Clinical trial NCT02703636
Conditions: Mild to Moderate Alzheimer's Disease
Keywords: Alzheimer's disease
Sponsor: Novartis Pharmaceuticals
Start date: 2016-05-09; Completion date: 2018-05-07
Enrollment: 118 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
To evaluate the efficacy of rivastigmine patch with 1-step titration on cognitive function measured as change from baseline to week 24 in the total score of Mini-Mental State Examination (MMSE) in mild to moderate Alzheimer's disease (AD) patients who failed to benefit from other cholinesterase inhibitors (ChEIs).

Detailed description:

Arms: arm 1: Alzheimer's disease patient who is applicable to 1 step titration method (initial loading dose is a rivastigmine patch 9.0 mg/day and will be up-titrated after 4 weeks to reach the maintenance dose of 18 mg/day). Rivastigmine patch is a marketed drug, therefore the dose, dose regimen and titration scheme are in accordance with product label.
Interventions: intervention 1: Rivastigmine Patch
Intervention descriptions: intervention 1: Alzheimer's disease patient who is applicable to 1 step titration method (initial loading dose is a rivastigmine patch 9.0 mg/day and will be up-titrated after 4 weeks to reach the maintenance dose of 18 mg/day). Rivastigmine patch is a marketed drug, therefore the dose, dose regimen and titration scheme are in accordance with product label.

Protocol documents:
Prot_000.pdf: 
[Exelon/Rivastigmine]
Clinical Trial Protocol [CENA713DJP02]
NCT02703636
[A 24-week, open-label, multicenter study to evaluate the 
efficacy, safety and tolerability of Exelon patch 
(Rivastigmine) with 1-step titration in patients with mild to 
moderate Alzheimer’s disease (MMSE 10–23) switched 
directly from cholinesterase inhibitors (Donepezil, 
Galantamine)]
Authors:
 
Document type:
Amended Protocol Version
EUDRACT number:
Not applicable
Version number:
v02 Clean
Clinical trial phase:
IV
Release date:
29-Aug-2016
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 03 (August 2015)


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................5
List of abbreviations............................................................................................................6
Glossary of terms.................................................................................................................7
Amendment 1 .............................................................................................................................8
Protocol summary................................................................................................................9
1
Introduction .......................................................................................................................12
1.1
Background............................................................................................................12
1.2
Purpose ..................................................................................................................13
2
Study objectives and endpoints .........................................................................................14
2.1
Primary objective(s)...............................................................................................14
2.2
Secondary objective(s)...........................................................................................14
15
2.4
Objectives and related endpoints...........................................................................15
3
Investigational plan ...........................................................................................................16
3.1
Study design...........................................................................................................16
3.2
Rationale for study design .....................................................................................17
3.3
Rationale for dose/regimen, route of administration and duration of treatment....18
3.4
Rationale for choice of comparator .......................................................................18
3.5
Purpose and timing of interim analyses/design adaptations..................................18
3.6
Risks and benefits..................................................................................................18
4
Population..........................................................................................................................19
4.1
Inclusion criteria ....................................................................................................20
4.2
Exclusion criteria...................................................................................................21
5
Treatment...........................................................................................................................23
5.1
Study treatment......................................................................................................23
5.1.1
Investigational and control drugs..........................................................23
5.1.2
Additional treatment..............................................................................24
5.2
Treatment arms ......................................................................................................24
5.3
Treatment assignment and randomization.............................................................24
5.4
Treatment blinding.................................................................................................24
5.5
Treating the patient................................................................................................24
5.5.1
Patient numbering .................................................................................24
5.5.2
Dispensing the study drug.....................................................................24


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5.5.3
Handling of study and additional treatment..........................................25
5.5.4
Instructions for prescribing and taking study treatment........................25
5.5.5
Permitted dose adjustments and interruptions of study treatment ........26
5.5.6
Rescue medication ................................................................................27
5.5.7
Concomitant medication .......................................................................27
5.5.8
Prohibited medication ...........................................................................27
5.5.9
Emergency breaking of assigned treatment code..................................29
5.6
Study Completion and Discontinuation.................................................................29
5.6.1
Study completion and post-study treatment..........................................29
5.6.2
Discontinuation of Study Treatment .....................................................29
5.6.3
Withdrawal of informed consent...........................................................30
5.6.4
Loss to follow-up ..................................................................................31
5.6.5
Early study termination by the sponsor.................................................31
6
Visit schedule and assessments .........................................................................................31
6.1
Information to be collected on screening failures..................................................33
6.2
Patient demographics/other baseline characteristics .............................................33
6.3
Treatment exposure and compliance .....................................................................34
6.4
Efficacy..................................................................................................................34
6.4.1
Mini-Mental state examination (MMSE)..............................................34
6.4.2
Neuropsychiatric Inventory-10 (NPI-10):.............................................35
6.4.3
J-CGIC (Japanese version of the Clinical global impression of 
change) ..................................................................................................35
6.4.4
Quality of Life- Alzheimer’s Disease (QOL-AD) ................................35
6.4.5
Modified Crichton Scale .......................................................................36
6.4.6
Appropriateness of efficacy assessments..............................................36
6.5
Safety.....................................................................................................................37
6.5.1
Physical examination ............................................................................37
6.5.2
Vital signs..............................................................................................37
6.5.3
Laboratory evaluations..........................................................................37
6.5.4
Electrocardiogram (ECG) .....................................................................38
6.5.5
Pregnancy and assessments of fertility .................................................38
6.5.6
Appropriateness of safety measurements..............................................38
6.6
Other assessments..................................................................................................38
6.6.1
Resource utilization...............................................................................39
6.6.2
Pharmacokinetics ..................................................................................39
7
Safety monitoring ..............................................................................................................39


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7.1
Adverse events.......................................................................................................39
7.2
Serious adverse events...........................................................................................40
7.2.1
Definition of SAE .................................................................................40
7.2.2
SAE reporting........................................................................................41
7.3
Liver safety monitoring .........................................................................................42
7.4
Renal safety monitoring.........................................................................................43
7.5
Reporting of study treatment errors including misuse/abuse ................................43
7.6
Pregnancy reporting...............................................................................................43
8
Data review and database management.............................................................................44
8.1
Site monitoring ......................................................................................................44
8.2
Data collection.......................................................................................................44
8.3
Database management and quality control............................................................44
8.4
Data Monitoring Committee..................................................................................45
8.5
Adjudication Committee........................................................................................45
9
Data analysis......................................................................................................................45
9.1
Analysis sets ..........................................................................................................45
9.2
Patient demographics and other baseline characteristics.......................................45
9.3
Treatments .............................................................................................................45
9.4
Analysis of the primary variable(s) .......................................................................46
9.4.1
Variable(s).............................................................................................46
9.4.2
Statistical model, hypothesis, and method of analysis..........................46
9.4.3
Handling of missing values/censoring/discontinuations.......................46
9.4.4
Sensitivity analyses ...............................................................................46
9.5
Analysis of secondary variables ............................................................................47
9.5.1
Efficacy variables..................................................................................47
9.5.2
Resource utilization...............................................................................47
9.5.3
Pharmacokinetics ..................................................................................48
9.6
Analysis of 
 variables ..........................................................................48
48
9.6.2
Safety variables .....................................................................................48
9.6.3
Other assessment...................................................................................48
9.7
Interim analyses .....................................................................................................49
9.8
Sample size calculation..........................................................................................49
10 Ethical considerations........................................................................................................49
10.1
Regulatory and ethical compliance........................................................................49
10.2
Informed consent procedures.................................................................................49


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10.3
Responsibilities of the investigator and IRB/IEC..................................................50
10.4
Publication of study protocol and results...............................................................50
11 Protocol adherence ............................................................................................................50
11.1
Protocol Amendments ...........................................................................................51
12 References .........................................................................................................................51
13 Appendix 1: Severity of adverse events, causal relationship to drug, and action taken 
for adverse events..............................................................................................................53
14 Appendix 2: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements.....................................................................................................................54
15 Appendix 3: Specific Renal Alert Criteria and Actions ....................................................56
List of tables
Table 2-1
Objectives and related endpoints- Objectives.......................................15
Table 5-1
Dosage form and drug content for 1 step titration ................................23
Table 5-2
Dosage form and drug content for 3 step titration ................................24
Table 5-3
Actions following dose interruption......................................................26
Table 6-1
Assessment schedule.............................................................................32
Table 14-1
Liver Event and Laboratory Trigger Definitions ..................................54
Table 14-2
Follow Up Requirements for Liver Events and Laboratory Triggers ...54
Table 15-1
Specific Renal Alert Criteria and Actions.............................................56
List of figures
Figure 3-1
Study design..........................................................................................17


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List of abbreviations
AChE
Acetylcholinesterase
AD
Alzheimer’s disease
AE
Adverse event
BuChE
Butyrylcholinesterase
CFR
Code of Federal Regulations
ChE
Cholinesterase
ChEI
Cholinesterase inhibitors
eCRF
electronic Case Report Form
CPO
Country Pharma Organization
CRO
Contract Research Organization
DS&E
Drug Safety & Epidemiology
DSM-IV
Diagnostic and Statistical Manual of Mental Disorders, 4th edition
EDC
Electronic Data Capture
EMEA
European Medicine Agency
FDA
Food and drug administration
GCP
Good Clinical Practice
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IRB
Institutional Review Board
J-CGIC
Japanese version of the Clinical global impression of change
MedDRA
Medical dictionary for regulatory activities 
MMSE
Mini – Mental State Examination
NPI-10
Neuropsychiatric Inventory-10
PD
Premature discontinuation
PDD
Parkinson’s disease dementia
QOL-AD
Quality of Life- Alzheimer’s Disease
SAE
serious adverse event
SUSAR
Suspected Unexpected Serious Adverse Reactions
WHO
World Health Organization


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Dementia of the 
Alzheimer’s
Type
This is defined according to the Diagnostic and Statistical Manual
of Mental Disorders, 4th edition (DSM-IV) criteria.
Dose level
The dose of drug given to the patient (total daily or weekly etc.)
Enrollment
Point/time of patient entry into the study at which informed consent 
must be obtained (i.e. prior to starting any of the procedures described 
in the protocol)
Investigational drug
The drug whose properties are being tested in the study; this definition 
is consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug” or “investigational medicinal product.”
Investigational treatment
All investigational drug(s) whose properties are being tested in the 
study as well as their associated treatment controls. 
This includes any placebos, any active controls, as well as approved 
drugs used outside of their indication/approved dosage or tested in a 
fixed combination. 
Investigational treatment generally does not include protocol-specified 
concomitant background therapies  when these are standard 
treatments in that indication
Protocol
A written account of all the procedures to be followed in a trial, which 
describes all the administrative, documentation, analytical and clinical 
processes used in the trial.
Probable Alzheimer’s 
Disease (AD)
Probable Alzheimer’s Disease is defined according to the National
Institute of Neurological and Communicative Disorders and Stroke
and the Alzheimer’s Disease and Related Disorders Association
(NINCDS/ADRDA) criteria. This is the term which will be used
in this protocol when defining the study population.
Premature subject/patient 
withdrawal
Point/time when the patient exits from the study prior to the planned 
completion of all study treatment administration and/or assessments; 
at this time all study treatment administration is discontinued and no 
further assessments are planned, unless the patient will be followed 
for progression and/or survival
Study drug/ treatment
Any single drug or combination of drugs administered to the patient as 
part of the required study procedures; includes investigational drug (s), 
active drug run-ins or background therapy 
Study/investigational 
treatment discontinuation
Point/time when patient permanently stops taking study/investigational 
treatment  for any reason; may or may not also be the point/time of 
premature patient withdrawal
Subject Number 
A number assigned to each patient who enrolls into the study 
Variable
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being 
tested in the study
1-step titration
1-step titration begins treatment with a rivastigmine patch 9 mg/day for 
4 weeks, followed by a dose increase to 18 mg/day.


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Amendment 1
Amendment rationale
The main purpose of this amendment is to revise and provide clarity on one of the key inclusion
criteria for AD patients who have lack or loss of efficacy with previous ChEIs. For the first item 
of inclusion criteria 9-1, definition of “in initial 3-month will be revised to clarify as within 
initial 3-month because it is not always necessary to take 3-month to decide the decline of 
MMSE. For the second item of inclusion criteria 9-1, definition of “last 6-month” will be 
supplementary explained by additional description, stating that it is “during 6-month prior to at 
screening visit. Exclusion criteria point 13 has also been updated to reflect patients with 
complication of gastrointestinal adverse events caused due to oral ChE inhibitors treatment are 
not eligible for inclusion in the study. These changes are briefly summarized in below section.
This study is in the start-up phase and enrolled/screened 16 / 28 patients at the time of this 
amendment. Changes mentioned below will not impact the study population, drug 
administration, objectives, endpoints, or study results.
Changes to the protocol
All changes to the protocol are summarized below.
In Section 1.2 (Purpose) and Section 4.1 (Inclusion criteria, point 9-1), criteria for lack or loss 
of efficacy with previous ChEIs are revised and defined as follows:

Patients who declined ≥ 2 points MMSE within the initial 3-month treatment with oral 
ChEIs, and continued to show insufficient treatment effect until at  baseline (lack of 
efficacy), and

During 6 months prior to screening visit, patients who declined ≥ 2 points MMSE with 
oral ChEI treatment and continued to show insufficient treatment effect until at baseline
(loss of efficacy).
These changes are also made in synopsis, page 12 to be consistent with the protocol body.
Section 4.2 (Exclusion criteria, point 13) is revised to reflect ‘patients with complication 
(instead of the term ‘a past medical history’ as per the previous protocol version) of 
gastrointestinal adverse events such as nausea and vomiting during oral ChE inhibitors 
treatment except for such gastrointestinal adverse events if it is apparent to be caused by other 
than oral ChE inhibitors are not eligible for inclusion in the study.
Section 4.2 (Exclusion criteria, point 22) is revised to reflect ‘serum creatinine (instead of the 
plasma creatinine as per the previous protocol version) and to align with protocol Japanese 
version.
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. The changes herein do NOT affect the trial specific model ICF.


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Protocol summary
Protocol number
CENA713DJP02
Title
A 24-week, open-label, multicenter study to evaluate the efficacy, safety 
and tolerability of Exelon patch (Rivastigmine) with 1-step titration in 
patients with mild to moderate Alzheimer’s disease (MMSE 10 – 23) 
switched directly from cholinesterase inhibitors (donepezil, galantamine)
Brief title
Phase IV study of rivastigmine patch with 1 step titration
Sponsor and Clinical 
Phase
Novartis 
Phase IV
Investigation type
Drug
Study type
Interventional
Purpose and rationale
It is unknown whether a patient gets a treatment benefit from switching 
other ChEIs to rivastigmine patch with 1 step titration. Our hypothesis is 
that rivastigmine patch with 1 step titration can be a suitable treatment 
option for patients with AD who failed to benefit from other ChEIs.
Primary Objective(s) 
To evaluate the efficacy of rivastigmine patch with 1-step titration on 
cognitive function measured as change from baseline to week 24 in the 
total score of MMSE in mild to moderate AD patients who failed to benefit 
from other cholinesterase inhibitors (ChEIs).
Secondary Objectives
To evaluate the safety, tolerability of rivastigmine patch with 1-step 
titration for up to 24 weeks.
To evaluate the efficacy of rivastigmine patch with 1-step titration 
measured as the MMSE score at week 8.
To evaluate the efficacy of rivastigmine patch with 1-step titration 
measured as the NPI-10 score at week 8 and week 24.
To evaluate the efficacy of rivastigmine patch with 1-step titration 
measured as QOL-AD score at week 24.
To evaluate the efficacy of rivastigmine patch with 1-step titration 
measured as the J-CGIC score at week 4, week 8, week 16, and week 24 
To evaluate the efficacy of rivastigmine patch with 1-step titration 
measured as Modified Crichton Scale score week 4, week 8, week 16, 
and week 24.
To evaluate the formulation usability of rivastigmine patch for up to 24 
weeks as measured by the formulation usability questionnaire answered 
by caregiver.
Study design
This is a 24-week, multi-center, open-label, single-arm (1-step titration) 
study in patients with mild to moderate AD (MMSE 10-23) switched 
directly from cholinesterase inhibitors (donepezil, galantamine) for AD. 
Population
The study population will consist of a representative group of male and 
female Japanese patients (50-85 years of age) with probable AD Mini –
Mental State Examination (MMSE 10-23), treated with donepezil or 
galantamine.
Key Inclusion criteria
Patient’s with 50-85 years of age at baseline.
Outpatient status at baseline.
Males, and females not of child-bearing potential (surgically sterile, or 
one year or more from last menses).
A diagnosis of dementia of the Alzheimer’s type according to the DSM-IV 
criteria.


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A clinical diagnosis of probable AD according to National Institute of 
Neurological and Communicative Disorders and Stroke - Alzheimer's 
Disease and Related Disorders Association (NINCDS-ADRDA) criteria.
Brain scan (magnetic resonance imaging [MRI], or computed tomography 
[CT]) were met diagnosis criteria conducted within 3 years prior to 
baseline.
Positron emission tomography (PET) or single photon emission 
computed tomography (SPECT) was met diagnosis criteria conducted 
within 3 years prior to baseline visit, as long as in the past a brain scan 
(MRI or CT) also was met.
MMSE score of ≥ 10 and ≤ 23 at screening and baseline.
Patients are currently on the oral monotherapy (donepezil, 5 mg), or 
galantamine (16-24 mg) for 4 weeks prior to baseline visit.
Patients who failed to receive enough treatment benefit from the   
previous treatment can be defined if the patients meet at least one of 
following conditions at screening and baseline (multiple choices allowed)
Patients who declined ≥2 points of MMSE despite of treatment of other 
oral ChE inhibitors within initial 3-month and continued to show 
insufficient treatment effect until at baseline.
During 6 months prior to screening visit, patients who declined ≥2 points 
of MMSE with other oral ChE inhibitors and continued to show insufficient 
treatment effect until at baseline.
Patients who show marked worsening of BPSD, or ADL (can be defined 
by 1 state progression of FAST) judged by a physician despite of 
treatment of other oral ChE inhibitors in initial 3-month or last 6-month 
with other oral ChE inhibitors
Patients having difficulties being treated orally with ChEIs (donepezil or 
galantamine) by physician's judgement.
Poor compliance or adverse event except GI symptoms
Patients with swallowing difficulties.
Key Exclusion criteria
Any medical or neurological condition other than AD that could explain 
the patient's dementia (e.g., abnormal thyroid function tests, vitamin B12 
or folate deficiency, posttraumatic conditions, syphilis, head injury, 
Huntington's disease, Parkinson's disease, subdural hematoma, normal 
pressure hydrocephalus, brain tumor) at baseline;
Any other DSM-IV Axis 1 diagnosis that may interfere with the evaluation 
of the patient’s response to study medication, including other primary 
neurodegenerative dementia, schizophrenia, or bipolar disorder.
An advanced, severe, progressive, or unstable disease of any type that 
may interfere with efficacy and safety assessments or put the patient at 
special risk.
Current diagnosis of an active skin lesion/disorder.
Patients with a history of hypersensitivity to any ingredients of 
rivastigmine or carbamate derivatives.
Each patient will be required to have a primary caregiver willing to accept 
responsibility for supervising treatment, assessing the patient’s condition 
throughout the study, and for providing input into efficacy assessments.
Study treatment
Rivastigmine patch: 9 and 18 mg patch (5 and 10 cm2, respectively)
Efficacy assessments
MMSE (primary), NPI-10, J-CGIC, QOL-AD and Modified Crichton Scale


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Key safety 
assessments
Adverse Events, Serious Adverse Events (SAE)
Other assessments
Formulation usability questionnaire
Treatment compliance
Data analysis
The change from baseline in MMSE total score will be analyzed using a 
mixed model repeated measures (MMRM) model. The model will contain 
visit as a fixed effect, baseline MMSE score as a covariate and subject as 
a random effect. An unstructured covariance matrix will be used to model 
the within-subject error. The estimated mean change at Week 24 along 
with a two-sided 95% confidence interval and p-value will be presented. 
In addition, as sensitivity analyses, the following will also be performed.
The change from baseline to Week 24 in MMSE total score will be 
analyzed using a t-test. The estimated mean change along with 95% 
confidence interval and p-value will be presented. This analysis will be 
performed on study completers only without any imputation of missing 
data.
The change from baseline to Week 24 in MMSE total score imputed with 
last observation carried forward (LOCF) method will be analyzed using a 
t-test. The estimated mean change along with 95% confidence interval 
and p-value will be presented.
Key words
Alzheimer, Dementia


