A Phase IV, Prospective, Multicenter, Open Label, Uncontrolled, Non-interventional, Single Arm Study to Measure Treatment Satisfaction of Multiple Sclerosis (MS) Patients on Rebif® After Discontinuing Initial First-line Treatment
Conditions: Multiple Sclerosis
Sponsor: Merck KGaA, Darmstadt, Germany

Interferon beta-1a
MESTRE–MS Study
EMR200136_597
Non-Interventional Study Protocol
Study Protocol Number
EMR200136_597
Title
A Phase 
IV, prospective, multicenter, open label, 
uncontrolled, non-interventional, single arm study to 
measure treatment satisfaction of multiple sclerosis (MS) 
patients on Rebif® after discontinuing initial first-line 
treatment
Study acronym/Short title
MESTRE–MS (MEasuring Satisfaction of Treatment with 
REbif after initial treatment of MS)
Protocol version identifier
Version 2.0
Date of last version of 
protocol
07 Oct 2016
Replaces Study Protocol 
Version
Version 1.0/20 May 2016
Active substance
International Nonproprietary Name (INN): Interferon 
beta-1a;
Pharmacotherapeutic Group: Immunostimulants;
Anatomical Therapeutic Chemical (ATC) Code: LO3AB07
Medicinal product
Rebif
Marketing authorisation
holder (MAH)
Merck Serono Europe Limited
Research question and 
objectives
The purpose of this study is to investigate treatment 
satisfaction of MS patients, who have discontinued first-line 
MS oral or injectable MS medication, and have initiated 
treatment with Rebif. 
Primary objective
x
To determine the level of treatment satisfaction as 
measured with the Treatment Satisfaction Questionnaire 
for Medication Version II (TSQM v II), in relapsing 
remitting MS (RRMS) patients who have discontinued 
their initial oral or injectable MS treatment, and have 
initiated treatment with Rebif.
Secondary objectives
x
To evaluate the change in annualized relapse rate (ARR) 
in patients changing from initial oral or injectable forms 
of treatment to Rebif
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1
Table of Contents
1 
Table of Contents..................................................................................3 
2 
List of Abbreviations ............................................................................6 
3 
Responsible Parties...............................................................................7 
3.1 
Responsibilities of the Investigator ....................................................10 
4 
Abstract...............................................................................................11 
5 
Amendments.......................................................................................17 
6 
Milestones...........................................................................................17 
7 
Rational and Background ...................................................................18 
8 
Research Question and Objectives .....................................................21 
8.1 
Primary Objective...............................................................................21 
8.2 
Secondary Objectives .........................................................................21 
8.3 
Other Objectives .................................................................................21 
9 
Research Methods...............................................................................21 
9.1 
Study Design.......................................................................................21 
9.1.1 
Design Overview ................................................................................22 
9.1.2 
Endpoints............................................................................................23 
9.2 
Setting.................................................................................................24 
9.2.1 
Study Population.................................................................................24 
9.2.2 
Definition of Study Cohorts and Description of Treatments..............25 
9.2.3 
Observation Period .............................................................................26 
9.2.4 
Frequency of Assessments..................................................................26 
9.2.5 
Withdrawal from the Study ................................................................28 
9.3 
Variables.............................................................................................29 
9.4 
Data Source.........................................................................................31 
9.5 
Study Size...........................................................................................31 
9.6 
Data Management...............................................................................31 
9.7 
Data Analysis......................................................................................32 
9.7.1 
Analysis Sets.......................................................................................32 
9.7.2 
Derived and Transformed Data ..........................................................32 
9.7.3 
Statistical Methods..............................................................................33 
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9.7.4 
Sequence of Analyses.........................................................................33 
9.8 
Quality Control ...................................................................................34 
9.8.1 
Monitoring..........................................................................................34 
9.8.2 
Archiving............................................................................................34 
9.8.3 
Quality Assurance and Audit..............................................................34 
9.9 
Limitations of the Research Methods.................................................34 
9.10 
Other Aspects......................................................................................35 
10 
Protection of Human Subjects ............................................................35 
10.1 
Independent Ethics Committee or Institutional Review Board ..........35 
10.2 
Subject Information and Informed Consent .......................................35 
10.3 
Subject Identification and Privacy......................................................36 
10.4 
Health Authorities...............................................................................37 
11 
Management and Reporting of Adverse Events .................................37 
11.1 
Adverse Events ...................................................................................37 
11.2 
Severity of Adverse Events ................................................................38 
11.3 
Causality Assessment .........................................................................38 
11.4 
Recording of Adverse Events in the Case Report Form.....................39 
11.5 
Safety Reporting to the Study Sponsor...............................................39 
11.6 
Regulatory Reporting to the Health Authorities.................................42 
12 
Plans for Disseminating and Communicating Study Results .............42 
12.1 
Study Report(s)...................................................................................42 
12.2 
Publication..........................................................................................42 
13 
References...........................................................................................44 
14 
Appendices .........................................................................................47 
15 
Annexes ..............................................................................................56 
15.1 
Signature pages and responsible persons for the study ......................57 
Signature Page – Protocol Lead.........................................................................................58 
Signature Page –Coordinating Investigator .......................................................................59 
Signature Page – Principal Investigator.............................................................................60 
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List of Tables
Table 1 
Schedule of Assessments and Evaluations .........................................28 
List of Figures
Figure 1 
Study Overview ..................................................................................23 
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2
List of Abbreviations
AE
Adverse Event
AR
Adverse Reaction
ARR
Annualized Relapse Rate
CI
Confidence Interval
CRF
Case Report Form
CRO
Contract Research Organization
DMD
Disease Modifying Drug
eCRF
Electronic Case Report Form
EDSS
Expanded Disability Status Scale
HCP
Health Care Professional
ICF
Informed Consent Form
IEC
Independent Ethics Committee
,)1ȕ
Interferon beta
IRB
Institutional Review Board
MAH
Marketing Authorisation Holder
MS
Multiple Sclerosis
MusiQoL
Multiple Sclerosis International Quality of Life Questionnaire
Q1
First Quartile
Q3
Third Quartile
RRMS
Relapsing Remitting Multiple Sclerosis
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SD
Standard Deviation
SmPC
Summary of Product Characteristics
TSQM v II
Treatment Satisfaction Questionnaire for Medication Version II
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Name
Contact Details
Phone: 
E-mail: 
Phone 
E-mail:
Sponsor representative responsible for the study
Name, Title
Contact Details
Merck B.V.
Tupolevlaan 41-61 
1119 NW Schiphol-Rijk
The Netherlands 
Phone: 
Mobile: 
Fax: 
E-mail: 
  
Merck Serono s.a.s. 
37 rue Saint-Romain
69008 Lyon, France 
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PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

Interferon beta-1a 
 
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Name, Title
Contact Details
Phone: 
E-mail: 
  
Principal Biostatistician
Phone: 
E-mail:
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PPD
PPD
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3.1
Responsibilities of the Investigator
The Investigator is responsible for the conduct of the study at his/her site. He/She will ensure 
that the study is performed in accordance with the protocol and will ensure the quality and 
integrity of data, following all applicable international and national guidelines.
This non-interventional study will not interfere with treatment prescription by Investigators. 
Accordingly, the Investigator will decide in advance the best therapeutic strategy for each patient 
according to current practice, regardless of the potential participation of this patient in the study. 
Subsequently, if the prescribed treatment is in line with the study protocol, the Investigator will 
consider the possibility of including the patient in the study.
The Investigator is responsible for adverse reaction (AR) recording and reporting, as specified in 
Section 11.
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Abstract
Title
A Phase IV, prospective, multicenter, open label, uncontrolled, 
non-interventional, single arm study to measure treatment satisfaction 
of multiple sclerosis (MS) patients on Rebif® after discontinuing 
initial first-line treatment
Study 
acronym/Short title
MESTRE–MS (MEasuring Satisfaction of Treatment with REbif after 
initial treatment of MS)
Study Protocol 
Date / Version
07 Oct 2016/Version 2.0
Rationale and 
background
The purpose of this study is to investigate treatment satisfaction in MS 
patients, who have discontinued first-line MS oral or injectable MS 
medication, and have initiated treatment with Rebif. MS patients who 
are starting their first treatment for MS currently can be treated with 
various oral or injectable medications. When solely considering the 
route of administration of these medications it may appear that the oral 
treatments are more patient friendly and convenient than the injectable 
ones. In addition, certain weekly or daily first-line injection treatments 
may be preferred over thrice weekly injections for unknown reasons. In 
clinical trials, discontinuation rates due to adverse events (AEs) of 
dimethyl fumarate (Tecfidera®) and of teriflunomide (Aubagio®)
treated patients is 16% in both DEFINE and TENERE studies, 
respectively. Furthermore, injectable treatment discontinuation varies 
between 14% and 47%. It is important for patients to optimally utilize 
first-line MS treatment options before escalating therapy to more 
potentially dangerous second line therapies such as natalizumab,
fingolimod or alemtuzumab.
This Phase IV clinical study is being proposed to support decision 
making for health care professionals (HCPs) and patients who have 
decided to initiate MS treatment, and use arguments of patient 
friendliness and convenience for their decision. Therefore, in this study 
treatment satisfaction of Rebif is measured in MS patients who have 
discontinued their initial MS treatment, and who have decided to start 
Rebif as their follow-up treatment. Currently there is no information 
describing the experiences with discontinuation of oral or injectable 
medication and the initiation of the injectable therapy Rebif. This 
information is crucial for HCPs and patients to be able to make a well 
informed decision on what to expect of their treatment. In this study, 
by measuring treatment satisfaction before and after Rebif treatment
we aim to evaluate the difference in treatment satisfaction (as 
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perceived by the patient), reasons to stop initial treatment, and 
experience after alternative treatment initiation. 
The clinical trial will contribute to the vast amount of data there is of 
Rebif. This study will add the additional data on the perception of 
treatment convenience and reasons for discontinuation of oral or 
injectable first-line treatment.
