Study design of PANGAEA 2.0, a non-interventional study on RRMS patients to be switched to fingolimod
Ziemssen et al. BMC Neurology
Study design of PANGAEA 2.0, a non- interventional study on RRMS patients to be switched to fingolimod
Tjalf Ziemssen 1
Raimar Kern 1
Christian Cornelissen 0
0 Novartis Pharma GmbH , Roonstr. 25, D-90429 Nuernberg , Germany
1 Zentrum für klinische Neurowissenschaften, Klinik und Poliklinik für Neurologie, Universitätsklinikum Carl Gustav Carus Dresden, Technische Universität Dresden , Fetscherstr. 43, D-01307 Dresden , Germany
Background: The therapeutic options for patients with Multiple Sclerosis (MS) have steadily increased due to the approval of new substances that now supplement traditional first-line agents, demanding a paradigm shift in the assessment of disease activity and treatment response in clinical routine. Here, we report the study design of PANGAEA 2.0 (Post-Authorization Non-interventional GermAn treatment benefit study of GilEnyA in MS patients), a non-interventional study in patients with relapsing-remitting MS (RRMS) identify patients with disease activity and monitor their disease course after treatment switch to fingolimod (Gilenya®), an oral medication approved for patients with highly active RRMS. Method/Design: In the first phase of the PANGAEA 2.0 study the disease activity status of patients receiving a disease-modifying therapy (DMT) is evaluated in order to identify patients at risk of disease progression. This evaluation is based on outcome parameters for both clinical disease activity and magnetic resonance imaging (MRI) , and subclinical measures, describing disease activity from the physician's and the patient's perspective. In the second phase of the study, 1500 RRMS patients identified as being non-responders and switched to fingolimod (oral, 0.5 mg/daily) are followed-up for 3 years. Data on relapse activity, disability progression, MRI lesions, and brain volume loss will be assessed in accordance to 'no evidence of disease activity-4' (NEDA-4). The modified Rio score, currently validated for the evaluation of treatment response to interferons, will be used to evaluate the treatment response to fingolimod. The MS management software MSDS3D will guide physicians through the complex processes of diagnosis and treatment. A sub-study further analyzes the benefits of a standardized quantitative evaluation of routine MRI scans by a central reading facility. PANGAEA 2.0 is being conducted between June 2015 and December 2019 in 350 neurological practices and centers in Germany, including 100 centers participating in the sub-study. Discussion: PANGAEA 2.0 will not only evaluate the long-term benefit of a treatment change to fingolimod but also the applicability of new concepts of data acquisition, assessment of MS disease activity and evaluation of treatment response for the in clinical routine.
Multiple sclerosis; Relapsing remitting; Fingolimod; Efficacy; Safety; Modified Rio score; NEDA; No evident disease activity; Clinical routine
In recent years, the therapeutic options for patients with
Multiple Sclerosis (MS) have steadily increased.
Substances such as Fingolimod (Gilenya®) supplement the
traditional first-line agents interferon (IFN) and
glatiramer acetate, offering physicians the opportunity to
optimize individual MS-treatment [
]. The safety and
tolerability profile of fingolimod and natalizumab is well
understood. However, experience with new treatment
options such as alemtuzumab, dimethylfumarate, and
teriflunomide is limited in comparison to former
approved substances, and especially data on the safety and
tolerability of sequentially changed disease-modifying
therapies (DMTs) are mostly not available. Since defined
treatment algorithms for individual patients have not yet
been developed, many MS patients may continue to
receive suboptimal treatment for long periods of time.
To optimize treatment, a switch to a more effective
medication generally needs to be considered if patients
do not respond to or fail with their current therapy [
It is well accepted that the earlier in MS pathogenesis
the therapy is adjusted (in the lower Expanded Disability
Status Scale [EDSS [
]] range up to 3), the higher would
be the benefit on long-term outcomes because MS
progression might be more difficult to slow down at later
]. Since magnetic resonance imaging (MRI)
parameters frequently assessed during therapy are
sensitive markers to identify patients who are insufficiently
responding to therapy , quantitative scoring systems
incorporating relapses and MRI activity have been
suggested as valuable diagnostic tools in clinical routine.
