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Clinical Development

Exelon® / Rivastigmine

Non-interventional Study Report

CENA713DDE25

EXUBAD: A non-interventional study with Exelon® patch to

determine the impact of a training, based on „Demenz aktiv begegnen“ on the burden of the caregivers of patients with

Alzheimer’s Dementia

Author XXXXXXXXXXXXXXXXXXXXX (CRO: Institut Dr. Schauerte)

Document Status Final Version 1.2

Date of last version of the study report

04 September 2015

Property of Novartis Confidential

May not be used, divulged, published or otherwise disclosed without the consent of Novartis

NI Report Template Version 31 January 2013

Novartis Confidential 2 Non-interventional study report Exelon

® patch/ CENA713DDE25

Table of contents

Table of contents ................................................................................................................. 2

List of abbreviations ............................................................................................................ 4

1 Synopsis ............................................................................................................................... 6

2 Marketing Authorization Holder ....................................................................................... 12

3 Study group ....................................................................................................................... 12

4 Milestones .......................................................................................................................... 13

5 Rationale and background ................................................................................................. 13

6 Research question and objectives ...................................................................................... 14

7 Amendments and updates to the protocol ......................................................................... 15

8 Research methods .............................................................................................................. 15

8.1 Study design........................................................................................................... 15

8.2 Setting .................................................................................................................... 16

8.3 Subjects .................................................................................................................. 16

8.3.1 Inclusion criteria .................................................................................... 17

8.3.2 Exclusion criteria .................................................................................. 18

8.4 Variables ................................................................................................................ 18

8.4.1 Start of observation/ initial visit ............................................................ 18

8.4.2 Evaluation of the training (only in the group of patients with

Exelon® patch plus training of caregiver) ............................................. 19

8.4.3 Follow-up checks during observation period ........................................ 19

8.4.4 End of the observation .......................................................................... 19

8.4.5 Observation plan ................................................................................... 20

8.5 Data sources and measurement .............................................................................. 21

8.6 Bias ........................................................................................................................ 22

8.7 Study size ............................................................................................................... 22

8.8 Monitoring ............................................................................................................. 22

8.9 Data transformation ............................................................................................... 22

8.10 Statistical methods ................................................................................................. 22

8.11 Quality control ....................................................................................................... 23

9 Results ............................................................................................................................... 23

9.1 Participants ............................................................................................................ 23

9.2 Descriptive data ..................................................................................................... 24

9.2.1 Demography .......................................................................................... 24

9.2.2 Living Conditions.................................................................................. 25



9.2.3 Diagnosis ............................................................................................... 27

9.2.4 Pretreatment of dementia ...................................................................... 27

9.2.5 Reason for switch and type of prescription of Exelon® patch .............. 29

9.2.6 Exelon®

patch daily dose ....................................................................... 30

9.2.7 Evaluation of the training “Demenz Aktiv Begegnen” ......................... 31

9.2.8 Follow-up visits ..................................................................................... 35

9.2.9 Mini-Mental State Examination ............................................................ 36

9.2.10 Discontinuation of the therapy with Exelon® patch .............................. 38

9.2.11 General circumstances of caregivers ..................................................... 39

9.2.12 Mini-Zarit assessment of caregiver burden ........................................... 43

9.2.13 GDS assessment of caregivers .............................................................. 45

9.3 Outcome data ......................................................................................................... 49

9.4 Main results ........................................................................................................... 49

9.5 Other analyses ........................................................................................................ 49

9.6 Adverse events and adverse reactions ................................................................... 50

9.6.1 Brief summary of adverse events .......................................................... 50

9.6.2 Display of adverse events ...................................................................... 51

9.6.3 Deaths, other serious events, and other significant adverse events ....... 59

10 Discussion .......................................................................................................................... 60

10.1 Key results ............................................................................................................. 60

10.2 Limitations ............................................................................................................. 62

10.3 Conclusion ............................................................................................................. 62

11 References ......................................................................................................................... 63



List of abbreviations

AD Alzheimer`s Dementia

ADR Adverse Drug Reaction

AE Adverse Event

AMG (deutsches) Arzneimittelgesetz – (German) Drug Law

BfArM Bundesinstitut für Arzneimittel und Medizinprodukte -

German Federal Institute for Drugs and Medical Devices

ChEI Cholinesterase Inhibitor

CRF Case Report/Record Form

CRO Contract Research Organization

e.g. exempli gratia (Latin); for example (English)

EMEA European Agency for the Evaluation of Medicinal Products

EU European Union

FSA Freiwillige Selbstkontrolle für die Arzneimittelindustrie – voluntary self-regulation

for the pharmaceutical industry

FU Follow-up

GDS Geriatric Depression Scale

i.e. id est (Latin); that is to say (English)

ICD International Statistical Classification of Diseases and Related Health Problems

IDS Institute Dr. Schauerte

INI Initial visit

MedDRA Medical Dictionary for Regulatory Activities

MMSE Mini Mental State Examination

N/A Not applicable

NIS Non-Interventional study

NMDA N-Methyl-D-Aspartate

nsADR Non-serious Adverse Drug Reaction

nsAEnr Non-serious Adverse Event non-related

PEI Paul-Ehrlich-Institut

PMS Post-marketing surveillance

PT Preferred Term

RMP Risk Management Plan

SADR Serious Adverse Drug Reaction

SAE Serious Adverse Event

SAEnr Serious Adverse Event non-related

SD Standard deviation



SmPC Summary of Product Characteristics

SOC System Organ Class

SOP Standard Operating Procedure

v Version

vs. Versus

VFA Verband Forschender Arzneimittelhersteller - Association of Researching

Pharmaceutical Manufacturers

WHO World Health Organization



1 Synopsis

Title EXUBAD: A non-interventional study (NIS) with Exelon® patch to determine

the impact of a training, based on „Demenz aktiv begegnen“ on the burden of the caregivers of patients with Alzheimer’s Dementia

Author(s): XXXXXXXXXXXXXXXXXX (CRO: Institut Dr. Schauerte)

Date: 04 SEP 2015

Keywords Exelon® patch, Alzheimer´s disease/ dementia, caregivers training, clinical

practice

Rationale and

background

Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the most common cause of dementia (50-70 % of cases). It is a fatal and progressive disease that destroys brain cells in its course. This leads to problems in memory, thinking skills and behavior severe enough to interfere with a person’s work and social life. Alzheimer’s primarily affects older adults over 60 years of age; its prevalence and incidence increases with age.

Although there is currently no cure for AD, there are medications that help control the symptoms of the disease. The active ingredient rivastigmine is the first and only approved transdermal cholinesterase inhibitor (Exelon

®

patch).

A systematic review of the effectiveness of educational programs in dementia care shows that combined drug and non-drug therapies can improve the quality of life of patients and their families (Perry et al, 2011). "Demenz aktiv begegnen" is a training concept by Novartis for the training of caregivers of patients with AD. The goal of the training is to provide information about AD to relatives/ caregivers and patients so that they are able to better cope with the disease.

This study intended to observe whether and to what extent this training is beneficial to patients and their caregivers with respect to the long-term clinical course of the therapy as well as the burden and quality of life of family caregivers.

Research question

and objectives

The study objective was to compare two groups: Patients with AD treated with Exelon

® patch versus patients treated with Exelon

® patch whose

caregivers additionally participated in a training session based on "Demenz aktiv begegnen".

The following parameters were observed:

• The long-term clinical course of the therapy with Exelon® patch over 12

months (assessed by Mini Mental State Examination; MMSE)

• The burden on caregivers of AD patients (Mini-Zarit and Geriatric Depression Scale (GDS))

• The persistence with the Exelon® patch therapy over 12 months

(assessed by information from investigators and caregivers as well as calculated from the quantities of prescriptions)

Study design This post-marketing surveillance (PMS) was an open, prospective, two-arm,



non-interventional, multicenter observational study and was carried out within an approved indication in accordance with guidelines of the European Agency for the Evaluation of Medicinal Products (EMEA, “Volume 9A of the Rules Governing Medicinal Products in the European Union”), the recommendations of the Association of Researching Pharmaceutical Manufacturers (VFA), and applicable local law(s) and regulation(s) of the Federal Institute for Drugs and Medical Devices (BfArM).

Setting It was planned to observe 350 patients (5 patients per site) in 70 sites.

The study population consisted of male and female outpatients with Alzheimer's disease who were treated with Exelon

® patch based on the

decision of the treating physician independent of the participation in this study.

Subjects and study

size, including

dropouts

A total of 206 AD patients were enrolled at 41 sites in Germany in this non-interventional study which was conducted between 15 April 2013 and 21 November 2014. Six enrolled patients were excluded from the safety population, mainly due to missing informed consent. Among the 200 patients valid for safety analysis, 40 patients were excluded from efficacy analysis, mainly due to loss to follow-up (not any follow-up information documented).

The following inclusion and exclusion criteria were applied:

Inclusion criteria:

• Male and female patients with a secured or probable clinical diagnosis of mild to moderate degenerative Alzheimer dementia (AD)

• Medication with Exelon® patch according to the approval criteria and the

current Summary of Product Characteristics (SmPC)

• Patients who were newly treated with cholinesterase inhibitors or patients who showed insufficient response to another cholinesterase inhibitor or memantine in terms of clinical efficacy

• The caregiver and patient had to be able to answer the questions asked

Exclusion criteria:

• Applicable contraindications, as listed in the SmPC of Exelon® patch

• Patient suffered from a serious or instable physical illness preventing the full participation in the study

• Patients with skin diseases and a risk of developing skin irritations (e.g. atopic dermatitis)

• Patient or caregiver participated in a training program for Alzheimer's disease in the last 6 months or was part of a professional caregiver project

Written informed consent was obtained from all patients included and their caregivers.

Variables and data

sources

Data were recorded on standardized case report forms (CRF).

All variables were analyzed by descriptive statistical methods. The number of data available as well as missing data, mean, standard deviation (SD), minimum, quartiles, median and maximum were calculated for metric data. Frequency tables were generated for categorical data.



Statistical analyses were primarily of an explorative and descriptive nature.

The statistical evaluation was performed using the SAS® software package

release 9.2.

Results Results Summary — Study objectives

Results are based on the efficacy population (n=160). 119 (74.4 %) patients were in the cohort without trained caregivers vs. 41 patients (25.6 %) in the cohort with trained caregivers. More female (56.9 %) than male patients (41.3 %) were included in the study. The mean age of patients was 77.5 ± 6.7 years. The majority of all patients (60.0 %) were between 75 - 85 years. Most patients (71.3 %) lived primarily with their family members. The majority of patients were cared for by their spouses (55.6 %). In the opinion of the physicians more than half of the caregivers were fully able to take care of their AD patients (56.9 %). The estimated ability of the trained cohort (n=37/41; 90.2 %) was twice as high as the non-trained cohort (45.4 %).

The mean duration of AD since its first diagnosis was 10.8 ± 17.7 months. According to International Statistical Classification of Diseases and Related Health Problems (ICD)-10 classification of diagnoses the vast majority of all observed patients as well as the great majority of patients within the stratified cohorts (trained caregivers cohort 63.4 %; non-trained cohort 59.7 %) were affected by late-onset Alzheimer’s dementia.

More than two-thirds of patients (68.8 %) were treatment naïve prior to enrolment compared to 28.8% pretreated patients. A much larger proportion of patients (72.3 %) was treatment naïve in the cohort with untrained caregivers compared to 58.5 % in the trained cohort. More patients (36.6 %) in the group with trained caregivers had already received an anti-dementive pretreatment compared to 26.1 % in the untrained group. Of the 46 patients with previous treatment, the most frequently prescribed treatments were Donepezil (23.9 %), Axura

® (19.6 %) and Exelon

® capsules (10.9 %). The

most frequently used application form was oral (89.1 %).

As reasons for the switch to the Exelon® patch, “insufficient efficacy of

premedication”, “other/ unknown” and “side effects/ adverse events” reasons were documented in 45.7 %, 43.5 % and 15.2 % of pretreated patients, respectively. In the majority of patients (83.8 %), the Exelon

® patch was

newly prescribed. In the cohort with trained caregivers all patients but one (97.6 %) were newly adjusted to the Exelon

® patch compared to 79.0 % in

the non-trained cohort. At baseline, the vast majority of patients (83.8 %) was prescribed 4.6mg/24 hours Exelon

® patches. 97.6 % of patients with a

trained caregiver were adjusted to the initial dose of 4.6mg/24 hours compared to 79.0% in the non-trained cohort. At the first follow-up visit after 4 to 6 months, half of all observed patients were treated with the 9.5mg Exelon

® patch. This proportion remained nearly constant in the further

course of the observation. About one quarter of patients received the Exelon

® patch 13.3mg/24 hours at the second and third follow-up visit. As a

result of dose adjustments at the last individually documented visit, 16.3 % of patients received the 4.6mg/24 hours Exelon

® patch whereas 32.5 % were

prescribed the 9.5mg/24 hours Exelon® patch and 20.6 % the 13.3mg/24

hours Exelon® patch.

41 caregivers participated in the “Demenz aktiv begegnen” trainings after 4-10 weeks (Training 1) and 3-6 months (Training 2). The main focus of both trainings was evaluated to be the “treatment of dementia” (Training 1: 95.1 %



vs. Training 2: 80.5 %) and “dementia in general” (Training 1: 82.9 % and Training 2: 46.3 %). Another important focus of Training 2 (68.3 %) and to a lesser extent of Training 1 (51.2 %) was the subject “everyday life with dementia patients”. The average evaluation of the usefulness of the training was 8.5 ± 1.3 for Training 1 and 8.7 ± 1.2 for Training 2.

Physicians documented one initial visit (baseline visit), up to two follow-up visits per patient (1st FU: after 4-6 months; 2nd FU: after 8-10 months) and one final visit at the end of the observation after approximately one year or in case of premature study termination. The mean duration from the initial to the first follow-up visit was 4.6 ± 1.7 months for all observed patients. Mean duration from the first to the second follow-up visit was documented as 4.0 ± 1.7 months and from the second to the third follow-up visit as 3.4 ± 1.2 months.

At baseline and at each follow-up visit, physicians could document the severity of dementia using the MMSE, if it was performed in routine clinical practice. The average sum score of MMSE for the total study population was 20.5 ± 4.2 points at the start of the observation compared to 19.9 ± 4.5 points at the last individual follow-up visit. The mean MMSE score decreased slightly from start of observation to last individual visit by 0.7 ± 3.1 points.

Premature discontinuation of Exelon® patch therapy was recorded for 47

(29.4 %) of all observed patients. 13 of these patients were in the cohort with trained caregivers and 34 in the non-trained cohort. Mean duration until discontinuation of therapy in total was 7.5 ± 4.3 months. The average duration in the trained cohort was 8.7 ± 5.1 months and 6.8 ± 3.7 months in the non-trained cohort. Reasons for premature discontinuation were “adverse events” and “patient did not return” in 16 patients, respectively, and “insufficient efficacy” and “patient died” in 2 patients, respectively.