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1
Introduction
1.1
Background
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by 
cognitive dysfunction including memory impairment. Within Japan 1.17 million patients, aged 
65 and older, were reported with AD in 2005, and it is estimated that there will be 1.82 million 
patients by 2015 and 2.40 million patients by 2025, respectively (Shimokata 2008). The 
symptoms of AD are directly related to the degeneration of cholinergic neurons of the cortex 
and hippocampus, which results in lower levels of acetylcholine and a reduction of cholinergic 
transmission (Davies and Maloney 1976). This cholinergic hypothesis led to the development 
of cholinesterase (ChE) inhibitors, which act by inhibiting the two enzymes responsible for the 
degradation of acetylcholine: acetylcholinesterase (AChE) or butyrylcholinesterase (BuChE). 
Cholinesterase inhibitors which act by inhibiting the degradation, and therefore elevating levels, 
of acetylcholine in functionally intact cholinergic synapses and in the brain parenchyma - form 
the mainstay of therapy for mild to moderate AD. Exelon ® (rivastigmine) is widely approved 
for the treatment of mild to moderate AD, and differs from other cholinesterase inhibitors by 
its shorter serum half-life and its slowly reversible inhibition of both enzymes involved in the 
breakdown of acetylcholine in the brain. It is a relatively brain-selective AChE and BuChE 
inhibitor of the carbamate type that does not induce upregulation of its target enzymes (Lane et 
al, 2006). 
In addition to the oral formulations (capsule and liquid oral concentrate), a transdermal patch 
formulation for rivastigmine has been developed to reduce adverse drug reactions such as 
nausea and vomiting, which had been observed with the oral formulation. Pharmacokinetic 
studies conducted with rivastigmine patch have shown that transdermal administration of 
rivastigmine prolongs tmax, lowers Cmax and reduces fluctuation in plasma concentration 
(Lefevre et al, 2008). 
The only approved AD treatment in Japan was donepezil hydrochloride (5 mg o.d. for mild to 
moderate AD, 10 mg o.d. for severe AD) until 2010. Rivastigmine patch (18 mg o.d. for mild 
to moderate AD) and galantamine (8 mg, 12 mg b.i.d. for mild to moderate AD) were approved 
in 2011 along with memantine (20 mg o.d for moderate to severe AD). Rivastigmine is the only 
patch formulation among these approved AD medications. Japanese pivotal PhIIb/III clinical 
study (CENA713D1301 study), a 24-week, double-blind, randomized, placebo control, in AD 
patients (MMSE 10-20) demonstrated that the rivastigmine patch 18 mg/day was statistically 
significant over placebo on the ADAS-J cog at week 24 (Nakamura. et al, 2011).
On the other hand, CENA713D1301 study showed that the most frequent adverse events (AEs) 
were related to skin/application site reactions. The AEs that lead to study discontinuation, 
application site pruritus, dermatitis contact, and application site erythema in rivastigmine patch 
groups were higher than in the placebo group. Nausea and vomiting resulting in study 
discontinuation were reported in < 1% in treatment groups.
In the current Japanese label, treatment with rivastigmine patch starts at 4.5 mg/day, and the 
dose should be further increased by 4.5 mg/day at 4-week intervals up to the maintenance dose 
of 18 mg/day (3-step titration scheme: 4.5 mg, 9 mg, 13.5 mg, 18 mg). As the rest of the world 
including Korea, Malyasia, and Hong Kong adopts 1 step titration scheme (9 mg, 18 mg), the 3 


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step titration scheme is particularly developed in Japan to ease gastrointestinal adverse events 
while maximizing the effective dosage exposure among AD patients. On the other hand, the 3 
step titration scheme requires a minimum of 12 weeks before reaching the effective dose, and 
a concern has been raised on a potential long-term use at doses below the effective dose. 
Therefore, these circumstances lead to conduct another clinical study (CENA713D1303/ONO 
code: 2540-04) to further evaluate the tolerability of the shorter titration (1-step titration) in a 
Japanese AD population.
Phase IIIb clinical study (CENA713D1303) 
A 24-week, multicenter, parallel-group, randomized, double-blind study to evaluate the 
tolerability, safety and efficacy of 2 different titration methods of rivastigmine patch 
(ENA713D/ONO-2540) in patients with mild to moderate Alzheimer’s disease (MMSE 10-20). 
The purpose of this study was to compare the tolerability, safety and efficacy of 3-step titration* 
(the current approved titration schedule in Japan) to those of 1-step titration** (the approved 
titration schedule in many countries worldwide including US and EU) in the mild to moderate 
AD Japanese patients. Data from this study was used to support a supplemental New Drug 
Application to allow the 1-step titration to be included into the label in Japan.
The study results showed the safety and tolerability of the 1-step titration scheme is comparable 
to the 3-step titration scheme in the Japanese mild to moderate AD population. The proportion 
of patients who discontinued the study drug treatment due to AEs were 15.0% (16/107) in the 
1-step titration group and 18.5% (20/108) in the 3-step titration group. The observed difference 
between treatments of the proportion of discontinuation due to AEs were -3.6% (95% CI: -17.0, 
9.6, Exact method). Since the point estimate of the observed difference falls within the pre-
specified acceptance range (i.e. [-9.0%, 9.0%]), the study met its primary objective. The study
showed similar efficacy between the 1-step titration and the 3-step titration group at week 24. 
At week 8, the 1-step titration group showed a slightly greater improvement compared to the 3-
step titration group in ADAS-J cog, potentially suggesting an earlier efficacy onset. Overall, 
the 1-step titration is comparably safe and efficacious to the currently approved the 3-step 
titration for Japanese patients with mild to moderate AD during the 24 week assessment period. 
* 3-step titration schedule: 4.5 mg/day for 4 weeks, 9 mg/day for 4 weeks, 13.5 mg/day for 4 
weeks, 18 mg/day (maintenance dose).
** 1-step titration schedule: 9 mg/day for 4 weeks, 18 mg/day (maintenance dose).
Based on the results of Study 1303, 1 step titration scheme is approved in additi on of 3 step 
titration scheme in Japan.
1.2
Purpose
The purpose of this study is to further evaluate the tolerability, safety and efficacy of 
rivastigmine patch with 1-step titration in applicable patients with mild to moderate AD 
switched directly from cholinesterase inhibitors (donepezil, galantamine). As rivastigmine 
patch with 1-step titration was approved in Aug 2015 in addition of 3-step titration, physicians
in Japan may be allowed considering 1-step titration method besides 3-step titration, depending 
on condition and tolerability of a patient, which allow AD patients to reach the maintenance
dose (18 mg/day) after 4 weeks of loading dose (9 mg/day). Although it can be expected to 


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improve AD treatment with both titration methods depending on conditions of patients, 
treatment benefits of rivastigmine patch with 1-step titration when AD patients switch from 
other ChEIs have not fully evaluated. One of many reasons for switching between ChE 
inhibitors is declining of cognitive function or worsening of demential symptoms despite of 
treatments. Therefore, this study aims at enrolling those AD patients as non-responders against 
the previous ChE inhibitors’ treatment by defining as lack and loss of efficacy* in terms of 
cognitive function and other dementia symptoms. It is beneficial for AD patients to evaluate if 
switching therapy from oral ChE inhibitors to rivastigmine patch with 1 step titration could be 
a suitable treatment option.
*: AD patients who have lack or loss of efficacy with previous ChEIs are defined as following 
criteria; 1) Patients who declined ≥ 2 points MMSE within the initial 3-month treatment with 
oral ChEIs, and continued to show insufficient treatment effect until at baseline (lack of 
efficacy), 2) During 6 months prior to screening visit, patients who declined ≥ 2 points MMSE 
with oral ChEI treatment and continued to show insufficient treatment effect until at baseline
(loss of efficacy), 3) Both in the above 1 and 2, patients who showed marked worsening of ADL, 
or BPSD judged by a physician.
Each Exelon® patch of 5 cm2 contains 9 mg of rivastigmine that delivers 4.6 mg/24 hours.
Each Exelon® patch of 10 cm2 contains 18 mg of rivastigmine that delivers 9.5 mg/24 hours.
2
Study objectives and endpoints
2.1
Primary objective(s)

To evaluate the efficacy of rivastigmine patch with 1-step titration on cognitive function 
measured as change from baseline to week 24 in the total score of MMSE in mild to 
moderate AD patients who failed to benefit from other ChEIs.
2.2
Secondary objective(s)

To evaluate the safety, tolerability of rivastigmine patch with 1-step titration for up to 24 
weeks.

To evaluate the efficacy of rivastigmine patch with 1-step titration measured as the MMSE 
score at week 8.

To evaluate the efficacy of rivastigmine patch with 1-step titration measured as the NPI-10 
score at week 8 and week 24.

To evaluate the efficacy of rivastigmine patch with 1-step titration measured as QOL-AD 
score at week 24.

To evaluate the efficacy of  rivastigmine patch with 1-step titration measured as the J-
CGIC score at week 4, week 8, week 16, and week 24 

To evaluate the efficacy of rivastigmine patch with 1-step titration measured as Modified 
Crichton Scale score week 4, week 8, week 16, and week 24.

To evaluate the formulation usability of rivastigmine patch for up to 24 weeks as 
measured by the formulation usability questionnaire answered by caregiver.


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2.4
Objectives and related endpoints
Table 2-1
Objectives and related endpoints- Objectives
OBJECTIVE
Endpoint Title, Description 
and Reporting Time Frame 
for analysis and Unit of 
Measure
Stat Analysis Section
Primary
To evaluate the efficacy of rivastigmine
patch with 1-step titration on cognitive 
function measured as change from 
baseline to week 24 in the total score of 
MMSE in mild to moderate AD patients 
who failed to benefit from other 
cholinesterase inhibitors (ChEIs)
Endpoint Title: Change from 
baseline to week 24 in the 
total score of MMSE
Time Frame : Up to week 24
Section 9.4
Secondary
To evaluate the safety, tolerability of 
rivastigmine patch with 1-step titration for 
up to 24 weeks.
Endpoint Title: Monitoring 
and recording of all adverse 
events (AEs) and serious 
adverse events (SAEs).
Time Frame: Up to week 24.
Section 9.5
To evaluate the efficacy of rivastigmine 
patch with 1-step titration measured as the 
MMSE score at week 8.
Endpoint Title: Change from 
baseline to Week 8 in MMSE 
total score.
Time Frame : Week 8
To evaluate the efficacy of rivastigmine 
patch with 1-step titration measured as the 
NPI-10 score at week 8 and week 24.
Endpoint Title: Change in 
NPI-10 score from baseline 
to week 8 and week 24
Time Frame : Week 8 and 
Week 24
To evaluate the efficacy of rivastigmine 
patch with 1-step titration measured as 
QOL-AD score at week 24.
Endpoint Title: Change in 
QOL-AD score from baseline 
to week 24
Time Frame : Week 24
Section 9.5
To evaluate the efficacy of rivastigmine
patch with 1-step titration measured as the 
J-CGIC score at week 4, week 8, week 16, 
and week 24.
Endpoint Title: Change in J-
CGIC score from baseline to 
week 4, 8, 16 and 24
Time Frame : Week 4, 8, 16, 
24


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OBJECTIVE
Endpoint Title, Description 
and Reporting Time Frame 
for analysis and Unit of 
Measure
Stat Analysis Section
To evaluate the efficacy of rivastigmine 
patch with 1-step titration measured as 
Modified Crichton Scale score week 4, 
week 8, week 16, and week 24.
Endpoint Title: Change in as 
Modified 
Crichton 
Scale 
score from baseline to week 
4, 8, 16 and 24
Time Frame : Week 4, 8, 16, 
24
To evaluate the formulation usability of 
rivastigmine patch for up to 24 weeks as 
measured by the formulation usability 
questionnaire answered by caregiver.
Endpoint Title: Formulation 
usability score up to week 24
Time Frame : Up to week 24
3
Investigational plan
3.1
Study design
This is a 24-week, multi-center, open-label, single-arm (1-step titration) study in patients with 
mild to moderate AD (MMSE 10-23) switched directly from cholinesterase inhibitors 
(donepezil, galantamine) for AD. 
The study will have three phases
1. Screening phase [2-4 weeks: week -4 (Day -28) to week -2 (Day -14 to Day -1)]. 
The Screening Visit (Visit 1) has to take place 2 – 4 weeks before the planned start of 
rivastigmine patch treatment. After signing the informed consent, all patients will undergo 
a preliminary evaluation (Screening Visit) to assess eligibility (Protocol section 4.1). 
Patients will continue their ChE inhibitors (donepezil or galantamine) during the Screening 
period, and patients are eligible to take their ChE inhibitors until the evening prior to start 
day of rivastigmine patch. For those patients who are eligible to enroll the study by the 
preliminary evaluation at Screening Visit, MMSE score during previous 6 months should 
be collected and recorded as much as possible. Their ChE inhibitors are discontinued on 
Baseline visit (Day 1). At the baseline visit (Visit 2), the patient will also undergo safety 
and efficacy assessments as per Table 6-1, and eligibility will be confirmed. Day 1 will be 
the day on which treatment with rivastigmine patch will be started. Patients will be starting 
on treatment with rivastigmine patch on the same day of the baseline visit (Day 1). When 
the patients already took their ChE inhibitors at the baseline visit (Visit 2, Day -1), the 


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patients will start on treatment with rivastigmine patch the next day (Day 1) after the 
baseline visit.
2. Titration phase [8 weeks: week 1 (Day 1) to week 8 (Day 56)].
On the same day or next day (Day 1) following baseline visit, patients will begin treatment 
with a rivastigmine patch 9.0 mg/day and will be up-titrated after 4 weeks to reach the 
maintenance dose of 18 mg/day. Should tolerability problems occur, the investigators can 
decide to interrupt the treatment temporarily or to reduce the dose (see Section 5.5.5). The 
highest well-tolerated dose for each individual patient should be established within the 
titration period. The investigators also can use their clinical judgement to switch those 
patients to slower 3-step titration scheme in order to reach the maintenance dose of 
18 mg/day or find the highest well-tolerated dose for each individual patient. Those patients 
will be allowed to stay in the study. During the titration period, visits will take place every 
4 weeks.
3. Maintenance phase [16 weeks: week 9 (Day 57) to week 24 (Day 168)].
The patients will be maintained on the maintenance dose of rivastigmine patch 18 mg/day 
(or highest well-tolerated dose) during the remaining period of the study and will undergo 
safety and efficacy assessments as per protocol. If 18 mg/day is not achieved at maintenance 
period, it will be increased up to 18 mg/day if possible. Patients not tolerating the 18 mg/day 
will stay on their highest tolerated dose in the study and will undergo safety and efficacy 
assessment as per protocol.
Figure 3-1
Study design
3.2
Rationale for study design
The patient population will be described in more detail in the Section 4 below.


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This study is a Phase IV study (post marketing study) to evaluate the efficacy, safety and 
tolerability of rivastigmine patch in patients with mild to moderate AD switching directly from 
oral ChE inhibitors (donepezil and galantamine) to  rivastigmine patch with 1 step titration. 
Since the purpose of this study is not to prove superiority/non-inferiority, double-blind, placebo 
or active-controlled study is not needed. 
The patients who are eligible to this study are those who are lack/loss of efficacy or having 
difficulties in administrating with previous oral ChE inhibitors. Active or placebo controlled 
study is not appropriate from an ethical point for patients. 
In previous reported switch study, direct switching from donepezil to rivastigmine patch, was 
safe and well-tolerated (Sadowsky 2010). Another switching study in Japan, a 24-week, open-
label, multicenter study to evaluate the efficacy, safety and tolerability of rivastigmine patch 
with 3-step titration in patients with mild to moderate Alzheimer’s disease demonstrated the 
safety and well-tolerability of direct switch to rivastigmine patch for AD patients who have 
difficulties being treated with ChE inhibitors (donepezil and galantamine). Therefore, no
washout period from the previous treatment is recommended for the study.
3.3
Rationale for dose/regimen, route of administration and duration 
of treatment
Rivastigmine patch is a marketed drug, therefore the dose, dose regimen and titration scheme 
are in accordance with product label.
An AD patient who is applicable to 1 step titration method (initial loading dose is a rivastigmine 
patch 9.0 mg/day and will be up-titrated after 4 weeks to reach the maintenance dose of 
18 mg/day) defined in Section 4.1 is subject to the enrollment of this study. In principle, 1 step 
titration method should be applied to all of patients as long as tolerated. 
The treatment period of 24-weeks is as per AD evaluation guideline EU (EMEA 2008), and 
Japanese guideline research (Homma 1998). FDA guidelines (Leber 1990) specify that at least 
3 months as treatment period is needed, and EU & Japanese guidelines mentioned that more 
than 6 months of treatment is required. Therefore, the treatment period for this study is also set 
for 24 weeks.
3.4
Rationale for choice of comparator
No comparator will be included based on the rationale of study design.
3.5
Purpose and timing of interim analyses/design adaptations
Not applicable.
3.6
Risks and benefits 
The risk to subjects in this trial will be minimized by compliance with the eligibility criteria 
and study procedures, close clinical monitoring.
Rivastigmine patch is approved in more than 90 countries around the world. Approximately 
17,144 patients received rivastigmine treatment in Novartis-sponsored investigational clinical 
trials. It is estimated from marketing experience (post-authorization exposure) that the 


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cumulative patient exposure of oral formulation is approximately 5,194,565 patient-years, and 
3,912,326 patient-years of treatment with the transdermal formulation. Tests done in this study 
at each visit are standard medical tests. The risks of taking blood may include fainting, pain 
and/or bruising at the site of needle puncture or finger sticks. The risk to subjects in this trial 
will be minimized by compliance with the inclusion/exclusion criteria and close clinical 
monitoring.
Japanese pivotal Phase IIb/III clinical study (CENA713D1301 study), a 24-week, double-blind, 
randomized, placebo control, in AD patients (MMSE 10-20) demonstrated that rivastigmine 
patch 18 mg/day was statistically significant over placebo on the ADAS-J cog at week 24 
(Nakamura. et al, 2011), and showed that most frequent observed AEs were application site 
erythema, application site pruritus, and contact dermatitis which developed regardless of 
starting dose and titration.
Overall, the incidence rate of skin reactions in the Japanese population was higher compared to 
the observed incidence rate in other global studies.
CENA713D1403 in Japan, a 24-week, open-label, multicenter study to evaluate the efficacy, 
safety and tolerability of rivastigmine patch with 3-step titration in patients with mild to 
moderate AD switched from ChE inhibitors (donepezil, galantamine) showed the safety and 
well-tolerability of direct switch to rivastigmine patch for those who had difficulties being 
treated with ChE inhibitors (donepezil and galantamine).
CENA713D1303 study results showed the safety and tolerability of the 1-step titration method 
is comparable to the slower 3-step titration method in the Japanese mild to moderate AD 
population. The tolerability of the 1-step titration method was evaluated by comparing the 
proportion of patients with AEs leading to discontinuation with the 3-step titration method. The 
proportion of patients who discontinued the study drug treatment due to AEs was 15.0% (16/107) 
in the 1-step titration group and 18.5% (20/108) in the 3-step titration group. The observed 
difference between treatments of the proportion of discontinuation due to AEs were -3.6% (95% 
CI: -17.0, 9.6, Exact method). Since the point estimate of the observed difference falls within 
the pre-specified acceptance range (i.e. [-9.0%, 9.0%]), the study met its primary objective. The 
study showed similar efficacy in ADAS-J cog and MMSE score between the 1-step titration 
and the 3-step titration group at week 24. At week 8, the 1-step titration group showed a slightly 
greater improvement compared to the 3-step titration group in ADAS-J cog, potentially 
suggesting an earlier efficacy onset with the quicker titration. 
In conclusion, it is clinically meaningful to assess a benefit of quicker titration method to reach 
the maintenance dose of 18 mg/day and to explore if switching therapy from oral ChE inhibitors 
to rivastigmine patch with 1 step titration could be a suitable treatment option.
4
Population
The study population will consist of a representative group of male and female Japanese patients 
(50-85 years of age) with probable AD Mini – Mental State Examination (MMSE 10-23), 
treated with donepezil or galantamine. 


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This is the multicenter study that will enroll a total of approximately 120 patients which will be 
switched to rivastigmine patch with 1-step titration in Japan. Since a 30% screening failure rate 
is expected, 170 patients have to be screened.
4.1
Inclusion criteria
Patients/subjects eligible for inclusion in this study must fulfill all of the following criteria:
1. Written informed consent of the patient and legal representative will be obtained before 
any assessment is performed (MUST be signed by the legal representative if a signed 
informed consent from patients is difficult, consent can only be obtained from the patients 
orally) at Screening.
2. Patients within the age of 50-85 years at Baseline.
3. Outpatient status at Baseline.
4. Males and females not of child-bearing potential.

Women are considered post-menopausal and not of child bearing potential if they 
have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical 
bilateral oophorectomy (with/without hysterectomy) or tubal ligation at least six 
weeks previously.
5. A diagnosis of dementia of the Alzheimer’s type according to the DSM-IV criteria.
6. A clinical diagnosis of probable AD according to National Institute of Neurological and 
Communicative Disorders and Stroke - Alzheimer's Disease and Related Disorders 
Association (NINCDS-ADRDA) criteria and meeting any of following criteria.

Brain scan (magnetic resonance imaging [MRI], or computed tomography [CT]) were 
met diagnosis criteria conducted within 3 years prior to baseline (Imaging within 1 
year prior to baseline is preferable).

