A Prospective, 16 Week, Phase IV Study to Evaluate Safety, Tolerability and Effectiveness in Patients With Severe Dementia of the Alzheimer's Type Exposed to Rivastigmine (Exelon)15cm2 Transdermal Patch
Phase: PHASE4
Conditions: Alzheimer's Disease
Sponsor: Novartis Pharmaceuticals

Official Title: 
A Prospective, 16 Week, Phase IV Study to Evaluate 
Safety, Tolerability and Effectiveness in Patients With 
Severe Dementia of the Alzheimer's Type Exposed to 
Rivastigmine (Exelon)15cm2 Transdermal Patch
NCT Number: 
Document Date: Clinical Study Protocol (Version 2.0): 21-December-2016    
NCT02989402 

Clinical Development 
Rivastigmine patch 
Clinical Trial Protocol CENA713DIN01 / NCT02989402
A prospective, 16 week, phase IV study to evaluate safety, 
tolerability and effectiveness in patients with severe dementia of 
the Alzheimer’s type exposed to rivastigmine (Exelon) 15 cm2 
transdermal patch 
Authors: 
, 
 
Document type: 
Clinical Trial Protocol 
Version number: 
V 02 (Original protocol) 
Development phase: 
IV 
Release date: 
21-Dec-2016
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
NCDS Template Version 03-Feb-2012 
PPD
PPD

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Clinical Trial Protocol (Version No. 02) 
 
Protocol No. CENA713DIN01 
 
Table of contents 
 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 5 
List of abbreviations ............................................................................................................ 5 
Glossary of terms ................................................................................................................. 6 
Protocol synopsis ................................................................................................................. 8 
1 
Introduction ....................................................................................................................... 11 
1.1 
Background ............................................................................................................ 11 
1.2 
Purpose .................................................................................................................. 11 
2 
Study objectives ................................................................................................................. 12 
2.1 
Primary .................................................................................................................. 12 
2.2 
Secondary objectives ............................................................................................. 12 
2.3 
Exploratory objectives ........................................................................................... 12 
3 
Investigational plan ........................................................................................................... 12 
3.1 
Study design........................................................................................................... 12 
3.2 
Rationale of study design. ...................................................................................... 13 
3.3 
Rationale of dose/regimen, route of administration and duration of treatment. .... 13 
3.4 
Rationale for choice of comparator ....................................................................... 13 
3.5 
Purpose and timing of interim analyses/design adaptations .................................. 13 
3.6 
Risks and benefits .................................................................................................. 13 
4 
Population .......................................................................................................................... 14 
4.1 
Inclusion criteria .................................................................................................... 14 
4.2 
Exclusion criteria ................................................................................................... 15 
5 
Treatment ........................................................................... Error! Bookmark not defined. 
5.1 
Protocol requested treatment ................................................................................. 15 
5.1.1 
Investigational treatment ....................................................................... 15 
5.1.2 
Additional study treatment .................................................................... 15 
5.2 
Treatment arms. ..................................................................................................... 15 
5.3 
Treatment assignment, randomization. .................................................................. 15 
5.4 
Treating the patient ................................................................................................ 15 
5.4.1 
Patient numbering ................................................................................. 15 
5.4.2 
Dispensing the investigational treatment .............................................. 15 
5.4.3 
Handling of study treatment. ................................................................. 15 
5.4.4 
Handling of investigational treatment ................................................... 15 
5.4.5 
Instructions for prescribing and taking study treatment ........................ 16 
5.4.6 
Permitted dose adjustments and interruptions of study treatment ........ 16 

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5.4.7 
Rescue medication ................................................................................ 16 
5.4.8 
Concomitant treatment .......................................................................... 16 
5.4.9 
Prohibited Treatment ............................................................................. 16 
5.4.10 
Discontinuation of study treatment and premature patient 
withdrawal ............................................................................................. 16 
5.4.11 
Emergency breaking of treatment assignment ...................................... 17 
5.4.12 
Study completion and post-study treatment .......................................... 17 
5.4.13 
Early study termination ......................................................................... 17 
6 
Visit schedule and assessments ......................................................................................... 17 
6.1 
Information to be collected on screening failures.................................................. 19 
6.2 
Patient demographics/other baseline characteristics ............................................. 19 
6.3 
Treatment exposure and compliance ..................................................................... 19 
6.4.1 
Efficacy assessment .............................................................................. 19 
6.4.2 
Appropriateness of efficacy assessments .............................................. 20 
6.5 
Safety ..................................................................................................................... 20 
6.5.1 
Physical examination ............................................................................ 20 
6.5.2 
Dermatology examination: .................................................................... 20 
6.5.3 
Vital signs.............................................................................................. 21 
6.5.4 
Height and weight ................................................................................. 21 
6.5.5 
Patch adhesion assessment: ................................................................... 21 
6.5.6 
Laboratory evaluations .......................................................................... 21 
6.5.7 
Appropriateness of safety measurements .............................................. 21 
6.6 
Other assessments .................................................................................................. 22 
6.6.1 
Treatment and compliance: ................................................................... 22 
6.6.2 
Health-related Quality of Life ............................................................... 22 
6.6.3 
Pharmacokinetics .................................................................................. 22 
6.6.4 
Pharmacogenetics/pharmacogenomics ................................................. 22 
6.6.5 
Other biomarkers: .................................................................................. 22 
7 
Safety monitoring .............................................................................................................. 22 
7.1 
Adverse events ....................................................................................................... 22 
7.2 
Serious adverse event reporting ............................................................................. 24 
7.3 
Pregnancy reporting ............................................................................................... 25 
8 
Data review and database management ............................................................................. 25 
8.1 
Site monitoring ...................................................................................................... 25 
8.2 
Data collection ....................................................................................................... 26 
8.3 
Database management and quality control ............................................................ 26 
8.4 
Data Monitoring Committee .................................................................................. 26 

