COMparison Between All immunoTherapies for Multiple Sclerosis. An Observational Long-term Prospective Cohort Study of Safety, Efficacy and Patient's Satisfaction of MS Disease Modulatory Treatments in Relapsing-remitting Multiple Sclerosis
Conditions: Relapsing-remitting Multiple Sclerosis
Sponsor: Karolinska Institutet

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COMBAT-MS (COMparison Between All immuno-
Therapies for Multiple Sclerosis) 
 
A prospective long-term cohort study of safety, efficacy 
and patient’s satisfaction of MS disease modulatory 
treatments in relapsing-remitting multiple sclerosis 
 
Study ID:  
COMBAT-MS 
Sponsor name:  
Fredrik Piehl 
 
 
Section of Neurology 
Department of Clinical Neuroscience 
 
 
Karolinska Institutet 
 
 
171 76 Stockholm 
 
 
Sweden 
 
 
Date of Protocol:  
2018-05-25 Version 3 
 
 

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AGREEMENT ON THE PROTOCOL 
The investigator agrees to conduct the study as outlined in this protocol in accordance 
with good clinical practice (ICH-GCP, http://www.ich.org/fileadmin/Pub-
lic_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R1_Guideline.pdf) and in accord-
ance with the Declaration of Helsinki: Ethical Principles for Medical Research Involving 
Human Subjects (1). 2 
The investigator agrees, by written consent to this protocol, to fully co-operate and al-
lowing direct access to all documentation, including source data, by regulatory authori-
ties. 
Significant changes to the protocol will be done only after approval from the Swedish 
Medical Products Agency, with the only exception where the immediate safety of the re-
search patient is concerned (LVFS2011:19). 
 
 
 
Approved consent in writing: 
 
  
Signature: 
 
 
 
Date: 
 
 
 
Professor Fredrik Piehl, Sponsor 
Coordinating Principal Investigator 
 
 
Signature: 
 
 
 
Date: 
 
 
 
Local Principal Investigator 
 
 
 
 
 
2018-05-28

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Abbreviation and Definition of Terms 
ADA 
Anti-drug antibodies 
AE 
Adverse event 
ARR 
Annualized relapse rate 
ASC 
Academic Specialist Centre, Stockholm County Council 
bRTX 
Biosimilar rituximab 
CEL 
Contrast-enhancing MRI lesions 
CIS 
Clinically isolated syndrome  
CNS 
Central Nervous System 
CRF 
Case record form 
DMF 
Dimethyl fumarate 
DMT 
Disease-modifying treatment 
EDSS 
Expanded Disability Status Scale 
FGL 
Fingolimod 
FSMC 
Fatigue Scale for Motor and Cognitive Functions 
GA 
Glatiramer Acetate 
 
GCP 
Good Clinical Practise 
IFN 
Interferon 
IMSE 
Immunomodulation and Multiple Sclerosis Epidemiology studies 
KS 
Karolinska Sjukhuset 
MAb 
Monoclonal Antibodies 
  
MPA 
Swedish Medical Products Agency 
MRI 
Magnetic resonance imaging 
MS 
Multiple sclerosis 
MSIS-29 
MS impact scale-29 
NAB 
Neutralizing drug antibodies 
NFL 
Neurofilament Light chain 
NA 
Not Applicable 
NTZ 
Natalizumab 

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PML 
Progressive multifocal leukoencephalopathy 
PCORI 
Patient-Centered Outcomes Research Institute (Washington DC) 
PPMS 
Primary Progressive MS 
QoL 
Quality of Life  
RA 
Rheumatoid Arthritis 
RCT 
Randomized controlled trial 
RRMS 
Relapsing-Remitting Multiple Sclerosis 
RTX 
Rituximab 
SAE 
Serious Adverse Event 
 
SAR 
Serious Adverse Reaction 
SDMT 
Symbol Digit Modalities Test 
SEK 
Swedish Krona 
SLE 
Systemic Lupus Erythematosus 
SMSreg 
Swedish MS registry 
SPMS 
Secondary Progressive MS 
 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TSQM-9 
Treatment Satisfaction Questionnaire 9  
 
Executive Committee (EC) 
Name and title 
 
Study function 
Fredrik Piehl, MD, PhD 
Consultant Neurologist 
Coordinating Principal Investigator 
 
Anders Svenningsson, MD, PhD 
Consultant Neurologist 
 
Principal Investigator 
 
 
Thomas Frisell, PhD 
Biostatistician, Karolinska Institutet 
Responsible statistician 
Ingrid Kockum, PhD 
Bioinformatician, Karolinska Institutet 
Responsible for data handling 
Anna Fogdell-Hahn 
Immunologist, Karolinska Institutet 
Responsible for laboratory testing and 
project manager 
Annette Langer-Gould, MD, PhD 
Kaiser Foundation Research Institute (Pas-
adena, USA) 
Principal Investigator 

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Clinical Advisory Team (CAT)  
 
Katharina Fink, MD, PhD 
Consultant Neurologist 
 
 
Principal Investigator 
Stockholm, KS 
Jonatan Salzer, MD, PhD 
Consultant Neurologist 
 
 
Principal Investigator 
Umeå 
Martin Gunnarsson, MD, PhD 
Consultant Neurologist 
 
 
Principal Investigator 
Örebro 
Jan Lycke, MD, PhD 
Consultant Neurologist 
 
 
Principal Investigator 
Göteborg 
Joachim Burman, MD, PhD 
Consultant Neurologist 
 
 
Principal Investigator 
Uppsala 
Magnus Vrethem, MD, PhD 
Consultant neurologist 
 
Principal Investigator 
Linköping 
 
Petra Nilsson, MD, PhD  
Consultant neurologist 
 
Eva Lindström, MD, PhD 
Consultant neurologist 
 
Principal Investigator 
Lund 
 
Principal Investigator 
Stockholm, ASC 
  
 
Scientific Advisory board and stakeholders 
 
Tomas Olsson, MD, PhD 
Consultant Neurologist 
 
 
Senior consultant 
 
Jan Hillert, MD, PhD 
Consultant Neurologist 
 
 
Senior consultant 
 
Jacques Roussel, Jr, (LA, 
USA) 
 
Stakeholder, MS patient 
USA 
His father and MS patient, 
Jacques Roussel Senior  
(LA, USA) 
 
Stakeholder, MS patient 
and caregiver, USA 
 
Mother and wife Linda 
Roussel (LA, USA) 
 
 
Stakeholder, caregiver USA 
 
Julie Stachowiak (Arizona, 
USA) 
 
 
Stakeholder 
 
Deanna Stoner (LA, USA) 
 
 
Stakeholder, Rituxan for 
MS facebook page (online 
support group)  

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Eva Helmersson, Neuro 
Sweden (Stockholm, Swe-
den) 
 
 
Stakeholder, MS patient 
advocacy group 
 
Jens Johansson, (Stock-
holm, Sweden) 
 
 
Stakeholder, MS patient 
Sweden 
 
Nicholas LaRocca, NMSS 
(New York City, USA) 
 
 
Stakeholder 
 
Pharmacy/Health Plan  
(LA, USA) 
 
 
Stakeholder 
 
Gavin Giovannoni, MBBCh,  
PhD, FCP (S.A., Neurol.), 
FRCP, FRCPath 
 
 
Stakeholder, Author of  
Barts MS Blog 
 
Swedish MS Society (Swe-
den) 
 
 
 
Stakeholder 
 
 

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Protocol Summary 
1. Background and Rationale 
1.1. Background 
 
Multiple sclerosis (MS) is an inflammatory disorder of the central nervous system (CNS) 
with onset primarily in young adults (2). The disease likely involves autoimmune mecha-
nisms towards antigens present in CNS myelin leading to demyelination and secondary 
axonal damage, in turn the basis for permanent neurological deficits. Isolated injuries on 
the myelin sheath may be reversible, which is not the case for axonal and neuronal dam-
age (3). 
In the majority of cases (80-90%) the disease starts with a relapsing-remitting (RRMS) 
course, but in most cases convert to a phase of continuous worsening, secondary pro-
gressive MS (SPMS), after a mean of about 15 years of disease (4). A proportion of pa-
tients displays a relatively benign disease course, but long-term follow-up studies indi-
cate that this fraction is at most 10 – 15 % of the whole MS population (5). The most 
conspicuous accumulation of disability occurs during the SP phase, but already at the 
time of diagnosis many patients display debilitating neuropsychological symptoms, signif-
icantly reduced quality of life and work capacity (6). 
 
Multiple disease modifying treatments (DMTs) have been approved for RRMS, all of which 
vary in efficacy, safety, tolerability, duration of effect and mode of administration. In 
contrast, no DMT has yet been approved for progressive MS. DMTs are generally divided 
into first-line and escalation agents depending on safety and efficacy data from two-year 
randomized controlled trials (RCTs), most of which have been placebo controlled. Efficacy 
data from RCTs of limited duration are difficult to extrapolate to the real world situation, 
as enrolled patients are not entirely representative of the general RRMS population and 
have different underlying risks of long-term disability. Notably, most RCTs have included 
mainly treatment naïve patients without significant co-morbidities, while many DMT deci-
sions are made for patients with signs of breakthrough disease or who display reduced 
tolerability with first-line DMTs, or with certain co-morbidities. Furthermore, relapse rate, 
the primary outcome of most RRMS RCTs, is a weak predictor of long-term disability and 
quality of life (QoL) (7); the outcomes ranked highest amongst the patients and other 
stakeholders. Therefore, patients and clinicians are left to make important treatment de-
cisions based on imperfect results from short term RCTs with limited generalizability to 
real-life situations.  
 
The treatment landscape for MS has changed considerably in the last two decades. The 
first-line treatments have up to recently only included treatments that involve self-ad-
ministered injections (interferons, IFN; glatiramer acetate, GA). IFNs often are associ-
ated with side effects such as flu-like reactions and injection site reactions and GA re-
quires daily subcutaneous injections often giving rise to local irritation and lipoatrophy at 
injection sites. In RCTs IFN and GA have been shown to decrease the annualized relapse 
rate (ARR) with 30–40% and inflammatory magnetic resonance imaging (MRI) activity 
with 60–85% (8, 9). Injectable DMTs is a common first line choice for newly diagnosed 
MS patients, or even from the first clinical episode (clinically isolated syndrome, CIS) 
(10). Data from controlled studies indicate a positive effect on the rate of disability accu-
mulation in the short-term and observational data from sources such as the Swedish MS 
registry (SMSreg) also indicate a positive effect on the long-term prognosis of the dis-
ease (11), even if contradictory results also have been produced, see e.g. (12).  
Depending on the individual formulation, the DMT cost per patient and year is between 
80 000 and 100 000 SEK. 
 

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The monoclonal antibody (MAb) natalizumab (NTZ, Tysabri®) was registered for the 
treatment of inflammatory active MS in 2006, based on two phase III RCTs. In AFFIRM 
NTZ was compared with placebo over two years in a largely treatment naïve population 
of RRMS patients (13). In SENTINEL NTZ was compared to placebo as add-on treatment 
in patients having a relapse on interferon-beta1a (14). Based on current evidence NTZ is 
considered to have higher efficacy and better tolerability than injectable platform thera-
pies (13). It must, however, be administered via intravenous infusions every four weeks, 
which impose burdens for the health care system and restricts the freedom for the pa-
tients. The effect on the disease is estimated to about 70% reduction of relapse fre-
quency and 90% reduction of MRI activity (13). According to presently used indications, 
NTZ is used mainly as a second-line therapy for patients not responding to first-line ther-
apies, or as first-line in patients with very high disease activity. Cessation of NTZ therapy 
has been associated with a rebound in disease activity, with increased risks of sometimes 
severe relapses. About 2-4% of patients develops neutralizing drug antibodies (NAB), 
which has been associated with loss of therapeutic effect and increased relapse risk. 
Apart from economical reasons, the main reason not to use NTZ as a first-line therapy is 
the documented increased risk to develop a severe opportunistic infection caused by JC 
virus; progressive multifocal leukoencefalopathy (PML). The frequency of PML in NTZ-
treated patients is estimated to be approximately 0.1-5‰ per year, depending on the 
profile of a set of risk factors for developing PML that now can be estimated on an indi-
vidual basis. For safety reasons more frequent MRIs are recommended in patients with 
increased risk of PML. The drug cost of NTZ is about 200 000 SEK yearly and it demands 
resources for monthly infusions as well. The increased efficiency, however, appears to 
lead to health economic gains through improved working capacity (15, 16).  
 
Fingolimod (FGL; Gilenya®) was approved for RRMS in 2011 (2010 in the US) based on 
three phase III RCTs; Freedoms I and II were two-year placebo-controlled and in Trans-
forms one year of FGL was compared with i.m interferon-beta1a (17, 18) (19). Compared 
with placebo FGL reduced ARR with 50-60%, and the risk of disability progression with a 
third in Freedoms I (not significant in Freedoms II). Compared to interferon, FGL reduced 
ARR with 40%. Alike NTZ, FGL in Sweden has been used mostly in patients displaying in-
sufficient effect on first line therapies. In addition, FGL has been a common choice for pa-
tients switching from NTZ due to positive serology for JC-virus, however, then incurring a 
significant risk of new relapses (20). The yearly cost per patient of FGL is 200 000 SEK. 
 
During the last two years, two oral treatments and another intravenously administered 
treatment have become available for treatment of RRMS. Teriflunomide (Aubagio®) is 
the active metabolite of leflunomide, an oral treatment approved for rheumatoid arthritis 
(RA). It was approved based on two phase III RCTs in RRMS; Temso and Tower (21, 22). 
In both studies two doses of teriflunomide were compared to placebo. At the highest 
dose (14 mg QD) teriflunomide reduced the risk of confirmed disability progression com-
pared to placebo, and the ARR with a little more than a third. Although generally well tol-
erated, teriflunomide carries risks of peripheral neuropathies and other potentially seri-
ous adverse events (SAE). It is also potentially teratogenic, which is a problem when 
treating fertile women. The yearly cost in Sweden is 90 000 SEK.  
Dimethylfumarate (DMF; Tecfidera®) is an oral compound with BID dosing. It was ap-
proved for RRMS based on two phase III RCTs in RRMS; CONFIRM and DEFINE (23, 24). 
In both studies DMF with BID or TID dosing were compared to placebo. DEFINE also in-
cluded a GA open label arm. In both studies ARR was reduced with about 50%. The risk 
of confirmed disability progression was reduced with a little more than a third in DEFINE, 
but was not significant in CONFIRM. DMF initially was perceived as having a beneficial ad-
verse event (AE) profile, but since its launch several cases of PML has now been docu-
mented. In addition, gastrointestinal discomforts and facial flush lead to reduced tolera-
bility. The cost of DMF on the Swedish market is 140 000 SEK annually.  

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The monoclonal antibody alemtuzumab (Lemtrada®) represents the first DMT with a re-
mission-inducing profile, which makes continuous immune suppression unnecessary. A 
treatment cycle involves two courses of repeated infusions and has a potential to induce 
long-term remission of disease activity through long-term ablation of immune memory 
cells (25). It is, however, associated with a number of autoimmune AEs, some of which 
are serious and potentially life-threatening, and therefore requires a diligent follow-up 
protocol. Alemtuzumab was approved based on two phase III RCTs in RRMS; Care MS I 
and Care MS II, where alemtuzumab was compared to s.c interferon-beta-1a (25, 26). 
Due to the lack of double blinding FDA initially decided not to approve alemtuzumab on 
the US market, however, this decision was later reversed. The price for two courses of 
alemtuzumab amounts to approximately 500 000 SEK, but about 30% of patients require 
additional treatment cycles.  
Daclizumab (Zinbryta®), a drug previously approved for limiting the risk of transplant re-
jections, was recently approved for RRMS (27). As daclizumab has been withdrawn from 
the market it will not be further considered here. 
Recently, two additional DMTs have been approved for RRMS; ocrelizumab (Ocrevus®), 
which is a novel anti-CD20 recognizing biological drug, and cladribine (Mavenclad®), 
which is an oral purine analogue that selectively suppresses lymphocytes. Ocrelizumab is 
indicated for active RRMS and cladribine for RRMS patients with highly active disease.  
 
The monoclonal antibody rituximab (RTX; Mabthera®) recognises the surface antigen 
CD20 on B-lymphocytes and induce cell mediated (ADCC) and complement mediated ly-
sis of these cells (28). After administration the number of B-lymphocytes in peripheral 
blood usually are below detection limits for 6–9 months after which they gradually return 
to normal values. RTX has been successfully used in many autoimmune conditions and is 
approved for RA, B cell lymphoma and systemic vasculitis (29). In neurological diseases 
it is also used off-label for neuroimmunological conditions such as neuromyelitis optica, 
myasthenia gravis and immune-mediated neuropathies. RTX is generally well tolerated 
and has very few severe side effects. The most feared complication of immunosuppres-
sive treatment in neurology is the development of PML (30). It is difficult to accurately 
assess the risk of developing PML as a consequence of RTX treatment when used in mon-
otherapy in non-immune compromised patients such as MS. Previous cases have almost 
inevitably been associated with the combination of RTX treatment and an underlying dis-
ease that involve increased risk for PML (e.g. lymphoma, SLE) or a combination with 
other immunosuppressive therapies such as methotrexate or cytotoxic drugs. Attempts 
to estimate the risk conferred by RTX itself has led to the conclusion that there is no 
proven over-risk for serious infections including PML by this treatment (31). In RA pa-
tients treated with RTX the risk of PML is estimated to approximately 1/25 000 treated 
individuals (32), which is even less than the estimated risk of developing PML in NTZ-
treated individuals testing negative for JCV antibodies. Furthermore, patients with RA 
that have developed PML have also received other immunosuppressive drugs in combina-
tion and are generally older and with more concomitant diseases than what is usually the 
case in MS. In conclusion, it is expected that the risk profile of RTX used as monotherapy 
is beneficial compared with most DMTs currently approved for MS. 
 
RTX has been tested in a placebo-controlled phase II study for RRMS, Hermes (33). After 
two infusions of 1000 mg RTX there was a significant reduction of exacerbation rate of 
more than 50% and >90% reduction of new or contrast-enhancing MRI lesions (CEL) 
(33). Patients in the study were followed for 48 weeks, a time point at which there were 
no sign of resuming MRI activity. In addition, RTX has been tested in a two-year placebo-
controlled phase II/III RCT study for PPMS, Olympus (34). Active drug was not associ-
ated with a decreased risk of disability progression as a whole, but was significant in 
younger patients with signs of active disease on MRI. More recently, a Swedish phase II 
trial demonstrated reduced subclinical inflammatory activity measured via MRI and CSF 
neurofilament light (NFL) concentration, when switching patients in a clinically stable 

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phase treated with injectables to RTX (35), at the same time as treatment satisfaction 
improved considerably (36). A retrospective Swedish comparative effectiveness observa-
tional study showed a 92% reduced risk for relapse when switching to RTX compared 
with switching to FGL in patients terminating NTZ because of positive JC virus serology 
(20). In another recent retrospective Swedish observational study comprising 822 pa-
tients with on average two years treatment duration the frequency of serious side effects 
were low and there were no life-threatening complications or side effects leading to any 
type of sequelae attributable to the RTX treatment (37). Notably, a lower than previously 
used dose of RTX, 500 mg as a single infusion every 6 months, was shown to be equally 
effective as 1000 mg with the same dosing interval. Potentially this may also further im-
prove a previously beneficial AE profile, in addition to reducing costs. The yearly drug 
cost per patient for this low dose regimen of two annual infusions of 500 mg is 25 000 
SEK. 
 
As noted previously, NTZ is associated with a 60-70% risk of rebound disease activity 4-
7 months after discontinuation (38). This rebound disease activity can be fatal and se-
verely disabling. Severe rebounds have been reported with pregnancy discontinuation 
(39), making choosing to continue or discontinue NTZ in JCV Ab+ patients or in women 
desiring pregnancy a major clinical challenge in RRMS with highly active disease at treat-
ment start (40). In contrast to other DMTs, only RTX has been documented to continue 
to control disease activity after discontinuation of NTZ. Thus, as mentioned above, an ob-
servational study of 256 patients switching from NTZ to either RTX or FGL due to JCV 
positivity at three large Swedish MS centers showed that the odds or hazard ratios for a 
clinical relapse, contrast enhancing MRI lesions and AEs with RTX compared to FGL were 
0.09, 0.01 and 0.50 (after correction for baseline differences), respectively (20). Lacking 
a formal RCT for this clinical situation and based on these findings RTX should be consid-
ered the most effective DMT for patients going off NTZ. 
 
Two other MAb directed at the CD20 epitope on B-lymphocytes are presently evaluated 
as a treatment for MS and both have shown excellent results in phase II trials (41, 42). 
The humanised MAb ocrelizumab is manufactured by the same company as RTX (Roche) 
and differs from RTX in being a humanized MAb and therefore can be assumed to be less 
immunogenic than the chimeric counterpart. The pharmacodynamic properties are other-
wise more or less identical by effectively depleting peripheral blood lymphocytes, but 
with more weight towards ADCC than complement mediated lysis as compared with RTX. 
In two recently published phase III trials ocrelizumab displayed a superior efficacy to 
prevent both relapses and accumulated disability compared with s.c interferon beta1a 
(43). Ocrelizumab was initially investigated also in RA but this program was terminated 
by the producer because of a signal for an increase in serious infections when combined 
with Methotrexate (44).  
 
There is no phase III study planned for RTX in RRMS by its manufacturer Roche. On the 
other hand, there is extensive experience in the world from treatment of autoimmune 
conditions with RTX that offers superior safety data compared with most DMTs approved 
for MS. The patent protection for RTX expired 2016 thwarting any commercial interests in 
performing additional trails needed to register RTX as a licensed MS medication. There-
fore, studies have to rely on investigator-initiated trials. A randomised phase III trial 
comparing RTX with DMF in early MS has been initiated in Sweden (RIFUND-MS, EudraCT 
2015-004116-38).  
 
Because of the apparent unique combination of efficacy on MS disease activity, favoura-
ble safety profile and patient-friendly treatment regime, RTX has already gained a wide-
spread use in MS in Sweden, despite not having a formal MS indication. In fact, it is now 
the single mostly used MS DMT, though with large regional differences. Alike all approved 
MS DMTs a fundamental objective is to provide data on efficacy and safety over longer 

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time periods. A structured follow-up of RTX outcomes in relation to other MS DMTs is 
therefore essential, which is the focus of the present study. 
 
Findings from this study will provide important information necessary to do well based 
health care decisions for patients in various phases of disease, with different treatment 
experiences and health profiles. This study will provide effectiveness and safety analyses 
of RTX, a drug that is accessible worldwide, compared with current approved MS DMTs. 
Furthermore, it will report outcomes that matter to patients and stakeholders and thus 
have the potential to gather data that can be used to improve the care for RRMS patients 
worldwide. 
We plan to perform analyses in two different settings. In a pure retrospective registry-
based study we will include all patients nationwide fulfilling inclusion criteria based on 
available data in the MS registry. However, the MS registry does not have complete cov-
erage for all parameters, which will impact negatively on the power and validity of find-
ings. In addition, the quality of registered data is difficult to assess accurately. In particu-
lar, this is a problem with one of the most important outcome measures, the EDSS rating 
scale of disability accumulation, since it will make disability outcome comparisons less re-
liable. This will be assessed in the COMBAT-MS study in which registered data will be val-
idated against medical records and structured prospective annual assessments will be 
performed, however, with a rigorous non-intervention design with regard to choice of MS 
DMT. 
 
2. Objectives of the Study 
The overarching goal of this study is to describe the effectiveness and safety of RTX in 
comparison to other commonly used approved DMTs in the largest real-world population-
based structured prospective follow-up cohort of RRMS patients. The study will include 
both treatment naïve patients on their first DMT and patients that have switched from a 
previous first line DMT (escalation/second-line). In keeping with the non-interventional 
design and real-world setting, we are not primarily interested in hypothesis testing of 
whether RTX is superior or non-inferior to a specific alternative DMT. Our main focus is 
instead in presenting point estimates and confidence limits for the range of alternative 
treatments currently used in clinical practice, with a range of alternative outcome 
measures. Different anti-CD20 DMTs will be analysed both as a group and separately. 
The three outcomes that were ranked highest by patients surveyed and our stakeholders 
when choosing a DMT were long-term disability, QoL and risk of serious life-ending or -
altering AEs. How specific MS DMTs affect early accumulation of permanent disability, a 
strong predictor of long-term disability (45), and QoL particularly in comparison with 
other DMTs in real life populations is not known.   
2.1 Primary Objective 
The two co-primary objectives of this study are  
1. To compare the long-term effectiveness for preventing disability and reduced QoL 
of RTX with the most commonly used escalation agents, DMF, NTZ and FGL, in 
RRMS patients who have experienced disease activity on first-line DMTs 
2. To compare the long-term effectiveness for preventing disability and reduced QoL 
of RTX with IFN, GA, NTZ, FGL and DMF in treatment-naïve RRMS patients  
 
 
2.2 Secondary Objectives 
The secondary objectives of the study are  

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• 
To compare the long-term safety of RTX with the most commonly used escalation 
agents, DMF, NTZ and FGL, in RRMS patients who have experienced disease activ-
ity on first-line DMTs 
• 
To compare the long-term safety of treatment with RTX with IFN, GA, NTZ, FGL 
and DMF in treatment-naïve RRMS patients 
• 
To compare drug survival, as a compound measure of effectiveness, side-effects 
and patient satisfaction, between RTX and IFN, GA, FGL, DMF and NTZ 
• 
To compare patient satisfaction, fatigue and health related quality of life between 
treatment with RTX and IFN, GA, FGL, DMF and NTZ  
• 
To study the occurrence of anti-drug antibodies (ADA) against RTX and their effect 
on B-lymphocyte levels and treatment efficacy. 
• 
To compare the effectiveness on preventing MRI CELs between treatment with 
RTX and IFN, GA, FGL, DMF and NTZ in first-line and second-line settings, respec-
tively. 
 
2.3 Tertiary Objectives 
The tertiary objectives of the study are  
• 
To make health economic assessments and compare cost-effectiveness between 
treatment with RTX and IFN, GA, FGL, DMF and NTZ 
• 
To compare the effectiveness, safety and patient satisfaction of RTX with other 
less frequent DMTs (teriflunomide, alemtuzumab). 
• 
To compare serum/plasma neurofilament light (NFL) levels in patients treated 
with RTX and IFN, GA, FGL, DMF and NTZ. 
 
 
3. Outcome Definitions 
3.1 Primary Outcomes 
The primary endpoints in this study are: 
• 
Proportion of patients with baseline EDSS ≤2.5 progressing to 12 months confirmed 
EDSS ≥3 over 3 years of follow up. 
• 
Proportion of patients with baseline EDSS ≥2.5 experiencing 12 months confirmed 
EDSS change +1 point over 3 years of follow up. 
• 
Change in MSIS-29 over 3 years of follow up (change from baseline; mean value 
±SD). 
 
End points will be tested in -First line RTX vs DMF/GA/IFN/NTZ/FGL and Second line/es-
calation (switching from DMF/GA/IFN) RTX vs NTZ/FGL/DMF. 
3.2 Secondary Outcomes  
Secondary analyses comprise comparisons between the different treatment regimens 
concerning: 
• 
Rate of malignancy, cardiovascular disease, serious infections and all-cause mor-
tality in populations on therapy and ever treated, respectively. Data on safety out-
comes will be obtained through linkage to the national Cancer, Patient, Prescribed 
Drug, and Causes of Death registers. 
• 
Annual relapse rate. 
• 
Mean number of CELs on yearly MRI. 
• 
Drug survival and reason to terminate treatment. 
• 
Yearly increase in mean and median EDSS. 
• 
Yearly proportion of patients with at least 1 step increase in EDSS. 

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• 
Evaluation of frequency, titre, kinetics and clinical relevance of anti-RTX ADA. 
• 
Yearly proportion of patients with No Evidence of Disease Activity (NEDA) -2 (free 
of exacerbations, new/enlarged T2-lesions and occurrence of CEL) as well as 
NEDA-3 (NEDA-2 plus no worsening of EDSS from baseline). 
• 
Mean levels of NFL in serum. 
• 
Yearly brain atrophy rate measured as brain parenchymal fraction (BPF) for differ-
ent DMTs in a sub-population of patients and in relation to baseline values. 
• 
Estimation of total societal costs per year after initiating treatment. 
• 
Evaluation of health related QoL, fatigue and patient satisfaction during the treat-
ment. 
• 
Evaluation of work ability. 
 
 
4. Study Design 
4.1 Description of Study Design 
This is a prospective non-interventional prospective cohort study assessing the long-term 
safety and efficacy of RTX treatment in MS compared with other common MS DMTs re-
garding both clinical and radiological parameters in a real-life population of patients with 
MS. 
 
Assessments of a range of parameters, presently performed on other MS drugs in Swe-
den as a follow up program (IMSE), will be performed annually. These include amongst 
others demographics for treated patients, relapse rate, MRI activity, previous drug his-
tory and reasons for discontinuation, as well as a panel of patient reported scales (Sym-
bol Digit Modalities Test, SDMT; MS check scale; MS impact scale-29, MSIS-29 and EQ-
5D). In addition to the IMSE protocol, also the FSMC and Treatment Satisfaction Ques-
tionnaire 9 (TSQM-9) will be assessed. 
Safety will be evaluated through linkage to national health care registers, with analysis 
describing the total numbers of SAEs, regardless of suspected causal association to a 
specific drug, and sensitivity analysis comparing rates while on drug, and ever after be-
ing exposed to the drug. Data availability through registers is limited by the annual up-
dates of the Patient and Cancer register, and administrative time for the register-holding 
authorities (The National Board of Health and Welfare, Statistics Sweden), which will not 
allow for real-time assessments or annual reports at specific time points. To supplement 
this system, we will also ensure real-time reporting of SUSARs, through the Neuroregis-
ter platform, and summarize such events in annual reports to the Medical Products 
Agency. The SUSAR collection is thus intended to fill the gap in real-time safety surveil-
lance of RTX, but will not form the basis of any comparative analyses across therapies. 
 
4.2 Justification of Study Design 
RTX is an existing drug with widespread use in autoimmune disorders, which since 2008 
has been used increasingly also for MS both within and outside of clinical trials. A com-
pound with identical mode of action (ocrelizumab) will likely be registered for MS in the 
near future, but the extensive clinical experience with RTX still makes this drug an attrac-
tive alternative treatment option in MS. RTX is furthermore considerably cheaper than 
formally approved MS drugs. The Swedish law allows the use of drugs outside of its ap-
proval (off-label) in certain situations. In case of RTX in MS, with a much expanding and 
systematic use a more structured follow-up of safety and effects is clearly warranted. In 
addition, a phase III trial with RTX compared to DMF for early RRMS has now been 
started in Sweden (EudraCT 2015-004116-38). However, alike the situation for several 

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other recently approved MS DMTs, there is a scarcity of long-term outcomes in real life 
patient populations. Given the high degree of registration of MS DMTs and a panel of dis-
ease related assessments in the SMSreg we can capitalize on already accumulated data 
that combined with structured annual prospective follow-ups can provide validated long-
term outcomes. The combination of retrospective validation of registered data and pro-
spective follow-up in a non-interventional design appears the most adequate design for 
this purpose.  
 
In keeping with the Good ReseArch for Comparative Effectiveness (GRACE) principles 
(http://www.pharmacoepi.org/pub/1c29f69f-2354-d714-5100-1ef2b0e9abd9), we will fo-
cus on a “new user design”, while using multiple comparator groups, representing the 
range of alternative DMTs available in clinical practice. We have pre-specified the overall 
outline of outcome measures and analyses to be done, and will document any later 
changes, including data driven specifications of covariate selection, in an updated study 
protocol for transparency.  
 
 
 
 
5. Study Visits  
5.1 Assessments during the Study 
The follow-up protocol will largely harmonize with the IMSE follow-up protocol that is ap-
plied on all new immunomodulatory drugs in Sweden since the approval of NTZ in 2006 
(ethical review board in Stockholm Dnr 2006/845-31/1, subsequent DMTs 2011/641-
31/4) according to the scheme below. To this follow up protocol two additional rating in-
struments have been added; the FSMC and the TSQ. Study visits will be performed once 
annually for effectiveness outcomes and twice annually for compliance assessments. 
 

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6 Study Population 
6.1 Number and Selection of Subjects 
Patients will be identified through the SMSreg. Inclusion into the COMBAT-MS study will 
be subject to written informed consent. Given the rigorous non-intervention design of the 
study and very limited study-specific procedures outside of clinical practise, we expect 
participation rates to be very high. Based on preliminary calculations from the SMSreg 
the projected number of participants will be 3700 patients, out of which at least 1000 are 
treated with RTX first or second-line. A vast majority will already have started MS DMT 
prior to inclusion into the study.  
  
TEST/CONTROL 
  
PRE-TREATMENT 
(BASELINE) 
EVERY 6 
MONTH 
YEARLY 
REGISTER IN SMSreg 
( www.neuroreg.se ) 
CONTROLS SPECIFIC FOR RITUXIMAB 
1 
EVALUATING % AND AB-
SOLUTE COUNTS OF B-
LYMPHOCYTES 
YES 
BEFORE EACH 
INFUSION 
 
YES 
CONTROLS ALL THERAPIES  
2 
CBC INCL DIFF, s-IgG, 
LFT, TSH, eGFR 
YES 
RTX, FGL, NTZ, 
DMF 
IFN, GA 
NO 
3 
MRI 
YES 
YES 
YES 
4 
EDSS 
YES 
  
YES 
YES 
5 
SDMT 
YES 
  
YES 
YES 
6 
MSIS-29 
YES 
  
YES 
YES 
7 
TSQ 
YES (if 2nd line) 
 
YES 
YES 
8 
FSMC 
YES 
 
YES 
YES 
6 
EQ-5D 
YES 
 
YES 
YES 
10 
“MS-CHECK SCALE” 
YES 
 
YES 
YES 
11 
SIDE EFFECTS 
 NO 
MONITORED EVERY VISIT 
YES 
12 
Serum/plasma/blood 
sample for ADA, NFL 
YES 
 
YES 
 
YES 

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6.2 Eligibility Criteria 
6.2.1 Inclusion Criteria 
The study population consists of all patients with CIS/RRMS diagnosed with the 2010 re-
vised McDonald criteria (46) who; 
• 
Initiate a first MS DMT (treatment naïve), or 
Initiate a second ever DMT, of a different drug class than the first, regardless of 
time between drugs or reason for discontinuation (“switchers”) from 1st Jan 2011 
to 30th June 2019, and 
• 
Are followed at any of the University clinics of Sweden, and 
• 
Consent to participation in COMBAT-MS core, and 
• 
Are expected to be capable to follow study assessments and have decision-making 
capacity, e.g. lucid and oriented x 4 as judged by the investigator; and 
• 
Are aged ≥18 years and ≤ 75 years at the day of signing the informed consent for 
inclusion into the prospective study (i.e. no age limit for retrospective data), and 
• 
In case of fertile women, have been given information on potential DMT-related 
teratogenic effects and what type of contraception is considered safe according to 
respective SmPC.  
 
6.2.2 Exclusion Criteria 
 
Patients who at inclusion have the following characteristics are excluded from study par-
ticipation; 
• 
progressive forms of MS at start of the inclusion therapy (first bullet above). 
• 
other neurological or other conditions that may interfere with follow study assess-
ments or decision-making capacity. 
• 
subjects with conditions listed as contraindications to the use of medicinal products 
used in the trial, e.g. gadolinium used for MRI scans. 
• 
ongoing participation in other trials with blinded study medication or that interfere 
with the study protocol. 
 
6.2.3 Retrospective Review of Inclusion/Exclusion Criteria  
Medical charts will be reviewed for all patients for whom inclusion and exclusion criteria 
are fulfilled based on available information in the MS registry. This will be done in order 
to validate, and in case of incomplete or discrepant information, update, curate and fill in 
gaps based on the information available in the medical charts. 
 
The following information will be reviewed and verified: 
• 
Disease Onset  
• 
MS diagnostic criteria 
• 
Disease course at start of therapy 
• 
Start/end of first MS treatment 
• 
Start/end of second MS treatment 
 
If fulfilling inclusion and exclusion criteria, the completeness of the following items will be 
checked: 
• 
Relapses within the first 2 years of start of treatment and up till inclusion 
• 
Reason for terminating treatment 

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• 
EDSS ratings, where special focus will be made to assess if EDSS at baseline was 
≤2.5 or ≥3. Missing EDSS information can be included if listed in medical charts or 
can be deduced from clinical status. 
• 
MRI scans: total number of T2 and gadolinium-enhancing lesions as given in the 
original radiology report. 
• 
If missing also MSIS-29, EQ5D, MS check scale, TSQ can be included if noted in 
medical charts. 
• 
Dates and doses of RTX infusions, as well as all moderate to severe infusion-re-
lated AEs 
 
7. Treatment within the Study 
 
Given the non-interventional design of the study, the protocol does not impose any regu-
lations as to the choice or administration of the studied DMTs. However, we expect that 
DMT administration to large degree will follow the respective SPCs and in the case of RTX 
recommendations by the Swedish MS Association (initial infusion with 1000 mg iv and 
thereafter 500–1000 mg iv every 6 months). Any deviations to the protocol will be rec-
orded in the SMSreg. 
 
 
8. Blinding within the Study 
There will be no blinding for neither treating physician nor patient within the study. 
9. Disease Activity within the Study 
Exacerbations will be evaluated according to standard clinical care and treated with 
methylprednisolone as determined justified by the treating physician. EDSS assessment 
according to a study specific protocol (appendix) will be performed at yearly visits. 
 
10. Definitions of Exacerbation 
A confirmed relapse is defined as new onset of neurological symptoms with a duration of 
more than 24 hours compatible with MS and preceded by a period of stable clinical symp-
toms of at least 30 days that does not have a more likely alternative explanation. Aggra-
vation of previous symptoms may be counted as exacerbation if they arise without fac-
tors that can trigger pseudo bouts and are accompanied with new objective findings (e.g. 
worsening of visual acuity in an eye with previous optic neuritis and also pain behind the 
eye). All suspected relapses will be adjudicated by the local site-PI. 
 
11. Withdrawal Criteria and Early Termination 
Individual subjects have the right to withdraw their consent to participate in COMBAT-
MS, but will then be followed up in the nationwide registry based study according to nor-
mal clinical routines. The investigator also has the right to withdraw subjects from the 
study in the event of change in eligibility or other reasons. 
 
12. Study Assessments 
The structure and content of scheduled visits in the study is given in the chart under 
point 5.1.  

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At the annual effectiveness outcome assessments, a standardized EDSS will be per-
formed (appendix) together with SDMT and EQ-5D. Patients will be encouraged and in-
structed how to fill in the remaining patient reported scales prior to the visit on line. In 
the case this has not been done or the patient opt not to do it on line, this will be done 
during the visit. The patient will be actively interrogated about any potential AEs that has 
occurred since the last visit or any other health related issue. Finally, a MRI investigation 
will be performed, preferably before the clinical visit. In order to standardize the collec-
tion of data a help document for the visit will be distributed to participating centers. A 
nurse visit will be performed approximately at 6 months from the effectiveness assess-
ment in order to check on compliance and safety issues. This can be done by telephone if 
deemed more convenient for the patient. 
 
 
13. Study Medication  
13.1 Study Medications included in the Study 
The following DMTs will be considered study drugs: 
IFN (Avonex®, Betaferon®, Extavia®, Plegridy®, Rebif®) 
GA (Copaxone®) 
DMF (Tecfidera®) 
Teriflunomide (Aubagio®) 
FGL (Gilenya®) 
NTZ (Tysabri®) 
Alemtuzumab (Lemtrada®) 
RTX (Mabthera®) 
bRTX (Ritemvia®) 
Ocrelizumab (Ocrevus®) 
Cladribine (Mavenclad®) 
13.2 Concomitant Medications and Non-Drug Therapies 
The focus of COMBAT-MS is effectiveness outcomes. Co-morbidities or concomitant medi-
cations will not be registered in the present study protocol. However, through cross-link-
age with national compulsory registries for in- and outpatient care and prescribed drugs 
such information will be retrieved for the final analysis. The linkage studies with national 
health care registries are subject to additional ethical approvals (EPN Stockholm 
2017/700-31/4).  
 
14. Safety Reporting 
14.1 Definition of a Serious Adverse Event 
An SAE is defined as any untoward medical occurrence or effect, that at any dose: 
• 
Results in death 
• 
Is life threatening 
• 
Requires hospitalization or prolongation of existing hospitalisation 
• 
Results in persistent or significant disability or incapacity 
• 
Is a congenital anomaly or a birth defect 
• 
Is another significant medical event 
An AE necessitating hospitalisation meets the regulatory definition for “serious” if the in-
patient hospital admission includes a minimum of an overnight stay in a health care facil-
ity. Any AE that does not meet one of the definitions of serious (e.g. an AE requiring an 
emergency room visit, outpatient surgery or requires urgent investigation) may be con-
sidered by the investigator to meet the “other significant medical event” criterion for 

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classification as a SAE. Examples include allergic bronchospasm, malignancies, convul-
sions and blood dyscrasias. 
 
14.2 Disease-Related Events and/or Disease-Related Outcomes Not Qualifying 
as SAE 
Relapses or symptoms associated to MS is not considered as an AE and should not be 
recorded as such irrespective of hospitalisation. Planned operations or examinations re-
quiring hospitalisations are not considered as SAE, only complications associated with the 
procedures specific for the study are considered as AEs or SAEs. 
 
14.3 Definition of a Serious Adverse Reaction (SAR) 
A SAR is an SAE where the investigator judges that the AE is at least possibly related to 
the use of any of the investigational medicinal products listed under 13.1. 
14.4 Definition of a suspected unexpected serious adverse reaction (SUSAR) 
A suspected unexpected serious adverse reaction (SUSAR) is any unexpected serious 
adverse reaction that is considered related to the study drug that; results in death, is life 
threatening (i.e. the subject was at risk of death at the time of the event); requires 
hospitalisation or prolongation of existing hospitalisation; results in persistent or 
significant disability or incapacity; is a congenital anomaly or birth defect. Furthermore, it 
is not expected when compared with the Reference Safety Information (RSI) in the most 
recent version of the SmPC for the respective DMT (se appendix).  
If updates of the SmPC as provided in the appendix (i.e. the Sponsor’s choice of RSI for 
this trial) will occur in the future, these updates will be submitted to MPA as substantial 
amendment applications with a statement that future SUSAR reports will determine ex-
pectedness based on the updated RSI. Upon approval, the updated SmPC will be commu-
nicated to all site PIs. 
14.5 Reporting of Adverse Events 
Each site PI is responsible for collection of SARs (as defined in Section 14.3) and report 
these regularly to the Sponsor, whose responsibility it is to summarize all SARs occurring 
in the study and provide the MPA with annual reports summarizing all accumulated 
events, both as line listings of all SARs and as a table specifying frequencies for each 
study drug sorted by SOC/PT (system organ class/preferred term). This annual report will 
also contain SUSARS (see below) be distributed to all sites in the study. 
For all suspected SUSARs, i.e. where the site PI cannot determine if the event qualifies as 
a SUSAR as defined in Section 14.4 or not, these should be reported in an expedited 
fashion to the Sponsor for adjudication. The Sponsor will determine if the event should 
be reported as a SUSAR. Fatal or life threatening events deemed as a SUSAR will be re-
ported within 7 days after the Sponsor first became aware of the reaction. A SUSAR, 
which is not fatal or life threatening, will be reported by the Sponsor within 15 days after 
becoming aware of the reaction. SUSAR reports will be prepared in CIOMS format and 
sent to registrator@mpa.se for uploading into EudraVigilance database, clinical trials 
module. During the study, an annual safety report (DSUR) on safety issues occurring 
among the trial subjects will be sent to the MPA and the relevant ethics committee, with 
a summary of events, separating the expected SARs (see above) from the unexpected 
SUSARs, and as well as providing information on the benefit-risk assessment, if changed 
since the study was approved. 
 

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15. Data Analysis and Statistical Considerations 
15.1 Sample Size Considerations 
The calculated study population is 3700 individuals and prospective inclusion will con-
tinue until 30th June 2019 or when the study is fully recruited. There is already over 
2000 patients registered in the SMSreg treated with RTX but data has been collected only 
semi-systematically according to the guidelines of the SMSreg. The minimal detectable 
difference between RTX and the comparator groups depend on the projected sample 
sizes, of which we are fairly certain given the substantial data already collected. For the 
primary effectiveness outcome, it also depends critically on the proportion with valid in-
formation on EDSS at baseline and evaluation visit which is currently available for just 
over half of the patients, but which we aim to improve, and will also further improve by 
using multiple imputation. Using the NTZ group (where we currently have the most data) 
as a benchmark, we can calculate predictions for the number of patients we will be able 
to include in analysis of EDSS change. Of patients currently enrolled who started NTZ and 
have at least 3 years of follow-up, ~60% remained on therapy at 3 years, ~70% of these 
had valid MSIS29 and ~40% had valid EDSS at both baseline and evaluation visit after 3 
years. Censoring for reasons other than drug discontinuation (death, emigration) is rare 
enough that it can be disregarded. Thus, while safety outcomes, drug persistence, and 
reasons for discontinuing therapy can be assessed among all patients initiating therapy, 
the change in EDSS can only be assessed in ~25% of patients, and the change in 
MSIS29 in 40-45%. By increasing the data capture of EDSS, through abstraction of clini-
cal documents, we hope to bring this number to ~50%, which would require valid EDSS 
data on baseline and evaluation visit for 80% of all patients who remain on therapy at 
three years. Dividing the group further by baseline disability (EDSS below or over 2.5) 
would roughly reduce the sample by half for each outcome. The resulting minimal detect-
able difference would then be -9%-+12% with current EDSS registration rates, and -7%-
+10% with improved EDSS rates; MSIS change (mean 0.3, SD 0.7) +/-0.10; remaining 
on drug +/- 5%; rate of malignancies (based on Bahmanyar et al. (47) with 5/1000) HR 
2.6 – 3.9. 
 
 
15.2 Key Elements of Analysis Plan 
During data collection, semi-annual data summaries will be made, describing the treated 
population regarding demographic data, collected efficacy data as well as reported side 
effects. These reports will be used in combination with ad hoc supporting analysis to 
identify bottlenecks and limitations in the data collection, and ensure a more complete 
data set.  
 
Effectiveness of therapy will be assessed primarily at an evaluation point 3 years after 
treatment initiation, measured as proportions experiencing disease progression, and pro-
portions who have discontinued therapy. Results represent patients remaining on therapy 
still after 3 years, and must be interpreted in light of the proportion who has discontinued 
therapy before this date. The reason for discontinuing therapy will be used as an addi-
tional (secondary) outcome measure. Patients who temporarily reach an EDSS of 3.0, but 
subsequently improve will not be considered as having reached the endpoint. Outcomes 
on RTX will be tested relative to comparator with drugs by line of therapy using multivar-
iable regression. Choice of covariates will be guided by observed baseline characteristics, 
but will at least include sex, age, several baseline disease activity measures (other than 
EDSS), and background demographic factors. The proportion remaining on therapy at 3 
years will be modelled in multivariable regression models as described above, but also 
studied continuously over time with Kaplan-Meier curves and multivariable Cox regres-
sion, with time since treatment start as time scale. As the main patient reported measure 

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of treatment effectiveness, we will analyze mean change in MSIS29 from treatment initi-
ation to evaluation visit in linear regressions. The distribution of delta values is expected 
to approximately follow the normal distribution, but if skewness is detected confidence 
intervals will be calculated using empirical bootstrapping. 
 
A major component in the proposed project is to increase the data capture of EDSS, 
where we currently have data on only about 50-70% of all visits, meaning that the ex-
pected proportion with EDSS data on both baseline and evaluation visit is only about 40-
50%. In addition to improving the data quality, we have the possibility to use multiple 
imputation to fill out missing values for EDSS, since we have access to several other 
measures with higher data coverage, including MSIS29. This imputation may provide 
some additional power, but will also help to assess the potential for, and to avoid, selec-
tion bias associated with measured baseline characteristics. 
 
Safety outcomes will analysed using linkage to relevant health registries and assessed in 
time-to-event analysis, with special consideration to the possibility for effect heterogene-
ity by time since treatment initiation. To take the potentially long latency of malignancies 
into account, overall and subtypes of malignancies will be analysed both in “ever 
treated”-analysis, including all follow-up after treatment initiation, and “on drug” where 
only follow-up time on active treatment is considered. Data will be presented as number 
of events, crude and age/sex-standardized incidence rates, and when sample size per-
mits (5+ events in smallest strata), hazard ratios from multivariable Cox regressions ad-
justing for sex, age, year of treatment start, baseline disease history, and additional co-
variates based on comparison of baseline characteristics across treatment cohorts.
 
 
 
16. Study Administration 
16.1 Definition of Source Data 
The SMSreg in combination with the patients’ medical chart will constitute the original 
data source. Note that this does not refer to the SMSreg as a quality registry, but the lo-
cal database at each center (beslutsstöd), which is considered part of the medical records 
system. In both instances, information about who and when changes have been per-
formed can be traced via electronic signatures that is retained in the system. 
 
16.2 Quality Control and Monitoring 
Each clinical site-PI agrees on performing the study-related tests according to the proto-
col and GCP standards. Local GCP certified staff will supervise data collection and entry of 
data into SMSreg. External monitoring with regular site visits (at least yearly) will be per-
formed by GCP qualified staff of the IMSE study coordination office, representing the 
Sponsor of the trial and independent of the clinical site monitored. The monitoring will 
comprise verification and checking against source data of all informed consents and iden-
tity of study subjects, as well as sample checks of other types of data. Central monitoring 
of data quality entered into SMSreg will be performed regularly by a biostatistician in or-
der to detect inconsistencies.    
 
16.3 Quality Assurance 
It is the investigator’s responsibility to ensure compliance with GCP and all applicable 
regulatory requirements. Regulatory agencies may conduct a regulatory inspection of this 

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trial. Such audits/inspections can occur at any time during or after completion of the 
trial. If an audit or inspection occurs, the investigator and institution agree to allow the 
auditor/inspector direct access to all relevant documents and to allocate his/her time and 
the time of his/her staff to the auditor/inspector to discuss findings and any relevant is-
sues. 
 
16.4 Study Closure 
The last study visit in COMBAT-MS will be performed by 1st July 2022, after which the da-
tabase will be locked. Final analyses and interpretation will be completed by 1st Oct 2022, 
with the draft final research report submission to the funder PCORI  1st Dec 2022. 
 
16.5 Records Retention 
The source data of the study is the SMSreg where collected data will be stored indefi-
nitely. Files with curated data will be stored in a secure database, with necessary backup 
files, for a minimum of ten years at the Karolinska Institutet to allow for easy and timely 
retrieval when needed and to allow any subsequent review of data in conjunction with 
assessment of the facility, supporting systems and staff. 
 
16.6 Case Report Forms 
The SMSreg will serve as electronic CRF. All outcome data will be documented in this reg-
ister (“beslutsstöd”), which is not considered a quality register, by each study team. 
SAEs will be reported separately on separate SAE forms stored at each study site after 
being reported to the Sponsor.  
16.7 Rules for Completing CRFs 
The study personnel must ensure that all information entered into the CRF is consistent 
with the source data. All test and questionnaire completed by the subjects in the study 
should be filed in the respective CRF.  
16.8 Corrections to CRFs 
Corrections are done by changing directly in the SMSreg. All changes are electronically 
traceable regarding when and by whom the change has been done. 
16.9 CRF Flow 
The study personnel are responsible to complete the CRF after each subject visit.  
17. Data Management 
Statistical analyses (see above) will be performed by the Sponsor or person having an 
ethical permission to perform analyses on the relevant data sets. The Sponsor should be 
notified and involved in the discussions regarding specific scientific projects related to the 
data collected within the framework of COMBAT-MS. 
 

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18. Finance and Insurance 
The study has received full financing by a research contract with PCORI (Washington DC) 
and will be conducted completely independent of any commercial interests. The start 
date for the project is the 1st of November 2016. 
Every subject participating in the study is covered by the patient national insurance (“Pa-
tientförsäkringen”). 
 
19. Publication Policy 
 
Yearly reports of aggregated data will be produced by the study administrator at the Ka-
rolinska Institutet and distributed to all participating trial sites. Scientific publications will 
be performed when the trial has reached an amount of data that is deemed clinically and 
scientifically relevant as determined by the steering committee. Substudies of scientific 
value will be performed as relevant research questions that may be answered by the da-
taset will emerge. 
In the event of a publication, the names of the authors and their order of appearance will 
most likely be as follows: Coordinating investigator as first or last author, other investi-
gators according to scientific contribution. All persons designated as authors should qual-
ify for authorship and all those who qualify should be listed. Each author should have 
participated sufficiently in the work to take public responsibility or appropriate portions of 
the content. Authorship credit should be based on (1) substantial contributions to con-
ception and design, acquisition of data or analysis and interpretation of data; (2) drafting 
the article or revising it critically for important intellectual content; (3) final approval of 
the version to be published. Authors should meet conditions 1, 2 and 3. In addition, a 
study group designated “COMBAT-MS study group” with involved study personnel will ap-
pear on the author list. 
 
Appendices 
EDSS rating scale, and other rating scales 
 
References 
1. World Medical Association. Declaration of Helsinki. Ethical Principles for 
Medical Research Involving Human Subjects. Last amended by the 52nd WMA General 
Assembly, Edingburgh, Scotland. 2000. 
2. Lassmann H. Mechanisms of demyelination and tissue destruction in multiple 
sclerosis. Clin Neurol Neurosurg. 2002;104(3):168-71. 
3. Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, Bo L. Axonal 
transection in the lesions of multiple sclerosis. N Engl J Med. 1998;338(5):278-85. 
4. Andersen O. Prevalence and incidence of multiple sclerosis in Gothenburg, 
Sweden, with a discussion on the possible influence of measles and rubella vaccination. 
In: Firnhaber W, Lauer K, editors. Multiple sclerosis in Europe An epidemiological update. 
Alsbach: Leuchtturm; 1994. p. 70-1. 
5. Pittock SJ, McClelland RL, Mayr WT, Jorgensen NW, Weinshenker BG, 
Noseworthy J, et al. Clinical implications of benign multiple sclerosis: a 20-year 
population-based follow-up study. Ann Neurol. 2004;56(2):303-6. 
6. Sundstrom P, Nystrom L, Svenningsson A, Forsgren L. Sick leave and 
professional assistance for multiple sclerosis individuals in Vasterbotten County, northern 
Sweden. Mult Scler. 2003;9(5):515-20. 

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Page 24 of 26 
7. Runmarker B, Andersson C, Odén A, O A. Prediction of outcome in multiple 
sclerosis based on multivariate models. J Neurol. 1994;241:597-604. 
8. Frohman E, Phillips T, Kokel K, Van Pelt J, O'Leary S, Gross S, et al. Disease-
modifying therapy in multiple sclerosis: strategies for optimizing management. 
Neurologist. 2002;8(4):227-36. 
9. Lublin F. History of modern multiple sclerosis therapy. J Neurol. 2005;252 
Suppl 3:iii3-iii9. 
10. Jacobs LD, Beck RW, Simon JH, Kinkel RP, Brownscheidle CM, Murray TJ, et 
al. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event 
in multiple sclerosis. CHAMPS Study Group. N Engl J Med. 2000;343(13):898-904. 
11. Tedeholm H, Lycke J, Skoog B, Lisovskaja V, Hillert J, Dahle C, et al. Time to 
secondary progression in patients with multiple sclerosis who were treated with first 
generation immunomodulating drugs. Multiple sclerosis. 2012. 
12. Arya R, Kothari H, Zhang Z, Han B, Horn PS, Glauser TA. Efficacy of 
nonvenous medications for acute convulsive seizures: A network meta-analysis. 
Neurology. 2015. 
13. Polman CH, O'Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, et 
al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. 
N Engl J Med. 2006;354(9):899-910. 
14. Rudick RA, Stuart WH, Calabresi PA, Confavreux C, Galetta SL, Radue EW, et 
al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med. 
2006;354(9):911-23. 
15. Wickström A, Nyström J, Svenningsson A. Improved ability to work after one 
year of natalizumab treatment in multiple sclerosis. Analysis of disease-specific and 
work-related factors that influence the effect of treatment. Mult Scler. 2013;19(5):622-
30. 
16. Olofsson S, Wickstrom A, Hager Glenngard A, Persson U, Svenningsson A. 
Effect of Treatment with Natalizumab on Ability to Work in People with Multiple Sclerosis: 
Productivity Gain Based on Direct Measurement of Work Capacity before and after 1 Year 
of Treatment. BioDrugs. 2011;25(5):299-306. 
17. Kappos L, Radue EW, O'Connor P, Polman C, Hohlfeld R, Calabresi P, et al. A 
placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. The New 
England journal of medicine. 2010;362(5):387-401. 
18. Cheriyan J, Kim S, Wolansky LJ, Cook SD, Cadavid D. Impact of inflammation 
on brain volume in multiple sclerosis. Archives of Neurology. 2012;69(1):82-8. 
19. Calabresi PA, Kieseier BC, Arnold DL, Balcer LJ, Boyko A, Pelletier J, et al. 
Pegylated interferon beta-1a for relapsing-remitting multiple sclerosis (ADVANCE): a 
randomised, phase 3, double-blind study. Lancet Neurol. 2014;13(7):657-65. 
20. Alping P, Frisell T, Novakova L, Islam-Jakobsson P, Salzer J, Bjorck A, et al. 
Rituximab versus fingolimod after natalizumab in multiple sclerosis patients. Ann Neurol. 
2016;79(6):950-8. 
21. O'Connor P, Wolinsky JS, Confavreux C, Comi G, Kappos L, Olsson TP, et al. 
Randomized trial of oral teriflunomide for relapsing multiple sclerosis. The New England 
journal of medicine. 2011;365(14):1293-303. 
22. Confavreux C, O'Connor P, Comi G, Freedman MS, Miller AE, Olsson TP, et al. 
Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, 
double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2014;13(3):247-56. 
23. Fox RJ, Miller DH, Phillips JT, Hutchinson M, Havrdova E, Kita M, et al. 
Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl 
J Med. 2012;367(12):1087-97. 
24. Gold R, Kappos L, Arnold DL, Bar-Or A, Giovannoni G, Selmaj K, et al. 
Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J 
Med. 2012;367(12):1098-107. 

Study ID 
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Page 25 of 26 
25. Coles AJ, Twyman CL, Arnold DL, Cohen JA, Confavreux C, Fox EJ, et al. 
Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying 
therapy: a randomised controlled phase 3 trial. Lancet. 2012;380(9856):1829-39. 
26. Cohen JA, Coles AJ, Arnold DL, Confavreux C, Fox EJ, Hartung HP, et al. 
Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-
remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet. 
2012;380(9856):1819-28. 
27. Kappos L, Wiendl H, Selmaj K, Arnold DL, Havrdova E, Boyko A, et al. 
Daclizumab HYP versus Interferon Beta-1a in Relapsing Multiple Sclerosis. N Engl J Med. 
2015;373(15):1418-28. 
28. Monson NL, Cravens PD, Frohman EM, Hawker K, Racke MK. Effect of 
rituximab on the peripheral blood and cerebrospinal fluid B cells in patients with primary 
progressive multiple sclerosis. Arch Neurol. 2005;62(2):258-64. 
29. Quartuccio L, Lombardi S, Fabris M, Masolini P, Saracco M, Pellerito R, et al. 
Long-term effects of rituximab in rheumatoid arthritis: clinical, biologic, and 
pharmacogenetic aspects. Ann N Y Acad Sci. 2009;1173:692-700. 
30. Fleischmann RM. Progressive multifocal leukoencephalopathy following 
rituximab treatment in a patient with rheumatoid arthritis. Arthritis Rheum. 
2009;60(11):3225-8. 
31. Salliot C, Dougados M, Gossec L. Risk of serious infections during rituximab, 
abatacept and anakinra treatments for rheumatoid arthritis: meta-analyses of 
randomised placebo-controlled trials. Ann Rheum Dis. 2009;68(1):25-32. 
32. Clifford DB, Ances B, Costello C, Rosen-Schmidt S, Andersson M, Parks D, et 
al. Rituximab-associated progressive multifocal leukoencephalopathy in rheumatoid 
arthritis. Archives of neurology. 2011;68(9):1156-64. 
33. Hauser SL, Waubant E, Arnold DL, Vollmer T, Antel J, Fox RJ, et al. B-cell 
depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med. 
2008;358(7):676-88. 
34. Hawker K, O'Connor P, Freedman MS, Calabresi PA, Antel J, Simon J, et al. 
Rituximab in patients with primary progressive multiple sclerosis: results of a randomized 
double-blind placebo-controlled multicenter trial. Ann Neurol. 2009;66(4):460-71. 
35. de Flon P, Gunnarsson M, Laurell K, Soderstrom L, Birgander R, Lindqvist T, et 
al. Reduced inflammation in relapsing-remitting multiple sclerosis after therapy switch to 
rituximab. Neurology. 2016;87(2):141-7. 
36. de Flon P, Laurell K, Söderström L, Gunnarsson M, Svenningson A. Improved 
treatment satisfaction after therapy switch to rituximab in relapsing-remitting MS. Mult 
Scler. 2016:DOI  10.1177/1352458516676643. 
37. Salzer J, Svenningsson R, Alping P, Novakova I, Björck A, Fink K, et al. 
Rituximab in multiple sclerosis: A retrospective observational study on safety and 
efficacy. Neurology. 2016:DOI 10.1212/WNL.0000000000003331. 
38. West TW, Cree BA. Natalizumab dosage suspension: are we helping or 
hurting? Ann Neurol. 2010;68(3):395-9. 
39. Haghikia A, Langer-Gould A, Rellensmann G, Schneider H, Tenenbaum T, 
Elias-Hamp B, et al. Natalizumab use during the third trimester of pregnancy. JAMA 
neurology. 2014;71(7):891-5. 
40. Fragoso YD, Arruda NM, Arruda WO, Brooks JB, Correa EC, Damasceno A, et 
al. We know how to prescribe natalizumab for multiple sclerosis, but do we know how to 
withdraw it? Expert Rev Neurother. 2014;14(2):127-30. 
41. Kappos L, Li D, Calabresi PA, O'Connor P, Bar-Or A, Barkhof F, et al. 
Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-
controlled, multicentre trial. Lancet. 2011;378(9805):1779-87. 
42. Sorensen PS, Lisby S, Grove R, Derosier F, Shackelford S, Havrdova E, et al. 
Safety and efficacy of ofatumumab in relapsing-remitting multiple sclerosis: A phase 2 
study. Neurology. 2014. 

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43. Hauser SL, Bar-Or A, Comi G, Giovannoni G, Hartung HP, Hemmer B, et al. 
Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis. N Engl J Med. 
2016. 
44. Emery P, Rigby W, Tak PP, Dorner T, Olech E, Martin C, et al. Safety with 
Ocrelizumab in Rheumatoid Arthritis: Results from the Ocrelizumab Phase III Program. 
PloS one. 2014;9(2):e87379. 
45. Langer-Gould A, Popat RA, Huang SM, Cobb K, Fontoura P, Gould MK, et al. 
Clinical and demographic predictors of long-term disability in patients with relapsing-
remitting multiple sclerosis: a systematic review. Arch Neurol. 2006;63(12):1686-91. 
46. Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, et al. 
Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann 
Neurol. 2011;69(2):292-302. 
47. Bahmanyar S, Montgomery SM, Hillert J, Ekbom A, Olsson T. Cancer risk 
among patients with multiple sclerosis and their parents. Neurology. 2009;72(13):1170-
7.