Among them, Lublin et al. [
] defined disease activity at
a particular time point on the basis of clinical relapses
and MRI activity in the previous 12 months. Sormani et
] modified the Rio score [
] to define treatment
response based on relapse activity and MRI activity over a
period of 1 year of treatment. However, the data
underlying the modified Rio score was obtained from clinical
studies on IFN-β [
], and the modified Rio score has
not been evaluated for other therapies or under real-life
conditions. Other scoring systems have been developed
that assess parameters besides relapse and MRI activity,
but there is currently no consensus among MS experts
on the most sensitive measures applicable in clinical
practice for identifying patients on suboptimal treatment
With the possibility to optimize treatment by
sequentially applying novel and highly effective MS
therapeutics, the MS community is increasingly accepting ‘no
evidence of disease activity’ (NEDA) as an early objective
for individual treatment. This new treatment paradigm
is based on the view that the mere reduction of relapse
rate and the attenuation of disease progression can no
longer be accepted as sufficient in clinical routine.
Therefore, NEDA was defined as no relapse activity,
no EDSS progression, and no new MRI lesions (T1
Gd + and/or active T2 lesion; [
]). Since these
measures may not be able to address all aspects of
the disease [
7, 15, 16
], brain volume loss (BVL) has
been suggested as fourth NEDA measure (NEDA-4)
to provide a more comprehensive and early picture of
the focal and diffuse damage occurring in MS. MS
experts recently proposed to further expand the
current concept of NEDA to include
neuropsychological aspects as well as other subclinical measures
with a potential predictive value for treatment
response . In daily clinical routine, implementation
of NEDA-4 as a treatment outcome goal,
complemented by these subclinical measures might therefore
offer the possibility of an early optimization of
Based on these considerations, we planned PANGAEA
2.0 (Post-Authorization Non-interventional GermAn
treatment benefit study of GilEnyA in MS patients), a
non-interventional study (NIS) to assess the benefits of a
treatment change to fingolimod in patients identified as
not responding to or having treatment failure with their
current therapy. Fingolimod is approved in over 80
countries for the treatment of adult patients with rapidly
progressing, severe RRMS or adult patients with high
levels of disease activity despite treatment with at least
one DMT [
]. As of Oct. 2015, it is estimated that
fingolimod has been used to treat approximately 134,000
patients, summing up to a total exposure of over
265,000 patient years . The well-established safety
profile of fingolimod is currently being expanded by
realworld data obtained during our predecessor study
], which included RRMS patients who were
either untreated or pre-treated with medications available
at study initiation. Since further novel substances have
subsequently been approved [
], PANGAEA 2.0 will
provide additional and more comprehensive data on the
safety of fingolimod in pretreated patients.
In this paper, we present the study protocol of
PANGAEA 2.0 and propose a comprehensive,
multidimensional approach for MS patient evaluation. By this
approach, we will assess the long-term benefits of a
treatment change to fingolimod in 1500 RRMS patients
identified as being non-responders or failing their
current first-line therapy. Disease activity at a given time
point will be determined according to the criteria of
] to identify sub-optimally treated patients.