More female (57.5 %) than male caregivers (34.4 %) took part in the study. The majority of all caregivers (43.8 %) were over 70 years old. 35.0 % of all caregivers reported carrying full responsibility for administering the prescribed medication to their patient (29.3 % “with training” and 37.0 % “without training”). 72.5 % of caregivers had never before taken care of a close relative over a period of several weeks (80.5 % “with training” and 69.7 % “without training”).

At the initial visit 56.9 % of all caregivers considered the patient’s age to be the cause of AD (73.2 % “with training” and 51.3 % “without training”) while only 47.5 % thought so at the last documented visit (51.2 % “with training” and 46.2 % “without training”). At the initial visit, all caregivers believed to an average extent of 6.3 ± 1.9 points in the helpfulness of AD treatment with medication (6.3 ± 2.3 points “with training” and 6.3 ± 1.7 points “without training”). At the last documented visit, the caregivers believed in the helpfulness of medication to a lesser extent of 6.1 ± 2.1 points due to a decreased score among caregivers with training (5.5 ± 2.0 points “with training” and 6.3 ± 2.1 points “without training”).

The symptoms most common among the caregivers at the initial visit were insomnia and fatigue (32.5 %, respectively), followed by backache (26.3 %). At the last documented visit, the most common symptom was fatigue (24.4 %), followed by insomnia and backache (22.5 %, respectively). Nearly 60 % of caregivers at the initial visit and nearly 40 % at the last documented visit reported not taking any medication from the classes of drugs listed. At the initial visit, caregivers most often took antidepressants and sleeping pills



(10.6 % and 8.1 %, respectively), which were also most often taken at the last documented visit (10.0 % and 9.4 %, respectively). At the initial visit, 12.5 % of caregivers had been hospitalized in the last half year, 5.6 % had been on sick leave, and 2.5 % had been to rehabilitation. In the course of the study, a stay in the hospital, rehabilitation and/or sick leave was needed at least once by 3.1 %, 1.9 % and 3.8 % of caregivers, respectively.

The Mini-Zarit scale was used to assess the burden on the caregivers. The average sum score of Mini-Zarit for all caregivers was 4.6 ± 1.8 points at the start of the observation compared to 4.5 ± 1.7 points at the last individual follow-up visit. The score decreased somewhat in the course of therapy. The mean sum scores were consistently lower, i.e., worse, for caregivers without training (4.2 ± 1.7 points at initial visit and 4.3 ± 1.7 points at the last documented visit) than for the caregivers overall, while the trained caregivers (5.5 ± 1.5 points at initial visit and 5.0 ± 1.4 points at the last documented visit) consistently had better average scores than all caregivers.

Further the GDS was used to assess the burden on caregivers. The average sum score of GDS for all caregivers was 3.1 ± 2.9 points at the start of the observation compared to 3.0 ± 2.2 points at the last individual follow-up visit. The score remained largely constant in the course of therapy. The mean sum scores were consistently higher, i.e., worse, for caregivers without training (3.3 ± 3.0 points at initial visit and 3.2 ± 2.4 points at the last documented visit) than for the caregivers overall, while the average scores of the trained caregivers (2.8 ± 2.7 points at initial visit and 2.6 ± 1.7 points at the last documented visit) were consistently better than those of all caregivers and decreased in the course of the study.

Results Summary — Safety

Safety evaluation was based on the population of evaluable patients (n=200). Over a quarter of patients (n=52/200, 26.0%) were affected by at least one adverse event (AE) of any nature. The rate was lower in the group with untrained caregivers (n=26/129, 20.2%) than with trained caregivers (n=26/71, 36.6%). Adverse drug reactions, i.e., nsADR and SADR, occurred in 36/200 (18.0%) and 2/200 patients (1.0%), respectively. 18 patients (9.0%) had serious AEs without drug-relation (SAEnr), 2 patients (1.0%) had serious adverse drug reactions (SADR). 30 cases of medication error (15%) and 4 cases of lack of drug effect (2%) were documented. 5 patient deaths were recorded in the study, 1 of which was assessed to be drug-related. In patients with AEs, the number of AEs of any nature was most frequently 1 per patient (10.5%), followed by 2 AEs per patient (7.5%). Of the 129 AEs that occurred altogether, 24 were non-serious and not drug-related (nsAEnr), 63 were non-serious adverse drug reactions (nsADR), 39 were serious and not drug-related (SAEnr), and 3 were serious adverse drug reactions (SADR). Most AEs belonged to the system organ classes (SOCs) "skin and subcutaneous tissue disorders" (16.3%), "psychiatric disorders" (14.7%), "nervous system disorders" (13.2%), "gastrointestinal disorders" (10.1%), "general disorders and administration site conditions" (10.1%) and "cardiac disorders" (8.5%). The preferred terms (PTs) for the most frequently recorded AEs of any group were "nausea" (4.7%) and "depression" (3.9%).

Discussion This NIS in patients with mild to moderate AD showed a better Mini-Zarit and GDS in trained than in untrained caregivers both at baseline and the last individual FU. These validated questionnaires pointed to a stable or slightly reduced burden preferably in non-trained, mainly familiar caregivers. Thus, a



more detailed information on the disease and its perspective might increase the feeling of burden in trained caregivers. So far, there are only few data on long-term therapy in AD. This NIS also demonstrated a nearly stable severity of the disease within one year of therapy with the rivastigmine patch, which was well tolerated with a low frequency of ADRs. Additional training may therefore help the familial caregivers in daily life to reduce the burden of disease and to increase patient persistence for symptomatic therapy in patients with mild to moderate AD.

Marketing

Authorization

Holder

Novartis Pharma GmbH

Name(s) and

Affiliation(s) of

Principal

Investigator(s)

XXXXXXXXXX XXXXXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXX XXXXXXXXXXX XXXXXXXXXXXXXXX XXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX



2 Marketing Authorization Holder


Roonstraße 25

D-90429 Nürnberg

3 Study group

Principle investigator XXXXXXXXXX XXXXXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXX XXXXXXXXXXX XXXXXXXXXXXXXXX XXXXXXXXXXXXXX XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX

Project Lead XXXXXXXXXXXXX


Roonstraße 25, D-90429 Nürnberg Phone 0911 273 XXXXX Fax 0911 273 XXXXX Email: [email protected]

Senior Expert

Phase IV Manager

XXXXXXXXXXXXXX



Safety Manager XXXXXXXXXXXXXXX



Project coordinator

and statistics

XXXXXXXXXXXXXXX Institut Dr. Schauerte (IDS) Finkenstraße 7, D-80333 München Phone: 089/ 641-XXXXX Fax: 089/ 641- XXXXX E-mail: [email protected]



4 Milestones

Table 4.1 Study milestones

Milestone Planned date Actual date

Start of data collection 1 March 2013 08 April 2013

End of data collection 31 November 2014 21 November 2014

Final report of study results 31 December 2014 04 September 2015

5 Rationale and background

Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the most common

cause of dementia (50-70% of cases). It is a fatal and progressive disease that destroys brain

cells in its course. This leads to problems in memory, thinking skills and behavior severe

enough to interfere with a person’s work and social life. Alzheimer’s primarily affects older

adults over 60 years of age; its prevalence and incidence increases with age (Alzheimer`s

Association, 2012).

Although there is currently no cure for AD, there are medications that help control the

symptoms of the disease. The active ingredient rivastigmine is the first and only approved

transdermal cholinesterase inhibitor (Exelon® patch).

Various acetylcholinesterase inhibitors (ChEI; active compounds rivastigmine, galantamine

and donepezil) and the N-methyl-D-aspartate (NMDA) antagonist memantine have been

approved to treat Alzheimer's symptoms (Cummings et al, 2002). The active ingredient

rivastigmine was approved in the EU in 2007 as the first and only transdermal cholinesterase

inhibitor (Exelon® patch). In many cases of chronic diseases it was shown that patients or

caregivers form opinions of their own about the cause of the disease, its nature (symptomatic

experience), the duration, the personal consequences or the resulting suffering and also about

the extent to which the disease can be controlled or cured. Patients also have opinions about

the type of treatment: This involves the perception of the necessity for treatment (such as the

absence of symptoms) and concerns about possible side effects. These views determine how

people deal with their disease in psychological and behavioral terms, such as compliance with

medication requirements (Horne & Weinman, 1999). As the disease progresses and treatment

options for the patients decline, the views of caregivers and physicians increasingly determine

the choice of treatment, adherence and persistence (Small & Dubois, 2007).

Persistence is defined as "the length of the time from the beginning to the discontinuation of a

treatment and is measured in units of time" (Hughes et al, 2007). A non-persistent behavior

occurs when the patient treatment is completely terminated - either because the patient

himself (or his supervisor) makes the decision to terminate or because the treating physician

decides to discontinue a particular treatment. Therefore, persistence is usually determined in

the form of an event history analysis; the patients either terminate the treatment before the end

of the observation or they continue to the end (e.g. right censored data). In one study,

persistence rates were 40% for twelve months; in several other studies, the observed

persistence was between 135-492 days (Small & Dubois, 2007).



So far, there are comparatively few studies that investigate which psychosocial therapies are

effective in improving the quality of life of caregivers of patients with dementia. A

systematic review of characteristics that can effect a response to such psychosocial therapies

has identified several parameters. Female caregivers are able to achieve the greatest effect by

training (Van Mierlo et al, 2012). A systematic review of the effectiveness of educational

programs in dementia care shows that combined drug and non-drug therapies can improve the

quality of life of patients and their families (Perry et al, 2011).

"Demenz aktiv begegnen" is a training concept by Novartis for the training of caregivers of

patients with AD. The goal of the training is to provide information about AD to relatives/

caregivers and patients so that they are able to better cope with the disease. The contents of

the training are information about AD itself, therapies, cognitive training, physical training as

well as legal and social aspects of the disease.

This study investigated whether and to what extent this training is beneficial to patients and

their caregivers with respect to the long-term clinical course of the therapy as well as the

burden and quality of life of family caregivers.

6 Research question and objectives

The study objective was to compare two patient groups: Patients with AD treated with

Exelon® patch versus patients treated with Exelon

® patch whose caregivers additionally

participated in a training based on "Demenz aktiv begegnen".

The following parameters were observed:

• The long-term clinical course of the therapy with Exelon® patch over 12 months (assessed

by Mini Mental State Examination; MMSE)

• The burden on caregivers of patients with AD (Mini-Zarit and GDS)

• The persistence with the Exelon® patch

therapy over 12 months (assessed by information

from investigators and caregivers as well as calculated from the quantities of

prescriptions)

The observation was meant to include newly adjusted patients in order to achieve an even

baseline at the time of the training of caregivers and, thus, to make the effects on the burden

of caregivers comparable.

Both groups of patients and their caregivers (with or without standard training) were included

in the NIS in accordance with routine clinical practice.



7 Amendments and updates to the protocol

Revision of Chapter "Adverse Events"

The changes in the European pharmacovigilance legislation concerning the

pharmacovigilance processes were adapted in the NIS and required a complete rewrite of

Chapter 7, "Adverse Events".

The following changes were made:

• Expansion of the term "adverse event"

• Modified reporting requirements and handling of adverse event notifications after

completion of the study

• Recurring manifestations, complications and similar events should be handled as a

follow-up

• Handling events of special interest (Risk Management Plan; RMP)

• Specification regarding handling of cases of "progression of the underlying disease"

Adjustment of the timeline

The timeline was updated.

8 Research methods

8.1 Study design

This post-marketing surveillance (PMS) was an open, prospective, two-arm, non-

interventional, multicenter observational study in accordance with section 4 paragraph 23

sentence 3 of German drug law (AMG, Arzneimittelgesetz) within an approved indication.

The treatment was performed according to clinical practice (including diagnosis and

monitoring) without a pre-defined observational test plan. The study was consistent with the

guidelines of EMEA (“Volume 9A of the Rules Governing Medicinal Products in the

European Union”), the “Freiwillige Selbstkontrolle für die Arzneimittelindustrie” (FSA)-

codex, the recommendations of the Federal Institute for Drugs and Medical Devices (BfArM)

and Paul-Ehrlich-Institut (PEI) for the planning, implementation and evaluation of

observational studies. In addition, the study was performed in accordance with the

Association of Researching Pharmaceutical Manufacturers (VFA) recommendations for

improving the quality and transparency of non-interventional studies.

The following visits were documented (if they took place):

Visit at the beginning of the observation: initial visit (INI)

Training 1 (Only for the group with training): after 4-10 weeks

Training 2 (Only for the group with training): after 3-6 months

1st follow-up visit (1. FU): after 4-6 months



2nd follow-up visit (2. FU): after 8-10 months

Visit at the end of the observation (3. FU): after approximately 1 year

Information was collected for the following patient groups during the observation:

Group with training: • patients with AD who were newly adjusted to Exelon® patch

• caregivers who participated in the training "Demenz aktiv

begegnen" in clinical practice

Group without training: • patients with AD who were newly adjusted to the Exelon® patch

• caregivers without training in clinical practice

All adverse events (AEs) had to be documented in designated report forms and sent to the

contract research organization (CRO) within 10 days after documentation. Serious adverse

events (SAEs) were recorded on a separate SAE form and had to be reported within 24 hours

to NOVARTIS Pharma GmbH, Drug Safety Department.

In case the study was prematurely discontinued, the reason had to be documented.

8.2 Setting

According to the observational plan, 350 patients with mild to moderate Alzheimer’s disease

were to be observed at 70 sites (5 patients per site). The participating investigators were

neurologists, psychiatrists, geriatricians, general practitioners and general practitioners

specialized in geriatrics. A total of 206 patients were actually enrolled at 41 sites. This non-

interventional study (NIS) was conducted between 15 April 2013 and 21 November 2014.

The study population consisted of male and female outpatients with Alzheimer's disease who

were treated with the Exelon® patch independently of participation in this study. Warnings

and contraindications were considered in accordance with the current Summary of Product

Characteristics (SmPC).

8.3 Subjects

A total of 206 patients were documented in this NIS. Six enrolled patients were excluded from

the safety population, mainly due to missing informed consent. Among the 200 patients valid

for safety analysis, 40 patients were excluded from efficacy analysis, mainly due to loss to

follow-up (not any follow-up information documented). The numbers of patients excluded

from either safety analysis or efficacy analysis are summarized in Figure 1 with detailed

reasons for exclusion.



