STATT A non-interventional study to investigate factors … · STATT – A non-interventional study to investigate factors ... 9.2.3 Information about patch (caregiver questionnaire)

Clinical Development

ENA-713 [Rivastigmin; Exelon®]

Non-interventional Study Report

Study Code: CENA713DDE23

STATT – A non-interventional study to investigate factors associated with adherence to Exelon

® patch for the treatment of

Alzheimer’s disease

Author Dr. Beate Müller Dr. Birgit Eschweiler Dr. Klaus Hechenbichler

Document Status Final

Date of last version of the study report

04 DEC 2013

EU PAS register number

Study not registered

Property of Novartis Confidential

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

Novartis Confidential Page 2 Non-interventional study report Study No. CENA713DDE23

Table of contents

1 Abstract .............................................................................................................................................. 7

2 Marketing Authorization Holder ...................................................................................................... 11

3 Investigators ..................................................................................................................................... 12

4 Ethics ................................................................................................................................................ 14

4.1 Independent ethics committee or institutional review board ............................................... 14

4.2 Patient information and consent ........................................................................................... 14

4.3 Legal and regulatory basis of the study ................................................................................ 14

5 Rationale and background ................................................................................................................ 15

6 Research question and objectives .................................................................................................... 16

7 Observational plan ........................................................................................................................... 17

7.1 Amendments and updates to the protocol ............................................................................ 17

8 Research methods ............................................................................................................................ 18

8.1 Study design ......................................................................................................................... 18

8.2 Subjects ................................................................................................................................ 18

8.3 Variables .............................................................................................................................. 19

8.4 Data sources and measurement ............................................................................................ 20

8.5 Study size ............................................................................................................................. 21

8.6 Data quality assurance .......................................................................................................... 21

8.6.1 Monitoring ........................................................................................................... 21

8.6.2 Quality control ..................................................................................................... 21

8.7 Statistical methods ............................................................................................................... 21

9 Results .............................................................................................................................................. 22

9.1 Participants ........................................................................................................................... 22

9.2 Baseline data (retrospective and 3 months after treatment initiation) .................................. 23

9.2.1 Information about patients (by caregivers and physicians) ................................. 23

9.2.2 Information about caregiver (by caregivers and physicians) ............................... 27

9.2.3 Information about patch (caregiver questionnaire) ............................................. 28

9.3 Descriptive data over time (by caregiver, 3 and 6 months) ................................................. 29

9.3.1 Application of patch and patient’s compliance ................................................... 29

9.3.2 Problems of caregiver within last 2 weeks .......................................................... 30

9.3.3 Opinion on AD .................................................................................................... 31

9.3.4 Usage of Exelon® patch ....................................................................................... 32

9.3.5 Opinion on Exelon®

patch ................................................................................... 33

9.3.6 Compliance .......................................................................................................... 35

9.3.7 Satisfaction with efficacy .................................................................................... 36


9.3.8 Application of the patch ...................................................................................... 37

9.4 Other analyses ...................................................................................................................... 38

9.5 Adverse events ..................................................................................................................... 38

9.5.1 Satisfaction of caregiver with tolerability ........................................................... 40

10 Discussion ........................................................................................................................................ 41

10.1 Key results ............................................................................................................................ 41

10.2 Safety conclusions ................................................................................................................ 43

11 References ........................................................................................................................................ 44

12 Appendix .......................................................................................................................................... 45

12.1 Sample study protocol including data entry forms .............................................................. 45

12.2 Table set ............................................................................................................................... 45

12.3 Signatures ............................................................................................................................. 45


List of tables

Table 8-1 Schedule of the STATT study ............................................................................................. 18

Table 9-1 Patient demographics and background characteristics (caregiver) ..................................... 23

Table 9-2 Clinical background (physician, retrospective information from patient’s files and

current information) ............................................................................................................ 24

Table 9-3 Prescribed patch, concomitant diseases and medication (physician, retrospective

information from patient’s files) ......................................................................................... 25

Table 9-4 Patient’s view about the disease and medication (caregiver questionnaire) ....................... 26

Table 9-5 Demographic data and medical condition of caregiver (caregiver questionnaire,

baseline visit) ...................................................................................................................... 27

Table 9-6 Caregivers physical ability to take care for the patient (physician, retrospective

information from patient’s files) ......................................................................................... 28

Table 9-7 Information on patch (caregiver questionnaire, baseline visit) ........................................... 28

Table 9-8 Extent of help with application of patch and patient’s compliance/adherence 3 and 6

months after treatment initiation (caregiver questionnaires) .............................................. 29

Table 9-9 Psychological problems caregivers experienced within 2 weeks before visits (caregiver

questionnaires, 3 and 6 months after treatment initiation) .................................................. 30

Table 9-10 Opinion on AD (3 months after treatment initiation, caregiver questionnaire) .................. 31

Table 9-11 Opinion on AD (6 months after treatment initiation, caregiver questionnaire) .................. 31

Table 9-12 Opinion about factors being the cause of AD (3 months after treatment initiation,

caregiver questionnaire) ...................................................................................................... 32

Table 9-13 Opinion about factors being the cause of AD (6 months after treatment initiation,

caregiver questionnaire) ...................................................................................................... 32

Table 9-14 Opinion on Exelon® patch (3 months after treatment initiation, caregiver questionnaire) . 33

Table 9-15 Opinion on Exelon® patch (6 months after treatment initiation, caregiver questionnaire) . 34

Table 9-16 Compliance with usage instructions (3 months after treatment initiation, caregiver

questionnaire) ...................................................................................................................... 35

Table 9-17 Compliance with usage instructions (6 months after treatment initiation, caregiver

questionnaire) ...................................................................................................................... 36

Table 9-18 Satisfaction with efficacy (3 months after treatment initiation, caregiver questionnaire) .. 36

Table 9-19 Satisfaction with efficacy (6 months after treatment initiation, caregiver questionnaire) .. 37

Table 9-20 Application of the patch (3 months after treatment initiation, caregiver questionnaire) .... 37

Table 9-21 Application of the patch (6 months after treatment initiation, caregiver questionnaire) .... 38

Table 9-22 Adverse events (patient based) ........................................................................................... 38

Table 9-23 Event-based classification of non-serious adverse drug reactions (nsADR) ...................... 39

Table 9-24 Event-based classification of serious adverse events not related (SAEnr) ......................... 39

Table 9-25 Event-based classification of serious adverse drug reactions (SADR) ............................... 40


List of abbreviations

AD Alzheimer’s disease

ADR adverse drug reaction

AE adverse event

AMG Arzneimittelgesetz (German Drug Law)

BAnz Bundesanzeiger (Federal Gazette)

BfArM Bundesinstitut für Arzneimittel und Medizinprodukte (Federal Institute for Drugs and

Medical Devices)

BIPQ Brief Illness Perception Questionnaire

BMQ Beliefs about Medication Questionnaire

CFR Code of Federal Regulations

CGI Clinical Global Impression

ChEI Cholinesterase-Inhibitor

CRA Clinical Research Associate

CRO Clinical Research Organisation

DMP Data Management Plan

EC European Commission

FDA Food and Drug Administration

FSA Freiwillige Selbstkontrolle für die Arzneimittelindustrie (Voluntary Self-

regulation for the Pharmaceutical Industry)

GAD Generalized Anxiety Disorder

GOÄ Gebührenordnung für Ärzte (German scale of fees for physicians)

MARS Medication Adherence Report Scale

MBOÄ Musterberufsordnung für Ärzte (Professional code of conduct)

MedDRA Medical Dictionary for Regulatory Activities

MMSE Mini–mental state examination

NICE The National Institute for Health and Clinical Excellence

NIS Non-interventional study

nsADR Non-serious adverse drug reaction

nsAEnr Non-serious adverse event not related

PEI Paul Ehrlich Institute

PHQ Patient Health Questionnaire

PT Preferred Term (MedDRA)


SADR Serious adverse drug reaction

SAE Serious adverse event

SAEnr Serious adverse event not related

SAP Statistical Analysis Plan

SDV Source Document Verification

SIMS Satisfaction with Information about Medicines Scale

SOC System Organ Class (MedDRA)

SOP Standard Operating Procedure

VFA Verband Forschender Arzneimittelhersteller (Association of Researching

Pharmaceutical Manufacturers)


1 Abstract

Title STATT – A non-interventional study to investigate factors associated with

adherence to Exelon® patch for the treatment of Alzheimer’s disease

Keywords Acetylcholinesterase inhibitors, adherence, Alzheimer’s disease, caregiver

satisfaction, rivastigmine patch, tolerability

Rationale and

background

Cholinesterase inhibitors (ChEIs) are a first-line treatment for mild-to-

moderate Alzheimer’s disease (AD). However, as in many therapeutic areas,

treatment adherence and persistence are often poor; this may be intentional or

unintentional and influenced by the ability of the patient to self-medicate,

caregiver perceptions of AD and the opinions of physicians.

Research question

and objectives

The primary objective of this study was to identify patient- and caregiver-

related sociodemographic, clinical and psychological factors associated with

adherence to rivastigmine patch.

Secondary outcomes were to identify patient- and caregiver-related factors

associated with persistence to patch therapy and caregiver satisfaction with

rivastigmine patch.

For safety evaluation, the treatment tolerability in clinical practice was

assessed by reporting of adverse events in the observation period.

No hypotheses were pre-specified, i.e. the study was of pure explorative

nature.

Study design Non-interventional study according to regulatory and legal requirements of

patients with mild-to-moderate AD, who were receiving rivastigmine patch.