During a 3-year observational phase, treatment response
to fingolimod will be evaluated by the modified Rio
] and by parameters that are based on both the
treatment objectives of NEDA-4 [
] and the 2D
Focussed Disability Scale (2D FDS) as part of our
multidimensional approach for MS patient evaluation. The
2D FDS comprises clinical and subclinical measures
representing both the patient’s and the physician’s
perspectives. To handle the resulting amount of data and to
assist neurologists in executing the complex processes
required for MS diagnosis, treatment initiation, and
long-term therapy, the software-based MS management
system MSDS3D will be employed [
Furthermore, a sub-study will assess the potential benefits of an
independent analysis of routine MRI scans by a central
reading facility. MRI analyses will additionally comprise
quantitative MRI parameters such as brain lesion
volume and brain lesion volume loss (BVL) that are
generally not part of routine MRI data analysis. Consequently,
PANGAEA 2.0 will expand the existing safety and
efficacy profile of fingolimod and evaluate the clinical
applicability of novel concepts for the evaluation of the
patient status and treatment response in clinical routine
. PANGAEA 2.0 was started in June 2015 and is
planned to continue until December 2019 in 350
neurological practices and centers in Germany, including 100
centers participating in the sub-study.
PANGAEA 2.0 is a multicenter non-interventional study
(NIS) in RRMS patients who switched to fingolimod
(oral, 0.5 mg daily [
]) because of non-responsiveness
to or treatment failure with their current therapy.
Accordingly, the PANGAEA 2.0 main study is divided in
two phases, an evaluation of the current patient status
to identify sub-optimally treated RRMS patients and, if
these patients are switched to fingolimod, an
observational prospective phase of up to 3 years (Fig. 1). The
aims of the study are to assess the clinical applicability
of the criteria of Lublin [
] to define disease activity as
well as the modified Rio score [
] to evaluate treatment
response (Fig. 2), and to investigate the long-term
benefits of a treatment change to fingolimod, as assessed by
parameters that are based on the treatment objectives of
NEDA-4 (Fig. 3; [
]). The study further aims at
investigating the power of a systematic collection of clinical
and subclinical measures that represent the physician’s
and the patient’s perspective (2D FDS, Fig. 4). The
PANGAEA 2.0 sub-study will additionally evaluate the benefits
of standardized MRI analyses obtained from a central
reading facility in daily clinical routine. The study started
in June 2015 and will end in December 2019. Recruitment
will end in December 2016 or after enrollment of 1500
patients who switched to fingolimod (Fig. 1).
PANGAEA 2.0 is conducted in line with the FSA
], the joint recommendations of the BfArM
(Federal Institute for Drugs and Medical Devices) and
the Paul-Ehrlich-Institute on planning, conducting, and
evaluating observational studies [
], and the VFA
(Research-based Pharmaceutical Companies)
recommendations on improving the quality and transparency of
]. The Ethics Committee of the Dresden
University of Technology approved PANGAEA 2.0. The study
is registered at the BfArM as NIS 6532 (https://
A total of 1500 female and male patients diagnosed
with RRMS [
] whose therapy is switched to
fingolimod (after evaluation of patient status) are being
included in PANGAEA 2.0. In Germany,
MSprevalence is approximately 150 cases per 100,000
residents (122,000 cases; [
]). Approximately 70 % of
patients are currently receiving DMTs. In a
retrospective analysis [
], 34 % of patients receiving
DMTs experienced at least one relapse (28,900).
Therefore, approximately 5 % of patients with active
disease (1500) are considered to be appropriate to
investigate the benefits of a treatment switch to
fingolimod. According to data provided by IMS Health, a
commercial vendor of prescription drug information
(source: IMS Xponent MAT 08/2014), most MS
patients (98 %) in Germany are treated in 2800
centers. Therefore, the number of 350 centers
participating in PANGAEA 2.0 seems to be sufficient to ensure
the representativeness of MS treatment strategies.
For the first phase of PANGAEA 2.0 (evaluation of the
patient status), participants are eligible if they were
diagnosed with RRMS [
] and have been treated with an
approved DMT except fingolimod, or in case of rapidly
progressing, severe RRMS, currently untreated patients
will also be included. Disease activity is required to be
confirmed according to Lublin (Fig. 2; [
]), and patients
are required to provide informed consent. To include
patients in the second phase of the study, the physician has
to decide to switch treatment to fingolimod or to
prescribe fingolimod as initial treatment due to high level of
disease activity. Prescription of fingolimod or other DMTs
is independent of the potential study participation.
