The PANGAEA study design – a prospective, multicenter, non-interventional, long-term study on fingolimod for the treatment of multiple sclerosis in daily practice
Ziemssen et al. BMC Neurology
The PANGAEA study design - a prospective, multicenter, non-interventional, long-term study on fingolimod for the treatment of multiple sclerosis in daily practice
Tjalf Ziemssen 0
Raimar Kern 0
0 Zentrum für klinische Neurowissenschaften, Klinik und Poliklinik für Neurologie, Universitätsklinikum Carl Gustav Carus Dresden, Technische Universität Dresden , Fetscherstr. 43, D-01307 Dresden , Germany
Background: Fingolimod (Gilenya®) is an oral medication for patients with highly active relapsing-remitting Multiple Sclerosis (RRMS). Clinical trials and post-marketing experience on more than 114,000 patients have established a detailed safety profile. Total patient exposure now exceeds 195,000 patient-years as stated in the last financial report (Dec 2014) of the Novartis Pharma AG, Basel, Switzerland. However, less is known about the safety of long-term fingolimod use in daily practice. Here, we describe the study design of PANGAEA (Post-Authorization Non-interventional German sAfety of GilEnyA in RRMS patients), a prospective, multicenter, non-interventional, long-term study to collect safety, efficacy, and pharmacoeconomic data on RRMS patients treated with fingolimod (0.5 mg/daily) under real-world conditions in Germany. Methods: PANGAEA is striving to assess a real-world safety and efficacy profile of fingolimod, based on data from 4,000 RRMS patients, obtained during a 60-month observational phase. A pharmacoeconomic sub-study of 800 RRMS patients further collects patient-reported outcome measures of disability, quality of life, compliance, treatment satisfaction, and usage of resources during a 24-month observational phase. Descriptive statistical analyses of the safety set as well as of stratified subgroups such as patients with concomitant diabetes mellitus and pretreated patients (e.g., natalizumab) will be conducted. Discussion: PANGAEA seeks to confirm the current safety profile of fingolimod obtained in phase I-III clinical trials. The study design presented here will additionally provide guidance on the therapeutic use of fingolimod in clinical practice and possibly assists physicians in making evidence-based decisions.
Multiple sclerosis; Relapsing remitting; RRMS; Fingolimod; Gilenya; Efficacy; Safety; Pharmacoeconomics; PANGAEA
In Europe, fingolimod (Gilenya®) has been approved as
an oral disease-modifying therapy (DMT) both for
patients who have a highly active relapsing-remitting MS
(RRMS) despite previous treatment with at least one
DMT, and for patients who have a rapidly evolving
severe RRMS .
Fingolimod is the prodrug of a sphingosine 1-phosphate
(S1P) receptor agonist  that undergoes phosphorylation
by sphingosine kinase in vivo . Phosphorylated
fingolimod interacts with S1P receptors expressed on the surface
of immune cells, neurons, and cells of the cardiovascular
system, leading to subsequent receptor internalization
from the cell membrane. Fingolimod then induces
polyubiquitination and degradation of internalized S1P
receptors, thereby preventing immune cells expressing S1P
receptors from sensing the S1P gradient between
lymphnodes and periphery and, hence, from exiting the
lymphoid tissue . This prevention consequently results in a
long-term functional antagonism that differentially affects
subsets of lymph-node immune cells and per se attenuates
autoimmune pathology [5, 6]. In MS, the mechanism of
action of fingolimod prevents infiltration of autoreactive
lymphocytes into the central nervous system. Preclinical
data further suggest that fingolimod has also direct effects
in the central nervous system, reducing demyelination
and promoting remyelination .
In 2010, two phase-III studies, FREEDOMS  and
TRANSFORMS , demonstrated the efficacy of
fingolimod in patients with RRMS. FREEDOMS, a
placebocontrolled trial, showed a relative reduction of the relapse
rate by 54 % to 60 % with corresponding effects on
disability progression and magnetic resonance imaging
(MRI)-related measures . These beneficial effects on
relapse rate were reproduced by FREEDOMS II .
TRANSFORMS then demonstrated superiority of
fingolimod over treatment with intramuscular interferon
beta1a, with significantly lower relapse rates and better MRI
Adverse events reported for patients treated with
fingolimod might be caused by its interaction with S1P
receptors both inside and outside the immune system. The
first dose of fingolimod needs to be applied under
medical supervision because heart rate and atrioventricular
conduction time might decrease within the first hours
after the first application of fingolimod [11, 12]. The risk of
certain infections might be increased by a dose-dependent
but reversible reduction of blood-lymphocyte counts by
fingolimod , but the overall rate of infections under
fingolimod is similar to placebo . However, since two
fatal cases of varicella-zoster virus infection were reported
in fingolimod-treated patients, , varicella-zoster virus
immune status has to be assessed before fingolimod
treatment initiation. In certain subsets of patients, such as
patients with diabetes mellitus or a history of
ophthalmological abnormalities, fingolimod has been further
associated with macular edema that occurred in 0.4 % of
fingolimod-treated patients and usually resolves after
discontinuation of medication [8, 9, 14].