Positron emission tomography (PET) or single photon emission computed 
tomography (SPECT) was met diagnosis criteria conducted within 3 years prior to 
baseline visit; as long as in the past a brain scan (MRI or CT) was also met (Imaging 
within 1 year prior to baseline is preferable).
7. An MMSE score of ≥ 10 and ≤ 23 at screening and baseline.
8. Patients are currently on the oral monotherapy (donepezil, 5 mg), or galantamine (16-
24 mg) for 4 weeks prior to baseline visit.
9. Patients who could not receive treatment benefits of previous oral ChEIs can be defined 
by meeting the following criteria, either 9-1, 9-2, or both.
-
9-1. Patients who are not responding to the previous treatment can be defined if the 
patients meet at least one of these conditions at screening and baseline

Patients who declined ≥ 2 points of MMSE despite of treatment of other oral ChE 
inhibitors within initial 3-month and continued to show insufficient treatment effect 
until at baseline.

During 6 months prior to screening visit, patients who declined ≥2 points of MMSE  
with other oral ChE inhibitors and continued to show insufficient treatment effect 
until at baseline.


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
Patients who show marked worsening of BPSD, or ADL (can be defined by 1 state 
progression of FAST) judged by a physician despite of treatment of other oral ChE 
inhibitors in initial 3-month or last 6-month with other oral ChE inhibitors
-
9-2. Patients having difficulties being treated orally with ChEIs (donepezil or 
galantamine) by physician's judgement. Difficulties are defined if the patients meet at 
least one of these conditions at screening and baseline:
Inadequate compliance with the ChE inhibitors at screening and baseline

Inadequate treatment (efficacious dose was not reached or inadequate compliance) 
with the ChE inhibitors because of AEs except gastrointestinal (GI) symptoms 
(nausea and vomiting) at screening and baseline

Patients with swallowing difficulties at screening and baseline
10. Sufficient education to be able to read, write, and communicate effectively during the 
premorbid state
11. Cooperative, willing to complete all aspects of the study, and capable of doing so, either 
alone or with the aid of a responsible caregiver
12. Residing with someone in the community throughout the study or, if living alone, in 
contact with the primary caregiver every day
13. A primary caregiver willing to accept responsibility for supervising the treatment, (e.g., 
application and removal of the patch daily at approximately the same time of the day) 
assessing the condition of the patient throughout the study, and for providing input to 
efficacy assessments in accordance with all protocol requirements. The caregiver was 
required to be able to directly assess the condition of the patient during the day and night 4 
or more days a week.
4.2
Exclusion criteria
Patients fulfilling any of the following criteria are not eligible for inclusion in this study. No 
additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.
1. Any medical or neurological condition other than AD that could explain the patient’s 
dementia (e.g., abnormal thyroid function tests, vitamin B12 or folate deficiency, 
posttraumatic conditions, syphilis, head injury, Huntington’s disease, Parkinson’s disease, 
subdural hematoma, normal pressure hydrocephalus, brain tumor) at baseline;
2. A current diagnosis of probable or possible vascular dementia according to the National 
Institute of Neurological Disorders and Stroke and the Association Internationale pour la 
Recherche et l’Enseignement en Neurosciences criteria (NINDS-AIREN) at baseline;
3. A current DSM-IV diagnosis of major depression, unless successfully treated with a stable 
dose of an antidepressant without anticholinergic properties for at least 4 weeks at 
baseline;
4. Any other DSM-IV Axis 1 diagnosis that may interfere with the evaluation of the patient’s 
response to study medication, including other primary neurodegenerative dementia, 
schizophrenia, or bipolar disorder at baseline;
5. A current diagnosis of active, seizure disorder at baseline;


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6. A history or current diagnosis of severe cerebrovascular disease (e.g., stroke, transient 
ischemic attacks, aneurysms) at baseline;
7. A current diagnosis of severe or unstable cardiovascular disease (e.g., cardiac failure 
congestive, angina unstable), hypertension, diabetes at baseline;
8. A current diagnosis of bradycardia (< 50 bpm), sick-sinus syndrome, or conduction 
defects (sino-atrial block, second or third degree atrio-ventricular block) at baseline;
9. A current diagnosis of acute, severe, or unstable asthmatoid conditions (e.g., severe 
chronic obstructive pulmonary disease (COPD) at baseline;
10. A current diagnosis of active, uncontrolled peptic ulceration or gastro-intestinal bleeding 
within the last 3 months from baseline;
11. Clinically significant urinary obstruction at baseline;
12. Patients with extrapyramidal disorders (e.g., Parkinson’s disease, Parkinson’s syndrome). 
13. Patients with complication of gastrointestinal adverse events such as nausea and vomiting 
during oral ChE inhibitors treatment except for such gastrointestinal adverse events if it is 
apparent to be caused by other than oral ChE inhibitors;
14. Patients with low body weight as judged by the investigators
15. Current diagnosis of an active skin lesion/disorder that would influence to the adhesion 
and potential skin irritation of the patch (e.g., atopic dermatitis, wounded or scratched skin 
in the area of the patch application) at baseline;
16. A disability that may prevent the patient from completing all study requirements (e.g., 
blindness, deafness, severe language difficulty) at baseline ;
17. Patients with a history of hypersensitivity to any ingredients of rivastigmine or carbamate 
derivatives;
18. Patients who have taken rivastigmine any time in the past;
19. Significantly change of content and frequency of rehabilitation, day care, day service 
during the 4 weeks prior to efficacy assessment at baseline;
20. Taken any investigational drug (including investigational biologics) in the 90 days prior to 
baseline or within 5 half-lives of the compound, whichever is longer;
21. Taken any of the following treatments (Potential topical or ophthalmic formulations of the 
following compounds will be allowed)

donepezil > 5 mg/day 4 weeks prior to baseline (Visit 2);

Any ChEIs (except for donepezil, galantamine), selegiline, centrally acting 
anticholinergic drugs, olanzapine or tricyclic and tetracyclic antidepressants during 
the 4 weeks prior to efficacy assessment at baseline;

Change of dosage and regimen of donepezil, galantamine, memantine (patients who 
have been on a stable dose of memantine during 4 weeks or more prior to efficacy 
assessment at baseline are allowed to enter the study and may continue to take 
memantine during the entire study without changing the dosage), psychotropic 
medication, antidepressants (except for tricyclic and tetracyclic antidepressants), 
anxiolytics (including benzodiazepine-type hypnotics), antiepileptics, drugs for 
Parkinson’s disease, hypnotics (except for short-acting hypnotics such as zolpidem 
tartrate and zopiclone etc), agents which improve cerebral circulation/metabolism, 
vitamin E and estrogens and peripheral anticholinergic agents (except for oxybutynin 


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hydrochloride and propiverine hydrochloride, tolterodine tatrate, solifenacin and 
imidafenacin etc), Yokukan-san, Yokukansankachimpihange during the 4 weeks prior 
to efficacy assessment at baseline;

Succinylcholine-type muscle relaxants, lithium during the 2 weeks prior to efficacy 
assessment at baseline;

Newly used benzodiazepine-type hypnotics of short duration, newly used or 
irregularly used zolpidem tartrate and zopiclone within 24 hours prior to efficacy 
assessment at baseline;
22. Result(s) of laboratory tests at the screening visit: 

total bilirubin 3.0 mg/dL or above;

AST (GOT) and/or ALT (GPT) 3 ×ULN or above;

serum creatinine 2.0 mg/dL or above;
23. History of malignancy of any organ system, treated or untreated, within the past 5 years 
whether or not there is evidence of local recurrence or metastases, with the exception of 
localized basal cell carcinoma of the skin;
24. Patients who, in the opinion of the investigator, will be otherwise unsuitable for inclusion 
in this clinical study (e.g., an advanced, severe, progressive, or unstable disease of any 
type that may interfere with efficacy and safety assessments or put the patient at special 
risk);
5
Treatment
5.1
Study treatment
5.1.1
Investigational and control drugs
Rivastigmine transdermal patch will be supplied as marketed drugs (9 mg, 18 mg patch). Two 
different rivastigmine strengths 9 mg (5 cm2) and 18 mg (10 cm2) patch will be used in this 
study. 
No control treatment is planned in this study.
Table 5-1
Dosage form and drug content for 1 step titration
Form
Loading dose / Content per 
one patch
Size
Exelon® patch 9 mg
9 mg rivastigmine
5 cm2
Exelon® patch 18 mg
18 mg rivastigmine
10 cm2
If patients cannot tolerate 1-step titration method to reach the maintenance patch dose of 
18 mg/day, the investigators can use their clinical judgement to switch those patients to slower 
3-step titration method in order to reach the maintenance dose of 18 mg/day or find the highest 
well-tolerated dose for each individual patient. Once the dose started at 4.5 mg of rivastigmine 
once a day, as a general rule, the dose should be increased to 4.5 mg a day at 4-week intervals 
to 18 mg once a day. Those patients will be allowed to stay in the study. Patients with doses 
below the planned dose will continue to participate in the study.


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Table 5-2
Dosage form and drug content for 3 step titration
5.1.2
Additional treatment
Not Applicable.
5.2
Treatment arms
This is an open-label, single arm study; all of the patients will be assigned to 1-step titration 
treatment.
5.3
Treatment assignment and randomization 
Not Applicable.
5.4
Treatment blinding
Treatment will not be blinded during the course of the study, as the study is open-label.
5.5
Treating the patient
Sponsor qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
5.5.1
Patient numbering
Each patient is uniquely identified in the study using 9-digit number which is combination of 
his/her 4-digit site number and a sequential 5-digit patient number. The site number is assigned 
by Novartis to the investigative site. Upon signing the ICF, the patient number is assigned a 
patient number by the investigator. At each site, the first patient is assigned the patient number 
1, and subsequent patients are assigned consecutive numbers (e.g. second patient is assigned 
patient number 2, and third patient is assigned patient number 3). Once assigned to a patient, 
the Subject Number will not be reused. Upon signing the informed consent form, the patient is 
assigned the next sequential number as given by the investigator using the next blank eCRF 
available from the electronic data capture (EDC) system. If the patient fails to be registered for 
any reason, the reason for not being registered will be entered on the Screening Log, and the 
Demography CRF/eCRF should also be completed.
5.5.2
Dispensing the study drug
Each patient will purchase the drugs from the local pharmacy.
Form
Loading dose / Content per 
one patch
Size
Exelon® patch 4.5 mg
4.5 mg rivastigmine
2.5 cm2
Exelon® patch 9 mg
9 mg rivastigmine
5 cm2
Exelon® patch 13.5 mg
13.5 mg rivastigmine
7.5 cm2
Exelon® patch 18 mg
18 mg rivastigmine
10 cm2


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5.5.3
Handling of study and additional treatment
5.5.3.1
Handling of study treatment
Upon receipt, all drugs should be stored according to the instructions specified on the drug 
labels.  Patients will be asked to bring all unused drug and packaging at the end of the study or 
at the time of drug discontinuation for evaluating the drug compliance.
Treatment compliance will be investigated by Physician in one of the following categories:

<25% Poor

25≦～＜50% Average

50≦～＜75% Good

75≦～≦100% Very good

> 100% Reason to be specified (overdose or misuse)
In case of over compliance (> 100% reason to be specified, e.g. patients who ran out of their 
drug due to overdose or misuse), the investigators record the reason (overdose or misuse) 
separately on eCRF.
5.5.4
Instructions for prescribing and taking study treatment
In general, one rivastigmine transdermal patch should be applied once daily by the caregiver on 
the back of the patient (alternatively, the patch can be applied to the upper arm or chest). The 
skin should be clean, and dry with no cuts, rashes, or other skin problems. The rivastigmine 
patch will be replaced every 24 hours and should be applied at approximately the same time. 
Additionally, the application site should be changed each time a new patch is applied to avoid 
skin irritation. When skin reactions appear, appropriate treatment including the use of topical 
steroids or topical antihistamines may be initiated. Also, other appropriate treatments including 
dose reductions, temporarily interruption or discontinuation of the treatment should be 
considered.
Screening Period (Week -4 / -2 to –Day -1)
During the screening period, patients will continue to receive donepezil or galantamine. At the 
baseline visit, patients discontinue previous treatment with donepezil or galantamine.
Titration Period (Week 1 to 8)
The day or following day (in case of a patient who takes his/her previous oral ChE inhibitors at 
the baseline visit) of the baseline visit (Day 1), all patients will start study treatment with one 
rivastigmine patch of 9 mg once a day. During the titration period, as a general rule, the dose 
should be increased to 18 mg once a day at 4 weeks later:
Week 1 – 4:
Rivastigmine patch 9 mg/day
Week 5 – 8: 
Rivastigmine patch 18 mg/day
Should tolerability problems occur during the titration period, the dose can be adjusted in a 
range not exceeding 18 mg a day as appropriate depending on the clinical symptoms until the 
dose reaches the maintenance dose. In the event of gastrointestinal disorders (e.g., nausea, 
vomiting) or other tolerability problems, the dose should be reduced or treatment should be 


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temporarily interrupted until these adverse effects resolve. Patch treatment can be resumed at 
the same dose or previous well tolerated dose if interruption of treatment is around or within 4 
days. Otherwise, treatment should be resumed at the initial starting dose (e.g. 4.5 mg or 9 mg). 
After treatment resumption, the dose at resumption should be maintained for a minimum of 2 
weeks. If the dose is shown to be well-tolerated, the dose can be increased to the pre-resumption 
dose at intervals of 2 weeks or more.
Rivastigmine patch dose adjustments required for tolerability problems will be according to the 
dose adjustment scheme defines in Section 5.5.5.
Maintenance Period (Week 9 to 24)
The patients will be maintained on the maintenance dose of 18 mg/day rivastigmine patch at 
the time of Visit 4 (start of the maintenance period) and will undergo safety and efficacy 
assessments as per protocol. Patients not tolerating the 18 mg/day will stay on their highest 
tolerated dose in the study and will undergo safety and efficacy assessment as per protocol.
Decreasing the dose required for tolerability problems will be allowed at any time during the 
Maintenance Period and conducted according to the dose adjustment scheme defined in Section 
5.5.5.
After reducing the dose, investigators can try to increase up to dose of 18 mg/day according to 
the dose adjustment scheme defined in Section 5.5.5.
All dosages prescribed to the patients and all dose changes during the study must be recorded 
to the Dosage Administration Record CRF (eCRF).
The investigator should promote compliance by instructing the patients and the caregivers to 
take the drug exactly as prescribed and by stating that compliance is necessary for the patient’s 
safety and the validity of the study. The patient should be instructed to contact their investigators 
if he or she is unable for any reason to take the drug as prescribed.
5.5.5
Permitted dose adjustments and interruptions of study treatment 
The dose can be adjusted in a range up to, but not exceeding 18 mg/day as appropriate 
depending on the clinical conditions until the dose reaches the maintenance dose. 
In the event of gastrointestinal disorders (e.g. nausea, vomiting) and other tolerability problems, 
the dose should be reduced or treatment should be temporarily interrupted until these adverse 
effects resolve. The following treatment adjustments should be applied, and the actions to be 
taken in the event of consecutive days of interruption are described in detail in Table 5-3.
Table 5-3
Actions following dose interruption
Consecutive days missed
Actions when patients with 9 mg/day patch
≤ 4 days
Can be resumed at the same dose (9 mg/day), and the dose at 
resumption should be maintained for a minimum of 2 week after 
treatment resumption. If the dose is shown to be well-tolerated, the dose 
can be increased to 18 mg/day.
≥ 5 days - ≤ 28 days
Treatment should be resumed at the initial starting dose (9 mg/day), and 
follow for 1 step titration method to reach the maintenance dose of 
18 mg/day.


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Consecutive days missed
Actions when patients with 9 mg/day patch
Patients who still have tolerability issues with 9 mg/day, consider to 
resume the treatment at the initial starting dose (4.5 mg/day)
When resumed at the initial dose of 4.5 mg/day, follow for 3 step titration 
method.
After treatment resumption, the dose at resumption should be 
maintained for a minimum of 2 weeks. If the dose is shown to be well-
tolerated, the dose can be increased to the pre-resumption dose at 
intervals of 2 weeks or more.
>28 days 
Must discontinue study drug administration.
Consecutive days missed
Actions when patients with 18 mg/day patch
≤ 4 days
Can be resumed at the same dose, 18 mg/day 
≥ 5 days - ≤ 28 days
Treatment should be resumed at the initial starting dose (9 mg/day) and 
follow for 1 step titration method to reach the maintenance dose of 
18 mg/day.
In case of patients showing some tolerability issue with 9 mg/day at this 
time, repeat same procedure with 9 mg/day described above
When resumed at the initial dose of 4.5 mg/day, follow for 3 step titration 
method.
After treatment resumption, the dose at resumption should be 
maintained for a minimum of 2 weeks. If the dose is shown to be well-
tolerated, the dose can be increased to the pre-resumption dose at 
intervals of 2 weeks or more.
>28 days
Must discontinue study drug administration.
These changes must be recorded on the Dosage Administration Record CRF (eCRF).
5.5.6
Rescue medication
Not applicable.
5.5.7
Concomitant medication
The investigator should instruct the patient to notify the study site about any new medications 
he/she takes after the patient was enrolled into the study. All medications, procedures and 
significant non-drug therapies (including physical therapy and blood transfusions) administered 
after the patient was enrolled into the study must be recorded.
5.5.8
Prohibited medication
The following medications are prohibited or restricted during specified periods (topical and 
ophthalmic formulations of the mentioned drugs below are allowed):
Prohibited concomitant medications 
Use of the following treatments is NOT allowed after the start of study drug (Day 1):
1. Any investigational drug (including topical and ophthalmic investigational drugs).


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2. Donepezil, galantamine.
3. Selegiline.
4. Centrally acting anticholinergic drugs.
5. Olanzapine.
6. Tricyclic and tetracyclic antidepressants.
7. Succinylcholine-type muscle relaxants.
8. Lithium.
Restricted concomitant medications / non-drug therapies
The following medications / non-drug therapies are permitted, but with some limitations:
1. Initiation of the following concomitant medications should be avoided during the 4 weeks 
prior to efficacy assessment at baseline to Visit 8/discontinuation. Patients who have been 
on a stable dose of these drugs during the 4 weeks or more prior to efficacy assessment at 
baseline should continue on the dose without changing the dosage and administration:
- Memantine
- Yokukan-san
- Yokukansankachimpihange
- Agents which improve cerebral circulation/metabolism
- Vitamin E- Estrogens 
2. Initiation of the following concomitant medications should be avoided during the 2 weeks 
prior to efficacy assessment at Visit 8 if possible. Patients who have been on a stable dose 
of these drugs during the 4 weeks or more prior to efficacy assessment at baseline should 
continue on the dose without changing the dosage and administration: 
- Psychotropic medication
- Antidepressants (tricyclic and tetracyclic antidepressants are prohibited)
- Anxiolytics (except benzodiazepine-type hypnotics)
- Antiepileptics
- Drugs for Parkinson’s disease
- Hypnotics:
3. A new treatment should be limited to the following medications, but the treatment should 
be at the lowest effective dose and shortest duration possible. Accumulated duration must 
be 14 days or less during each visit.
- Psychotropic medication: tiapride hydrochloride
- Antidepressants : trazodone hydrochloride
- Nonbenzodiazepine hypnotic of short duration : zolpidem tartrate zopiclone and 
eszopiclone . Additionally new initiation of treatment and irregular treatment such as 
on-demand use are prohibited during the 24 hours prior to efficacy assessment at 
Visit 2, 4, and 8.
4. The following drugs are allowed to use, but not recommended to use.
- Benzodiazepine anxiolytic (Newly initiation of treatment is prohibited during the 
previous 24 hours prior to efficacy assessment at Visit 2, 4, and 8): rilmazafone 
hydrochloride, brotizolam , lormetazepam, triazolam.