Research question 
and objectives
Primary objective
x To determine the level of treatment satisfaction as measured with 
the Treatment Satisfaction Questionnaire for Medication Version II
(TSQM v II), in relapsing remitting MS (RRMS) patients who have 
discontinued their initial oral or injectable MS treatment, and have 
initiated treatment with Rebif.
Secondary objectives
x To evaluate the change in annualized relapse rate (ARR) in patients 
changing from initial oral or injectable forms of treatment to Rebif
x To assess therapy adherence to Rebif
x To determine the change in quality of life with Multiple Sclerosis 
International Quality of Life Questionnaire (MusiQoL) between 
Baseline, Month 6 and Month 12
x To document the reasons for discontinuation of initial MS treatment
x To evaluate the potential correlations between the following 
measurements: 
TSQM 
v II, 
ARR, 
adherence, 
reasons for 
discontinuation, MusiQoL and TSQM v II subscales
x To assess the difference between TSQM v II subscales between 
Baseline, Month 6 and Month 12.
Study Design
This is a
prospective, multicenter, open
label, uncontrolled, 
non-interventional, single arm study to measure treatment satisfaction 
of RRMS patients on Rebif after discontinuing initial first-line 
treatment.
This study consists of three visits:
x Visit 1: Baseline 
x Visit 2: Month 6
x Visit 3: Month 12
This study will enroll RRMS patients who have discontinued their oral 
or injectable first–line MS medication and have decided to initiate
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subcutaneous Interferon beta-1a (IFNȕ-1a) (Rebif) treatment before 
Baseline measurements. MusiQoL and TSQM v II will be measured at
Baseline, Month 6 and Month 12. Relapses and adherence will be 
assessed at Month 6 and Month 12. Adherence to Rebif therapy will be 
collected electronically using RebiSmart 2.0.
Since this is a non-interventional study, there will not be any study 
required clinical interventions and laboratory assessments.
Population
RRMS patients who have discontinued their initial MS treatment and 
for whom MS treatment is required according to the decision of the 
HCP and patient.
Inclusion Criteria:
The patient can be included when the patient
x Is male or female, 18 to 65 years of age (both inclusive), at the time 
of informed consent
x Is diagnosed with RRMS according to McDonald criteria 2010
x Has discontinued treatment with dimethyl fumarate (Tecfidera), 
teriflunomide 
(Aubagio), 
glatiramer 
acetate 
(Copaxone®),
LQWUDPXVFXODU
,)1ȕ-1a 
(Avonex®), 
pegylated 
interferon 
(Plegridy®), subcutaneous ,)1ȕ-1b (Betaferon®) or fingolimod 
(Gilenya®) within 6 months prior to Visit 1
x Is currently treated with Rebif using RebiSmart 2.0, for a maximum 
of 6 months prior to Visit 1
x Has a score on the Expanded Disability Status Scale (EDSS) 
between 0 to 5.0 inclusive
x Is willing and able to give informed consent.
Exclusion Criteria
The patient cannot be included when the patient
x Has known planned surgical procedures at the time of the informed 
consent that will prevent adherence to treatment with Rebif through 
RebiSmart 2.0
x Is diagnosed with primary progressive, secondary progressive, or 
progressive relapsing MS
x Is pregnant or lactating, or planning to become pregnant
x In the opinion of the Investigator has significant renal or hepatic 
impairment or other significant disease (e.g., cognitive or visual 
impairment) that would compromise adherence and completion of 
the study
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x Reports any reason that he/she cannot complete the 1 year study
x Has a history of hypersensitivity to natural or recombinant 
interferon, or any other component of the formulation
x Is contraindicated for the treatment with subcutanHRXV ,)1ȕ-1a 
therapy as per summary of product characteristics or currently 
approved specific country product information
x Has any other factor that in the opinion of the Investigator would 
make the subject unsuitable for participation in this study
x Have significant psychiatric symptoms that, in the opinion of the 
Investigator, would impact patient ability to comply with treatment 
recommendations.
Variables
The variables that will be evaluated in this study include 
demographics, MS history, prior and current medication, pertinent 
medical history, treatment satisfaction score determined with 
TSQM v II, ARR, treatment adherence, quality of life determined with 
MusiQoL questionnaire, reasons for discontinuation of previous 
therapy and AEs.
Primary Endpoint:
x Treatment satisfaction score determined with TSQM v II from 
Baseline to Month 6 and to Month 12.
Secondary Endpoints:
x ARR (after 12 months of Rebif treatment) 
x Adherence (after 6 and 12 months of Rebif treatment) 
x MusiQoL (compare Baseline with after 6 and 12 months of Rebif 
treatment) 
x Reason/s for discontinuation of initial MS treatment (oral or 
injectable).
Additional Secondary Endpoints: 
x Correlation between TSQM v II and ARR; TSQM v II and 
adherence; TSQM v II and reason for discontinuation
x Correlation between MusiQoL and ARR; MusiQoL and adherence; 
MusiQoL and reason for discontinuation
x Correlation between TSQM v II subscales and adherence
x Correlation between TSQM v II subscales and reasons for 
discontinuation
x Difference between TSQM v II subscales at Baseline and after 6 and 
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12 months of Rebif treatment
x ARR before study entry compared to ARR at study end 
x Association between ARR and treatment adherence.
Data Sources
The source of information will be data collected from the medical 
records, prescription records, laboratory reports and/or routine 
interview of patients. Data will be entered into the electronic case 
report form by the Investigator site staff. 
Study Size
133 patients diagnosed with RRMS will be enrolled (63 in the 
Netherlands, 40 in Switzerland and 30 in Belgium).
Sample size 
justification
A sample size of 106 subjects will be required to have 85% power to 
detect at least an 8 point difference in mean TSQM scores between 
Baseline and Month 6 or Month 12 measurements, with the standard 
deviation of 27.5 and a two sided significance level of 5%. Assuming a 
20% dropout rate, approximately 133 patients will be enrolled into the 
study in the Netherlands, Switzerland and Belgium.
Data Analysis
Statistical analysis will be mainly descriptive. Descriptive statistics (n, 
mean, standard deviation, median, first quartile [Q1], third quartile 
[Q3], minimum, maximum) will be provided for continuous variables. 
Frequencies and percentages will be presented for categorical and 
ordinal variables. Where appropriate, 95% confidence intervals (CIs) 
will be presented.
All analyses will be performed on subjects who received at least one 
dose of Rebif following enrollment in the study.
Primary Endpoint analysis: 
A paired two-sided t-test of the global satisfaction score (TQSM score)
will be used to test the null hypothesis that there is no difference in the 
global satisfaction score (TQSM score) between 6, 12 months and 
Baseline. The corresponding 95% two-sided CI will be presented.
Secondary Endpoint analysis:
ARR and its associated 95% CI before study entry and after 12 months 
of Rebif treatment will be summarized overall and by previous MS 
therapy.
Reasons for discontinuation of previous therapy and adherence after 6
and 12 months of Rebif treatment will be summarized descriptively 
and overall.
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Changes in MusiQoL after 6 and 12 months of Rebif treatment versus 
Baseline will be analysed using same methodology as for Primary 
Endpoint.
Analysis of additional Secondary Endpoints as correlation analysis 
between TSQM and MusiQoL versus ARR, adherence and reason for 
discontinuation will be described in the statistical analysis plan.
Milestones
First Patient First Visit (FPFV): September 2016
First Patient Last Visit (FPLV): September 2017
Last Patient First Visit (LPFV): September 2017
Last Patient Last Visit (LPLV): September 2018
Database lock: November 2018
Final Clinical Study Report: March 2019
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5
Amendments
None
6
Milestones
Milestone
Planned date
Start of data collection 
September 2016
End of data collection 
September 2018
Database lock
November 2018
Final report of study results 
March 2019
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Rational and Background
Multiple sclerosis (MS) is a chronic inflammatory, autoimmune, demyelinating disease that 
affects the central nervous system (1). Relapsing remitting MS (RRMS) is the most common 
type of MS, affecting approximately 80% to 85% of all patients with MS, and is characterized by 
unpredictable acute attacks (known as relapses) accompanied by worsening of symptoms, 
followed by periods of remission during which there is a full or partial recovery from the deficits
acquired during the relapse (2). Relapse activity is associated with an increased risk of disability 
progression (3), although disability can advance independently of relapse activity (secondary 
progressive MS) (4). The increasing number of first-line and second-line treatment options, 
together with the variable course of the disease and patient lifestyles and expectations, makes the 
therapeutic decision a real challenge (5).
Disease Modifying Drugs and Interferon beta –la (IFNȕ-1a) treatment
Treatment of RRMS typically consists of direct symptom management, brief corticosteroid 
administration for acute exacerbations, and the regular use of Disease Modifying Drugs (DMDs).
Currently approved immunomodulator treatments for RRMS include recombinant beta 
LQWHUIHURQV ,)1ȕ-1a, Avonex® ,)1ȕ-1a, Rebif®; ,)1ȕ-1b, Betaferon® and Extavia®) and 
glatiramer acetate (Copaxone®). Additional first-line immunosuppressant therapies include 
dimethyl fumarate (Tecfidera®) and teriflunomide (Aubagio®). Natalizumab (Tysabri®),
alemtuzumab (Lemtrada®), and fingolimod (Gilenya®) are also available for treatment of MS as 
second-line therapy in more severe disease (6), while in Switzerland fingolimod can be 
prescribed as first-line medication.
Interferons are a family of naturally occurring proteins that are produced by eukaryotic cells in 
response to viral infections and other biological inducers. Human interferons have 
anti-inflammatory, antiviral and antigrowth properties. They exert their biological effect by 
binding to specific receptors on the surface of cells, initiating a complex cascade of intracellular 
events; however the mechanism of action of IFNȕ-1a in MS remains unclear.