The experience both in clinical trials and in the
postmarketing setting now exceeds 114,000 fingolimod-treated
patients or 195,000 patient-years on fingolimod . This
experience has established a well-characterized safety and
efficacy profile of fingolimod. However, validity for the
real-world treatment setting might be considered being
different to the situation in clinical trials due to the number
of patients enrolled and selection criteria applied [11, 16].
We therefore sought to obtain a more generalizable safety
and efficacy profile on the basis of long-term experience
with fingolimod in daily routine practice. To address the
above mentioned and other safety cenocerns, a detailed
data acquisition and monitoring algorithm taking the Risk
Management Plan (RMP) of the European Medicines
Agency (EMA) into consideration was established within
the study design, also to support physicians in
implementing the RMP in daily clinical practice.
Here we report the study design of the prospective,
multicenter, non-interventional, long-term study PANGAEA
((Post-Authorization Non-interventional German sAfety
of GilEnyA in RRMS patients). PANGAEA will provide
data of German RRMS patients treated with fingolimod
under real-life conditions over a period of 5 years. The
primary aim of this study is to confirm the safety and
efficacy profile of fingolimod obtained in phase I-III clinical
trials in real-world conditions. In addition,
pharmacoeconomic data will be collected from a subset of patients.
PANGAEA is a prospective, multicenter, non-interventional,
long-term study in RRMS patients treated by fingolimod
(0.5 mg daily) in routine practice. To confirm the safety
and efficacy profile of fingolimod in real-world conditions,
data from approx. 4,000 RRMS patients from approx. 500
neurological centers and practices in Germany were
included into PANGAEA. The number of participants per
practice or center ranges from 1 to 50 and more. In
addition, a pharmacoeconomic sub-study with 800 RRMS
patients treated in approx. 180 neurological clinics and
practices will systematically collect patient-reported
measures on disability, quality of life (QoL), compliance,
treatment satisfaction, and consumption of resources. Centers
experienced in phase IV observational trials were asked to
participate in this sub-study. Selection criteria included
participation in former Novartis sponsored observational
trials, experienced in the documentation of patient
reported outcome measurements, center size, and scientific
interest in the sub-study. The recruitment period of the
PANGAEA main study and sub-study started in April
2011. In the PANGAEA main, data are obtained during a
60-month observational phase per patient and
observations will be completed on December 2018 (Fig. 1). The
documentation of the sub-study data ends after 24 months.
Fig. 1 Timeline of the PANGAEA main study and pharmacoeconomic
sub-study. Main study and sub-study will include 4,000 and 800 RRMS
patients treated with fingolimod (0.5 mg/daily), and the observational
phase will be 60 months and 24 months, respectively (* in the
pharmacoeconomic sub-study, recruitment will end after 800 patients)
Patients participating in the sub-study will continue the
main-study documentation until month 60. This
observational study was sponsored and executed by the Novartis
Pharma GmbH, Nuremberg, Germany.
Participants are eligible if they were diagnosed with
RRMS , if their physicians decide to prescribe
fingolimod independently of participation in the study, and
after informed consent has been provided. All
fingolimod receiving patients are included into PANGAEA.
This includes patients that receive fingolimod for the
first time in PANGAEA (main- and sub-study) and
patients that are already treated with fingolimod and
started the therapy within a former clinical trial (only
into the main study). There are no exclusion criteria
except for the contraindications mentioned in the
respective summary of the product information .
The prevalence of MS in Germany is estimated to be
150 cases per 100,000 inhabitants, which is equivalent to
about 122,000 MS patients . Assuming an
enrollment of 5 patients per practice or 4,000 patients in total,
the enrolled number of study participants as well as the
duration of the observational study period of 60 months
is deemed sufficient to detect the most commonly
occurring adverse events (AEs). Sample size of the
pharmacoeconomic sub-study was limited to 180 MS-centers
or 800 MS patients.
According to routine practice and as recommended by
the German Society of Neurology , in the
mainstudy visits take place every 3 months for a period of
60 months, once the first month of treatment is over
(first visit). Data for pharmacoeconomic sub-study are
documented every 3 months for a period of 24 months
Demographic and clinical data of participants are
obtained from interviews or medical examinations and are
collected by the treating neurologist. Questionnaires on
patient-reported outcomes are completed by participants
at regular visits in the presence of a health professional.