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5. The following new medication for atypical psychotropic must not be started after starting 
the study drug (Day1)
- Risperidone, quetiapine fumarate, perospirone hydrochloride
6. Peripheral anticholinergic agents:
Patients who have been on a stable dose of these drugs during the 4 weeks or more prior to 
efficacy assessment at baseline should continue on the dose without changing the dosage 
and administration. When new-onset urinary urgency or urinary incontinence during the 
study constitutes an intolerable symptom that cannot be overcome by non-
pharmacological measures, initiation of treatment with peripheral anticholinergics such as 
oxybutynin hydrochloride, propiverine hydrochloride, tolterodine tatrate solifenacin and 
imidafenacin are permitted.
7. Antitussive agents, cold medicine or antihistamic antiallergy agents: 
As a rule, these agents are prohibited 1 week prior to efficacy assessment at baseline and 
Visit 8. 
8. Rehabilitation, day care and day service: 
Any rehabilitation day care and day service during 4 weeks or more prior to efficacy 
assessment at baseline must not be changed significantly with content and frequency (new 
start / discontinuation).
9. Short stay (hospital / nursing home):
Short stay should be limited during the previous 2 weeks prior to efficacy assessment at 
baseline and Visit 8. 
5.5.9
Emergency breaking of assigned treatment code
Emergency breaking is not applicable as this is an open-label study.
5.6
Study Completion and Discontinuation 
5.6.1
Study completion and post-study treatment
At a minimum, caregivers of the patients who complete this study or discontinue the drug, 
including those who refuse to return for a final visit, will confirm the onset (or no onset) of a 
SAE during at least 30 days following the last dose of study drug or at the patient’s last visit, 
and the result should be recorded in the source document & in eCRF.
5.6.2
Discontinuation of Study Treatment 
The drug must be discontinued for a given patient if the investigator determines that continuing 
it would result in a significant safety risk for that patient. The following circumstances require 
drug discontinuation:
1. Where an adverse event has occurred that, in the judgment of the investigator, warrants 
discontinuation of treatment; 
2. Where an abnormal laboratory value has been found that, in the judgment of the 
investigator, warrants discontinuation of treatment; 
3. Where aggravation of the condition has occurred that, in the judgment of the investigator, 
warrants discontinuation of treatment; 


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4. Where necessary observation and examination after the initiation of treatment has become 
impossible for the patient’s or his/her caregiver’s personal reasons; 
5. Where any important deviation from the protocol has become clear;
In addition to these requirements for drug discontinuation, the investigator should discontinue 
the drug for a given patient if, on balance, he/she thinks that continuation would be detrimental 
to the patient’s well-being.
The investigator should record the last known date a patient takes the drug and select primary 
reason for premature discontinuation from the following reasons on the study completion page 
in eCRF.
1. Adverse Event(s)
2. Abnormal lab value(s)
3. Abnormal test procedure result(s)
4. Unsatisfactory therapeutic effect
5. Subject’s condition no longer requires study
6. Protocol deviation
7. Subject withdrew consent
8. Lost to follow-up
9. Administrative problem
10. Death
Patients who discontinue the drug should NOT be considered withdrawn from the study. See 
Section 6 for the required assessments of these patients after discontinuation of the treatment.
5.6.3
Withdrawal of informed consent
Patients/subjects may voluntarily withdraw consent to participate in the study for any reason at 
any time. Withdrawal of consent from the study is defined as when a patient:

Does not want to participate in the study anymore
and

Does not want any further visits or assessments
and

Does not want any further study related contacts
and

Does not allow analysis of already obtained biologic material
In this situation, the investigator must make every effort (e.g. telephone, e-mail, letter) to 
determine the primary reason for the patient’s decision to withdraw his/her consent and record 
this information on medical chart. 
The drug must be discontinued and no further assessments conducted, and the data that would 
have been collected at subsequent visits will be considered missing. 
Further attempts to contact the patient are not allowed unless safety findings require 
communicating or follow-up.


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All efforts should be made to complete the assessments prior to study withdrawal.
Patients who are prematurely withdrawn from the study will not be replaced by an equal number 
of newly enrolled patients.
5.6.4
Loss to follow-up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw, the investigator should show "due diligence" by contacting the patient, 
family or family physician as agreed in the informed consent and by documenting in the source 
documents steps taken to contact the patient, e.g. dates of telephone calls, registered letters, etc.
A patient cannot be considered as lost to follow-up until the time point of his/her scheduled end 
of study visit has passed.
5.6.5
Early study termination by the sponsor
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit risk assessment of participating in the study, practical reasons, or for 
regulatory or medical reasons (including slow enrolment). Should this be necessary, the patient 
must be seen as soon as possible and treated as a prematurely withdrawn patient. The 
investigator may be informed of additional procedures to be followed in order to ensure that 
adequate consideration is given to the protection of the patient’s interests. The investigator will 
be responsible for informing the Institutional Review Board/Independent Ethics Committee 
(IRBs/IECs) of the early termination of the trial.
6
Visit schedule and assessments
Table 6-1 lists all of the assessments and indicates with an “x” when the visits are performed.
Patients must be seen for all visits on the designated day, or as close to it as possible as allowed 
“visit window” of “x” days. Missed or rescheduled visits should not lead to automatic 
discontinuation. Patients who prematurely discontinue the study for any reason should be 
scheduled for a visit as soon as possible, at which time all of the assessments listed for the final 
visit will be performed. At this final visit, all drugs should be reconciled for compliance purpose 
and the adverse event and concomitant medications reconciled on the eCRF.
Patients/subjects will be contacted for safety evaluations during the 30 days following the last 
administration of study treatment.


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Table 6-1
Assessment schedule
Period
Screening f)
Titration
Maintenance
Visit number
1 (Screening)
2 
(BL)g)
3
4
5
6
7
8/disc
ontinu
ation
h)
Visit Day
-28 ~ -14
1
28
56
84
112
140
168
Visit week
-4 ~ -2
1
4
8
12
16
20
24
Visit Window
-56 ~ -14
-7
~
1
21
~
35
49
~
63
77
~
91
105
~
119
126
~
154
161
~
182
Inclusion/Exclusion criteria
X
X
Obtain Informed consent
X
Patient demographics/other 
baseline characteristics
X
X
Problem of previous ChE inhibitors 
treatment a)
X
X
Medical history
X
Previous treatment/concomitant 
medication/therapy
X
X
X
X
X
X
X
X
Brain scan if required b)
X
MMSE
X
X
X
Xe)
NPI-10
X
X
Xe)
QOL-AD
X
Xe)
J-CGIC
X
X
X
Xe)
Modified Crichton Scale
X
X
X
X
Xe)
Adverse events
X
X
X
X
X
X
X
Vital sign
X
X
X
X
X
X
X
X
Laboratory evaluation 
Regular hematology, blood 
chemistry, cholinesterase, urine
test
X
X
Additional Screening blood test for 
differential diagnosis if necessary
X
ECG
X
X
Formulation usability questionnaire
c) 
X
Treatment compliance d)
X
X
X
X
X
X
(a) Based on the short interview to caregiver by the physician, however, inclusion and exclusion will be 
judged by physician. This is confirmatory information from caregiver for screening the patients.
(b) Imaging test can be performed at screening visit if latest imagings of a patient are more than 3 
years old from baseline.
(c) Based on answer of questionnaire from the caregiver
(d) Based on the interview and assessment by investigators 
(e) These assessments are not mandatory at discontinuation due to adverse events
(f) During the screening period, patients will continue receiving their previous medication (donepezil or 
galantamine)
(g) At the baseline visit, patients discontinue their previous ChE inhibitors (donepezil, galantamine) 
and could start the initial dose of 9 mg/day rivastigmine patch after cleared all necessary assessment 
for enrollment. If patients already take their previous ChE inhibitors on the day of baseline visit, the 
patients should start the initial dose of 9 mg/day rivastigmine patch on the following day (Day 1).


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(h) If a patient discontinues the study, scheduled assessment should be performed as soon as 
possible, but visit window is not set.
6.1
Information to be collected on screening failures
For patients who provided written informed consent but did not complete the baseline visit 
(withdrawn during the screening period), the investigator will record the withdrawal until 
baseline visit on the Screening Log, and will record the patient identifier, age, gender and the 
reason for not being registered on the eCRF.
6.2
Patient demographics/other baseline characteristics 
The following items should be investigated at the day of obtaining informed consent to baseline 
visit or before. Then, the other necessary items such as prior medication, MMSE, vital signs, 
ECG, and laboratory tests should be investigated or conducted for confirming eligibility.
Patient demographics
Investigate the following items, and record the results in the clinical record and the eCRF. About 
medical history, only diseases which are related to the Inclusion/Exclusion Criteria or which 
are judged significant by investigator will be investigated and recorded. Record the problems 
associated with prior use of oral anti-AD medications
Investigation items
Sex, date of birth, family history, relation of caregiver, date of diagnosis, date of disease onset, 
years of education, living situation, height, weight, current medical condition, medical history, 
problems with administration of oral anti-AD medications, 
 
. 
Additionally, diagnosis of dementia of Alzheimer’s type (DSM-IV, NINCDS-ADRDA, 
NINDS-AIREN) and MHIS should be investigated and recorded in the source document.
Brain scan
A brain scan (MRI or CT) is required at screening but only if one has not been performed in the 
last three years prior to baseline although the brain scan within one year prior to baseline is 
preferable. Taking into account the patient burden, these previous brain scan data can be used 
to confirm diagnosis if the signed informed consent of the patient and legal representative allow 
the use of this data. Alternatively, if at screening a PET or SPECT is available, which had been 
performed in the last three years, any MRI or CT conducted in the past will be sufficient.
These scans are performed to establish that entry criteria are met. As outlined above, with the 
consent of the patient, scans performed before the study will be allowed to reduce the patient 
burden.
Screening Test (Laboratory test) if necessary
The special laboratory tests are to be performed to exclude non-Alzheimer type dementias 
during the screening period.
Investigation items


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Folic acid, vitamin B12, triiodothyronine (T3), total thyroxine (T4), and thyroid stimulating 
hormone (TSH)
Methods of collection, processing and storage of blood samples
Approximately 9-mL sample of venous blood will be collected in an AutoSep vacutainer for 
each patient. After blood sampling, each investigator should follow the blood test procedure of 
each study site where he/she belongs to. 
6.3
Treatment exposure and compliance 
Previous treatment
At screening and baseline visit, all treatments which had been received within 4 weeks before 
and during the screening period, will be reviewed and record name of drug and therapy, dosage 
and administration, period/duration and reasons for use in the eCRF.
Concomitant medication/therapy
Record the drug names, dosage and administration, period/duration and reasons for use in the 
eCRF for all treatment used concomitantly during treatment period.
6.4
Efficacy
To ensure the sensitivity and reliability of the efficacy assessments, the same rater for a given 
instrument will, whenever possible, assess the status of a given patient in every evaluation. All 
efficacy assessments will be conducted as specified in Table 6-1. The result of these 
assessments will be recorded in the eCRF. All efficacy assessments at discontinuation will not 
be conducted if patients discontinue because of an adverse event.
6.4.1
Mini-Mental state examination (MMSE)
MMSE will be conducted at Visit 1, 2, 4 and 8 (refer Table 6-1). MMSE at premature 
discontinuation will not be conducted if patient discontinues because of adverse event.
Assessment Items
The MMSE is a brief, practical screening test for cognitive dysfunction. The MMSE consists 
of 2 parts: language (time orientation, registration and attention) and performance (recall, 
response to written/verbal commands, writing ability and reproduction of complex polygons), 
and the total possible score is 30. Lower score indicates more severe impairment (Folstein MR 
et al, 1975).
Method of assessment
Throughout the study, the same rater (an attending physician of a given patient, a psychologist, 
or a medical staff who has been trained in psychologist equivalent and carried out MMSE 
scoring more than 50 times) will assess the status of a given patient whenever possible.


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6.4.2
Neuropsychiatric Inventory-10 (NPI-10): 
NPI-10 will be conducted at Visit 2, 4 and 8 (refer Table 6-1). NPI-10 at premature 
discontinuation will not be conducted if patient discontinues because of adverse event.
Assessment Items
The NPI-10 is a scale for neuropsychiatric symptoms. The NPI assesses a wide range of 
behaviors encountered in dementia patients to provide a means of distinguishing frequency and 
severity of behavioral changes, and facilitates rapid behavioral assessment through the use of 
screening questions (Cummings et al. 1994). Ten behavioral domains are evaluated through an 
interview of the caregiver. The scale includes both frequency and severity ratings of each 
domain as well as a composite domain score (frequency x severity). The sum of the composite 
scores for the 10 domains yields the NPI-10 total score. A higher score indicates more severe 
impairment.
Method of assessment
Throughout the study, the same rater (e.g. an attending physician of a given patient, a 
psychologist, or a medical staff who has been trained in psychologist equivalent) will assess the 
status of a given patient whenever possible.
6.4.3
J-CGIC (Japanese version of the Clinical global impression of change)
J-CGIC will be conducted at Visit 2, 3, 4, 6 and 8 (refer Table 6-1). J-CGIC at premature 
discontinuation will not be conducted if patient discontinues because of adverse event.
Assessment Items
The J-CGIC is simple 7 grade investigator’s impression scale (1. Markedly improved, 2. 
Improved, 3. Slightly improved, 4. No change, 5. Slightly aggravated, 6. Aggravated, 7. 
Markedly aggravated) (Homma et al, 2000). The J-CGIC is an assessment which requires a 
clinician to make a judgment of severity or change with minimal guidelines. This rating 
instrument is based upon the clinician’s experience. 
Method of assessment
Throughout the study, the same rater (an attending physician) will assess the status of a given
patient.
6.4.4
Quality of Life- Alzheimer’s Disease (QOL-AD)
QOL-AD will be conducted at Visit 2, and 8 (refer Table 6-1). QOL-AD at premature 
discontinuation will not be conducted if patient discontinues because of adverse event.
Assessment Items
QOL-AD is a 13-item questionnaire to assess the quality of life of Alzheimer’s patients from 
the perspectives of patients and their caregivers. It covers several aspects, for example, the 
perception of health status, mood, functional capacity, personal relationships and leisure, 
financial situation, and life as a whole (Logsdon et al, 1999). Each item is quantified using a 
Likert scale with score one classified as poor, and score four as excellent where total scores 
range from 13 to 52. 


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Method of assessment
Caregivers complete the measure as a questionnaire about their patients’ QOL, while patients 
complete it in interview format about their own QOL. The form should be handed to the 
participant, so that he or she may look at it as a rater gives the instructions. Assessment of QOL 
of a given patient by his/her caregiver should be considered as primary measurement while 
assessment of QOL of a given patient by his/herself will be recorded as reference. Throughout 
the study, the same rater (e.g. an attending physician of a given patient, a psychologist, or a 
medical staff who has been trained in psychologist equivalent) will give the instructions to both 
caregivers and patients.
6.4.5
Modified Crichton Scale
Modified Crichton scale will be conducted at Visit 2, 3, 4, 6 and 8 (refer Table 6-1). Modified
Crichton scale at premature discontinuation will not be conducted if patient discontinues 
because of adverse event.
Assessment Items
The following 7 items will be evaluated by caregiver. Total score is in the 0 to 5 6 range. Higher 
score means more severe impairment.
Orientation, Conversation, Cooperation with family and caregiver, Restlessness, Dressing and 
clothes, Job and social activities/roles, Leisure activities (Homma 2000).
A higher score means more severe impairment.
Method of assessment
The assessment will be performed by caregiver with using the care diary and the results will be 
recorded on the eCRF.
6.4.6
Appropriateness of efficacy assessments 
The MMSE is a brief, practical screening test for cognitive dysfunction. It is the most common 
and simple cognitive scale for AD (Folstein 1975).
To confirm whether worsening AD symptom is observed after switching from ChE-inhibitors, 
assessment of J-CGIC is scheduled at every 4-week for the first 2 months and at every 8-week 
for the rest of the study. J-CGIC is simple 7 grade investigator’s impression scale (Homma 
2000).
Modified Crichton Scale is to assess basic activation of daily living, communication functions, 
and quality of life (Homma 2000).
Neuropsychiatric Inventory (NPI) is developed to assess neuropsychiatric symptoms and 
psychopathology of patients with Alzheimer’s disease and other neurodegenerative disorders 
through the use of screening questions (Cummings et al. 1994). NPI is commonly used in both 
clinical trials and clinical practices for assessing behavioral and psychological symptoms of 
dementia.
QOL-AD is a 13-item questionnaire to assess the quality of life of Alzheimer’s patients from 
the perspectives of both patients and their caregivers. It is simple to administer and rating 


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consistency of score between patients and their caregivers has been validated (Logsdon et al. 
2002). In addition, multinational translational version of original QOL-AD including Japanese 
has been validated (Matsui et al. 2006).
6.5
Safety 
Safety assessments will consist of monitoring and recording all adverse events (AEs) and 
serious adverse events (SAEs).
6.5.1
Physical examination
Medical examination will be conducted at patient visit. The investigator will check the patient’s 
condition by direct medical examination. Subjective symptoms will be monitored for at length 
by direct medical interview with the patients. The care diary will be referred in medical 
examination. Any abnormality recognized as such compared to pre-administration will be 
recorded as an adverse event.
6.5.2
Vital signs
The following items will be measured at patient visit (refer to Table 6-1).
Examination items
Systolic/diastolic blood pressure, pulse rate, body weight
Methods of monitoring
Systolic/diastolic blood pressure and pulse rate will be measured in a sitting position. Body 
weight will be measured.
6.5.3
Laboratory evaluations
The following items will be measured at patient visit (refer to Table 6-1).
Laboratory items
Hematology;
Erythrocyte count, leukocyte count, hemoglobin, hematocrit, platelet count.
Blood chemistry;
Total protein, uric acid, ALP, AST, ALT, LDH, cholinesterase, BUN, creatinine, Na, K, Cl, 
total cholesterol, triglycerides, CPK, albumin, Ca, P, total bilirubin, amylase.
Urinalysis
Glucose, protein, occult blood.
Amounts of test samples to be collected as standard guidance

Hematology: App. 2.0-mL sample of blood will be collected at screening visit and Visit 8 
or discontinuation for a total of app. 4.0 mL.


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
Blood chemistry: At screening, app. 9.0 mL sample of blood, and app. 4.0 mL blood at 
Visit 8 or discontinuation will be collected in an AutoSep vacutainer for a total of app. 
13 mL.
Methods of collection, processing and storage of test samples
Samples of venous blood will be collected.
After blood sampling, each investigator should follow the blood test procedure of each study 
site where he/she belongs to.
Laboratory measuring these items
The hematology and blood chemistry tests will be performed by the laboratory measurement 
described on [Appendix 2].
6.5.3.1
Urinalysis

Urinalysis: App. 5-mL sample of urine will be collected at each of 2 points for a total of 
app. 10 mL

For urinalysis, each investigator should follow urine sample procedure of each study site 
where he/she belongs to.
6.5.4
Electrocardiogram (ECG) 
ECG will be measured at patient visit (refer to Table 6-1).
Assessment items
Standard 12-lead ECG, ECG readings (heart rate, PR interval, QRS duration, QT interval,
QTcB*, QTcF*)
*: These data will be calculated by EDC system, and the calculated data is input to eCRF
automatically.
Method of assessment
ECG will be taken in a supine position after rest.
Clinically significant abnormalities must be recorded on the relevant section of the medical 
history/Current medical conditions/AE eCRF page as appropriate.
6.5.5
Pregnancy and assessments of fertility
Please refer to Section 7.6.
6.5.6
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/patient population.
6.6
Other assessments
Formulation usability questionnaire


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The Formulation usability preference questionnaire will be used to compare the previous oral 
AD drugs versus the patch in this study and will be completed at Visit 8 (or discontinuation). 
The caregiver will select one of the following answers (1. Very easy to use, 2. Easy to use, 3. 
No change, 4. Not easy to use, 5. Not easy to use at all, 6. Unknown). The caregiver answer in 
the questionnaire should be recorded in eCRF. The reason for the answer should be recorded in 
eCRF as possible.
Treatment compliance
The status of application of study drug patches will be investigated at every visit between Visit 
3 and Visit 8 (or discontinuation).
Investigation Items
The status of application of rivastigmine patches
Methods of investigation
Treatment compliance will be investigated by Physician in one of the following category:

<25%  Poor

25≦～＜50% Average

50≦～＜75% Good

75≦～≦100% Very good

> 100% Reason to be specified (overdose or misuse)

In case of over compliance (> 100% Reason to be specified, e.g. patients who ran out of 
their drug due to overuse or misuse), the investigators record the reason (overdose or 
misuse) separately on eCRF.
The results of treatment compliance should be recorded in eCRF by the interview to either 
patients or caregivers. “Applied day” is defined as a date when patch has been applied for more 
than 16 hours.
6.6.1
Resource utilization 
Not applicable.
6.6.2
Pharmacokinetics 
Not applicable.
7
Safety monitoring 
7.1
Adverse events 
An adverse event (AE) is appearance of worsening of any undesirable sign, symptom or medical 
condition occurring after starting study treatment, even if the event is not considered to be 
treatment-related. Study treatment includes the study medication under evaluation given during 
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Medical conditions/diseases present before starting study treatment will only be considered AEs 
if they worsen after starting study treatment. Non-serious AEs occurring before starting study 
treatment but after signing the informed consent form will be recorded on the Medical 
History/Current Medical Conditions pages in eCRF. Abnormal laboratory values or test results 
constitute adverse events only if they induce clinical signs or symptoms, are considered 
clinically significant or require therapy. The occurrence of adverse events should be sought by 
non-directive questioning of the patient at each visit during the study. Adverse events also may 
be detected when they are volunteered by the patient during or between visits or through 
physical examination, laboratory test, or other assessments. All adverse events which were 
observed from the first treatment of the drug to the last treatment of the drug must be recorded 
on the Adverse Events eCRF with the following information: 
The severity grade (mild, moderate, severe)
Its relationship to the drug(s) of interest (suspected/not suspected)
Its duration (start and end dates or if continuing at final exam)
Whether it constitutes a serious adverse event (SAE- see Section 7.2 for definition of SAE)
All adverse events should be treated appropriately. Treatment may include one or more of the 
following: no action taken (i.e. further observation only); the drug dosage adjusted/temporarily 
interrupted; the drug permanently discontinued due to this adverse event; concomitant 
medication given; non-drug therapy given; patient hospitalized/patient’s hospitalization 
prolonged. The action taken to treat the AE should be recorded on the AE pages in eCRF. 
Once an adverse event is detected, it should be followed until its resolution or until it is judged 
to be permanent, and assessment should be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the drug, the interventions required to
treat it, and the outcome.
Information about common side effects already known about the drug can be found in the 
Package Insert (PI) or will be communicated between PI updates in the form of individual safety 
report or periodic safety update report and others. This information will be included in the 
patient informed consent and should be discussed with the patient during the study as needed.
7.2
Serious adverse events
7.2.1
Definition of SAE
An SAE is defined as any adverse event (appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s) or medical conditions(s) which meets any one of the following 
criteria:

is fatal or life-threatening 

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
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
routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 

social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

is medically significant, i.e. defined as an event that jeopardizes the patient or may require 
medical or surgical intervention to prevent one of the outcome listed above e.g. may require 
treatment on an emergency outpatient basis for an event not fulfilling any of the SAE 
definition criteria and not resulting in hospitalization.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All AEs (serious and non-serious) are captured on the eCRF, SAEs also require individual 
reporting to Novartis Drug Safety & Epidemiology department (DS&E) as per section 7.2.2.
7.2.2
SAE reporting
Each Serious Adverse Event (SAE), regardless of suspected causality, occurring after the 
patient has provided informed consent and until 30 days after the patient has stopped study 
participation (defined as time of last dose of drug taken or last visit whichever is later) will be 
reported by the investigator to Novartis DS&E by FAX within 24 hours of learning of its 
occurrence, even if it is not felt to be treatment-related. 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form. The principle investigator must assess the relationship of any SAE to the drug, complete 
the SAE Report Form, and send the completed, signed form by fax within 24 hours to Novartis 
Drug Safety and Epidemiology Department. In case of emergency, investigator other than 
principle investigator or staff can act for it instead of the principle investigator. The telephone 
and telecopy number of the contact persons in the local department of Clinical -Drug Safety 
and Epidemiology, specific to the site, are listed in the investigator folder provided to each site. 
The principle investigator must submit to Novartis monitor the original SAE report. The 
original copy of the SAE Report Form and the fax confirmation sheet must be kept with the 
case report form documentation at the study site.
Any SAEs experienced after this 30 day period should only be reported to Novartis DS&E by 
FAX if the investigator suspects a causal relationship to the drug. 
Recurrent episodes, complications, or progression of the initial SAE must be reported as follow-
up to the original episode, regardless of when the event occurs. This report must be submitted 
within 24 hours of the investigator receiving the follow-up information by the principle 
investigator. An SAE that is considered completely unrelated to a previously reported one 
should be reported separately as a new event. 