Reimbursement of physicians was calculated in
accordance with governmental regulations and approved by an
independent ethics committee. There are no exclusion or
selection criteria except for the fingolimod
contraindications as listed and described in the product characteristics
]. Eligible patients will be enrolled in the
sequence in which they present at the physician’s
Only patients who switch to fingolimod will be
prospectively followed-up in the 3-year observational phase.
Patients not switching to fingolimod after the initial
study visit as well as patients who discontinue
fingolimod treatment during the 3-year follow-up can be
documented as part of the MSDS3D database, but will
discontinue study documentation of PANGAEA 2.0.
The study design of PANGAEA 2.0 is outlined in Table 1.
In a first phase at visit 0 the current patient status before
a potential switch to fingolimod is evaluated. Patients
that switch to fingolimod after the initial visit 0 enter a
3 year observational second phase starting with the
documentation of the first dose at visit 1. In the
observational phase, study visits are scheduled every 3 months
(visit 2–14), as recommended by the German Society of
The evaluation of patient status (visit 0) includes the
documentation of demographic data, disease history
and clinical characteristics, the assessment of disease
activity according to Lublin et al. (Fig. 2, Table 1; [
also includes the assessment of a wide range of
functional domain parameters (2D FDS; Fig. 4), clinical
parameters as well as patient reported outcomes,
representing both the physician’s [
3, 37, 38
] and the
patient’s perspectives [
Patients who are identified as non-responding to or
failing treatment with their current therapy and are switched
to fingolimod treatment continue documentation in visit
1. According to the summary of product characteristics
(SmPC) the switch to fingolimod requires several pre- first
dose observations as well as first dose monitoring as
described previously [
]. Clinical parameters such as blood
cell counts, liver function values, ophthalmological and
pulmonological examinations, the documentation and
assessment of cardiac diseases and concomitant medication
as well as the assessment of the Varicella zoster virus
immune status and the pregnancy status are recommended
before the first dose of fingolimod and documented in
visit1. The monitoring of the first dose of fingolimod
includes a 12-channel ECG at before and 6 h after the first
dose. Heart rate, blood pressure, and symptoms of
bradycardia are examined at 1 h intervals during the post-dose
period. In case of the occurrence of clinical relevant
cardiac symptoms, clinical management is initiated according
to the product information [
]. First-dose monitoring
is also required if fingolimod therapy has been interrupted
and is re-initiated.
During the 3-year observational phase (visits 2–14
[Fig. 1, Table 1]), data on relapses and disability
progression as well as MS activity, including MRI lesions and
MS-related BVL are regularly obtained and interpreted
according to the modified Rio-score (Fig. 2; [
NEDA-4 (Fig. 3; [
]). For the calculation of the
modified Rio-score, a cut-off of four MRI lesions to identify
responder/non-responder was applied. In addition,
clinical and subclinical measures included in the 2D FDS
are evaluated at month 6, 12, 24, and 36 (Fig. 4, Table 1).
Premature discontinuation and interruption of therapy
along with the reasons therefor and the date of last
administration will be documented at any study visit.
Investigators will document the occurrence of adverse
events at every study visit beginning at visit 1 after
switch to fingolimod. Adverse events are defined and
will be handled as described previously [
In the PANGAEA 2.0 sub-study, 100 MS centers will
submit MRI data obtained in accordance with a
standardized protocol to a central reading facility (Mediri
GmbH, Heidelberg) for qualitative and quantitative
evaluation (Fig. 4). Results including data on the number
and volume of Gd + T1 lesions, T2/FLAIR hyperintense
lesions, new or enlarging hyperintense T2/FLAIR
lesions, T1 hypo-intense lesions, and changes of the brain
volume will then be reported to the treating physician
immediately after evaluation (within approximately 5–7
To collect data and to assist physicians to document and
manage all visits and examinations, the MSDS3D will be
]. Data will be recorded by the physician or
MS nurse responsible either using the web-based
MSDS3D electronic case report form or using the locally
installed MSDS3D software, both collecting data into the
same database. Anonymity of data and content
protection are ensured by a complex security process
including an encrypted data transfer .
Electronic measures of communication facilitate
analysis and interpretation of data and are well accepted by
]. The MSDS3D interface displays a
vertical timeline and horizontally arranged boxes
representing procedures to be executed (e.g., documentation of
EDSS, patient questionnaires). The corresponding data
input menu can be directly opened from these boxes,
and additional procedures can be added to a selected
visit. Green color indicates that a procedure has been
completed by the MS nurse (e.g., patient questionnaire,
SDMT) or the treating neurologist (e.g., EDSS, adverse
effects). When all procedures of a visit have been
completed, the visit is set as ‘approved’, and data can be
transferred to the central PANGAEA 2.0 database.
Entries will be automatically controlled for plausibility at
the time of data entry and daily reviewed by the database
coordinator. All data management processes will be
overseen by the data management team of the Clinical
Research Organization responsible (Winicker Norimed
GmbH Medical Research).
Descriptive statistics will be used for analysis of data.
The full analysis set used for analysis includes all
patients switching to fingolimod with at least one available
post-dose data recording. Median, mean ± standard
deviation, minimum, maximum, 5 % percentile, 1st quartile,
3rd quartile, 95 % percentile, number of valid and
missing values will be presented in tabular form. For nominal
and ordinal-level data, distributions of absolute and
relative frequencies will be reported. Incidence rates of all
safety outcomes will be evaluated for the patient
population switching to fingolimod. For all analyses, the SAS®
Version 9.2 will be used.
Here, we report the study design of PANGAEA 2.0, a
multicenter NIS on disease active RRMS patients whose
therapy is switched to fingolimod. In its first phase, this
study evaluates the patient status to support the
identification of patients at risk of disease progression. In the
second phase, 1500 patients who switch to fingolimod
(after the first patient status evaluation) are entering a
3year observation period. The study is conducted at 350
neurological practices and MS centers in Germany,
including 100 centers participating in the PANGAEA 2.0
sub-study on the benefits of a standardized quantitative
MRI analysis in daily clinical routine. PANGAEA 2.0
aims not only to expand the fingolimod safety and
effectiveness profile, but also to evaluate the applicability
of measures for the assessment of treatment response
and disease activity in routine clinical conditions.
With the possibility of optimizing individual MS
treatment by switching to a more effective medication
before severe neurological deterioration occurs the
identification of non-responders to the current MS
therapy has gained fundamental importance. However,
without a standardized definition of non-responders
for clinical routine, the decision when to switch
therapy is challenging. Prediction of treatment efficacy
based exclusively on the traditional measures relapse
rate and EDSS progression has been shown to be of
limited value [
]. Since frequent MRI has been
demonstrated to predict non-response to IFN-β at early
], Rio et al. proposed a combined
assessment of clinical relapses, EDSS progression, and
active MRI lesions after 1 year of treatment [
on the observation that patients who were positive
for two of these three parameters had a higher
probability of disability progression and relapse activity,
Sormani et al. [
] proposed the modified Rio Score
(Fig. 2). The modified Rio score combines short-term
changes (during 1 year of IFN-β treatment) in relapse
frequency and MRI lesions as a surrogate marker for
long-term disability progression [
]. Patients are
classified as high, medium, and low-risk patients
according to the number of relapses and new T2 lesions
within 1 year of IFN-β treatment. Medium-risk
patients are then re-assessed after 1.5 years of treatment
. The modified Rio score then allows to identify
patients at risk for non-responding to IFN-β
treatment in the long-term [
In 2014, Lublin et al. [
] refined the established MS
phenotypes by adding disease activity as an additional
descriptor of MS pathogenesis. Active disease is defined
by relapses, acute or sub-acute episodes of new or
increasing neurological dysfunction during the previous
12 months, or contrast enhancing T1 or new or
unequivocally enlarging T2 hyperintense lesions. In
PANGAEA 2.0, the criteria of Lublin will be employed to
assess disease activity at visit 0 in order to identify
patients at risk of non-response, while the modified Rio
score will be used to evaluate treatment response during
the first year of treatment (Fig. 2). Signs of disease
activity or progression might then indicate the need to
initiate therapy of treatment-naïve patients or to switch
therapy of patients who are not responding to their
current medication. Since the modified Rio score has
not been used to identify patients who are not
responding to therapies other than IFN-β, PANGAEA 2.0 will
provide further insights into the applicability of this
score to evaluate treatment response to fingolimod in
NEDA has evolved both as a concept for treatment
success of individual MStreatment [
] and as an
outcome measure of DMTs in clinical trials [
]. Cohen et
] assessed the proportion of IFN-β1a and
fingolimod-treated patients who achieved NEDA after
1 year and 2 years of treatment (defined as no relapses,
no 3-month confirmed disability progression, and no
MRI activity) and found a higher NEDA-proportion
among fingolimod-treated patients than among
IFNβ1a-treated patients, as well as an increased
NEDAproportion among the IFN-β1a group after the switch to
fingolimod. Importantly, the authors demonstrated the
value of NEDA assessment during the first year of
treatment for the prediction of long-term outcomes.
However, there is still controversy with regards to the most
relevant measurements for the assessment of treatment
response in RRMS patients. Other scores using different
algorithms taking disability progression, relapses, and
MRI assessments into account to evaluate a treatment
response have also been proposed [
11, 12, 25, 58
Due to the complexity and the heterogeneous
course of the disease, additional outcome measures
such as BVL have been suggested to complement the
NEDA criteria. BVL begins at early MS-stages and is
associated with disability progression and cognitive
]. Since treatment effects on BVL
correlate with those on disability progression, this
parameter might provide predictions of future outcomes
]. In this study, we will therefore assess
treatment response according to the NEDA-4 parameters
(relapse rate, MRI activity, BVL, disability progression
[Fig. 3]) as well as subclinical measures summarized
in the 2D FDS (Fig. 4). Since deterioration not only
occurs in the motor, visual, and sensory systems, this
scale additionally includes cognitive changes, mood
swings, fatigue, bowel and bladder function, sexual
dysfunction, quality of life, as well as work
productivity and activity to obtain a comprehensive picture of
the patient’s disease status [
]. All the above
measures,, are integrated into our proposed approach for
patient evaluation aimed to comprise optimal patient
management, ‘state of the art’ evaluation of patient
status, and quantitative evaluation of MRI in daily
clinical practice (Fig. 4).
For the assessment of NEDA-4 parameters a frequent
MRI monitoring (e.g., annual), carried out under
standardized conditions is required. We have therefore
planned a sub-study that evaluates the value of routine
MRI scans performed in accordance with a standardized
protocol to ensure comparability of results. MRI scans
are examined by a central reading facility to consistently
obtain quality controlled standardized quantitative
results according to lesion number, lesion volume and
brain volume (Fig. 4).
The processing of large quantities of data obtained in
this study demands intense data management [
MSDS3D software already employed in the predecessor
study PANGAEA [
] allows the documentation and
management of visits and examinations as well as the
integration of data input from different sources. The
MSDS3D-PANGAEA 2.0 module will assist physicians
in all processes required for the identification of
patients at risk of disease progression and potential
fingolimod switch patients (Fig. 4; [
The main objective of PANGAEA 2.0 is to expand
the knowledge on the safety and effectiveness of a
switch to fingolimod in RRMS patients who are
notresponding to or having treatment failure with their
current MS medication. In the predecessor study,
PANGAEA, most RRMS patients who started
fingolimod (Gilenya®) therapy had been pretreated with
injectable BRACE therapies (Betaferon®, Rebif®, Avonex®,
Copaxone®, Extavia®) or natalizumab (Tysabri®). Few
patients were treatment naïve at the time of inclusion or
pretreated with Azathioprine (Imuran®)/Mitoxantrone
(Novantron® and Mitoxantron Ebewe®). Other substances
such as alemtuzumab (Lemtrada®), dimethyl fumarate
(Tecfidera®), and teriflunomide (Aubagio®) have been
approved since the end of the PANGAEA recruitment phase.
PANGAEA 2.0 will therefore provide new information on
the safety of fingolimod in RRMS patients pretreated with
these therapies in routine clinical practice. Furthermore,
the predecessor study, PANGAEA [
], focused on the
post approval fingolimod safety profile, comprising
precautions to treatment and first dose monitoring, as well as
on parameters regarding global symptomatology (CGI
]) and disability (EDSS [
]). PANGAEA 2.0 will hence
add useful information on the effectiveness of fingolimod
by additionally assessing early and subtle signs of disease
activity, including data on MRI activity and BVL, as
well as on subclinical changes in, for example,
cognition, fatigue, and activity (Fig. 4). Valuable data on
comparative DMT effectiveness have recently been
obtained by registry-based research such as MSBase
]. Since registry- and trial-based
research are subject to different requirements, the
comparison of results will provide additional information
on the effectiveness of different treatment algorithms.
In summary, PANGAEA 2.0 will assess not only the
long-term benefit of a treatment change to fingolimod,
but also the applicability of clinical and subclinical
parameters and definitions for the assessment of disease
activity, as defined by Lublin et al., disability progression
and treatment response evaluated by the he modified
Rio score, the definition of individual treatment concepts
according to NEDA-4, and the clinical and subclinical
measures of 2D FDS [
]. The data to be obtained in
PANGAEA 2.0 will expand the existing safety and
effectiveness profile of fingolimod and will contribute to the
establishment of novel concepts of decision making in
2D FDS, 2D Focussed Disability Scale; BfArM, Federal Institute for Drugs and
Medical Devices; BVL, brain volume loss; CGI, Clinical Global Impression; DMT,
disease-modifying therapy; EDSS, Expanded Disability Status Scale; EQ-5D,
EuroQuol-5D; FSMC, Fatigue Scale for Motor Fatigue and Cognitive Functions;
IFN, interferon; MRI, magnetic resonance imaging; MS, Multiple Sclerosis;
NEDA4, no evidence of disease activity-4; NIS, non-interventional study; PANGAEA 2.0,
Post-Authorization Non-interventional GermAn treatment benefit study of
GilEnyA in MS patients; RRMS, relapsing-remitting MS; SDMT, symbol digit
modality test; SmPC, summary of product characteristics; UKNDS, United
Kingdom Neurological Disability Scale; VFA, Research-based Pharmaceutical
Companies; WPAI-MS, work productivity and activities impairment
Financial support for medical editorial assistance was provided by Novartis
Pharma GmbH. We thank Dr. Stefan Lang for his medical editorial assistance
with this manuscript.
This observational study is sponsored by Novartis Pharma GmbH,
TZ developed the study design, which is part of this manuscript, and
contributed to this manuscript. RK participated in the design of the study
and contributed to the manuscript. CC initiated the drafting of the report
and wrote the manuscript. All authors read and approved the final
Tjalf Ziemssen has served on scientific advisory boards, and has received scientific
grants and speaker honoraria from Bayer, Biogen Idec, Genzyme, TEVA, Merck
Serono and Novartis. Raimar Kern has received speaker honoraria from Bayer,
Biogen Idec, Genzyme, TEVA, Merck Serono and Novartis. Christian Cornelissen is
an employee of the Novartis Pharma GmbH, Nuremberg, Germany.
Ethics approval and consent to participate
The Ethics Committee of the Dresden University of Technology approved
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