All data are collected using standardized electronic case
report forms. Data are entered online at study sites,
using either a customized web-based data entry tool or
the software-based MS management system 3D (MSDS
3D; ). The PANGAEA MSDS 3D module further
guides neurologists and MS-nurses through treatment
management, including first dose monitoring,
ophthalmological examinations, and regular laboratory follow
ups. On the software interface, all procedures are
displayed in clickable boxes leading to menus for data
entry. Upon authorization, data might be entered by the
neurologist (e.g., EDSS, adverse effects) or the MS-nurse
(e.g., questionnaires). From the MSDS 3D start screen,
details of upcoming, past, and missed appointments can
be directly assessed (Fig. 2a,b). Anonymity and data
protection are ensured by a complex process including
At the time of entry, data quality is ensured by
validation checks. Data are daily reviewed by the database
coordinator. Data management is overseen by the data
management team of the Clinical Research Organization
responsible (Kantar Health GmbH).
Measures main study
All measurements are summarized in Table 1. At
baseline, patient histories are documented in addition to the
patient informed consent and demographic patient
characteristics. Among others, data on the patient’s history
include the time since first symptoms and diagnosis of
MS, the number of lesions in T2-weighted MRI and
gadolinium-enhancing (Gd+) lesions, and the number of
relapses within 12 and 24 months before study start.
As PANGAEA documents daily clinical practice, MRI
data were asked to be documented by the neurologist of
the center if a MRI was performed. Therefore MRI
acquisition was not part of the study protocol and was not
performed via standardized protocols. MRI read outs
were not evaluated via a central reading facility.
First dose observation
The first dose of fingolimod is applied under clinical
observation because of the potential risk of bradycardia
and decreased atrioventricular conduction. In detail, at
baseline as well as 6 h after the first dose of fingolimod,
a 12-channel ECG is performed to identify
abnormalities. Furthermore, heart rate, blood pressure, and the
occurrence of symptoms that might indicate bradycardia
are examined at 1 h intervals during the 6 h post-dose
period. A continuous monitoring of heart function by
long-term (Holter) ECG is recommended during this
period. If heart rate is lowest at the end of the post-dose
observation, monitoring is extended for at least two
hours. If patients develop clinically significant symptoms
indicating bradycardia or atrioventricular block, clinical
management should be initiated as required, and
monitoring is continued at least overnight and until the
symptoms resolve. This first-dose monitoring should additionally
be performed if patients required pharmacological
intervention during first-dose monitoring (second-dose
monitoring), and, importantly, if fingolimod therapy has been
Precautions for treatment
Varicella zoster status, previous immunomodulatory
treatments, concomitant drugs and concomitant diseases
Fig. 2 MSDS 3D PANGAEA module. Baseline and follow up visits are horizontally presented with boxes representing examinations. The lower part
of the screen exemplary shows the EDSS data entry menu (a). b depicts in detail the horizontal presentation of completed and uncompleted
visits and examinations (denoted by colors as indicated)
such as diabetes mellitus, impaired lung function, and
chronic infections are documented at baseline. Other
safety precautions include the assessment of blood
pressure, heart rate, complete blood count (lymphocyte count),
and clinical chemistry such as liver enzymes
(transaminases) and blood lipids (triglycerides, high-density and
low-density lipoprotein [HDL, LDL]) at every visit
beginning at baseline. Ophthalmological examinations are
performed after 3 months or at any visit if required. Female
patients are tested for pregnancy at baseline and, if
required, at follow-up visits. Premature discontinuation of
Monitoring of disease progression
Global symptomatology and treatment response are
assessed by the Clinical Global Impression scale (CGI;
) at every visit beginning at baseline. Disability is
scored by means of the Kurtzke’s Expanded Disability
Status Scale (EDSS) . MS-relapses and number of MRI
lesions, where available, are documented at every visit
beginning at month 1. In some centers, additional data
Table 1 Data to be obtained during the PANGAEA main study
Baseline Month 1
Final visit (60 months)
Precautions for treatment
Concomitant diseases and drugs
Impaired lung function
Monitoring of disease progression
– additionally before first dose and when restarting fingolimod after treatment interruption –
– every 6 months –
HR: heart rate, BP: blood pressure, CBC: complete blood count, CGI: Clinical Global Impression scale, EDSS: Kurtzke’s Expanded Disability Status Scale, MSFC: Multiple
Sclerosis Functional Composite, SDMT: Symbol Digit Modalities Test, MRI: Magnetic Resonance Imaging, AE: Adverse events, SAE: Serious Adverse Events
aMSFC and SDMT are assessed in a subset of practices and centers
Table 2 Data to be obtained during the PANGAEA
EQ-5D, PRIMUS-A, PRIMUS-L
Consumption of resources
UKNDS: UK (Guy’s) Neurological Disability Scale; EQ-5D: Euro quality of life
questionnaire, PRIMUS: Patient Reported Outcome Indices for Multiple Sclerosis
(subscale A: activity, L: quality of life); TSQM-9: Treatment Satisfaction Questionnaire
on MS symptomatology and cognitive processes most
frequently affected by MS are obtained by the Multiple
Sclerosis Functional Composite (MSFC , every visit
beginning at baseline) and the Symbol Digit Modalities
Test, respectively (SDMT , every 6 months).