Retrospective patient socio-demographic, clinical and psychosocial data at

the time of first prescription were reported by the physician 3 months after

treatment initiation. Caregivers provided cross-sectional information on

patients 3 months after treatment initiation. The completion visit was

performed 3 months later (i.e. 6 months after treatment initiation).

Setting Patients with mild-to-moderate AD, who were prescribed rivastigmine patch

by a participating physician.

Further inclusion criteria: written informed consent by the patients or by a

legally acceptable representative of the patient.

No further inclusion or exclusion criteria were specified. Patients with

contra-indications for treatment with rivastigmine as stated in the Summary

of Product Characteristics were not to be enrolled.

Subjects and study

size, including

dropouts

140-150 patients (or caregivers and corresponding physicians) were planned

to be enrolled, whereas data from 127 caregivers (reporting about 127

patients) and 18 physicians (documenting 129 patients) at baseline (3 months

after treatment initiation) and from 110 caregivers at completion visit (6

months after treatment initiation) were collected.


Variables and data

sources

Caregivers were asked to provide information about the patient, as well as on

their own age, physical health, mood, treatment- and disease-related beliefs

and expectations, and satisfaction with patch 3 months and 6 months post

treatment initiation.

Physicians were asked to provide retrospective information on socio-

demographic and clinical data about the patient who had been described with

Exelon® patch (from patient’s files), as well as current information (CGI,

adverse events) about the patient and patch usage 3 months post-treatment

initiation.

Results Baseline information: 50.4% of the patients with AD were female (n=64)

and the mean age was 78.2 years at the time of data recording.

Physicians’ information: majority of the patients presented with mild

(24.8%), mild to moderate (38.8%), or moderate (23.3%) AD at the time of

treatment initiation and the mean ± SD MMSE-score was 20.8 ± 3.3 points

(out of 30), corresponding to mild dementia. Three months after treatment

initiation, most physicians estimated that the CGI would be much improved

(35.7%) or a little improved (30.2%). No change was seen by 21.7% of

physicians and 7.8% physicians saw a deterioration of the AD.

High dose Exelon® patch (9.5 mg/ 24 h) was prescribed in 53.5% (n=69) and

the low dose patch in 42.6% (n=55) of patients by the physicians. Both doses

were prescribed for 5 patients (3.9%) within the 3 months since treatment

start.

Patient’s opinion: Most patients thought, that their AD was caused by their

age (76.4%, n=97). Second most common causes were thought to be genetic

endowments (26.0%, n=33) or other (26.0%, n=33). Patch application were

more favored than other types of medications (pills or liquids). Most patients

(63.0%, n=80) preferred or highly preferred patches as type of medication.

Information about caregiver: Most of the caregivers (70.9%) were female

and had a mean age of 66.4 ± 13.9 years. The majority (75.6%) never cared

for relatives before and more than half of the caregivers saw the patient most

of the time daily (59.1%). At the time of treatment initiation, the patient was

supervised by the spouse (57.4%, n=74/129), the daughter (21.7%,

n=28/129), a paid caregiver (5.4%, n=7/129), another person (3.1%,

n=4/129), or the son (3.1%, n=4/129); 8.5% of patients were supervised by

more than one person (e.g. spouse and daughter). At the time of first

treatment initiation, the ability of the caregiver to take care for the patient

was not at all restricted in 62.8% and little restricted in 17.8% of caregivers

(physician’s information).

Caregiver information over time (3 and 6 months): Most caregivers had

full responsibility (34.6%) or had to help a lot (33.9%) with the application

of the patch at baseline and no relevant changes in the extent of help was

seen 3 months later. At baseline, most of the patients were compliant with the

Exelon® patch, i.e. mostly (44.1%) or always (33.1%) supported their

caregivers when fixing the patch. In addition, the majority of the patients


adhered to the medication and always (55.9%) or mostly (26.8%) kept the

patch as long as necessary. Compliance and adherence data were comparable

6 months after treatment start.

Most of the caregivers had no psychological problems at all (about 57% to

63% in the four domains) or only on several days (about 20% to 24%) at

baseline. This proportion of caregivers without any significant problems

remained largely unchanged up to the completion visit.

At the first documentation, the mean score values of the “Opinion on AD”

questionnaire mostly were in the middle range of the scale (around 4.1 to

6.9), showing that patients but also caregivers were distinctly affected by the

AD, although none of the mean scores achieved extreme values. Only the

question on the duration of the disease showed that caregivers were aware of

the very long duration (mean score 8.5). At the final documentation, mean

score values were almost the same as after 3 months.

Both at 3 and 6 months after treatment start, the factors age, other factors and

genetics were ticked most often by the caregivers and thought to be the most

important factors for causing AD.

The proportion of patients who were still using the patch after treatment

initiation was 88.2% (n=112/127) at first visit (missing 7.9%) and also 88.2%

(n=97/110) at final visit (missing 4.5%). Only 5 patients (3.9%) discontinued

the Exelon® patch before baseline visit and further 5 patients (4.5%) before

final visit.

More than half of the caregivers agreed (agreed or completely agreed) with

the statements that “health would depend on the patch” (54.3%) and that the

“patch would protect the patients from feeling worse” (73.2%). Most

caregivers disagreed (disagreed or disagreed at all) with the following

statements: “worry about usage of patch” (73.2%), “patch disturbs life”

(70.9%), “concerns about addiction” (61.4%), “patch is a mystery” (52.8%),

“could not live without patch” (48.0%), and “thoughts about long-term

effects of the patch” (42.5%). At the final documentation, the level of

acceptance to the statements that caregivers had agreed with 3 months earlier

has increased slightly. Also the level of rejection with those statements

previously disagreed has increased slightly. Only with the statements “could

not live without patch” (disagreed 45.5%, 39.1% did not know) and “patient

would be very ill without the patch” (agreed 43.6%, 34.5% did not know) the

level of agreement has decreased and more caregivers ticked the “I don’t

know” boxes.

At both visits, both the caregivers and the patients were highly compliant. At

the first documentation time, most caregivers stated that she/he had never

“omitted that patch sometimes” (74.8%), “interrupted the patch for a while”

(73.2%), or “changed the fixing patch time” (64.6%). At the final

documentation time (6 months after treatment initiation), the proportion of

caregivers who have never forgotten to fix or remove the patch or who have

changed patch usage has slightly increased compared to the first

documentation. Within the last 2 weeks before the first/final documentation,


69.3%/70.0% of caregivers stated that there was no day of irregular use of

patch.

At the final visit, the level of satisfaction with the efficacy has increased

compared to the first documentation, with 16.4% of caregivers being very

satisfied and 64.5% satisfied with the effect on behavior and emotions,

15.5% very satisfied and 66.4% satisfied with effect on activities, and 11.8%

being very satisfied and 56.4% satisfied with the effect on memory. The

proportion of caregivers being unsatisfied has decreased compared to the first

documentation.

More than 85% of caregivers found that opening of the package, make the

patient to use it, fixing and removing of patch was easy or very easy at both

documentation timepoints.

Safety: In the observation period, 16 adverse events which occurred in 9

patients were reported. Of these, one event was considered to be a serious

adverse event not related, and another event was considered to be a serious

adverse drug reaction. This patient died during the observation period. 14

adverse events in 8 patients were reported to be related to Exelon® patch

treatment, but not serious.

Conclusions In conclusion, most caregivers and their patients adhered to the treatment

with rivastigmine (Exelon® patch) during the 6 months observation period.

The application of the patch was considered by the caregivers as easy to use,

efficacious and satisfying for both the patient and the caregiver.

Rivastigmine (Exelon® patch) proved to be a well-tolerated drug for the

treatment of patients with Alzheimer’s disease, as demonstrated by the low

incidence rate of adverse events. The nature and frequency of adverse events

occurring during the 6 months therapy were consistent with the established

safety profile of rivastigmine. The current NIS did not reveal any suspicion

of unknown risks related to the treatment with rivastigmine.

Marketing

Authorization

Holder

Novartis Pharma AG, Basel, Switzerland

Name(s) and

Affiliation(s) of

Principal

Investigator(s)

Professor Dr. med. Matthias Riepe, Ludwig Heilmeyer Straße 2, D-89312

Günzburg, Germany


2 Marketing Authorization Holder

Novartis Pharma AG, WSJ-790.1., CH-4002 Basel, Switzerland


3 Investigators

The co-ordinating investigator ("Leiter der klinischen Prüfung" [LKP] according to German Drug Law)

was:

Professor Dr. med Matthias Riepe

Ludwig Heilmeyer Straße 2

D-89312 Günzburg, Germany

Telefon: +49 8221 96-2355

A total of 18 active (by screening) study sites in Germany participated in this study. A list of the site

investigators is available by request.

The project manager was:

Dr. Beate Müller

Roonstraße 25

D-90429 Nuremberg. Germany

Phone: +49 911 273 12-046

Fax: +49 911 273 15-046

Email: [email protected]

and the Phase IV Manager NIS:

Dr. Alfons Müller

Roonstraße 25

D-90429 Nuremberg, Germany

Phone: +49 911 273 12-897

Fax: +49 911 273 15-897



and the Safety Manager:

Dr. Katharina Salb

Roonstraße 25

D-90429 Nuremberg, Germany

Phone : +49 911 273 13-271

Fax : +49 911 273 12-985


Project Implementation and Statistical Analysis was performed by:

Institut Dr. Schauerte

Kolpingring 18

D-82041 Oberhaching, Germany

Telefon: +49 89 641 804-0

Fax: +49 89 641 52 72

EMail: [email protected]

mailto:[email protected]


4 Ethics

4.1 Independent ethics committee or institutional review board

According to the joint publication of the Federal Institute for Drugs and Medical Devices (BfArM) and

the Paul Ehrlich Institute (PEI) as well as the recommendations of the VFA to improve quality and

transparency of non-interventional studies, a properly constituted Independent Ethics Committee

(Ethics Committee University Ulm) was consulted before study start.