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8.5 
Adjudication Committee ........................................................................................ 26 
9 
Data analysis ...................................................................................................................... 26 
9.1 
Analysis sets .......................................................................................................... 26 
9.2 
Patient demographics and other baseline characteristics ....................................... 27 
9.3 
Treatments ............................................................................................................. 27 
9.4 
Analysis of the primary and key secondary variable(s)......................................... 27 
9.4.1 
Primary Variable ................................................................................... 27 
9.4.2 
Statistical model, hypothesis, and method of analysis .......................... 27 
9.4.3 
Handling of missing values/censoring/discontinuations. ...................... 27 
9.4.4 
Supportive analyses ............................................................................... 27 
9.5 
Analysis of secondary variables ............................................................................ 27 
9.5.1 
Efficacy variables .................................................................................. 27 
9.5.2 
Safety variables ..................................................................................... 28 
9.5.3 
Resource utilization ............................................................................... 28 
9.5.4 
Health-related Quality of Life ............................................................... 28 
9.5.5 
Pharmacokinetics .................................................................................. 28 
9.5.6 
Pharmacogenetics/pharmacogenomics ................................................. 28 
9.5.7 
Biomarkers ............................................................................................ 28 
9.5.8 
PK/PD ................................................................................................... 28 
9.6 
Interim analyses ..................................................................................................... 28 
9.7 
Sample size calculation .......................................................................................... 28 
10 Ethical considerations ........................................................................................................ 29 
10.1 
Regulatory and ethical compliance ........................................................................ 29 
10.2 
Informed consent procedures ................................................................................. 29 
10.3 
Responsibilities of the investigator and IRB/IEC .................................................. 29 
10.4 
Publication of study protocol and results............................................................... 30 
11 Protocol adherence ............................................................................................................ 30 
11.1 
Protocol Amendments ........................................................................................... 30 
12 References: ........................................................................................................................ 30 
13 Appendix 1– Caregiver Medication Questionnaire ........................................................... 31 
14 Appendix 2: Patient Instructions for use and handling exelon patch ................................ 34 
 
 
 
 
 

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List of tables 
List of abbreviations 
AE 
Adverse event 
AD                      Alzheimer’s disease   
b.i.d. 
twice a day 
CMQ                 Caregiver Medication Questionnaire 
CRF 
Case Report/Record Form (paper ) 
CPO 
Country Pharma Organization 
CRO 
Contract Research Organization 
ECG 
Electrocardiogram 
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
i.v. 
Intravenous 
IRB 
Institutional Review Board 
MMSE                Mini-Mental State Examination  
o.d. 
once a day 
p.o. 
oral 
SAE 
serious adverse event 
 

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Glossary of terms 
 
Assessment 
A procedure used to generate data required by the study 
Control drug 
Drugs(s) used as a comparator to reduce assessment bias, 
preserve blinding of investigational drug, assess internal study 
validity, and/or evaluate comparative effects of the investigational 
drug 
Enrollment 
Point/time of patient entry into the study; the point at which 
informed consent must be obtained (i.e. prior to starting any of the 
procedures described in the protocol) 
Epoch  
The planned stage of the subjects’ participation in the study. Each 
epoch serves a purpose in the study as a whole. Typical epochs 
are: determination of subject eligibility, wash-out of previous 
treatments, exposure of subject to treatment or to follow-up on 
subjects after treatment has ended. 
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 other 
treatments administered as concomitant background therapy 
required or allowed by the protocol when used within approved 
indication/dosage 
Medication number 
A unique identifier on the label of each investigational/study drug 
package in studies that dispense medication using an IRT system 
Subject Number  
A number assigned to each patient who enrolls into the study  
Part  
A subdivision of a single protocol into major design components. 
These parts often are independent of each other and have different 
populations or objectives. For example, a single dose design, a 
multiple dose design that are combined into one protocol, or the 
same design with different patient populations in each part. 
Period 
A subdivision of a cross-over study 
Premature patient withdrawal 
Point/time when the patient exits from the study prior to the 
planned completion of all investigational/study treatment 
administration and all assessments (including follow-up) 
Randomization number 
A unique identifier assigned to each randomized patient, 
corresponding to a specific treatment arm assignment 
Stop study participation 
Point/time at which the patient came in for a final evaluation visit or 
when study/investigational treatment was discontinued whichever 
is later 
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 
Point/time when patient permanently stops taking 

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Protocol No. CENA713DIN01 
discontinuation 
study/investigational treatment  for any reason; may or may not 
also be the point/time of premature patient withdrawal 
Variable 
Information used in the data analysis; derived directly or indirectly 
from data collected using specified assessments at specified time 
points 
 

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Protocol No. CENA713DIN01 
Protocol synopsis 
  
Protocol number 
CENA713DIN01 
Title 
A prospective, 16 week, phase IV study to evaluate safety, 
tolerability and effectiveness in patients with severe dementia of the 
Alzheimer’s 
type 
exposed 
to 
rivastigmine 
(Exelon)15cm2 
transdermal patch 
Brief title 
 
Study of safety and effectiveness  of Rivastigmine  in Alzheimer 
patients  
 
Sponsor and Clinical 
Phase 
Novartis  
 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and rationale 
The present phase IV study is mandated by Indian health authority 
(HA) as a part of conditional approval to market authorization of 
rivastigmine 27 mg -15 cm2 transdermal patch for treatment of 
severe dementia secondary to Alzheimer’s disease (AD). The HA 
mandated phase IV study in their approval letter. Due to non- 
availability of Indian data for rivastigmine 27 mg -15 cm2 
transdermal patch in severe dementia secondary to Alzheimer’s 
disease (AD) patients, marketing authorization of the same has been 
granted condition to phase IV study. As per HA letter, interventional 
study is to be conducted. 
Thus the present 16 week study will be conducted to evaluate safety, 
tolerability and effectiveness in patients with severe dementia of the 
Alzheimer’s type exposed to rivastigmine 27 mg -15 cm2 
transdermal patch as mandated by HA. Most frequent AEs in 
ACTION study were application site erythema/ dermatitis and UTI, 
the present study shall assess application site reaction and urine 
examination.  
 
 
Primary Objective(s) 
and Key Secondary 
Objective 
To obtain safety data in patients with severe dementia of the 
Alzheimer’s type treated with rivastigmine 27 mg -15 cm2 
transdermal patch for 16 weeks  
Secondary Objectives 
 
 To assess patients compliance of  rivastigmine 27 mg -15 cm2 
transdermal patch during 16 weeks treatment period 

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Protocol No. CENA713DIN01 
 To assess the skin tolerability (irritation and adhesion) during 16 
weeks treatment period 
 To assess the proportion of patients with UTI during 16 weeks 
treatment period 
 To evaluate treatment effect by rivastigmine 27 mg -15 cm2 
transdermal patch by assessing the changes in Mini-Mental State 
Examination (MMSE)  
 
To evaluate treatment efficacy by rivastigmine 27 mg -15 cm2 
transdermal patch by assessing the changes in ADCS-Activities of 
Daily Living Inventory – Severe Impairment Version (ADCS-ADL SIV) 
Score 
 
 
Study design 
This is a multicenter, prospective, phase IV study evaluating safety, 
tolerability and effectiveness of rivastigmine 27 mg -15 cm2   
transdermal patch prescribed in patients with severe dementia of 
the Alzheimer’s type as per discretion of treating physician.  
The prescription decision shall be independent of decision for 
inclusion in the study. Patients treated according to local routine 
clinical practice will be enrolled in the study upon signing an 
Informed Consent. Eligibility for study entry will be determined by 
the study investigator, in accordance with the selection criteria 
below. Signing of the Informed Consent defines the study entry 
visit. Routine urine examination shall be done to detect any UTI. 
Compliance to treatment directions shall be reviewed by treating 
investigator at every visit. 
After 8 week and at 16 week, it is expected for the physician to 
follow up as per routine practice in India. The treating physician will 
assess the safety, tolerability and effectiveness of the rivastigmine 
27 mg -15 cm2  transdermal patch and may consider continuing or 
changing the therapy 
Population 
Alzheimer’s disease patients 
Inclusion criteria 
1. Patients willing to participate in the study by providing written 
informed consent. 
2. Patients diagnosed with severe dementia secondary to 
Alzheimer’s disease (AD) 
 