At every visit, the investigators evaluate the occurrence of
AEs and serious AEs. AEs are defined as any unfavorable
change in the patients’ pretreatment condition, regardless
of their potential relation to treatment and irrespective of
whether medication was taken as intended. Each AE is to
be characterized by type. The time of first occurrence,
duration, and intensity of an AE, as well as the causal
relationship to therapy, counteractive measures and outcomes
of AEs are to be documented. Serious AEs comprise lethal
or life threatening events, hospitalizations, events leading
to major incapacity, persistent or significant disability or
incapacity, congenital anomaly or birth, and events that
are otherwise medically significant. The latter may also
apply to abnormal laboratory values and test results.
Measurements of the pharmacoeconomic sub-study
comprise patient-reported disability, QoL, treatment
compliance, treatment satisfaction, and consumption of resources
(Table 2). At baseline and after 12 and 24 months, the
patients’ perceived disability is assessed by the UK (Guy’s)
Neurological Disability Scale (UKNDS; ). At
baseline and every 6 months, patient-reported QoL is
evaluated by both the standardized EuroQol (EQ)-5D
questionnaire , and the QoL- and activity subscale
of the Patient Reported Outcome Indices for Multiple
Sclerosis (PRIMUS; ).
Data on the patient-reported compliance with therapy
are obtained through the use of a compliance
questionnaire at baseline and every 3 months. The compliance
questionnaire consists of five yes/no questions asking
whether and when treatment was eventually
discontinued; one free text field asks for the number of days the
MS-medication was not taken. Treatment satisfaction is
evaluated by the Treatment Satisfaction Questionnaire
for Medication (TSQM-9; ) at baseline and every
3 months. In this questionnaire, patients are asked to
rate their satisfaction with nine different aspects of
MS-treatment on a 7-point Likert scale ranging from
‘1’ (very dissatisfied) to ‘7’ (very satisfied).
The questionnaire on patient-reported consumption of
resources is completed at baseline and every 3 months.
Several multiple-choice questions ask for information on
demographic details, on employment, and on health and
long-term-care insurances. Yes/no-questions combined
with free text fields ask patients about their expenditures
on medication, treatments, and devices, the type of
outpatient treatment and specialized medical consultations,
their participation in patient and education programs,
and their responsibility for relatives. There are additional
free text fields in which patients are asked to specify the
type and extent of inpatient and outpatient care caused
by MS-relapses. In one question, patients are asked to
assess their work productivity on a 10-point Likert scale
with ‘0’ corresponding to being ‘not affected’ and ‘10’
corresponding to being ‘completely affected by MS’.
All analyses are based on the safety population defined as
all included patients who received at least one dose of
fingolimod. Patients are excluded if no follow-up information
is available. Missing data are not replaced. Continuous
data are described as mean ± standard deviation (SD),
minimum, median, maximum, 5th percentile, 1st and 3rd
quartile, 95th percentile, and number of non-missing
values. Nominal- and ordinal-level data are reported in
terms of absolute and relative frequencies. The incidence
rates with 95 %-confidence intervals are determined for all
safety outcomes. Incidence rates for pre-specified
subgroups such as patients with concomitant diabetes
mellitus and pretreated patients will additionally be evaluated
(e.g., interferons, glatirameracetat, mitoxantrone,
azathioprine, natalizumab). For all analyses, the statistical
software program SAS® Version 9.2 (and above) is used.