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Follow-up information is sent to the same person to whom the original SAE Report Form was 
sent, using a new SAE Report Form stating that this is a follow-up to the previously reported 
SAE and giving the date of the original report by FAX. The follow-up information should 
describe whether the event has resolved or continues, if and how it was treated, and whether the 
patient continued or withdrew from study participation.
If the SAE is thought to be related to the drug, a Drug Safety and Epidemiology Department 
associate may urgently require further information from the investigator for Health Authority 
reporting. Novartis may need to issue an individual safety report and others to inform all 
investigators involved in any study with the same drug that this SAE has been reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with Directive 
2001/20/EC or as per national regulatory requirements in participating countries. 
7.3
Liver safety monitoring 
To ensure patient safety and enhance reliability in determining the hepatotoxic potential of the 
drug, a standardized process for identification, monitoring and evaluation of liver events has to 
be followed. 
The following two categories of abnormalities / adverse events have to be considered during 
the course of the study (irrespective of whether classified/reported as (S)AE):

Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter

Liver events, which will require close observation, follow-up monitoring and completion of 
the standard base liver CRF pages
Please refer to Table 14-1 in Appendix 2 for complete definitions of liver laboratory triggers 
and liver events. 
Every liver laboratory trigger or liver event as defined in Table 14-1 of Appendix 2 should be 
followed up by the investigator or designated personal at the trial site as summarized below. 
Detailed information is outlined in Table 14-2 in Appendix 2.
For the liver laboratory trigger:

Repeating the liver function test (LFT) to confirm elevation as appropriate.
Repeat laboratory tests must be entered on the appropriate unscheduled local laboratory CRF 
page.

If the elevation is confirmed, close observation of the patient will be initiated, including 
consideration of treatment interruption if deemed appropriate.
For the liver events:

Repeating the LFT to confirm elevation as appropriate

Discontinuation of the drug if appropriate

Hospitalization of the patient if appropriate

A causality assessment of the liver event via exclusion of alternative causes (e.g., disease, 
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
An investigation of the liver event which needs to be followed until resolution. 
These investigations can include serology tests, imaging and pathology assessments, 
hepatologist’s consultancy, based on investigator’s discretion. All follow-up information, and 
the procedures performed must be recorded on appropriate CRF pages, including the liver event 
overview CRF pages.
7.4
Renal safety monitoring
The following two categories of abnormal renal laboratory values have to be considered during 
the course of the study:
•
Serum event:
•
Confirmed (after ≥24h) increase in serum creatinine of ≥25% compared to baseline 
during normal hydration status
•
Urine event
•
New onset (≥1+) proteinuria; confirmed by doubling in the urinary albumin-
creatinine ratio (ACR) or urinary protein-creatinine ratio (PCR) (if applicable)
•
New onset (≥1+), hematuria or glycosuria 
Every renal laboratory trigger or renal event as defined in Table 15-1 in Appendix 3 should be 
followed up by the investigator or designated personnel at the trial site as summarized in 
Appendix 3.
7.5
Reporting of study treatment errors including misuse/abuse
Not applicable
7.6
Pregnancy reporting 
To ensure patient safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications.
Pregnancy must be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the drug. 
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form.
Pregnancy outcomes should be collected for the female partners of any males who took the drug
in this study. Consent to report information regarding these pregnancy outcomes should be 
obtained from the female partner.


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8
Data review and database management 
8.1
Site monitoring
Before study initiation, at a site initiation visit, a CRO working on behalf of Novartis will review 
the protocol and eCRFs with the investigators and their staff. During the study, the field monitor 
will visit the site regularly to check the completeness of patient records, the accuracy of entries 
on the eCRFs, the adherence to the protocol, to Good Clinical Practice (GCP) and Good Post-
marketing Study Practice (GPSP), the progress of enrollment. Key study personnel must be 
available to assist the field monitor during these visits.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or
assessments. All information on eCRFs must be traceable to these source documents in the 
patient's file. [Data not requiring a separate written record will be defined before study start 
and will be recorded directly on the CRFs.] The investigator must also keep the original 
informed consent form signed by the patient (a signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the eCRF entries. Novartis monitoring standards require full verification for 
the presence of informed consent, adherence to the inclusion/exclusion criteria, documentation 
of SAEs, and the recording of data that will be used for all primary and safety variables. 
Additional checks of the consistency of the source data with the eCRFs are performed according 
to the study-specific monitoring plan. No information in source documents about the identity 
of the patients will be disclosed.
8.2
Data collection
Designated investigator staff will enter the data required by the protocol into the EDC system 
(OC/RDC system). Designated investigator site staff will not be given access to the system until 
they have been trained. 
Automatic validation programs check for data discrepancies and, by generating appropriate 
error messages, allow the data to be confirmed or corrected before transfer of the data to the 
CRO working on behalf of Novartis. The Investigator must certify that the data entered into the 
Electronic Case Report Forms are complete and accurate. After database lock, the investigator 
will receive copies of the patient data for archiving at the investigational site. 
8.3
Database management and quality control
A CRO working on behalf of Novartis reviews the data entered into the eCRFs by 
investigational staff for completeness and accuracy, and instructs the site personnel to make any 
required corrections or additions. Queries are sent to the investigational site using an electronic 
data query. Designated investigator site staff is required to respond to the query and confirm or 
correct the data. 
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 


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Concomitant procedures, non-drug therapies and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked and made available for data analysis. Any changes to the database after that time can 
only be made after written agreement by Novartis Japan Head of Medical Division.
8.4
Data Monitoring Committee
Not required.
8.5
Adjudication Committee
Not required.
9
Data analysis 
The analysis will be conducted on all subject data at the time the trial ends.
9.1
Analysis sets 
Full Analysis Set (FAS)
The FAS will include all patients who received at least one dose of drug and had at least a 
baseline and any post-baseline assessment on treatment. This population will be used for all 
efficacy analyses.
Per protocol Set (PP)
The per protocol set will include all patients in FAS without any major deviations from the 
protocol procedures. The major protocol deviations will be specified prior to database lock.
Safety Set (SAF)
The safety set will consist of all patients who received at least one dose of drug and had at least 
one post-baseline safety assessment.
9.2
Patient demographics and other baseline characteristics
Descriptive statistics for background and demographic characteristics will be summarized.
The number and percentage of patients according to reasons of study participation should be 
provided (based on inclusion criteria: lack/loss efficacy or intolerability to previous ChE 
inhibitors).
9.3
Treatments 
A data listing of the drug doses administered by patients will be provided. The number and 
percentage of patients exposed will be provided as well as the summary statistics for the 
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The number and percentage of patients who could stay on 1-step titration and switched 3 step 
titration should be provided.
The number and percentage of patients receiving concomitant medications and significant non-
drug therapy will be summarized by preferred term (coded by World Health Organization 
[WHO] and Anatomic Therapeutic Chemical classification [ATC]).
9.4
Analysis of the primary variable(s)
The primary objective is to evaluate the efficacy of rivastigmine patch with 1-step titration on 
cognitive function for mild to moderate AD patients who failed to benefit from other ChEIs as 
change from baseline to Week 24 in the total score of Mini-Mental State Examination (MMSE).
9.4.1
Variable(s)
The primary variable is change from baseline at Week 24 in the total score of 11 items included 
in the Mini-Mental State Examination (MMSE) for the FAS. 
9.4.2
Statistical model, hypothesis, and method of analysis
The change from baseline in MMSE total score will be analyzed using a mixed model repeated 
measures (MMRM) model. The model will contain visit as a fixed effect, baseline MMSE score 
as a covariate and subject as a random effect. An unstructured covariance matrix will be used
to model the within-subject error. The estimated mean change at Week 24 along with a two-
sided 95% confidence interval and p-value will be presented. P-values will be used in 
descriptive manner.
Further, the MMSE total score and change from baseline will be summarized using standard 
descriptive statistics by visits.
9.4.3
Handling of missing values/censoring/discontinuations
The primary analysis will be performed using a MMRM model, which assumes that missing 
data is missing at random (MAR) given the preceding observed data. 
No other imputation methods will be considered.
9.4.4
Sensitivity analyses
As supportive analysis, the primary endpoint will be analyzed for the FAS as follows:
1. The change from baseline to Week 24 in MMSE total score will be analyzed using a t-test. 
The estimated mean change along with 95% confidence interval and two-sided p-value 
will be presented. This analysis will be performed on study completers only without any 
imputation of missing data.
2. The change from baseline to Week 24 in MMSE total score imputed with last observation 
carried forward (LOCF) method will be analyzed using a t-test. The estimated mean 
change along with 95% confidence interval and p-value will be presented.
The p-values obtained in the supportive analyses will be descriptive in nature. 


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Subgroup analyses will be performed as necessary. The details will be described in the 
Statistical Analysis Plan.
9.5
Analysis of secondary variables
9.5.1
Efficacy variables
All secondary efficacy variables will be analyzed using the FAS.
MMSE score at Week 8
The change from baseline to Week 8 in MMSE total score will be summarized descriptively 
and analyzed using the same MMRM model used for the primary analysis. The estimated mean 
change along with two-sided 95% confidence interval will be presented. 
Neuropsychiatric Inventory (NPI) score
The neuropsychiatric symptoms will be assessed by the 10-item Neuropsychiatric Inventory 
(NPI). The NPI-10 total score is a sum of the 10 items, where the score for a domain is defined 
as the product of frequency (range: 1-4) and severity (range: 1-3). Each domain has a maximum 
score of 12 and all domains are equally weighted for the total score (thus the range for the total 
score is 0 to 120). The NPI-10 total score and for each sub-item will be summarized 
descriptively at visits 4 and 8.
For change from baseline to Week 24, summary statistics and 95% CI of the mean will be 
derived for FAS.
J-CGIC
J-CGIC is a global assessment scale to assess change of the patient’s clinical symptoms, which 
are assessed subjectively by clinicians with seven grades. (1: Marked improvement, 2: 
Moderate improvement, 3: Mild improvement, 4: Unchanged, 5: Mild Worsening, 6: Moderated 
Worsening, 7: Marked Worsening) The number and percentage of patients in each grade will 
be displayed at week 4, 8, 16 and 24. Also, proportion and 95% confidence interval for the 
proportions of the patients without worsening (1: Marked improvement, 2: Moderate 
improvement, 3: Mild improvement, 4: Unchanged) and with improvement (1: Marked 
improvement, 2: Moderate improvement, 3: Mild improvement) will also be provided.
Modified Crichton Scale
Modified Crichton Scale total score is defined as the sum of 7 items. If at least one missing item 
exists, the total score is set as missing. 
Modified Crichton Scale total score will be summarized at visits 4, 8, 16, 24.
For change from baseline, summary statistics and 95% CI of the mean will be derived for FAS 
at Week 4, 8, 16, and Week 24.
9.5.2
Resource utilization
Not applicable.


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9.5.3
Pharmacokinetics 
Not applicable.
9.6
Analysis of 
 variables 
QOL-AD score
The QOL-AD is a brief, 13-item measure designed to obtain a rating of the patient’s Quality of 
Life from the caregiver. A lower score indicates more severe impairment.
The change from baseline at Week 24 in the QOL-AD total and sub-item scores (by patients or 
caregivers) will be summarized along with 95% confidence interval of the mean for the FAS.
Assessment of QOL of a given patient by his/her caregiver should be considered as primary 
measurement while assessment of QOL of a given patient by his/herself will be recorded as 
reference.
9.6.2
Safety variables 
All safety variables will be reported using the safety set.
Adverse events
All adverse events will be coded utilizing the MedDRA dictionary, tabulated, and analyzed by 
primary system organ class and preferred term.
These adverse events will be summarized by overall, by study periods Week 1 to Week 4 (while 
on Rivastigmine 9 mg/day) and by every 4 week period starting Week 4 to Week 24 (while on 
Rivastigmine 18 mg/day), severity, relationship to study drug, death, serious adverse events 
(SAE), adverse event leading to study drug discontinuation, adverse event leading to study drug 
interruption/adjustment.
Vital signs
Summary statistics of absolute value and change from baseline will be provided by visit. 
Abnormal values/changes will be summarized and listed.
9.6.3
Other assessment 
Formulation usability questionnaire
This questionnaire data is used to assess if the rivastigmine patch is preferred over the previous 
ChIE treatment by the majority (greater than 50%) of AD patient caregivers. This will be 


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assessed using the direct preference question in the follow-up questionnaire. The proportion of 
caregivers choosing the patch over the previous medication will be summarized with two-sided 
95% confidence intervals for the FAS.
In addition, reasons for medication preference in the questionnaire will be summarized by 
presenting the frequencies of endorsed reasons for those preferring the previous pill medication 
and for those preferring the patch.
Treatment retention during the last 8 weeks of maintenance period:
Treatment retention rate will be summarized for the FAS.
Here, “treatment retention” is considered to be successful when a patient meets all of the 
following condition:

complete the study,

receive rivastigmine 18 mg treatment during the last 8 weeks of maintenance period,

never decrease the dose during the last 8 weeks of maintenance period, 

comply with drug application ≥75% during the last 8 weeks of maintenance period 
(compliance will be categorized as  >0% to 25%, >25% to 50%, >50% to75%, >75% to 
100% and >100%).
9.7
Interim analyses
Not applicable.
9.8
Sample size calculation
The sample size is determined as precision-based for the change from baseline in MMSE score 
at week 24. Ninety-seven patients will ensure that the half-width of 95% confidence interval 
for the change from baseline in MMSE score at week 24 would be 0.6, assuming SD=3.0 which 
is estimated from 1301, 1303 and 1403 study. Assuming drop-outs, a total of 120 patients will 
be enrolled to achieve at least 97 evaluable subjects.
10
Ethical considerations
10.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC, US Code of Federal Regulations Title 
21, and Japanese Ministry of Health, Labor, and Welfare[GCP, GPSP]), and with the ethical 
principles laid down in the Declaration of Helsinki.
10.2
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent, or, if incapable of doing 
so, after such consent has been provided by a legally acceptable representative(s) of the patient. 


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In cases where the patient’s representative gives consent, the patient should be informed about 
the study to the extent possible given his/her understanding. If the patient is capable of doing 
so, he/she should indicate assent by personally signing and dating the written informed consent 
document or a separate assent form. Informed consent must be obtained before conducting any 
study-specific procedures (i.e. all of the procedures described in the protocol). The process of 
obtaining informed consent should be documented in the patient source documents. 
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH GCP guideline and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed to by Novartis before submission to the IRB/IEC, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC approval.
Women of child bearing potential should be informed that taking the study treatment may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study.
In the event that Novartis wants to perform testing on the samples that are not described in this 
protocol, additional Institutional Review Board and/or Ethics Committee approval will be 
obtained.
10.3
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, subject recruitment procedures (e.g., 
advertisements) and any other written information to be provided to patients/subjects. Prior to 
study start, the investigator is required to sign a protocol signature page confirming his/her 
agreement to conduct the study in accordance with these documents and all of the instructions 
and procedures found in this protocol and to give access to all relevant data and records to 
Novartis monitors, auditors, Novartis Quality Assurance representatives, designated agents of 
Novartis, IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site 
is requested by a regulatory authority, the investigator must inform Novartis immediately that 
this request has been made.
10.4
Publication of study protocol and results
The key design elements of this protocol will be posted in a publicly accessible database such 
as clinicaltrials.gov. In addition, upon study completion and finalization of the study report the 
results of this trial will be either submitted for publication and/or posted in a publicly accessible 
database of clinical trial results.
11
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of patients/subjects should 


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be administered as deemed necessary on a case by case basis. Under no circumstances is an 
investigator allowed to collect additional data or conduct any additional procedures for any 
research related purpose involving any investigational drugs under the protocol.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be implemented. 
11.1
Protocol Amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. Only amendments that are intended to eliminate an apparent immediate hazard 
to patients/subjects may be implemented immediately provided the health authorities are 
subsequently notified by protocol amendment and the reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 7 Safety Monitoring must be followed. Novartis should be 
notified of this action and the IRB at the study site should be informed within 10 working days.
12
References
References are available upon request
1. Cummings JL, Mega M, Gray K (1994). The Neuropsychiatric Inventory: 
comprehensive assessment of psychopathology in dementia. Neurology 44;2308-14.
2. Davies P, Maloney AJ. Selective loss of central cholinergic neurons in Alzheimer's 
disease. Lancet. 1976 Dec 25;2(8000):1403.
3. EMEA. Guidance on medicinal products for the treatment of Alzheimer’s disease and 
other dementias. London, July 2008.
4. Folstein MR, Folstein SE, McHugh PR (1975). "Mini-mental state": a practical method 
for grading the cognitive state of patients for the clinician. J Psychiatr Res;12:189-98
5. Homma A. Guidelines for the clinical evaluation of antidementia drugs. IYAKUHIN 
KENKYU 1998; 29: 835-46.
6. Homma A, et al. Clinical efficacy and safety of donepezil on cognitive global function 
in patients with Alzheimer's disease. A 24-week, multicenter, double-blind, placebo-
controlled study in Japan. E2020 Study Group. Dement Geriatr Cogn Disord 2000; 
11 : 299-313.
7. Lane RM, Potkin SG, Enz A (2006). Targeting acetylcholinesterase and 
butyrylcholinesterase in dementia. Int J Neuropsychopharmacol; 9:101-24.
8. Leber P. Guidelines for the clinical evaluation of antidementia drugs. First draft 
November 8, 1990.


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9. Lefevre G, Sedek G, Jhee SS, et al. Pharmacokinetics and pharmacodynamics of the 
novel daily rivastigmine transdermal patch compared with twice-daily capsules in 
Alzheimer’s disease patients. Clin. Pharmacol. Therap 2008; 83: 106-114.
10. Logsdon RG, Gibbons LE, McCurry SM, Teri L. Quality of life in Alzheimer's disease: 
patient and caregiver reports. J Ment Health Aging. 1999;5:21–32.
11. Logsdon RG, Gibbons LE, McCurry SM, Teri L. Assessing quality of life in older adults 
with cognitive impairment. Psychosom Med 2002; 64:510-519.
12. Matsui T, Nakaaki S, Murata Y, et al. Determinants of the quality of life in Alzheimer’s 
disease patients as assessed by the Japanese version of the Quality of Life-Alzheimer’s 
disease scale. Dement Geriatr Cogn Disord. 2006; 21(3):182-91.
13. Nakamura Y, et al. A 24-week, randomized, double-blind, placebo-controlled study to 
evaluate the efficacy, safety and tolerability of the rivastigmine patch in Japanese 
patients with Alzheimer’s disease. Dement Geriatr Cogn Disord Extra 2011; 1 :163-79.
14. Sadowsky CH, et al. Switching from oral donepezil to rivastigmine transdermal patch 
in Alzheimer’s disease: 20-week extension phase results. Prim Care Companion J Clin 
Psychiatry 2010; 12 (5) : e1-8
15. Shimokata H. Epidemiological studies on Alzheimer’s disease in Japan. Nippon Rinsho 
2008; 66 : 23-7.