Exclusion criteria 
1. Contraindication as per PI 
2. Patients simultaneously participating in other studies 
 

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Protocol No. CENA713DIN01 
Investigational and 
reference therapy 
Rivastigmine patch  15cm2 
Efficacy assessments 
 
Mini-Mental State Examination (MMSE) 
 ADCS-Activities 
of 
Daily 
Living 
Inventory 
– 
Severe 
Impairment Version (ADCS-ADL SIV) Score 
 
 
Safety assessments 
 
Urine examination 
 
Skin reaction at patch  
 
Patch adhesion     
 
Adverse events  
Other assessments 
 
Compliance by Caregiver medication 
questionnaire 
 
Data analysis 
The primary safety objective of this study will be assessed by 
collecting adverse events. The key secondary objective of this study 
will be assessed by compliance measured by caregiver 
questionnaire, skin reaction and change in MMSE from baseline 
Key words 
Alzheimer, Rivastigmine, 
 

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1 
Introduction 
1.1 
Background  
1.2 
Purpose  
Alzheimer’s disease (AD), a progressive neurodegenerative disorder, is the most prominent 
cognitive disorder of the elderly. The prevalence of AD in people over the age of 65 is 5-10%, 
and increases up to 50% in those over the age of 85 (Small GW, 1995). The Alzheimer’s 
Association estimates that in 2008, as many as 5.2 million Americans have AD (Alzheimer’s 
Association, 2008). 
Multiple deficits of neurotransmitters occur in the brain of AD patients. However, the most 
common is a decrease in levels of acetylcholine (ACh), which is due to a loss of presynaptic 
cholinergic nerve terminals. These cholinergic deficits are most apparent in the areas of the 
brain involved in memory and cognition, i.e., the frontal cortex and hippocampus (Perry et al, 
1978). 
Currently, there are two compounds approved in the US for the treatment of severe dementia 
of the Alzheimer’s type, the cholinesterase inhibitor donepezil and the glutamate modifying 
agent memantine. Both are often used together. With only one agent in each class available to 
treat patients with severe dementia of the Alzheimer’s type, there is significant medical need 
to have other approved agents available, including those that have an alternative route to oral 
administration. 
A number of treatment strategies involving the cholinergic system have been evaluated. 
Cholinesterase inhibitors (ChEIs), including rivastigmine (also known as ENA713 and 
Exelon®), have been shown to be effective in improving cognitive and global functioning in 
mild to moderate AD patients (Kumar et al, 1991; Knapp et al, 1994; Rogers et al, 1998; 
Corey-Bloom et al, 1998; Rösler et al, 1999; Raskind et al, 2000; Tariot et al, 2000). 
Memantine has established efficacy in moderate to severe dementia of the Alzheimer’s type 
(Reisberg et al, 2003; Tariot et al, 2004; van Dyck et al, 2007) and can be used as an 
augmenting agent with ChEIs. 
The need for effective and well-tolerated treatments for AD (both symptomatic and disease 
modifying) remains great. Exelon® transdermal patch, prescribed once-daily, has the potential 
to offer improved caregiver and patient convenience in severe dementia of the Alzheimer’s 
type, which may contribute to an improvement in patient compliance. In addition, this 
formulation is useful for patients unable to take oral medication. Exelon® (rivastigmine) is a 
slowly reversible (pseudo-irreversible), brain selective, dual inhibitor of Acetyl cholinesterase 
(AChE) and Butyryl cholinesterase inhibitors (BuChE) of the carbamate type. Exelon® exerts 
its therapeutic effect by enhancing cholinergic function. This is accomplished by increasing 
the concentration of acetylcholine through reversible cholinesterase inhibition. The present 
study is mandated by Indian health authority (HA) as a part of conditional approval to market 
authorization of rivastigmine 27 mg- 15 cm2 transdermal patch for treatment of severe 
dementia secondary to Alzheimer’s disease (AD).  

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Thus the present 16 week study will be conducted to evaluate safety, tolerability and 
effectiveness in patients with severe dementia of the Alzheimer’s type exposed to 
rivastigmine 27 mg -15 cm2 transdermal patch as mandated by HA. Most frequent AEs in 
ACTION study were application site erythema/ dermatitis and UTI, the present study shall 
assess application site reaction and urine examination 
2 
Study objectives 
 
2.1 
Primary  
Primary objective: To obtain safety data in patients with severe dementia of the Alzheimer’s 
type treated with rivastigmine 27 mg -15 cm2 transdermal patch for 16 weeks  
2.2 
Secondary objectives 
Secondary objectives:  
 To assess patients compliance of  rivastigmine 27 mg -15 cm2 transdermal patch during 
16 weeks treatment period 
 To assess the skin tolerability (irritation and adhesion) during 16 weeks treatment period 
 To assess the proportion of patients with UTI during 16 weeks treatment period 
 To evaluate treatment effect by rivastigmine 27 mg -15 cm2 transdermal patch by 
assessing the changes in Mini-Mental State Examination (MMSE)  
 To evaluate treatment efficacy by rivastigmine 27 mg -15 cm2 transdermal patch by 
assessing the changes in ADCS-Activities of Daily Living Inventory – Severe Impairment 
Version (ADCS-ADL SIV) Score 
 
2.3 
Exploratory objectives  
None   
3 
Investigational plan 
3.1 
Study design 
This is a multicenter, prospective, phase IV study evaluating safety, tolerability and 
effectiveness of rivastigmine 27 mg -15 cm2 transdermal patch prescribed in patients with 
severe dementia of the Alzheimer’s type as per discretion of treating physician.  
The prescription decision shall be independent of decision for inclusion in the study. Patients 
treated according to local routine clinical practice will be enrolled in the study upon signing 
an Informed Consent. Eligibility for study entry will be determined by the study investigator, 
in accordance with the selection criteria below. Signing of the Informed Consent defines the 

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Protocol No. CENA713DIN01 
study entry visit. Routine urine examination shall be done to detect any UTI. Compliance to 
treatment directions shall be reviewed by treating investigator at every visit. 
After 8 week and at 16 week, it is expected for the physician to follow up as per routine 
practice in India. The treating physician will assess the safety, tolerability and effectiveness 
of the rivastigmine 27 mg -15 cm2 transdermal patch and may consider continuing or 
changing the therapy. 
3.2 
Rationale of study design. 
This is open label study to examine the safety, effectiveness, and tolerability of the treatment 
in routine clinical practice, to determine how the treatment works under ordinary and variable 
conditions, prescribed by clinicians with varying degrees of expertise and practicing across 
the spectrum of health care settings, to treat a heterogeneous group of patients.  
3.3 
Rationale of dose/regimen, route of administration and duration 
of treatment. 
 Dose and regimen is as per approved label in India for rivastigmine. 
3.4 
Rationale for choice of comparator 
No comparator is used in study  
3.5 
Purpose and timing of interim analyses/design adaptations 
Not applicable  
3.6 
Risks and benefits  
 