The steering committee consisting of neurologists,
internists, and pharmaco-epidemiologists advises on study
design and data analysis, and an independent data
monitoring committee is responsible for review of the ongoing
safety of patients enrolled in the study. Regionally
competent ethics committees are consulted in accordance with
both the codex of the Voluntary Self-Regulation of the
Pharmaceutical Industry (FSA; ) and
recommendations dealing with quality aspects of non-interventional
observational studies [30, 31]. The study is registered at
Here we report on the study design of the prospective,
multicenter, non-interventional, long-term study PANGAEA in
fingolimod-treated RRMS patients. This large,
methodologically precise study evaluates safety-relevant data of
fingolimod treatment under routine practice conditions in
Germany over a period of 5 years. In addition, long-term
efficacy data as well as pharmacoeconomic data will be
collected. Although there is growing clinical experience
with fingolimod, data on the long-term use of the
medication in daily routine are currently still limited. PANGAEA
has therefore been designed to provide definitive,
longterm data on patient- and treatment-related parameters
that have been identified as safety relevant in clinical trials
and post-marketing experience.
To manage the large amounts of data that accumulate
during long-term treatment, the software-based
management system MSDS 3D is employed in some centers and
practices participating in PANGAEA. MSDS 3D was
developed in 2010 to interactively collect patient data, to
facilitate analysis and interpretation, and to assist
neurologist in executing complex processes required for MS
diagnosis, treatment initiation, and long-term therapy
. Due to the modular structure of MSDS 3D,
neurologists are guided through all necessary medical
investigations . Importantly, both the MSDS 3D-software
and the PANGAEA study design also provides guidance
on the therapeutic use of fingolimod in clinical practice,
starting with preparatory examinations, first-dose
application, and long-term treatment. Since the structure
and content of data acquisition described in this design
reflects the RMP, the treatment and monitoring
algorithm provided will ensure the best possible safety for
RRMS patients treated with fingolimod in the long term.
Due to exclusion criteria subjects of clinical MS trials
might represent a subgroup of patients with less
concomitant diseases in comparison to the general MS population
that might suffer from concurrent conditions such as
hypertension, coronary artery, diabetes mellitus, and
ocular disease. The study design of PANGAEA, along with
both the proposed high number of patients and the long
study duration, will therefore enable us to assess efficacy
and safety parameters in certain subgroups of patients, for
example those with concomitant diabetes mellitus.
In patients with diabetes mellitus, fingolimod
treatment might cause a higher risk of macular edema. In
renal transplant studies, the rate of macular edema after
fingolimod treatment was higher in patients with
diabetes mellitus than in patients without . However, in
these studies, fingolimod doses were up to 10-fold
higher than the dose approved for MS. Since RRMS
patients with diabetes mellitus were excluded from
phase-III clinical trials, the incidence of macular edema
in fingolimod-treated (0.5 mg) RRMS patients with
diabetes is currently unknown and needs clarification. Until
now, only case reports have been published on
fingolimod treated RRMS patients with concomitant diseases.
PANGAEA will further analyze the effects of
concomitant and prior medications on efficacy and safety issues
with fingolimod, thereby considerably strengthen its safety
profile. One post-marketing case report, for example,
documented worsening MS under fingolimod given after a
period of natalizumab pretreatment . However, no
causal relationship could be established, and a recent
observational study in France  demonstrated that the
occurrence of relapses during the natalizumab washout
period is the only prognostic factor for MS relapses after
fingolimod initiation. The authors therefore recommended
limiting the washout period to less than 3 months.
PANGAEA will additionally allow the analysis of and
recommendation for subgroups of MS patients as defined by
other previous immunomodulatory therapies such as
interferons, glatirames acetate, mitoxantrone, and azathioprine.
As the first oral DMT approved for the treatment of MS
, fingolimod may increase treatment adherence over
that observed with parenteral therapies. Although patients
who struggle with adherence to injectable medications
because of needle phobia, injection-site reactions, and side
effects might decide to initiate fingolimod, clinicians need to
be aware of the developing safety profile of fingolimod.
Therefore, the long-term data being collected during
PANGAEA will allow a significantly broadened evaluation
of the well described safety profile of Fingolimod
established from phase I-III clinical trials and will allow
physicians to make informed, evidence-based decisions
regarding its use in daily practice.
Tjalf Ziemssen has served on scientific advisory boards, and has received
scientific grants speaker honoraria from Bayer, Biogen Idec, Genzyme, TEVA,
Merck Serono and Novartis. Christian Cornelissen is an employee of the
Novartis Pharma GmbH, Nuremberg, Germany.
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 manuscript.
1Zentrum für klinische Neurowissenschaften, Klinik und Poliklinik für
Neurologie, Universitätsklinikum Carl Gustav Carus Dresden, Technische
Universität Dresden, Fetscherstr. 43, D-01307 Dresden, Germany. 2Novartis
Pharma GmbH, Roonstr. 25, D-90429 Nuernberg, Germany.
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