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13
Appendix 1: Severity of adverse events, causal relationship 
to drug, and action taken for adverse events
Adverse Events
Severity of adverse events
The severity of adverse events (signs and symptoms) should be assessed in the following 3 
grades, based in principle on the indicated criteria, and recorded on the eCRF: 
1. Mild: 
An adverse event that allows continued treatment without intervention.
2. Moderate: An adverse event that allows continued treatment with some intervention.
3. Severe: 
An adverse event that requires discontinuation of treatment. 
Causal relationship to study drug
The causal relationship of adverse events to the study drug should be assessed according to the 
following 2 categories. When it is assessed as not suspected, the reason should be documented 
on the eCRF: 
0.
Not suspected: Time relationship to the study drug is indefinite, and the occurrence can 
be fully explained by concomitant medication, other therapeutic intervention or patient 
background factors. 
1.
Suspected: Time relationship to the study drug exists, and the occurrence cannot be fully 
explained by concomitant medication, other therapeutic intervention or patient 
background factors. 
Action taken for adverse events
When any action is taken for adverse events, its content should be specified from among the 
following 5 categories (More than one may be chosen): 
1. Study drug dosage adjusted/temporarily interrupted. 
2. Study drug permanently discontinued due to the adverse event.
3. Concomitant medication taken.
4. Non-drug therapy given.
5. Hospitalization/prolonged hospitalization


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14
Appendix 2: Liver event and Laboratory trigger Definitions 
and Follow-up Requirements
Table 14-1
Liver Event and Laboratory Trigger Definitions
Definition/ threshold
LIVER LABORATORY TRIGGERS

3 x ULN < ALT / AST ≤5 x ULN

1.5 x ULN < TBL ≤2 x ULN
LIVER EVENTS

ALT or AST > 5 × ULN

ALP > 2 × ULN (in the absence of known bone pathology)

TBL > 2 × ULN (in the absence of known Gilbert syndrome)

ALT or AST > 3 × ULN and INR > 1.5 

Potential Hy’s Law cases (defined as ALT or AST > 3 × ULN and 
TBL > 2 × ULN [mainly conjugated fraction] without notable 
increase in ALP to > 2 × ULN)

Any clinical event of jaundice (or equivalent term)

ALT or AST > 3 × ULN accompanied by (general) malaise, 
fatigue, abdominal pain, nausea, or vomiting, or rash with 
eosinophilia

Any adverse event potentially indicative of a liver toxicity*
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-
related conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver 
neoplasms
TBL: total bilirubin; ULN: upper limit of normal 
Table 14-2
Follow Up Requirements for Liver Events and Laboratory Triggers
Criteria
Actions required
Follow-up monitoring
Potential Hy’s Law 
casea

Discontinue the study treatment 
immediately

Hospitalize, if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion)
ALT or AST
> 8 × ULN

Discontinue the study treatment 
immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion)
> 3 × ULN and 
INR > 1.5

Discontinue the study treatment 
immediately

Hospitalize, if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion)
> 5 to ≤ 8 × ULN

Repeat LFT within 48 hours

If elevation persists, continue follow-up 
monitoring

If elevation persists for more than 2 
weeks, discontinue the study drug

Establish causality
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion)


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Criteria
Actions required
Follow-up monitoring

Complete liver CRF
> 3 × ULN 
accompanied by 
symptomsb

Discontinue the study treatment 
immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion)
> 3 to ≤ 5 × ULN 
(patient is 
asymptomatic)

Repeat LFT within the next week

If elevation is confirmed, initiate close 
observation of the patient
Investigator discretion
Monitor LFT within 1 to 4 weeks 
ALP (isolated)
> 2 × ULN (in the 
absence of known 
bone pathology)

Repeat LFT within 48 hours

If elevation persists, establish causality

Complete liver CRF
Investigator discretion
Monitor LFT within 1 to 4 weeks or at 
next visit
TBL (isolated)
> 2 × ULN (in the 
absence of known 
Gilbert syndrome)

Repeat LFT within 48 hours

If elevation persists, discontinue the 
study drug immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion)
Test for hemolysis (e.g., reticulocytes, 
haptoglobin, unconjugated [indirect] 
bilirubin)
> 1.5 to ≤ 2 × ULN
(patient is 
asymptomatic)

Repeat LFT within the next week

If elevation is confirmed, initiate close 
observation of the patient 
Investigator discretion
Monitor LFT within 1 to 4 weeks or at 
next visit
Jaundice

Discontinue the study treatment 
immediately

Hospitalize the patient

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion)
Any AE potentially 
indicative of a liver 
toxicity*

Consider study treatment interruption or 
discontinuation 

Hospitalization if clinically appropriate

Establish causality

Complete liver CRF
Investigator discretion
a Elevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × 
ULN
b (General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia 
c Resolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable 
values at three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level 
after a maximum of 6 months, (4) liver transplantation, and (5) death.


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15
Appendix 3: Specific Renal Alert Criteria and Actions
Table 15-1
Specific Renal Alert Criteria and Actions
Serum Event
Serum creatinine increase
25 – 49% compared to baseline
Confirm 25% increase after 24-48h 
Follow up within 2-5 days
Acute Kidney Injury: Serum creatinine increase ≥
50% compared to baseline
Follow up within 24-48h if possible
Consider study treatment interruption 
Consider patient hospitalization /specialized treatment
Urine Event
New dipstick proteinuria ≥1+
Albumin- or Protein-creatinine ratio increase ≥2-fold
Albumin-creatinine ratio (ACR) ≥30 mg/g or 
≥3 mg/mmol;
Protein-creatinine ratio (PCR )≥150 mg/g 
or >15 mg/mmol
Confirm value after 24-48h
Perform urine microscopy
Consider study treatment interruption / or 
discontinuation 
New dipstick glycosuria ≥1+ not due to diabetes
Blood glucose (fasting)
Perform serum creatinine, ACR 
New dipstick hematuria ≥1+ not due to trauma
Urine sediment microscopy
Perform serum creatinine, ACR 
For all renal events:
Document contributing factors in the CRF: co-medication, other co-morbid conditions, and additional diagnostic 
procedures performed 
Monitor patient regularly (frequency at investigator’s discretion) until either: 
Event resolution: sCr within 10% of baseline or protein-creatinine ratio within 50% of baseline, or
Event stabilization: sCr level with ±10% variability over last 6 months or protein-creatinine ratio stabilization at a 
new level with ±50% variability over last 6 months.

SAP_001.pdf: 
Medical Affairs
[Exelon/Rivastigmine]
Clinical Trial Protocol [CENA713DJP02]                               
NCT02703636
[A 24-week, open-label, multicenter study to evaluate the 
efficacy, safety and tolerability of Exelon patch 
(Rivastigmine) with 1-step titration in patients with mild to 
moderate Alzheimer’s disease (MMSE 10–23) switched 
directly from cholinesterase inhibitors (Donepezil, 
Galantamine)]
Statistical Analysis Plan (SAP)
Author:
Trial Statistician, 
Lead Statistician, 
 
Document type:
SAP Documentation
Document status:
Addendum 1
Release date:
23-January-2019
Number of pages:
35


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CENA713DJP02
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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CENA713DJP02
Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted 
(Current)
21-Mar-
16
Prior 
to 
FPFV
NA
Final 2.0
NA
7-June-
2018
Prior 
to 
DBL 
-Calculation 
of 
Compliance 
data 
updated
-Added 
imputation 
rules for AE 
and CM
-Added  
SAS code 
for Step-
wise 
Regression 
Model
-Updated 
PD list
Amendment 1
Section 2.4.1
Section 5.1
Section 5.3.4
Section 5.2
12-
June-
2018
Prior 
to
DBL
- 2 
subgroup 
analysis 
categories 
added for 
patients 
satisfying 
inclusion 
criteria
Amendment 2
Section 2.2.1.1


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CENA713DJP02
Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted 
(Current)
23-
January-
2019
Post 
DBL
-Removed 
the 
screening 
time point 
from the 
subgroup 
analysis for 
Patients 
satisfying 
protocol 
inclusion 
criteria in 
Section 
2.2.1.1 and 
also 
updated the 
categories 
for the 
same.
-Added 
subgroup 
‘weight’ in 
the 2nd point 
in Amongst 
AE’s of 
Special 
Interest in 
Section 
2.2.1.2
-Added
analysis for 
Only
concomitant 
medications 
in Section 
2.4.2.
-Added 
change 
from 
baseline for 
laboratory 
parameters 
in section 
2.7.1.
Addendum 1
Section 2.1.1.5
Section 2.2.1.1
Section 2.2.1.2
Section 2.4.2.
Section 2.7.1


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Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted 
(Current)
- Divided 
the Patient-
reported 
outcomes 
into Patient 
reported 
outcomes, 
Caregiver 
reported 
outcomes 
and clinical 
reported 
outcomes.
-Removed 
the word 
‘Stepwise’ 
from the 
analysis 
described in 
Section 
2.8.1.1 for 
QOL-AD 
total score
-Added 
details 
Section 4. 
Section 2.8             
Added section 
2.9 and 2.10
Section 2.8.1.1
Section 4


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Table of contents
Table of contents .................................................................................................................6
List of abbreviations............................................................................................................8
1
Introduction .........................................................................................................................9
1.1
Overall study design ................................................................................................9
1.2
Study objectives and endpoints .............................................................................10
2
Statistical methods.............................................................................................................12
2.1
Data analysis general information .........................................................................12
2.1.1
General definitions................................................................................12
2.2
Analysis sets ..........................................................................................................13
2.2.1
Subgroup of interest ..............................................................................14
2.3
Patient disposition, demographics and other baseline characteristics ...................16
2.3.1
Patient disposition.................................................................................16
2.3.2
Medical history/current medical condition ...........................................16
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................16
2.4.1
Study treatment exposure / compliance ................................................16
2.4.2
Prior, concomitant and post therapies...................................................17
2.5
Analysis of the primary objective..........................................................................18
2.5.1
Primary endpoint...................................................................................18
2.5.2
Statistical hypothesis, model, and method of analysis..........................18
2.5.3
Handling of missing values/censoring/discontinuations.......................18
2.5.4
Supportive analyses...............................................................................18
2.6
Analysis of secondary objectives...........................................................................19
2.6.1
Efficacy endpoints.................................................................................19
2.6.2
Safety analyses......................................................................................19
2.7
Other safety data....................................................................................................21
2.7.1
Laboratory data .....................................................................................21
2.7.2
Vital signs..............................................................................................22
2.7.3
ECG.......................................................................................................23
2.8
Patient-reported outcomes .....................................................................................23
2.9
Caregiver-reported outcomes.................................................................................23
2.10
Clinician-reported outcomes..................................................................................24
2.11
Other analyses........................................................................................................24
2.11.1
Treatment retention during the last 8 weeks of maintenance period: ...24
25


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25
25
2.13
Interim analysis......................................................................................................25
3
Sample size calculation .....................................................................................................26
4
Change to protocol specified analyses ..............................................................................26
5
Appendix ...........................................................................................................................26
5.1
Imputation rules.....................................................................................................26
5.2
Rule of exclusion criteria of analysis sets..............................................................29
5.3
SAS codes for statistical analyses..........................................................................34
5.3.1
Mixed Model Repeated Measures (MMRM) analysis..........................34
5.3.2
MMRM model of subgroup analysis ....................................................34
5.3.3
Student’s t-test.......................................................................................35
5.3.4
Regression Model..................................................................................35


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List of abbreviations
AE
Adverse event
CSR
Clinical Study report
FAS
Full Analysis Set
eCRF
Electronic Case Report Form
MedDRA
Medical Dictionary for Drug Regulatory Affairs
o.d.
Once Daily
PPS
Per-Protocol Set
PRO
Patient-reported Outcomes
qd
Qua’que di’e / once a day
QoL
Quality of Life
RAP
Report and Analysis Process
SAP
Statistical Analysis Plan
SOC
System Organ Class
TFLs
Tables, Figures, Listings
WHO
World Health Organization


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1
Introduction
This document contains details of the statistical methods which will be used in the phase IV 
post-marketing clinical trial CENA713DJP02. The statistical analysis described in this SAP is 
based on the final study protocol and will be presented in the Clinical Study Report. This is a
24-week, open-label, multicenter study to evaluate the efficacy, safety and tolerability of Exelon 
patch (Rivastigmine) with 1-step titration in patients with mild to moderate Alzheimer’s disease 
(MMSE 10 – 23) switched directly from cholinesterase inhibitors (donepezil, galantamine) in 
Japan.
1.1
Overall study design
This study will have three phases:
Screening phase [2-4 weeks: week -4 (Day -28) to week -2 (Day -14 to Day -1)]. 
The Screening Visit (Visit 1) has to take place 2 – 4 weeks before the planned start of 
rivastigmine patch treatment. After signing the informed consent, all patients will undergo a 
preliminary evaluation (Screening Visit) to assess eligibility (Appendix 16.1.1-Protocol-
Section 4.1). Patients will continue their ChE inhibitors (donepezil or galantamine) during the 
Screening period, and patients are eligible to take their ChE inhibitors until the evening prior to 
start day of rivastigmine patch. For those patients who are eligible to enroll the study by the 
preliminary evaluation at Screening Visit, MMSE score during previous 6 months should be 
collected and recorded as much as possible. Their ChE inhibitors are discontinued on Baseline 
visit (Day 1). At the baseline visit (Visit 2), the patient will also undergo safety and efficacy 
assessments as per Appendix 16.1.1-Protocol-Table 6-1, and eligibility will be confirmed. Day 
1 will be the day on which treatment with rivastigmine patch will be started. Patients will be 
starting on treatment with rivastigmine patch on the same day of the baseline visit (Day 1). 
When the patients already took their ChE inhibitors at the baseline visit (Visit 2, Day -1), the 
patients will start on treatment with rivastigmine patch the next day (Day 1) after the baseline 
visit.
Titration phase [8 weeks: week 1 (Day 1) to week 8 (Day 56)].
On the same day or next day (Day 1) following baseline visit, patients will begin treatment with 
a rivastigmine patch 9.0 mg/day and will be up-titrated after 4 weeks to reach the maintenance 
dose of 18 mg/day. Should tolerability problems occur, the investigators can decide to interrupt 
the treatment temporarily or to reduce the dose (see Appendix 16.1.1-Protocol-Section 5.5.5). 
The highest well-tolerated dose for each individual patient should be established within the 
titration period. The investigators also can use their clinical judgement to switch those patients 
to slower 3-step titration scheme in order to reach the maintenance dose of 18 mg/day or find 
the highest well-tolerated dose for each individual patient. Those patients will be allowed to 
stay in the study. During the titration period, visits will take place every 4 weeks.
Maintenance phase [16 weeks: week 9 (Day 57) to week 24 (Day 168)].
The patients will be maintained on the maintenance dose of rivastigmine patch 18 mg/day (or 
highest well-tolerated dose) during the remaining period of the study and will undergo safety 
and efficacy assessments as per protocol. If 18 mg/day is not achieved at maintenance period, 


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it will be increased up to 18 mg/day if possible. Patients not tolerating the 18 mg/day will stay 
on their highest tolerated dose in the study and will undergo safety and efficacy assessment as 
per protocol.
Figure 1-1
Study design
The planned number of patients to be enrolled in the study is 97. There are no planned interim 
analyses.
1.2
Study objectives and endpoints
Objectives
Endpoint Title, Description 
and Reporting Time Frame 
for analysis and Unit of 
Measure
Protocol Statistical
Analysis Section
Primary
To evaluate the efficacy of rivastigmine 
patch with 1-step titration on cognitive 
function measured as change from 
baseline to week 24 in the total score of 
MMSE in mild to moderate AD patients 
who failed to benefit from other 
cholinesterase inhibitors (ChEIs) 
Endpoint Title: Change from 
baseline to week 24 in the 
total score of MMSE
Time Frame : Up to week 24
Appendix16.1.1-Protocol-
Section 9.4
Secondary
To evaluate the safety, tolerability of 
Exelon® patch with 1-step titration for up to 
24 weeks.
Endpoint Title: Monitoring 
and recording of all adverse 
events (AEs) and serious 
adverse events (SAEs).
Time Frame: Up to week 24.
Appendix 16.1.1-Protocol-
Section 9.5


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Objectives
Endpoint Title, Description 
and Reporting Time Frame 
for analysis and Unit of 
Measure
Protocol Statistical
Analysis Section
To evaluate the efficacy of Exelon® patch 
with 1-step titration measured as the 
MMSE score at week 8.
Endpoint Title: Change from 
baseline to Week 8 in MMSE 
total score.
Time Frame : Week 8
To evaluate the efficacy of Exelon® patch 
with 1-step titration measured as the NPI-
10 score at week 8 and week 24.
Endpoint Title: Change in 
NPI-10 score from baseline 
to week 8 and week 24
Time Frame : Week 8 and 
Week 24
To evaluate the efficacy of Exelon® patch 
with 1-step titration measured as QOL-AD 
score at week 24.
Endpoint Title: Change in 
QOL-AD score from baseline 
to week 24
Time Frame : Week 24
Appendix 16.1.1-Protocol-
Section 9.5
To evaluate the efficacy of Exelon® patch 
with 1-step titration measured as the J-
CGIC score at week 4, week 8, week 16, 
and week 24.
Endpoint Title: Change in J-
CGIC score from baseline to 
week 4, 8, 16 and 24
Time Frame : Week 4, 8, 16, 
24
To evaluate the efficacy of Exelon® patch 
with 1-step titration measured as Modified 
Crichton Scale score week 4, week 8, 
week 16, and week 24.
Endpoint Title: Change in as 
Modified Crichton Scale 
score from baseline to week 
4, 8, 16 and 24
Time Frame : Week 4, 8, 16, 
24
To evaluate the formulation usability of 
Exelon® patch for up to 24 weeks as 
measured by the formulation usability 
questionnaire answered by caregiver.
Endpoint Title: Formulation 
usability score up to week 24
Time Frame : Up to week 24


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2
Statistical methods
This section contains information that will be used to draft CSR Section 9.7 on statistical 
analysis.
2.1
Data analysis general information
All data will be analyzed by Novartis using the statistical software SAS version 9.4 according 
to the data analysis section 9 of the study protocol which is available in Appendix 16.1.1 of the 
CSR.  Important information is given in the following sections and details are provided, as 
applicable, in Appendix 16.1.9 of the CSR.
In general, the continuous variables will be summarized using standard descriptive statistics 
(mean, median, standard deviation, first (Q25) and third (Q75) quartile, minimum and 
maximum) and the categorical variables will be summarized in terms of the number and 
percentage of patients in each category.
2.1.1
General definitions
2.1.1.1
Study treatment
In this study aims to evaluate the tolerability, safety and efficacy of rivastigmine patch with 1-
step titration in applicable patients with mild to moderate AD switched directly from 
cholinesterase inhibitors (donepezil, galantamine). Therefore, for these patients who had 1-step 
titration, study treatments are:
Form
Size
Exelon® patch 9 mg
5 cm2
Exelon® patch 18 mg
10 cm2
However, for patients who cannot tolerate 1-step titration method to reach the maintenance 
patch dose of 18 mg/day, the investigators will use their clinical judgement to switch those 
patients to slower 3-step titration method in order to reach the maintenance dose of 18 mg/day 
or find the highest well-tolerated dose for each individual patient. Once the dose started at 
4.5 mg of rivastigmine once a day, as a general rule, the dose should be increased to 4.5 mg a 
day at 4-week intervals to 18 mg once a day. Therefore for these patients, study treatments are:
Patients who cannot tolerate 1-step titration will be allowed to participate in the study but will 
be excluded from the per protocol analysis only.
No control treatment is planned in this study.
Form
Size
Exelon® patch 4.5 mg
2.5 cm2
Exelon® patch 9 mg
5 cm2
Exelon® patch 13.5 mg
7.5 cm2
Exelon® patch 18 mg
10 cm2


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2.1.1.2
Study day
Study day is defined with respective to the first day on which treatment with rivastigmine patch 
starts. The date of first administration of study medication is defined as Day 1 and the day 
before is defined as Day -1. There is no Day 0 is a study.
Therefore, for any particular date, study day will be calculated as follows:

for dates on or after the first date of study medication administration,
Study day = Assessment date – Date of first administration of study medication + 1;

for dates prior to the first date of study medication administration,
Study day = Assessment date – Date of first administration of study medication.
2.1.1.3
Baseline definition
Baseline visit (typically Visit 2) is defined as the day on which patients discontinue their prior 
ChE inhibitors. The baseline visit (Visit 2) may or may not be the same as Day 1. . 