Rivastigmine is approved for the treatment of mild to moderately severe dementia of the 
Alzheimer type (and in some countries mild to moderately severe dementia associated with 
PD and severe dementia of the Alzheimer’s type). In most cases the drug is used as a 
monotherapy, although in some cases it is used along with memantine. Prescription of the 
medication is initiated at a low dose and increased according to the patient’s response and 
tolerance. Total period prescription numbers of the oral formulations are steadily decreasing 
to be replaced by increasing numbers of prescriptions of the transdermal (Patch) formulations. 
The treatment is initiated at patch 5cm2 and increased to patch 10 cm² after a minimum of 
four weeks of treatment if well tolerated and then, if appropriate to patch 15 cm2.  
 
The benefit of rivastigmine has been seen in multiple clinical trials, in both placebo and 
active-controlled trials (using low dose Exelon as the active comparator). The ability of 
rivastigmine to positively affect the symptoms of AD and Parkinson's disease dementia has 
been demonstrated in six randomized double-blind, placebo-controlled clinical trials with 
4517 patients with mild to moderate AD and in one randomized double blind placebo 
controlled trial with Parkinson's disease dementia with 541 patients. There was one 
(ENA713D2340) active controlled trial in mild to moderate AD with 1582 patients. There was 
one active controlled trial (US44 and US44E1) with extension for severe AD. 
 

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Clinically significant improvement in AD and Parkinson's disease dementia symptoms were 
observed in all but one clinical trial with response rates, in the transdermal formulations, 
achieved predominantly in patch 10 cm² and patch 15 cm2 users. Dementia improvement was 
seen in all tested demographics. The most frequently reported AEs were nausea, vomiting and 
diarrhea. This is consistent with Exelon’s cholinergic effects and with results seen with 
Exelon® capsule. Action study with 15 cem Patch has demonstrated The 13.3 mg/24 h patch 
demonstrated superior efficacy to 4.6 mg/24 h patch on Severe Impairment Battery (SIB) and 
AD Cooperative Study–Activities of Daily Living scale–Severe Impairment Version (ADCS-
ADL-SIV), without marked increase in AEs, suggesting higher-dose patch has a favorable 
benefit-to-risk profile in severe AD.  
 
No pivotal clinical trials are ongoing except for CENA713D2409 which is a PASS drug 
utilization study to assess medication errors and misuse and multiple patch use in particular. 
All identified and potential risk are discussed in the Exelon RMP (version 8.0) and PSUR 24 
(DLP 31 Jan 2016) and no new risks have been added and several have been removed in the 
last 2 PSURs. The sole risk with an ongoing risk minimization strategy is for medication 
errors(specifically multiple patch use) which is currently being actively implemented . 
Previous clinical trial results have been data-mined as a means for expanding MAH 
knowledge of the previously unstudied population of patients with pre-existing renal 
compromise and pre-existing cardiac disorders. No risk for use of rivastigmine in these 
populations has been detected to date. The company is continuing to investigate the increased 
reporting rate of skin reactions in the Japanese population which may result from intensive 
local pharmacovigilance collection techniques and determine if further measures are 
necessary. 
 
The risk benefit ratio for Exelon (oral and transdermal formulations) remains positive. 
4 
Population 
The study population will consist of male and female patients diagnosed with Alzheimer’s 
disease and prescribed with rivastigmine 27mg -15 cm2 transdermal patch as per discretion of 
treating physician. Inclusion and exclusion criteria follow the approved indication and 
contraindications, as mentioned in package insert (PI) in India 
4.1 
Inclusion criteria 
Patients eligible for inclusion in this study have to fulfill all of the following criteria: 
 Patients willing to participate in the study by providing written informed consent. 
 Patients diagnosed with severe dementia secondary to Alzheimer’s disease (AD) 
 Patient’s prescribed with rivastigmine 27mg -15 cm2 transdermal patch as per 
discretion of treating physician  
 

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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. 
Exclusion criteria: 
1. Contraindication as per PI 
2. Patients simultaneously participating in other studies 
4.3 
Protocol requested treatment 
4.3.1 
Investigational treatment 
The study will include the following open-label drug: 
Exelon© patch: 15 cm2 patch sizes loaded with 27 mg of rivastigmine 
4.3.2 
Additional study treatment 
No additional treatment beyond investigational treatment is requested for this trial. 
4.4 
Treatment arms. 
 Single arm study 
4.5 
Treatment assignment, randomization. 
 No protocol specific treatment will be assigned to subjects.  
4.6 
Treating the patient 
4.6.1 
Patient numbering  
Each patient is uniquely identified by a Subject Number which is composed by the site 
number assigned by Novartis and a sequential number assigned by the investigator. 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 
by the investigator. The reason for not being treated will be entered on the Screening Epoch 
Study Disposition CRF. 
4.6.2 
Dispensing the investigational treatment 
 Commercial Novartis drugs will be locally purchased. 
4.6.3 
Handling of study treatment. 
Not applicable.  
4.6.4 
Handling of investigational treatment 
Not applicable. 

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4.6.5 
Instructions for prescribing and taking study treatment 
The investigator should promote compliance by instructing the patient to take the study 
treatment 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 the investigator 
if he/she is unable for any reason to take the study treatment as prescribed. 
Refer to appendix 2 for instruction for applying the patch  
4.6.6 
Permitted dose adjustments and interruptions of study treatment 
 
For patients who are unable to tolerate the protocol-specified dosing scheme, dose  
adjustments and interruptions are permitted in order to keep the patient on study drug. If 
necessary, the patient may be instructed to skip certain doses for a prescribed length of time 
(e.g., skip one or two day’s doses) until tolerability has improved. The following treatment  
adjustment scheme is recommended:  
• If tolerability problem arises: The caregiver should remove the patch(es) on the day 
the tolerability problems arise and skip 1 or 2 days of treatment. 
• Tolerability should be reassessed after the patient has skipped the recommended days 
of treatment.  
• If tolerability problems have improved, and consecutive days of missed doses is ≤ 3 
days, treatment may be restarted at the same DL.  
• If tolerability is still an issue, restart treatment at the next lower DL. 
• The patient should then resume the titration schedule if tolerability issues have 
improved. 
• If subsequent titration again leads to a tolerability problem, doses may again be 
skipped and the DL should be decreased to the next lower DL 
• Further attempts to titrate the dose upward are at the investigator’s discretion (i.e., if 
necessary for tolerability, titration to the target dose need not be achieved) 
4.6.7 
Rescue medication 
Not applicable 
4.6.8 
Concomitant treatment 
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. 
4.6.9 
Prohibited Treatment 
No prohibited medication  
4.6.10 
Discontinuation of study treatment and premature patient withdrawal 
The planned duration of the study is 16  weeks (+/- 2 weeks) and patients should be followed until 
the end of the study except if any of the following conditions for early termination are met:  
 
Voluntary discontinuation (withdrawal of consent to collect or use their data)  

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 
Treatment discontinuation (patient no longer take the medication under observation)  
 
Addition of second AD treatment (patient no longer on monotherapy)  
 
All data generated up to the time of voluntary discontinuation (withdrawal of consent) and the 
reason(s) for discontinuation will be recorded. Patients who choose to withdraw consent will no 
longer be contacted for follow up information.  
 
