-Blind Treatment Period (using the Safety Population as the denominator)
−
OTAEs
−
OTAEs by MedDRA System Organ Class Only
−
OTAEs occurring in ≥2%, 5%, and 10% in EITHER treatment arm
−
OTAEs judged by the investigator to be at least possibly related to study
medication
−
OTAEs by maximum intensity (Grade 1 mild, Grade 2 moderate, and Grade 3
severe)
−
OTAEs resulting in discontinuation from study medication
−
SAEs.  SAEs will be tabulated (separately) as All SAEs, Non-Fatal SAEs and
Fatal SAEs.
−
SAEs judged by the investigator to be at least possibly related to study medication
−
OTAEs resulting in Death
−
OTAEs resulting in Death judged by the investigator to be at least possibly related
to study medication
−
An analysis of Adverse Reactions (defined as events occurring with higher
incidence in the Intepirdine arm) will be provided via a tabulation of these
OTAEs.
•
Post-Treatment Period (using the Safety Population as the denominator)
−
AEs
−
SAEs
−
Deaths
The time to first onset of OTAEs will be presented using the following bins of onset, where the 
bins are defined from the start dose of study medication.  As the bins are defined by exposure, 
events occurring after the date of last dose are not included in this analysis. 
•
0 to 2 weeks
•
>2 to 4 weeks
•
>4 to 8 weeks
•
>8 to 12 weeks
•
>12 to 16 weeks
•
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•
>24 weeks
Time to first onset for select OTAEs will be presented via Kaplan-Meier plots and a log-rank 
statistic will be calculated (stratified by randomization baseline MMSE score).  These events will 
include: 
•
OTAE resulting in discontinuation from study medication
•
SAE
•
Death
•
Falls (a pre-specified secondary endpoint)
−
SOC=Injury, poisoning, and procedural complications, PT=Fall.  PT's of fracture
and contusion may also be investigated.
•
The most common events (based on incidence of 2% or more, subject to adjustment
depending on actual observed incidence in the study)
The Incidence of Adverse Events Occurring after Last Dose of Double-Blind Study Medication 
by Time to Onset of Event (1 to 14 days, >14 to 30 days, and >30 days) will be presented.  This 
will include all events that occur with a start-date that is 1 or more days AFTER the date of the 
last dose of study medication. 
9.2. 
Clinical Laboratory 
Clinical laboratory parameters will be presented using three methods: 
1. Tabulations of observed values over time.  Group-mean plots (mean and standard error) 
over time will also be provided.  Reference lines for the upper and lower normal values 
will be provided:  where there are difference reference ranges for males and females, the 
highest (or lowest) value will be used as the reference line.
2. Tabulations of the incidence of potentially clinically significant (PCS) values.  A focus 
will be on new-onset PCS values, ie, patients 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 for a 
parameter (for a given patient) will be used.  Thus, a patient 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 14 and for hematology in 
Table 15.
3. Shifts from baseline to on-treatment, where values are categorized as low, normal, or 
high according to the lab normal values.  For purposes of this analysis, the most extreme 
on-treatment values will be used (most extreme low and most extreme high).  Shifts from 
baseline will be based on laboratory normal ranges as provided by the central laboratory 
(see Appendix 1). 
In addition, the incidence of OTAEs relating to hematology and serum chemistry laboratory 
parameters during the Double-Blind Treatment Period will be presented.  These laboratory AEs 
will be identified from a review of the adverse events and select SOC and PTs will be included. 


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Table 13: 
Serum Chemistry Potentially Clinically Significant Criteria (Study RVT-101-
3001) 
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 
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 29 
NA 
Random glucose (mmol/L) 
Male/Female 2.9 
NA 
Potassium (mmol/L) 
Male/Female 3.4 
5.6 
Sodium (nmol/L) 
Male/Female 129 
151 
Table 14: 
Haematology and Differentials Potentially Clinically Significant Criteria 
(Study RVT-101-3001) 
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 
9.3. 
Vital Signs 
Vital sign data (blood pressure [BP], pulse, and weight) will be summarized by treatment, visit, 
and planned time and listed by subject, visit, treatment, planned time and actual date and time.  
Change from baseline will also be summarized.  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 15. 
Table 15: 
List of Potentially Clinically Significant Ranges for Vital Sign Parameters 
(Study RVT-101-3001) 
Systolic blood pressure: 