It will be same as Day 1 if the patients already stop their ChE inhibitors prior to Day 1 and 
starts treatment with revastigmine patch from Day 1.

on the otherhand, baseline visit (Visit 2, Day -1) will be one day before the Day 1 start of 
study treatment if the patients already took their ChE inhibitors at Visit 2.
In general, all assessments taken prior to the start of study treatment at Visit 2 will be 
considered as the baseline assessment. However, if the baseline assessments for MMSE, vital 
signs and laboratory parameters at Visit 2 are missing, then the measurements taken at Visit 1 
(if available, as per protocol assessment schedule Table 6-1) will be used as baseline.
2.1.1.4
Post-baseline assessments
Post-baseline values are defined as assessments taken after the start of study treatment.
When change from baseline is of interest the following formula will be used for each scheduled 
visit and time-point where baseline and post-baseline values are both available: Change from 
baseline = post-baseline value – baseline value.
2.2
Analysis sets
Full Analysis Set (FAS)
The FAS will include all patients who received at least one dose of study treatment and had at 
least a baseline and any post-baseline assessment on treatment.  This is the primary analysis 
population and will also be used for all efficacy analyses.
Per protocol Set (PP set)
The per protocol set will include all patients in the FAS who had only 1 step titration  without 
any major deviations from the protocol procedures. The major protocol deviations will be 
specified prior to database lock.


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Safety Set (SAF)
The safety set will consist of all patients who received at least one dose of drug and had at least 
one post-baseline safety assessment.
2.2.1
Subgroup of interest
 
2.2.1.1
Subgroup analyses for efficacy endpoints
The following subgroup analyses will be performed for the change from baseline in the total 
MMSE score at each post-baseline visit (i.e., Week 8 and Week 24):

age (≤ 60 years, > 60 years)*

weight (≤ median, > median, in kg, to be determined from the data)

MMSE at baseline (10-14, 15-23 and further 15-23 into 15-19 and 20-23)*

treatment regimen (e.g., overall, 1-step and 3-step titration)

reason for switching to 3-step titration (as captured in the DAR page of CRF, e.g., 
adverse events, lab or test abnormality, lack of efficacy)

Overall compliance to study medication (<75% and 75-100%)

Patient profile analysis1a: Use of skin moisturizer at baseline (yes/no)*
Total
Compliance to study medication (<75% and 75-100%)
Note: skin moisturizer will be identified using the data captured in the prior and 
concomitant medication CRF page and confirmed by the clinical team.

Patient profile analysis 1b: Use of skin management at least one time during study 
period (yes/no)*
Total
Compliance to study medication (<75% and 75-100%)
Note: skin management will be identified using the data captured in the prior and 
concomitant medication CRF page and confirmed by the clinical team.

Patients satisfying protocol inclusion criteria 9-1 only,  9-2 only and both,
respectively captured in the CRF page, are specified below:*
Inclusion criteria 9-1: Patients who are not responding to the previous 
treatment can be defined if the patients meet at least one of these conditions 
at baseline: 
-
Patients who declined ≥ 2 points of MMSE despite of treatment of 
other oral ChE inhibitors within initial 3-month and continued to show 
insufficient treatment effect until at baseline.
-
During 6 months prior to screening visit, Patients who declined ≥2 
points of MMSE with other oral ChE inhibitors and continued to show 
insufficient treatment effect until at baseline.
-
Patients who show marked worsening of BPSD, or ADL (can be 
defined by 1 state progression of FAST) judged by a physician despite 


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of treatment of other oral ChE inhibitors in initial 3-month or last 6-
month with other oral ChE inhibitors
Inclusion criteria 9-2: Patients having difficulties being treated orally with 
ChEIs (donepezil or galantamine) by physician's judgement. Difficulties 
are defined if the patients meet at least one of these conditions at baseline:*
-
Inadequate compliance with the ChE inhibitors at screening and 
baseline
-
Inadequate treatment (efficacious dose was not reached or inadequate 
compliance) with the ChE inhibitors because of AEs except 
gastrointestinal (GI) symptoms (nausea and vomiting) at screening and 
baseline
-
Patients with swallowing difficulties at screening and baseline
Further, a subgroup analysis will be presented for patients satisfying inclusion criteria 
-
9-1 only, 9-2 only and both 9-1 and 9-2
-
9-1-1 only, 9-1-2 only, 9-1-3 only, and 9-1-1 and 9-1-3, and 9-1-2 and 
9-1-3
-
(9-1-1 or 9-1-2) versus (9-1-2 and 9-1-3) versus 9-1-3 only
-
9-1 versus 9-2
-
(9-1 only) versus (9-1 and 9-2) or (9-2 only)
-
(9-2 only) versus (9-1 and 9-2) or (9-1 only)

Patients with concomitant use of memantine (yes/no)

Patients satisfying treatment retention criteria as in Section 2.9.1 (yes/no)
Note: * items will also be illustrated using figures for the CSR.
2.2.1.2
Subgroup analyses for safety endpoints
The following subgroup analyses will be performed for all adverse events summaries as 
mentioned in Section 2.6.2.1:

age (≤ 65 years, > 65 years)

weight (</≥ 40 kg, </≥ 50 kg, </≥ 60 kg)

treatment regimen (overall, 1-step and 3-step titration)

reason for switching to 3-step titration (as captured in the DAR page of CRF, e.g., 
adverse events, lab or test abnormality, lack of efficacy etc.)

Patients satisfying treatment retention criteria as in Section 2.9.1 (yes/no)

overall compliance to study medication (<75% and 75-100%)

Patient profile analysis1a: Use of skin moisturizer at baseline (yes/no)*
Total
Compliance to study medication (<75% and 75-100%)
Note: skin moisturizer will be identified using the data captured in the prior and 
concomitant medication CRF page and confirmed by the clinical team.

Patient profile analysis 1b: Use of skin management at least one time during study 
period (yes/no)*


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Total
Compliance to study medication (<75% and 75-100%)
Note: skin management will be identified using the data captured in the prior 
and concomitant medication CRF page and confirmed by the clinical team.
Amongst AEs of special interest,
1. Gastrointestinal symptoms will be summarized by age, weight and patient profile 
analysis 1a and 1b subgroups as described above,
2. Application site skin reactions and irritations will be summarized by age, weight 
and patient profile analysis 1a and 1b subgroups as described above.
2.3
Patient disposition, demographics and other baseline 
characteristics
Patient demographic and baseline characteristics will be captured at Visit 1 or Visit 2 (only if 
the variable is not already captured at Visit 1). All the baseline and demographic characteristics
will be summarized using the FAS in the CSR. 
2.3.1
Patient disposition
The FAS will be used for the summary and listing of patient disposition.
The number and percentage of patients screened, completed and discontinued the study (and/or 
treatment) will be summarized for FAS population. 
The overall number of patients who were screened, completed the study and discontinued from 
the study (and/or treatment) will also be summarized with reasons for premature discontinuation. 
Patient identification number and whether they completed or discontinued from the study 
(and/or treatment) will be listed, with date of last dose and primary reason for premature 
discontinuation. 
2.3.2
Medical history/current medical condition
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
terminology (MedDRA, current version at database lock). History/conditions will be
summarized for the safety set by primary system organ class and preferred term, and overall. 
Verbatim recorded history/conditions will be listed together with the coded terms, date of 
diagnosis/surgery and whether the problem was ongoing at start of the study. 
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment exposure / compliance
Duration of exposure to the study treatment (rivastigmine patch) will be calculated as the 
number of days exposed to the treatment with rivastigmine patch over the specified period 
(expressed as: Duration of exposure = last known date of rivastigmine patch administration  –
first known date of rivastigmine patch administration + 1).


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The duration of exposure (in days) will be summarized for the safety set as 

a continuous variable with the standard descriptive statistics, and 

a categorical variable classified into <=4 weeks, >4 to <=8 weeks, >8 to <=12 weeks, >12 
to <=16 weeks, >16 to <=20 weeks and >20 to <=24 weeks.
A data listing of the drug doses administered by patients will be provided.
The number and percentage of patients who could stay on 1-step titration and switched 3 step 
titration will also be provided separately.
Investigator reported compliance from eCRF
Compliance will be calculated based on the DAR data. Compliance data will be summarized 
descriptively as a continuous and categorical variable. 
The number and percentages of patients in each of the compliance categories mentioned in the 
eCRF, i.e., Poor (< 25%), Average (≥ 25% to < 50%), Good (≥ 50% to <75%), Very good (≥ 
75% to ≤100%) and Overdose or misuse (>100%) will be summarized In case of over 
compliance (> 100%) the reason will be listed.
Additional summaries will be presented for each compliance category stated above for the 
following subgroups,

use of skin moisturizer at baseline (yes/no)

use of skin management at least one time during study period (yes/no)

inadequate compliance with the ChE inhibitors at screening and baseline (yes/no)

inadequate treatment (efficacious dose was not reached or inadequate compliance) 
with the ChE inhibitors because of AEs except gastrointestinal (GI) symptoms 
(nausea and vomiting) at screening and baseline (yes/no)

swallowing difficulties at screening and baseline (yes/no)
2.4.2
Prior, concomitant and post therapies
Each medication has the start and end dates recorded. Prior medications are defined as those 
medications which were taken and stopped prior to the first dose of study drug. Concomitant 
medications are defined as those medications which were taken on or after the first dose of 
study drug but not prior to the first dose of study drug. Prior/concomitant medications are 
defined as those medications which were taken prior to and continued after the first dose of the 
study drug. All prior and concomitant medications will summarized by primary system organ 
class and preferred term. All prior/concomitant medications will be summarized as concomitant 
medications, and will not be included in prior medication outputs. All concomitant medications 
is also summarized by primary system organ class and preferred terms. 
Surgical and medical procedures (non-drug therapies) will be summarized by primary system 
organ class and preferred term. All summaries will be on the safety set.


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2.5
Analysis of the primary objective
The primary objective is to evaluate the efficacy of rivastigmine patch with 1-step titration on 
cognitive function for mild to moderate AD patients who failed to benefit from other ChEIs as 
change from baseline to Week 24 in the total score of Mini-Mental State Examination (MMSE).
2.5.1
Primary endpoint
The primary variable is change from baseline at Week 24 in the total score of 11 items included 
in the Mini-Mental State Examination (MMSE) for the FAS. Of note, the primary analysis will 
include all patients in the FAS population irrespective of the treatment regimen.
2.5.2
Statistical hypothesis, model, and method of analysis
The change from baseline in MMSE total score will be analyzed using a mixed model repeated 
measures (MMRM) model. The model will contain visit as a fixed effect, baseline MMSE score 
as a covariate and subject as a random effect. An unstructured covariance matrix should be used. 
The estimated mean change at Week 24 along with a two-sided 95% confidence interval and p-
value will be tabulated and presented graphically. P-values will be used in descriptive manner.
Further, the MMSE total score and change from baseline will be summarized using standard 
descriptive statistics by visits.
In addition, the primary endpoint will be summarized and analyzed by subgroups specified in 
Section 2.2.1.1.
The MMRM model of subgroup analysis will contain visit, subgroup (categories) and 
visit*subgroup as fixed effects, baseline MMSE score as a covariate and subject as a random 
effect. An unstructured covariance matrix should be used. The estimated mean change at Week 
24 along with a two-sided 95% confidence interval and p-value will be presented. P-values will 
be used in descriptive manner. Figures will only be provided for selected subgroup analysis as 
specified in Section 2.2.1.1.
2.5.3
Handling of missing values/censoring/discontinuations
The primary analysis will be performed using a MMRM model, which assumes that missing 
data is missing at random (MAR) given the preceding observed data. 
The discontinuations data has been handled as explained in Section 4, point 3. No other 
imputation methods will be considered.
2.5.4
Supportive analyses
As supportive to the primary analysis,
1. The change from baseline at Week 24 in MMSE total score analysis will be repeated using 
the similar MMRM analysis for (1) the Per protocol set and (2) the FAS 3-step set. These 
two analyses will separately present the results for patients who has 1-step and 3-step 
titrations respectively. Tables and corresponding figures will be presented.
2. The change from baseline to Week 24 in MMSE total score will be analyzed using a t-test
for the FAS. The estimated mean change along with 95% confidence interval and two-


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sided p-value will be presented. This analysis will be performed on study completers only 
without any imputation of missing data.
3. The change from baseline to Week 24 in MMSE total score imputed with last observation 
carried forward (LOCF) method will be analyzed using a t-test for the FAS. The estimated 
mean change along with 95% confidence interval and p-value will be presented.
The p-values obtained in the supportive analyses will be descriptive in nature. 
2.6
Analysis of secondary objectives
2.6.1
Efficacy endpoints
All following secondary efficacy variables will be analyzed using the FAS, PP set and subset 
of patients in FAS who had 3-step titration
2.6.1.1
MMSE score at Week 8
The change from baseline to Week 8 in MMSE total score will be summarized descriptively 
and analyzed using the same MMRM model used for the primary analysis. The estimated mean 
change along with two-sided 95% confidence interval will be presented. 
Same figure will present the estimates and 95% confidence intervals of change from baseline 
in MMSE score at both Week 8 and Week 24.
2.6.2
Safety analyses
All safety variables will be reported using the safety set.
In addition, the adverse events, serious adverse events and adverse events of special interest 
summaries described in the following sub-sections will also be presented by the safety 
subgroups specified in Section 2.2.1.2.
2.6.2.1
Adverse events (AEs)
All adverse events starting on or after the first treatment will be included in all summaries and 
will also be listed. Adverse events occurring after signing of the informed consent prior to the 
start of study treatment will be listed only.
These adverse events will also be summarized by overall, by study periods as Week 1 to Week 
4, Week 4 to Week 8, Week 8 to Week 12, Week 12 to Week 16, Week 16 to Week 20 and 
Week 20 to Week 24 by the following variables.
Adverse events by SOC and PT
All adverse events starting on or after the first treatment will be coded utilizing the MedDRA 
dictionary, tabulated, and analyzed by primary system organ class and preferred term.
Primary system organ classes will be sorted alphabetically and, within each primary system 
organ class, the preferred terms will be sorted in descending order of frequency. 
If a patient reported more than one adverse event with the same preferred term, the adverse 
event will be counted only once. If a patient reported more than one adverse event within the 


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same primary system organ class, the patient will be counted only once at the system organ 
class level. 
AEs by severity
All adverse events will be summarized by maximum severity, primary system organ class and 
preferred term. If a patient reports more than one adverse event within the same primary system 
organ class, only one adverse event will be counted for that patient at the highest severity level 
in the total row for each primary system organ class. If a patient reported more than one adverse 
event with the same preferred term, the highest (maximum) severity will be presented. Missing 
severity will be assumed to be severe in the summary table.
AEs suspected to be related to study drug
The treatment emergent adverse events suspected to be related to study drug (according to the 
investigators) will be summarized by primary system organ class and preferred term. 
Relationship to study drug is considered as suspected for those events where "Relationship to 
study drug" is answered by the investigator as "Suspected".
AEs leading to permanent study drug discontinuation
Treatment emergent adverse events leading to permanent study drug discontinuation, regardless 
of study drug relationship, will be summarized by primary system organ class and preferred 
term.
AEs requiring dose adjustment or interruption
Treatment emergent adverse events requiring dose adjustment or interruption, regardless of 
study drug relationship, will be summarized by primary system organ class and preferred term.
2.6.2.2
Serious adverse events (SAE)
Number and percentage of patients with serious adverse events, regardless of study drug 
relationship, will be presented by primary system organ class and preferred term. These SAEs
will also be summarized by overall, by study periods as Week 1 to Week 4, Week 4 to Week 
8, Week 8 to Week 12, Week 12 to Week 16, Week 16 to Week 20 and Week 20 to Week 24.
Additionally separate tables will be provided for SAEs occurring more than 30 days after the 
last treatment administration for patients who discontinued the study treatment but remained in 
the study for more than 30 days and for SAEs which happened between Visit 1 (screening) and 
the time of first treatment for all patients in the safety set.
SAEs will also be listed separately.
2.6.2.3
Adverse events of special interest / grouping of AEs
The adverse events of special interest (Gastrointestinal events and skin events) will be 
summarized separately for the safety set by overall and chronologically by study periods as 
Week 1 to Week 4, Week 4 to Week 8, Week 8 to Week 12, Week 12 to Week 16, Week 16 to 
Week 20 and Week 20 to Week 24. A listing of such AEs will also be presented including action 
taken and outcome.


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AEs of special interest are defined as the following terms. These will be taken from the latest 
MedDRA dictionary at the time of database lock.
GI event (“Gastrointestinal symptoms”)
-HLT “Diarrhoea (excl infective)”
-HLT “Nausea and vomiting symptoms”
Skin event (“Application site skin reactions and irritations”)
-HLT “Application and instillation site reactions”
-PT “Dermatitis allergic”
-PT “Dermatitis contact”
-PT “Administration site reaction”
-PT “Administration site pain”
-PT “Administration site infection”
2.6.2.4
Deaths
All the deaths in the clinical database will be listed with the investigator-reported principal 
cause. Deaths occurring after the first administration of study treatment until 30 days after the 
date of last treatment will be summarized with numbers and percentages.
2.7
Other safety data
2.7.1
Laboratory data
Laboratory measurements will include Hematology (Erythrocyte count, leukocyte count, 
hemoglobin, hematocrit, platelet count); Blood chemistry (Total protein, uric acid, ALP, AST, 
ALT, LDH, cholinesterase, blood urea nitrogen, creatinine, Na, K, Cl, total cholesterol, 
triglycerides, CPK, albumin, Ca, P, total bilirubin, amylase) and Urinalysis (Glucose, protein, 
occult blood).
All data will be converted into SI units (except Cholinesterase, which will be reported as 
collected (in U/L)) listed for the safety set with abnormal values flagged. A listing of all patients 
in the safety set will be provided. 
The change from baseline at Week 24 is provided for Hematology and Chemistry. For urinalysis, 
descriptive statiscs is provided for baseline and Week 24.
Liver function tests
The metabolism of a drug can have an impact on the safety profile of the drug. To evaluate 
potential drug-induced liver injury, the patients with newly occurring or worsening 
abnormalities in liver function tests at any time post-baseline will be listed based on the 
following criteria:
Notable Liver events:


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Definition/ threshold
LIVER EVENTS

ALT or AST > 5 × ULN

ALP > 2 × ULN (in the absence of known bone pathology)

TBL > 2 × ULN (in the absence of known Gilbert syndrome)

ALT or AST > 3 × ULN and INR > 1.5 

Potential Hy’s Law cases (defined as ALT or AST > 3 × ULN and TBL > 2 
× ULN [mainly conjugated fraction] without notable increase in ALP to > 2 
× ULN)

Any clinical event of jaundice (or equivalent term)

ALT or AST > 3 × ULN accompanied by (general) malaise, fatigue, 
abdominal pain, nausea, or vomiting, or rash with eosinophilia

Any adverse event potentially indicative of a liver toxicity*
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-related 
conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver neoplasms
TBL: total bilirubin; ULN: upper limit of normal 
2.7.2
Vital signs
Vital signs measurements include systolic and diastolic blood pressure (SBP and DBP), pulse 
rate, and body weight. The following summaries will be presented for the safety set:
2.7.2.1.1 Summary of absolute values and change from baseline
Vital signs including the changes from baseline will be summarized at the scheduled visits and 
time points. The maximum and minimum post-baseline SBP, DBP, and pulse rate values will 
also be summarized including the respective changes from baseline. 
Body weight will be summarized by scheduled visits.
2.7.2.1.2 Notable absolute values and change from baseline
The number and percentage of patients with newly occurring or worsening notable values, 
including notable change from baseline, will be summarized by vital sign parameter and post-
baseline visit. An additional section will be included for abnormalities occurring at any time 
point over the treatment period, considering all post-baseline data from scheduled, unscheduled 
and premature discontinuation visits. Notable absolute values and notable changes from 
baseline for each vital sign parameter are defined as:
Table 2-1
FDA (DNDP) Criteria:  Clinically Notable Vital Signs Abnormalities
Variable
Change Relative to Baseline
Pulse Rate
> 120 bpm
And an
Increase of  >= 15 bpm
<  50 bpm
And a 
Decrease of >= 15 bpm
Systolic  BP
> 180 mmHg
And an
Increase of >= 20 mmHg
<   90 mmHg
And a
Decrease of >= 20 mmHg
Diastolic BP
> 105 mmHg
And an
Increase of >= 15 mmHg
<   50 mmHg
And a
Decrease of >= 15 mmHg


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Weight
Increase of >= 7%
Decrease of >= 7%
A listing of all patients with notable vital sign values and changes will be provided for the safety 
set.
2.7.3
ECG
ECG measurements include heart rate, QT interval, RR interval, PR interval, QRS duration, 
QTcF and QTcB, taken in a supine position after rest will be summarize descriptively for safety 
set. Listing will be provided for all patients.
2.8
Patient-reported outcomes
The following secondary endpoint related to patient reported outcome will be analyzed:
2.8.1.1
QOL-AD score
The QOL-AD is a brief, 13-item measure designed to obtain a rating of the patient’s Quality of 
Life from the caregiver. A lower score indicates more severe impairment.
The change from baseline at Week 24 in the QOL-AD total and sub-item scores (by patients or 
caregivers) will be summarized along with 95% confidence interval of the mean for the FAS.
Assessment of QOL of a given patient by his/her caregiver should be considered as primary 
measurement while assessment of QOL of a given patient by his/herself will be recorded as 
reference.
In addition, association between QOL-AD total score and each of MMSE total score, NPI-10 
total score, J-CGIC and Modified Crichton Scale total score will be explored. A logistic 
regression will be considered to select the appropriate factors and thereafter to test whether or 
not the selected factors are associated with QOL-AD.
Similarly, the association between QOL-AD and number of gastrointestinal AEs and 
Application skin AEs will be explored using a regression analyses. 
2.9
Caregiver-reported outcomes
The following secondary endpoints related to caregiver reported outcomes will be analyzed:
2.9.1.1
Neuropsychiatric Inventory (NPI) score
The neuropsychiatric symptoms will be assessed by the 10-item Neuropsychiatric Inventory 
(NPI). The NPI-10 total score is a sum of the 10 domains, where the score for a domain is 
defined as the product of frequency (range: 1-4) and severity (range: 1-3). Each domain has a 
maximum score of 12 and all domains are equally weighted for the total score (thus the range 
for the total score is 0 to 120). The NPI-10 total score and individual domain scores will be 
summarized descriptively at visits 2, 4 and 8 respectively. For where, N/A or absent has been 
marked in the crf, value 0 is considered for the same. 