Patients who discontinue treatment or patients who are no longer on monotherapy should be asked 
to return for an early discontinuation assessment. For patients who are lost to follow-up (i.e. those 
patients whose status is unclear because they fail to appear for study visits without stating an 
intention to withdraw), the physician should show "due diligence" by contacting the patients and 
asking them to return for a final assessment. Every effort should be made to obtain reason for 
discontinuation. The physician should document in the source documents steps taken to contact 
the patient, e.g. dates of telephone calls, registered letters, etc. 
4.6.11 
Emergency breaking of treatment assignment 
Not applicable  
4.6.12 
Study completion and post-study treatment 
Study completion for an individual patient will be 16 weeks. At the end of study, patient would 
continue to receive treatment as per the discretion of Investigator. 
4.6.13 
Early study termination 
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible and treated for 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 IRBs and/or ECs of the early termination of the 
trial. 
5 
Visit schedule and assessments 
 
Error! Reference source not found. lists all of the assessments and indicates with an “x” 
when the visits are performed. 
 

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EOS = End of Study 
X = Assessment to be recorded on CRF 
*Physical examination includes examination of general appearance, skin, neck (including thyroid), eyes (excluding fundus), 
ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, and extremities. In addition, a neurological exam consisting of 
cranial nerve, motor and sensory assessments as performed in routine clinical practice. It also includes recording of pulse 
and blood pressure as per routine clinical care. 
** Height is assessed only at Visit 1 
At a minimum, patients will be contacted for safety evaluations during the 30 days following 
the last study visit or following the last administration of study treatment), including a final 
contact at the 30-day point. Documentation of attempts to contact the patient should be 
recorded in the source documentation.  
 
Examination 
Baseline Visit 
1 
(Day 1) 
Visit-2 
(8 ± 2 
weeks) 
EOS Visit 3 
(16 ± 2 
weeks) 
Informed consent 
X 
 
 
Patient demographics (sex, age, etc) 
X 
 
 
Relevant medical history 
X 
 
 
Vitals  
X 
X 
X 
Physical examination*  
X 
X 
X 
Height** and weight 
X 
X 
X 
Inclusion/Exclusion criteria 
X 
 
 
MMSE score 
X 
X 
X 
ADCS-ADL SIV score 
X 
 
X 
Concomitant medications  
 
X 
X 
Treatment for AD 
X 
X 
X 
Urine examination 
X 
X 
X 
Skin irritation assessment 
 
X 
X 
Patch adhesion assessment 
 
X 
X 
Adverse Events (AEs)and Serious Adverse Events (SAEs) 
recording 
X 
X 
X 
Compliance assessment using caregiver questionnaire 
 
X 
X 
EOS 
 
 
X 

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5.1 
Information to be collected on screening failures 
For all patients who have signed informed consent and are entered into the next epoch of the 
study will have all adverse events occurring after informed consent is signed recorded on 
the Adverse Event CRF. 
Investigators will have the discretion to record abnormal test findings on the medical history 
CRF whenever in their judgment, the test abnormality occurred prior to the informed consent 
signature. 
5.2 
Patient demographics/other baseline characteristics 
 Date of birth or age and gender 
 Relevant Medical history  
At subsequent visits throughout the observation period, the following information will be 
updated: 
 Change in concomitant medications 
 Treatment taken for  AD 
 Physical examination which includes examination of general appearance, skin, neck 
(including thyroid), eyes (excluding fundus), ears, nose, throat, lungs, heart, abdomen, 
back, lymph nodes, and extremities. In addition, a neurological exam consisting of 
cranial nerve, motor and sensory assessments as performed in routine clinical 
practice.It also includes recording of pulse and blood pressure as per routine clinical 
care 
 Mini-Mental State Examination (MMSE) 
 ADCS-ADL SIV score 
5.3 
Treatment exposure and compliance 
 
Study drug patch administered during the course of the study will be recorded on the 
corresponding Dosage Administration Record CRF 
Other drugs administered prior to and continuing at start of study medication will be entered 
on the ‘Concomitant medications/significant non-drug therapies prior to the start of study’ 
CRF. 
Compliance will be assessed by the investigator and/or study personnel at each visit using 
information provided by the patient. This information should be captured in the source 
document at each visit 
 
5.4 
Efficacy 
5.4.1 
Efficacy assessment  
Mini-Mental State Examination (MMSE):  
Assessing the changes in Mini-Mental State Examination (MMSE): The MMSE is a brief, 
practical screening test for cognitive dysfunction (Folstein et al. 1975). The test consists of 

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five sections (orientation, registration, attention-calculation, recall, and language & Praxis) 
and results in a total possible score of 30, with higher scores indicating better function. 
MMSE shall be recorded at the start and at each visit as mentioned in table 5.1as a part of 
routine clinical practice.  
ADCS-ADL SIV score*: 
This is a tool to assess the ability of patients with moderate to severe dementia to perform 
activities of daily living.  ADCS-ADL SIV score is done at start and end of visit. This 
includes 19 questions and total score is 54. Administration instructions and Instruction card 
for the rater to use when administering the scale is separately provided  
 
*“Used with permission from the NIA Alzheimer’s Disease Cooperative Study (NIA Grant AG10483)”. 
5.4.2 
Appropriateness of efficacy assessments  
MMSE and ADCS-ADL SIV score is standard assessment tool for cognitive examination 
5.5 
Safety 
5.5.1 
Physical examination 
A complete physical examination will include the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, vascular and neurological. If indicated based on medical history and/or 
symptoms, rectal, external genitalia, breast, and pelvic exams will be performed. 
Information for all physical examinations must be included in the source documentation at the 
study site. Significant findings that are present prior to signing informed consent must be 
included in the Medical History part of the CRF. Significant findings made after signing the 
informed consent which meet the definition of an Adverse Event must be recorded on the 
Adverse Event section of the CRF. 
5.5.2 
Dermatology examination:  
The following score system will be used to assess skin irritation: 
I. Dermal response: 
0 = No erythema (normal skin) 
1 = Erythema barely visible 
2 = Mild erythema 
3 = Moderate erythema 
4 = Severe erythema 
5 = Severe erythema with vesicles or blisters 
II. Other effects: 
O : Edema 
P : Papules (many small, red, solid, elevated lesions, surface of reaction with granular feeling) 
V : Small vesicles (< 0.5 cm) circumscribed elevations with visible fluid 
B : Large blister (> 0.5 cm) circumscribed elevations with visible fluid 