Rebif is a human IFNȕ-1a used for the treatment of MS. The amino acid sequence of Rebif is 
identical to the natural interferon derived from human fibroblasts. ,)1ȕ-1a is produced by 
recombinant deoxyribonucleic acid (DNA) technology using genetically engineered Chinese 
hamster ovary cells into which the human gene has been inserted (7,8).
Rebif Drug information
The currently marketed formulation of Rebif (,)1ȕ-1a) has been evaluated in a series of well
controlled MS studies which have demonstrated that Rebif significantly reduces clinical attack 
rate, magnetic resonance image lesion activity, accumulation of new lesion burden, and disability
progression (9,10,11,12,13). Rebif is the only disease modifying agent for MS available today to 
have demonstrated efficacy on all four of these efficacy measures in RRMS. Long term data 
have also demonstrated that Rebif at either 22 mcg or 44 mcg three times a week maintains these
clinical benefits in a dose related manner (14,15,16) and that high frequency administration, 
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i.e., three times a week, at the highest dose available, i.e., 44 mcg, provides more clinical benefit 
than 30 mcg administered once a week (17).
Existing data show that, overall, Rebif is well tolerated at the doses intended for use in the MS
population, namely 44 mcg three times a week administered by the subcutaneous route. The 
22 mcg three times a week dosage is recommended for patients who cannot tolerate the high 
dose. Patients using Rebif are likely to experience the known undesirable effects to interferon,
such as influenza-like-syndrome; injection site reaction (from the common mild inflammatory 
reactions to the uncommon injection site necroses); asymptomatic
hepatic enzymes 
abnormalities, especially alanine aminotransferase elevation; white and red blood cell counts
decrease; and skin reactions, usually rash. The majority of adverse reactions (ARs) observed 
with Rebif is usually mild and reversible, and respond well to dose reductions. Details are 
disclosed in the currently approved product information (for further information, please see the 
summary of product characteristics (SmPC) (18).
Since its introduction in the market in 1998, the cumulative exposure to Rebif by end of March
2014 can be estimated to amount to more than 1,259,436 patient-years in the post marketing
setting. During 15 years of Rebif's post-marketing surveillance a series of adverse events (AEs) 
have been identified, such as ARs, including Quincke's edema, anaphylaxis, urticaria, serious 
cutaneous reactions, including Stevens-Johnson syndrome, hepatitis with or without icterus, or 
injection site infection and cellulitis, which could be severe, as with any protein therapeutic 
agent, cases of thrombotic microangiopathy including fatal cases, have been reported during 
treatment of MS with interferon beta products. Most thrombotic microangiopathy cases
presented as thrombotic thrombocytopenic purpura or haemolytic uraemic syndrome. Rebif 
therapy may induce the formation of antibodies. Despite the full significance of the formation of 
neutralizing antibodies remains unclear, it may represent an efficacy rather than a safety issue
(11,12,13,19,20,21,22,23,24,25).
An electronic, handheld, multidose, autoinjection device that incorporates a dosing history log 
has been developed to improve the injection experience, patient satisfaction and treatment 
adherence among patients self-administering subcutaneous
,)1ȕ-1a. In a multicentre, 
international user trial, this device was considered 'very suitable' or 'suitable' for self-injection by 
71.6% of patients and 92.2% reported some degree of suitability (26). The incidence of infusion 
site reactions was decreased with the autoinjector compared to manual injection, coupled with 
ease of use of the autoinjector, suggest that it could improve compliance, and therefore 
therapeutic outcomes in some patients (27). Cramer et al., showed the evidence of significant 
improvements in all subscales of the MS treatment concerns questionnaire, including global 
patient satisfaction (but with the exception of ‘flu-like’ symptoms), and all pain measures after 
patients with MS switched from using the RJ auto injector to the RJII device (28).
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Study Rationale
Since MS is a currently incurable, chronic disease, long term DMD therapy is required, 
necessitating commitment from patients to continue their treatment (29).
Patient’s and health care professionals (HCPs) decision for MS treatment frequently is based on 
subjective perception of convenience.
Some patients may need to discontinue their MS treatment due to lack of efficacy or side effects.
At present, there is limited real world information regarding which therapy provides the best 
clinical response in patients with RRMS following a switch (2).
MS patients who are starting their first treatment for MS currently can be treated with various
oral or injectable medications. When solely considering the route of administration of these 
medications it may appear that the oral treatments are more patient friendly and convenient than 
the injectable ones. In addition, certain weekly or daily first-line injection treatments may be 
preferred over thrice weekly injections for unknown reasons. In clinical trials, discontinuation 
rates due to AEs of dimethyl fumarate (Tecfidera) and of teriflunomide (Aubagio) treated 
patients are 16% in both DEFINE and TENERE studies, respectively. Furthermore, injectable 
treatment discontinuation varies between 14% and 47% (20). It is important for patients to 
optimally utilize first-line MS treatment options before escalating therapy to more potentially 
dangerous second line therapies such as natalizumab, fingolimod or alemtuzumab.
This Phase IV clinical study is being proposed to support decision making for HCPs and patients 
who have decided to initiate MS treatment, and use arguments of patient friendliness and 
convenience for their decision. Therefore, in this study treatment satisfaction of Rebif is 
measured in MS patients who have discontinued their initial MS treatment, and who have 
decided to start Rebif as their follow-up treatment. Currently there is no information describing 
the experiences with discontinuation of oral or injectable medication and the initiation of the 
injectable therapy Rebif. This information is crucial for HCPs and patients to be able to make a 
well informed decision on what to expect of their treatment.
The clinical trial will contribute to the vast amount of data there is of Rebif. This study will add 
the additional data on the perception of treatment convenience and reasons for discontinuation of 
oral or injectable first-line treatment.
Benefit-Risk Balance
The benefits clearly outweigh the risks of patients treated with Rebif (30). Patients and HCPs 
decision for MS treatment frequently is based on subjective perception of convenience. Currently 
there is no information describing the experiences with discontinuation of oral or injectable 
medication and the initiation of the injectable therapy Rebif. This information is crucial for 
HCPs and patients to be able to make a well informed decision on what to expect of their 
treatment. In this study, by measuring treatment satisfaction before and after Rebif treatment we 
aim to evaluate the difference in treatment satisfaction (as perceived by the patient), reasons to 
stop initial treatment, and experience after alternative treatment initiation. The current lack of 
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understanding to which DMD the patients can most optimally be transitioned justifies this study 
and will provide benefit for the patients.
8
Research Question and Objectives
The purpose of this study is to investigate treatment satisfaction of MS patients, who have 
discontinued first-line MS oral or injectable MS medication, and have initiated treatment with 
Rebif.
8.1
Primary Objective
To determine the level of treatment satisfaction as measured with the Treatment Satisfaction 
Questionnaire for Medication Version II (TSQM v II), in RRMS patients who have discontinued 
their initial oral or injectable MS treatment and have initiated treatment with Rebif.
8.2
Secondary Objectives
x To evaluate the change in annualized relapse rate (ARR) in patients changing from initial oral 
or injectable forms of treatment to Rebif
x To assess therapy adherence to Rebif
x To determine the change in quality of life with Multiple Sclerosis International Quality of Life 
Questionnaire (MusiQoL) between Baseline, Month 6 and Month 12
x To document the reasons for discontinuation of initial MS treatment
x To evaluate the potential correlations between the following measurements: TSQM v II, ARR, 
adherence, reasons for discontinuation, MusiQoL and TSQM v II subscales
x To assess the difference between TSQM v II subscales between Baseline, Month 6 and 
Month 12.
8.3
Other Objectives
None
9
Research Methods
9.1
Study Design
This is a prospective, multicenter, open label, uncontrolled, non-interventional, single arm study 
to measure treatment satisfaction of RRMS patients on Rebif after discontinuing initial first-line 
treatment.
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9.1.1
Design Overview
This is a Phase IV, prospective, multicenter, open label, uncontrolled, non-interventional, single 
arm study to measure treatment satisfaction of RRMS patients on Rebif after discontinuing initial
first-line treatment.
This study will enroll RRMS patients who have discontinued their oral or injectable first–line 
MS medication like dimethyl fumarate (Tecfidera), teriflunomide (Aubagio), glatiramer acetate 
&RSD[RQH LQWUDPXVFXODU ,1)ȕ-a (Avonex), pegylated interferon (Plegridy), subcutaneous 
,)1ȕ-1b (Betaferon) or fingolimod (Gilenya - if permitted as first-line in the country) and have
initiated
subcutaneous ,1)ȕ-a
(Rebif) before
Baseline measurements. Approximately 
133 patients will be enrolled at approximately 33 centers in Europe (the Netherlands, 
Switzerland and Belgium) over a period of 1 year. 
The reasons for discontinuing oral or injectable first-line MS treatment in daily clinical practice 
currently are not well described. Furthermore, the treatment satisfaction of patients who are 
treated with injectable MS medication after discontinuing oral treatment is unknown. Whether an 
association between treatment satisfaction or quality of life on the one hand and treatment 
adherence, ARR and reasons for discontinuation on the other exist also is not known and will be 
investigated as part of this study. 
As part of the secondary measures in this study ARR will be measured, and the potential 
association between clinical effect and medication change will be investigated. Furthermore, 
therapy adherence will be measured with RebiSmart 2.0 in MS patients who have discontinued 
their initial oral or injectable MS treatment and have decided to start Rebif treatment. In order to 
be able to analyze a broader spectrum of convenience perception and satisfaction of treatment 
also the MusiQoL questionnaire is completed by the patient and a potential correlation between 
these quality of life outcomes and clinical measures will be explored.
The study consists of 3 visits including Visit 1 (Baseline), Visit 2 (Month 6) and Visit 3
(Month 12). At Baseline, Month 6 and 12 visits, the TSQM v II and MusiQoL will be measured, 
and relapses and adherence will be measured at Month 6 and 12 visits. Adherence to Rebif 
therapy will be collected electronically using RebiSmart 2.0.
The reason for discontinuation of the initial treatment will be requested by the study team and 
documented in the patient file at the Baseline Visit. The collection of AEs will be a regular part 
of each visit and will be documented and communicated according to safety policies.