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For change from baseline in NPI-10 total score at Week 24, summary statistics and 95% CI of 
the mean change will be derived for FAS.
2.9.1.2
Modified Crichton Scale
Modified Crichton Scale total score is defined as the sum of 7 items. If at least one missing item 
exists, the total score is set as missing.. 
Modified Crichton Scale total score  will be summarized at visits 2, 3, 4, 6 and 8.
For change from baseline (visit 2), summary statistics and 95% CI of the mean will be derived 
for FAS at visits 3, 4, 6 and 8.
2.9.1.3
Formulation usability questionnaire
This questionnaire data is used to assess if the usability rivastigmine patch is preferred by the 
majority (greater than 50%) of AD patient caregivers or not. This will be assessed using the 
questionnaire in the CRF. The proportion of caregivers preferring the patch will be summarized 
with two-sided 95% confidence intervals for the FAS.
In addition, reasons for questionnaire answers will be summarized by presenting the frequencies 
of endorsed reasons.
2.10
Clinician-reported outcomes
The following secondary endpoint related to clinician reported outcome will be analyzed:
2.10.1.1 J-CGIC
J-CGIC is a global assessment scale to assess change of the patient’s clinical symptoms, which 
are assessed subjectively by clinicians with seven grades. (1: Marked improvement, 2: 
Moderate improvement, 3: Mild improvement, 4: Unchanged, 5: Mild Worsening, 6: Moderated 
Worsening, 7: Marked Worsening). The number and percentage of patients in each grade will 
be displayed at visits 3, 4, 6 and 8. Also, proportion and 95% confidence interval for the 
proportions of the patients without worsening (1: Marked improvement, 2: Moderate 
improvement, 3: Mild improvement, 4: Unchanged) and with improvement (1: Marked 
improvement, 2: Moderate improvement, 3: Mild improvement) will also be provided.
2.11
Other analyses
2.11.1
Treatment retention during the last 8 weeks of maintenance period:
Treatment retention rate will be summarized for the FAS.
Here, “treatment retention” is considered to be successful when a patient meets all of the 
following condition:

complete the study,

receive rivastigmine 18 mg treatment during the last 8 weeks of maintenance period,

never decrease the dose during the last 8 weeks of maintenance period, 


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
comply with drug application ≥75% during the last 8 weeks of maintenance period 
(compliance will be categorized as  Poor (< 25%), Average (≥ 25% to < 50%), Good (≥ 50% 
to <75%), Very good (≥ 75% to ≤100%) and Overdose or misuse (>100%)).
As stated in Section 2.2.1, Subgroup analysis, change from baseline in MMSE score at 
Week 24 and adverse events will be summarized by subgroup of patients satisfying 
treatment retention (yes/no).
Further, treatment retention rate will be summarized in these subgroups as below:

Patient profile analysis 1a: Use of skin moisturizer at baseline (yes/no)*
Total
Compliance to study medication (<75% and 75-100%)

Patient profile analysis 1b: Use of skin management at least one time during study 
period (yes/no)*
Total
Compliance to study medication (<75% and 75-100%)
Note: skin moisturizer or other skin management will be obtained from the prior and 
concomitant medication CRF as captured in the database and confirmed by the study 
medical experts.
2.13
Interim analysis
Not applicable.


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3
Sample size calculation
The sample size is determined as precision-based for the change from baseline in MMSE score 
at week 24. Ninety-seven patients will ensure that the half-width of 95% confidence interval 
for the change from baseline in MMSE score at week 24 would be 0.6, assuming SD=3.0 which 
is estimated from 1301, 1303 and 1403 studies. Assuming drop-outs, a total of 120 patients will 
be enrolled to achieve at least 97 evaluable patients.
4
Change to protocol specified analyses
The following are considered for the analysis which was not planned during the time of protocol 
development:
1. Rate of responses for change from baseline in MMSE total score has been provided
based on Full Analysis Set, Per Protocol Set and subjects with 3-step titration.   
A responder is defined as those patients whose MMSE total score has remained 
unchanged from baseline till Week 24 or, patients whose MMSE total score has 
improved at Week 24 compared to baseline. 
2. For Neuropsychiatric Inventory (NPI), the value 0 is considered wherever N/A or 
Absent has been marked in the eCRF page. 
3. Visit Window for discontinuations: The study does not have a pre-defined visit windows 
for the entire study period. However, correct visit re-mapping for the discontinued 
patients was performed for summarizing and listing the efficacy and safety variables by 
visits. The last records of the discontinued patients are re-mapped to the actual visit 
when they discontinued rather than the Visit 8/discontinuation as per the assessment 
schedule of the protocol.  Re-mapping was done for the discontinued patients to the 
nearest planned visit as per their actual discontinuation/ assessment date for each 
variable.  
The following efficacy assessments: MMSE, NPI-10, QOL-AD, J-CGIC and Modified 
Crichton Scale were re-mapped for the considered discontinued patients as described 
above. 
Under safety assessment, Vitals were considered for re-mapping for the discontinuation 
patients as described above. For other safety assessments, this re-mapping had no impact.  
5
Appendix
This appendix gives details about statistical methods in addition to the report text. All analyses 
will be performed by using SAS version 9.4.
5.1
Imputation rules
1. Adverse events 
AE START DATE IMPUTATION (CENA713D2340)
where AE start date is XX-MON-YYYY and Treatment start date is XX-TRTM-TRTY,


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If YYYY<TRTY and MON missing, then AE start date=1-JULY-YYYY which is prior to 
start of trt
If YYYY<TRTY and MON<TRTM, then AE start date=15-MON-YYYY which is prior to 
start of trt
If YYYY<TRTY and MON=TRTM, then AE start date=15-MON-YYYY which is prior to 
start of trt
If YYYY<TRTY and MON>TRTM, then AE start date=15-MON-YYYY which is prior to 
start of trt
If YYYY=TRTY and MON missing, then AE start date=TRTSTDT+1 
If YYYY=TRTY and MON<TRTM, then AE start date=15-MON-YYYY which is prior to 
start of trt
If YYYY=TRTY and MON=TRTM, then AE start date=max (1-MON-YYYY, TRTSTDT 
+1)
If YYYY=TRTY and MON>TRTM, then AE start date=max (1-MON-YYYY, TRTSTDT 
+1)
If YYYY>TRTY and MON missing, then AE start date=1-JAN-YYYY 
If YYYY>TRTY and MON<TRTM, then AE start date=max (1-MON-YYYY, TRTSTDT 
+1) 
If YYYY>TRTY and MON=TRTM, then AE start date=max (1-MON-YYYY, TRTSTDT 
+1)
If YYYY>TRTY and MON>TRTM, then AE start date=max (1-MON-YYYY, TRTSTDT 
+1)
AE END DATE IMPUTATION (CQVA149A2340)
AE end date = min (last visit date, last know date of contact for discontinued patients, DEC 
31, date of death), if MON is missing and YYYY is present.
AE end date = min (last visit date, last know date of contact for discontinued patients, last day 
of the Month, date of death), if day is missing, MON and YYYY present.
Impute Date Flag (CQVA149A2340)
If not a complete date:
• If year of the imputed date <> YYYY then date flag = Y (not possible since missing dates 
will not be imputed),
• else if month of the imputed date <> MON then date flag = M,
• else if day of the imputed date <> day of original date then date flag = D,
• else date flag = null.
___________________________________________________________________________
_______________________________________________
2. Concomitant medication 
CM start date imputation


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Rules for imputing the CMD start date:
Here TRTSTDT = treatment start date,
1.
If the CMD start date year value is missing, the imputed CMD start 
date is set to TRTSTDT-1, if not after the CMD end date. Thus the 
imputed CMD start date = minimum (TRTSTDT-1, CMD end date).
2.
If the CMD start date year value is less treatment start date year 
value, the CMD started before treatment start. Therefore:
a)
If the CMD year is less than treatment start year and the 
CMD month is missing, the imputed CMD start date is set to 
01JulYYYY.
b)
Else if the CMD year is less than the treatment start year 
and the CMD month is not missing, the imputed CMD start date 
is set to 15MONYYYY.
3. If the CMD start date year value is greater than treatment start 
date year value, the CMD started after treatment start. Therefore:
a) If the CMD year is greater than the treatment start year and 
the CMD month is missing, the imputed CMD start date is set to 
01JanYYYY.
b) Else if the CMD year is greater than the treatment start 
year and the CMD month is not missing, the imputed CMD start 
date is set to 01MONYYYY.
4. If the CMD start date year value is equal to treatment start date 
year:
a) If the CMD month is missing or the CMD month is equal to 
treatment start month, then the imputed CMD start date is set 
to the minimum (TRTSTDT-1, CMD end date).
b) Else if the CMD month is less than the treatment start 
month, the imputed CMD start date is set to 15MONYYYY.
c) Else if the CMD month is greater than the treatment start 
month, the imputed CMD start date is set to 01MONYYYY.
CMD end date imputing:
1.
If the CMD end date is completely missing (and "Ongoing at final 
examination" was not answered "Yes"), the CMD end date will be the 
maximum of treatment end date +1 day and CMD start date.
2.
If a partial CMD end date is reported (day is missing or day and 
month are missing), the CMD end date will be imputed by the maximum 
possible date, i.e., 

the end of the reported month if day is missing, or 


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
the end of the reported year if day and month are missing 
provided that the imputed date is not before the CMD start 
date, 

otherwise CMD end date will be equal to CMD start date.
3. CMTime since first symptoms of AD noticed by patient/caregiver (in 
years), for the partial dates in the data, the dates will be imputed as:

If month and year are present, the 1st of the month is considered 
as the date. For example, if March 2015 is present, it will be 
imputed as 1st March 2015. 

If only year is present, January will be considered as the month 
and 1st as the date. For example, only 2015 is present, it will 
be imputed  as 1st January 2015.
5.2
Rule of exclusion criteria of analysis sets 
The protocol deviations defined for this study are the followings:
Table 1
Protocol deviations that cause patients to be excluded


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Deviation
Code
Text Description
Severity/ Analysis 
Classify action Code
E01
Any medical or neurological condition other than AD 
that could explain the patient’sdementia at baseline.
1
E02
Current diagnosis of probable vascular dementia 
according to National Institute of Neurological 
Disorders & Stroke and AIREN criteria at baseline.
1
E03
A current DSM-IV diagnosis of major depression, 
unless successfully treated with a stable dose of an 
antidepressant without anticholinergic properties for 
at least 4 weeks at baseline
49
E04
Any other DSM-IV Axis1 diagnosis interfering with 
evaluation of patient’s response to study medication 
including other primary neurodegenerative 
dementia,schizophrenia or bipolar disorder at 
baseline.
49
E05
A current diagnosis of active, seizure disorder at 
baseline
49
E06
A history or current diagnosis of severe 
cerebrovascular disease at baseline
49
E07
A current diagnosis of severe or unstable 
cardiovascular disease, hypertension, diabetes at 
baseline
49
E08
A current diagnosis of bradycardia (< 50 bpm), sick-
sinus syndrome, or conduction
defects (sino-atrial block, second or third degree 
atrio-ventricular block) at baseline
49
E09
A current diagnosis of acute, severe, or unstable 
asthmatoid conditions at baseline
49
E10
A current diagnosis of active, uncontrolled peptic 
ulceration or gastro-intestinal bleeding
within the last 3 months from baseline
49
E11
Clinically significant urinary obstruction at baseline
49
E12
Patients with extrapyramidal disorders
49
E13
Patient with complication of gastrointestinal (GI) 
adverse events during oral ChE inhibitors treatment 
except for GI adverse events caused by drugs other 
than oral ChE inhibitors
49
E14
Patients with low body weight as judged by the 
investigators at Visit 1 and/or 2 date
49
E15
Current diagnosis of an active skin lesion/disorder 
that would influence to the adhesion and potential 
skin irritation of the patch at baseline
49
E16
A disability that may prevent the patient from 
completing all study requirements at baseline
49
E17
Patients with a history of hypersensitivity to any 
ingredients of rivastigmine or carbamate
derivatives
49


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E18
Patients who have taken rivastigmine anytime in the 
past
(Please consider partial dates)
49
E19
Any rehabilitation day care and day service during 4 
weeks or more prior to efficacy assessment at 
baseline must not be changed significantly with 
content and frequency (new
start/discontinuation)
49
E20
Taken any investigational drug (including 
investigational biologics) in the 90 days prior to 
baseline or within 5 half-lives of the compound, 
whichever is longer;
49
E21A
Use of donepezil > 5 mg/day 
4 weeks prior to baseline (Visit 2)
1
E21B
Any ChEIs(except 
donepezil,galantamine),selegiline,centrally acting 
anticholinergic drug,olanzapine or tricyclic & 
tetracyclic antidepressants,lithium during 4 weeks 
prior to efficacy assessment at V2
1
E21C
Change of dosage, frequency of donepezil, 
galantamine, memantine during the 4 weeks prior to 
efficacy assessment at baseline (V2)
1
E21D
Succinylcholine-type muscle relaxants, lithium 
during the 2 weeks prior to efficacy
assessment at Visit 2
49
E21E
Newly used benzodiazepine-type hypnotics of short 
duration, newly used or
irregularly used zolpidem tartrate and zopiclone 
within 24 hours prior to efficacy
assessment at Visit 2
49
E21F
Change of dosage and frequency of other specified 
drugs during the 4 weeks prior to efficacy 
assessment at baseline (V2)
49
E22A
Total bilirubin 3.0 mg/dL or above at
Visit1
49
E22B
AST (SGOT) and/or
ALT (SGPT) 3 x ULN
or above at
Visit 1
49
E22C
Plasma creatinine
2.0 mg/dL or above
at Visit1
49
E23
History of malignancy treated or untreated within 
past 5 years with exception of localized basal cell 
carcinoma of skin.
49
E24
Patients diagnosed by investigator as unsuitable for 
inclusion in this clinical study
49


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I01
No written informed consent from patient and/or 
his/her Caregiver at V1
8
I02
Aged ≤49 or ≥86
49
I03
Out patient status at baseline
49
I04
Female with child- bearing potential
49
I05
No diagnosis of mild to moderate AD (dementia of 
the Alzheimer’s type) according to DSM-IV criteria
1
I06
No clinical diagnosis of probable mild to moderate 
AD as per NINCDS-ADRDA criteria
1
I07
A MMSE score of <
10 or > 23 at Visit1 & V2
1
I08A
Patients are not currently on the oral monotherapy 
(donepezil, 5 mg), within 4 weeks prior to baseline 
visit.
49
I08B
Patients are not currently on the galantamine (16-
24 mg) within 4 weeks prior to baseline visit.
49
I09
"Date of MMSE examination " provided must be 
within six months and 14 days prior to screening 
visit date.
49
I09A
Patients who could not receive treatment benefits of 
previous oral ChEIs as defined by meeting either 9-
1 and   9-2 or both, of Inclusion criteria 9 of protocol
49
I10
Unable to read, write, and communicate effectively 
during the premorbid state
49
I11
Could not complete all aspects of the study alone or 
without care giver help
49
I12
Not Residing with someone/ not having daily 
caregiver support /living alone throughout the study
49
I13
Primary caregiver un-willing to accept responsibility 
for supervising treatment, assessing condition of 
patient &  providing input to efficacy assessment
49
M01A
Newly initiation or use prohibit concomitant 
medications/non- drug therapies during the study
1
M01B
Newly initiation or use of prohibit concomitant 
medications (Donepezil and/or Galantamine) during 
the study.
1
M02
New initiation or use/change in restricted 
concomitant medications/non-drug 
therapies/rehabiliation/day care and day 
service/short stay during study, more than prescibed 
dose or duration.
49
O02
Different rater from baseline perform QOL-AD at the 
visit
49
O03
Different rater from visit 3 perform J- CGIC at the 
visit
49
O04
Labelling details of the sample collected
49
O05
Modified Crichton Scale evaluation was not 
completed by caregiver at visits 2,3,4,6 and 8
49


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O06
Additional screening blood test for differrential
diagnosis not performed even though required
49
S01
Applied patch location on body other than back, 
shoulder or chest
49
S02
1-step titration begins treatment with a rivastigmine 
patch 9 mg/day for 4 weeks, followed by a dose 
increase to 18 mg/day.
1
S03
Dose was not maintained for 2 weeks after reducing
the dose due to safety or tolerebility
49
S04
Patient who decreased more than two-dose- levels 
without doctors prescription
1
S05
Different Dose Level applied from protocol specified 
or doctor prescribing. ex) wrong DL was used, more 
than three patches / prescribed number of patches 
were applied,
49
S06
Treatment was not discontinued incase of >28 days 
interruption
6
S07
Restart study drug without prescribed dose 
adjustment after interruption
49
S08
Decrease in the dose- level without prescribed dose 
adjustment by doctor
49
S09
Treatment Not discontinued in case of unfavorable
events/results
49
S10
Non-adherence to patch treatment for less than 50 
percent of study period
1
S11
No rivastigmine medication administered during the 
study period
0
S12
Use expired study drug during study period
49
Table 2 Subject Classification
Analysis Set
PD severity codes that cause a 
subject to be excluded
Criteria that cause a subject to be excluded
FAS
0, 6, 8
Enrolled but no study drug received
PPS
0, 1, 6, 8
NA
SAF
8
Table 3 Severity codes with action taken
Code              Action
0                     Exclude from all efficacy analysis 
1                     Exclude from per protocol analysis
6                     Exclude from Main Analysis Set


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8                     Exclude from all analysis
49                   Report relevant protocol deviation – include in all analyses
5.3
SAS codes for statistical analyses.
5.3.1
Mixed Model Repeated Measures (MMRM) analysis
The change from baseline in MMSE total score will be analyzed using a mixed model repeated 
measures (MMRM) model. The model will contain visit as a fixed effect, baseline MMSE score 
as a covariate and subject as a random effect. An unstructured covariance matrix should be used.
proc mixed data = xxx ;
class visit subjid;
model chg = visit base /noint ddfm =KR alpha = 0.05;
repeated visit /type =UN subject =subjid ;
lsmeans visit /cl;
run;
where,  
chg: change from baseline in MMSE total score
visit: study visits as per protocol assessment schedule,
base: baseline MMSE score
subjid: subject identifier.
5.3.2
MMRM model of subgroup analysis
The MMRM model of subgroup analysis will contain visit, subgroup (categories) and 
visit*subgroup as fixed effects, baseline MMSE score as a covariate and subject as a random 
effect. An unstructured covariance matrix should be used.
proc mixed data = xxx ;
class visit subgrcat subjid;
model chg = visit subgrcat visit*subgrcat base / noint ddfm = KR alpha = 0.05;
repeated visit /type =UN subject =subjid ;
lsmeans visit*subgrcat /cl;
run;
where  
chg: change from baseline in MMSE total score,
visit: study visits as per protocol assessment schedule,
subgrcat: subgroup categories,
visit*subgrcat: interaction effect of visit and subgrcat,
base: baseline MMSE score,


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subjid: subject identifier.
5.3.3
Student’s t-test
The change from baseline to Week 24 in MMSE total score will be analyzed using a t-test.
proc ttest data=xxx;
var chg;
run;
where  
chg: change from baseline in MMSE total score.
5.3.4
Regression Model
Regression Model: QOL-AD total score = MMSE total score + NPI-10 
score + J-CGIC grade + Modified Crichton total score.
Use SAS code:
proc reg data = xxxx;
model QOL-AD total score = MMSE total score NPI-10 score J-CGIC grade Modified 
Crichton total score / selection = forward slentry = 0.95;
run;