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Low: < 90 and decrease ≥30 mm Hg 
High: ≥ 180 and increase ≥ 20 mm Hg 
Diastolic blood pressure: 
Low: < 50 and decrease ≥20 mm Hg 
High: >90 and increase ≥20 mm Hg 
Pulse 
Low: <50 bpm and Decrease ≥30 bpm 
High: >100 and Increase ≥30 bpm 
Weight 
≥ 10% increase from baseline 
≥ 10% decrease from baseline 
9.4. 
Physical Examination 
Physical examination data will be listed by patient and time point.  
9.5. 
ECGs 
ECG data will be summarized by treatment, visit, and planned time and listed by subject, visit, 
treatment, planned time and actual date and time.  Change from baseline will also be 
summarized.   
The ECG analysis will include a careful review of QTcF values.  As part of this review, a 
summary of the number (percent) of patients with QTcF values in the following ranges will be 
provided:  ≤450 msec, >450 to ≤480 msec, >480 to ≤500 msec, and >500 msec.  This will be 
performed by visit as well as at ANY time during the double-blind treatment period (where the 
highest QTcF value will be used for that assessment). 
The overall Investigator interpretation of ECG by visit (shifts from baseline) will be tabulated. 
The incidence of PCS values will be presented, with a focus on new-onset PCS values.   
Table 16: 
List of Potentially Clinically Significant Ranges for ECG Parameters (Study 
RVT-101-3001) 
QTcF Interval 
High: ≥500 msec only 
High: Increase ≥ 60 msec only 
High: ≥500 and Increase ≥60 
9.6. 
Pregnancy 
If any female subjects or female partners of male subjects become pregnant during the study, a 
listing will be provided. 


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9.7. 
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. 
•
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 shift table to present changes from pre-treatment to any time post-first-dose will be assessed, 
with the number (and percent) of subjects showing a worsening from baseline on any of the four 
endpoints.   
The C-SSRS was collected at screening (and the assessment was based on patient recall from the 
past year), while on-treatment collection was based on outcomes ‘since the prior visit’.  Thus, the 
analysis will be done in two ways: 
1.
Shifts from screening, where C-SSRS is relative to patient recall of the past year
(using Screening value C-SSRS, and is shifts to each post-screening time point).


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2. 
Shifts from baseline, where C-SSRS is collected relative to patient recall since the 
PREVIOUS visit, using Baseline value C-SSRS and is shifts to each post-baseline 
time point). 
Table 17 presents the general manner in which these data will be tabulated. 
Table 17: 
Sample Table Demonstrating How C-SSRS Outcomes will be Presented 
(Study RVT-101-3001) 
 
 A listing of all C-SSRS data will be provided, while a listing of patients who demonstrated a 
worsening on any one of the four endpoints will also be provided.  These listings will include the 
Study Day (relative to first dose of double-blind treatment) the C-SSRS was collected.   


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10.
PHARMACOKINETIC /PHARMACODYNAMIC ANALYSES
Plasma intepirdine and donepezil concentrations will be listed and summarized by treatment 
group and visit and included in the CSR. 
Intepirdine population PK analyses will be described in a separate population PK/PD analysis 
plan and reported separately to the main CSR.  Population PK analyses may pool data from the 
current study and prior Phase 1 and Phase 2 studies, as appropriate, and evaluate any impact of 
donepezil on the PK of intepirdine. 
No population PK analysis is planned for donepezil.  Donepezil concentrations collected before 
and after initiation with intepirdine will be descriptively compared, and compared to literature 
steady state values (mean ± SD) [Tiseo 1998] to assess a pharmacokinetic interaction: 
•
5 mg Cmin=21.4 ± 3.8 and Cmax= 34.1 ± 7.3 ng/mL
•
10 mg Cmin=38.5 ± 8.6 and Cmax=60.5 ± 10.0 ng/mL
In addition, the following analyses of donepezil concentrations will also be performed: 
•
Comparison of donepezil concentrations
The donepezil concentration by visit will be compared between subjects taking 
intepirdine and subjects taking placebo.  
•
Comparison of donepezil trough concentrations
In patients with a value of ≥20 hours between time of last donepezil dose and collection 
of the PK blood sample, the mean donepezil concentration will be compared by visit 
between subjects taking intepirdine and subjects taking placebo 
10.1. 
Exposure-Efficacy Analyses 
The relationship between intepirdine exposure and the ADAS-Cog-11 score and ACDS-ADL 
endpoints will be assessed using a longitudinal population PK/PD model, similar to that 
previously described [Holford 1992].  Intepirdine population PK/PD analyses will be described 
in a separate population PK/PD analysis plan and reported separately to the main CSR.  This 
analysis also will include endpoint data from the prior Phase 2 study AZ3110866 and may 
include donepezil trough concentrations as a covariate. 
10.2. 
Exposure-Safety Analyses 
Intepirdine exposure-safety analyses will initially consist of a series of exploratory plots (scatter 
plots, box-plots, or similar) to evaluate any relationship between intepirdine or donepezil 
exposure and frequency or severity of a select group of AEs or laboratory findings (to be 
determined after initial evaluation of the AE profile of the subjects enrolled in the current study).  
The Week 12 (Visit 6) intepirdine and donepezil pre-dose trough concentration will be used for 
these exploratory plots.  Further model-based analyses may be conducted based on the findings 
of these exploratory graphical outputs, and incorporate other exposure metrics (such as AUCτss, 
Cmax-ss, and Cmin-ss). 