Since this is an observational study to observe the usual practice, there will not be any study 
required clinical interventions and laboratory assessments. 
Upon site initiation, each investigator site will enroll subjects who meet the eligibility criteria.
Enrollment will be in a consecutive manner until the site enrollment target is reached. The 
recruitment period is planned to be between September 2016 and September 2017. However, this 
may be extended if the recruitment target is not met. In this study subjects will be treated with 
Rebif three times weekly delivered through electronic autoinjector device (the RebiSmart 2.0).
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Treatment regimen will be as per Investigators routine practice and in accordance with the 
licensed SmPC label or currently approved specific country product information.
The study will receive approval from the governing institutional review board (IRB) or 
independent ethics committee (IEC) when required and in accordance with the ethical regulation 
of the country. 
An informed consent form (ICF) will be signed by the subject, and subjects are free to withdraw 
at any time without prejudice to their medical care, and that they are not obliged to state their 
reasons. The diagram below summarizes the study plan (see Figure 1).
Figure 1
Study Overview
TSQM v II = Treatment Satisfaction Questionnaire for Medication Version II
MusiQoL = Multiple Sclerosis International Quality of Life Questionnaire
MS = Multiple Sclerosis
9.1.2
Endpoints
9.1.2.1
Primary
x Treatment satisfaction score determined with TSQM v II from Baseline to Month 6 and to 
Month 12.
9.1.2.2
Secondary
Key Secondary Endpoints: 
x ARR (after 12 months of Rebif treatment)
x Adherence (after 6 and 12 months of Rebif treatment)
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x MusiQoL (compare Baseline with after 6 and 12 months of Rebif treatment)
x Reason/s for discontinuation of initial MS treatment (oral or injectable).
Additional Secondary Endpoints: 
x Correlation between TSQM v II and ARR; TSQM v II and adherence; TSQM v II and reason 
for discontinuation
x Correlation between MusiQoL and ARR; MusiQoL and adherence; MusiQoL and reason for 
discontinuation
x Correlation between TSQM v II subscales and adherence
x Correlation between TSQM v II subscales and reasons for discontinuation
x Difference between TSQM v II subscales at Baseline and after 6 and 12 months of Rebif 
treatment
x ARR before study entry compared to ARR at study end 
x Association between ARR and treatment adherence.
9.1.2.3
Others
None
9.2
Setting
This study will be conducted in 3 European countries: Belgium, Switzerland and the 
Netherlands. In this study, the patients diagnosed with RRMS will be enrolled at around 33 sites 
across Europe region.
9.2.1
Study Population
RRMS patients who have discontinued their initial MS treatment and for whom MS treatment is 
required according to the decision of the HCP and patient.
The study population will be identified according to the below inclusion and exclusion criteria. 
Inclusion Criteria:
The patient can be included in the study when the patient
x Is male or female, 18 to 65 years of age (both inclusive), at the time of informed consent
x Is diagnosed with RRMS according to McDonald criteria 2010
x Has discontinued treatment with dimethyl fumarate (Tecfidera), teriflunomide (Aubagio), 
glatiramer acetate (Copaxone), LQWUDPXVFXODU ,)1ȕ-1a (Avonex), pegylated interferon 
(Plegridy), subcutaneous ,)1ȕ-1b (Betaferon) or fingolimod (Gilenya) within 6 months prior 
to Visit 1
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x Is currently treated with Rebif, using RebiSmart 2.0 for a maximum of 6 months prior to 
Visit 1
x Has a score on the Expanded Disability Status Scale (EDSS) between 0 to 5.0 inclusive
x Is willing and able to give informed consent.
Exclusion Criteria:
The patient cannot be included when the patient
x Has known planned surgical procedures at the time of the informed consent that will prevent 
adherence to treatment with Rebif through RebiSmart 2.0
x Is diagnosed with primary progressive, secondary progressive, or progressive relapsing MS
x Is pregnant or lactating, or planning to become pregnant
x In the opinion of the Investigator has significant renal or hepatic impairment or other 
significant disease (e.g., cognitive or visual impairment) that would compromise adherence 
and completion of the study
x Reports any reason that he/she cannot complete the 1 year study
x Has a history of hypersensitivity to natural or recombinant interferon, or any other component 
of the formulation
x Is contraindicated for the treatment with subcutaneous ,)1ȕ-1a therapy as per SmPC or 
currently approved specific country product information
x Has any other factor that in the opinion of the Investigator would make the subject unsuitable 
for participation in this study
x Have significant psychiatric symptoms that, in the opinion of the Investigator, would impact 
patient ability to comply with treatment recommendations.
9.2.2
Definition of Study Cohorts and Description of Treatments
There are no study cohorts in this study.
Treatment
Subjects will be treated with Rebif three times weekly, delivered through an electronic 
autoinjector device (Rebismart 2.0). Treatment regimen will be as per Investigators routine 
practice and in accordance with the licensed SmPC label or currently approved specific country 
product information.
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9.2.3
Observation Period
Study observation period starts from subjects signing the informed consent and continues until
Visit 3 (Month 12). This is estimated to be about 12 months.
9.2.4
Frequency of Assessments
Table 1 summarizes the assessments in each visit. Further details of each are given in the 
subsequent sections.
This study consists of 3 visits. The study procedure and assessment contents are as follows:
x
Visit 1 (Baseline)
x
Visit 2 (Month 6)
x
Visit 3 (Month 12).
1.
Visit 1 (Baseline):
At the initial study visit, the subject will be informed of the study objectives and overall 
requirements, and written informed consent will be obtained prior to any study specific 
assessments. The subject will then undergo a brief clinical evaluation to ensure compliance with 
the inclusion and exclusion criteria to determine the eligibility (see Section 9.2.1).
The following data will be collected at Baseline Visit 
x
Demographic details including age, gender, height and weight
x
Current medical condition and past medical history including concomitant diseases
x
MS history (including relapses within 2 years before study entry)
x
Prior MS medication
x
Prior MS medication related AEs and associated concomitant medications
x
Vital signs
x
Physical examination
x
Neurological examination
x
TSQM v II evaluation
x
MusiQoL evaluation
x
Document reasons for discontinuation of previous MS therapy
x
Therapy with Rebif

Date of initiation of Rebif
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
Initial Dose of Rebif.
Visit 2 (Month 6):
At Visit 2, the treating physician will assess the patient within standard clinical routine practice.
The following data will be collected at Visit 2 (Month 6):
x
Vital signs
x
Physical examination
x
Neurological examination
x
Relapse assessment
x
TSQM v II evaluation
x
MusiQoL evaluation
x
Therapy with Rebif

Date and dose of Rebif

Details of dose adjustments of Rebif if any
x
Treatment adherence
x
Safety recording and reporting according to Section 11.4 and Section 11.5
x
MS medication related AEs and associated concomitant medications
Visit 3 (Month 12):
Visit 3 (Month 12) will be similar to the above described procedure for Visit 2 (Month 6). After 
the Month 12 visit the study ends. 
The following data will be collected at Visit 3 (Month 12):
x
Vital signs
x
Physical examination
x
Neurological examination
x
Relapse assessment
x
TSQM v II evaluation
x
MusiQoL evaluation
x
Therapy with Rebif

Date and dose of Rebif

Details of dose adjustments of Rebif if any
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x
Treatment adherence
x
Safety recording and reporting according to Section 11.4 and Section 11.5
x
MS medication related AEs and associated concomitant medications
Table 1
Schedule of Assessments and Evaluations
Activity
Visit 1
Baseline
Visit 2
Month 6
Visit 3
Month 12
(End of 
Study 
Visit)
Patient Informed Consent
X
Inclusion/Exclusion Criteria
X
Demographic information
X
Medical History / Concomitant diseases / Prior MS 
medications
X
Multiple Sclerosis History (including relapses within 2 years
before study entry)
X
MS medication related adverse events and associated 
concomitant medications
X
X
X
Vital Signs
X
X
X
Physical Examination
X
X
X
Neurological Examination
X
X
X
Relapse Assessment
X
X
TSQM Version II evaluation
X
X
X
MusiQoL evaluation
X
X
X
Document reasons for discontinuation of previous MS 
therapy
X
Therapy with Rebif
X
X
X
Evaluation of Adherence to Therapy
X
X
Safety Recording and Reporting
X
X
9.2.5
Withdrawal from the Study
Subjects are free to discontinue the study at any time without giving their reasons. Subjects will 
be withdrawn from the study for any of the following reasons:
x Subject is lost to follow up
x Occurrence of AE / serious adverse event (SAE), if discontinuation of Rebif is desired or 
considered necessary by the Investigator and/or the subject
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x There is an occurrence of an exclusion criterion
x Subject withdraws consent.
x Discontinuation of Rebif for any reason.
9.3
Variables
The variables that will be evaluated in this study include demographics, MS history, prior and 
current medication, pertinent medical history, treatment satisfaction score determined with 
TSQM v II, ARR, treatment adherence, quality of life determined with MusiQoL questionnaire,
reasons for discontinuation of previous therapy and AEs.
Primary Endpoint variables:
x
Treatment Satisfaction Questionnaire for Medication Version II (31)
TSQM v II was designed as a general measure of treatment satisfaction with medication, suitable 
for use across a wide variety of medication types and illness conditions. Findings in the 
development of this questionnaire indicated that the three dimensions on which patients evaluate 
their medication are: effectiveness, adverse effects and convenience. There was an additional 
overall satisfaction rating, representing individual balanced judgment across these three specific 
treatment attributes, potentially most predictive of patient satisfaction and adherence. The final 
version of the questionnaire is included in Appendix 1.
TSQM v II evaluation will be done at Baseline, Month 6 and Month 12.