Figure 1 Disposition of patients

8.3.1 Inclusion criteria

The inclusion and exclusion criteria for patients were:

Inclusion criteria:

• Male and female subjects with a secured or probable clinical diagnosis of mild to

moderate degenerative AD

• Medication with Exelon® patch according to the approval criteria and the current safety

information

• Patients who were newly treated with cholinesterase inhibitors or patients who showed

insufficient response to another cholinesterase inhibitor or memantine

• Ability of caregiver and patient to answer the questions asked

Total study population (n=206)

Exclusions from efficacy population N (%)

Total Safety Population 200 (100.0)

Lost to follow-up 38 (19.0)

Violation of inclusion/exclusion criteria 3 (1.5)

Retrospective recruitment 6 (3.0)

Missing documented prescription of Exelon® patch

at baseline

2 (1.0)

Total Efficacy Population 160 (80.0)

*Multiple responses possible

Exclusions from safety population N (%)

Total 206 (100.0)

No documented prescription of Exelon® patch 1 (0.5)

No written informed consent 5 (2.4)

Total Safety Population 200 (97.1)

Efficacy population (n=160)

Safety population (n=200)



8.3.2 Exclusion criteria

Exclusion criteria:

• Applicable contraindications, as listed in the Summary of Product Characteristics (SmPC)

of Exelon®

patch

• Serious or instable physical illness preventing the patient’s full participation in the study

• Skin diseases and a risk of patient for developing skin irritations (e.g. atopic dermatitis)

• Patient or caregiver participated in a training program for Alzheimer's disease in the last 6

months or was part of a professional caregiver project

Written informed consent was obtained from all patients included and their caregivers.

8.4 Variables

In this non-interventional study, only diagnostic procedures and therapeutic indications of

Exelon® patch conducted according to routine clinical practice were documented by the

physicians.

8.4.1 Start of observation/ initial visit

• Patient consent: A signed informed consent was required from the patient (and/ or his

[legal] representative) as well as from the caretaker (not in the legal, but the nursing sense)

prior to inclusion into the observation. The signed informed consent forms had to be

archived by the respective investigator.

• Demographic data (age, sex, height and weight)

• Diagnosis, medical history

• Any pre-treatment with another antidementive medication

• Prescription of Exelon® patch: dose strength and pack size

• MMSE score of the patient (only if recorded)

• Housing and living conditions of the patient (at home, in a nursing home)

• Relationship between caretaker and patient

• Suitability assessment of the caretaker by the treating physician

• Extent to which the patient is responsible for his own medication

• Time requirements for nursing/ care

• Caregiver:

- Age, gender

- Health status (physical, stress situation, depression)

- Opinion and attitude towards AD

- Expectations regarding the effectiveness of Exelon® patch



- Physical health (mood, treatment status and medical interventions)

- Psychotropic medication

8.4.2 Evaluation of the training (only in the group of patients with Exelon® patch plus training of caregiver)

• Date of training

• General conditions (duration, number of participants)

• Topics covered

• Evaluation form by the caregiver

8.4.3 Follow-up checks during observation period

• Date of observation

• Persistence


• Patient MMSE score (if recorded)

• Documentation of adverse events

• Changes in time requirements for nursing

• Caregiver:


- Opinion and attitude towards AD


- Physical health (mood, status of treatment EXUBAD v 1.0 observation plan including

Amendment 1 11/06/2013 Page 13 medical interventions)


8.4.4 End of the observation

In accordance with clinical practice, the final observation was conducted approximately 12

months after initiation of treatment with the Exelon® patch.

The following observation parameters were collected:

• Date of observation

• Persistence


• Patient MMSE score (if recorded)



• Documentation of adverse events

• Changes in time requirements for nursing

• Caregiver:


- View and attitude towards AD


- Physical health (mood, treatment status and medical interventions)


8.4.5 Observation plan

Table 8.1 Observation plan

Only if recorded Observation

start*

Training 1 Training 2 1st

Follow-up

2nd

Follow-up

End of ob-

servation**

(Group with training)

Visits Baseline 4-10 weeks 3-6

months

4-6

months

8-10

months 12 months

Inclusion /

exclusion criteria x

Informed consent x

Information about the

caregiver (age, health

status, relationship to

the patient)

x

Training (only for the

group with training) x x

Information about

training and evaluation x x

Information about the

persistence (physician

and caregiver)

x (x) x

MMSE (if done) x x (x) x

Information about

caregivers’ knowledge

of the disease and

expectations regarding

therapy

x x x

Information about

caregivers’ burden

(health status, Mini-

Zarit and GDS)

x x x

Adverse events x x x x x x

* Screening and baseline could take place simultaneously

** Or premature study discontinuation



8.5 Data sources and measurement

Data were recorded on standardized case report forms (CRF). All data management activities

and statistical analyses were performed by Institute Dr. Schauerte (IDS), Munich. All CRFs

were tracked and entered (single data entry) into the study database. Subsequently,

implausible and missing data were checked according to the query plan. Queries concerning

discrepant data were generated and sent to the study sites for resolution.

All CRFs were checked for hidden adverse events. Reporting of (S)AEs was performed

according to the project pharmacovigilance contract and relevant standard operating

procedures (SOPs) of Novartis Pharma GmbH. Adverse events were coded according to

Medical Dictionary for Regulatory Activities (MedDRA) 17.1. After closure of the study

database, all adverse events were reconciled and the data validation process was performed

according to the validation plan.

The term “adverse event” (AE) describes any unfavorable and unintended sign (including an

abnormal laboratory finding), symptom, or disease temporally associated with the use of a

medicinal product, whether or not related to this drug. Further details concerning the

definition of special AEs can be found in the observational plan, Chapter 7. Additionally, in

the observational plan it was pointed out to the physician that a worsening of MMSE (in the

sense of a progression of the underlying disease) had to be reported as AE under specific

circumstances.

Generally, a distinction is made between non-serious and serious adverse events, the latter

required to be reported to the Novartis Pharmacovigilance department within 24 hours of

awareness. A serious adverse event is any event which:

• results in death

• is life-threatening

• requires inpatient hospitalization or prolongation of existing hospitalization

• results in persistent or significant disability or incapacity

• leads to a congenital anomaly or birth defect

• is medically significant (i.e. an important medical event which significantly affects the

patient, but does not meet any of the above criteria)

Overall, adverse events are distinguished into four types based on the distinction serious/non-

serious and the causal relationship to Exelon®:

• nsAEnr: non-serious adverse events not related (investigator does not suspect a causal

relationship with Exelon®)

• nsADR: non-serious adverse drug reactions (causality assured, probable, possible or not

assessable)

• SAEnr: serious adverse events not related (investigator does not suspect a causal

relationship with Exelon®)

• SADR: serious adverse drug reaction (causality assured, probable, possible or not

assessable)



In order to ensure the safety of every patient treated with Exelon®, every pregnancy had to be

reported to the Novartis Pharmacovigilance department within 24 hours of awareness. The

pregnancy had to be documented on a separate pregnancy form (Post Marketing Surveillance

Pregnancy Form) in English and had to be reported by the treating physician directly to the

Pharmacovigilance of Novartis Pharma GmbH.

8.6 Bias

N/A

8.7 Study size

Data were to be collected from up to 350 patients at 70 study sites. 206 patients were actually

included at 41 sites. The participating investigators were neurologists, psychiatrists,

geriatricians, general practitioners and general practitioners specializing in geriatrics.

In accordance with the non-interventional character of this study, the group of patients treated

with Exelon® patch and with trained caregivers were recruited at study sites where training

was performed as a routine practice. Overall, 15 sites conducting training participated in this

study versus 26 sites not performing training.

8.8 Monitoring

Source Data Verification was performed at a total of 6 sites (3 per study arm) to check if all

information on the CRFs was consistent with and traceable to the source documents. Full

verification of the following was required: presence of informed consent, adherence to the

inclusion/ exclusion criteria, demographic data, documentation of SAEs, and the recording of

data required for the analyses of all primary and safety variables. For further details, please

refer to the Monitoring Plan.

8.9 Data transformation

N/A

8.10 Statistical methods

All variables were analyzed by descriptive statistical methods. The number of data available

as well as missing data, mean, standard deviation, minimum, quartiles, median and maximum

were calculated for metric data. Frequency tables were generated for categorical data.

Statistical analyses were primarily of an explorative and descriptive nature.

The statistical evaluation was performed using the SAS® software package release 9.2.



Methods used to examine subgroups and interactions

N/A

Missing data

The handling of missing values and discontinuations of therapy were described and justified

in the statistical analysis plan.

Sensitivity analyses

N/A

Any amendment to the plan of data analysis included in the study protocol, with a

rationale for the change

N/A

8.11 Quality control

Details of patient validity, data consistency checks and permissible data modifications are

described in the Data Management Plan.

9 Results

A total of 206 patients were enrolled at 41 sites in Germany in this non-interventional study

which was conducted between 15 April 2013 and 21 November 2014.

9.1 Participants

All parameters described in this section are based on the efficacy population (n=160). Of

these, 119 (74.4 %) patients were in the cohort without trained caregivers vs. 41 patients

(25.6 %) in the cohort with trained caregivers. The reason for this small number of caregivers

with training was that there haven`t been so many sites who performed this training during

their routine clinical practice. Due to this imbalance in numbers, the results of the two groups

have to be interpreted with caution.



Table 9.1 Population “with/ without training”

Training “Demenz Aktiv Begegnen” N (%)

Total 160 (100.0)

No 119 (74.4)

Yes 41 (25.6)

Source: Table 1/2; Table compendium

9.2 Descriptive data

9.2.1 Demography

Demographic data are summarized in Table 9-2 to Table 9-4.

Overall, more female (56.9 %) than male patients (41.3 %) were included in this non-

interventional study. In the patient group “with training” nearly two-thirds (65.9 %) were

female compared to 31.7 % male patients, whereas the proportion in the stratification group

“without training” was more balanced (female: 53.8 % vs. male: 44.5 %).

The mean age ± standard deviation (SD) of all patients was 77.5 ± 6.7 years. The average age

of patients in the trained caregivers group was 79 ± 5.6 years and without training 77 ± 6.9

years. The majority of all patients (60.0 %) were between 75 - 85 years.

Table 9.2 Sex, “with/ without training”

Sex

Training

Total No Yes

N (%) N (%) N (%)

Total 160 (100.0) 119 (100.0) 41 (100.0)

Missing 3 (1.9) 2 (1.7) 1 (2.4)

Male 66 (41.3) 53 (44.5) 13 (31.7)

Female 91 (56.9) 64 (53.8) 27 (65.9)

Source: Table 2.1/3; Table compendium

Table 9.3 Age (quantitative analysis), “with/ without training”

Age [years]

Training

Total No Yes

n = 160 n = 119 n = 41

Mean 77.5 77.0 79.0

SD 6.7 6.9 5.6

Median 77.0 77.0 79.0

Range 48.0 - 96.0 48.0 - 96.0 69.0 - 92.0




Table 9.4 Age in decades, “with/ without training”

Age [years]

Training

Total No Yes

N (%) N (%) N (%)

Total 160 (100.0) 119 (100.0) 41 (100.0)

Missing 1 (0.6) 1 (0.8) 0 (-)

< 65 3 (1.9) 3 (2.5) 0 (-)

≥ 65 - < 75 42 (26.3) 35 (29.4) 7 (17.1)

≥ 75 - < 85 96 (60.0) 69 (58.0) 27 (65.9)

≥ 85 18 (11.3) 11 (9.2) 7 (17.1)


9.2.2 Living Conditions

With respect to living conditions, the majority of patients (71.3 %) lived primarily with their

family members. This proportion was minimally higher in the trained caregivers’ cohort

(73.2 %) compared to the non-trained cohort (70.6 %). Less than one-fifth of the patients with

a trained caregiver (17.1 %) lived alone, as did slightly more patients in the non-trained cohort

(23.5 %).

Table 9.5 Living conditions, “with/ without training”

Living condition

Training

Total No Yes

N (%) N (%) N (%)

Total 160 (100.0) 119 (100.0) 41 (100.0)

Missing 0 (-) 0 (-) 0 (-)

Solitary 35 (21.9) 28 (23.5) 7 (17.1)

With family 114 (71.3) 84 (70.6) 30 (73.2)

Nursing home 9 (5.6) 6 (5.0) 3 (7.3)

Other 2 (1.3) 1 (0.8) 1 (2.4)

Unknown 0 (-) 0 (-) 0 (-)


Concerning patients’ relation to their caregivers, the majority of patients were cared for by

their spouses (55.6 %; n=89/160). More than half of the patients with untrained caregivers

were cared for by their spouses (58.8 %; n=70/119) and less than one-fifth by other untrained

relatives (18.5 %; n=22/119). However, in the group with training over two-fifths of the

spouses (46.3 %; n=19/41) and other relatives (41.5 %; n=17/41) were trained. For further

details, please refer to Table 9.6.



Table 9.6 Patient´s relation to his attendant, “with/ without training”

Patient’s relation to his attendant

Training

Total No Yes

N (%) N (%) N (%)

Total 160 (100.0) 119 (100.0) 41 (100.0)

Missing 0 (-) 0 (-) 0 (-)

No attendant 17 (10.6) 15 (12.6) 2 (4.9)

Spouse 89 (55.6) 70 (58.8) 19 (46.3)

Other relative 39 (24.4) 22 (18.5) 17 (41.5)

Paid caregiver 0 (-) 0 (-) 0 (-)

Nursing service 2 (1.3) 2 (1.7) 0 (-)

Other 2 (1.3) 2 (1.7) 0 (-)

Unknown 0 (-) 0 (-) 0 (-)

No regular caregiver / partner / spouse 1 (0.6) 1 (0.8) 0 (-)

No regular caregiver / other 2 (1.3) 2 (1.7) 0 (-)

Partner / spouse / other relative 3 (1.9) 2 (1.7) 1 (2.4)

Partner / spouse / nursing service 1 (0.6) 1 (0.8) 0 (-)

Partner / spouse / other 1 (0.6) 1 (0.8) 0 (-)

Other relative / nursing service 2 (1.3) 0 (-) 2 (4.9)

Partner / spouse / other relative / nursing

service 1 (0.6) 1 (0.8) 0 (-)


Physicians were asked to assess the impairment of the caregiver’s ability to take care of the

patient. In the opinion of the physicians more than half of the caregivers were fully able to

take care of their AD patients (n=91/160; 56.9 %). The estimated ability of the trained cohort

(n=37/41; 90.2 %) was twice as high as the non-trained cohort (n=54/119; 45.4 %). Results of

further stratified analyses can be found in Table 4/6 in the Table compendium.

Table 9.7 Impairment of the caregiver, “with/ without training”

Impairment of the caregiver

Training

Total No Yes

N (%) N (%) N (%)

Total 160 (100.0) 119 (100.0) 41 (100.0)

Missing 12 (7.5) 12 (10.1) 0 (-)

Not at all 91 (56.9) 54 (45.4) 37 (90.2)

Slightly 41 (25.6) 37 (31.1) 4 (9.8)

Strongly 9 (5.6) 9 (7.6) 0 (-)

Unknown 7 (4.4) 7 (5.9) 0 (-)




9.2.3 Diagnosis

Table 9.8 Alzheimer´s dementia known for [months], “with/ without training”

Alzheimer´s dementia known for [months]

Training

Total No Yes

n = 160 n = 119 n = 41

Mean 10.8 11.3 9.3

SD 17.7 18.4 15.7

Median 3.5 4.0 3.0

Range 0 - 106.0 0 - 106.0 0 - 62.0


The mean duration of AD since its first diagnosis was 10.8 ± 17.7 months. When comparing

both groups, the average duration of AD was slightly longer in the group without training

(11.3 ± 18.4 months) compared to the cohort with trained caregivers (9.3 ± 15.7 months).

