Randomized, Double-blind, Placebo-controlled, Multicenter Phase 2 Trial Assessing the Effect of IMU-838 on Disease Activity, as Measured by Magnetic Resonance Imaging (MRI), as Well as Safety and Tolerability in Patients With Relapsing-remitting Multiple Sclerosis (RRMS)
Phase: PHASE2
Conditions: Relapsing-Remitting Multiple Sclerosis (RRMS)
Sponsor: Immunic AG

 
CLINICAL TRIAL PROTOCOL 
 
Randomized, double-blind, placebo-controlled, multicenter 
Phase 2 trial assessing the effect of IMU-838 on disease 
activity, as measured by magnetic resonance imaging (MRI), 
as well as safety and tolerability in patients with relapsing-
remitting multiple sclerosis (RRMS) 
(EMPhASIS) 
 
 
EudraCT No: 
2018-001896-19 
Protocol no.: 
P2-IMU-838-MS 
Sponsor: 
Immunic AG 
Lochhamer Schlag 21 
82166 Graefelfing, Germany 
Coordinating investigator: 
Robert J. Fox, MD 
Staff Neurologist, Mellen Center for MS 
Vice-Chair for Research, Neurological 
Institute, Cleveland Clinic 
9500 Euclid Ave, JJ-36  
Cleveland, OH 44195 
United States of America 
Protocol version and date: 
Final 3.0, 28-Aug-2020  
Previous protocol versions and date: 
Final 2.0, 15-Oct-2019 
 
Final 1.0, 04-Sep-2018 
This clinical trial protocol must be kept strictly confidential. Disclosure of the contents (in whole 
or part) to third parties is permissible only with written consent of Immunic AG. 

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REVISION CHRONOLOGY  
• Original version: Version 1.0, dated 04-Sep-2018 
• Version 2.0, dated 15-Oct-2019 
The following changes were included in Version 2.0 compared with Version 1.0: 
o 
Section 1 and Section 9.2 (Inclusion Criterion 5), and Section 11.3: 
Clarified that barrier methods of contraception include all kinds of condoms without 
any further specifications. 
o 
Section 1 and Section 9.2 (Inclusion Criterion 2 for optional extended treatment 
period): 
1. 24 weeks of main treatment  
2. Valid baseline MRI and Week 24 MRI, as well as 2 additional post-dose MRIs  
Replaced by 
1. Completed 24 weeks of main treatment  
2. Baseline MRI and Week 24 MRI, as well as 2 additional post-dose MRIs  
o 
Section 1 and Section 9.2: 
Continuation criteria for optional extended treatment period included as follows 
1. In case the initial Week 24 MRI was not evaluated at least partially assessable, 
availability of a repeated Week 24 MRI  
2. Week 24 MRI (initial or repeated one, if applicable) evaluated at least partially 
assessable 
o 
Section 1 and Section 9.3 (Exclusion Criterion 18), and Section 15.2.5: 
Clarified that a positive HIV-Ag/Ab test at Screening will be followed up by further 
HIV testing based on Nucleic Acid Amplification Technology (NAAT). A patient will 
only be considered HIV positive when both tests are positive.  
o 
Section 1 and Section 9.3 (Exclusion Criterion 18), Section 4, Section 15.2.5 and 
Section 15.2.6: 
− HCV replaced by HCV antibody or HCV-Ab, respectively. 
o 
Table 1: 
− To avoid redundancy, assessments of blood biochemistry, hematology, and 
urinalysis deleted for S1 as all 3 assessments are part of the screening labs, which 
will be done at S1. 
− Lab Kits for genotyping (G) and miR-122 (BM) assessment were listed separately. 

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− Under Lab Kits included that there will be 2 BM Kits at V0 because miR-122 will 
be assessed 2x at V0, at 0 and 4 hours after first IMP administration. 
− Clarified that the extended treatment period can be blinded or unblinded (respective 
heading and footnote added). 
− Included that the Week 24 MRI can be repeated if the initial MRI was not at least 
partially assessable. 
− Time window for V2 (Week 6) changed from ±7 days to -7/+4 days, because the 
amount of IMP supplied at V1 lasts only for a maximum of 46 days.  
o 
Section 1, Section 7.2: 
− ‘Time to relapse at time of final analysis of main part’ added as secondary efficacy 
endpoint. 
− Time periods for ‘mean annualized relapse rate’ specified i.e. ‘during main and 
extended treatment period.’ 
− Timepoints to assess ‘proportion of relapse-free patients’ changed from ’12-week 
intervals’ to ‘up to Week 24 and at extended periods thereafter.’ 
− All 3 endpoints above combined to ‘relapse-related clinical endpoints, assessed for 
and compared between all individual treatments and between the pooled 30 mg/day 
and 45 mg/day groups and placebo.’ 
− ‘Time to treatment discontinuation for any reason’ and ‘Rate of treatment 
discontinuations up to Week 24’ added as secondary safety endpoints. 
o 
Section 1 and Section 22: 
Trial periods adjusted as recruitment was much faster than expected. 
o 
Section 2 and Section 6: 
− Outside vendors were added for HIV testing based on the NAAT and population 
PK modeling. 
− Contact details were updated for IMGM Laboratories (only Section 2). 
o 
Section 4 (definition of MS relapse) and Section 13.2: 
− Bullet 1: ‘Neurological abnormality…’ replaced by ‘Neurological deficit…’ 
− Paresthesia deleted in ‘The occurrence of paresthesia, fatigue, mental symptoms, 
and/or vegetative symptoms without any additional symptom will not classify as a 
relapse,’ because paresthesia is the most common manifestation of a relapse. 

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o 
Section 5.1.1 (3rd paragraph): 
‘Genetic susceptibility plays a role in disease initiation [5,6] but currently unidentified 
environmental factors are also involved. [7]’ 
Replaced by  
‘A genetic basis plays a role in susceptibility to MS [5,6] and environmental factors 
such as hypovitaminosis D and Epstein-Bar virus infections have been identified. [7]’ 
o 
Section 5.1.2 and Section 9.3: 
For consistency reasons MOG-IgG-associated encephalomyelitis replaced by MOG-
associated encephalomyelitis. 
o 
Section 5.3 (2nd paragraph): 
‘In a Phase 2 trial of teriflunomide on patients with relapsing forms of MS, a 
statistically significant decrease in combined unique active (CUA) lesions was 
observed with teriflunomide compared to placebo after 1 week of treatment.’ 
Corrected to: 
‘In a Phase 2 trial of teriflunomide on patients with relapsing forms of MS, a 
statistically significant decrease in combined unique active (CUA) lesions was 
observed with teriflunomide compared to placebo after 12 weeks of treatment.’ 
o 
Section 8.2 (6th paragraph): 
Brackets in ‘The schedule of MRI testing selected is more frequent (every 6 weeks) 
than usually used in clinical routine, as Gd+ lesions offer the best evidence of recent 
inflammatory white matter lesions (which cause clinical attacks).’ removed since not 
every white matter lesion causes a clinical attack. 
o 
Section 10.5: 
Patient identifier changed from ‘YY-XXZZ’ to ‘YYXX-ZZ.’ 
o 
Section 12.2: 
To avoid confusion ‘evaluating physician’ was replaced by ‘independent MRI reader’ 
in the following sentence under Screening Visit 2: 
‘The quality of the baseline MRI will be assessed centrally and may be repeated as 
soon as possible, if considered necessary by the evaluating physician independent 
MRI reader.’ 
o 
Section 12.3 under Visit 5/EoMT (Week 24): 
Added that the Week 24 MRI can be repeated if it turns out to be not at least partially 
assessable and that patients without an at least assessable Week 24 MRI (initial or 
repeated one) must be withdrawn from the extended treatment period. 

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o 
Section 13.4: 
− Added that the treating physician will also be informed about the results of the 
central MRI assessment in case of any unexpected finding on the MRI likely not 
related to the underlying MS disease. 
− MRI restriction rules, Bullet 3a:To be consistent with Section 12.2 (Re-screening) 
the time window for re-screening changed from ‘…re-screened earliest 30 days after 
the end of the MS attack  ’ to ‘…re-screened earliest 30 days after the onset of the 
MS attack…’ 
o 
Section 14.2.1: 
‘Neurofilaments are indicative of neurodegenerative disease and will be assessed as 
detailed in Table 1’ replaced by ‘Neurofilaments light chain are an emerging serum 
biomarker for acute and chronic neuronal damage and will be assessed as detailed 
in Table 1.’ 
o 
Section 14.2.3 and Section 15.2.4: 
Lab Kit G/BM replaced by either Lab Kit G (for genotyping) or Lab Kit BM (for 
miR-122). 
o 
Section 15.1.1.3: 
Clarified that ‘new malignancies that occur during the participation in the trial are 
defined as important medical events and must be reported as SAEs.’ 
o 
Section 15.2.6: 
Missing parameters (i.e. lymphocytes and eGFR [CKD-EPI]) in Lab Kit S included; in 
2nd bullet ‘hematology’ added. 
o 
Section 17, patient withdrawal: 
− To clarify that the listed reasons for withdrawal represent stopping rules for a 
patient, the following was added before the withdrawal reasons: ‘Patients will be 
withdrawn from the study for any of the following reasons’. 
o 
To 
increase 
consistency, 
‘steroid’ 
and 
‘glucocorticosteroid’ 
replaced 
by 
‘corticosteroid’.  
o 
Editorial changes. 
• Version 3.0, dated 28-Aug-2020 
The protocol was primarily amended to include a Cohort 2 sub-trial with the objective to 
obtain more data for pharmacodynamic modelling of IMU-838 by evaluating a lower 
IMU-838 dose in the presumed effective dose range, i.e. 10 mg/day IMU-838. The analysis 
of the main treatment period showed equal safety and efficacy between the 30 mg/day and 
45 mg/day doses. The sub-trial will be randomized, double-blind and placebo-controlled 

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with patients being randomized 1:4 to placebo and 10 mg/day IMU-838 for 24 weeks. The 
total number of patients will be approximately 60. Based on the results from an interim 
analysis of the ongoing Trial P2-IMU-838-UC, the 10 mg dose is part of the possible 
effective dose range of IMU-838 in immunological diseases. Assessments and procedures 
will mostly follow those described for the main treatment period in the main trial. An 
unblinded interim analysis on main parameters is planned to be performed after 12 weeks 
of treatment. Details of this Cohort 2 sub-trial study are described in an Appendix 
(Appendix 3) and a summary is included in Section 1. This Cohort 2 sub-trial will not be 
valid in Romania. 
Additional changes included in Version 3.0 compared with Version 2.0 were: 
o 
Title page and Section 2: 
Sponsor address changed. 
o 
Table 1: 
− Clarified that blood collection to determine IMU-838 trough levels at EoT will only 
be performed until the last patient in the Cohort 2 sub-trial has completed the last 
sub-trial visit. 
− Description of visits for patients continuing from Cohort 2 was added. 
o 
Section 1 and Section 22: 
Trial duration adjusted. 
o 
Section 4 
Updated 
o 
Section 6 
Additional eCRF provider added 
o 
Section 11.2.3: 
Added that special care must be taken if ibuprofen is used as concomitant medication 
and whenever possible therapeutic alternatives should be used. 
o 
Section 15.2: 
Clarified that clinically significantly abnormal values must be reported as AE, unless 
there are known circumstances unrelated to a disease or the medication (such as patient 
activities or sample handling) that are a likely explanations for the abnormal value. 
o 
Section 15.2.2.1 
Added that serum samples collected at Baseline, stored but not used for the primary 
analysis (“B-sample”), may be used in future research to evaluate other MS related 
serum markers (e.g. Epstein-Barr Virus) and address MS-related research questions 
that may arise after trial completion. 

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o 
Editorial changes 
 
 

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1 
Summary and flow chart 
Trial code  
P2-IMU-838-MS 
Title of the trial  
Randomized, double-blind, placebo-controlled, multicenter Phase 2 trial assessing the effect of 
IMU-838 on disease activity, as measured by magnetic resonance imaging (MRI), as well as safety 
and tolerability in patients with relapsing-remitting multiple sclerosis (RRMS) 
Short title  
PhasE 2 MRI trial to exPlore the efficAcy and Safety of IMU-838 in relapsing remitting multiple 
Sclerosis (EMPhASIS) 
Principal investigators and trial centers  
Planned: about 40 centers in Romania, Bulgaria, Ukraine, and Poland; potential additional centers 
in Hungary and Croatia  
Coordinating investigator: Robert J. Fox, MD, Cleveland Clinic, Cleveland, United States of 
America 
Clinical phase: 2 
Trial duration  
Cohort 1:  
Actual start: 
February 2019 (first patient in) 
Actual recruitment period: 
8 months 
Actual end main treatment period: 
April 2020 (main part: last patient out)  
Estimated end extended treatment period: 
December 2029 (last patient end-of-study [EoS] 
visit) 
Cohort 2 (Planned, not valid in Romania):  
Estimated start: 
October 2020 (first patient in) 
Estimated recruitment period: 
3 months 
Estimated interim analysis: 
March 2021 (main part: last patient completing 
Week 12 assessments) 
Estimated end main treatment period: 
May 2021 (main part: last patient out)  
Estimated end extended treatment period: 
December 2029 (last patient EoS visit) 
Trial periods  
Screening, main treatment period, optional extended treatment period  

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Trial objectives 
Primary 
• To evaluate the efficacy of 45 mg/day IMU-838 in the treatment of RRMS based on MRI 
assessments  
Secondary 
• To evaluate the efficacy of 30 mg/day IMU-838 in the treatment of RRMS based on MRI 
assessments  
• To evaluate the safety and tolerability of 30 mg/day and 45 mg/day IMU-838 in RRMS 
patients 
Tertiary 
• To evaluate pharmacodynamic (PD) effects of IMU-838 in RRMS patients 
• To evaluate IMU-838 trough values and population pharmacokinetics (PK)  
• To evaluate the effects of IMU-838 on treatment satisfaction in patients with RRMS  
Methodology 
This is a Phase 2 multicenter, double-blind, placebo-controlled, randomized, parallel-group trial to 
assess the efficacy and safety of 2 once-daily oral doses of IMU-838 (30 mg/day and 45 mg/day) 
in patients with RRMS and evidence of active disease.  
The trial consists of a screening period, a blinded 24-week main treatment period, and an optional 
initially blinded, then open-label extended treatment period of up to 9.5 years. 
The trial includes 2 patient cohorts: 
• Cohort 1 main trial: main Phase 2 trial with assessment of primary and key secondary 
endpoints. 
• Cohort 2 sub-trial: additional sub-trial with a small double-blind, placebo-controlled, 
randomized, parallel-group assessment of a low IMU-838 dose (i.e. 10 mg/day) to provide 
additional data for pharmacodynamic modelling. No formal statistical analysis will be 
performed, however in addition to analysis of Cohort 2 a pooled exploration of Cohorts 1 
and 2 for pharmacodynamic modeling will be performed (this Cohort 2 sub-trial will not 
be valid in Romania). 
Screening period 
After the patient provided written informed consent, eligibility criteria will be checked and 
screening laboratory tests as well as a physical examination (including vital signs and 
electrocardiogram [ECG]) will be performed (Screening Visit 1).  

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For eligible patients based on the assessments of Screening Visit 1, a baseline MRI (Screening 
Visit 2) will be performed which will serve as MRI reference for subsequent MRI assessments 
during the main treatment period. The quality of the baseline MRI will be evaluated by a central 
independent MRI reader; if the quality of the MRI is unacceptable, the baseline MRI may be 
repeated once per patient, and the repeated MRI will be used as baseline MRI. The central 
independent MRI reader will also assess the presence of Gadolinium-enhancing (Gd+) lesions as 
well as the number and volume of T2 lesions on the baseline MRI. 
Main treatment period 
On Day 0, eligible patients will be randomized in a 1:1:1 ratio to once-daily oral treatment with 
30 mg IMU-838 or 45 mg IMU-838, or placebo for 24 weeks. All patients will receive half the 
assigned dose during the first 7 days of the main treatment period (1 tablet per day) and then start 
taking the full assigned dose from Day 7 onwards (2 tablets once daily). Clinic visits after Day 0 
during the main treatment period will be scheduled at Day 7, and at Weeks 6, 12, 18, and 24, 
including trial MRI examinations at Weeks 6, 12, 18, and 24. At Week 24 (end-of-main treatment 
period, EoMT), patients will have the option to continue into the extended treatment period if they 
meet respective eligibility criteria including an MRI at Week 24 (see Inclusion criteria for optional 
extended treatment period and Exclusion criteria for optional extended treatment period). 
Extended treatment period (optional) 
During the extended treatment period, patients will receive 30 mg/day or 45 mg/day IMU-838 for 
up to 9.5 years. All patients will be randomized. Patients receiving placebo will be randomized to 
30 or 45 mg/day IMU-838. Patients on active treatment during the main treatment period will be 
randomized to continue their previous treatment assignment. Identical to the start of the main 
treatment period, all patients will receive half the assigned dose during the first 7 days of the 
extended treatment period and will then continue with the full assigned dose.  
Clinic visits during the extended treatment period will be scheduled every 12 weeks.  
Once the results of the main treatment period are available, investigators and patients currently in 
the extended treatment period will be unblinded and investigators will receive a top-line summary 
of trial results of the main treatment period. Considering these results, investigators may then 
recommend switching the dose for those patients currently remaining in the extended treatment 
period after time of study unblinding or thereafter (after discussion and in consultation with the 
patient). A potential dose switch can occur several times and at any clinic visit. A dose switch may 
allow patients to switch to a more effective dose or to an equally effective dose but with a lower 
risk for adverse events (AEs). 
If at any time during this trial (main and extended treatment periods) a patient experiences between 
scheduled clinic visits symptoms indicative for a multiple sclerosis (MS) relapse or a clinically 

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relevant AE, which in the investigator’s opinion requires additional safety assessments, the patient 
will be appropriately assessed at an unscheduled clinic visit.  
End-of-study visit 
All patients discontinuing treatment, as scheduled or prematurely, will undergo an EoS visit 
30 days (+14 days) after last investigational medicinal product (IMP) administration. 
Cohort 2 sub-trial 
The objective of the Cohort 2 sub-trial is to obtain exploratory data on the dose response of 
IMU-838 by evaluating a lower IMU-838 dose i.e. 10 mg/day to provide additional data for 
pharmacodynamic 
modelling. 
The 
sub-trial 
will 
be 
randomized, 
double-blind 
and 
placebo-controlled with patients being randomized 1:4 to placebo and 10 mg/day IMU-838 for 
24 weeks. The total number of patients will be approximately 60. Assessments and procedures will 
mostly follow those described for the main treatment period in the main trial. Only MRI machines 
with a field strength of 1.5 Tesla will be allowed (the main trial allowed ≥1.5 Tesla). In addition, 
an unblinded interim analysis of selected MRI data is planned to be performed after 12 weeks of 
treatment. Details of this sub-trial are described in an appendix and will not be further referred to 
in this synopsis (this Cohort 2 sub-trial will not be valid in Romania). 
Treatments 
Test product 
IMU-838 (vidofludimus calcium), a small molecule inhibitor of dihydroorotate dehydrogenase 
(DHODH) 
Formulation:  
Tablets with 15 mg and 22.5 mg IMU-838 
Administration:  
Tablets will be taken once daily 
Main treatment period:  
 
Days 0 to 6: 
1 tablet once daily, i.e. 15 mg/day or 22.5 mg/day 
IMU-838 
Day 7 to Week 24 (EoMT):  
2 tablets once daily, i.e. 30 mg/day or 45 mg/day IMU-838  
Extended treatment period:  
 
Days 0 to 6: 
1 tablet once daily, i.e. 15 mg/day or 22.5 mg/day 
IMU-838 
Day 7 to end-of-treatment:  
2 tablets once daily, i.e. 30 mg/day or 45 mg/day IMU-838 
Reference product (only applicable during main period) 
Matching placebo, once-daily oral administration of 1 or 2 tablets, as described for the test product 

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Administration 
Tablets will be taken once daily in the morning in fasted state (no food after midnight, unrestricted 
intake of water is always allowed) and taken with a glass of water approximately 15 minutes to 
1 hour before breakfast. 
Number of patients (total and for each treatment) planned 
In total, 195 patients are planned to be randomized 1:1:1 to treatment with 30 mg/day or 45 mg/day 
IMU-838, or placebo (65 patients each) in the main treatment period. During the extended 
treatment period, patients will be re-randomized such that patients previously on placebo will be 
re-randomized 1:1 to treatment with 30 g/day or 45 mg/day IMU-838, all other patients will be re-
randomized to the same treatment they previously received.  
Inclusion criteria 
Main treatment period 
1. Male or female patient (age ≥18 to 55 years, inclusive) 
2. Diagnosis of RRMS according to the revised McDonald criteria (2017)1 
Note: The diagnosis of MS (including “dissemination in time”) must have been established 
before the patient is screened for the trial.  
3. Disease activity evidenced  
o by either at least 2 relapses in the last 24 months, or at least 1 relapse in the last 12 months 
before randomization (relapses must have been assessed and documented by a physician 
in the patient files), AND 
o ≥1 documented Gd+ MS-related brain lesion, in the last 6 months before informed 
consent (date of MRI examination as well as copy of MRI report or representative image 
has to be available and accessible as patient source data at the study site) 
4. Expanded Disability Status Scale (EDSS) score between 0 and 4.0 (inclusive) at Screening 
Visit 1 
5. Female patients  
o must be of non-child-bearing potential i.e. surgically sterilized (hysterectomy, bilateral 
salpingectomy, bilateral oophorectomy at least 6 weeks before Screening Visit 1) or 
post-menopausal (where postmenopausal is defined as no menses for 12 months without 
an alternative medical cause), or 
o if of child-bearing potential, must have a negative pregnancy test at Screening Visit 1 
(blood test) and before the first IMP intake (Day 0 urine test). They must agree not to 
attempt to become pregnant, must not donate ova, and must use a highly effective 
 
1 Thompson AJ, Banwell BL, Barkhof F, Carroll WM, Coetzee T, Comi G, et al. Diagnosis of multiple sclerosis: 
2017 revisions of the McDonald criteria. Lancet Neurol 2018;17(2):162-73. 

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contraceptive method (see below) together with a barrier method between trial consent 
and 30 days after the last intake of the of the IMP. 
Highly effective forms of birth control are those with a failure rate less than 1% per year 
and include: 
− oral, intravaginal, or transdermal combined (estrogen and progestogen containing) 
hormonal contraceptives associated with inhibition of ovulation 
− oral, injectable, or implantable progestogen-only hormonal contraceptives 
associated with inhibition of ovulation 
− intrauterine device or intrauterine hormone-releasing system 
− bilateral tubal occlusion 
− vasectomized partner (i.e. the patient’s male partner underwent effective surgical 
sterilization before the female patient entered the clinical trial and is the sole sexual 
partner of the female patient during the clinical trial) 
− sexual abstinence (acceptable only if it is the patient’s usual form of birth 
control/lifestyle 
choice; 
periodic 
abstinence 
[e.g. 
calendar, 
ovulation, 
symptothermal, postovulation methods] and withdrawal are no acceptable methods 
of contraception) 
Barrier methods of contraception include: 
− Condom  
− Occlusive 
cap 
(diaphragm 
or 
cervical/vault 
caps) 
with 
spermicidal 
gel/film/cream/suppository 
6. Male patients must agree not to father a child or to donate sperm starting at Screening Visit 1, 
throughout the clinical trial and for 30 days after the last intake of the IMP. Male patients 
must also  
o abstain from sexual intercourse with a female partner (acceptable only if it is the patient’s 
usual form of birth control/lifestyle choice), or 
o use adequate barrier contraception during treatment with the IMP and until at least 
30 days after the last intake of the IMP, and 
o if they have a female partner of childbearing potential, the partner should use a highly 
effective contraceptive method as outlined in inclusion criterion 5 
o if they have a pregnant partner, they must use condoms while taking the IMP to avoid 
exposure of the fetus to the IMP 
7. Willingness and ability to comply with the protocol  
8. Written informed consent given prior to any trial-related procedure 

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Inclusion criteria for optional extended treatment period 
1. Completed 24 weeks of main treatment  
2. Baseline MRI, a Week 24 MRI as well as 2 additional post-dose MRIs 
Continuation criteria for optional extended treatment period 
1. In case the initial Week 24 MRI was not evaluated at least partially assessable, availability 
of a repeated Week 24 MRI  
2. Week 24 MRI (initial or repeated one, if applicable) evaluated at least partially assessable 
Exclusion criteria 
MS-related exclusion criteria 
1. Any disease other than MS that may better explain the signs and symptoms, including 
history of complete transverse myelitis 
2. Signs and symptoms suggestive of transmissible spongiform encephalopathy, or family 
members who suffer(ed) from these 
3. Clinical signs or presence of laboratory findings suggestive for neuromyelitis optica (NMO) 
spectrum 
disorders 
or 
myelin 
oligodendrocyte 
glycoprotein 
(MOG)-associated 
encephalomyelitis (i.e. presence of anti-NMO [aquaporin-4] antibodies or anti-MOG-
antibodies)  
4. MS types other than RRMS 
5. Any MRI finding, atypical for MS, including but not limited to a longitudinally extensive 
spinal cord lesion 
6. Any active and uncontrolled coexisting autoimmune disease, other than MS (except for type 
1 diabetes mellitus and inflammatory bowel disease) 
7. An MS relapse within 30 days before Screening Visit 1 and/or during the screening period 
(until Day 0) 
Therapy exclusion criteria 
8. Any previous or current use of the following MS treatments: monoclonal antibodies 
(natalizumab, alemtuzumab, daclizumab, ocrelizumab, anti-CD4, rituximab or belimumab, 
including their biosimilars), total lymphoid irradiation, bone marrow transplantation, stem 
cell transplantation, or any use of DHODH inhibitors, including teriflunomide (Aubagio™) 
or leflunomide (Arava™) 
9. Any use of the following MS treatments within 12 months before the date of informed 
consent: any cytokine (other than interferon) or anti-cytokine therapy, intravenous 
immunoglobulin, mitoxantrone, cytotoxic or immunosuppressive therapy (including, but not 
limited to azathioprine and cyclophosphamide, excluding only systemic corticosteroids or 
adrenocorticotrophic hormone [ACTH]), tofacitinib, methotrexate, mycophenolate mofetil, 

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mycophenolate sodium, fingolimod, any calcineurin inhibitors (e.g. tacrolimus, 
cyclosporine, or pimecrolimus) 
10. Any use of the following MS treatments within 30 days before the date of informed 
consent: interferon-β, glatiramer acetate, dimethyl fumarate and plasmapheresis 
11. Within 30 days before the baseline MRI: Use of systemic corticosteroids (intravenous or 
oral) or ACTH. 
12. Use of the following concomitant medications is prohibited at Screening Visit 1 and 
throughout the duration of the trial:  
o any medication known to significantly increase urinary elimination of uric acid, in 
particular lesinurad (Zurampic™) as well as uricosuric drugs such as probenecid  
o treatments for any malignancy, in particular irinotecan, paclitaxel, tretinoin, bosutinib, 
sorafinib, enasidenib, erlotinib, regorafenib, pazopanib and nilotinib  
o any drug significantly restricting water diuresis, in particular vasopressin and 
vasopressin analogs  
o use of rosuvastatin at daily doses higher than 10 mg 
13. Use of any investigational product within 8 weeks or 5 x the respective half-life before 
the date of informed consent, whichever is longer, and throughout the duration of the trial 
Immune response exclusion criteria 
14. Conditions negatively affecting the immune response such as previous organ transplant  
15. Clinically significantly low lymphocyte and/or neutrophil count (Common Terminology 
Criteria for AEs Grade of 2 or higher), i.e.  
o lymphocyte count <800/mm³ (0.8 x 109/L), and/or 
o neutrophil count <1,500/mm³ (1.5 x 109/L) 
16. History of chronic systemic infections within 6 months before the date of informed consent, 
including but not limited to tuberculosis, human immunodeficiency virus (HIV), hepatitis B 
or C  
17. Positive interferon-gamma release assay for Mycobacterium tuberculosis at Screening 
Visit 1 
18. Positive hepatitis B virus surface antigen, hepatitis B core antibody, positive hepatitis C 
virus antibody and/or HIV-antigen-antibody test2 at Screening Visit 1 
19. Any live vaccinations within 30 days before the date of informed consent except for the 
influenza vaccine 
 
2 A positive HIV-Ag/Ab test will be confirmed by further testing based on Nucleic Acid Amplification Technology 
(NAAT). If the NAAT test is negative, the patient will be considered HIV negative.  

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Other medical history and concomitant disease exclusion criteria 
20. Presence of the following laboratory values at Screening Visit 1:  
o platelet count <100,000/mm³ (<100 109/L) 
o serum creatinine >1.5 x upper limit of normal (ULN) 
o total bilirubin, alanine aminotransferase, or gamma-glutamyl transferase >1.5 x ULN 
o Serum uric acid levels at Screening Visit 1 >1.2 x ULN (for women >6.8 mg/dL, for 
men >8.4 mg/dL) 
o indirect (unconjugated) bilirubin >1.2 x ULN (i.e. >1.1 mg/dL) 
21. Known history of nephrolithiasis or underlying condition with a strong association of 
nephrolithiasis, including hereditary hyperoxaluria or hereditary hyperuricemia  
22. History or clinical diagnosis of gout 
23. Renal impairment defined as estimated glomerular filtration rate3 ≤60 mL/min/1.73m²  
24. Known or suspected Gilbert syndrome 
25. Diagnosis or suspected liver function impairment which may cause fluctuating liver function 
tests during this trial, as assessed by the investigator  
26. History or presence of serious or acute heart disease such as uncontrolled cardiac 
dysrhythmia or arrhythmia, uncontrolled angina pectoris, cardiomyopathy, or uncontrolled 
congestive heart failure (New York Heart Association [NYHA] class 3 or 4) 
Note: NYHA class 3: Cardiac disease resulting in marked limitation of physical activity. 
Patients are comfortable at rest. Less than ordinary activity causes fatigue, palpitation, 
dyspnea, or anginal pain. NYHA class 4: Cardiac disease resulting in inability to carry on 
any physical activity without discomfort. Symptoms of heart failure or the anginal syndrome 
may be present even at rest. If any physical activity is undertaken, discomfort is increased.  
27. Clinically relevant, severe pulmonary diseases, uncontrolled hypertension, or poorly 
controlled diabetes 
28. Concurrent malignancy or prior malignancy within the previous 10 years except for the 
following: adequately-treated non-melanoma skin cancer and adequately-treated cervical 
cancer 
29. History or presence of any major medical or psychiatric illness (such as severe depression, 
psychosis, bipolar disorder), history of suicide attempt, or current suicidal ideation that in 
the opinion of the investigator could create undue risk to the patient or could affect 
adherence with the trial protocol 
30. Epilepsy or seizures not adequately controlled by treatment 
 
3 Calculated according to the Chronic Kidney Disease Epidemiology Collaboration equation. 

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Page 17 of 134 
 
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31. Any other substantial medical condition that in the opinion of the investigator could create 
undue risk to the patient or could affect adherence with the trial protocol 
General exclusion criteria 
32. Current or past (within 12 months of Screening Visit 1) alcohol or drug abuse 
33. Any condition that would prevent the patient from undergoing an MRI scan, including: 
o claustrophobic conditions 
o unable to receive Gd-based MRI-contrast agents due to history of hypersensitivity to 
Gd-based contrast agents, or severe renal insufficiency 
o presence of metallic implants incompatible with brain MRI 
34. Legal incapacity, limited legal capacity, or any other condition that makes the patient unable 
to understand the patient information and informed consent form 
35. Pregnant or breastfeeding 
36. An employee of an investigator or sponsor or an immediate relative of an investigator 
37. Patients institutionalized due to judicial or administrative order 
Exclusion criteria for optional extended treatment period 
1. Any ongoing, clinically significant (as assessed by the investigator) treatment-emergent 
(started after intake of IMP) AE or laboratory abnormality (including blood chemistry and 
urinalysis)4  
2. Significant treatment or trial non-compliance during the main treatment period (as assessed 
by the investigator), and/or inability or unwillingness to follow instructions by trial 
personnel 
3. Treatment compliance <70% during the main treatment period 
4. Significant protocol deviations during the main treatment period that are assessed by the 
investigator to negatively affect further patient cooperation in this trial 
Endpoints 
Primary 
Efficacy 
Difference between 45 mg/day IMU-838 and placebo in the cumulative number of combined 
unique active (CUA)5  MRI lesions up to Week 24 
 
4 If treatment-emergent AEs are the reason for exclusion from the extended treatment period, the eligibility can be 
re-assessed up to 30 days following the last treatment in the main treatment period. 
5 Sum of the number of all new Gd+ lesions on T1-weighted MRI and the number of all new or substantially enlarged 
lesions on T2-weighted MRI (non-enhancing on T1-weighted MRI), avoiding double counting. 

P2-IMU-838-MS, EMPhASIS 
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Page 18 of 134 
 
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Key secondary (hierarchical testing to primary efficacy) 
Efficacy 
Difference between 30 mg/day IMU-838 and placebo in the cumulative number of CUA MRI 
lesions up to Week 24  
Secondary 
Efficacy 
• Difference between 45 mg/day IMU-838 and 30 mg/day IMU-838 in the cumulative 
number of CUA MRI lesions at Week 24  
• Difference between 30 mg/day IMU-838 and placebo, 45 mg/day IMU-838 and placebo, 
and 30 mg/day and 45 mg/day IMU-838 for the following MRI parameters: 
o Mean number of CUA lesions per patient per scan at Weeks 6, 12, 18 and 24 
o Cumulative number of CUA MRI lesions up to Weeks 6, 12, and 18  
o Volume changes of T2 lesions at Weeks 6, 12, 18 and 24 compared to Baseline 
o T2-lesion load at Weeks 6, 12, 18 and 24 compared to Baseline 
o T1-lesion load at Weeks 6, 12, 18 and 24 compared to Baseline 
o Cumulative number of new Gd+ lesions up to Weeks 6, 12, 18 and 24 
o Cumulative number of new T2 lesions up to Weeks 6, 12, 18 and 24 
o Cumulative number of new T1 lesions up to Weeks 6, 12, 18 and 24 
o Proportion of patients without new Gd+ lesions over 24 weeks  
o Proportion of patients without new or enlarging T2-weighted lesions over 24 weeks 
o Proportion of patients with CUA lesions at Week 24 
o Proportion of patients with Gd+ lesions at Week 24 
o Proportion of patients with T2 lesions at Week 24  
• Differences between individual treatments and between the pooled 30 mg/day and 
45 mg/day groups and placebo in the following relapse-related clinical endpoints: 
o Mean annualized relapse rate (during main and extended treatment period)  
o Proportion of relapse-free patients up to Week 24 and at extended periods thereafter 
o Time to relapse at time of final analysis of main part 
• Differences between treatments in changes of disease activity as measured by the following 
clinical parameters: 
o Mean change in the EDSS as compared to Baseline during the main and extended period 
(every 12 weeks starting at Week 12)  
o Proportion of patients with EDSS progression during the main and extended period 
(every 12 weeks starting at Week 12, and cumulatively) 

P2-IMU-838-MS, EMPhASIS 
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• Correlation of MRI-based assessments with quartiles of IMU-838 trough levels at Week 6 
and Week 24 
Safety 
• AEs, serious AEs and clinically significant laboratory abnormalities (as assessed by the 
investigator) 
• AEs of special interest:  
o Red blood cell urine positive, at least of moderate intensity 
o Hematuria 
o Retroperitoneal colicky pain with suspected or confirmed nephrolithiasis 
• Proportion of patients treated with 30 mg/day or 45 mg/day IMU-838 as compared to 
placebo who experienced at least one of the following AEs: 
o Neutropenia 
o Lymphopenia 
o Diarrhea 
o Alopecia 
o Hemorrhage 
o Abnormalities in alanine aminotransferase, aspartate aminotransferase, gamma glutamyl 
transferase, and total bilirubin with both elevations ˃1.5 x ULN and ≥35% elevated 
compared to Baseline 
• ECG, physical examination, and vital signs 
• Micro ribonucleic acid-122 expression (Change from Baseline to 4 hours after first dose) 
• Presence of John Cunningham virus (JCV) deoxyribonucleic acid (DNA) in urine in 
patients with detectable JCV-DNA in urine at Screening Visit 1, at Week 24, and at EoS 
• Time to treatment discontinuation for any reason 
• Rate of treatment discontinuations up to W24 
Pharmacokinetics  
• Population PK at Week 6 (3-10 hours post-dose) 
• Plasma trough levels of IMU-838 at Days 7 and Weeks 6, 12, 18, and 24 
Pharmacodynamics 
• Changes from Baseline in lymphocyte subset parameters as measured by flow cytometry at 
Weeks 6 and 24 (in selected Biomarker Centers only) 
• Changes from Baseline in biased T-cell clonal repertoire based on T-cell receptor deep 
sequencing at Weeks 6 and 24 (in selected Biomarker Centers only) 

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Page 20 of 134 
 
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• Changes from Baseline in serum neurofilament at Week 24 
Health outcome 
• Treatment Satisfaction Questionnaire for Medication at Week 6, Week 24 and EoS  
Statistical methods 
The primary analysis will be performed after the end of the main treatment period and will be based 
on the full analysis set. The primary and key secondary endpoints (cumulative number of CUA 
MRI lesions at Week 24) will be analyzed with a generalized linear model with a negative binomial 
distribution and a logarithmic link function. Treatment group, baseline volume of T2 lesions, field 
strength of the MRI machine (1.5 or 3.0 Tesla), and number of Gd+ lesions (the latter 2 are factor 
groups used for stratification) will be included as independent effects in the models. The primary 
and the key secondary efficacy endpoints will be analyzed with a hierarchical testing procedure. 
Both tests will be performed at a significance level of 0.1 (1-sided). In case of a non-significant 
result for the primary endpoint, the hierarchical testing procedure will be stopped, and the analysis 
of the key secondary endpoint will be exploratory. 
The sample size calculation is based on the primary endpoint assessed at Week 24 after the main 
treatment period.  
Assumptions:  
Primary endpoint: cumulative number of CUA MRI lesions up to Week 24  
Randomization ratio: 
 
 
1:1 (45 mg/day IMU-838:placebo) 
Power:  
 
 
80% 
Significance level:  
 
 
0.1, 1-sided 
Average exposure time: 
 
 
24 weeks 
Mean event rate per 24 weeks for 45 mg/day IMU-838: 
4.5 
Mean event rate per 24 weeks for placebo:  
8.0 
Negative binomial dispersion parameter:  
1.7 
 
Based on these assumptions the necessary sample size per group is 51. Assuming a drop-out rate 
of 25%, about 65 patients will be randomized to each of the dose groups. 

P2-IMU-838-MS, EMPhASIS 
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Page 21 of 134 
 
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Schedules of assessments and flow chart 
Figure 1: 
Trial flow chart 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a Can be interrupted/extended, if the baseline MRI must be repeated due to poor quality (to be done as soon as possible). If results of the central MRI assessment are not available 
in time for randomization, the screening period can be extended by up to 7 days, if needed. 
b After unblinding of the main treatment period, the investigator can decide with the patient if and at which dose the treatment will be continued. 
BL = baseline, D = day, EoMT = end-of-main treatment, EoS = end-of-study, EoT = end-of-treatment, exam = examination, MRI = magnetic resonance imaging, 
R = randomization, Scr. = screening, W = Week. 
 
 
 
 
 
Blinded 
Screening up to 28 daysa 
Main treatment period 24 weeks 
Extended treatment period up to ~9.5 years (optional) 
Unblinded 
Scr. exam BL MRI 
R 
Placebo 
R 
45 mg IMU-838 
30 mg IMU-838 
EoMT 
EoMT 
EoMT 
30 mg IMU-838 
30 or 45 mg IMU-838b 
30 mg IMU-838 
30 or 45 mg IMU-838b 
EoS 
45 mg IMU-838 
30 or 45 mg IMU-838b 
EoT 
EoT 
EoT 
45 mg IMU-838 
30 or 45 mg IMU-838b 
EoT 
D-28                 D-14      D0                                                                   W24/EoMT              At time of final analysis of main part                                W516/EoT            EOS  
 -9                       -3                                                                             End of main part                        Visits every 12 weeks                                                                      (EoT+30d)    
                                                                                                               1 analysis 

P2-IMU-838-MS, EMPhASIS 
Clinical trial protocol  
Final 3.0 (28-Aug-2020)  
Page 22 of 134 
 
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Table 1: 
Schedule of assessments  
 
Screening 
Blinded treatment 
Blinded and unblindedq 
 
Unscheduled visit  
EoS  
 
BL 
MRI 
Main treatment (MT) period 
Extended treatment (ET) 
period (optional) 
 
 
due to 
MS-
related 
symptoms 
due to 
safety 
(end of 
study 
visit) 
S1a 
S2k 
V0 
V1 
V2 
V3 
V4 
V5/ 
EoMT 
V6t 
V7 to 
V45t 
V46/ 
EoTt 
D-28 - 
D-9 
D-14 - 
D-3 
D0 
D7 
W6 
W12 
W18 
W24 
W36t 
Every 12 
weeks 
W516t 
 
 
 
 30 d after 
last IMP  
Assessments 
 
±1 d 
-7/+4 d 
±7 d 
±7 d 
±7 d 
±14 d 
±14 d 
±14 d 
 
 
 
 
+14 d 
Informed consent 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In-/exclusion criteria 
• 
 
• 
 
 
 
 
(•)p 
 
 
 
 
 
 
 
 
Randomization 
 
 
• 
 
 
 
 
(•)j,p 
 
 
 
 
 
 
 
 
Medical historyb 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Previous therapy 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medications/procedures 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
 
• 
• 
 
• 
MS disease history 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
• 
 
• 
 
 
 
 
• 
 
 
• 
 
• 
• 
 
• 
New MS related 
neurological symptoms 
(treating physician) 
• 
 
• 
• 
• 
• 
• 
• 
• 
• 
• 
 
• 
 
 
 
EDSS  
(evaluating physician) 
• 
 
• 
(•)m 
(•)m 
• 
(•)m 
• 
• 
• 
• 
 
(•)m 
 
 
 
MS relapse  
(treating physician) 
 
 
• 
(•)m 
(•)m 
• 
(•)m 
• 
• 
• 
• 
 
(•)m 
 
 
 
MRI scan 
 
• 
 
 
• 
• 
• 
•r 
 
 
 
 
 
 
 
 
continued 
 

P2-IMU-838-MS, EMPhASIS 
Clinical trial protocol  
Final 3.0 (28-Aug-2020)  
Page 23 of 134 
 
Confidential 
 
 
Table 1: 
Schedule of assessments (continued) 
 
Screening 
Blinded treatment 
Blinded and unblindedq 
 
Unscheduled visit  
EoS  
 
BL 
MRI 
Main treatment (MT) period 
Extended treatment (ET) 
period (optional) 
 
 
due to 
MS-
related 
symptoms 
due to 
safety 
(end of 
study 
visit) 
S1a 
S2k 
V0 
V1 
V2 
V3 
V4 
V5/ 
EoMT 
V6t 
V7 to 
V45t 
V46/ 
EoTt 
D-28 - 
D-9 
D-14 - 
D-3 
D0 
D7 
W6 
W12 
W18 
W24 
W36t 
Every 12 
weeks 
W516t 
 
 
 
 30 d after 
last IMP  
Assessments 
 
±1 d 
-7/+4 d 
±7 d 
±7 d 
±7 d 
±14 d 
±14 d 
±14 d 
 
 
 
 
+14 d 
Central MRI quality & 
eligibility assessment as 
well as BL stratification 
variables 
 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central MRI assessment 
of efficacy variables 
 
 
 
 
• 
• 
• 
• 
 
 
 
 
 
 
 
 
PRO questionnaires 
(TSQM) 
 
 
 
 
• 
 
 
• 
 
 
 
 
 
 
 
• 
Laboratory assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central screening labs, 
incl. blood pregnancy 
testf 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Local screening lab 
(Tbc-IGRA) 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood biochemistry 
 
 
• 
• 
• 
• 
• 
• 
• 
• 
• 
 
• 
• 
 
• 
Hematology 
 
 
• 
• 
• 
• 
• 
• 
• 
• 
• 
 
• 
• 
 
• 
Coagulationg 
 
 
• 
• 
 
 
 
• 
 
 
 
 
 
 
 
 
IMU-838 trough levelg 
 
 
• 
• 
• 
• 
• 
• 
 
 
 
 
 
 
 
•s 
continued 
 

P2-IMU-838-MS, EMPhASIS 
Clinical trial protocol  
Final 3.0 (28-Aug-2020)  
Page 24 of 134 
 
Confidential 
 
 
Table 1: 
Schedule of assessments (continued) 
 
Screening 
Blinded treatment 
Blinded and unblindedq 
 
Unscheduled visit  
EoS  
 
BL 
MRI 
Main treatment (MT) period 
Extended treatment (ET) 
period (optional) 
 
 
due to 
MS-
related 
symptoms 
due to 
safety 
(end of 
study 
visit) 
S1a 
S2k 
V0 
V1 
V2 
V3 
V4 
V5/ 
EoMT 
V6t 
V7 to 
V45t 
V46/ 
EoTt 
D-28 - 
D-9 
D-14 - 
D-3 
D0 
D7 
W6 
W12 
W18 
W24 
W36t 
Every 12 
weeks 
W516t 
 
 
 
 30 d after 
last IMP  
Assessments 
 
±1 d 
-7/+4 d 
±7 d 
±7 d 
±7 d 
±14 d 
±14 d 
±14 d 
 
 
 
 
+14 d 
Urinalysis 
 
 
• 
• 
• 
• 
• 
• 
• 
• 
• 
 
• 
• 
 
• 
Population PKg   
 
 
 
 
•l 
 
 
 
 
 
 
 
 
 
 
 
Local urine pregnancy 
testd 
 
 
•i 
 
• 
• 
• 
• 
• 
• 
• 
 
 
 
 
• 
Genotyping 
 
 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
miR-122g 
 
 
0+4h 
 
 
 
 
 
 
 
 
 
 
 
 
 
JCV-DNA in urine 
• 
 
 
 
 
 
 
• 
 
 
 
 
 
 
 
• 
PBMC-based PD 
parameterse 
 
 
• 
 
• 
 
 
• 
 
 
 
 
 
 
 
 
Neurofilamentg 
 
 
• 
 
• 
 
 
• 
 
 
 
 
 
 
 
 
Lab kits used 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening lab kit 
S 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Trial lab kit 
 
 
A 
A 
B 
B 
B 
A 
C 
C 
C 
 
C 
C 
 
C 
JCV-DNA 
JCV 
 
 
 
 
 
 
JCV 
 
 
 
 
 
 
 
JCV 
miR-122  
 
 
2xBM 
 
 
 
 
 
 
 
 
 
 
 
 
 
Genotyping 
 
 
G 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neurofilament 
 
 
NFL 
 
NFL 
 
 
NFL 
 
 
 
 
 
 
 
 
PK kit  
 
 
PK 
PK 
2xPK 
PK 
PK 
PK 
 
 
 
 
 
 
 
PKs 
PD kit (PBMC)e 
 
 
PD 
 
PD 
 
 
PD 
 
 
 
 
 
 
 
 
continued 

P2-IMU-838-MS, EMPhASIS 
Clinical trial protocol  
Final 3.0 (28-Aug-2020)  
Page 25 of 134 
 
Confidential 
 
 
Table 1: 
Schedule of assessments (continued) 
 
Screening 
Blinded treatment 
Blinded and unblindedq 
 
Unscheduled visit  
EoS  
 
BL 
MRI 
Main treatment (MT) period 
Extended treatment (ET) 
period (optional) 
 
 
due to 
MS-
related 
symptoms 
due to 
safety 
(end of 
study 
visit) 
S1a 
S2k 
V0 
V1 
V2 
V3 
V4 
V5/ 
EoMT 
V6t 
V7 to 
V45t 
V46/ 
EoTt 
D-28 - 
D-9 
D-14 - 
D-3 
D0 
D7 
W6 
W12 
W18 
W24 
W36t 
Every 12 
weeks 
W516t 
 
 
 
 30 d after 
last IMP  
Assessments 
 
±1 d 
-7/+4 d 
±7 d 
±7 d 
±7 d 
±14 d 
±14 d 
±14 d 
 
 
 
 
+14 d 
Shipment to central lab 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ambient temperature 
• 
 
• 
• 
• 
• 
• 
• 
• 
• 
• 
 
• 
• 
 
• 
Dry ice 
 
 
 
 
•o 
 
 
•o 
 
 
 
 
 
 
 
•n 
Safety 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE assessment 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
 
• 
• 
 
• 
12-lead ECG 
• 
 
 
 
• 
 
 
• 
 
 
• 
 
 
• 
 
 
Vital signs 
•c 
 
•c 
•c 
 
•c 
 
•c 
•c 
•c 
•c 
 
 
 
 
•c 
IMP 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP administrationh 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP dispensing 
 
 
• 
 
• 
• 
• 
• 
• 
• 
 
 
 
 
 
 
No. of bottles disp. 
 
 
1 
 
2 
2 
2 
3 
3 
3 
 
 
 
 
 
 
IMP accountability 
 
 
 
 
• 
• 
• 
• 
• 
• 
• 
 
 
 
 
 
Assessments in brackets (•) indicate assessments which must not always be performed. Refer to the respective footnote. 
a 
Within 28 days from Baseline (Day 0). If the baseline MRI is repeated, the screening period maybe extended. However, patients must be randomized within 14 days of the 
repeated baseline MRI. Screening Visit 1 assessments will be valid for up to 60 days until the day of randomization, but will have to be repeated if exceeding 60 days. If results 
of the baseline MRI assessments are not available within 14 days (either after the first or, if applicable, after the repeated MRI) randomization can be delayed by up to 7 days, 
which may also result in an extension of the screening period. 
b 
Including the history of autoimmune diseases (other than MS). 
c 
Including height (only at Screening), respiratory rate, weight, blood pressure, pulse rate, and body temperature. 
d 
Any positive local urine pregnancy test has to be followed up with a confirmatory local blood pregnancy test. 
e 
Includes PBMC-based lymphocyte subset analysis and T-cell clonal repertoire. To be performed in a subset of patients and at selected “Biomarker Centers” only. 
f 
Serum pregnancy test at central laboratory. 
g 
Samples to be stored at -20°C until next scheduled dry-ice shipment to central laboratory. 

P2-IMU-838-MS, EMPhASIS 
Clinical trial protocol  
Final 3.0 (28-Aug-2020)  
Page 26 of 134 
 
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h 
During the first week of treatment in the main and extended treatment period: 1 tablet once daily; other weeks: 2 tablets once daily. 
i 
The result of this local pregnancy test must be available and negative before the first IMP can be taken. 
j 
Patients who received placebo during the main treatment period will be re-randomized to 30 mg or 45 mg IMU-838. Patients previously on IMU-838 will be re-randomized to 
the same treatment they received during the main treatment period. 
k 
If the central reader evaluates the quality of the baseline MRI as not sufficient, the MRI must be repeated as soon as possible. 
l 
Taken at 3 to 10 hours post-dose (in addition to the sample which is collected pre-dose at the same day for IMU-838 trough values). 
m 
If, based on new neurological symptoms of the patient, the treating physician suspects that the patient may have an MS relapse (as defined in this protocol), an EDSS 
assessment by the evaluating physician and an assessment of MS relapse by the treating physician (based on the EDSS) must be performed at this visit. 
n 
The sample can be stored at -20°C for up to 1 year and dry ice shipment can be combined with another dry ice shipment. 
o 
The dry ice shipment should be generally done immediately after the Week 6, Week 24 or EoS visit. However, it may be delayed by up to 2 weeks if the dry ice shipment can be 
combined with the dry ice shipment for another patient at the same site.  
p 
Only for patients who continue into the extended treatment phase. 
q 
Blinded until the data base lock and final analysis of the main treatment part; thereafter unblinded. 
r 
Can be repeated if initial MRI scan is not at least partially assessable. 
s 
To be performed only up to the time of last patient last visit of the main treatment period in the Cohort 2 sub-trial (Week 24). Investigators will be notified immediately. 
t 
The extended treatment period will be terminated for patients in the Cohort 2 sub-trial, at the day the last patient of the Cohort 1 main trial has completed or discontinued the 
extended treatment period (which allows up to 9.5 years of ET period). The ET period for these patients will thus be shorter (approximately up to 8.5 years). 
 
AE = adverse event, BL = baseline, D = day, disp. = dispensed, DNA = deoxyribonucleic acid, ECG = electrocardiogram, EDSS = Expanded Disability Status Scale, EoMT = end-
of-main treatment, EoS = end-of-study, EoT = end-of-treatment, ET = extended treatment, IMP = investigational medicinal product, incl. = including, JCV = John Cunningham 
virus, miR-122 = micro ribonucleic acid-122, MRI = magnetic resonance imaging, MS = multiple sclerosis, MT = main treatment, No = number, PBMC = peripheral blood 
mononuclear cell,  PD = pharmacodynamic, PK= pharmacokinetic, PRO = patient reported outcome, S = screening, Tbc-IGRA = Tuberculosis interferon gamma release assay, 
TCR =T-cell receptor, TSQM = Treatment Satisfaction Questionnaire for Medication, V = Visit; W = Week. 
 
 

P2-IMU-838-MS, EMPhASIS 
Clinical trial protocol  
Final 3.0 (28-Aug-2020) 
Page 27 of 134 
 
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Study P2-IMU-838-MS 
 
Reminder what should be considered for patient visits at the trial center 
 
• Patients should be reminded throughout the trial to drink a generous amount 
of fluid per day (approximately 1.5 liters per day are recommended) to ensure 
adequate urine flow.  
• At all visits throughout the trial: 
o Patients should arrive at the center in fasted condition (no food after 
midnight and in the morning before visit) but patients are allowed to drink 
water even during periods of fasting (from midnight to next day visit). 
o For an individual patient visits should be scheduled at the same time in the 
morning so that visits are all within ±2 hours of the Day 0 visit. 
o At each visit, patients need to bring the IMP container to the center. 
 
• Applies only to main treatment period:  
o Patients should arrive at the center without having taken the IMP. 
o If patients have inadvertently taken the IMP within 1.5 hours of arriving at 
the trial center, blood samples for trough levels will still be drawn. If the 
IMP intake was longer than 1.5 hours before arriving at the trial center, 
trough levels will not be determined. Either case will be recorded as 
protocol deviation. Blood samples for biochemistry can be collected in any 
case and no additional visit to collect a blood sample for trough plasma 
levels needs to be scheduled. 

P2-IMU-838-MS, EMPhASIS 
Clinical trial protocol  
Final 3.0 (28-Aug-2020) 
Page 28 of 134 
 
Confidential 
 
 
2 
Addresses and responsibilities 
Sponsor’s signatory 
Dr Andreas Mühler  
Chief Medical Officer, Immunic AG 
Lochhamer Schlag 21 
82166 Graefelfing, Germany 
Office:  
 +49 89 2080 477 02 
Mobile:  
+49 176 7873 8359 
Fax:     
+49 89 2080 477 66 
 
Coordinating investigator 
Robert J. Fox, MD 
Staff Neurologist, Mellen Center for MS 
Vice-Chair for Research, Neurological Institute, 
Cleveland Clinic 
9500 Euclid Ave, JJ-36  
Cleveland, OH 44195, United States of America 
Phone: 
+1 (216) 445 1915 
Fax:  
+1 (216) 445 5192 
Email:  
foxr@ccf.org 
 
Drug safety officer and 
pharmacovigilance services 
Dr med. Dipl. Inf. Susanne Kienzle-Horn 
SCRATCH Pharmacovigilance GmbH 
Schlossstrasse 25 
35510 Butzbach, Germany 
Phone:  
+49 6033 74535 50 
Fax:     
+49 6033 74535 59 
Email: 
safety-immunic@scratch-pv.com 
 
Project manager for global 
project management  
 
 
Dr Stefan Hess 
FGK Clinical Research GmbH 
Heimeranstrasse 35 
80339 München, Germany 
Phone:  
+49 89 893 119 53 
Fax:     
+49 89 893 119 20 
Email: 
stefan.hess@fgk-cro.com 
 

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Central safety laboratory 
LKF - Laboratorium für Klinische Forschung GmbH 
Lise-Meitner-Strasse 25-29 
24223 Schwentinental, Germany 
Phone:  
+49 4307 8276 0 
Fax: 
+49 4307 8276 79 
Email: 
project@lkf-kiel.de 
 
HIV testing based on Nucleic 
Acid Amplification Technology 
Labor Lademannbogen 
 
Lademannbogen 61 
22339 Hamburg, Germany 
Phone:  
+49 40 53805 0 
Fax: 
+49 40 53805 701 
Email: 
info@labor-lademannbogen.de 
 
Central biomarker laboratory 
Univ.-Prof. Dr med. Heinz Wiendl 
Univ.-Prof. Dr med. Luisa Klotz 
Institut für Translationale Neurologie 
Universitätsklinikum Münster 
Albert-Schweitzer-Campus 1, Gebäude A1 
48149 Münster, Germany 
Phone: 
+49 251 83 48140 
Fax:  
+49 251 83 45379 
Email: 
luisa.klotz@ukmuenster.de 
 
Biostatistics and data 
management 
FGK Clinical Research GmbH 
Heimeranstrasse 35 
80339 München, Germany 
Phone:  
+49 89 893 119 0 
Fax:     
+49 89 893 119 20 
 

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Central magnetic resonance 
imaging assessments 
Siena Imaging S.R.L. 
Managing Director: Marco Battaglini 
Via Fiorentina 1 
53100 Siena, Italy 
Phone:  
+ 39 0577 231299 
Fax:     
+ 39 0577 233411 
Email: 
battaglini@sienaimaging.it 
 
Medical Reviewer: 
Prof. Nicola de Stefano 
Email: 
destefano@unisi.it 
 
 
Imaging contract research 
organization 
Keosys Medical Imaging 
13 Impasse Serge Reggiani 
44800 Saint-Herblain, France 
Phone:  
+ 33 (2) 53 59 12 90  
Email: 
help@imagys.com 
 
Medical Monitor 
Assoc. Prof. Dr. Johann Sellner 
Christian Doppler Medical Center, Paracelsus 
Medical University, Salzburg, Austria 
Mobile:  
+ 43 664 88693442 
Email: 
johann.sellner@immunic.de 
 
Pharmacokinetics & IMP 
labeling, packaging, and 
distribution 
Nuvisan GmbH 
Wegenerstrasse 13 
89231 Neu-Ulm, Germany 
Phone:  
+49 731 9840 0 
Fax:     
+49 731 9840 226  
Email: 
bdinfo@nuvisan.com 
 
Pharmacokinetics (population 
PK modeling) 
PharmaLex Belgium 
5 rue Belin  
1435 Mont-Saint-Guibert, Belgium 
Phone:  +32 10 46 10 10 

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Micro ribonucleic acid-122 (miR-
122) assessment and genotyping 
IMGM Laboratories GmbH 
Lochhamer Str. 29a 
82152 Martinsried, Germany 
Phone:  
+ 49 89 4524 667 0 
Fax:     
+ 49 89 4524 667 410 
 
 
Local contract research organizations for local project management and monitoring 
Bulgaria and Croatia 
Resbiomed Ltd 
136A Positano str; 1309 Sofia, Bulgaria 
Main contact: Plamen Borisov Gurov 
Phone.  
+359 2 80 81 865 
Mobile:  
+359 887 26 13 73 
Fax:  
+359 2 85 48 741 
Email:  
ImmunicMS@resbiomed.com 
 
 
Romania and Hungary 
Clinical Trial Center SRL 
Iulia Tabacaru, MD 
2 Rapsodiei street 
300732 Timisoara, Romania 
Phone: 
+40 356 101637 
Fax: 
+40 356 101513 
Email: 
emphasis@clinicaltrial.ro 
 
 
Poland and Ukraine 
Verum.de GmbH 
Sembdnerstrasse 5 
82110 Germering, Germany 
Phone:  
+49 89 800 777 60 
Fax:  
+49 89 800 777 88 
Email:  
verum@verum.de  
 
A complete list of trial personnel will be available in the trial master file. 

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3 
Table of contents 
 
Page 
REVISION CHRONOLOGY .................................................................................................. 2 
1 
SUMMARY AND FLOW CHART ............................................................................... 8 
2 
ADDRESSES AND RESPONSIBILITIES ................................................................. 28 
3 
TABLE OF CONTENTS .............................................................................................. 32 
4 
ABBREVIATIONS AND DEFINITION OF TERMS .............................................. 37 
5 
INTRODUCTION ......................................................................................................... 42 
5.1 
Multiple sclerosis ........................................................................................ 42 
5.1.1 
Background .................................................................................................. 42 
5.1.2 
Clinical variants ........................................................................................... 42 
5.2 
IMU-838 ...................................................................................................... 43 
5.2.1 
Background .................................................................................................. 43 
5.2.2 
Mode of action ............................................................................................. 43 
5.2.3 
Non-clinical studies ...................................................................................... 44 
5.2.4 
Clinical trials ................................................................................................ 44 
5.2.5 
Safety of IMU-838 ....................................................................................... 46 
5.3 
Rationale for the trial ................................................................................. 46 
6 
INVESTIGATORS, TRIAL ADMINISTRATIVE STRUCTURE, AND 
COMMITTEES ............................................................................................................. 47 
7 
TRIAL OBJECTIVES AND ENDPOINTS ................................................................ 49 
7.1 
Trial objectives ........................................................................................... 49 
7.2 
Trial endpoints ........................................................................................... 49 
8 
TRIAL DESIGN AND DESIGN RATIONALE ........................................................ 52 
8.1 
Overall trial design ..................................................................................... 52 
8.1.1 
Design overview ........................................................................................... 52 
8.1.2 
Screening period and baseline MRI ............................................................. 52 
8.1.3 
Main treatment period .................................................................................. 53 
8.1.4 
Optional extended treatment period ............................................................. 53 
8.2 
Trial design rationale ................................................................................. 54 
8.3 
Risk-benefit assessment ............................................................................. 56 

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9 
PATIENT SELECTION ............................................................................................... 58 
9.1 
Sample size .................................................................................................. 58 
9.2 
Inclusion criteria ........................................................................................ 58 
9.3 
Exclusion criteria ....................................................................................... 60 
10 
RANDOMIZATION, BLINDING AND UNBLINDING PROCEDURES ............. 64 
10.1 
Blinding ....................................................................................................... 64 
10.2 
Two-physician concept ............................................................................... 65 
10.2.1 
Treating physician ........................................................................................ 65 
10.2.2 
Evaluating physician .................................................................................... 65 
10.3 
Patient’s identification card ...................................................................... 66 
10.4 
Emergency unblinding ............................................................................... 66 
10.5 
Patient identification .................................................................................. 66 
10.6 
Randomization ............................................................................................ 66 
11 
TREATMENTS ............................................................................................................. 67 
11.1 
Investigational medicinal product ............................................................ 67 
11.1.1 
IMU-838 ....................................................................................................... 67 
11.1.2 
Placebo ......................................................................................................... 68 
11.1.3 
Packaging, labeling and dispensing ............................................................. 68 
11.1.4 
Storage and stability ..................................................................................... 68 
11.1.5 
Treatment dose, dose selection, and administration ..................................... 68 
11.1.6 
Drug accountability and patient compliance ................................................ 69 
11.2 
Prior and concomitant medications .......................................................... 70 
11.2.1 
Permitted therapies ....................................................................................... 70 
11.2.1.1 
Corticosteroid treatment of MS relapses ................................................................. 70 
11.2.1.2 
Plasma exchange due to MS relapses ...................................................................... 70 
11.2.1.3 
Patient’s self-medication ......................................................................................... 70 
11.2.2 
Prohibited medication .................................................................................. 71 
11.2.3 
Restricted medications ................................................................................. 72 
11.3 
Precautions and restrictions ...................................................................... 73 
12 
TRIAL SCHEDULE ..................................................................................................... 74 
12.1 
Trial conduct ............................................................................................... 74 

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12.2 
Screening ..................................................................................................... 75 
12.3 
Main treatment period ............................................................................... 75 
12.4 
Extended treatment period ........................................................................ 76 
12.5 
Unscheduled visit ........................................................................................ 77 
12.5.1 
Unscheduled visit due to symptoms indicative for an MS relapse .............. 77 
12.5.2 
Unscheduled visit due to safety .................................................................... 77 
12.6 
Premature termination .............................................................................. 77 
12.7 
End of study visit (EoS; 30 days +14 days after the EoT) ...................... 78 
13 
EFFICACY ASSESSMENTS AND PROCEDURES ................................................ 78 
13.1 
Demographics and other baseline assessments ........................................ 78 
13.2 
Neurological assessments and MS relapse ............................................... 78 
13.3 
Expanded Disability Status Scale ............................................................. 80 
13.4 
Magnetic resonance imaging ..................................................................... 81 
14 
PHARMACOKINETICS, PHARMACODYNAMICS, AND HEALTH 
OUTCOME ASSESSMENTS ...................................................................................... 82 
14.1 
Pharmacokinetics ....................................................................................... 82 
14.2 
Pharmacodynamics .................................................................................... 83 
14.2.1 
Neurofilament .............................................................................................. 83 
14.2.2 
Peripheral blood mononuclear cell-based biomarkers ................................. 83 
14.2.3 
Blood genotyping ......................................................................................... 84 
14.3 
Health outcome assessment ....................................................................... 84 
15 
SAFETY ASSESSMENTS ........................................................................................... 84 
15.1 
Adverse events documentation and reporting ......................................... 84 
15.1.1 
Definitions .................................................................................................... 84 
15.1.1.1 
Adverse events ........................................................................................................ 84 
15.1.1.2 
Adverse drug reactions and unexpected adverse drug reactions ............................. 85 
15.1.1.3 
Serious adverse events ............................................................................................. 86 
15.1.1.4 
Suspected unexpected serious adverse reaction ...................................................... 86 
15.1.2 
Classification of adverse events ................................................................... 87 
15.1.3 
Adverse events of special interest ................................................................ 88 
15.1.4 
Documentation of adverse events ................................................................ 89 

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15.1.5 
Documentation and reporting of immediately reportable adverse events .... 89 
15.1.6 
Follow-up of adverse events ........................................................................ 91 
15.1.7 
Handling of events typical for MS ............................................................... 91 
15.1.8 
Pregnancies .................................................................................................. 92 
15.2 
Laboratory investigations .......................................................................... 93 
15.2.1 
Pregnancy tests ............................................................................................. 93 
15.2.2 
Blood chemistry, hematology, and coagulation ........................................... 93 
15.2.2.1 
Assessments ............................................................................................................ 93 
15.2.2.2 
Monitoring of hepatotoxicity ................................................................................... 95 
15.2.3 
Urinalysis ..................................................................................................... 95 
15.2.3.1 
Assessments ............................................................................................................ 95 
15.2.3.2 
Monitoring of red blood cells in urine ..................................................................... 96 
15.2.4 
miR-122 expression and John Cunningham virus DNA .............................. 96 
15.2.5 
Serology ....................................................................................................... 97 
15.2.6 
Screening laboratory .................................................................................... 97 
15.3 
Vital signs, physical examination, and ECG ............................................ 97 
15.4 
Steering committee ..................................................................................... 98 
16 
BIOSTATISTICAL METHODS ................................................................................. 99 
16.1 
Sample size calculation .............................................................................. 99 
16.2 
Analysis sets and types of analyses ......................................................... 100 
16.3 
Statistical analyses .................................................................................... 101 
16.4 
Primary and key secondary efficacy analyses ....................................... 101 
17 
PATIENT WITHDRAWAL FROM TRIAL PARTICIPATION .......................... 101 
18 
ETHICAL AND LEGAL REQUIREMENTS .......................................................... 103 
18.1 
Ethical conduct of the trial ...................................................................... 103 
18.2 
Independent ethics committee ................................................................. 103 
18.3 
Patient information and consent procedure .......................................... 103 
18.4 
Insurance coverage ................................................................................... 104 
18.5 
Submission to authorities ........................................................................ 104 
18.6 
Patient confidentiality .............................................................................. 104 
19 
CRITERIA FOR PREMATURE TERMINATION OF THE TRIAL AND 
CRITERIA FOR INITIALIZING AND CLOSING A TRIAL CENTER ............ 105 

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19.1 
Criteria for halting or terminating the trial .......................................... 105 
19.2 
Criteria for closing a trial center ............................................................ 105 
20 
TRIAL PROTOCOL, DOCUMENTATION AND ARCHIVING OF 
DATA ........................................................................................................................... 106 
20.1 
Amendments to the protocol ................................................................... 106 
20.2 
Protocol deviations ................................................................................... 106 
20.3 
Data retention ........................................................................................... 107 
21 
DATA COLLECTION, MONITORING AND QUALITY ASSURANCE ........... 108 
21.1 
Data collection .......................................................................................... 108 
21.2 
Source data ............................................................................................... 108 
21.3 
Monitoring ................................................................................................ 109 
21.4 
Audits and inspections ............................................................................. 109 
21.5 
Data management procedures ................................................................ 109 
21.6 
Trial report and publications .................................................................. 110 
22 
TRIAL PERIODS ....................................................................................................... 110 
23 
REFERENCES ............................................................................................................ 111 
24 
APPROVAL AND SIGNATURES ............................................................................ 113 
25 
APPENDICES ............................................................................................................. 115 
Appendix 1 
Expanded Disability Status Scale and Neurostatus form.......... 115 
Appendix 2 
Treatment satisfaction questionnaire for medication ................ 119 
Appendix 3 
Dose response Cohort 2 sub-trial (not valid in Romania) ........ 122 
 
Table of tables 
Table 1: 
Schedule of assessments ................................................................................... 22 
Table 2: 
Schedule of assessments - Cohort 2 sub-trial (main treatment period) .......... 131 
 
Table of figures 
Figure 1: 
Trial flow chart ................................................................................................. 21 
Figure 2: 
Trial flow chart - Cohort 2 sub-trial ................................................................ 126 
 

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4 
Abbreviations and definition of terms 
ACTH 
Adrenocorticotrophic hormone 
ADR 
Adverse drug reaction 
AE 
Adverse event 
AESI 
AEs of special interest 
ALT 
Alanine aminotransferase 
AP 
Alkaline phosphatase 
ARR 
Annual relapse rate 
AST 
Aspartate aminotransferase 
BCRP 
Breast cancer resistance protein 
BUN 
Blood urea nitrogen 
C4 
7α-hydroxy-4-cholesten-3-one 
CA 
Competent authority 
Ca 
Calcium 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration  
Cl 
Chloride 
CNS 
Central nervous system 
CRO 
Contract research organization 
CRP 
C-reactive protein 
CUA 
Combined unique active 
CYP 
Cytochrome P450  
DHODH 
Dihydroorotate dehydrogenase 
DMF 
Dimethylfumarate 
DMT 
Disease modifying treatment 
DNA 
Deoxyribonucleic acid 
EAE 
Experimental autoimmune encephalomyelitis 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDSS 
Expanded Disability Status Scale 
eGFR 
Estimated glomerular filtration rate 
EMA 
European Medicines Agency 
EoMT 
End-of-main treatment 
EoS 
End-of-study 
EoT 
End-of-treatment 
EU 
European Union 
FAS 
Full analysis set 
FGF-19 
Fibroblast growth factor 19 

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GCP 
Good Clinical Practice 
Gd(+) 
Gadolinium (enhancing) 
GGT 
Gamma glutamyl transferase 
HBcAb 
Hepatitis B core antibody 
HBsAg 
Hepatitis B surface antigen 
HCV(-Ab) 
Hepatitis C virus(-antibody) 
HDL 
High-density lipoprotein  
HIV(-Ag/Ab) 
Human immunodeficiency virus(-antigen/antibody) 
HPF 
High powered field 
i.v. 
Intravenous 
ICH 
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use 
IEC 
Independent ethics committee  
IFNγ 
Interferon gamma  
IgG(M) 
Immunoglobulin G(M) 
IL 
Interleukin 
IMP 
Investigational medicinal product 
INR 
International normalized ratio 
IWRS 
Interactive web-based response system  
JCV 
John Cunningham virus 
K 
Potassium 
MCH 
Mean corpuscular hemoglobin 
MCV 
Mean corpuscular volume  
miR-122 
Micro ribonucleic acid-122 
MOG 
Myelin oligodendrocyte glycoprotein 
MR(I) 
Magnetic resonance (imaging) 
MS 
Multiple sclerosis 
Na 
Sodium 
NMO 
Neuromyelitis optica 
NYHA 
New York Heart Association 
OAT1(3) 
Organic anion transporter 1(3) 
OATP1B1(3) 
Organic anion transporting polypeptide 1B1(3) 
P 
Inorganic phosphate 
PBMC 
Peripheral blood mononuclear cell 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
PP 
Per-protocol set 

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RA 
Rheumatoid arthritis 
RBC 
Red blood cells 
RRMS 
Relapsing-remitting multiple sclerosis 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAR 
Serious adverse reaction 
SUSAR 
Suspected unexpected serious adverse reaction 
Tbc-IGRA 
Mycobacterium tuberculosis IFNγ-release assay  
TEAE 
Treatment-emergent adverse event 
TSQM 
Treatment Satisfaction Questionnaire for Medication 
UGT1A1 
UDP-glucuronosyltransferase 1A1 
ULN 
Upper limit of normal 
URAT1 
Urate anion transporter 1 
USA 
United States of America 
 
Drugs 
 
4SC-101 
Tablet or capsule formulation containing vidofludimus free acid 
IMU-838  
Tablet formulation containing vidofludimus calcium 
 
If not indicated otherwise ‘investigator’ as used throughout this protocol refers to the 
treating physician (or deputy) of this trial. 
 
Definitions  
 
RRMS 
Relapsing-remitting multiple sclerosis, as defined by the revised 2017 
McDonald criteria [1] 
Gd-lesion 
Acute multiple sclerosis (MS) lesion in the brain that disrupts the 
blood-brain barrier and is characterized by enhancement with 
Gadolinium (Gd)-containing contrast agents in post-contrast 
T1-weighted magnetic resonance (MR) images, at least 3 mm in size 
T2-lesion 
Focal supratentorial ovoid lesions observed as hyper- or hypointense 
area on T2-weighted MR images, at least 3 mm in size 

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CUA lesions 
(combined unique 
active) lesions 
Sum of the number of all new Gd-enhanced (Gd+) lesions on 
T1-weighted magnetic resonance imaging (MRI) and the number of all 
new or substantially enlarged lesions on T2-weighted MRI (non-
enhancing on T1-weighted MRI), avoiding double counting. 
MS relapse: 
All of the following criteria must be met for a clinical event to qualify 
as a relapse: 
1. Neurological deficit, either newly appearing or re-appearing, 
with abnormality specified by both 
o Neurological abnormality separated by at least 30 days from 
onset of a preceding relapse, 
AND 
o Neurological abnormality lasting for at least 24 hours 
2. Absence of fever or known infection (i.e. temperature [axillary, 
oral, or intra-auricular] ≤37.5ºC) 
3. Neurological impairment, defined as either 
o Increase in at least one of the functional systems of the 
Expanded Disability Status Scale (EDSS), 
OR 
o Increase of the total EDSS score. 
In both cases, the increase in EDSS must correlate with the 
patient’s reported symptoms 
The occurrence of fatigue, mental symptoms, and/or vegetative 
symptoms without any additional symptom will not classify as a 
relapse. 
The treating physician will decide if the observed signs and symptoms 
qualify as a relapse; the EDSS results will be provided by the blinded 
evaluating physician.  
Only relapses confirmed by the investigator and meeting the above 
criteria will be reported in the electronic case report form (eCRF). 
Relapses and their underlying neurological symptoms will not be 
reported as adverse events (AE), as they represent an important 
efficacy parameter. 

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EDSS progression: 
An increase of the EDSS score compared to Baseline: 
• of at least 1.0 point for patients with a baseline EDSS score of 
1 to 4.0,  
OR 
• of at least 1.5 points for patients with a baseline EDSS score 
of 0. 
 
In case of inconsistencies between text in the protocol and the schedule of assessments (Table 1), 
the schedule will predominate. 

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5 
Introduction 
5.1 
Multiple sclerosis 
5.1.1 
Background 
Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous 
system (CNS) and is one of the most common causes of neurological disability in young adults. 
It affects up to 2.5 million people worldwide. Its prevalence varies between races and 
geographical latitudes, ranging from more than 100 per 100,000 people in Northern and Central 
Europe to 50 per 100,000 people in Southern Europe. 
It is characterized by multi-focal recurrent events of neurological symptoms and signs, with 
variable recovery. Most patients eventually develop a progressive clinical course. [2-4] 
The exact cause of MS is unknown, although an autoimmune process is implicated. A genetic 
basis plays a role in susceptibility to MS [5,6] and environmental factors such as 
hypovitaminosis D and Epstein-Bar virus infections have been identified. [7] In one hypothesis, 
CNS auto-reactive lymphocytes are triggered outside the CNS, become active, and proliferate 
in the peripheral secondary lymphoid organs. Upon migration via the blood circulation, the 
expression of adhesion molecules on the surface of these encephalitogenic lymphocytes permits 
adhesion to activated brain or spinal cord endothelial cells, with subsequent migration into the 
CNS compartment. These cells again proliferate upon interacting with CNS myelin antigens and 
initiate a pro-inflammatory cascade within the brain that results in either target-directed immune 
damage or bystander damage. Important cellular and humoral elements are T-and B-
lymphocytes, macrophages, microglial cells, and metalloproteinases, chemokines and 
cytokines, including interferon-gamma (IFNγ) and tumor necrosis factor-alpha. [8-11] 
5.1.2 
Clinical variants 
Four clinical forms of MS are recognized: primary progressive, progressive-relapsing, 
secondary progressive, and relapsing-remitting. [12] 
Patients with relapsing-remitting multiple sclerosis (RRMS) have acute exacerbations or MS 
attacks with subsequent variable recovery (remission). At the onset of MS, 80% to 85% of 
patients will have RRMS. In most cases of RRMS, Expanded Disability Status Scale (EDSS) 
scores are below 4.  
Over the past few years myelin oligodendrocyte glycoprotein (MOG) was shown to be a disease 
entity distinct from classic MS and from Aquaporin 4-IgG-positive neuromyelitis optica 
spectrum disorders, and which is now often referred to as MOG-associated encephalomyelitis. 
MOG-associated encephalomyelitis is relevant not only for differences in clinical and 

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paraclinical presentation, but more importantly also for treatment response and prognosis. 
[11,13,14]  
5.2 
IMU-838  
5.2.1 
Background 
Vidofludimus free acid (SC12267) was previously developed by 4SC AG using capsules or 
tablets containing amorphous vidofludimus (4SC-101). Immunic AG acquired all rights and 
data of SC12267 and has developed a new pharmaceutical form containing the calcium salt of 
vidofludimus (INNM: vidofludimus calcium) in a new pharmaceutical formulation (tablets 
containing a specific polymorph).  
Both formulations depend on the same active moiety i.e. vidofludimus which is released from 
the tablets in the gut and enters the blood stream. Hence, the 2 formulations share the same 
mechanism of action, pharmacology, and toxicology. Vidofludimus calcium may exhibit, 
however, superior pharmaceutical properties compared with the former vidofludimus free acid 
film-coated tablet. 
5.2.2 
Mode of action 
The investigational medicinal product (IMP) IMU-838 (vidofludimus calcium) is a new 
compound that selectively inhibits the human enzyme dihydroorotate dehydrogenase 
(DHODH). As it is chemically and structurally different from teriflunomide, a DHODH 
inhibitor approved in the United States of America (USA) and European Union (EU) for the 
treatment of RRMS, it also differs in the mode of DHODH inhibition. 
The mechanism of action in all therapeutic indications proposed for IMU-838 is the targeting of 
lymphocytes, which are activated through the inflammatory process. Thus, IMU-838 selectively 
affects activated, rapidly proliferating lymphocytes through inhibition of DHODH, which plays 
a major role in the de-novo pyrimidine synthesis and is specifically expressed at high levels in 
proliferating or activated lymphocytes. Resting lymphocytes satisfy their pyrimidine 
requirements through a DHODH-independent salvage pathway. The metabolic stress secondary 
to DHODH inhibition leads to a reduction of pro-inflammatory cytokine release including 
interleukin (IL)-17 (IL-17A and IL-17F) and IFNγ, and to an increased apoptosis in activated 
lymphocytes. [15] IMU-838-mediated DHODH inhibition does not induce unselective 
immunosuppression and therefore offers to patients the selective targeting of disease-relevant 
effector cells.  
IMU-838 is further characterized by a short blood half-life of 30-40 hours making it ideal for 
once-daily dosing and resulting in only little accumulation after daily dosing (steady state 

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concentrations are reached within 4-8 days with an accumulation factor of 2). Importantly due 
to the short blood half-life, the wash-out period for IMU-838 is considerably shorter than for 
teriflunomide. 
5.2.3 
Non-clinical studies 
Pharmacodynamics 
Vidofludimus strongly inhibits activated lymphocytes and reduces the release of pro-
inflammatory cytokines and other physiologic effects of activated lymphocytes in in-vivo 
studies.  
The metabolism of vidofludimus involves primarily cytochrome P450 (CYP)1A1 (about 60%), 
followed by CYP2C8 (about 20%) and CYP2E1 (about 10%). Vidofludimus is primarily 
eliminated via feces (about 70%).  
Vidofludimus mildly to moderately inhibits several transport systems, including the urate anion 
transporter 1 (URAT1), the breast cancer resistance protein (BCRP), the organic anion 
transporters (OAT)1 and OAT3, the organic anion transporting polypeptides (OATP)1B1 and 
OATP1B3, and the bile salt export pump. 
Consistent with the important role of DHODH for viral replication in human cells, vidofludimus 
inhibited viral replication of hepatitis C virus (HCV) in an in-vitro assay. 
Inhibition of lymphocyte proliferation of vidofludimus was tested in vitro on lymphocytes from 
mouse, rat and human. Vidofludimus is about 200-fold less active on rat lymphocytes, but an 
about 10 times more potent inhibitor of activated human lymphocytes than teriflunomide, the 
active metabolite of leflunomide.   
In a spinal cord extract-induced experimental autoimmune encephalomyelitis (EAE) model in 
rats, vidofludimus showed dose-dependent inhibition of EAE motor symptoms with a strong 
and comparable effect at the doses 20 and 60 mg/kg. In addition, even the lowest dose of 
4 mg/kg reduced the weight loss caused by EAE. 
5.2.4 
Clinical trials 
Except for two Phase 1 trials performed with IMU-838 and an ongoing Phase 2 trial in ulcerative 
colitis, all previous clinical trials were performed using vidofludimus free acid (4SC-101). So 
far, no clinical trials have been performed in MS. However, vidofludimus showed beneficial 
clinical effects in other autoimmune and chronic inflammatory diseases. 
Two clinical trials investigated the beneficial effects of 4SC-101 in patients with rheumatoid 
arthritis (RA). 4SC-101 improved various clinical parameters versus placebo. A pronounced 
effect was observed for inflammatory parameters.  

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In a small Phase 2 trial in patients with corticosteroid-dependent inflammatory bowel disease 
(Crohn’s disease and ulcerative colitis), 4SC-101 showed beneficial effects in the remission 
maintenance therapy. Compared with historical placebo data, 4SC-101 treatment showed a 
significantly higher response rate (88.5% total response) as well as a corticosteroid sparing 
effect.   
No 4SC-101-associated clinically significant adverse reactions were observed at doses of 
<70 mg once daily including the potential target organs liver and kidney as identified in 
non-clinical or early clinical trials. At higher 4SC-101 doses (>70 mg/day or single doses of 
210 mg) potential drug-related increases of red blood cells (RBC) in urine and hematurias were 
observed (see also Section 8.3).  
Two Phase 1 clinical trials were performed for calcium vidofludimus (IMU-838). In Trial 
P1-IMU-838-SAD, doses from 10 to 40 mg IMU-838 resulted in dose-linear blood 
pharmacokinetics (PK) under fasted conditions. For the 30 mg dose (the dose expected to be 
closest to an effective dose), the terminal plasma half-life was approximately 40 hours and the 
median concentration peaked at 5 hours. Comparing single dosing of 10 mg under fasted and 
fed conditions, no detrimental effect of food intake was found. Single oral doses of 10 to 40 mg 
IMU-838 were well tolerated. No adverse events of special interest (AESI; including hematuria 
or clinically significant RBC in urine high) were observed in that clinical trial. 
In Trial P1-IMU-838-MAD, repeated oral dosing of IMU-838 over 14 days in doses from 30 to 
50 mg resulted in dose-proportional blood PK under fasted conditions. Geometric mean half-life 
at steady state ranged from 28.6 to 30.4 hours. Overall, median peak concentration following 
multiple oral doses of IMU-838 occurred between 2 to 3 hours after the first and after repeated 
dosing. Steady-state levels were reached within about 4 days for 25 mg IMU-838, within 6-8 
days for 30 mg, within about 6 days with 40 mg, and within about 8 days with 50 mg IMU-838. 
Repeated once-daily oral doses of 30 to 50 mg IMU-838 over 14 consecutive days were well 
tolerated. Mild or moderate treatment-emergent AEs (TEAEs) were reported by 31 subjects 
(59.6%); overall 53 TEAEs, reported by 29 subjects (55.8%) were considered drug-related. The 
number of subjects with drug-related TEAEs or the number of drug-related TEAEs did not 
increase with increasing dose.  
Most individual laboratory values were within the normal ranges. There were no clinically 
relevant differences between pre- and post-dose assessments and between the treatment groups 
for any parameter. 

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5.2.5 
Safety of IMU-838 
To date, 351 individuals have been exposed to vidofludimus. Of these 351 subjects, 299 were 
dosed with 4SC-101 and 52 with IMU-838.  
The safety analysis of all exposed subjects provided the following findings:  
• No deaths 
• No serious adverse event (SAE) during Phase 1 with IMU-838 
• The most frequent AEs for IMU-838 during Phase 1 were: 
o 
Headache  
o 
Flatulence  
o 
Common cold  
o 
Positive urine dipstick for hemoglobin 
Importantly, vidofludimus (free acid) at a daily dose of 35 mg showed no increase of adverse 
reactions compared with placebo, and no increased infection rate. 
IMU-838 is a selective DHODH inhibitor and did not inhibit any kinase (of a panel of over 100 
tested protein kinases) at blood concentrations that are found at therapeutic dose levels. 
However, both teriflunomide and IMU-838 inhibit organic anion transporters such as URAT1, 
which potentially could affect renal uric acid elimination. 
In conclusion, IMU-838 is expected to have a favorable safety profile, as in more than 
350 patients (with rheumatoid arthritis or inflammatory bowel disease) or volunteers no 
increased events of diarrhea, nausea, alopecia or headache as well as no increases in abnormal 
liver function tests were observed. 
5.3 
Rationale for the trial  
MS is a chronic disorder of the CNS, which affects up to 2.5 million people worldwide. Efficacy, 
safety and tolerability of the currently approved MS therapeutics are regarded to be substantially 
different among the available treatment options. As all these therapeutic agents have to be 
administered chronically, a high treatment adherence is required, and therefore the need to 
increase the tolerability of the drug.   
Among the available disease modifying treatments (DMTs), oral administration is preferred by 
patients with MS. One of the available DMTs for MS with oral administration is the DHODH 
inhibitor teriflunomide. In a Phase 2 trial of teriflunomide on patients with relapsing forms of 
MS, a statistically significant decrease in combined unique active (CUA) lesions was observed 
with teriflunomide compared to placebo after 12 weeks of treatment.  

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As outlined above, IMU-838 selectively inhibits pyrimidine synthesis in activated cells via 
inhibition of DHODH, which seems to be a promising approach to treat MS. Teriflunomide, 
currently approved in the USA and EU to treat RRMS, showed consistent effects across multiple 
markers of MS burden and activity, including annual relapse rate (ARR) and risk of disability 
progression in several clinical trials. However, teriflunomide is associated with hepatotoxicity 
and clinically important AEs, such as diarrhea, alopecia and neutropenia which are thought to 
be off-target effects related to inhibition of certain kinases and which limit the use of 
teriflunomide in patients with RRMS. Current data suggest that IMU-838 may show an 
improved safety and tolerability profile compared with teriflunomide. In addition, because 
teriflunomide has a prolonged half-life of 19 days in patients with MS, accelerated elimination 
with cholestyramine or charcoal may be considered when a treatment with teriflunomide must 
be terminated. The blood half-life of IMU-838 is roughly 30-40 hours and therefore well suited 
for once daily oral administration and a quick wash-out after treatment discontinuation. 
Based on these data and the pharmacodynamics (PD) of vidofludimus, IMU-838 may represent 
a novel and efficacious oral treatment option for RRMS patients. Thus, trial P2-IMU-838-MS 
will evaluate the efficacy and safety of 2 different doses of IMU-838 in patients with RRMS. 
6 
Investigators, trial administrative structure, and committees 
The clinical trial is funded by Immunic AG and it is planned to include about 40 trial centers in 
a variety of countries including Romania, Bulgaria, Ukraine, and Poland and potential additional 
centers in Hungary and Croatia.  
At each center, a 2-physician concept will be established with at least 2 treating physicians and 
at least 2 evaluating physicians for each patient (i.e. one main physician and one deputy each, 
for details refer to Section 10.2). 
The sponsor, Immunic AG, will be responsible for the overall supervision and administration of 
the trial. Global project management, data management, statistical analysis and report writing 
will be done by FGK Clinical Research GmbH, München, