Rationale, design, and methods of a non-interventional study to establish safety, effectiveness, quality of life, cognition, health-related and work capacity data on Alemtuzumab in multiple sclerosis patients in Germany (TREAT-MS)
Ziemssen et al. BMC Neurology
Rationale, design, and methods of a non- interventional study to establish safety, effectiveness, quality of life, cognition, health-related and work capacity data on Alemtuzumab in multiple sclerosis patients in Germany (TREAT-MS)
Tjalf Ziemssen 0
Ulrich Engelmann 2
Sigbert Jahn 2
Alexandra Leptich 1
Raimar Kern 0
Lina Hassoun 0
Katja Thomas 0
0 Center of Clinical Neuroscience, Carl Gustav Carus University Hospital , Dresden , Germany
1 Clinical Study Unit, Sanofi-Aventis Deutschland GmbH , Frankfurt am Main , Germany
2 Medical Affairs, Genzyme GmbH , Neu-Isenburg , Germany
Background: Alemtuzumab, a humanized monoclonal antibody directed against the cell surface glycoprotein CD52, is licensed in Europe since October 2013 as treatment for adult patients with active relapsing-remitting multiple sclerosis (RRMS). In three randomized, rater-blinded active comparator clinical trials studies, alemtuzumab administered in two annual courses, had superior efficacy as compared to subcutaneous interferon beta-1a, and durable efficacy over 5 years in an extension study with a manageable safety profile in RRMS patients. Data on the utilization and the outcomes of alemtuzumab under clinical practice conditions are limited. Methods: Here we describe the rationale, design and methods of the TREAT-MS study (non-interventional long-Term study foR obsErvAtion of Treatment with alemtuzumab in active relapsing-remitting MS). Discussion: TREAT-MS is a prospective, multicenter, non-interventional, long-term study to collect data on safety, effectiveness, quality of life, cognition and other aspects from 3200 RRMS patients treated with alemtuzumab under the conditions of real-world clinical practice in Germany. Trial registration: As non-interventional trial in Germany.
Alemtuzumab; Non-interventional trial; Risk-management plan; MSDS3D; Real worl data; Multiple sclerosis
Multiple sclerosis (MS) is generally considered a primarily
T-cell mediated autoimmune disease of the central nervous
system (CNS). To date, no cures exist for MS – the disease
will progress to a worse stadium with higher disability
sooner or later. Only disease course-modifying therapies
(DMTs) are available for patients [
]. Treatments for the
mild and moderate relapsing remitting MS (RRMS) courses
are interferons-β and glatiramer acetate, DMTs which have
been used since 20 years [
]. On average, these injectable
drugs cut the annual relapses by a third, and they are
effective with side effects like flu like symptoms or injection site
]. In 2013, teriflunomide [
] and in 2014,
] have been introduced as oral agents
for RRMS treatment.
Given that first-line therapies might fail to adequately
control disease activity in some patients, it has been
recommended to switch these patients early to a therapy of
higher efficacy more rigorously [
]. Among treatments
for (highly) active RRMS offering higher effectivity but also
accompanied by significant side effects are DMTs such as
fingolimod and natalizumab . Fingolimod reduces the
amount of lymphocytes that exit the lymph node by
binding to sphingosine-1-phosphate receptors on the cell
surface. While annual relapse rates (ARRs) are reduced by
more than half [
], cardiac side effects and macular
edemas are among the side effects [
]. Natalizumab, a
humanized monoclonal anti-α4-integrin antibody,
prevents lymphocytes’ crossing the blood-brain barrier [
was shown that it can reduce ARRs by 68 %; however, an
especially dangerous adverse effect of natalizumab is
progressive multifocal leukoencephalopathy (PML), a brain
infection by the John Cunningham (JC) virus [
]. For this
complication, a lethality of 20 % in MS patients treated
with natalizumab has been reported [
Alemtuzumab (Lemtrada®, marketed by Genzyme) has been
approved in Europe 2013 and is marketed as a treatment
for RRMS with active disease defined by clinical or imaging
]. In the USA, the drug has been approved in
November 2014 for RRMS and PRMS treatment, but only
for patients who did not have a satisfying response to two
or more drugs (i.e. for second-line therapy).
Alemtuzumab is a humanized monoclonoal antibody
against the lymphocyte surface protein CD52 [
covers about 5 % of the entire surface of lymphocytes; apart
from them, it occurs on cells as diverse as macrophages
and endothelial cells [
]. After binding of alemtuzumab to
CD52, lymphocytes are destroyed either by
complementinduced or antibody-dependent cell-mediated cytotoxicity
16, 18, 19
]. As a consequence it is assumed that B- and
Tcell repopulation takes place [
] by which – compared
with the pre-treatment stage – the proportions of
lymphocyte subgroups are shifted; the numbers of regulatory T
cells and memory B- and T-cells are increased, and cell
populations of innate immunity are also affected [
Overall, alemtuzumab appears to re-organize the
immune repertoire, which manifests in the special kinetics
of immune cell population, the increased production of
antiinflammatory cytokines, and last but not least the
very long duration of action [
Three randomized, rater-blinded clinical trials about the
effectiveness of alemtuzumab in MS treatment, using an
effective comparator drug, have been performed, CAMMS223
], CARE-MS I [
], and CARE-MS II [
12 mg alemtuzumab per day, CAMMS223 and CARE-MS I
showed a 69 and 55 % higher reduction of relapses than
interferon-β 1a (IFNB-1a). Long-term effectivity of
alemtuzumab was also superior compared with IFNB-1a:
CAREMS II showed a reduction of the sustained accumulation of
disability (SAD) within 6 months of 42 % and a reduction of
relapses per year of 49 %. SAD reduction in a 5-year
perspective was 69 %, and reduction of relapses 66 % in this
long-term outlook [
]. In sum, alemtuzumab drastically
slowed down progression of MS.
Important adverse effects elicited by alemtuzumab are
secondary autoimmune reactions, in particular (for
unknown reasons) reactions targeting the thyroid gland
]. In the studies, 26, 18 and 16 %, respectively, of
patients were diagnosed with thyroid autoimmune disease
(AID) . Furthermore, a few cases of Goodpasture
Syndrome were observed [
]. In this AID, the basement
membrane of kidneys is attacked, which can lead to kidney
failure. Idiopathic thrombocytopenic purpura has also been
described as a serious adverse effect, causing severe
]. Last, like with natalizumab, reactivation of
the JC virus can lead to potentially lethal PML which has
been reported in hematological diseases where
alemtuzumab was often administered concurrently with
immunosuppressive therapy [
]. Up to now, there was only one
carry over PML MS case switching from natalizumab to
Regular tests before, during and after administration of
alemtuzumab have been recommended to recognize and
terminate further development of such serious adverse
drug reactions [
]. The implementation of a
systematic safety monitoring program allows for the early
detection and management of autoimmune and other known
Rationale of the TREAT-MS study
Randomized controlled trials (RCTs) are the “gold
standard” for generating evidence of the efficacy and safety of a
drug. However, enrolment criteria, timelines, and atypical
comparators of RCTs limit relevance to standard clinical
practice. Real-world data (RWD) provide longitudinal
information on comparative effectiveness and tolerability
of drugs, as well as their impact on resource use, medical
costs, pharmacoeconomic outcomes, and patient-reported
]. Regarding alemtuzumab, the collected
data from clinical studies provide a sound body of
evidence on the efficacy and the safety profile in the
treatment of RRMS. However, data on the utilization and the
treatment outcomes of the drug under clinical
practice conditions are limited to few reports on small
Here we describe the rationale, design and methods of
the recently established non-interventional open,
uncontrolled, prospective, multicenter, and long-term study
TREAT-MS (non-interventional long-Term study foR
obsErvAtion of Treatment with Alemtuzumab in active
The main goal of TREAT-MS is to establish a broader
real-world dataset on the utilization and safety,
effectiveness, quality of life and other aspects of the drug in
everyday clinical practice. The study encompasses a risk
management plan to recognize and counter each occurring
adverse effect as early as possible, which will also support
physicians who treat MS patients with alemtuzumab in
their daily clinical practice [
]. TREAT will additionally
investigate how the risk management plan is transferred into
clinical practice which is crucial for alemtuzumab with
necessary longterm monitoring [
TREAT-MS is a prospective, multicenter, non-interventional
long-term study. Data are collected from around 300
neurologists in specialized MS centers (clinical centers or
outpatient departments) in all parts of Germany. Patients
are eligible for documentation, if they fulfill the EMA label.
The study does not stipulate any diagnostic or treatment
Alemtuzumab has not been administered to minors
(<18 years). Patients have received a diagnosis of active
RRMS from their neurologists. As non-interventional
study (NIS) no specific inclusion resp. exclusion criteria
apply in order to avoid selection bias in this real world
study beyond the relative or absolute contraindications
of the alemtuzumab EMA label [
Figure 1 and the Table 1 provide an overview on the
study flow and the items to be documented. At the
baseline visit, current and retrospective data on the patient
and MS are collected; thereafter patients are followed up
in a prospective way. All patients will be monitored for
60 months after the first administration altogether, and
for almost 48 months after the second administration of
alemtuzumab to vouchsafe a complete realization of the
risk management plan. Demographic and clinical data of
participants are gathered from medical examinations and
other sources (e.g. MS nurse). Information about
patientreported outcomes is completed by participants during
their visits in clinics and centers in the presence of a
health care professional. Neurologists and MS nurses will
be guided by the MSDS 3D-Lemtrada-TREAT-MS
module through the entire management of treatment,
including monitoring of the first and second infusions, necessary
examinations, and regular laboratory screenings.
Documentation by clinicians
Treatment preparations Taking into consideration the
well-known side-effects and contraindications of
alemtuzumab, a detailed patient history and physical examination
should be performed to exclude possible contraindications
]. Recommended lab tests before starting treatment
with alemtuzumab should be done before every
alemtuzumab infusion later on. The vaccination status is checked at
baseline. Lacking vaccinations (e.g., varicella) are to be
administered no later than six weeks before start of
alemtuzumab treatment. Tests for various infectious agents
(tuberculosis, hepatitis B and C, varicella-zoster and JC
virus) are performed to avoid infectious disease
complications after infusion.
A specific interest of TREAT study will be the different
pretreatment status of the patients as the strategy how to
initiate the treatment with alemtuzumab depends on
pretreatment status of the patient. As direct switching
from interferon-beta or glatiramer Acetate to
alemtuzumab is possible, prior therapy with natalizumab represents
a special situation as the switching protocol depends on
the actual PML risk which is closely linked to the JCV
status and natalizumab treatment duration [
Disease progression and clinical monitoring Before
commencement of treatment, history and disease course
of the patient’s MS, including previous therapeutic
interventions, are assessed. In particular, the number of
relapses in the last year and the year before and
comorbidities are documented. The number of relapses
is an effectiveness criterion in this study, and thus
closely followed up. A relapse is defined as an episode of
neurological symptoms that happens at least 30 days after
any previous episode began, lasts at least 24 h and is not
attributable to another cause and occurs in the absence of an
infection or fever. It has to be accompanied by either new
clinical signs, i.e. changes in the neurological examination, or
an increase in the disability (EDSS) score. If magnetic
resonance tomography (MRI) examinations are performed
routinely, at every visit results are documented. This includes
number of lesions in T2-weighted MRI and
gadoliniumenhancing lesions due to analysis of the local radiologist.
Alemtuzumab application Alemtuzumab infusion is
documented in a detailed way including concomitant
medication and adverse events.
Laboratory monitoring Total and differential blood
count, serum creatinine and urine status are evaluated
every month after alemtuzumab infusion to gain reference
values for measuring the impact of alemtuzumab
administration on these health parameters. In addition, thyroid
function is assessed every 3 months using TSH. All tests
are repeated for 4 years after the last alemtuzumab infusion,
and the results are documented in the system.
Further instruments applied by physicians include the
Expanded Disability Status Scale (EDSS) and the Clinical
Global Impression (CGI) (severity) until termination of
the observation phase.
Expanded disability status scale The EDSS is a
clinician-rated scale based on neurological history and
physical examination, which is used to determine the
degree of neurological disability in patients with multiple
]. As part of the EDSS Neurostatus, eight
functional systems are assessed: pyramidal, cerebellar,
brainstem, sensory, bowel and bladder, visual, cerebral and
other. The rating is performed by certified health care
professionals, most usually a neurologist. It normally takes
20-30 min to complete the rating. The EDSS gives a score
from 0 (normal neurological examination) to 10 (death
from multiple sclerosis), with half points from 1 upwards.
In the TREAT study, EDSS and functional system scores
Clinical global impression The CGI, developed by the
National Institute of Health originally for use in psychiatry,
is a three-item scale used to assess treatment response [
The present study uses item 2 only, on seven-point scale (1
= very much improved to 7 = very much worse). The CGI
is robust, simple (clinically understandable), and sensitive
Patient-related self-reported outcomes
The study puts great emphasis on the documentation of
patient-related outcomes including functionality, quality
of life and ability to work. Thus, patients are requested
to fill out various questionnaires at inclusion and at
6-month intervals thereafter.
Symbol digit modality test The SDMT, developed by
Wechsler et al., is a neuropsychological test measuring
]. It is brief, easy to administer, and has
demonstrated remarkable sensitivity in detecting not only the
presence of brain damage, but also changes in cognitive
functioning over time and in response to treatment. The
SDMT involves a simple substitution task: Using a
reference key, the test taker has 90 s to pair specific numbers
with given geometric figures. Responses can be written or
given orally, and administration time is just five minutes
for either response mode.
Patient-reported outcome indices for MS PRIMUS,
published in 2009 by Galen Research [
], is a disease
specific patient-reported outcome questionnaire that measures
quality of life (QoL) of MS patients. The questionnaire
consists of three scales: quality of life (22 questions), symptoms
(8 questions) and activity status (15 questions), which can
either be used by the patient together or as standalone
measures. On the QoL scale, questions are to be answered
with yes or no, and items are summed to yield a total score
ranging from 0 to 22 (with high scores indicating low QoL).
The activity limitations scale contains 15-items describing
specific physical tasks, and respondents rate the degree to
which they are able to perform the tasks on a three point
scale. Here, items are summed to give a total score that can
range from 0 to 30, with higher scores representing greater
activity limitation. Both scales have been shown to be
unidimensional and to have good reproducibility and validity in
a number of languages [
Euro-Qol 5D-3 L The EQ-5D questionnaire, developed by
the EuroQol group [
], is a standardized measure of health
status, applicable to a wide range of health conditions and
treatments. The descriptive system of health-related quality
of life states consists of five dimensions (mobility, self-care,
usual activities, pain/discomfort, anxiety/depression) each of
which can take one of five responses. The responses record
five levels of severity (no problems/slight
problems/moderate problems/severe problems/extreme problems) within a
particular EQ-5D dimension. In addition, self-assessed
quality of life is measured using a 0–100 visual analogue scale.
The EQ-5D provides a simple descriptive profile and a
single index value for health status that can be used in the
clinical and economic evaluation of health care as well as in
population health surveys [
Work productivity and activity impairment
questionnaire The WPAI:MS questionnaire consists of 6 questions
(1 = currently employed; 2 = hours missed due to health
problems; 3 = hours missed other reasons; 4 = hours
actually worked; 5 = degree health affected productivity while
working (using a 0 to 10 Visual Analogue Scale (VAS)); 6
= degree health affected productivity in regular unpaid
activities (VAS). The recall period for the questions 2 to 6
is seven days. Thus, the questionnaire measures
absenteeism, presenteeism as well as the impairments in unpaid
activity because of health problems during the past seven
]. It has been validated to quantify work
impairments for numerous diseases such including asthma,
psoriasis, irritable bowel syndrome, ankylosing spondylitis and
Crohn’s disease. In addition, the WPAI questionnaire has
been used to compare work impairments between
treatment groups in clinical (studies and) trials or between
subjects with different disease severity levels.
Adverse events reporting At every visit, patients are
asked for the occurrence of adverse events (AEs). As
alemtuzumab is a product under special observation (due to its
novelty and immunological effects), each adverse effect
occurring during alemtuzumab therapy must be reported,
irrespective of a causal connection attributed to
alemtuzumab. Time, duration, intensity and outcomes of
each AE are documented. Further, the treating
physician is asked to assess in terms of a causal connection
to alemtuzumab treatment. Severe adverse events are
life-threatening or lead to death, hospitalization, to
lasting or severe disability, incapacity or congenital
anomaly. Adverse events are documented locally in the
MSDS 3D-Alemtuzumab-TREAT-Module (see below)
and sent automatically to the pharmacovigilance
department of Sanofi-Aventis/Genzyme. A list of AEs of
special interest is presented in Table 2.
Risk Management Plan (RMP) For prescribing doctors
and medical specialists who participate in the care for MS
patients treated with alemtuzumab, a risk management
plan was developed by the drug manufacturer, and
approved by the regulatory authorities. It informs precisely
about the risks and possible severe adverse effects which
can occur during alemtuzumab treatment. Moreover,
information is provided to physicians about the required
regular tests to ensure clinical vigilance. The
documentation system MSDS 3D (see next section) will be used to
document all data from the patient according the RMP
and expert information for alemtuzumab.
MS documentation system for physician, nurse and patient
Due to the chronicity of MS and its long-term treatment
including a post-treatment observation phase, an
electronic data recording system which captures all steps of
the treatment on a timeline and allows interaction of the
participants of the treatment process (physician, nurse,
and patient) is very useful or even required for optimal
care. Also, large amounts of data arise in the
treatment process and should be managed in a systematic
For these tasks, the MSDS3D software has been
developed at Dresden University of Technology (Germany)
]. It emerged from MSDS Clinic which gathers
the personal data of the patient, her/his treatment details
and disease course, data from clinical examinations and
clinical scores . The software interface presents all
procedures in clickable boxes which lead to data entry
menus. Then, upon authorization, a MS nurse or
neurologist can enter the relevant data (e.g., EDSS, adverse
MSDS3D provides a standardized management and
documentation for treatment and disease course of the patient; it
can also be used to import data into various database
systems as MS BASE [
]. In addition to the features of MSDS
Clinic, information can be directly shared with the patient
and feedback can be received from him. The patient can
deliver information by using a touchscreen in the
neurological center, or he can log into the system from his home
computer to enter information or reply to queries. For
example, by solving a questionnaire about the symptoms of
adverse effects in immunomodulatory treatments of MS the
patient can help detect severe AEs such as PML or
Goodpasture Syndrome early [
In addition to MSDS3D, the online-based
MSDS3DTREAT electronic case report form (eCRF) (Fig. 2a to c)
can be used to document patient data, the local MSDS3D
software and the MSDS3D web tool are linked to the same
database (Fig. 3). These are labelled with a code that does
not permit identification of the patient; only physicians or
people authorized by the project administration possess
access rights to this code.
The MSDS3D interface introduces a feature known from
eCRFs. The user sees a vertical timeline, while the
procedures which have to be executed during the treatment
process are arranged horizontally and shown as clickable
‘procedure boxes’. These lead to input menus for the
procedure which is to be executed, e.g. EDSS screening or
registration of adverse effects.
Moreover, MSDS3D can create physician’s reports either
through entering free text or by using text modules. The
system was modified to document immunomodulatory
treatments such as alemtuzumab, natalizumab and
fingolimod. Before a drug is administered, e.g. as an infusion, the
system asks for all relevant health checks, and after all
checks have been performed successfully, the treatment is
authorized by the neurologist. In the visit module, specific
instruments (categorized tasks) are attributed to every
visit. Color marks and other signs point to the processing
stage of the tasks. In addition, the toolbar contains buttons
for concurrent medications and queries about data
documented within the system. Red and blue colors show open
or answered queries, respectively.
Different MS treatment cohorts have been already
followed up using MSDS3D (eg. Fingolimod [
56, 59, 60
]) which will allow comparisons between
different treatment groups. Identification and mitigation of
biases and careful consideration of study power are key
factors for designing appropriate RWE studies. Various
biases exist, which require careful consideration in selecting
appropriate comparators, patient populations, data sources,
outcomes, and statistical analyses .
Data management and statistical aspects
Data management has been described in a separate data
management plan, which includes a data validation plan.
A population size of 3200 patients means that adverse
events with an incidence of 1:1068 or more will occur at
least once in the alemtuzumab patient population.
For the portion of patients with a premature
termination of the risk management plan, 95 % confidence
intervals according to the method of Clopper and Pearson
are determined. Proportional hazards model will be used
to assess whether certain patient subgroups are more
likely than other to terminate the RMP early. In general,
for continuous variables numbers of patients, mean and
standard deviation, the five point summary (minimum,
lower quartile, median, upper quartile, maximum) and
possibly further appropriate percentiles will be
determined. For categorical variables absolute and percentage
frequencies will be calculated.
For means and estimated probabilities – and, if
significant, for further parameter as well – 95 % confidence
intervals will be determined. The evaluations will also be
performed for subgroups which are defined before in the
statistical analysis plan. Depending on the number of
subgroups defined in the plan the confidence level will
possibly be raised. The evaluations of the used
questionnaires SDMT, EQ-5D, PRIMUS, CGI-S (versions for
physician and patient) and WPAI are performed according to
validated and published algorithms. All statistical
evaluations are of exploratory nature.
Timelines The study started in November 2014 and
recruitment is planned until December 2016, however, it will
be stopped as soon as a sufficient number of patients have
been enrolled. Observation of patients and documentation
will continue until September 2022.
In recent years, innovative immunotherapies have offered
new treatment options, better disease control and improved
the quality of life in patients with MS. With the
introduction of natalizumab in 2006 and fingolimod in 2011 as
therapies for RRMS, safety aspects became more prominent. In
order to address those comprehensively, clearly defined
cooperations between MS specialists and doctors from
other disciplines, such as radiologists, cardiologists or
ophthalmologists needed to be established. In 2013, with
teriflunomide and alemtuzumab, further immunotherapeutics
for MS were approved, that require before and during
application regular check-ups to ensure safe use. The most
extensive catalogue of requirements for
pharmacovigilance arises in the application of the new anti-CD52
antibody alemtuzumab, which has received a broad
labelling in Europe which does not exclude first-line use.
On top of the body of evidence from 1500 patients that
received alemtuzumab in the randomized controlled trials
], CARE-MS I [
] and CARE- II [
the clinical experience with the agent has substantially
increased since market introduction. Nevertheless there
are only few reports yet on the long-term use of the drug
in the routine of physicians and MS centers. TREAT-MS
will fill this gap, and will document physician and patient
experience in daily clinical practice for 6 years. Data in this
non-interventional study will be collected on a widely
unselected patient population eligible for alemtuzumab
treatment. It is expected that compared to the clinical
studies, patients with more concomitant diseases and/or
more concomitant medications will be documented.
Together with the high patient numbers and long follow-up
period, a substantial number of patient years will be
documented and the option for relevant subgroup analyses
As the registry protocol was developed based on the
risk management plan for alemtuzumab, by participation
in the study, physicians are reminded about the
investigations and precautions which are needed for the safe
use of this potent immunological drug [
]. Thus, the
study serves the additional purpose to optimize the drug
utilization according to the conditions specified by the
The documentation system MSDS3D has been shown to
be efficient to guide physicians through the study
procedures and to collect the relevant information in clinical
practice and for the use in previous non-interventional
studies such as PANGAEA [
]. It interactively collects
data, but also assists neurologists in the execution of
complex processes required for comprehensive management
of MS patients.50
The planned number of 3200 patients in TREAT-MS
are recruited from centers in all parts of the country and
different types of centers (office-based, various types and
sizes of hospitals), which makes the study representative
for the situation in Germany. Thus – apart from
triplicating the number of documented individuals treated
with alemtuzumab– the evidence of benefits and risks of
alemtuzumab for patients as well as for physicians will
appear in much higher resolution and depth when the
study ends. A two- or three-times longer post-treatment
observation phase (compared with the pre-market trials)
with monthly clinical checks will also contribute to this
effect and lead to more secure information of the
incidence of secondary autoimmune diseases and other
TREAT could serve in future as part of a personalized
medicine approach in MS, where MS patients are
characterized by a detailed clinical profiling and followed up by
prospective longterm documentation [
]. This data can
be used to analyze treatment response patterns of
alemtuzumab and allow personalized treatment approaches.
Predictive models could be implemented using this data [
So TREAT data will assist in complex treatment decisions
in future. It will be interesting to investigate different
baseline profiles (de novo patients, patients escalated from first
line therapies, patients switching from escalation
therapies) and treatment response and safety of alemtuzumab.
Among the limitations of TREAT-MS as an
noninterventional, open study is the absence of blinding,
neither on the patients’ nor on the physicians’ side.
Further, there is no comparator group. The expectation to
treat or be treated with a novel anti-MS drug might lead
to a higher amount of reported positive effects than
observed in a study with blinded subjects or physicians.
Moreover, physicians may assign patients to the study
based on the severity of their disease, the observation
that they did not respond well to conventional drugs, or
the presence of complex comorbidities; this might bias
study results. Through such possibly biased allocation of
participants, assessing the correlation between treatment
and outcomes will be difficult.
AE, adverse event; AID, autoimmune disease; ARR, annual relapse rate; CGI, cl
inical global impression; CNS, central nervous system; CRF, Case report form; DMT,
disease course-modifying therapy; EDSS, expanded disability status scale; EMA,
European medicine agency; IFNB-1a, Interferon beta-1a; JC, John Cunningham;
MRI, magnetic resonance imaging; MS, multiple sclerosis; NIS, non-interventional
trial; PML, progressive multifocal leukencephalopathy; QoL, quality of life; RCT,
randomized controlled trial; RRMS, relapsing-remitting multiple sclerosis; RWD, real
world data; SAD, sustained accumulation of disability; SDMT, symbol digit modality
test; TREAT-MS study, non-interventional long-Term study foR obsErvAtion of
Treatment with alemtuzumab in active relapsing-remitting MS; TSH,
Thyroidstimulating hormone; WPAI, Work Productivity and Activity Impairment
Input to the report was given by David Pittrow, MD, PhD, Seefeld, Germany.
Financial support for medical editorial assistance was provided by Genzyme
GmbH. Parts of the present manuscript have been presented at the congress
of the AAN 2015 on 23 April 2015.53
The TREAT study is funded by Sanofi Genzyme Gmbh Germany.
Availability of data and materials
German protocol and CRF available on request.
TZ and UE developed the study design, which is a central element of this
manuscript, and contributed to this manuscript. SJ, AL, RK participated in the
design of the study and contributed to the manuscript. UE initiated the drafting
of the report and wrote the manuscript together with TZ. All authors read and
approved the final version of this manuscript.
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. Ulrich Engelmann and Sigbert Jahn are employee
of the Sanofi Genzyme GmbH, Neu-Isenburg, Germany. Katja Thomas has
served on scientific advisory boards, and has received scientific grants speaker
honoraria from Biogen Idec, Genzyme, TEVA and Novartis. Raimar Kern has
served on scientific advisory boards, and has received scientific grants speaker
honoraria from Bayer, Biogen Idec, Genzyme, TEVA, Merck Serono and Novartis.
Alexandra Leptich is an employee of the Sanofi-Aventis Deutschland GmbH,
Berlin. Lina Hassoun has nothing to disclose.
Consent of publication
Ethics approval and consent to participate
All study materials were approved by the Ethics Committee of the Medical
Faculty, Technical University of Dresden. Patient’s written informed consent is
mandatory before start of documentation.
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