According to ICD-10 (according to World Health Organization, WHO), diagnoses were

classified as follows: G.30.0 – Alzheimer’s dementia with early onset (<65 years), G.30.1 –

Alzheimer’s dementia with late onset (≥65 years), G30.9 – Alzheimer’s dementia,

unspecified, and “other” disease. The vast majority of all observed patients as well as the

great majority of patients within the stratified cohorts (trained caregivers cohort 63.4 %; non-

trained cohort 59.7 %) were affected by late-onset Alzheimer’s dementia. For further details,

please refer to the following table as well as Table 2.2/3 in the Table compendium.

Table 9.9 Diagnosis by ICD 10, “with/ without training”

Diagnosis by ICD 10

Training

Total No Yes

N (%) N (%) N (%)

Total 160 (100.0) 119 (100.0) 41 (100.0)

Missing 1 (0.6) 1 (0.8) 0 (-)

G30.0 Alzheimer´s dementia with early onset 2 (1.3) 2 (1.7) 0 (-)

G30.1 Alzheimer´s dementia with late onset 97 (60.6) 71 (59.7) 26 (63.4)

G30.9 Alzheimer´s dementia, unspecified 24 (15.0) 16 (13.4) 8 (19.5)

Other 36 (22.5) 29 (24.4) 7 (17.1)


9.2.4 Pretreatment of dementia

Of the 160 patients enrolled, more than two-thirds (68.8 %; n=110/160) were treatment naïve

prior to enrolment compared to 28.8 % (n=46/160) pretreated patients. According to the

physicians’ documentation, a much larger proportion of patients (72.3 %; n=86/119) was

treatment naive in the cohort with untrained caregivers compared to 58.5 % (n=24/41) patients

in the trained cohort. Conversely, more patients (36.6 %; n=15/41) in the group with trained

caregivers had already received an anti-dementive pretreatment compared to 26.1 %



(n=31/119) in the untrained group. Of those patients with previous treatment (n=46), the most

frequently prescribed treatments were Donepezil (n=11; 23.9 %), Axura® (n=9; 19.6 %) and

Exelon®

capsules (n=5; 10.9 %). The most frequently used application form was oral (89.1 %;

n=41/46). For further details, please refer to Table 9-10 to 9-12.

Table 9.10 Pretreatment yes/ no, “with/ without training”

Pretreatment

Training

Total No Yes

N (%) N (%) N (%)

Total 160 (100.0) 119 (100.0) 41 (100.0)

Yes 46 (28.8) 31 (26.1) 15 (36.6)

No 110 (68.8) 86 (72.3) 24 (58.5)

Unknown 4 (2.5) 2 (1.7) 2 (4.9)


Table 9.11 Last pretreatment medication, “with/ without training”

Last pretreatment medication

Training

Total No Yes

N (%) N (%) N (%)

Total* 46 (100.0) 31 (100.0) 15 (100.0)

Missing 6 (13.0) 4 (12.9) 2 (13.3)

Exelon® capsule 5 (10.9) 5 (16.1) 0 (-)

Rivastigmine (generic drug) 2 (4.3) 1 (3.2) 1 (6.7)

Aricept® 4 (8.7) 3 (9.7) 1 (6.7)

Donepezil (generic drug) 11 (23.9) 4 (12.9) 7 (46.7)

Reminyl® 1 (2.2) 1 (3.2) 0 (-)

Galantamine (generic drug) 1 (2.2) 1 (3.2) 0 (-)

Axura® 9 (19.6) 8 (25.8) 1 (6.7)

Ebixa® 1 (2.2) 1 (3.2) 0 (-)

Memantine (generic drug) 1 (2.2) 0 (-) 1 (6.7)

Other 5 (10.9) 3 (9.7) 2 (13.3)

*Only pretreated patients; Multiple answers possible




Table 9.12 Application form of medication, “with/ without training”

Application form of medication

Training

Total No Yes

N (%) N (%) N (%)

Total* 46 (100.0) 31 (100.0) 15 (100.0)

Missing 2 (4.3) 1 (3.2) 1 (6.7)

Oral 41 (89.1) 28 (90.3) 13 (86.7)

Transdermal 3 (6.5) 2 (6.5) 1 (6.7)

Other 0 (-) 0 (-) 0 (-)

*Only pretreated patients


9.2.5 Reason for switch and type of prescription of Exelon® patch

When looking at the reasons for the switch to the Exelon® patch, “insufficient efficacy of

premedication”, “other/ unknown” reasons and “side effects/ adverse events” were

documented by the physicians in 45.7 %, 43.5 % and 15.2 % of pretreated patients,

respectively. In the majority of patients (83.8 %; n=134/160), the Exelon® patch was newly

prescribed. In the cohort with trained caregivers all patients but one (97.6 %; n=40/41) were

newly adjusted to the Exelon® patch compared to 79.0 % (n=94/119) in the non-trained

cohort.

Table 9.13 Reasons for switch to Exelon® patch other than poor compliance, “with/ without

training”

Reasons for switch to Exelon® patch

other than poor compliance

Training

Total No Yes

N (%) N (%) N (%)

Total* 46 (100.0) 31 (100.0) 15 (100.0)

Insufficient efficacy of premedication 21 (45.7) 18 (58.1) 3 (20.0)

Side effects / Adverse events 7 (15.2) 1 (3.2) 6 (40.0)

Other / unknown 20 (43.5) 14 (45.2) 6 (40.0)

*Only pretreated patients; Multiple answers possible




Table 9.14 Type of prescription of Exelon

® patch, “with/ without training”

Type of prescription

Training

Total No Yes

N (%) N (%) N (%)

Total 160 (100.0) 119 (100.0) 41 (100.0)

Missing 3 (1.9) 3 (2.5) 0 (-)

First prescription 134 (83.8) 94 (79.0) 40 (97.6)

Follow-up prescription 23 (14.4) 22 (18.5) 1 (2.4)


9.2.6 Exelon® patch daily dose

Exelon® patch therapy was documented at the start of the observation and at each single

follow-up visit. The following dosage forms were predefined within the case report form:

Exelon®

patch 4.6mg/24 hours (5cm2 size containing 9mg rivastigmine), Exelon

® patch

9.5mg/24 hours (10cm2 size containing 18mg rivastigmine) and Exelon

® patch 13.3mg/24

hours (15cm2 size containing 27mg rivastigmine).

According to the Summary of Product Characteristics, the treatment is initiated with 4.6mg/24

hours Exelon® patch. After a minimum of four weeks of treatment and if well-tolerated, the

dose of the patch should be increased to the recommended daily effective dose of 9.5mg/24

hours as long as this dose is beneficial. After a minimum of six months of therapy with a dose

of 9.5mg/24 hours and a significant cognitive impairment or functional decline, the dose

could be increased to 13.3mg/24 hours.

Again, of note is that the total numbers in the stratification cohorts (trained caregivers; n=41

vs. non-trained; n=119) differ by one-third.

At baseline, the vast majority of patients (83.8 %; n=134/160) was prescribed 4.6mg/24 hours

Exelon® patches. Looking at the subgroup-specific results, patients with a trained caregiver

were adjusted to the initial dose of 4.6mg/24 hours in 97.6 % of cases (n=40/41) compared to

79.0 % (n=94/119) in the non-trained cohort. For further details, please refer to Table 9.15.

At the first follow-up visit after 4-5 months, half of all observed patients were treated with the

9.5mg Exelon® patch. This proportion remained nearly constant in the further course of the

observation. Regarding the Exelon® patch 13.3mg/24 hours, about one quarter of patients

received this strength at the second (2nd FU: n=28) and third follow-up visit (3rd FU: n=30).

As a result of dose adjustments at the last individually documented visit, 16.3 % of patients

received the 4.6mg/24 hours Exelon® patch (n=26/160) whereas 32.5 % (n=52/160) of

patients were prescribed the 9.5mg/24 hours Exelon® patch and 20.6 % (33/160) the

13.3mg/24 hours Exelon® patch. Comparing the two different subgroups at the last

documented visit, the proportions were distributed as follows in the cohorts without training

vs. with training: 12.6 % (n=15/119) vs. 26.8 % (n=11/41) of patients were treated with

4.6mg/24 hours Exelon®

patch. 37.0 % (n=44/119)/ 19.5 % (n=8/41) received the

recommended maintenance strength of 9.5mg/24 hours and 20.2 % (24/119)/ 22.0 % (n=9/41)



of patients were administered the maximum dose of 13.3mg/24 hours. Results of further

stratified analyses can be found in Table 2.3/8 to 2.3/9 and 4/3 in the Table compendium.

Table 9.15 Exelon® patch daily dose

Exelon® patch daily dose At initial visit 1st FU visit 2nd FU visit 3rd FU visit

Last

documented

visit*

N (%) N (%) N (%) N (%) N (%)

Total

Total 160 (100.0) 157 (100.0) 123 (100.0) 109 (100.0) 160 (100.0)

Missing 12 (7.5) 9 (5.7) 5 (4.1) 2 (1.8) 2 (1.3)

4.6mg Exelon® 134 (83.8) 57 (36.3) 30 (24.4) 29 (26.6) 26 (16.3)

9.5mg Exelon® 11 (6.9) 78 (49.7) 60 (48.8) 48 (44.0) 52 (32.5)

13.3mg Exelon® 3 (1.9) 13 (8.3) 28 (22.8) 30 (27.5) 33 (20.6)

Discontinuation 47 (29.4)

Without training

Total 119 (100.0) 118 (100.0) 97 (100.0) 81 (100.0) 119 (100.0)

Missing 12 (10.1) 9 (7.6) 5 (5.2) 2 (2.5) 2 (1.7)

4.6mg Exelon® 94 (79.0) 34 (28.8) 16 (16.5) 16 (19.8) 15 (12.6)

9.5mg Exelon® 11 (9.2) 68 (57.6) 52 (53.6) 40 (49.4) 44 (37.0)

13.3mg Exelon® 2 (1.7) 7 (5.9) 24 (24.7) 23 (28.4) 24 (20.2)


With training

Total 41 (100.0) 39 (100.0) 26 (100.0) 28 (100.0) 41 (100.0)

4.6mg Exelon® 40 (97.6) 23 (59.0) 14 (53.8) 13 (46.4) 11 (26.8)

9.5mg Exelon® 0 (-) 10 (25.6) 8 (30.8) 8 (28.6) 8 (19.5)

13.3mg Exelon® 1 (2.4) 6 (15.4) 4 (15.4) 7 (25.0) 9 (22.0)


*Last documented visit: 1st FU, 2nd FU or 3rd FU (end of observation)


9.2.7 Evaluation of the training “Demenz Aktiv Begegnen”

To determine the impact of training based on “Demenz aktiv begegnen” on the burden of

caregivers, 41 caregivers participated in the respective trainings after approximately 4-10

weeks (Training 1) and 3-6 months (Training 2). Physicians documented training dates as well

as questions concerning basic training information and an assessment of the respective

training. Questionnaires were completed immediately after each training.

Physicians were asked to complete the questionnaires after each training. The questionnaire

regarding basic training information contained the following questions:

• Did any adverse events occur since the last visit?

• How long did the current training take?



• How many participants attended in total? (number of patients/ number of caregivers)

• Which contents were covered during training?

More than half of the participating caregivers indicated that both trainings (Training 1,

56.1 %; Training 2, 70.7 %) took up to one hour. Only 39.0 % of the caregivers participating

in Training 1 and 22.0 % in Training 2 reported that the duration was between one to two

hours without a break.

Table 9.16 How long did the current event take? Only for population with training

How long did the current event take?

Training 1

(after 4-10 weeks)

Training 2

(after 3-6 months)

N (%) N (%)

Total 41 (100.0) 41 (100.0)

Missing 2 (4.9) 3 (7.3)

Up to one hour 23 (56.1) 29 (70.7)

Between one and two hours (without a break) 16 (39.0) 9 (22.0)


According to the physicians, almost half of the caregivers attended Training 1 alone (48.8 %)

whereas two-thirds attended Training 2 alone (65.9 %). The remaining caregivers participated

in groups of 2-12 participants in Training 1 (46.3 %, n=19) and Training 2 (26.8 %; n=11).

Over two-fifths of patients also attended Training 1 (41.5 %) alone versus approximately two-

thirds who attended Training 2 (68.3 %) alone. The remaining patients attended within a

group of 2-6 participants in Training 1 (29.3 %, n=12) and Training 2 (7.3 %, n=3). Further

details are presented in the following tables.



Table 9.17 How many patients participated in total?

How many patients participated in total?

Training 1

(after 4-10 weeks)

Training 2

(after 3-6 months)

N (%) N (%)

Total 41 (100.0) 41 (100.0)

Missing 2 (4.9) 3 (7.3)

0 10 (24.4) 7 (17.1)

1 17 (41.5) 28 (68.3)

2 1 (2.4) 2 (4.9)

3 8 (19.5) 1 (2.4)

4 1 (2.4) 0 (-)

5 1 (2.4) 0 (-)

6 1 (2.4) 0 (-)


Table 9.18 How many caregivers participated in total?

How many caregivers participated in total?

Training 1

(after 4-10 weeks)

Training 2

(after 3-6 months)

N (%) N (%)

Total 41 (100.0) 41 (100.0)

Missing 2 (4.9) 3 (7.3)

1 20 (48.8) 27 (65.9)

2 3 (7.3) 3 (7.3)

3 1 (2.4) 1 (2.4)

4 0 (-) 2 (4.9)

5 6 (14.6) 5 (12.2)

7 7 (17.1) 0 (-)

10 1 (2.4) 0 (-)

12 1 (2.4) 0 (-)


Furthermore, the patients’ caregivers were asked about the topics that were covered during the

trainings. In the following, the answers to these questions are summarized in Table 9-19 – 9-

21. The main focus of both trainings was the “treatment of dementia” (Training 1: 95.1 % vs.

Training 2: 80.5 %) and the topic “dementia in general” (Training 1: 82.9 % and Training 2:

46.3 %). Another important focus of Training 2 (68.3 %) and to a lesser extent of Training 1

(51.2 %) was the subject “everyday life with dementia patients”. While the focus of

“treatment of dementia” was placed on “drug therapy” (Training 1: 61.5 % and Training 2:

45.5 %), the target subject in “everyday life with dementia patients” was a discussion of

“behavior and handling” (Training 1: 61.9 % and Training 2: 82.1 %). For the complete

analysis of other training contents, please refer to Table 3/7 in the Table compendium.



Table 9.19 Which contents were covered during training?

Which contents were covered during training?