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Pu : Pustules (inflammatory small elevations containing purulent exudate) 
H : Hyperpigmentation (increase of the usual pigmentation limited to the patch test area) 
W : Weeping or oozing (may be a sign of vesiculation or blistering manifested by crusting) 
S : Extension of the reaction beyond patch-test site (on skin area where no test product was 
applied) 
A : Marked reaction to adhesive patch 
5.5.3 
Vital signs 
5.5.4 
Vital signs include Body temperature, BP and pulse and respiratory 
rate measurements. Height and weight 
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram [kg] in indoor 
clothing, but without shoes) will be measured. 
5.5.5 
Patch adhesion assessment: 
 
For the patients randomized to the Exelon® patch treatment, patch adhesion to the skin will 
be evaluated by the caregiver. An estimate of the patch adherence will be provided and graded 
according to the patch adhesiveness score for the intervals between the scheduled outpatient 
visits. 
 
Following scores should be used to capture comments relating to patch adhesion: 
0 = 90 % adhered (essentially no lift off of the skin) 
1 = 75% to < 90% adhered (some edges only lifting off of the skin) 
2 = 50% to < 75% adhered (less than half of the patch lifting off the skin) 
3 = < 50% adhered but not detached (more than half the system lifting off of the skin without 
falling off) 
            4 = the patch was completely detached 
 
5.5.6 
Laboratory evaluations 
5.5.6.1 
Urinalysis 
 
Complete urine examination will be done at baseline,   visit 2 and end of study visit. 
5.5.7 
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/patient population. 

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5.6 
Other assessments 
5.6.1 
Treatment and compliance:  
Caregiver medication questionnaire: Caregiver evaluation of the medications used for AD will 
be assessed using the Caregiver Medication Questionnaire (CMQ). The CMQ contains 4 
items, which focus on caregiver evaluation of medication administration and following 
schedule, and 2 global items asking about caregiver perceived compliance and satisfaction.. 
The CMQ questionnaire asks the caregiver to respond to the items based on the patch that the 
patient was taking during this study.  
 
5.6.2 
Health-related Quality of Life 
Not done  
5.6.3 
Pharmacokinetics 
Not done  
5.6.4 
Pharmacogenetics/pharmacogenomics 
Not done 
5.6.5 
Other biomarkers:  
Not done  
6 
Safety monitoring 
6.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 
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. 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
 they induce clinical signs or symptoms,  
 they are considered clinically significant,  
 they require therapy.  

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Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patient with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
patient and identifying adverse events. Alert ranges for labs and other test abnormalities are 
included in Appendix 1. 
Adverse events should be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them accompanied by the following information. 
 the severity grade  
 mild: usually transient in nature and generally not interfering with normal activities 
 moderate: sufficiently discomforting to interfere with normal activities 
 severe: prevents normal activities 
 its relationship to the study treatment (no/yes), or 
its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved should be reported. 
 whether it constitutes a serious adverse event (SAE)  
 action taken regarding study treatment  
 whether other medication or therapies have been taken (concomitant medication/non-drug 
therapy) 
 its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown) 
An SAE is 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 
hospitalization is for  
 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 outcomes listed above. 

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All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Unlike routine safety assessments, SAEs are monitored continuously and have special 
reporting requirements; see Section 7.2. 
All adverse events should be treated appropriately. Treatment may include one or more of the 
following: no action taken (i.e. further observation only); [study treatment/investigational] 
treatment dosage adjusted/temporarily interrupted; study drug(s) permanently discontinued; 
concomitant medication given; non-drug therapy given. The action taken to treat the adverse 
event should be recorded on the Adverse Event CRF.  
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 study treatment, the 
interventions required to treat it, and the outcome. 
Information about common side effects already known about the investigational drug can be 
found in the package insert. This information will be included in the patient informed consent 
and should be discussed with the patient during the study as needed. 
The investigator should also instruct each patient to report any new adverse event (beyond the 
protocol observation period) that the patient, or the patient’s personal physician, believes 
might reasonably be related to study treatment. This information should be recorded in the 
investigator’s source documents, however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis. 
6.2 
Serious adverse event reporting 
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days [after the last study visit/ following the last 
administration of study treatment if there are post-treatment follow-up visits with no required 
procedures] must be reported to Novartis within 24 hours of learning of its occurrence. Any 
SAEs experienced after the 30 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to study treatment.  
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. An SAE 
that is considered completely unrelated to a previously reported one should be reported 
separately as a new event. 
Information about all SAEs (either initial or follow up information) is collected and recorded 
on the paper Serious Adverse Event Report Form. The investigator must assess the 
relationship to drug, complete the SAE Report Form in English, and send the completed, 
signed form by email/fax within 24 hours after awareness of the SAE to the local Novartis 
Patient Safety Department. The contact details of local Patient Safety are listed in the 
investigator folder provided to each site. The original copy of the SAE Report Form and 
acknowledgement must be kept with the case report form documentation at the study site. 
Follow-up information should be provided using a new paper SAE Report Form stating that 
this is a follow-up to a previously reported SAE 

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Follow- up information provided should describe whether the event has resolved or continues, 
if and how it was treated, whether the treatment code was broken or not and whether the 
patient continued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs. 
If the SAE is not previously documented in the Package Insert (new occurrence) and is 
thought to be related to the investigational treatment, a Novartis Patient Safety Department 
associate may urgently require further information from the investigator for Health Authority 
reporting. Novartis may need to issue Biannual Suspected Unexpected Serious Adverse 
Reaction (SUSAR) Line listing to inform all investigators involved in any study with the same 
investigational treatment that this SAE has been reported. All SAE 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. 
6.3 
Pregnancy reporting 
 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
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 should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the local Novartis Patient Safety Department. Pregnancy follow-up should be 
recorded on the same form and should include an assessment of the possible relationship to 
the study treatment. 
Any SAE experienced during pregnancy must be reported on the SAE Report Form.  
7 
Data review and database management 
7.1 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and CRFs 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 CRFs, the adherence to the protocol and to Good 
Clinical Practice, the progress of enrollment, and to ensure that study. treatment is being 
stored, dispensed, and accounted for according to specifications. 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 CRFs 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 