Secondary Endpoint variables:
x
Annualized relapse rate
ARR is defined as the number of relapses per year and will be calculated using the below 
formula
Annualized Relapse Rate = (No. of Relapses / Time on Study) × 365.25
where, Time on Study (days) = (Date of Study Completion or Date of study discontinuation -
Date of first Rebif administration +1)
A relapse is defined as the appearance of a new clinical sign or symptom attributable to MS, or 
FOLQLFDOZRUVHQLQJRI D SUHYLRXVVLJQRUV\PSWRPWKDWKDGEHHQVWDEOH IRUGD\VDQGWKDW
SHUVLVWHGIRUKours without fever. Relapses are reported by the patient and confirmed by the 
treating physician. Generally this will occur within several days of the event but is left to the 
discretion of the neurologist to determine if the event should be recorded as a relapse. Criteria 
published in the literature describing symptoms accompanied by an increase of at least half a 
point in the EDSS score, of one point in each of two EDSS functional system scores, or of two 
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points in one EDSS functional-system score (excluding scores for the bowel–bladder or cerebral 
functional systems) will be provided to the physician prior to the initiation of the study but the 
final determination is made by the physician.
Relapse history will be collected at Baseline and relapse assessment will be done at Month 6 and 
Month 12. ARR before study entry will be compared to ARR at study end.
x
Multiple Sclerosis International Quality of Life Questionnaire (MusiQoL) (32)
To evaluate health-related quality of life, all subjects will be asked to complete the MusiQoL.
The MusiQoL is a disease-specific validated 31-item multi-dimensional, self-administered 
questionnaire. It has nine dimensions:
x Activities of daily living (ADL, 8 items);
x Psychological well-being (PWB, 4 items);
x Symptoms (SPT, 3 items);
x Relationships with friends (RFr, 4 items);
x Relationships with family (RFa, 3 items);
x Relationship with the healthcare system (RHCS, 3 items);
x Sentimental and sexual life (SSL, 2 items);
x Coping (COP, 2 items); and
x Rejection (REJ, 2 items).
Each item is scored from 1 (never/not at all) to 5 (always/very much) or 6 if not applicable.
Negatively worded item scores are reversed so that higher scores indicated a higher level of 
quality of life.
All nine dimensions are linearly transformed to a 0 to 100 scale, where 0 indicates the worst 
possible level of quality of life and 100 indicates the best level. The index score is computed as 
the mean of these subscales scores.
If fewer than half of the items were missing, the mean of the non-missing items is substituted for 
the missing items.
The final version of the questionnaire is included in Appendix 2.
MusiQoL evaluation will be done at Baseline Visit, Month 6 and Month 12. Baseline MusiQoL
score will be compared with after 6 and 12 months of Rebif treatment.
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x
Reasons for discontinuation of initial MS treatment 
Reasons for discontinuation of initial MS treatment will be collected at Baseline.
x
Treatment Adherence
Adherence to Rebif therapy will be collected electronically using RebiSmart 2.0. The data on 
adherence will be collected after 6 and 12 months of Rebif treatment.
Further details on Endpoints are provided in Section 9.1.2.
9.4
Data Source
The data to be collected in the study will be obtained by mean of an electronic case report form 
(eCRF). Data will be entered into the eCRF by the investigator site staff. Subjects will attend the 
investigator site for regular visits during their treatment with Rebif according to local clinical 
practice. Assessments conducted during these visits will be according to clinical practice. 
Table 1 defines assessments that the Investigator will enter in the eCRF if the assessments have 
been undertaken during subject visits. Demographic information, MS history, prior and current 
medication will be captured from the subjects medical records, prescription records, laboratory 
reports and/or routine interview of patients.
Subjects will complete the MusiQoL and TSQM v II questionnaires and the information will be 
transcribed into the eCRF by the investigator site staff.
All data collected during the course of this study must be documented in eCRF on an ongoing 
basis in a complete, accurate, legible and timely fashion. The data in the eCRF should be 
consistent with the relevant source documents. Further details are provided in Section 9.6.
9.5
Study Size
A sample size of 106 subjects will be required to have 85% power to detect at least an 8 point 
difference in mean TSQM scores between Baseline and Month 6 or Month 12 measurements,
with the standard deviation (SD) of 27.5 and a two sided significance level of 5%. Assuming a 
20% dropout rate, approximately 133 patients will be enrolled into the study in the Netherlands, 
Switzerland and Belgium.
9.6
Data Management
The main purpose of the eCRF is to obtain data required by the non-interventional study protocol 
in a complete, accurate, legible and timely manner. The data in the eCRF should be consistent 
with the relevant source documents.
Data protection and privacy regulations will be implemented in capturing, forwarding, 
processing, and storing subject data. Patients will provide written informed consent prior to data 
abstraction and any data handling procedures in accordance with local regulations. 
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A unique subject number will be assigned to each participating patient. This number will serve as 
the patient’s identifier in this observational study database.
The Investigator or designee is responsible for ensuring that the data collected in the course of 
this study is accurate and documented appropriately on all applicable forms. They will then be 
processed, evaluated, and stored in anonymous form in accordance with applicable data 
protection regulations. The Investigator must ensure that the eCRFs and any other associated 
documents forwarded to Sponsor or its designated organization contain no mention of any 
subject names.
The data will be entered into a validated database. The Sponsor/Contract Research Organization 
(CRO) or its designee will be responsible for data processing, in accordance with the 
Sponsor’s/CRO’s data management procedures. Quality control and data validation procedures 
will be applied to ensure the validity and accuracy of the database. The data management plan 
will detail the data entry, cleaning, clarification, and validation procedures to be followed by all 
relevant study staff. Database lock will occur once quality assurance procedures have been 
completed.
9.7
Data Analysis
All analyses will be performed on subjects who received at least one dose of Rebif following 
enrollment in the study.
Descriptive statistics (n, mean, SD, median, first quartile [Q1], third quartile [Q3], minimum, 
maximum) will be provided for continuous variables. Frequencies and percentages will be 
presented for categorical and ordinal variables. 
All data analyses will be performed by the CRO after the study is completed and the database is 
locked. Statistical programming and analyses will be performed using SAS 9.1.3 (or higher).
Detailed methodology for summary and statistical analyses of data collected in this study will be 
documented in a statistical analysis plan (SAP).
9.7.1
Analysis Sets
Safety Analysis Set:
Safety analysis set is defined as all the subjects who provided informed consent and who 
received at least one dose of study treatment.
9.7.2
Derived and Transformed Data
Missing information will be captured for quantitative as well as qualitative variables by the 
category “Missing” in the summary statistics. If there are no missing values this will be indicated 
by “0” unless otherwise specified. Missing data will not be imputed.
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9.7.3
Statistical Methods
The statistical analyses described in this section will be performed as further outlined in the SAP, 
which will be finalized prior to database lock and will be included in the clinical study report for 
this protocol. The final SAP will take into account any amendment to the protocol. 
General Statistical Methodology:
Descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, maximum) will be provided for 
continuous variables. Frequencies and percentages will be presented for categorical and ordinal 
variables. Where appropriate, 95% confidence intervals (CIs) will be presented.
All analyses will be performed on safety analysis set.
Primary Endpoint Analysis:
A paired two-sided t-test of the global satisfaction score (TQSM score) will be used to test the 
null hypothesis that there is no difference in the global satisfaction score (TQSM score) between 
6, 12 months and Baseline. The corresponding 95% two-sided CI will be presented.
Secondary Endpoints Analyses:
ARR and its associated 95% CI before study entry and after 12 months of Rebif treatment will be 
summarized overall and by previous MS therapy.
Reasons for discontinuation of previous therapy and adherence after 6 and 12 months of Rebif 
treatment will be summarized descriptively and overall.
Changes in MusiQoL after 6 and 12 months of Rebif treatment versus Baseline will be analysed 
using same methodology as for Primary Endpoint.
Analysis of additional Secondary Endpoints as correlation analysis between TSQM and 
MusiQoL versus ARR, adherence and reason for discontinuation will be described in the SAP.
9.7.4
Sequence of Analyses
No interim analysis will be carried out for this study.
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9.8
Quality Control
9.8.1
Monitoring
Risk based monitoring will be performed for this study. Risk based monitoring is the process of 
ensuring the quality of clinical trials by identifying, assessing, monitoring and mitigating the 
risks that could affect the quality or safety of a study. It can facilitate efficient trial delivery 
without compromising patient safety or data quality. A Sponsor or an appointed CRO will 
identify critical data and processes, performs a risk assessment and then develops a monitoring 
plan that focuses on the important and likely risks to critical data and processes.
A Sponsor or an appointed CRO Monitor may perform visits to the site, if required, at any time 
during the study. For hospitals where potential quality risks are identified, on-site visits can 
verify that the study is being carried out according to the protocol. 
9.8.2
Archiving
The archive should be maintained for the period specified by local regulations, where applicable. 
All original subject files (medical records) must be stored at the site (hospital, research institute, 
or practice) for the longest possible time permitted by the applicable regulations. In the absence 
of applicable regulations, the archive should be maintained for at least 5 years after the final 
study report or the first publication of study results, whichever comes later. In any case, the 
Investigator should ensure that no destruction of medical records is performed without the 
written approval of the Sponsor.
9.8.3
Quality Assurance and Audit
In compliance with regulatory requirements, the Sponsor, a third party on behalf of the Sponsor, 
regulatory agencies, or IEC/IRB may conduct quality assurance audits/inspections at any time 
during or following a study. The Investigator must agree to allow auditors/inspectors direct 
access to all study related documents, including source documents, and must agree to allocate his 
or her time and the time of his or her study staff to the auditors/inspectors in order to discuss 
findings and issues. 
The protocol, each step of the data capture procedure, and the handling of the data, as well as the 
eventual study report, will be subject to independent clinical quality assurance. Audits may be 
conducted at any time during or after the study to ensure the validity and integrity of the study 
data.