Training 1

(after 4-10 weeks)

Training 2

(after 3-6 months)

N* (%) N* (%)

Total 41 (100.0) 41 (100.0)

Missing 2 (4.9) 3 (7.3)

Dementia in general 34 (82.9) 19 (46.3)

Treatment of dementia 39 (95.1) 33 (80.5)

Everyday life with dementia patients 21 (51.2) 28 (68.3)

Rights and social affairs 14 (34.1) 8 (19.5)

Others 3 (7.3) 7 (17.1)

*Multiple answers possible


Table 9.20 Content – Treatment of dementia

Treatment of dementia

Training 1

(after 4-10 weeks)

Training 2

(after 3-6 months)

N* (%) N* (%)

Total 39 (100.0) 33 (100.0)

Missing 8 (20.5) 4 (12.1)

Non-drug therapy 9 (23.1) 5 (15.2)

Drug therapy 24 (61.5) 15 (45.5)

Handling the Exelon® patch 23 (59.0) 23 (69.7)



Table 9.21 Content – Everyday life with dementia patients

Everyday life with dementia patients

Training 1

(after 4-10 weeks)

Training 2

(after 3-6 months)

N* (%) N* (%)

Total 21 (100.0) 28 (100.0)

Missing 7 (33.3) 4 (14.3)

Behavior and handling 13 (61.9) 23 (82.1)

Safety in the household 9 (42.9) 11 (39.3)



The second part of the evaluation questionnaire concerned the usefulness and atmosphere of

training.

Both evaluations were documented on a visual analogue scale ranging from 0 = “not helpful”

to 10 = “extremely helpful” for the question “Were the contents of training helpful for you?”.

The average evaluation of this question was 8.5 ± 1.3 for Training 1 and 8.7 ± 1.2 for in

Training 2. The training atmosphere (ranging from 0 = unpleasant / tense to 10 = very



comfortable / relaxed) was similarly well-rated for both trainings (Training 1: 9.3 ± 0.8;

Training 2: 9.2 ± 0.8).

Table 9.22 Evaluation: Were the contents of training helpful for you?

Were the contents of the training helpful for you?

0=not helpful, 10=extremely helpful

Training 1

(after 4-10 weeks)

Training 2

(after 3-6 months)

n = 24 n = 19

Mean 8.5 8.7

SD 1.3 1.2

Median 8.5 9.0

Range 6.0 – 10.0 6.0 – 10.0


Table 9.23 Evaluation: How was the atmosphere in training?

How was the atmosphere in training for you?

0=unpleasant/tense, 10=very comfortable/relaxed

Training 1

(after 4-10 weeks)

Training 2

(after 3-6 months)

n = 24 n = 18

Mean 9.3 9.2

SD 0.8 0.8

Median 9.0 9.0

Range 8.0 – 10.0 8.0 – 10.0


In addition, the participants were asked to answer three general questions regarding the

contents in the trainings:

• What did you particularly like?

• What could be improved?

• What information would you still need?

For details concerning these questions, please refer to Table 3/10 – 3/12 in the Table

compendium.

9.2.8 Follow-up visits

Physicians documented one initial visit (baseline visit), up to two follow-up visits per patient

(1st FU: after 4-6 months; 2nd FU: after 8-10 months) and one final visit at the end of the

observation after approximately one year or in case of premature study termination. The mean

duration from the initial to the first follow-up visit was 4.6 ± 1.7 months for all observed

patients. Looking at the mean duration from the first to the second follow-up visit, this was

documented as 4.0 ± 1.7 months and from the second to the third follow-up visit as 3.4 ± 1.2

months. In the trained caregivers cohort, the longest mean observation duration (5.8 months ±

1.8 months) was between the initial and the first follow-up visit whereas the shortest

observation time was between the second and the third follow-up visit (3.2 months ± 1.0



months). The average intervals between visits in the non-trained cohort were similar to those

documented for the total study population. Further details can be found in Table 9.24.

Table 9.24 Time interval between visits

Time interval between visits [months] Initial visit – 1st FU 1st FU – 2nd FU 2nd FU – 3rd FU

Total n = 160 n = 125 n = 104

Mean 4.6 4.0 3.4

SD 1.7 1.7 1.2

Median 4.6 3.5 3.3

Range 0.9 – 11.2 0.2 – 10.3 0.4 – 9.2

Without training n = 119 n = 96 n = 81

Mean 4.2 4.1 3.4

SD 1.5 1.8 1.3

Median 4.4 3.7 3.4

Range 0.9 – 9.8 0.2 – 10.3 0.4 – 9.2

With training n = 41 n = 29 n = 23

Mean 5.8 3.4 3.2

SD 1.8 0.9 1.0

Median 5.6 3.2 3.2

Range 2.4 – 11.2 1.8 – 6.2 1.7 – 6.0


9.2.9 Mini-Mental State Examination

The severity of dementia was assessed by the Mini-Mental State Examination (MMSE) which

is a widely used screening instrument for Alzheimer’s disease. It covers various cognitive

functions including memory function, attention, language, visual-spatial skills, ability to

follow simple commands, language and orientation by assessing simple questions and

problems in a number of areas: the time and place of the test, repeating and recall of a list of

words, arithmetic such as the serial sevens, language use and comprehension, and basic motor

skills. The maximum MMSE score is 30 points. Any score greater than or equal to 27 points

(out of 30) is effectively normal (intact). Below this, scores can indicate severe (<10 points),

moderate (10-19 points) or mild (20-26 points) impairment.

At baseline and at each single follow-up visit, physicians were asked to document the result of

the MMSE for their patients, if it was performed in routine clinical practice. The average sum

score of MMSE for the total study population was 20.5 ± 4.2 points at the start of the

observation compared to 19.9 ± 4.5 points at the last individual follow-up visit. The mean

MMSE score decreased slightly in the course of therapy (see Table 9.25). In the stratification

cohort with trained caregivers, the lowest average MMSE score (16.9 ± 4.6 points) was

observed at the second follow-up visit whereas the mean MMSE score was always >20 points

http://en.wikipedia.org/wiki/Memory

http://en.wikipedia.org/wiki/Orientation_(mental)

http://en.wikipedia.org/wiki/Serial_sevens



in the cohort with untrained caregivers. For further details, please refer to Table 9.25 and

Table 4/4 in the Table compendium.

Table 9.25 Mini-Mental State Examination (MMSE) per visit, “with/ without training”

Mini-Mental State

Examination total

score

Initial visit 1st FU 2nd FU 3rd FU Last documented

visit*

Total n = 133 n = 108 n = 70 n = 72 n = 94

Mean 20.5 20.1 19.8 19.9 19.9

SD 4.2 4.7 4.7 4.6 4.5

Median 21.0 20.0 20.0 20.0 20.0

Range 10 – 28 4 – 30 8 – 30 5 – 30 5 – 30

Without training n = 98 n = 79 n = 56 n = 54 n = 71

Mean 20.7 20.3 20.5 20.2 20.2

SD 3.9 4.5 4.4 4.0 4.1

Median 21.0 20.0 20.0 20.0 20.0

Range 10 – 28 5 – 30 8 – 30 12 – 30 10 – 30

With training n = 35 n = 29 n = 14 n = 18 n = 23

Mean 19.9 19.7 16.9 18.8 18.9

SD 4.7 5.2 4.6 6.0 5.3

Median 20.0 20.0 17.0 20.5 20.0

Range 11 – 27 4 – 27 9 – 24 5 – 27 5 – 27

* Last documented visit: 1.FU, 2.FU or 3.FU (end of the study)


Table 9.26 shows the mean decrease of MMSE. Regarding all observed patients, the mean

MMSE score decreased slightly from start of observation to last individual visit by 0.7 ± 3.1

points. The MMSE score in the small cohort with trained caregivers decreased from baseline

to last follow-up visit by 1.0 ± 3.1 points in average compared to 0.6 ± 3.1 points in the group

without trained caregiver. For more details please refer to Table 9-26.



Table 9.26 Change** of Mini-Mental State Examination total score, “with/ without training”

Change** of Mini-Mental State

Examination total score 1st FU 2nd FU 3rd FU

Last documented

visit*

Total n = 94 n = 68 n = 68 n = 87

Mean -0.2 -0.3 -0.8 -0.7

SD 2.5 2.7 3.2 3.1

Median 0.0 0.0 0.0 0.0

Range -8.0 – 6.0 -8.0 – 7.0 -10.0 – 7.0 -10.0 – 7.0

Without training n = 68 n = 54 n = 52 n = 66

Mean -0.1 0.1 -0.6 -0.6

SD 2.5 2.3 3.2 3.1

Median 0.0 0.0 0.0 0.0

Range -8.0 – 6.0 -5.0 – 7.0 -10.0 – 7.0 -10.0 - 7.0

With training n = 26 n = 14 n = 16 n = 21

Mean -0.2 -1.8 -1.6 -1.0

SD 2.5 3.4 3.3 3.1

Median 0.0 -1.0 -0.5 0.0

Range -8.0 – 3.0 -8.0 – 3.0 -9.0 – 3.0 -9.0 – 3.0

* Last documented visit: 1. FU, 2. FU or 3. FU (end of the study)

** MMST (visit) – MMST (baseline)


9.2.10 Discontinuation of the therapy with Exelon® patch

Premature discontinuation of Exelon® patch therapy was recorded for 29.4 % (n=47/160) of

all observed patients (31.7 % “with training” and 28.6 % “without training”; Table 5/1 in the

Compendium). Mean duration until discontinuation of therapy in total was 7.5 ± 4.3 months.

The average duration in the trained cohort was 8.7 ± 5.1 months and 6.8 ± 3.7 months in the

non-trained cohort. Reasons for premature discontinuation were “adverse events” and “patient

did not return” in 16 patients (10.0 %, respectively) and “insufficient efficacy” and “patient

died” in 2 patients (1.3 %, respectively). Other reasons were documented for 11 patients

(6.9 %). For further information as well as details of “other” reasons for premature

discontinuation, please refer to Table 5/1 to Table 5/4 in the Compendium.



9.2.11 General circumstances of caregivers

Demographic data are summarized in Table 9.27 and Table 9.28.

Overall, more female (57.5 %) than male caregivers (34.4 %) took part in this non-

interventional study. In the caregiver group “with training” nearly two-thirds (61.0 %) were

female compared to 39.0 % male caregivers, whereas the proportion in the stratification group

“without training” was 56.3 % female vs. 32.8 % male caregivers.

The majority of all caregivers (43.8 %) were over 70 years old. This was also the largest age

group of caregivers “with training” (39.0 %) and “without training” (45.4 %).

Table 9.27 Sex of caregiver, “with/ without training”

Sex

Training

Total No Yes

N (%) N (%) N (%)

Total 160 (100.0) 119 (100.0) 41 (100.0)

Missing 13 (8.1) 13 (10.9) 0 (-)

Male 55 (34.4) 39 (32.8) 16 (39.0)

Female 92 (57.5) 67 (56.3) 25 (61.0)


Table 9.28 Age of caregiver, “with/ without training”

Age [years]

Training

Total No Yes

N (%) N (%) N (%)

Total 160 (100.0) 119 (100.0) 41 (100.0)

Missing 14 (8.8) 14 (11.8) 0 (-)

< 35 3 (1.9) 3 (2.5) 0 (-)

≥ 35 - < 50 18 (11.3) 7 (5.9) 11 (26.8)

≥ 51 - < 60 28 (17.5) 22 (18.5) 6 (14.6)

≥ 61 - < 70 27 (16.9) 19 (16.0) 8 (19.5)

≥ 70 70 (43.8) 54 (45.4) 16 (39.0)


Over one-third (35.0 %) of all caregivers reported carrying full responsibility for

administering the prescribed medication to their patient (29.3 % “with training” and 37.0 %

“without training”; Table 6.1/3 in the Compendium). The vast majority (72.5 %) of caregivers

had never before taken care of a close relative over a period of several weeks (80.5 % “with

training” and 69.7 % “without training”; Table 6.1/4 in the Compendium).



The following table shows that at the initial visit over half (56.9 %) of all caregivers

considered the patient’s age to be the cause of AD (73.2 % “with training” and 51.3 %

“without training”) while only 47.5 % thought so at the last documented visit (51.2 % “with

training” and 46.2 % “without training”). A genetic disposition was initially thought to be the

cause by 22.5 % of caregivers (22.0 % “with training” and 22.7 % “without training”) and by

23.1 % of caregivers at the end of the study (14.6 % “with training” and 26.1 % “without

training”).

Table 9.29 What does caregiver think is the cause of patient’s AD?

Cause of AD At initial visit 1st FU visit 3rd FU visit

Last documented

visit*

N (%) N (%) N (%) N (%)

Total

Total 160 (100.0) 157 (100.0) 109 (100.0) 160 (100.0)

Missing 17 (10.6) 39 (24.8) 24 (22.0) 54 (33.8)

Age 91 (56.9) 80 (51.0) 63 (57.8) 76 (47.5)

Genetic disposition 36 (22.5) 42 (26.8) 30 (27.5) 37 (23.1)

Diet 4 (2.5) 3 (1.9) 5 (4.6) 5 (3.1)

Infection/ virus 2 (1.3) 1 (0.6) 1 (0.9) 1 (0.6)

Other 30 (18.8) 17 (10.8) 13 (11.9) 18 (11.3)

Without training

Total 119 (100.0) 118 (100.0) 81 (100.0) 119 (100.0)

Missing 16 (13.4) 31 (26.3) 18 (22.2) 41 (34.5)

Age 61 (51.3) 59 (50.0) 47 (58.0) 55 (46.2)


Diet 4 (3.4) 3 (2.5) 3 (3.7) 3 (2.5)

Infection/ virus 2 (1.7) 1 (0.8) 0 (-) 0 (-)

Other 22 (18.5) 10 (8.5) 6 (7.4) 10 (8.4)

With training

Total 41 (100.0) 39 (100.0) 28 (100.0) 41 (100.0)

Missing 1 (2.4) 8 (20.5) 6 (21.4) 13 (31.7)

Age 30 (73.2) 21 (53.8) 16 (57.1) 21 (51.2)


Diet 0 (-) 0 (-) 2 (7.1) 2 (4.9)

Infection/ virus 0 (-) 0 (-) 1 (3.6) 1 (2.4)

Other 8 (19.5) 7 (17.9) 7 (25.0) 8 (19.5)

*Last documented visit: 1st FU or 3rd FU (end of observation); Multiple responses possible


Caregivers opinion regarding the helpfulness of AD drug treatment was assessed on a visual

analogue scale ranging from 0 = “not helpful” to 10 = “extremely helpful”. At the initial visit,

all caregivers believed to an average extent of 6.3 ± 1.9 points in the helpfulness of AD

treatment with medication (6.3 ± 2.3 points “with training” and 6.3 ± 1.7 points “without



training”; Table 9.30). At the last documented visit the caregivers believed in the helpfulness

of medication to a lesser extent of 6.1 ± 2.1 points due to a decreased score among caregivers

with training (5.5 ± 2.0 points “with training” and 6.3 ± 2.1 points “without training”).