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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 CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
patients will be disclosed. 
7.2 
Data collection 
Designated investigator staff must enter the information required by the protocol onto the 
Novartis CRFs that are printed on X [specify number of copies – i.e. 3-part]-part, non-carbon-
required paper. Field monitors will review the CRFs for completeness and accuracy and 
instruct site personnel to make any required corrections or additions. The CRFs are forwarded 
to the Medical Documents Reception Center of Novartis [or CRO working on behalf of 
Novartis] by field monitors or by the investigational site, with one copy being retained at the 
investigational site. Once the CRFs are received by Novartis [or CRO working on behalf of 
Novartis], their receipt is recorded, the original copy is placed in Central Files, and the non-
carbon-required copy is forwarded to the responsible Data Management staff for processing 
7.3 
Data Monitoring Committee 
Not required. 
7.4 
Adjudication Committee 
Not required. 
8 
Data analysis 
All analyses will be performed by Novartis or a designated CRO.  
Descriptive analyses will include n, mean, standard deviation, median, first quartile, third 
quartile and ranges for continuous variables and frequencies and percentages for categorical 
variables. Summaries will be presented together with estimates and corresponding 95% 
confidence intervals (CI) as appropriate 
8.1 
Analysis sets 
The intend to treat (IIT) set will include all patients having signed the Informed Consent, 
who have at least one post baseline assessment.  
The safety set will include all patients who provide Informed Consent to collect information 
and who were treated with at least one patch of rivastigmine 27 mg- 15 cm2 transdermal patch 
during this study,. Of note, the statement that a patient had no AE also constitutes a safety 
assessment. 

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All analyses will be carried out on the ITT set, while adverse event analyses will be conducted 
in the safety set.   
All patient demographics, medical history, prior treatments, and other baseline characteristics 
will be presented using standard descriptive statistics. Use of concomitant medication will be 
summarized using frequency counts and percentages by treatment group for patients in the 
Safety Set 
8.2 
Patient demographics and other baseline characteristics 
All patient demographics, medical history, prior treatments, and other baseline characteristics 
will be presented using standard descriptive statistics  
8.3 
Treatments 
Use of concomitant medication will be summarized using frequency counts and percentages 
by treatment group for patients in the Safety Set. 
8.4 
Analysis of the primary and key secondary variable(s) 
8.4.1 
Primary Variable 
8.4.2 
Statistical model, hypothesis, and method of analysis 
The primary variable analysis will be performed on the safety set.  No hypothesis is built for 
the study 
8.4.3 
Handling of missing values/censoring/discontinuations. 
  
LOCF (last observation carried forward) method will be used for missing values at week 16 
8.4.4 
Supportive analyses 
Not planned 
8.5 
Analysis of secondary variables 
8.5.1 
Efficacy variables 
The change from baseline in MMSE total score of 11 items will be summarized for the study. 
For Responses on the Caregiver Medication Questionnaire Mean scores will be computed for 
each of the other items in CMQ  
 
Change in the ADCS-Activities of Daily Living Inventory – Severe Impairment Version 
(ADCS-ADL SIV) Score will be summarized  for the study 
 

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8.5.2 
 Safety variables 
All safety analyses will be performed on the Safety Set. Adverse events (AEs) will be coded 
utilizing the MedDRA dictionary. AEs will be summarized by presenting the number and 
percentage of patients having any adverse event, having an adverse event in each body system 
and having each individual adverse event. For the safety analysis, all treatment emergent 
adverse events will be summarized and listed. The following treatment emergent adverse 
event summaries will be produced: overall by system organ class and preferred term, overall 
by system organ class, preferred term and maximum severity, suspected drug-related adverse 
events by system organ class and preferred term, serious adverse event by system organ class 
and preferred term, and adverse events leading to permanent discontinuation of study-
medication by system organ class and preferred term. Any other information collected (e.g. 
severity or relatedness to study medication) will also be summarized as appropriate. For each 
skin irritation scale, summary statistics will be provided by time and treatment group. When 
appropriate, two-sided 95%-confidence intervals for means and/or proportions as well as p-
values will be provided. The p-values will be used in a non-confirmatory manner. 
 
Further details will be outlined in the SAP 
8.5.3 
Resource utilization 
NA 
8.5.4 
Health-related Quality of Life 
8.5.5 
Pharmacokinetics 
8.5.6 
Pharmacogenetics/pharmacogenomics 
NA 
8.5.7 
Biomarkers 
NA 
8.5.8 
PK/PD 
NA 
8.6 
Interim analyses 
No interim analyses planned 
8.7 
Sample size calculation 
Incidence of adverse event data of ACTION study (74.60%) for Rivastigmine patch per day 
over a 24-week study period in patients with severe AD.  
Sample size is determined based on a precession approach considering normal approximation. 
A sample of 93 subjects will be able to estimate the incidence rate with an maximum error of 

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10% of the true population proportion with 90% of the cases. We assumed, the true 
population proportion is 0.746 (what is observed in US44) 
Similarly, a sample of 41 subjects will be able to estimate the incidence rate with an 
maximum error of 10% of the true population proportion with 85% of the cases and sample of 
23 subjects of the true population proportion with 80% of the cases. 
Considering drop out of 10% and true population proportion with 90%, 102 patients shall be 
enrolled. 
9 
Ethical considerations 
9.1 
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), and with the ethical principles laid 
down in the Declaration of Helsinki. 
9.2 
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 of the patient. 
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. 
9.3 
Responsibilities of the investigator and IRB/IEC 
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC) before study start. A signed and dated statement that the protocol and 

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informed consent have been approved by the IRB/IEC must be given to Novartis before study 
initiation. 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 Clinical 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. 
9.4 
Publication of study protocol and results 
Novartis assures that 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. 
10 
Protocol adherence 
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the 
trial to request approval of a protocol deviation, as requests to approve deviations will not be 
granted. 
This protocol defines the study objectives, the study procedures and the data to be collected 
on study participants.  Under no circumstances should an investigator collect additional data 
or conduct any additional procedures for any research related purpose involving any 
investigational drugs.  
If the 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 it cannot be implemented. All significant protocol 
deviations will be recorded and reported in the CSR. 
10.1 
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. Only 
amendments that are required for patient safety may be implemented prior to IRB/IEC 
approval. 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, Novartis should be notified of this action and the IRB/IEC at the study site should be 
informed within 10 working days or less, if required by local regulations. 
11 
References: 
1.Small GW. (1995) Alzheimer’s disease and other Dementing Disorders. In: Kaplan HI, Sadock BJ, (eds.) 
Comprehensive Textbook of Psychiatry/VI, volume 2, 6th ed; Maryland, Williams & Wilkins, p. 2562-2565.  
 

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2.Alzheimer’s Association (2008) 2008 Alzheimer’s Disease Facts and Figures, [online].Available from: 
http://www.alz.org/national/documents/report_alzfactsfigures2008.pdf 
3.Perry EK, Perry RH, Blessed G, et al. (1978) Changes in brain cholinesterases in senile dementia of Alzheimer 
type. Neuropath and Appl Neruobio, 4: 273-277.  
4. 
Kumar V, Calache M. (1991) Treatment of Alzheimer’s disease with cholinergic drugs. Int J of Clin 
Pharmacology, Therapy and Toxicology; 29(1): 23-37. 
5.   Knapp MJ, Knopman DS, Solomon PR, et al. (1994) A 30-Week randomized controlled trial of high-dose 
tacrine in patients with Alzheimer’s disease. JAMA; 271(13): 985-991.  
6. Rogers SL, Farlow MR, Doody RS, et al. (1998) A 24-week, double-blind, placebo-controlled trial of 
donepezil in patients with Alzheimer’s disease. Neurology, 50: 136-145 
7. Corey-Bloom J, Anand R, Veach J. (1998) A randomized trial evaluating the efficacy and safety of ENA 713 
(rivastigmine tartrate), a new acetylcholinesterase inhibitor, in patients with mild to moderately severe 
Alzheimer’s disease. Int J Geriatr Psychopharm; 1: 55-65. 
8. Rosler M, Anand R, Cicin-Sain A, et al. (1999) Efficacy and safety of rivastigmine in patients with 
Alzheimer’s disease: international randomized controlled trial. BMJ, 318: 633-640. 
9. Raskind MA, Peskind ER, Wessel T, et al. (2000) Galantamine in AD, A 6-month randomized, placebo-
controlled trial with a 6-month extension. Neurology, 54: 2261-2268. 
10. Tariot PN, Solomon PR, Morris JC, et al. (2000) A 5-month, randomized placebo-controlled trial of 
galantamine in AD. Neurology, 54: 2269-2276. 
11. Reisberg B, Doody R, Stoffler A, et al. (2003) Memantine in moderate-to-severe Alzheimer’s disease. N 
Engl J Med, 348: 1333-1341. 
12. Van Dyck CH, Tariot PN, Meyers B, et al. (2007) A 24-week randomized, controlled trial of memantine in 
patients with moderate-to-severe Alzheimer’s disease. Alzheimer’s Dis Assoc Disord, 21: 136-143. 
13. Folstein, M., Folstein, S.E., McHugh, P.R. (1975). “Mini-Mental State” a Practical Method for Grading the 
Cognitive State of Patients for the Clinician. Journal of Psychiatric Research, 12(3); 189-198. 
14. Farlow M, Grossberg G, Sadowsky CH, Meng X, Somogyi M. (2013) A 24-Week, Randomized, Controlled 
Trial of Rivastigmine Patch 13.3 mg/24 h Versus 4.6 mg/24 h in Severe Alzheimer's Dementia. CNS 
Neuroscience & Therapeutics, 19(10): 745–752 
12 
Appendix 1– Caregiver Medication Questionnaire 
 
For each part of every question, please choose only one answer per row. Please mark your 
answers by placing an ‘X’ in the box or circling a number.  
Please answer all of the questions as honestly as you can and without help from anyone. There 
are no wrong answers. 
All of the information you provide will be kept confidential 

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13 
Appendix 2: Patient Instructions for use and handling 
exelon patch 
Only one patch should be worn at a time. Remove the previous day’s Exelon Patch 
before applying a new one. Do not cut the patch into pieces. 
Where to apply Exelon Patch 
 
Before you apply Exelon Patch, make sure that your skin is: 
- 
clean, dry and hairless 
- 
free of any powder, oil, moisturiser, or lotion (that could keep the patch from sticking 
to your skin properly) 
- 
free of cuts, rashes and/or irritations. 
 
Every 24 hours, please gently remove any existing Exelon patch before putting on a 
new one. Having multiple patches on your body could expose you to an excessive 
amount of this medicine which could be potentially dangerous. 
 
Apply ONLY ONE patch per day to ONLY ONE of the following locations (shown in the 
figures below):  
o 
upper arm, left or right side, or  
o 
chest, left or right side, or 
o 
upper back, left or right side, or  
o 
lower back, left or right side,  
Avoid places where the patch can be rubbed off by tight clothing. 
 

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When changing your patch, you must remove the previous day’s patch before you apply your new 
patch to a different area of skin (for example on the right side of your body one day, then on the left 
side the next day). Do not apply a new patch to that same area for at least one week. 
How to apply Exelon Patch 
The patch is a thin, opaque, plastic patch that sticks to the skin. Each patch is sealed in a sachet that 
protects it until you are ready to put it on. Do not open the sachet or remove a patch until just before 
you apply it. 
Every 24 hours, please gently remove any existing Exelon patch before putting on a new one. 
Having multiple patches on your body could expose you to an excessive amount of this 
medicine which could be potentially dangerous. 
 
• 
Each patch is sealed in its own protective sachet.  
You should only open the sachet when you are ready to 
apply the patch. 
 
Tear or cut the sachet at the notch and remove the patch.  
 
• 
A protective liner covers the adhesive side of the patch.  
Peel off one side of the protective liner and do not touch 
the sticky part of the patch with the fingers. 
 
 
 
 
 
 
 
 
 
 
 
• 
Put the sticky side of the patch on the upper or lower 
back, upper arm or chest and then peel off the second 
side of the protective liner. 
 
 
• 
Then press the patch firmly in place for at least 30 
seconds using the palm of the hand to make sure that 
the edges stick well. 
 
 
 
 

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• 
If it helps you, you may write (e.g. the day of the week) on the Exelon Patch with a thin 
ball point pen. 
Exelon Patch should be worn continuously until it is time to replace it with a new patch. You may wish 
to experiment with different locations when applying a new patch, to find ones that are most 
comfortable for you and where clothing will not rub on the patch. 
How to remove Exelon Patch 
Gently pull at one edge of the Exelon Patch to remove it 
completely from the skin. 
 
In case the adhesive residue is left over on your skin, gently soak the area with warm water and 
mild soap or use baby oil to remove it. Alcohol or other dissolving liquids (nail polish remover or 
other solvents) should not be used. 
 
 
How to dispose Exelon Patch 
After the patch has been removed, fold it in half with the adhesive sides on the inside and press them 
together. Return the used patch to its original sachet and discard safely out of the reach and sight of 
children. Wash your hands with soap and water after removing the patch. In case of contact with eyes 
or if the eyes become red after handling the patch, rinse immediately with plenty of water and seek 
medical advice if symptoms do not resolve.  
Can you wear the patch when bathing, swimming, or in the sun? 
 
Bathing, swimming, or showering should not affect the patch. When swimming, you can wear 
the patch under your swimming costume. Make sure the patch does not loosen during these 
activities.  
 
The patch should not be exposed to any external heat sources (excessive sunlight, saunas, 
solarium) for long periods of time.  
What to do if Exelon Patch falls off 
If the patch falls off, a new patch should be applied for the rest of the day, then replace the patch the 
next day at the same time as usual.