9.9
Limitations of the Research Methods
This study is open label and observational, and therefore has inherent limitations in terms of 
susceptibility to bias, confounding and restricting the ability to define causality. There is limited 
control over patient assessment as patient monitoring and diagnostics are per standard of care; no 
additional clinical monitoring is generally conducted. Patient specific methodological challenges 
such as potential biases from patient selection, loss of patients through study attrition, and overall 
patient recall are also other limitations. However, observational study strengths include that they 
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reflect daily clinical practice more closely than randomized controlled trials, both in terms of the 
heterogeneous patient populations that are included, and the medical interventions that they 
receive. Real-life observational data is essential to assess and improve clinical practice 
worldwide and complement randomized controlled trials by providing clinically-relevant, 
real-world data and provide considerable health economic information.
9.10
Other Aspects
None
10
Protection of Human Subjects
10.1
Independent Ethics Committee or Institutional Review 
Board
Prior to commencement of the study at a given site, the protocol will be submitted together with 
its associated documents (subject information and ICF in the languages to be used) to the 
responsible IEC/IRB for its favorable opinion/approval. The written favorable opinion/approval 
of the IEC/IRB will be filed by the Investigator and a copy will be sent to the Sponsor.
The study must not start at a site before the Sponsor has obtained written confirmation of 
favorable opinion/approval from the concerned IEC/IRB. The IEC/IRB will be asked to provide 
documentation of the date of the meeting at which the favorable opinion/approval was given, and 
of the members and voting members present at the meeting. Written evidence of favorable 
opinion/approval that clearly identifies the study, the protocol version, and the subject 
information and consent form version reviewed should be provided. Where possible, copies of 
the meeting minutes should be obtained.
Amendments to the protocol will also be submitted to the concerned IEC/IRB, before 
implementation in case of substantial changes.
10.2
Subject Information and Informed Consent
An unconditional prerequisite for a subject’s participation in the study is his/her written informed 
consent. The subject’s written informed consent to participate in the study must be given before 
any study related activities are carried out.
Adequate information must therefore be given to the subject by the Investigator before informed 
consent is obtained (a person designated by the Investigator may give the information, if 
permitted by local regulations). A subject information sheet in the local language will be 
provided by the Sponsor for the purpose of obtaining informed consent. In addition to providing 
this written information to a potential subject, the Investigator or his/her designee will inform the 
subject verbally of all pertinent aspects of the study (the language used in doing so must be 
chosen so that the information can be fully and readily understood by laypersons). Depending on 
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national regulations, a person other than the Investigator may inform the subject and sign the 
ICF.
The ICF must be signed and personally dated by the subject and the Investigator. The signed and 
dated declaration of informed consent will remain at the Investigator’s site, and must be safely 
archived by the Investigator. A copy of the signed and dated information and consent form 
should be provided to the subject prior to participation.
Whenever important new information becomes available that may be relevant to the subject’s 
consent, the written subject information sheet and any other written information provided to 
subjects will be revised by the Sponsor and be submitted again to the IEC/IRB for review and 
favorable opinion. The agreed, revised information will be forwarded to each subject in the 
study. The Investigator will explain the changes to the previous version.
10.3
Subject Identification and Privacy
A unique subject number will be assigned to each subject at inclusion. This number will serve as 
the subject’s identifier in the study as well in the study database.
The Investigator must ensure that the subjects’ anonymity is maintained. On the case report 
forms (CRFs) or other documents submitted to the Sponsor, subjects should not be identified by 
their names, but by their assigned identification numbers. If subject names are included on copies 
of documents submitted to the Sponsor, the names (except for initials) must be obliterated and 
the assigned subject numbers added to the documents.
The Investigator should keep a separate log of subjects’ identification numbers, names, 
addresses, telephone numbers and hospital numbers (if applicable). Documents not for 
submission to the Sponsor, such as signed ICFs, should be maintained in strict confidence by the 
Investigator.
Only authorized persons will have access to identifiable personal details, if required for data 
verification. The subject’s original medical data that are reviewed at the site during source data 
verification by the Monitor, audits, and Health Authority inspections will be kept strictly 
confidential. The Investigator agrees to provide direct access to these documents to the Sponsor 
and to Health Authority representatives. The Investigator is responsible for retrieving 
information from personal medical records.
Data protection and privacy regulations will be observed in capturing, forwarding, processing, 
and storing subject data. Subjects will be informed accordingly, and will be requested to give 
their consent on data handling procedures in accordance with national regulations.
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10.4
Health Authorities
The protocol and any applicable documentation (subject information and consent form) will be 
submitted or notified to the National Health Authorities in accordance with the regulations of the 
country or countries involved in the study.
11
Management and Reporting of Adverse Events
Safety of Rebif will mainly be evaluated by the recording of all AEs.
11.1
Adverse Events
Adverse Event
An AE is any untoward medical occurrence in a patient or clinical study subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be 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 considered related to the medicinal product.
Adverse Reaction
An AR is a response to a medicinal product which is noxious and unintended.
Response in this context means that a causal relationship between a medicinal product and an AE
is at least a reasonable possibility. 
ARs may arise from use of the product within or outside the terms of the marketing authorisation 
or from occupational exposure. Conditions of use outside the marketing authorisation include 
off-label use, overdose, misuse, abuse and medication errors.
Serious Adverse Event/Serious Adverse Reaction
A SAE/reaction is any AE/AR as defined above, which also fulfills at least one of the 
seriousness criteria below:
x
Results in death
x
Is life-threatening1)
x
Requires in-patient hospitalization or prolongation of existing hospitalization
x
Results in persistent or significant disability/incapacity
x
Is a congenital anomaly/birth defect
x
Is otherwise considered as medically important2)
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1)Life-threatening in this context refers to a reaction in which the patient was at risk of death 
at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if more severe.
2)Medical and scientific judgement should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalisation but might jeopardise the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation
or development of dependency or abuse.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious AR.
Events not to be considered as AEs
Medical conditions present at study start, that do not worsen in severity or frequency during the 
study are defined as Baseline medical conditions, and are NOT to be considered AEs.
11.2
Severity of Adverse Events
Investigators should assess the severity/intensity of any AEs as follows:
Mild:
The subject is aware of the event or symptom, but the event or symptom is 
easily tolerated.
Moderate:
The subject experiences sufficient discomfort to interfere with or reduce his or 
her usual level of activity.
Severe:
Significant impairment of functioning: the subject is unable to carry out usual 
activities.
11.3
Causality Assessment
Investigators must assess the causal relationship between AEs and study drug (including any 
other non-medicinal product, radiation therapy, etc.) considering temporal relationship between 
the AE onset and study drug administration, safety profile of study drug (known side effects), the 
patient's condition (medical history, underlying disease), concomitant medication, and study 
procedures.
Related:
Suspected to be reasonably related to any study medication. 
Not related: Not suspected to be reasonably related to any study medication. A reasonable 
alternative explanation must be available.
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11.4
Recording of Adverse Events in the Case Report Form
The recording period for AEs begins, when the subject is initially included in the study (date of 
signature of first informed consent) and continues until the End of the Study (Visit 3 or 
premature withdrawal).
All SAEs (related and not related) and non SAEs (related AEs) must be collected in the eCRF.
Each AE, as specified above, occurring during the study, must be documented by the 
Investigator within 24 hours of awareness and must be recorded in the eCRF, including its 
description, severity, duration (onset and resolution dates), causal relationship (i.e., confirmation 
that the AR is suspected to be reasonably related to the study treatment), any other potential 
causal factors, actions taken with the study drug (dose reduction, withdrawal), required 
treatment, and outcome. In addition, for all serious ARs, seriousness criteria must be documented 
and a specific safety report form must be completed and sent to the Sponsor, as described below
Death, disability, and hospitalization are considered outcomes in the context of safety reporting 
and not usually considered ARs/AEs. Therefore the primary cause of death, disability or 
hospitalization should be recorded and reported as an SAE/AR, and the outcome should be 
recorded in a separate data field. However, a term for the outcome will be selected if it is the 
only information reported or provides significant clinical information.
If death occurs, the primary cause of death or event leading to death should be recorded and 
reported as an SAE. “Fatal” will be recorded as the OUTCOME of this respective event and not 
be as separate event. Only, if no cause of death can be reported (for example, sudden death, 
unexplained death), the death per se might then be reported as an SAE.
Medication Errors, Overdose, Abuse, and Misuse
Events of medication errors, overdose, abuse and misuse of study drug are also to be recorded in 
the eCRF, even if occurring without AE.
Pregnancy and Lactation
If encountered on this study exposure to study drug during pregnancy or lactation is to be 
recorded in the eCRF and to be reported to the study sponsor. 
11.5
Safety Reporting to the Study Sponsor
Safety data collection forms:
The following safety data collection forms are used in this study:
x
SAE Report Form 
x
Pregnancy Report Form
x
Parent-Child/Foetus AE Report Form
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Reportable events:
The following events are reportable to the Safety Check Desk at CRO within 24 hours of 
awareness:
x
All SAEs (related or unrelated) are to be reported independent of their relationship to the 
study drug by using the SAE report form.
x
Non-serious ARs*)
x
Pregnancies to be reported independent of the relationship to an AE by using the 
Pregnancy Report Form.
x
All events that occur in a Child/Foetus of a pregnant woman who was exposed to the 
study drug are to be reported by using the Parent-Child/Foetus Report Form 
x
Special considerations including medication errors, overdose, abuse, misuse; exposure 
during pregnancy and/or lactation should be reported on the SAE report form by 
indicating whether serious or not. 
*) All non-serious suspected adverse drug reactions (related to any study medication) only need to be 
recorded in the eCRF; those are downloaded daily by the Sponsor into the Sponsor Global Drug 
Safety Database. 
Procedure for Safety Data Reporting (completion and forwarding): 
In the event of any new safety data that have to be reported as specified above, the Investigator 
must immediately (within 24 hours after becoming aware of the event) inform the Sponsor or its 
designee. For all events that require a written form to the Sponsor, the Investigator completes the 
respective Safety Data Collection Form within 24 hours in English and sends the report by email 
or fax to the CRO Safety Check Desk. The Investigator must respond to any request by CRO for 
follow-up information within the same timeline as noted above for initial reports for further 
forwarding the report to the Global Drug Safety. The sponsor has to meet strict regulatory 
timelines associated with expedited safety reporting obligations.
CRO Safety Check Desk:
x
Email: 
CRO mailbox address, ideally as per project
x
Fax:
CRO Fax number, ideally as per project
Global Drug Safety: 
x
Email: 
x
Fax: 
The data entered on the safety data collection forms must be consistent with the information 
recorded in the eCRF. If some data are missing, the form should be completed with the available 
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data and a follow-up report will be sent as soon as possible. The minimum information to be 
included in the initial report is the following:
x Investigator name and contact details
x Subject identification (e.g., ID number, sex, age)
x Product (including lot/ batch number)
x Description of SAE/ Adverse Drug Reaction/ Special considerations
The report should contain causality and seriousness information (for AEs) and must be signed off 
by the Investigator.
When AE information is communicated via telephone, a written/electronic data capture (EDC)
report must be sent immediately within 24 hours thereafter by fax or e-mail. In such cases the
“clock start” for case reporting to Health Authorities is the date and time of the telephone 
communication. 
Exposure during Pregnancy
All pregnancies with an estimated conception date in the period from the date of informed 
consent signature (where applicable) until the last post-treatment safety visit, or as defined in the
protocol, must be recorded by convention in the AE page/section of the eCRF. The same rule
applies to pregnancies in female subjects and to pregnancies in female partners of male subjects. 
The Investigator must notify the Sponsor in an expedited manner of any pregnancy using the 
Pregnancy Report Form, which must be transmitted according to the same process as described 
for SAE reporting. The Sponsor must be notified about any pregnancy independent whether the 
pregnancy is associated with an AE or not.
Investigators must actively follow up, document, and report to the Sponsor on the outcome of all 
these pregnancies and deliveries even if the subject is withdrawn from the study. If an abnormal 
outcome occurs, the respective safety data collection form (Pregnancy Report Form, 
Parent-Child/Foetus AE Report Form) is to be completed and sent to the Sponsor.
Procedure for Follow-up information
The Investigator must promptly respond to any request for follow-up information or questions 
from the Sponsor or delegate (e.g. CRO). Such requests will be sent to the Investigator via the 
CRO Safety Check Desk. SAEs occurring during the study must be monitored and followed up 
by the Investigator until stabilization or until the outcome is known, unless the subject is lost to 
follow-up.
The Investigator will ensure any necessary additional therapeutic measures and follow-up 
procedures are recorded and reported via a follow-up report form. For all serious cases missing 
information such as outcome, confounders, and causality is to be provided. Additionally, follow-
up information of non-serious adverse drug reactions may be required by the Sponsor for 
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medical assessment. Reasonable attempts to obtain follow-up information must be made and 
documented.
Reporting of any new information on a previously reported SAE or non-serious adverse drug 
reaction (follow-up) will follow the procedures and timelines of the original report.
11.6
Regulatory Reporting to the Health Authorities
Expedited reporting of SAEs and non-serious adverse drug reactions to Health Authorities is 
performed by the Sponsor local drug safety officer/Pharmacovigilance responsible at shared 
service center according to applicable global and local requirements. 
Serious ARs, including those associated with the comparator drug (if applicable), will be 
expedited by the Sponsor to Health Authorities according to local regulations, which usually 
require a maximum period of 15 days.
In addition, the Investigator will comply with any applicable local pharmacovigilance 
requirements to report appropriate safety data, to national pharmacovigilance systems (e.g. 
Yellow Card Scheme in UK), as required by country specific reporting requirements. 
12
Plans for Disseminating and Communicating Study Results
After completion of the study, the selected CRO shall prepare a final report of study results, in 
close collaboration with the coordinating Investigator and the Sponsor.
All publications and presentations should be based on the final study report.
All information provided by the Sponsor regarding this study will be the sole property of the 
Sponsor and must be considered as confidential. No confidential information will be disclosed to 
third parties without the prior written consent of the Sponsor and it will be used only for 
conducting this study.
12.1
Study Report(s)
The completed study will be summarized in a final report that accurately and completely presents 
the study objectives, methods, results, limitations of the study, and interpretation of the findings.
12.2
Publication
The first publication will be a publication of the results of the analysis of the Primary Endpoint 
that will include data from all study sites.
The Investigator will inform the Sponsor in advance about any plans to publish or present data 
from the study. Any publications and presentations of the results (abstracts in journals or 
newspapers, oral presentations, etc.), either in whole or in part, by Investigators or their 
representatives will require pre-submission review and approval by the Sponsor.
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The Sponsor will not suppress or veto publications, but maintains the right to delay publication 
in order to protect intellectual property rights.
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13
References
1.
Calabresi PA. Diagnosis and management of multiple sclerosis. Am Fam Physician 2004; 
70: 1935-44.
2.
Bergvall N, Makin C, Lahoz R, et al. Relapse rates in patients with multiple sclerosis 
switching from interferon to fingolimod or glatiramer acetate: a US claims database study.
PLoS One. 2014;9(2): e88472.
3.
Lublin FD, Baier M, Cutter G. Effect of relapses on development of residual deficit in 
multiple sclerosis. Neurology 2003;61: 1528–32.
4.
Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an 
international survey. National Multiple Sclerosis Society (USA) Advisory Committee on 
Clinical Trials of New Agents in Multiple Sclerosis. Neurology 1996;46: 907–11.
5.
Lugaresi A, di Ioia M, Travaglini D, et al. Neuropsychiatr Dis Treat. 2013;9:893-914.
6.
Gasperini C, Ruggieri S, Mancinelli CR, et al. Advances in the treatment of relapsing-
remitting multiple sclerosis - critical appraisal of fingolimod. Ther Clin Risk Manag.
2013;9 73–85.
7.
Dhib-Jalbut S, Marks S. Interferon-beta mechanisms of action in multiple sclerosis. 
Neurology 2010; 74(Suppl 1): S17–24.
8.
Cree BAC. Multiple sclerosis. In: Brust JCM, ed. Current Diagnosis and Treatment in 
Neurology. New York: Lange Medical Books/McGraw-Hill Medical; 2007.
9.
PRISMS Study Group. Randomized double-blind placebo-controlled study of interferon 
beta-1a in relapsing/remitting multiple sclerosis. Lancet. 1998;352(9139):1498-504.
10.
Li DK, Paty DW, PRISMS Study Group. Magnetic resonance imaging results of the 
PRISMS study: A randomized, double-blind, placebo-controlled study of interferon beta-1a 
in relapsing-remitting multiple sclerosis. Ann Neurol. 1999;46(2):197-206.
11.
PRISMS Study Group and the University of British Columbia MS/MRI Analysis Group. 
PRISMS-4: Long-term efficacy of interferon beta-1a in relapsing MS. Neurology 
2001;56(12):1628-36.
12.
SPECTRIMS Study Group, Hughes RAC. Randomized controlled study of interferon beta-
1a in secondary progressive MS: Clinical results. Neurology. 2001;56(11):1496-504.
13.
Panitch H, Goodin D, Francis G, et al. Benefits of high-dose, high-frequency interferon 
beta-1a in relapsing-remitting multiple sclerosis are sustained to 16 months: final 
comparative results of the EVIDENCE trial. J Neurol Sci. 2005;239(1):67-74.
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14.
Trapp BD, Peterson J, Ransohoff RM, et al. Axonal transection in the lesions of multiple 
sclerosis. N Engl J Med. 1998;338(5):278-85.
15.
Alam J, McAllister A, Scaramucci J, et al. Pharmacokinetics and Pharmacodynamics of 
interferon beta-1a (IFNB-1a) in healthy volunteers after intravenous, subcutaneous or 
intramuscular administration. Clin Drug Invest. 1997; 14(1):35-43.
16.
Ferguson B, Matyszak MK, Esiri MM, et al. Axonal damage in acute multiple sclerosis 
lesions. Brain. 1997;120 ( Pt 3):393-9.
17.
Barkhof F, Filippi M, Miller DH, et al. Comparison of MRI criteria at first presentation to 
predict conversion to clinically definite multiple sclerosis. Brain. 1997;120(Pt 11):2059-69.
18.
Rebif solution for injection in cartridges-SPC, Last Updated on eMC 16-Jul-2015.
19.
Acheson ED. Epidemiology of multiple sclerosis. Br Med Bull. 1977;33(1):9-14.
20.
Devonshire V, Lapierre Y, Macdonell R, et al. The Global Adherence Project (GAP): A
multicenter observational study on adherence to disease-modifying therapies in patients 
with relapsingremitting multiple sclerosis. Eur J Neurol. 2011;18: 69-77.
21.
PRISMS Study Group. Randomized double-blind placebo-controlled study of interferon 
beta-1a in relapsing/remitting multiple sclerosis. Lancet. 1998;352(9139):1498-504.
22.
Panitch H, Goodin DS, Francis G, et al. Randomized, Comparative Study of Interferon 
beta-1a Treatment Regimens in MS: The EVIDENCE Trial. Neurology 2002;59(10): 1496-
506.
23.
Giovannoni G, Barbarash O, Casset-Semanaz F, et al. Safety and immunogenicity of a new 
formulation of interferon beta-1a (Rebif New Formulation) in a Phase IIIb study in patients 
with relapsing multiple sclerosis: 96-week results. MultScler. 2009;15(2):219-28.
24.
Neutralizing antibodies during treatment of multiple sclerosis with interferon beta-1b: 
experience during the first three years. IFNB Multiple Sclerosis Study Group, University of 
British Columbia MS/MRI Analysis Group. Neurology. 1996;47:889-94.
25.
Rudick R, Simonian N, Alam J, et al. Incidence and significance of neutralizing antibodies 
to interferon beta-1a in multiple sclerosis. Neurology.1998;(50):1266-72.
26.
Devonshire V, Arbizu T, Borre B, et al. Patient-rated suitability of a novel electronic 
device for self-injection of subcutaneous interferon beta-1a in relapsing multiple sclerosis: 
an international, single-arm, multicentre, Phase IIIb study. BMC Neurol. 2010, 
Apr 30;10:28.