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11.
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 methods. Additional analyses (including subgroup assessment) for 
select variables have been added.   Further, key secondary endpoints were identified and 
multiplicity and alpha control were addressed through a hierarchical testing strategy for these 
endpoints.  


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12. 
REFERENCES 
 
Brickman AM, Riba A, Bell K, et al.. Longitudinal assessment of patient dependence in 
Alzheimer disease. Arch Neurol. 2002;59(8):1304-1308. 
Folstein MF, Folstein SE, McHugh PR. “Mini-Mental State”: A practical method for grading the 
cognitive state of patients for the clinician. J Psychiatry Res. 1975;12:189-198. 
model. Technical report 97-04, Dept. of Statistics, The Pennsylvania State University. 
Holford NH, Peace KE. Methodologic aspects of a population pharmacodynamic model for 
cognitive effects in Alzheimer patients treated with tacrine. Proceedings of the National 
Academy of Sciences. 1992;89(23):11466-11470.  Available at: 
http://www.pnas.org/content/89/23/11466.long.  Accessed 9-feb-2017. 
Mohs RC, Knopman D, Petersen RC, et al. Development of cognitive instruments for use in 
clinical trials of antidementia drugs: additions to the Alzheimer's Disease Assessment Scale that 
broaden its scope. The Alzheimer's Disease Cooperative Study. Alzheimer Dis Assoc 
Disord. 1997;11(Suppl 2):S13–21. 
Rabin R, deCharro F. EQ-5D: a measure of health status from the EuroQol Group. Ann Med. 
2001;33(5):337-343. 
Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer’s disease. Am J Psychiatry. 
1984;141:1356-1364. 
Rubin D, Schenker N. Multiple Imputation for Interval Estimation from Simple Random 
Samples with Ignorable Nonreponse.  Journal of the American Statistical Association.  June 
1986, Vol 81, No 394. 
Rubin D.  Inference and Missing Data. Biometrika, Vol. 63, No. 3 (Dec., 1976), pp. 581-592 
Schafer, J.L. (1997) Imputation of missing covariates under a multivariate linear mixed 
Schneider L, Olin J, Doody R, et al. and the ADCS. Validity and reliability of the Alzheimer’s 
disease cooperative study‐clinical global impression of change. Alzheimer Dis Assoc Disord. 
1997;11(2):S22‐S32. 
Tiseo PJ, Rogers SL, Friedhoff LT. Pharmacokinetic and pharmacodynamics profile of donepezil 
HCl following evening administration. Br J Clin Pharm. 1998;46:Suppl 1:13-18. 
Wimo A, Wetterholm AL, Mastey V, Winblad B. Evaluation of the resource utilization and 
caregiver time in Anti-dementia drug trials - a quantitative battery. In: Wimo A, Jonsson B, 
Karlsson G, Winblad B, editors. The Health Economics of dementia. London: John Wiley & 
Sons; 1998. Pp1. 465-499. 


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APPENDIX 1. CENTRAL LABORATORY REFERENCE RANGES 


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