Table 9.30 To what extent in the opinion of the caregiver can treatment with medication help the AD

patient, “with/ without training”

Treatment with medication:

0= not helpful,

10= extremely helpful

Initial visit 1st FU 3rd FU Last documented

visit*

Total n = 137 n = 116 n = 80 n = 101

Mean 6.3 6.2 6.2 6.1

SD 1.9 2.1 2.0 2.1

Median 6.0 6.5 6.0 6.0

Range 1.0 – 10.0 0.0 – 10.0 0.0 – 10.0 0.0 – 10.0


Mean 6.3 6.3 6.6 6.3

SD 1.7 2.0 1.9 2.1

Median 7.0 7.0 7.0 7.0

Range 2.0 – 10.0 0.0 – 10.0 2.0 – 10.0 0.0 – 10.0


Mean 6.3 5.8 5.1 5.5

SD 2.3 2.5 2.0 2.0

Median 6.0 6.0 5.0 6.0

Range 1.0 – 10.0 0.0 – 10.0 0.0 – 8.0 0.0 – 8.0

* Last documented visit: 1st FU or 3rd FU (end of the study)


As shown in the following table, the symptoms most common among the caregivers at the

initial visit were insomnia and fatigue (32.5%, respectively), followed by backache (26.3%),

brooding or repeated thoughts (25.0 %) and exhaustion (23.8 %). At the last documented visit,

the most common symptom was fatigue (24.4%), followed by insomnia and backache (22.5%,

respectively). Details of stratification by training status can be found in Table 6.1/7 in the

Compendium.



Table 9.31 Does the caregiver suffer from one of the following symptoms?

Symptom At initial visit 1st FU visit 2nd FU visit 3rd FU visit

Last

documented

visit*

N (%) N (%) N (%) N (%) N (%)

Total 160 (100.0) 157 (100.0) 123 (100.0) 109 (100.0) 160 (100.0)

Missing 44 (27.5) 65 (41.4) 54 (43.9) 45 (41.3) 73 (45.6)

Insomnia 52 (32.5) 37 (23.6) 24 (19.5) 25 (22.9) 36 (22.5)

Fatigue 52 (32.5) 40 (25.5) 34 (27.6) 29 (26.6) 39 (24.4)

Headache 22 (13.8) 18 (11.5) 21 (17.1) 20 (18.3) 25 (15.6)

Backache 42 (26.3) 32 (20.4) 30 (24.4) 26 (23.9) 36 (22.5)

Permanent sadness 16 (10.0) 8 (5.1) 4 (3.3) 3 (2.8) 6 (3.8)

Exhaustion 38 (23.8) 29 (18.5) 26 (21.1) 15 (13.8) 21 (13.1)

Loss of appetite and weight 4 (2.5) 6 (3.8) 3 (2.4) 2 (1.8) 3 (1.9)

Diminished ability to think

and concentrate 26 (16.3) 12 (7.6) 9 (7.3) 7 (6.4) 13 (8.1)

Loss of self-confidence 8 (5.0) 7 (4.5) 6 (4.9) 4 (3.7) 9 (5.6)

Brooding or repeated

thoughts 40 (25.0) 33 (21.0) 15 (12.2) 20 (18.3) 29 (18.1)

Difficulty to make decisions 16 (10.0) 6 (3.8) 5 (4.1) 4 (3.7) 9 (5.6)

*Last documented visit: 1st FU, 2nd FU or 3rd FU (end of observation); Multiple responses possible


Nearly 60 % of caregivers at the initial visit and nearly 40 % at the last documented visit

reported not taking any medication from the classes of drugs listed in Table 9.32. At the initial

visit caregivers most often took antidepressants and sleeping pills (10.6 % and 8.1 %,

respectively), which were also most often taken at the last documented visit (10.0 % and

9.4 %, respectively). Details of stratification by training status can be found in Table 6.1/8 in

the Compendium.

Table 9.32 Is the caregiver presently taking medication from one of the following classes of drugs?

Class At initial visit 1st FU visit 2nd FU visit 3rd FU visit

Last

documented

visit*

N (%) N (%) N (%) N (%) N (%)

Total 160 (100.0) 157 (100.0) 123 (100.0) 109 (100.0) 160 (100.0)

Missing 29 (18.1) 50 (31.8) 41 (33.3) 36 (33.0) 61 (38.1)

Antidepressants 17 (10.6) 11 (7.0) 12 (9.8) 12 (11.0) 16 (10.0)

Sedatives 6 (3.8) 7 (4.5) 6 (4.9) 6 (5.5) 6 (3.8)

Sleeping pills 13 (8.1) 12 (7.6) 9 (7.3) 11 (10.1) 15 (9.4)

Anxiolytics 1 (0.6) 0 (-) 0 (-) 0 (-) 0 (-)

Other neurological/

psychiatric medication 8 (5.0) 9 (5.7) 6 (4.9) 5 (4.6) 8 (5.0)

No, none 95 (59.4) 73 (46.5) 54 (43.9) 45 (41.3) 63 (39.4)

*Last documented visit: 1st FU, 2nd FU or 3rd FU (end of observation); Multiple responses possible




Table 9.33 summarizes the medical interventions on behalf of the caregiver in the last half

year before the start of the study and in the course of the study, stratified by training status. At

the initial visit, 12.5 % of caregivers had been hospitalized in the last half year, 5.6 % had

been on sick leave, and 2.5 % had been to rehabilitation. In the course of the study, a stay in

the hospital, rehabilitation and/or sick leave was needed at least once by 3.1 %, 1.9 % and

3.8 % of caregivers, respectively. Details of stratification by training status can be found in

Table 6.1/9 in the Compendium.

Table 9.33 Medical interventions on behalf of the caregiver

Training

Total No Yes

N (%) N (%) N (%)

In the last half year before study start

Total 160 (100.0) 119 (100.0) 41 (100.0)

Hospitalization 20 (12.5) 15 (12.6) 5 (12.2)

Rehabilitation treatment 4 (2.5) 3 (2.5) 1 (2.4)

Sick leave 9 (5.6) 6 (5.0) 3 (7.3)

In the course of the study

Total 160 (100.0) 119 (100.0) 41 (100.0)

Hospitalization 5 (3.1) 2 (1.7) 3 (7.3)

Rehabilitation treatment 3 (1.9) 2 (1.7) 1 (2.4)

Sick leave 6 (3.8) 5 (4.2) 1 (2.4)

Multiple responses possible


9.2.12 Mini-Zarit assessment of caregiver burden

The Mini-Zarit scale is used to assess the burden on caregivers of AD patients. The possible

answers to the following seven items are assigned points (“never” 1 point, “occasionally” 0.5

points, “more often” 0 points / total score range 0 to 7) and constitute the sum score. The

questionnaire was filled out by the caregiver at the initial visit and the first and third follow-up

visit (or end of observation). The following analyses are based on the total of available

questionnaires.

1. Difficulties in the family

In total, the most frequent answers of the caregivers were “never” (n=85/144, 59.0 %) at the

initial visit and “never” (n=67/112, 59.8 %) at the last documented visit. The percentage

among caregivers without training was slightly lower (53.4 % at initial visit and 57.0 % at the

last documented visit), while the trained caregivers more often reported never having

difficulties in the family (73.2 % at initial visit and 66.7 % at the last documented visit). In

both groups of caregivers the answers remained consistent in the course of the study.



2. Difficulties with friends, leisure time or job

The total number of caregivers most often responded with “never” (n=81/144, 56.3 %) at the

initial visit and “never” (n=67/112, 59.8 %) at the last documented visit. The percentage

among caregivers without training was somewhat lower (50.5 % at initial visit and 58.2 % at

the last documented visit), while the trained caregivers more often reported never having such

difficulties (70.7 % at initial visit and 63.6 % at the last documented visit).

3. Impact on health (physical and/or mental)

Most of all caregivers responded with “never” (n=60/144, 41.7 %) at the initial visit and

“occasionally” (n=50/112, 44.6 %) at the last documented visit. Caregivers without training

most frequently reported an occasional impact on their health (48.5 % at initial visit and

41.8% at the last documented visit), while the trained caregivers initially most often

responded with “never” (73.2 %) and most often with “occasionally” (51.5 %) at the last

documented visit.

4. Do you have the impression that you don’t recognize the patient anymore?

Caregivers most frequently responded with “never” (n=93/144, 64.6 %) at the initial visit and

“never” (n=65/112, 58.0 %) at the last documented visit. In particular, the percentage among

caregivers without training was somewhat lower (60.2 % at initial visit and 55.7 % at the last

documented visit), while the trained caregivers more often reported never having such an

impression (75.6 % at initial visit and 63.6 % at the last documented visit).

5. Are you worried about the patient’s future?

The answers most often provided by caregivers were “occasionally” (n=67/144, 46.5 %) at the

initial visit and “occasionally” (n=55/112, 49.1 %) at the last documented visit. The

percentage among caregivers without training was slightly higher (46.6 % at initial visit and

50.6 % at the last documented visit), while the trained caregivers slightly less often reported

such occasional worries (46.3 % at initial visit and 45.5 % at the last documented visit).

6. Would you like (more) support in caring for the patient?

The most frequent answers by caregivers overall were “occasionally” (n=68/144, 47.2 %) at

the initial visit and “occasionally” (n=54/112, 48.2 %) at the last documented visit. Caregivers

without training responded more often with “occasionally” (53.4 % at initial visit and 55.7 %

at the last documented visit), while the trained caregivers most often reported never wanting

more support (56.1 % at initial visit and 54.5 % at the last documented visit).

7. Do you feel burdened when caring for the patient?

Caregivers in total most often responded with “never” (n=59/144, 41.0 %) at the initial visit

and “occasionally” (n=54/112, 48.2 %) at the last documented visit. Caregivers without

training answered most often with “occasionally” (38.8 % at initial visit and 45.6 % at the last

documented visit), while the trained caregivers most frequently never felt burdened at the

initial visit (56.1 %) and most often felt occasionally burdened at the last documented visit

(54.5 %).



For further details please refer to Table 6.2/1 to Table 6.2/7 in the Compendium.

The average sum score of Mini-Zarit for all caregivers was 4.6 ± 1.8 points at the start of the

observation compared to 4.5 ± 1.7 points at the last individual follow-up visit. The score

decreased somewhat in the course of therapy (see Table 9.34). The mean sum scores were

consistently lower, i.e., worse, for caregivers without training (4.2 ± 1.7 points at initial visit

and 4.3 ± 1.7 points at the last documented visit) than for the caregivers overall, while the

trained caregivers (5.5 ± 1.5 points at initial visit and 5.0 ± 1.4 points at the last documented

visit) consistently had better average scores than all caregivers.

Table 9.34 Sum score of Mini-Zarit, “with/ without training”

Sum score Mini-Zarit Initial visit 1st FU 3rd FU Last documented

visit*

Total n = 138 n = 124 n = 88 n = 110

Mean 4.6 4.5 4.4 4.5

SD 1.8 1.6 1.7 1.7

Median 5.0 4.8 4.5 4.8

Range 0.0 – 7.0 0.0 – 7.0 0.5 – 7.0 0.0 - 7.0


Mean 4.2 4.2 4.2 4.3

SD 1.7 1.6 1.7 1.7

Median 4.5 4.5 4.5 4.5

Range 0.0 – 7.0 0.0 – 7.0 0.5 – 7.0 0.0 - 7.0


Mean 5.5 5.4 4.9 5.0

SD 1.5 1.3 1.5 1.4

Median 6.0 5.5 5.0 5.0

Range 1.5 – 7.0 2.5 – 7.0 1.5 – 7.0 1.5 – 7.0



For stratifications of the Mini-Zarit sum score by age and sex please refer to Table 6.2/9 and

Table 6.2/10 in the Compendium.

9.2.13 GDS assessment of caregivers

The Geriatric Depression Scale (GDS) was used in this study to further assess the burden on

caregivers of AD patients. The possible answers to the following 15 items are “yes” or “no”,

with the answers indicative of depression being assigned 1 point and constituting the sum



score. A score > 5 points is suggestive of depression. The GDS questionnaire was filled out by

the caregiver at the initial visit and the first and third follow-up visit (or end of observation).

The following analyses are based on the total of available questionnaires.

1. Are you basically satisfied with your life?

In total, the vast majority of caregivers answered in the affirmative at the initial visit

(n=132/142, 93.0 %) and at the last documented visit (n=103/110, 93.6 %). The percentage of

“yes” among caregivers without training was comparable (94.1 % at initial visit and 91.0 % at

the last documented visit), while all the trained caregivers were satisfied at the end of the

study (90.2 % at initial visit and 100.0 % at the last documented visit).

2. Have you dropped many of your activities and interests?

The total number of caregivers more often responded with “no” at the initial visit (n=91/142,

64.1 %) and at the last documented visit (n=68/110, 61.8 %). The percentage of “no” among

caregivers without training was somewhat lower (61.4 % at initial visit and 61.5 % at the last

documented visit), while the trained caregivers more often reported not having dropped many

activities or interests (70.7 % at initial visit and 62.5 % at the last documented visit).

3. Do you feel that your life is empty?

The majority of all caregivers responded with “no” at the initial visit (n=125/142, 88.0 %) and

at the last documented visit (n=99/110, 90.0 %). The percentage of “no” was somewhat higher

among caregivers without training (91.1 % at initial visit and 91.0 % at the last documented

visit) and lower among the trained caregivers (80.5 % at initial visit and 87.5 % at the last

documented visit).

4. Do you often get bored?

Caregivers more frequently responded with “no” at the initial visit (n=133/142, 93.7 %) and at

the last documented visit (n=105/110, 95.5 %). This was comparable to the percentage of

“no” among caregivers without training (95.0 % at initial visit and 94.9 % at the last

documented visit) and among the trained caregivers (90.2 % at initial visit and 96.9 % at the

last documented visit).

5. Are you in good spirits most of the time?

The answer more often provided by caregivers was “yes” at the initial visit (n=108/142,

76.1 %) and at the last documented visit (n=77/110, 70.0 %). The percentage of “yes” was

somewhat lower among caregivers without training (75.2 % at initial visit and 66.7 % at the

last documented visit) and higher among the trained caregivers (78.0 % at initial visit and

78.1 % at the last documented visit).

6. Are you afraid that something bad is going to happen to you?

The more frequent answer by caregivers overall was “no” at the initial visit (n=116/142,

81.7 %) and at the last documented visit (n=88/110, 80.0 %). This was comparable to the

percentage of “no” among caregivers without training (82.2 % at initial visit and 78.2 % at the



last documented visit) and among the trained caregivers (80.5 % at initial visit and 84.4 % at

the last documented visit).

7. Do you feel happy most of the time?

Caregivers in total more often responded with “yes” at the initial visit (n=122/142, 85.9 %)

and at the last documented visit (n=95/110, 86.4 %). The percentage of “yes” was slightly

lower among caregivers without training (85.1 % at initial visit and 85.9 % at the last

documented visit) and slightly higher among the trained caregivers (87.8 % at initial visit and


8. Do you often feel helpless?

In total, the more frequent answer of the caregivers was “no” at the initial visit (n=118/142,

83.1 %) and at the last documented visit (n=99/110, 90.0 %). The percentage of “no” was




9. Do you prefer to stay at home, rather than going out and doing new things?

The total number of caregivers more often responded with “yes” at the initial visit (n=86/142,

60.6 %) and at the last documented visit (n=62/110, 56.4 %). The percentage of “yes” was

comparable among caregivers without training (61.4 % at initial visit and 56.4 % at the last

documented visit) and slightly lower among the trained caregivers (58.5 % at initial visit and


10. Do you feel you have more problems with memory than others?

The majority of all caregivers responded with “no” at the initial visit (n=126/142, 88.7 %) and

at the last documented visit (n=96/110, 87.3 %). The percentage of “no” was higher among

caregivers without training (93.1 % at initial visit and 88.5 % at the last documented visit) and

lower among the trained caregivers (78.0 % at initial visit and 84.4 % at the last documented

visit).

11. Do you think it is wonderful to be alive now?

Caregivers more frequently responded with “yes” at the initial visit (n=113/142, 79.6 %) and

at the last documented visit (n=83/110, 75.5 %). The percentage of “yes” was somewhat

lower among caregivers without training (77.2% at initial visit and 73.1 % at the last

documented visit) and higher among the trained caregivers (85.4 % at initial visit and 81.3 %

at the last documented visit).

12. Do you feel pretty worthless the way you are now?

The answer more often provided by caregivers was “no” at the initial visit (n=131/142,

92.3 %) and at the last documented visit (n=106/110, 96.4 %). The percentage of “no” among

caregivers without training was comparable (93.1 % at initial visit and 94.9 % at the last



documented visit), while all the trained caregivers negated feeling worthless at the end of the

study (90.2 % at initial visit and 100.0 % at the last documented visit).

13. Do you feel full of energy?

The more frequent answer by caregivers overall was “no” at the initial visit (n=90/142,


somewhat higher among caregivers without training (66.3 % at initial visit and 61.5 % at the

last documented visit) and lower among the trained caregivers (56.1 % at initial visit and

59.4 % at the last documented visit), meaning that more of the latter felt full of energy.

14. Do you feel that your situation is hopeless?

Caregivers in total more often responded with “no” at the initial visit (n=129/142, 90.8 %) and

at the last documented visit (n=102/110, 92.7 %). The percentage of “no” was somewhat

lower among caregivers without training (89.1 % at initial visit and 89.7 % at the last

documented visit) and higher among the trained caregivers, all of whom felt their situation

was not hopeless at the end of the study (95.1 % at initial visit and 100.0 % at the last

documented visit).

15. Do you think that most people are better off than you are?

In total, the more frequent answer of the caregivers was “no” at the initial visit (n=104/142,





For further details please refer to Table 6.3/1 to Table 6.3/15 in the Compendium.

The average sum score of GDS for all caregivers was 3.1 ± 2.9 points at the start of the

observation compared to 3.0 ± 2.2 points at the last individual follow-up visit. The score

remained largely constant in the course of therapy (see Table 9.35). The mean sum scores

were consistently higher, i.e., worse, for caregivers without training (3.3 ± 3.0 points at initial

visit and 3.2 ± 2.4 points at the last documented visit) than for the caregivers overall, while

the average scores of the trained caregivers (2.8 ± 2.7 points at initial visit and 2.6 ± 1.7 points

at the last documented visit) were consistently better than those of all caregivers and

decreased in the course of the study.



Table 9.35 Sum score GDS, “with/ without training”

Sum score GDS Initial visit 1st FU 3rd FU Last documented

visit*

Total n = 127 n = 108 n = 79 n = 96

Mean 3.1 3.1 3.1 3.0

SD 2.9 2.4 2.3 2.2

Median 2.0 3.0 3.0 3.0

Range 0.0 – 15.0 0.0 – 13.0 0.0 – 10.0 0.0 – 10.0


Mean 3.3 3.3 3.4 3.2

SD 3.0 2.5 2.4 2.4

Median 2.0 3.0 3.0 3.0

Range 0.0 – 13.0 0.0 – 13.0 0.0 – 10.0 0.0 – 10.0


Mean 2.8 2.6 2.4 2.6

SD 2.7 1.9 1.7 1.7

Median 2.0 2.0 2.0 3.0

Range 0.0 – 15.0 0.0 – 7.0 0.0 – 6.0 0.0 – 6.0



For stratifications of the GDS sum score by age and sex please refer to Table 6.3/17 and

6.3/18 in the Compendium.

9.3 Outcome data

N/A

9.4 Main results

N/A

9.5 Other analyses

N/A



9.6 Adverse events and adverse reactions

Safety evaluation is based on the population of evaluable patients (n=200).

9.6.1 Brief summary of adverse events

As shown in Table 9/36, over a quarter of patients (n=52/200, 26.0%) were affected by at

least one adverse event (AE) of any nature. The rate was lower in the group with untrained

caregivers (n=26/129, 20.2%) than with trained caregivers (n=26/71, 36.6%). Adverse drug

reactions, i.e., nsADR and SADR, occurred in 36/200 (18.0%) and 2/200 patients (1.0%),

respectively. 18 patients (9.0%) had serious AEs without drug-relation (SAEnr), 2 patients

(1.0%) had serious adverse drug reactions (SADR). 30 cases of medication error (15%) and 4

cases of lack of drug effect (2%) were documented. 5 patient deaths were recorded in the

study, 1 of which was assessed to be drug-related (see Narratives in the Appendix). In patients

with AEs, the number of AEs of any nature was most frequently 1 per patient (10.5%),

followed by 2 AEs per patient (7.5%; Table 7/2 in the Compendium).

Of the 129 AEs that occurred altogether, 24 were non-serious and not drug-related (nsAEnr),

63 were non-serious adverse drug reactions (nsADR), 39 were serious and not drug-related

(SAEnr), and 3 were serious adverse drug reactions (SADR; Table 7/9 in the Compendium).

Most AEs belonged to the SOCs "skin and subcutaneous tissue disorders" (16.3%),

"psychiatric disorders" (14.7%), "nervous system disorders" (13.2%), "gastrointestinal

disorders" (10.1%), "general disorders and administration site conditions" (10.1%) and

"cardiac disorders" (8.5%; Table 7/8 in the Compendium). The preferred terms (PTs) for the

most frequently recorded AEs of any group were "nausea" (4.7%) and "depression" (3.9%).

Detailed classifications of all AEs are given in the following section.

Table 9.36 Number of adverse events by patient

Training

Total No Yes

n* % n* % n* %

Total patients 200 100.0 129 100.0 71 100.0

Any adverse events 52 26.0 26 20.2 26 36.6

Non-serious adverse events (nsAEnr) 13 6.5 4 3.1 9 12.7

Non-serious adverse drug reactions (nsADR) 36 18.0 19 14.7 17 23.9

Serious adverse events (SAEnr) 18 9.0 4 3.1 14 19.7

Serious adverse drug reactions (SADR) 2 1.0 1 0.8 1 1.4

Cases of death 5 2.5 4 3.1 1 1.4

Medication error 30 15.0 18 14.0 12 16.9

Lack of drug effect 4 2.0 2 1.6 2 2.8





9.6.2 Display of adverse events

The most frequent AEs by MedDRA PT are summarized in the following table.

The most common SOC was "skin and subcutaneous tissue disorders", affecting 7.5%

(n=15/200) of patients (Table 7/3 in the Compendium). The most frequent PTs in this SOC

were "erythema", "skin irritation" and "skin reaction" in 4/200 (2.0%) patients, respectively,

followed by "pruritus" and "rash" (1.5%, respectively). AEs belonging to the SOC

"psychiatric disorders" were reported for a total of 12/200 (6.0%) patients. The PT

"depression" occurred in 5/200 (2.5%) patients, followed by "aggression" in 3 patients and

"agitation" in 2 patients. Patients were further affected in about equal parts by the SOCs

"general disorders and administration site conditions" (5.5%), "gastrointestinal disorders"

(5.0%) and "nervous system disorders" (5.0%), the most common PT of administration site

conditions being "application site erythema" in 4 patients (2.0%) and the most common PT of

gastrointestinal disorders being "nausea" in 6 patients (3.0%).

Table 9.37 Patient-based classification of adverse events by MedDRA PT (only PTs ≥1.0%)

Adverse events

MedDRA System Organ Class (SOC) / Preferred Term (PT) n* %

Total patients 200 100.0

All patients with AEs 52 26.0

All patients without AEs 148 74.0

Cardiac disorders Myocardial infarction 2 1.0

Ear and labyrinth disorders Vertigo 3 1.5

Gastrointestinal disorders Abdominal pain upper 2 1.0

Diarrhoea 3 1.5

Nausea 6 3.0

General disorders and administration site

conditions

Application site erythema 4 2.0

Application site pruritus 2 1.0

Death 2 1.0

Infections and infestations Pneumonia 2 1.0

Injury, poisoning and procedural

complications

Fall

2 1.0

Investigations Mini mental status examination abnormal 2 1.0



Adverse events


Metabolism and nutrition disorders Vitamin B12 deficiency 2 1.0

Nervous system disorders Headache 2 1.0

Paraesthesia 2 1.0

Polyneuropathy 2 1.0

Psychiatric disorders Aggression 3 1.5

Agitation 2 1.0

Depression 5 2.5

Skin and subcutaneous tissue disorders Erythema 4 2.0

Pruritus 3 1.5

Rash 3 1.5

Skin irritation 4 2.0

Skin reaction 4 2.0



Stratification of AEs by caregiver training is shown in Table 7/3 in the Compendium.

Table 9/38 summarizes the most frequent nsAEnr by MedDRA PT.

The most common SOC was "psychiatric disorders", affecting 3.5% (n=7/200) of patients

(Table 7/4 in the Compendium). The most frequent PTs in this SOC were "depression" in

4/200 (2.0%) patients and "aggression" (n=2/200, 1.0%). nsAEnr belonging to the SOC

"nervous system disorders" were reported for a total of 4/200 (2.0%) patients, with the PT

"paraesthesia" occurring in 2/200 (1.0%) patients. 2 patients (1.0%) were affected by the PT

"vitamin B12 deficiency" in the SOC "metabolism and nutrition disorders".

Table 9.38 Patient-based classification of non-serious adverse events by MedDRA PT (only PTs

≥1.0%)

Non-serious adverse events not related



All patients with nsAEnr 13 6.5

All patients without nsAEnr 187 93.5



Non-serious adverse events not related


Metabolism and nutrition disorders Vitamin B12 deficiency 2 1.0

Nervous system disorders Paraesthesia 2 1.0

Psychiatric disorders Aggression 2 1.0

Depression 4 2.0



Stratification of nsAEnr by caregiver training is shown in Table 7/4 in the Compendium. A

listing of the nsAEnr can be found in Table 7/10 in the Compendium.

The following table shows the most frequent nsADR by MedDRA PT.

The by far most common SOC was "skin and subcutaneous tissue disorders", affecting 7.5%

(n=15/200) of patients (Table 7/5 in the Compendium). The most frequent PTs in this SOC

were "erythema", "skin irritation" and "skin reaction" in 4/200 (2.0%) patients, respectively,

followed by "pruritus" and "rash" (1.5%, respectively). nsADR belonging to the SOC

"gastrointestinal disorders" were reported for a total of 7/200 (3.5%) patients. The PT

"nausea" occurred in 5/200 (2.5%) patients, followed by "diarrhoea" in 3 patients. Patients

were further affected by the SOC "general disorders and administration site conditions"

(n=6/200, 3.0%), the most common PTs being "application site erythema" in 4 patients (2.0%)

and "application site pruritus" in 2 patients (1.0%). 3 patients (1.5%) were affected by the PT

"vertigo" in the SOC "ear and labyrinth disorders".



Table 9.39 Patient-based classification of non-serious adverse drug reactions by MedDRA PT (only

PTs ≥1.0%)

Non-serious adverse drug reactions



All patients with nsADR 36 18.0

All patients without nsADR 164 82.0

Ear and labyrinth disorders Vertigo 3 1.5

Gastrointestinal disorders Diarrhoea 3 1.5

Nausea 5 2.5


conditions

Application site erythema 4 2.0

Application site pruritus 2 1.0

Investigations Mini mental status examination abnormal 2 1.0

Nervous system disorders Headache 2 1.0

Psychiatric disorders Agitation 2 1.0

Skin and subcutaneous tissue disorders Erythema 4 2.0

Pruritus 3 1.5

Rash 3 1.5

Skin irritation 4 2.0

Skin reaction 4 2.0



Stratification of nsADR by caregiver training is shown in Table 7/5 in the Compendium. A

listing of the nsADR can be found in Table 7/11 in the Compendium.

Table 9/40 summarizes the most frequent SAEnr by MedDRA PT.

The most common SOC was "cardiac disorders" in 3.0% (n=6/200) of patients (Table 7/6 in

the Compendium), with the PT "myocardial infarction" affecting 1.0% (n=2/200) of patients.

SAEnr belonging to the SOC "nervous system disorders" were reported for a total of 5/200

(2.5%) patients, with the PT "polyneuropathy" occurring in 2/200 (1.0%) patients. Patients



were further affected by the SOC "general disorders and administration site conditions"

(n=4/200, 2.0%), the most common PT being "death" in 2 patients (1.0%).

Table 9.39 Patient-based classification of serious adverse events by MedDRA PT

Serious adverse events not related



All patients with SAEnr 18 9.0

All patients without SAEnr 182 91.0

Blood and lymphatic system disorders Anaemia 1 0.5

Cardiac disorders Atrial fibrillation 1 0.5

Cardiac failure 1 0.5

Cardiomyopathy 1 0.5

Left ventricular failure 1 0.5

Myocardial infarction 2 1.0

Tricuspid valve incompetence 1 0.5

Gastrointestinal disorders Abdominal pain upper 1 0.5

Nausea 1 0.5

Pancreatic steatosis 1 0.5


conditions

Cardiac death 1 0.5

Death 2 1.0

Gait disturbance 1 0.5

Pyrexia 1 0.5

Infections and infestations Pneumonia 2 1.0

Sepsis 1 0.5

Injury, poisoning and procedural

complications

Anaemia postoperative 1 0.5

Fall 2 1.0

Femur fracture 1 0.5

Post procedural haematoma 1 0.5

Investigations Troponin increased 1 0.5



Serious adverse events not related


Metabolism and nutrition disorders Diabetes mellitus 1 0.5

Nervous system disorders Brain injury 1 0.5

Cerebrovascular accident 1 0.5

Coma 1 0.5

Epilepsy 1 0.5

Polyneuropathy 2 1.0

Psychiatric disorders Delirium 1 0.5

Renal and urinary disorders Renal cyst 1 0.5

Renal failure acute 1 0.5

Respiratory, thoracic and mediastinal

disorders

Acute respiratory failure 1 0.5

Pneumonia aspiration 1 0.5

Vascular disorders Deep vein thrombosis 1 0.5

Hypertension 1 0.5



Stratification of SAEnr by caregiver training is shown in Table 7/6 in the Compendium. A

listing of the SAEnr can be found in Table 7/12 in the Compendium.

Table 9/41 shows all SADR by MedDRA SOC and PT.

SADR occurred in 2 patients. The SOC "cardiac disorders" (n=1/200, 0.5%) included the PTs

"angina pectoris" (0.5%) and "pulseless electrical activity" (0.5%) and the SOC

"musculoskeletal and connective tissue disorders" (n=1/200, 0.5%) the PT "back pain" (0.5%;

Table 7/7 in the Compendium).



Table 9.40 Patient-based classification of serious adverse drug reactions by MedDRA SOC and PT

Serious adverse drug reactions



All patients with SADR 2 1.0

All patients without SADR 198 99.0

Cardiac disorders Angina pectoris 1 0.5

Pulseless electrical activity 1 0.5

Musculoskeletal and connective tissue

disorders

Back pain 1 0.5



Stratification of SADR by caregiver training is shown in Table 7/7 in the Compendium. A

listing of the SADR can be found in Table 7/13 in the Compendium.

The event-based classification of AEs by MedDRA PT is summarized in Table 9/42. Most

AEs belonged to the SOCs "skin and subcutaneous tissue disorders" (n=21/129, 16.3%),

"psychiatric disorders" (14.7%), "nervous system disorders" (13.2%), "gastrointestinal

disorders" (10.1%), "general disorders and administration site conditions" (10.1%) and

"cardiac disorders" (8.5%; Table 7/8 in the Compendium). The most frequent PTs were

"nausea" (n=6/129, 4.7%) in the SOC "gastrointestinal disorders" and "depression" (3.9%) in

the SOC "psychiatric disorders". Stratification by the types of AEs revealed all skin and

subcutaneous tissue disorders to be nsADR.

Table 9.41 Event-based classification of adverse events by MedDRA PT (only PTs ≥1.0%)

MedDRA SOC / PT

All adverse

events

nsAEnr

nsADR

SAEnr

SADR

n % n % n % n % n %

Total AEs 129 100.0 24 100.0 63 100.0 39 100.0 3 100.0

Cardiac disorders Myocardial infarction 2 1.6 0 - 0 - 2 5.1 0 -

Ear and labyrinth

disorders

Vertigo 4 3.1 0 - 4 6.3 0 - 0 -

Gastrointestinal

disorders

Abdominal pain upper 2 1.6 0 - 1 1.6 1 2.6 0 -

Diarrhoea 3 2.3 0 - 3 4.8 0 - 0 -



MedDRA SOC / PT

All adverse

events

nsAEnr

nsADR

SAEnr

SADR

n % n % n % n % n %

Nausea 6 4.7 0 - 5 7.9 1 2.6 0 -

General disorders and

administration site

conditions

Application site

erythema

4 3.1 0 - 4 6.3 0 - 0 -

Application site pruritus 2 1.6 0 - 2 3.2 0 - 0 -

Death 2 1.6 0 - 0 - 2 5.1 0 -

Infections and

infestations

Pneumonia 2 1.6 0 - 0 - 2 5.1 0 -

Injury, poisoning and

procedural complications

Fall 2 1.6 0 - 0 - 2 5.1 0 -

Investigations Mini mental status

examination abnormal

2 1.6

0

-

2

3.2

0

-

0

-

Metabolism and nutrition

disorders

Vitamin B12 deficiency 2 1.6

2

8.3

0

-

0

-

0

-

Nervous system

disorders

Headache 3 2.3 0 - 3 4.8 0 - 0 -

Paraesthesia 2 1.6 2 8.3 0 - 0 - 0 -

Polyneuropathy 2 1.6 0 - 0 - 2 5.1 0 -

Psychiatric disorders Aggression 3 2.3 2 8.3 1 1.6 0 - 0 -

Agitation 2 1.6 0 - 2 3.2 0 - 0 -

Depression 5 3.9 4 16.7 1 1.6 0 - 0 -

Skin and subcutaneous

tissue disorders

Erythema 4 3.1 0 - 4 6.3 0 - 0 -

Pruritus 3 2.3 0 - 3 4.8 0 - 0 -

Rash 3 2.3 0 - 3 4.8 0 - 0 -

Skin irritation 4 3.1 0 - 4 6.3 0 - 0 -

Skin reaction 4 3.1 0 - 4 6.3 0 - 0 -


Stratification of the AEs by caregiver training is shown in Table 7/8 in the Compendium.



As shown in Table 9/43, the outcome of most AEs was "complete recovery" (n=57/129,

44.2%), followed by "condition unchanged" (20.9%) and "death" (10.9%). Stratification by

the types of AEs revealed the vast majority of AEs with the outcome "complete recovery" to

be nsADR.

Table 9.42 Outcome of adverse events

Outcome

All adverse

events nsAEnr nsADR SAEnr SADR

n % n % n % n % n %

Total 129 100.0 24 100.0 63 100.0 39 100.0 3 100.0

Not reported 18 14.0 9 37.5 3 4.8 4 10.3 2 66.7

Complete recovery 57 44.2 5 20.8 43 68.3 9 23.1 0 -

Condition improving 10 7.8 0 - 5 7.9 5 12.8 0 -

Condition deteriorated 2 1.6 0 - 2 3.2 0 - 0 -

Condition unchanged 27 20.9 10 41.7 10 15.9 7 17.9 0 -

Recovered with sequelae 1 0.8 0 - 0 - 1 2.6 0 -

Death 14 10.9 0 - 0 - 13 33.3 1 33.3


Stratification of the outcome by caregiver training is shown in Table 7/9 in the Compendium.

9.6.3 Deaths, other serious events, and other significant adverse events

9.6.3.1 Listing of deaths, serious adverse events and other significant adverse events

Listings of fatal SAEnr and fatal SADR can be found in Table 7/14 and Table 7/15 in the

Compendium, respectively.

All events concerning drug ineffectiveness and medication errors are listed in Table 7/16.

Medication errors that happened in this study were raising the dose directly from 4.6 mg to

13.3 mg, staying below the minimum 6-month use of 9.5 mg patches before raising the dose

to 13.3 mg, decrease of dosage, inappropriate use of patch, and multiple patch use.

AEs of excluded patients are listed in Table 7/17.

9.6.3.2 Narratives of deaths

Case narratives of fatal serious adverse events can be found in the Appendix.



10 Discussion

10.1 Key results

For the last decade, a great amount of research on pharmacological treatment of AD has been

made, including research on existing symptomatic therapy of AD like cholinesterase-

inhibitors, e.g. rivastigmine (Rainer, 2013; Seibert et al, 2012).

This post-marketing NIS was performed to compare an up to 12-month treatment with the

rivastigmine (Exelon®) patch in newly diagnosed AD patients with or without training of

caregivers according to "Demenz aktiv begegnen". The course of the disease, the persistence

to therapy and the quality of life of family caregivers under daily-life conditions were

investigated. To assess these parameters, the MMSE was used as a well-established scale to

screen for cognitive function in the course of AD (Arevalo‐Rodriguez et al, 2015), the Mini-

Zarit as validated measure of burden on caregivers with 7/22 instead of 12/22 items (original

version: Zarit et al, 1980; mini-Zarit: Revel Da Rocha et al, 2002) and the GDS to determine

potential depressive symptoms in caregivers with 15/22 items (original version: Gauggel &

Birkner, 1999; 15 items: Sheikh & Yesavage, 1986).

A total of 160 out of 206 patients enrolled at 41 sites in Germany between April 2013 and

November 2014 were valid for analysis. Both sex (56.9% female and 41.3% male) and age

distribution (with an average age of 77.5 years) did not match recent prevalence data for AD

(Bickel, 2014; S3-Leitlinie, 2009). In addition, differing from a general AD population, >90%

of patients were living at home with/without their family and had a short median history of

AD (3.5 months). Thus, older patients (>85 years) and patients with a long AD history were

underrepresented. These differences were in accordance with the objectives and inclusion

criteria for this study. It was expected to include patients starting with a therapy and

caregivers getting their first training in an earlier stage of the disease. This is also attributed to

the use of Exelon® patch, which is licensed for patients with mild-to-moderate AD (Exelon

®

SmPC), i.e. patients with severe AD were not to be included. Thus, Exelon® patch was the

first specific treatment of AD in 2/3 of the evaluable patients.

Caregivers of 41 AD patients (mean age of patients 79.0 years) attended the training in

contrast to caregivers of 119 patients (mean age of patients 77.0 years) who didn`t have the

opportunity to attend such training. As training was only performed in sites routinely offering

trainings, this imbalance gives a good impression about the current care situation. The

impairment of the caregiver’s ability to take care of the patient in the two study arms varied.

About 90% of caregivers with training were not impaired, but about 50% of those without

training were impaired to different extents. This might result from a different patient selection

of sites that performed training.

Overall, assessment of the disease severity by the MMSE sum score (mean ±SD) was nearly

stable with 20.5 ±4.2 points (N=133) at baseline and 19.9 ±4.5 points (N=94) after 12 month

of rivastigmine patch therapy or the last individual FU visit, independent from training.

Similar persistence of MMSE results was obtained from other studies after treatment with the

rivastigmine patch over 24 weeks (e.g., Adler et al, 2014; see for review: Dhillon, 2011) or

even a reduced MMSE decline using rivastigmine tablets versus no treatment for up to 5 years

(Small et al, 2005). In short-term patch studies, MMSE even showed an improvement up to 4



months (Seibert et al, 2012). In this study, 29.4% of all patients had prematurely discontinued

dosing at the last individual FU visit, including 10% who withdrew due to AEs and 1.3%

documented to be non-responders according to physician’s judgment. The average treatment

duration for those patients who discontinued the study prematurely was shorter with 8.7 ±5.1

months (trained cohort) and 6.8 ±3.7 months (untrained cohort). This difference between the

trained and untrained group suggests a benefit of training the caregivers on the persistence of

the antidementive therapy which is in accordance with a previous study (Riepe et al, 2015).

Rivastigmine patch doses were increased from 4.6 mg at baseline (84%) to 9.5/13.3 mg in

more than half of patients. This increase is lesser then observed in other studies (Adler et al,

2014; Articus et al, 2011).

Two Training sessions “Demenz Aktiv Begegnen” has been attended by 41/160 (25.6%) of

caregivers who perceived both trainings as helpful to uttermost helpful in an outmost friendly

atmosphere. Surprisingly, caregivers with training felt that their burden concerning the

Alzheimer`s dementia of their relatives was not eased but rather increased, whereas caregivers

without training rated this burden more often as eased. This is in contrast to the lesser

impairment of caregivers in the training-group but could result from a more detailed

information on the disease and its perspective that might increase the feeling of a burden in

general (Beinart et al, 2012; Hauber et al, 2014).

Validated caregiver questionnaires were available at baseline for 90.0% (Mini-Zarit) and

88.8% (GDS) of all patients, with a rate of 100% from the 41 trained caregivers. This rate was

reduced to 70.0%/68.8% (Mini-Zarit/GDS) for all caregivers and to 80.5%/78.0% for trained

caregivers at the last individual FU, respectively. The 7-item Mini-Zarit was consistently

higher (better) for all items with an average sum score from baseline versus the last individual

FU for trained caregivers (5.5 ±1.5 vs. 5.0 ±1.4 points) than for caregivers without training

(4.2 ±1.7 vs. 4.3 ±1.7 points). Again, these results reflected a slightly increasing burden

during this study for caregivers with, but not for those without training for possible reasons

stated above. Overall, there was no change in the Mini-Zarit (4.6 ±1.8 vs. 4.5 ±1.7 points). In

a previous study where rivastigmine has been co-administered with memantine over 28

weeks, there has been a statistically significant improvement (Dantoine et al, 2006). However,

regarding the most important issues (Bachner et al, 2007; Ballesteros et al, 2012; Braun et al,

2010; Cheng et al, 2014) 2 (trouble outside family), 5 (fear about future of patient) and 7

(burden while caring), there was rather a stable or improved outcome for these items in this

study.

Interestingly, the GDS mean sum scores were also consistently lower (i.e., better) for trained

caregivers (2.8 ±2.7 vs. 2.6 ±1.7 points) than for caregivers without training (3.3 ±3.0 vs. 3.2

±2.4 points). The trained caregivers scored better than the untrained caregivers on nearly all

15 items of the abbreviated GDS questionnaire with negligible improvements during the NIS

in both groups. This difference might be due to the lesser impairment of the caregivers in the

group with training but might also result from the higher interaction and information they

received during the training sessions.

Nevertheless, in view of the relatively long observation period in the present study with the

rivastigmine patch alone, it remains remarkable, that overall results of the MMSE remained



nearly constant and caregivers stated no more than a small increase in disease burden, mainly

for their relatives, if at all.

Safety evaluation comprised the documentation and analysis of treatment-emergent

AEs/SAEs. Overall, 52/200 of the patients (26.0%) in this NIS experienced at least 1 AE or

SAE. A total of 5 patients died. The cause of death was documented as “natural death”

(twice), “electromechanical decoupling after anterior myocardial infarction”, “cardiac failure,

sepsis and poly-uric acute renal failure”, and “reflective cardiac death, hypoxic cerebral

death”, respectively. In 36 (18.0%) patients with AEs and 2 (1.0%) patients with SAEs, these

were classified as ADR/SADR. Considering the low patient number, this study showed

similar tolerability of rivastigmine patch compared to other non-interventional (Articus et al,

2011) or clinical studies (Winblad et al, 2007).

10.2 Limitations

In contrast to clinical trials, a NIS is not designed to prove the efficacy and tolerability of a

drug, but can provide valuable information on drug use in real-life settings. Besides the

relative small number of patients, in particular patients with trained caregivers, the restriction

of reported outcome measures to the widely used and validated MMSE and GSD – for

feasibility reasons in a NIS – does not reflect all relevant capabilities of daily life in patients

with a complex disease. The imbalance between the small number of 41 patients with trained

and 119 patients with untrained caregivers might have impaired the validity of results of this

statistical comparison.

10.3 Conclusion

This NIS in patients with mild to moderate AD showed a better Mini-Zarit and GDS in trained

than in untrained caregivers both at baseline and the last individual FU. These validated

questionnaires pointed to a stable or slightly reduced burden preferably in non-trained, mainly

familiar caregivers. Thus, a more detailed information on the disease and its perspective might

increase the feeling of burden in trained caregivers. So far, there are only few data on long-

term therapy in AD. This NIS also demonstrated a nearly stable severity of the disease within

one year of therapy with the rivastigmine patch, which was well tolerated with a low

frequency of ADRs. Additional training may therefore help the familial caregivers in daily life

to reduce the burden of disease and to increase patient persistence for symptomatic therapy in

patients with mild to moderate AD.



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