4.2 Patient information and consent

Patients had to be provided with written information about aims and type of the study and amount of

documentation before inclusion into the study. As this was a post-marketing observational study, a

special information that exceeds the scope of the product of summary characteristics, was not necessary

in this NIS.

Eligible patients were only enrolled into the study after providing written informed consent for the

documentation of data within the NIS as well as for inspection of the patients’ medical files, or after

such consent had been provided by a legally acceptable representative of the patient. In cases where the

patient's representative gave consent, the patient had to be informed about the study to the extent

possible, given his/her understanding. The confidential nature of any patient information recorded was

maintained according to the EU Directive 95/46/EC and the national data protection law.

4.3 Legal and regulatory basis of the study

This NIS is based on Novartis internal SOPs, which are based on the following recommendations and

guidelines:

German Drug Law (§ 4 paragraph 23, third sentence (AMG))

§ 67 paragraph 6 of the German drug law (AMG)

§ 63 b of the German Drug law (AMG)

Directive 2001/83/EC of the European Parliament and of the Council

Pharmacovigilance Guidelines of Volume 9A of ‘The Rules Governing Medicinal Products in

the EU’

Recommendations of the Federal Institute for Drugs and Medical Devices (BfArM) and the

Paul-Ehrlich-Institute (PEI) on the planning, implementation and evaluation of observational

studies of 7 July 2010 (in German)

Recommendations of the Association of Research-Based Pharmaceutical Companies (VFA) to

improve further the quality and transparency of non-interventional studies of 31.01.2007 and

23.04.2007

FSA-Codex for the cooperation with specialists –Federal Gazette of 07.05.2008


5 Rationale and background

Cholinesterase inhibitors (ChEIs) are a first-line treatment for mild to moderate Alzheimer’s disease

(AD). However, as in many therapeutic areas, treatment adherence and persistence are often poor; this

may be intentional or unintentional and influenced by the ability of the patient to self-medicate,

caregiver perceptions of AD and the opinions of physicians.

Hence, the aim of the observational study was to evaluate factors that would help physicians to identify

those patients that might benefit from transdermal patch treatment and who are likely to adhere to the

treatment over an extended period.


6 Research question and objectives

The primary objective of this study was to identify patient- and caregiver-related sociodemographic,

clinical and psychological factors, associated with adherence to rivastigmine patch.

Secondary outcomes were to identify patient- and caregiver-related factors associated with persistence

to patch therapy and caregiver satisfaction with rivastigmine patch.

For safety evaluation, the treatment tolerability in clinical practice was assessed by reporting of adverse

events in the observation period and analyzed descriptively.

No hypotheses were pre-specified, i.e. the study was of pure explorative nature.


7 Observational plan

The study was conducted according to the original protocol, dated September 2011 (Code: 2011/31 30

57), which can be found in Section 12. Also, the sample blank CRF can be found in Section 12. The

statistical analyses performed for this study are defined in the statistical analysis plan (SAP) (see

Section 8.7).

7.1 Amendments and updates to the protocol

N/A


8 Research methods

8.1 Study design

This was a non-interventional study according to regulatory and legal requirements (see Section 4.3) of

patients with mild-to-moderate AD, who were receiving rivastigmine patch.

Retrospective patient socio-demographic, clinical and psychosocial data at the time of first prescription

were reported by the physician 3 months after treatment initiation: caregivers will provide cross-

sectional information on patients 3 months after treatment initiation. The completion visit was

performed 3 months later (i.e. 6 months after treatment initiation).

Table 8-1 Schedule of the STATT study

Date of contact Baseline Visit 1

(3 months after

treatment initiation)

Completion Visit

(6 months after

treatment initiation)

Inclusion/exclusion criteria x

Informed consent x

Baseline data (demographic data,

patch information, concomitant

diseases) x

Clinical data x x

Patient assessment by physician x x

Caregiver information about

patient x

Information about caregiver x x

Caregiver Satisfaction (AD

caregiver preference

questionnaire) x x

Adherence of patient (adherence

report scale) x x

Persistence of patient (persistence

scale) x x

Adverse events x x

8.2 Subjects

The study population consisted of patients with mild-to-moderate AD, who were prescribed with

rivastigmine patch by a participating physician.

Further inclusion criteria: written informed consent by the patients or by a legally acceptable

representative of the patient.

No further inclusion or exclusion criteria were specified. Patients with contra-indications for treatment

with rivastigmine as stated in the Summary of Product Characteristics were not to be enrolled.


The decision to include a patient into the study had to be taken after the decision on the treatment and

the prescription of the patch and had to be independent of treatment decisions.

8.3 Variables

The following baseline information was collected at visit 1 (3 months after treatment initiation):

Caregiver questionnaire:

Information about patient (sex, school attendance, age, smoking behavior, concomitant

diseases, cause of AD (patients’ view), preferred medication, extent of help with application of

patch, compliance)

Information about caregiver (sex, age, concomitant diseases, problems in the last 2 years,

frequency of patient contact, previous caregiver experience)

Opinion on AD (several aspects of AD, each rated on a 0 (no influence) to 10 (strongly

impacted) scale, quantitative analysis)

About Exelon® patch (usage, opinion on patch, compliance, number of days with irregular use,

satisfaction with efficacy, tolerability, application of patch, information on patch)

Physician questionnaire:

Retrospective information (prescribed patch, socio-demographic and clinical data about AD,

MMSE score, caregiver, drawback of caregiver’s physical ability to take care for patient,

patient’s behavior drawback for using patch)

Current information (Clinical Global Impression - CGI-score, listing of prescribed patches

including package sizes and dose)

Adverse events

The Mini-Mental State Examination (MMSE) is a brief 30-point questionnaire test that is used to

screen for cognitive impairment. Any score greater than or equal to 27 points (out of 30) indicates

normal cognition. Below this, scores can indicate severe (≤9 points), moderate (10-18 points) or mild

(19-24 points) dementia [Folstein et al 1975].

The following information was collected at visit 2 (6 months after treatment initiation):

Caregiver questionnaire:

Information about patient (extent of help with application of patch, compliance)

Information about caregiver (problems in the last 2 weeks)

Opinion on AD (quantitative analysis)

About Exelon® patch (as in visit 1)

Primary outcomes assessed compliance, persistence (self-reported (2-item measure) and physicians’

prescription data) and caregiver’s opinion and satisfaction with the Exelon® patch (self-reported;

shortened adaptation of AD Caregiver Preference Questionnaire) 3 and 6 months after the start of

treatment.


8.4 Data sources and measurement

Caregiver data (socio-demographic information about patient, patients’ view, experience with Exelon®

patch, information about caregiver, caregiver satisfaction) were gained from self-reported

questionnaires to be completed 3 and 6 months after treatment initiation.

Retrospective data (physician questionnaire) were obtained from the patient’s file and were transferred

at the baseline visit into the physician questionnaire. All current information was recorded directly in

the data capture form.

Safety related measurements

Adverse events that first occurred or worsened after start of study treatment had to be documented by

the physicians. Severity, outcome, and relatedness of these adverse events were listed.

Adverse events (AE) were defined as any untoward medical occurrence associated with the use of a

drug in a patient, whether or not considered to be drug related.

All adverse events had to be documented according to event type, first occurrence, duration and

severity in the enclosed CRF. In addition, it had to be documented whether the AE is considered to be

related to a drug, and if so, to which drug. The action taken due to the adverse event as well as the

event outcome also had to be documented.

Generally, a distinction is made between non-serious and serious adverse events, which have to be

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

adverse event is any events 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

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

assessable)

SAEnr: serious adverse events not related

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 Surveilance Pregnany Form) in English

language and had to be reported by the treating physician directly to the Pharmacovigilance of Novartis

Pharma GmbH.


8.5 Study size

Sample size calculation and power calculation was based on the primary outcome of adherence

according to self-reported data to be assessed by means of the Medication Adherence Report Scale

(MARS) score 3 months after treatment initiation. Details can be found in the original study protocol.

Based on these calculations, a sample size of at least 120 patients was calculated. A sample size of 140-

150 patients was required to compensate for drop-outs.

8.6 Data quality assurance

8.6.1 Monitoring

Source Data Verification was performed to check if all information on the CRFs was consistent with

and traceable to these source documents. Full verification of the following was required: presence of

informed consent, adherence to the inclusion/exclusion criteria, demographic data, documentation of

SAEs, concomitant diseases, concomitant medication, and the recording of data required for the

analyses of all primary and safety variables.

8.6.2 Quality control

All quality assurance procedures within the scope of the quality management system were stated in the

study specific Data Management Plan (DPM) and for each stage of the procedure specified:

Review of the CRFs for completeness and accuracy before data recording

Plausibility checks within the score of data recording

Data query form including a catalog of questions leading to queries at the study site

Implementation of an audit trail according to FDA CFR21 Part 11 Standard

Matching of CRF and database within the scope of a database audit

Protection of data integrity by documented database closing

Data Handling Report for the management of data inconsistencies relevant for data analysis that

persist after database closing. The Data Handling Report is integral part of the SAP.