27.
Mikol D, Lopez-Bresnahan M, Taraskiewicz S, et al. A randomized, multicentre, open-
label, parallel-group study of the tolerability of interferon beta-1a (Rebif) administered by 
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auto injection or manual injection in relapsing-remitting multiple sclerosis. MultScler. 
2005;11:585-91.
28.
Cramer JA, Cuffel BJ, Divan V, et al. Patient satisfaction with an injection device for
multiple sclerosis treatment. ActaNeurol Scand. 2006;113:156-62
29.
Gasperini C, Ruggieri S, Mancinelli CR, et al. Advances in the treatment of relapsing-
remitting multiple sclerosis - critical appraisal of fingolimod. Ther Clin Risk Manag.
2013;9 73–85.
30.
Filippini G, Del Giovane C, Vacchi L, et al. Comparative efficacy and risk-benefit balance 
of modulator and suppressant drugs of the immune system in people with multiple sclerosis 
(MS). Cochrane Database Syst Rev. 2013;Jun 6;6:CD008933.
31.
Atkinson MJ, Kumar R, Cappelleri JC et al. Hierarchical construct validity of the treatment 
satisfaction questionnaire for medication (TSQM version II) among outpatient pharmacy 
consumers. Value Health. 2005; Nov-Dec;8:S9-S24.
32.
Simeoni M, Auquier P, Fernandez O et al.; MusiQoL study group. Validation of the
Multiple Sclerosis International Quality of Life questionnaire. Mult Scler. 2008 
Mar;14(2):219-30.
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14
Appendices
1.
Appendix 1: TSQM Version II Questionnaire
Treatment Satisfaction Questionnaire for Medication (TSQM) Version II
Instructions:
Please take some time to think about your level of satisfaction or dissatisfaction with the 
medication you are taking in this clinical study. We are interested in your evaluation of the 
effectiveness, side effects, and convenience of the medication over the last two to three weeks, or 
since you last used it. For each question, please place a single check mark next to the response 
that most closely corresponds to your own experiences.
1. How satisfied or dissatisfied are you with the ability of the medication to prevent or treat
the condition?
1 Extremely Dissatisfied
2 Very Dissatisfied
3 Dissatisfied
4 Somewhat Satisfied
5 Satisfied
6 Very Satisfied
7 Extremely Satisfied
2.
How satisfied or dissatisfied are you with the way the medication relieves symptoms?
1 Extremely Dissatisfied
2 Very Dissatisfied
3 Dissatisfied
4 Somewhat Satisfied
5 Satisfied
6 Very Satisfied
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7 Extremely Satisfied
3.
As a result of taking this medication, do you experience any side effects at all?
1 Yes
0 No
4.
How dissatisfied are you by side effects that interfere with your physical health and ability
to function (e.g., strength, energy levels)?
1 Extremely Dissatisfied
2 Very Dissatisfied
3 Somewhat Dissatisfied 
4 Not Applicable 
5 Slightly Dissatisfied
6 Not at all Dissatisfied
5.
How dissatisfied are you by side effects that interfere with your mental function (e.g., 
ability to think clearly, stay awake)?
1 Extremely Dissatisfied
2 Very Dissatisfied
3 Somewhat Dissatisfied
4 Slightly Dissatisfied
5 Not at all Dissatisfied
6.
How dissatisfied are you by side effects that interfere with your mood or emotions (e.g., 
anxiety/fear, sadness, irritation/anger)?
1 Extremely Dissatisfied
2 Very Dissatisfied
3 Somewhat Dissatisfied
4 Slightly Dissatisfied
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5 Not at all Dissatisfied
7.
How satisfied or dissatisfied are you with how easy the medication is to use?
1 Extremely Dissatisfied
2 Very Dissatisfied
3 Dissatisfied
4 Somewhat Satisfied
5 Satisfied
6 Very Satisfied
7 Extremely Satisfied
8.
How satisfied or dissatisfied are you with how easy it is to plan when you will use the 
medication each time?
1 Extremely Dissatisfied
2 Very Dissatisfied
3 Dissatisfied
4 Somewhat Satisfied
5 Satisfied
6 Very Satisfied
7 Extremely Satisfied
9.
How satisfied or dissatisfied are you by how often you are expected to use/take the 
medication?
1 Extremely Dissatisfied
2 Very Dissatisfied
3 Dissatisfied
4 Somewhat Satisfied
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5 Satisfied
6 Very Satisfied
7 Extremely Satisfied
10.
How satisfied are you that the good things about this medication outweigh the bad things?
1 Extremely Dissatisfied
2 Very Dissatisfied
3 Dissatisfied
4 Somewhat Satisfied
5 Satisfied
6 Very Satisfied
7 Extremely Satisfied
11.
Taking all things into account, how satisfied or dissatisfied are you with this medication?
1 Extremely Dissatisfied
2 Very Dissatisfied
3 Dissatisfied
4 Somewhat Satisfied
5 Satisfied
6 Very Satisfied
7 Extremely Satisfied
SCALE SCORING ALGORITHM: TSQM Scale scores range from 0 to 100 and no computed 
score should be lower or higher than these limits.
())(&7,9(1(66>,WHP,WHPí@GLYLGHGE\î
SIDE EFFECTS: ([Sum RI,WHPWR,WHPí@ divided by 12) × 100
If one item is missing: ([(Sum of the two completed LWHPVí@GLYided by (8) × 100
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&219(1,(1&(>6XPRI,WHPWR,WHPí@ divided by 18) × 100
If one item is missing: ([(Sum of the two completed LWHPVí@GLYLGHGE\î
GLOBAL SATISFACTION: ([Sum of Item 10 WR,WHPí@GLYLGHGE\î
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2.
Appendix 2: Multiple Sclerosis International Quality of Life (MusiQoL) Questionnaire
Quality of Life Questionnaire: MusiQoL Version 5.4
You are invited to complete this questionnaire concerning different aspects of your life with MS. 
It is anticipated that this will help towards a better understanding of the real impact of your 
health problems. 
Please answer the questions by ticking (¥) or checking (_) the box that describes best your 
feelings during the last 4 weeks. 
Some questions relate to your private life; these are necessary to evaluate all aspects of your 
health. However, if you think that a question is not relevant to you, or if you do not want to 
answer a question, please move on to the next one. 
C O N F I D E N T I A L
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Interferon beta-1a
MESTRE–MS Study
EMR200136_597
Due to your MS, during the past 4 weeks, have you…
For each question, check the response that is closest to your 
feelings
Never 
Not at 
all
Rarely 
A little
Sometimes 
Somewhat
Often 
A lot
Always 
Very 
much
1
Had difficulty walking or moving outside?
2
Had difficulty with outdoor activities: i.e. shopping, going 
out to a movie?
3
Had difficulty walking or moving around at home?
4
Been troubled by your balance or walking problems?
5
Had difficulty with leisure activities at home: i.e. do-it-
yourself, gardening?
6
Had difficulty with your occupational activities: i.e. 
integration, interruption, limitation?
7
Been quickly tired?
8
Been short of energy?
9
Felt anxious?
10
Felt depressed or gloomy?
11
Felt like crying?
12
Felt nervous or irritated by a few things or situations?
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Interferon beta-1a
MESTRE–MS Study
EMR200136_597
Due to your MS, during the past 4 weeks, have you…
For each question, check the response that is closest to 
your feelings
Never 
Not at 
all
Rarely 
A little
Sometimes 
Somewhat
Often 
A lot
Always 
Very 
much
13
Been troubled by loss of memory?
14
Had difficulty concentrating: i.e. when reading, 
watching a film, following a discussion?
15
Been 
troubled 
by 
your 
vision: 
worsened 
or 
unpleasant?
16
Experienced unpleasant feelings: i.e. hot, cold?
17
Talked with your friends?
18
Felt understood by your friends?
19
Felt encouraged by your friends?
20
Talked with your spouse/partner or your family?
21
Felt understood by your spouse/partner or your 
family?
22
Felt encouraged by your spouse/partner or your 
family?
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Interferon beta-1a
MESTRE–MS Study
EMR200136_597
Due to your MS, during the past 4 weeks, have you…
For each question, check the response that is closest to 
your feelings
Never 
Not at 
all
Rarely 
A little
Sometimes 
Somewhat
Often 
A lot
Always 
Very 
much
23
Felt satisfied with your love life?
24
Felt satisfied with your sex life?
25
Felt that your situation is unfair?
26
Felt bitter?
27
Been upset by the stares of other people?
28
Been embarrassed when in public?
29
Been satisfied with the information on your disease 
or the treatment given by the doctors, nurses, 
psychologists… taking care of your MS?
30
Felt 
understood 
by 
the 
doctors, 
nurses, 
psychologists… taking care of your MS?
31
Been satisfied with your treatments?
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Interferon beta-1a
MESTRE–MS Study
EMR200136_597
15
Annexes
None
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Interferon beta-1a
MESTRE–MS Study
EMR200136_597
15.1
Signature pages and responsible persons for the study
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Interferon beta-1a
MESTRE–MS Study
EMR200136_597
Signature Page – Principal Investigator
Study Title
A Phase IV, prospective, multicenter, open label, 
uncontrolled, non-interventional, single arm study to 
measure treatment satisfaction of multiple sclerosis 
(MS) patients on Rebif after discontinuing initial 
first-line treatment
Study Protocol Date / Version
07 Oct 2016 / Version 2.0
Center Number
Principal Investigator
I, the undersigned, am responsible for the conduct of the study at this site and affirm that I 
understand and will conduct the study according to the study protocol, any approved protocol 
amendments, Good Pharmaco-epidemiology Practices (GPP) and all applicable Health Authority 
requirements and national laws.
_____________________________________
____________________________
Signature
Date of Signature
Name, academic degree:
Function / Title:
Institution:
Address:
Telephone number:
Fax number:
E-mail address:
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