The contracted CRO’s SOPs are the basis of all data management procedures.

8.7 Statistical methods

All analyses were performed by the designated CRO Institute Dr. Schauerte, Germany.

All documented data in this NIS were analyzed and reported by adequate statistical methods. No

hypotheses were pre-specified, i.e. the study was of pure explorative nature. The planned statistical

evaluation is provided in the SAP. However, due to the exploited timelines of this study and the lower

number of patients that could be included, the originally planned analysis was not performed.

All data were analyzed by descriptive statistics. Data were summarized with respect to demographic

and baseline characteristics, observations at the two visits (caregiver’s experience, opinion and

satisfaction), and safety observations and measurements. Categorical variables were summarized by

absolute and relative frequencies. Continuous variables were summarized by descriptive statistics of

the number of valid and missing observations, mean, standard deviation, minimum, median, and

maximum.


9 Results

9.1 Participants

The study started in October 2011. Data collection started for the first participant in January 2012. The

last participant completed the study in February 2013. Further details on administrational data can be

found in Section 12.

A total of 127 caregivers (reporting about 127 patients) and a total of 18 physicians (documenting 129

patients) in Germany completed the respective questionnaires at the baseline visit (3 months after

initiation of Exelon® patch). In addition, 110 caregiver questionnaires were completed at the

completion visit (6 months after treatment start). Thus, three different populations can be analyzed,

based on completed caregiver questionnaires at 3 months (N = 127), completed caregiver

questionnaires at 6 months (N = 110), and completed physician questionnaires at 3 months (N = 129).


9.2 Baseline data (retrospective and 3 months after treatment initiation)

At baseline visit, data about the patient, the disease and experience with the Exelon® patch made within

the previous 3 months was gained both from caregivers and treating physicians.

9.2.1 Information about patients (by caregivers and physicians)

Socio-demographic data and clinical background from the patient are summarized in Table 9-1 and

Table 9-2.

Table 9-1 Patient demographics and background characteristics (caregiver)

Variable N

missing Total (N=127)

Sex, n (%) 5 male 58 (45.7)

female 64 (50.4)

Age, years 9 mean (SD) 78.2 (6.8)

median (min, max) 78.5 (56-101)

School attendance, n (%) 8 not specified 37 (29.1)

6-7 years 5 (3.9)

8 years 50 (39.4)

9 years 4 (3.1)

10 years 14 (11.0)

> 10 years 9 (7.1)

Smoking, n (%) 6 Yes 9 (7.1)

No 112 (88.2)

Concomitant diseases, n (%)* 0 diabetes 36 (28.3)

anxiety disorder 8 (6.3)

cancer 18 (14.2)

heart disease 42 (33.1)

AD = Alzheimer’s disease, SD = standard deviation; *multiple responses possible out of pre-defined answers,

Source: Table Set Section 1.1, Table 1.1 to 1.5

According to caregiver’s information, half of the patients (50.4%) with AD were female (n=64) and the

mean age was 78.2 years at the time of data recording. Most patients attended school for 8 years or 10

years; no information about time of school attendance was provided for about one third (29.1%, n=37)

of patients.

The majority of patients were non-smokers (88.2%, n=112). Heart disease (33.1%, n=42) and diabetes

(28.3%, n=36) were marked most often from the four pre-defined concomitant diseases.

Demographic and clinical data were also documented by physicians, who took the information from the

patient’s files retrospectively (see Table Table 9-2).


Table 9-2 Clinical background (physician, retrospective information from patient’s files and current information)

Variable N missing /

not assessed Total (N=129)

Retrospective information (at the time of treatment initiation)


median (min, max) 78 (56-101)

Weight, kg 15 mean (SD) 73.2 (11.9)


Severity of AD 1 beginning mild 14 (10.9)

mild 32 (24.8)

mild to moderate 50 (38.8)

moderate 30 (23.3)

ending moderate 2 (1.6)

MMSE score 60 mean (SD) 20.8 (3.3)


Living 0 at home with caregiver 94 (72.9)

at home alone 21 (16.3)

nursing home 13 (10.1)

somewhere else 1 (0.8)

Current information (3 months after treatment initiation)

Estimated CGI score 5 very much improved 1 (0.8)

much improved 46 (35.7)

a little improved 39 (30.2)

no change 28 (21.7)

a little worse 9 (7.0)

much worse 1 (0.8)

AD = Alzheimer’s disease, CGI = clinical global impression, MMSE = Mini–mental state examination, SD = standard

deviation

Source: Table Set Section 3.1, Table 3.2 to 3.5, 3.8, Section 3.2, Table 3.12

According to the physicians’ information (from patients’ files), the majority of patients presented with

mild (24.8%), mild to moderate (38.8%), or moderate (23.3%) AD at the time of treatment initiation

and the mean ± SD MMSE-score was 20.8 ± 3.3 points (out of 30), corresponding to mild dementia.

Three months after treatment initiation (current information at first study visit), most physicians

estimated that the CGI would be much improved (35.7%) or a little improved (30.2%). No change was

seen by 21.7% of physicians and 10 physicians saw a deterioration of the AD.

Information about prescribed drug, concomitant diseases and other concomitant medications at the time

of treatment initiation is given in Table 9-3.


Table 9-3 Prescribed patch, concomitant diseases and medication (physician, retrospective information from patient’s files)

Variable N missing Total (N=129)

Retrospective information (at the time of treatment initiation)

Prescribed patch, n (%) 0 4.6 mg/24 h 55 (42.6)

9.5 mg/24 h 69 (53.5)

both 5 (3.9)

Concomitant diseases*, n (%) 0 Hypertension 50 (38.8)

Heart disease 42 (32.6)

Diabetes 35 (27.1)

Clinical depression 20 (15.5)

Cancer 17 (13.2)

Gastrointestinal

disorders 9 (7.0)

Skin disease 8 (6.2)

Anxiety disorder 6 (4.7)

Arthritis 6 (4.7)

Dysphagia 2 (1.6)

Concomitant medication, number 4 mean (SD) 3.0 (2.3)


AD = Alzheimer’s disease, h = hour, SD = standard deviation; *multiple responses possible out of pre-defined answers,

Source: Table Set Section 3.1, Table 3.1, 3.6 to 3.7

At the time of treatment initiation, the high dose Exelon® patch (9.5 mg/ 24 h) was prescribed in 53.5%

(n=69) and the low dose patch in 42.6% (n=55) of patients by the physicians. Both doses were

prescribed for 5 patients (3.9%) within the 3 months since treatment start..

Most often, patients suffered from concomitant hypertension (38.8%), heart disease (32.6%), diabetes

(27.1%) and clinical depression (15.5%). The mean number of concomitant medication was 3.0 ± 2.3 at

the time of treatment initiation.

At the first study visit, physicians had prescribed a total of 414 Exelon® packages. Most often

prescribed package sizes were N3 with 90 patches (46.9%, 194/414), N1 with 30 patches (22.2%,

92/414) and N2 with 60 patches (13.8%, 57/414). Residual packages (71/414) had other sizes. Most of

these were at a dose of 9.5 mg/24 h (53.6%, 222/414) and second most at a dose of 4.6 mg/24 h

(46.1%, 191/414). The dose was not specified in one case.

Patient’s view about the disease (multiple answers possible), and the compliance/adherence to the patch

were recorded by the caregiver 3 months after treatment initiation (see


Table 9-4).


Table 9-4 Patient’s view about the disease and medication (caregiver questionnaire)

Variable N

missing Total (N=127)

AD cause (patient’s view), n (%)* 0 age 97 (76.4)

genetic endowments 33 (26.0)

nutrition 12 (9.4)

infection/virus 5 (3.9)

other 33 (26.0)

Preferred medication (patients’ view)

Pills, n (%) 14 not preferred 19 (15.0)

little preferred 21 (16.5)

moderate 48 (37.8)

preferred 22 (17.3)

highly preferred 3 (2.4)

Liquids, n (%) 14 not preferred 16 (12.6)


moderate 48 (37.8)

preferred 22 (17.3)


Patches, n (%) 9 not preferred 10 (7.9)


moderate 18 (14.2)

preferred 47 (37.0)


AD = Alzheimer’s disease

Source: Table Set Section 1.1, Table 1.6 to 1.7

Most patients thought, that their AD was caused by their higher age (76.4%, n=97). Second most

common causes were thought to be genetic endowments (26.0%, n=33) or other (26.0%, n=33).

Patches were more favored than other types of medications (pills or liquids). Most patients preferred or

highly preferred patches as type of medication. Patches were not preferred by 7.9% of patients

(n=10/127). Pills and liquids were moderately preferred (both 37.8%) and preferred (both 17.3%) by

most patients.


9.2.2 Information about caregiver (by caregivers and physicians)

Information about the caregiver provided by the caregiver was also recorded, as summarized in Table

9-5.

Table 9-5 Demographic data and medical condition of caregiver (caregiver questionnaire, baseline visit)

Variable N missing Total (N=127)

Sex, n (%) 13 male 24 (18.9)

female 90 (70.9)


median (min, max) 70 (32, 90)

Concomitant diseases affecting...,

n (%)* 0 mobility 33 (26.0)

vision 21 (16.5)

strength / stamina 16 (12.6)

usage of hands 10 (7.9)

Did you care for relatives before?

n (%) 8 yes 23 (18.1)

no 96 (75.6)

How often do you see the patient?

n (%) 10 daily (most of the time) 75 (59.1)

daily (4-7 hours) 13 (10.2)

daily (1-3 hours) 21 (16.5)

1-2 times/week 8 (6.3)

AD = Alzheimer’s disease, SD = standard deviation; *multiple responses possible out of pre-defined answers,

Source: Table Set Section 1.2, Table 1.10 to 1.12 and 1.14 to 1.15.

Most of the caregivers (70.9%, n=90/127) were female and had a mean age of 66.4 ± 13.9 years. When

asked for concomitant diseases, those affecting mobility (26.0%) and vision (16.5%) were recorded

most often by the caregivers, corresponding to their higher age. The majority (75.6%) never cared for

relatives before and more than half of the caregivers see the patient most of the time daily (59.1%).

Information about the caregiver was also provided by the physician at baseline.

At the time of treatment initiation, the patient was supervised by the spouse (57.4%, n=74/129), the

daughter (21.7%, n=28/129), a paid caregiver (5.4%, n=7/129), another person (3.1%, n=4/129), or the

son (3.1%, n=4/129). A total of 11 patients (8.5%) were supervised by more than one person (e.g.

spouse and daughter) (Source: Table Set Section 3.1, Table 3.9).

Physicians were also asked to evaluate if there were any drawbacks of the caregiver’s physical ability

to take care for the patient (see Table 9-6).


Table 9-6 Caregivers physical ability to take care for the patient (physician, retrospective information from patient’s files)

Drawback of caregiver's physical ability N %

Total 129 100.0

Missing 4 3.1

Not at all 81 62.8

A little 23 17.8

Medium 12 9.3

Rather 7 5.4

Very much 2 1.6

Source: Table Set Section 3.1, Table 3.10.

At the time of first treatment initiation, the ability of the caregiver to take care for the patient was not at

all restricted in 62.8% and little restricted in 17.8% of caregivers.

The majority of patients (98.4%, n=127/129) did not show any behavior that would suggest a restricted

fixing, using or removing of the patch at the time of treatment initiation (Source: Table Set Section 3.1,

Table 3.11).

9.2.3 Information about patch (caregiver questionnaire)

Caregivers were asked to evaluate the information they received with the Exelon® patch (see Table

9-7).

Table 9-7 Information on patch (caregiver questionnaire, baseline visit, n=127)

Information on

patch Missing

Not

necessary Nothing

received Too little Too much Adequate

N % N % N % N % N % N %

Reason for

patch 9 7.1 1 0.8 2 1.6 7 5.5 2 1.6 106 83.5

When to use

patch 10 7.9 1 0.8 - - 7 5.5 4 3.1 105 82.7

When to fix

patch 9 7.1 2 1.6 3 2.4 12 9.4 5 3.9 96 75.6

How to change

side 11 8.7 2 1.6 2 1.6 12 9.4 7 5.5 93 73.2

How to remove

patch 10 7.9 4 3.1 1 0.8 6 4.7 7 5.5 99 78.0

What to do in

case of AEs 9 7.1 3 2.4 3 2.4 19 15.0 2 1.6 91 71.7

Source: Table Set Section 1.4, Table 1.25.


Most caregivers (>70%) assessed the amount of information as adequate in all aspects. A total of

15.0% (n=19/127) found there was too little information about what to do in case of AEs. In addition,

9.4% of caregivers found it was too little information about when to fix the patch and 9.4% about how

to change side.

9.3 Descriptive data over time (by caregiver, 3 and 6 months)

9.3.1 Application of patch and patient’s compliance

Problems with the application of the patch within the last 2 weeks before questionnaire completing and

compliance / adherence of the patient were assessed 3 and 6 months after treatment initiation (see Table

9-8).

Table 9-8 Extent of help with application of patch and patient’s compliance/adherence 3 and 6 months after treatment initiation (caregiver questionnaires)

Variable 3 months 6 months

N miss Total

(N=127) N miss Total

(N=110)

Extent of help with

application of Exelon®

patch, n (%) full responsibility 12 44 (34.6) 7 39 (35.5)

help a lot 43 (33.9) 40 (36.4)

help moderately 11 (8.7) 11 (10.0)

help only a little 17 (13.4) 13 (11.8)

Compliance, n (%)

patient supports

fixing of patch never 17 3 (2.4) 11 3 (2.7)

sometimes 9 (7.1) 5 (4.5)

mostly 56 (44.1) 43 (39.1)

always 42 (33.1) 48 (43.6)

Adherence, n (%)

patient keeps patch as

long as necessary never 15 0 9 1 (0.9)

sometimes 7 (5.5) 4 (3.6)

mostly 34 (26.8) 33 (30.0)

always 71 (55.9) 63 (57.3)

Source: Table Set Section 1.1, Table 1.8 to 1.9 and Section 2.1, Table 2.1 to 2.2.

Most caregivers had full responsibility (34.6%) or had to help a lot (33.9%) with the application of the

patch at baseline and no relevant changes in the extent of help was seen 3 months later (35.5% and

36.4%, respectively).

At baseline, most of the patients were compliant with the Exelon® patch, i.e. mostly (44.1%) or always

(33.1%) supported their caregivers when fixing the patch. In addition, the majority of the patients

adhered to the medication and always (55.9%) or mostly (26.8%) kept the patch as long as necessary.

Compliance and adherence data were comparable 6 months after treatment start.


9.3.2 Problems of caregiver within last 2 weeks

Caregivers were also asked about any psychological problems that they experienced within the last 2

weeks before questionnaire completing (see Table 9-9).

Table 9-9 Psychological problems caregivers experienced within 2 weeks before visits (caregiver questionnaires, 3 and 6 months after treatment initiation)

Variable 3 months 6 months

n (%) N miss Total

(N=127) N miss Total

(N=110)

No interest or joy in

doing something not at all 9 75 (59.1) 8 63 (57.3)

several days 29 (22.8) 27 (24.5)

more than half of the time 10 (7.9) 9 (8.2)

almost every day 4 (3.1) 3 (2.7)

Being depressed or

hopeless not at all 9 74 (58.3) 6 62 (56.4)

several days 30 (23.6) 25 (22.7)



Being nervous,

anxious or irritable not at all 9 79 (62.2) 6 63 (57.3)

several days 26 (20.5) 32 (29.1)



No stop or control of

sorrowful thoughts not at all 9 73 (57.5) 6 67 (60.9)

several days 30 (23.6) 22 (20.0)



Source: Table Set Section 1.1, Table 1.13 and Section 2.2, Table 2.3

Most of the caregivers had no psychological problems at all (about 57% to 63% in the four domains) or

only on several days (about 20% to 24%) at baseline. This proportion of patients without any

significant problems remained largely unchanged up to the completion visit. The proportion of

caregivers with problems more than half of the time or almost every day had slightly increased during

the further 3 months of observation, though the absolute numbers of caregivers were low. For example,

being depressed or hopeless for more than half of the day were 7.9% (n=10/127) at baseline and 11.8%

(n=13/110) after further 3 months.


9.3.3 Opinion on AD

The caregiver’s opinion and beliefs about AD and the extent to which the patient is impacted by the

disease, each rated on a 0 (no) to 10 (strong, very much) scale, were assessed at both visits (see Table

9-10 and Table 9-11).

Table 9-10 Opinion on AD (3 months after treatment initiation, caregiver questionnaire, n=127)

Question Non-missing Mean SD

How strong does AD impact life of your patient? 118 6.2 2.2

How long will the AD last? 117 8.5 2.3

How strongly can the patient control the AD? 116 4.1 2.8

To what extent can the medication help to manage the AD? 118 6.3 2.3

How much is the patient suffering from the AD? 115 5.5 1.9

How much are you concerned by the AD? 115 6.9 2.2

How much do you understand about the AD? 118 6.0 2.5

How much is the patient emotionally affected by the AD? 118 5.6 2.4

AD = Alzheimer’s disease, SD = standard deviation

Source: Table Set Section 1.3, Table 1.16

The mean score values of the “Opinion on AD” questionnaire mostly were in the middle range of the

scale (around 4.1 to 6.9), showing that patients but also caregivers were distinctly affected by the AD,

although none of the mean scores achieved extreme values. Only the question on the duration of the

disease showed that caregivers were aware of the very long duration (mean score 8.5).

Table 9-11 Opinion on AD (6 months after treatment initiation, caregiver questionnaire, n=110)

Question Non-missing Mean SD

How strong does AD impact life of your patient? 104 6.3 2.2

How long will the AD last? 104 8.4 2.4

How strongly can the patient control the AD? 104 4.3 2.6

To what extent can the medication help to manage the AD? 104 6.4 2.2

How much is the patient suffering from the AD? 103 5.5 2.0

How much are you concerned by the AD? 104 6.9 2.1

How much do you understand about the AD? 104 6.3 2.4

How much is the patient emotionally affected by the AD? 103 5.2 2.3

AD = Alzheimer’s disease, SD = standard deviation


The mean score values of the “Opinion on AD” questionnaire also ranged in the middle of the scale

(4.3 to 6.9), except for the question on the duration of AD (8.4). Mean score values were almost the

same as after 3 months.


Furthermore, caregivers were asked to select the three most important factors from a given list that may

have caused the AD. This question was asked after 3 and after 6 months of treatment initiation (Table

9-12 and Table 9-13). Originally, caregivers were to rate the most important factors on a scale of 1 to 3

(1 being the most important factor). However, many caregivers just ticked some of the factors instead.

Table 9-12 Opinion about factors being the cause of AD (3 months after treatment initiation, caregiver questionnaire, n=127)

Most

important

factors

Not ticked Ticked 1 2 3

N % N % N % N % N %

Age 18 14.2 60 47.2 32 25.2 8 6.3 9 7.1

Genetics 58 45.7 30 23.6 11 8.7 22 17.3 4 3.1

Diet 114 89.8 3 2.4 2 1.6 2 1.6 1 0.8

Infection/virus 111 87.4 8 6.3 - - - - 5 3.9

Environment 84 66.1 18 14.2 2 1.6 7 5.5 12 9.4

Other 60 47.2 26 20.5 7 5.5 14 11.0 17 13.4


Table 9-13 Opinion about factors being the cause of AD (6 months after treatment initiation, caregiver questionnaire, n=110)

Most

important

factors

Not ticked Ticked 1 2 3

N % N % N % N % N %

Age 13 11.8 59 53.6 24 21.8 10 9.1 4 3.6

Genetics 58 52.7 22 20.0 8 7.3 14 12.7 8 7.3

Diet 104 94.5 1 0.9 - - 3 2.7 - -

Infection/virus 95 86.4 8 7.3 1 0.9 3 2.7 1 0.9

Environment 75 68.2 14 12.7 3 2.7 5 4.5 12 10.9

Other 58 52.7 24 21.8 6 5.5 6 5.5 16 14.5


Both at 3 and 6 months after treatment start, the factors age, other factors and genetics were ticked most

often and thought to be the most important factors for causing AD. Most patients ticked age as first,

genetics as second and other factors as third most important causes. Diet and infection/virus were not

ticked by most caregivers (>80%). Also environment was not considered as important cause (not ticked

by 66.1% after 3 months and by 68.2% after 6 months). Although genetics belonged to the three most

important factors, it was not ticked by 45.7% of caregivers after 3 and 52.7% after 6 months. Taken

together, age was the predominant factor for AD.

9.3.4 Usage of Exelon® patch

The proportion of patients who were still using the patch after treatment initiation was 88.2%

(n=112/127) at first visit (missing 7.9%) and also 88.2% (n=97/110) at final visit (missing 7.3%). Only

5 patients (3.9%) discontinued the Exelon® patch before baseline visit and further 5 patients (4.5%)

before final visit (Source: Table Set Section 1.4, Table 1.17-1.18 and 2.4, Table 2.5-2.6).


9.3.5 Opinion on Exelon® patch

Caregivers were asked about their opinions about some statements of other persons made on the

Exelon® patch 3 and again 6 months after treatment initiation (Table 9-14 and


Table 9-15).

Table 9-14 Opinion on Exelon® patch (3 months after treatment initiation, caregiver questionnaire, n=127)

Opinion on

Exelon® patch

Missing I don't

agree at all I don't

agree I don't

know I agree I completely

agree

N % N % N % N % N % N %

Health depends on

patch 10 7.9 1 0.8 7 5.5 40 31.5 59 46.5 10 7.9

Worry about usage

of patch 11 8.7 60 47.2 33 26.0 9 7.1 12 9.4 2 1.6

Could not live

without patch 11 8.7 34 26.8 27 21.3 47 37.0 7 5.5 1 0.8

Thoughts about

long-term effects 11 8.7 34 26.8 20 15.7 25 19.7 35 27.6 2 1.6

Very ill without

patch 12 9.4 7 5.5 21 16.5 31 24.4 49 38.6 7 5.5

Patch is a mystery

14 11.0 50 39.4 17 13.4 29 22.8 14 11.0 3 2.4

Future health

depends on patch 11 8.7 11 8.7 7 5.5 44 34.6 49 38.6 5 3.9

Patch disturbs

life 11 8.7 67 52.8 23 18.1 20 15.7 4 3.1 2 1.6

Concerns about

addiction 11 8.7 61 48.0 17 13.4 23 18.1 15 11.8 - -

Patch protects from

feeling worse 11 8.7 1 0.8 6 4.7 16 12.6 76 59.8 17 13.4


More than half of the caregivers agreed (agreed or completely agreed) with the statements that “health

would depend on the patch” (54.3%) and that the “patch would protect the patients from feeling worse”

(73.2%). Slightly less than half of the caregivers agreed with the statements that the patient would “be

very ill without the patch” (44.1%, 24.4% did not know) and that the patient’s “future would depend on

the patch” (42.5%, 34.6% did not know). Most caregivers disagreed (disagreed or disagreed at all) with

the following statements: “worry about usage of patch” (73.2%), “patch disturbs life” (70.9%),

“concerns about addiction” (61.4%), “patch is a mystery” (52.8%), “could not live without patch”

(48.0%, 37.0% did not know), and “thoughts about long-term effects of the patch” (42.5%).


Table 9-15 Opinion on Exelon® patch (6 months after treatment initiation, caregiver questionnaire, n=110)

Opinion on

Exelon® patch

Missing I don't

agree at all I don't

agree I don't

know I agree I completely

agree

N % N % N % N % N % N %

Health depends on

patch 7 6.4 1 0.9 8 7.3 31 28.2 54 49.1 9 8.2

Worry about usage

of patch 6 5.5 65 59.1 20 18.2 8 7.3 9 8.2 2 1.8

Could not live

without patch 6 5.5 21 19.1 29 26.4 43 39.1 10 9.1 1 0.9

Thoughts about

long-term effects 7 6.4 48 43.6 8 7.3 22 20.0 20 18.2 5 4.5

Very ill without

patch 6 5.5 8 7.3 10 9.1 38 34.5 42 38.2 6 5.5

Patch is a mystery

8 7.3 51 46.4 8 7.3 26 23.6 13 11.8 4 3.6

Future health

depends on patch 6 5.5 9 8.2 16 14.5 30 27.3 44 40.0 5 4.5

Patch disturbs

life 8 7.3 67 60.9 14 12.7 14 12.7 7 6.4 - -

Concerns about

addiction 7 6.4 68 61.8 10 9.1 11 10.0 14 12.7 - -

Patch protects

from feeling worse 6 5.5 4 3.6 3 2.7 11 10.0 64 58.2 22 20.0


At final visit (6 months after treatment initiation), the level of acceptance (agreed or completely agreed)

to the statements that “health would depend on the patch” (57.3%), that the “patch would protect the

patients from feeling worse” (78.2%), and that the patient’s “future would depend on the patch”

(44.5%, 27.3% did not know) has increased slightly compared to the documentation 3 months earlier.

Also the level of rejection (disagreed or disagreed at all) has increased slightly regarding the following

statements: “worry about usage of patch” (77.3%), “patch disturbs life” (73.6%), “concerns about

addiction” (70.9%), “patch is a mystery” (53.6%), and “thoughts about long-term effects of the patch”

(50.9%). This shift of answers can be attributed to the fact that less patients ticked the “I don’t know”

box with the respective questions. Only with the statements “could not live without patch” (disagreed

45.5%, 39.1% did not know) and “patient would be very ill without the patch” (agreed 43.6%, 34.5%

did not know) the level of (dis-)agreement has decreased and more caregivers ticked the “I don’t know”

boxes.


9.3.6 Compliance

Caregivers were asked to what extent they deviated from the physician’s instructions or on the package

leaflet (consciously or unconsciously, see Table 9-16 and Table 9-17).

Table 9-16 Compliance with usage instructions (3 months after treatment initiation, caregiver questionnaire, n=127)

Compliance Missing Always Often Sometimes Rarely Never

N % N % N % N % N % N %

Forgotten to fix

patch 8 6.3 2 1.6 5 3.9 19 15.0 28 22.0 65 51.2

Forgotten to

remove patch 8 6.3 - - 7 5.5 17 13.4 21 16.5 74 58.3

Patch paused for

a while 9 7.1 2 1.6 5 3.9 5 3.9 13 10.2 93 73.2

Patch omitted

sometimes 9 7.1 2 1.6 2 1.6 9 7.1 10 7.9 95 74.8

Change of time

for fixing patch 8 6.3 1 0.8 8 6.3 14 11.0 14 11.0 82 64.6


At the first documentation time, most caregivers stated that she/he had never “omitted that patch

sometimes” (74.8%), “paused the patch for a while” (73.2%), or “changed the fixing patch time”

(64.6%). A total of 58.3% of caregivers never have “forgotten to remove the patch” and 29.9%

sometimes or rarely. Similarly, 51.2% of caregivers never have “forgotten to fix the patch” and 37.0%

did so sometimes or rarely.

Within the last 2 weeks before first documentation, 69.3% of caregivers (n=88/127) stated that there

was no day of irregular use of patch, 8.7% had one day (n=11/127), 5.5% with 1-2 or 2 days (n=7/127)

and 6.3% with more than 2 days of irregular use (n=8/127). There was missing information for 13

caregivers (10.2%) (Source: Tablet Set Section 1.4, Table 1.21).


Table 9-17 Compliance with usage instructions (6 months after treatment initiation, caregiver questionnaire, n=110)

Compliance Missing Always Often Sometimes Rarely Never

N % N % N % N % N % N %

Forgotten to fix

patch 9 8.2 5 4.5 5 4.5 15 13.6 17 15.5 59 53.6

Forgotten to

remove patch 6 5.5 4 3.6 6 5.5 14 12.7 15 13.6 65 59.1

Patch paused for

a while 6 5.5 4 3.6 7 6.4 3 2.7 8 7.3 82 74.5

Patch omitted

sometimes 6 5.5 2 1.8 5 4.5 6 5.5 5 4.5 86 78.2

Change of time

for fixing patch 6 5.5 1 0.9 8 7.3 12 10.9 11 10.0 72 65.5


Overall, at the final documentation time (6 months after treatment initiation), the proportion of

caregivers who have never forgotten to fix or remove the patch or who have changed patch usage has

slightly increased compared to the first documentation.

There was also a high proportion of caregivers who stated that the number of days with irregular use

was zero (70.0%). A total of 10.0% (n=11/110) had 1 day and 9.1% (n=10/110) with more than 1 day

of irregular use (Source: Tablet Set Section 2.4, Table 2.9).

9.3.7 Satisfaction with efficacy

Caregivers were asked about their satisfaction with the efficacy of the Exelon® patch at both visits (see

Table 9-18 and Table 9-19).

Table 9-18 Satisfaction with efficacy (3 months after treatment initiation, caregiver questionnaire, n=127)

Satisfaction with

efficacy Missing

Very

unsatisfied Unsatisfied Satisfied Very

satisfied

N % N % N % N % N %

Memory 10 7.9 2 1.6 31 24.4 79 62.2 5 3.9

Activities 10 7.9 - - 20 15.7 88 69.3 9 7.1

Behaviour and emotions 10 7.9 3 2.4 21 16.5 83 65.4 10 7.9


At the first visit, the majority of caregivers was satisfied with the efficacy of the patch on the ability to

undertake activities (69.3%), on behavior and emotions (65.4%), and on memory (62.2%). Very

satisfied were 7.1%, 7.9% and 3.9%, respectively. Unsatisfied with the efficacy of the patch on

memory were 24.4% of caregivers, on behavior and emotions 16.5%, and activities 15.7%.


Table 9-19 Satisfaction with efficacy (6 months after treatment initiation, caregiver questionnaire, n=110)

Satisfaction with

efficacy Missing

Very

unsatisfied Unsatisfied Satisfied Very

satisfied

N % N % N % N % N %

Memory 9 8.2 1 0.9 25 22.7 62 56.4 13 11.8

Activities 7 6.4 1 0.9 12 10.9 73 66.4 17 15.5

Behaviour and emotions 7 6.4 2 1.8 12 10.9 71 64.5 18 16.4


At the final visit, the level of satisfaction with the efficacy has increased compared to the first

documentation, with 16.4% of caregivers being very satisfied and 64.5% satisfied with the effect on

behavior and emotions, 15.5% very satisfied and 66.4% satisfied with effect on activities, and 11.8%

being very satisfied and 56.4% satisfied with the effect on memory. The proportion of caregivers being

unsatisfied has decreased compared to the first documentation.

9.3.8 Application of the patch

Caregivers were asked to evaluate the ease of application of the patch at the two visits (see Table 9-20

and Table 9-21).

Table 9-20 Application of the patch (3 months after treatment initiation, caregiver questionnaire, n=127)

Application of patch Missing Very difficult Difficult Easy Very easy

N % N % N % N % N %

Open of package 10 7.9 - - 4 3.1 58 45.7 55 43.3

Make patient to use it 9 7.1 1 0.8 5 3.9 57 44.9 55 43.3

Fix patch 9 7.1 1 0.8 3 2.4 57 44.9 57 44.9

Remove patch 9 7.1 - - 1 0.8 57 44.9 60 47.2


At the first documentation, more than 85% of caregivers found that opening of the package, make the

patient to use it, fixing and removing of patch was easy or very easy.


Table 9-21 Application of the patch (6 months after treatment initiation, caregiver questionnaire, n=110)

Application of patch Missing Very

difficult Difficult Easy Very easy

N % N % N % N % N %

Open of package 12 10.9 - - 4 3.6 47 42.7 47 42.7

Make patient to use it 9 8.2 1 0.9 2 1.8 47 42.7 51 46.4

Fix patch 9 8.2 - - 2 1.8 47 42.7 52 47.3

Remove patch 9 8.2 - - 1 0.9 50 45.5 50 45.5


At the final documentation, more than 85% if caregivers found that opening of the package, make the

patient to use it, fixing and removing of patch was easy or very easy. Data were comparable to those at

the first documentation.

9.4 Other analyses

N/A

9.5 Adverse events

Adverse events were reported for a 6 month observation period, retrospectively from start of treatment

until the 6 month documentation of the caregivers. Some answers on the questionnaires, especially

those related to tolerability, could potentially indicate the existence of a hidden adverse event. In such

cases, the investigator was contacted and asked, if there was an adverse event or not. If the physician

confirmed an adverse event, it was documented and subsequently sent to Institute Dr. Schauerte.

In the observation period, 16 adverse events which occurred in 9 patients (7.0%) were reported. Of

these, one event was considered to be a serious adverse event not related (SAEnr, 0.8% of patients),

and another event was considered to be a serious adverse drug reaction (SADR, 0.8% of patients). This

patient died during the observation period. 14 adverse events in 8 patients (6.2%) were reported to be

related to Exelon® patch treatment, but not serious. A patient based overview of all types of adverse

events is displayed in Table 9-22. Event based listings of all types of adverse events are displayed in

Error! Reference source not found. to Table 9-24.

Table 9-22 Adverse events (patient based)

All AE nsAEnr nsADR SAEnr SADR

N % N % N % N % N %

Total 129 100.0 129 100.0 129 100.0 129 100.0 129 100.0

Patients with event 9 7.0 0 0.0 8 6.2 1 0.8 1 0.8

Patients without event 120 93.0 129 100.0 121 93.8 128 99.2 128 99.2



Table 9-23 Event-based classification of non-serious adverse drug reactions (nsADR)

Patient

ID

Event (German

original term)

MedDRA

SOC

MedDRA

PT Action taken

Duration

[days] Outcome

401 Pflasterallergie Skin and subcutaneous

tissue disorders

Dermatitis

contact

Exelon withdrawn,

switch to tablets

Missing Not recovered

yet

3702 Rezidiv. Stürze Injury, poisoning and

procedural complications

Fall Exelon patch

interrupted

7 Recovered

3702 Durchfall Gastrointestinal

disorders

Diarrhoea Exelon patch

interrupted for 3

days

1 Recovered

4102 Störung des Tag-

Nacht-Rhythmus

Nervous system

disorders

Circadian

rhythm sleep

disorder

Exelon withdrawn 15 Recovered

4102 Jucken unterhalb

des Pflasters

Skin and subcutaneous

tissue disorders

Pruritus Exelon withdrawn 15 Recovered

4505 Pflasterallergie Skin and subcutaneous

tissue disorders

Dermatitis

contact


4505 Übelkeit Gastrointestinal

disorders

Nausea Exelon withdrawn Not recovered

yet

4609 Nässende

Hautrötung, Ulcera

an Klebestelle

General disorders and

administration site

conditions

Application

site ulcer


4609 Nässende

Hautrötung, Ulcera

an Klebestelle


tissue disorders

Erythema Exelon withdrawn 15 Recovered

4803 Fall which caused

haematoma in face

Injury, poisoning and

procedural complications

Fall Missing Missing Missing

4803 Fall which caused

haematoma in face

Vascular disorders Haematoma Missing Missing Missing

5003 Allergische

Hautreaktion


tissue disorders

Dermatitis

allergic


5005 Juckende

Hautrötung

(Pflasterbereich)


administration site

conditions

Application

site erythema

Exelon withdrawn

(second size patch)

3 Recovered

5005 Juckende

Hautrötung

(Pflasterbereich)


administration site

conditions

Application

site pruritus

Exelon withdrawn

(second size patch)

3 Recovered


Table 9-24 Event-based classification of serious adverse events not related (SAEnr)

Patient

ID

Event (German

original term)

MedDRA

SOC

MedDRA

PT

Action

taken

Duration

[days] Outcome

4803 Rektum Karzinom

ICD: C20

Neoplasms benign, malignant and

unspecified (incl cysts and polyps)

Rectal cancer Missing Missing Missing



Table 9-25 Event-based classification of serious adverse drug reactions (SADR)

Patient

ID

Event (German

original term)

MedDRA

SOC

MedDRA

PT

Action

taken

Duration

[days] Outcome

3102 Tod - Ursache

unbekannt


administration site conditions

Death Missing Missing Death


All 14 non-serious adverse events were assessed to be related to Exelon® patch treatment (causality

probable, possible, assured, or not assessable).

Of the 14 non-serious adverse drug reactions, 5 were of mild intensity, 5 of moderate and 2 of severe

intensity (2 missings). Treatment with Exelon® patch was withdrawn due to 10 non-serious adverse

drug reactions, 2 times the treatment was interrupted (2 missings). The outcome of the non-serious

adverse drug reactions was documented as recovered for 10 events and not yet recovered for 2 events

(2 missings).

A total of 2 serious adverse events were experienced by 2 patients, for which the causality was

documented as not assessable / no causal relation. One patient died due to unknown cause. This event

(causality not assessable) was upgraded by Novartis according to conservative policy and submitted to

German health authority. Information about the outcome of the other serious event rectal cancer was

missing. For a more detailed listing of adverse events, separately for non-serious adverse drug reactions

(nsADR), serious adverse events not related (SAEnr), and serious adverse drug reactions (SADR),

please refer to the Table Set, Table 3.17 to 3.20.

9.5.1 Satisfaction of caregiver with tolerability

Caregivers were asked to assess their satisfaction with the tolerability of the patch 3 and 6 months after


At the first documentation, 47.2% of caregivers (n=60/127) assessed the tolerability of the patch as

good and 43.3% (n=55/127) as very good. Two caregivers assessed the tolerability of the patch as not

good and 2 caregivers as not good at all.

At the final documentation, satisfaction with the tolerability of the patch has increased, with 37.3% of

caregivers (n=41/110) assessing the tolerability of the patch as good and 52.7% (n=58/110) as very

good. Four caregivers (3.6%) assessed the tolerability of the patch as not good and one caregiver

(0.9%) as not good at all.


10 Discussion

10.1 Key results

A total of 127 caregivers (reporting about 127 patients) and a total of 18 physicians (documenting 129

patients) in Germany completed the respective questionnaires at the baseline visit (3 months after

initiation of Exelon® patch). In addition, 110 caregiver questionnaires were completed at the

completion visit (6 months after treatment start). Thus, three different populations can be analyzed,

based on completed caregiver questionnaires at 3 months (N = 127), completed caregiver

questionnaires at 6 months (N = 110), and completed physician questionnaires at 3 months (N = 129).

Baseline information: According to caregiver’s information, half of the patients (50.4%) with AD

were female (n=64) and the mean age was 78.2 years at the time of data recording. Most often, patients

suffered from concomitant hypertension (38.8%), heart disease (32.6%), diabetes (27.1%) and clinical

depression (15.5%). The mean number of concomitant medication was 3.0 ± 2.3 at the time of


According to the physicians’ information, majority of the patients presented with mild (24.8%), mild to

moderate (38.8%), or moderate (23.3%) AD at the time of treatment initiation and the mean ± SD

MMSE-score was 20.8 ± 3.3 points (out of 30), corresponding to mild dementia.

At the time of treatment initiation, the high dose Exelon® patch (9.5 mg/ 24 h) was prescribed in 53.5%

(n=69) and the low dose patch in 42.6% (n=55) of patients by the physicians. Both doses were

prescribed for 5 patients.

Three months after treatment initiation (current information at first study visit), most physicians

estimated that the CGI would be much improved (35.7%) or a little improved (30.2%). No change was

seen by 21.7% of physicians and 10 times physicians saw a deterioration of AD.

Patient’s opinion: Most patients thought that their AD was caused by their age (76.4%, n=97). Second

most common causes were thought to be genetic endowments (26.0%, n=33) or other (26.0%, n=33).

Patches were more favored than other types of medications (pills or liquids). Most patients preferred or

highly preferred patches as type of medication. Patches were not preferred by 7.9% of patients

(n=10/127). Pills and liquids were moderately preferred (both 37.8%) and preferred (both 17.3%) by

most patients.

Information about caregiver: Most of the caregivers (70.9%, n=90/127) were female and had a mean

age of 66.4 ± 13.9 years. The majority (75.6%) never cared for relatives before and more than half of

the caregivers see the patient most of the time daily (59.1%). At the time of treatment initiation, the

patient was supervised by the spouse (57.4%, n=74/129), the daughter (21.7%, n=28/129), a paid

caregiver (5.4%, n=7/129), another person (3.1%, n=4/129), or the son (3.1%, n=4/129). A total of 11

patients (8.5%) were supervised by more than one person (e.g. spouse and daughter). At the time of

first treatment initiation, the ability of the caregiver to take care for the patient was not at all restricted

in 62.8% and little restricted in 17.8% of caregivers (physician’s information).

Caregiver information over time (3 and 6 months): Most caregivers had full responsibility (34.6%)

or had to help a lot (33.9%) with the application of the patch at baseline and no relevant changes in the

extent of help was seen 3 months later (35.5% and 36.4%, respectively). At baseline, most of the

patients were compliant with the Exelon®

patch, i.e. mostly (44.1%) or always (33.1%) supported their

caregivers when fixing the patch. In addition, the majority of the patients adhered to the medication and


always (55.9%) or mostly (26.8%) kept the patch as long as necessary. Compliance and adherence data

were comparable 6 months after treatment start.

Most of the caregivers had no psychological problems at all (about 57% to 63% in the four domains) or

only on several days (about 20% to 24%) at baseline. This proportion of patients without any

significant problems remained largely unchanged up to the completion visit.

At the first documentation, the mean score values of the “Opinion on AD” questionnaire mostly were

in the middle range of the scale (around 4.1 to 6.9), showing that patients but also caregivers were

distinctly affected by the AD, although none of the mean scores achieved extreme values. Only the

question on the duration of the disease showed that caregivers were aware of the very long duration

(mean score 8.5). At the final documentation, mean score values were almost the same as after 3

months.

Both at 3 and 6 months after treatment start, the factors age, other factors and genetics were ticked most

often by the caregivers and thought to be the most important factors for causing AD.

The proportion of patients who were still using the patch after treatment initiation was 88.2%

(n=112/127) at first visit (missing 7.9%) and also 88.2% (n=97/110) at final visit (missing 7.3%). Only

5 patients discontinued the Exelon® patch before baseline visit and further 5 patients before final visit.

More than half of the caregivers agreed (agreed or completely agreed) with the statements that “health

would depend on the patch” (54.3%) and that the “patch would protect the patients from feeling worse”

(73.2%). Slightly less than half of the caregivers agreed with the statements that the patient would “be

very ill without the patch” (44.1%, 24.4% did not know) and that the patient’s “future would depend on

the patch” (42.5%, 34.6% did not know). Most caregivers disagreed (disagreed or disagreed at all) with

the following statements: “worry about usage of patch” (73.2%), “patch disturbs life” (70.9%),

“concerns about addiction” (61.4%), “patch is a mystery” (52.8%), “could not live without patch”

(48.0%, 37.0% did not know), and “thoughts about long-term effects of the patch” (42.5%). At final

documentation, the level of acceptance to the statements that caregivers had agreed with 3 months

earlier has increased slightly. Also the level of rejection with those statements previously disagreed has

increased slightly. Only with the statements “could not live without patch” (disagreed 45.5%, 39.1%

did not know) and “patient would be very ill without the patch” (agreed 43.6%, 34.5% did not know)

the level of (dis-)agreement has decreased and more caregivers ticked the “I don’t know” boxes.

At both visits, both the caregivers and the patients were highly compliant. At the first documentation

time, most caregivers stated that she/he had never “omitted that patch sometimes” (74.8%), “paused the

patch for a while” (73.2%), or “changed the fixing patch time” (64.6%). A total of 58.3% of caregivers

never have “forgotten to remove the patch” and 29.9% sometimes or rarely. Similarly, 51.2% of

caregivers never have “forgotten to fix the patch” and 37.0% did so sometimes or rarely. Within the

last 2 weeks before first documentation, 69.3% of caregivers (n=88/127) stated that there was no day of

irregular use of patch. At the final documentation time (6 months after treatment initiation), the

proportion of caregivers who have never forgotten to fix or remove the patch or who have changed

patch usage has slightly increased compared to the first documentation. There was also a high

proportion of caregivers who stated that the number of days with irregular use was zero (70.0%).

At the final visit, the level of satisfaction with the efficacy has increased compared to the first

documentation, with 16.4% of caregivers being very satisfied and 64.5% satisfied with the effect on

behavior and emotions, 15.5% very satisfied and 66.4% satisfied with effect on activities, and 11.8%

being very satisfied and 56.4% satisfied with the effect on memory. The proportion of caregivers being

unsatisfied has decreased compared to the first documentation.


More than 85% if caregivers found that opening of the package, make the patient to use it, fixing and

removing of patch was easy or very easy at both documentations.

In conclusion, most caregivers and their patients adhered to the treatment with rivastigmine (Exelon®

patch) during the 6 months observation period. The application of the patch was considered by the

caregivers as easy to use, efficacious and satisfying for both the patient and the caregiver.

10.2 Safety conclusions

In the observation period, 16 adverse events which occurred in 9 patients were reported. Of these, one

event was considered to be a serious adverse event not related, and another event was considered to be

a serious adverse drug reaction. This patient died during the observation period. 14 adverse events in 8

patients were reported to be related to Exelon® patch treatment, but not serious.

Rivastigmine (Exelon® patch) proved to be a well-tolerated drug for the treatment of patients with

Alzheimer’s disease, as demonstrated by the low incidence rate of adverse events. The nature and

frequency of adverse events occurring during the 6 months therapy were consistent with the established

safety profile of rivastigmine. The current NIS did not reveal any suspicion of unknown risks related to

the treatment with rivastigmine.


11 References

Folstein MF, Folstein SE, McHugh PR (1975). ""Mini-mental state". A practical method for grading

the cognitive state of patients for the clinician". Journal of Psychiatric Research 12 (3): 189–98.


12 Appendix

12.1 Sample study protocol including data entry forms

12.2 Table set

12.3 Signatures

I certify that this report accurately describes the conduct and the results of this clinical study.

Project Lead CRO: Caroline Schneider

Signature Date

Statistical Lead: Klaus Hechenbichler

Signature Date

I certify that this report accurately describes the conduct and the results of this clinical study.

Medical Advisor: Beate Müller

Signature Date

I have read this report and confirm to the best of my knowledge it accurately describes safety results

from the study.

Medical Safety Expert DS&E:

Katharina Salb

Signature Date

I have read this report and confirm that to the best of my knowledge it accurately describes the conduct

and results of the study.

TA Head: Alexander Fuchs

Signature Date

Documents

STATT A non-interventional study to investigate factors … · STATT – A non-interventional study to investigate factors ... 9.2.3 Information about patch (caregiver questionnaire)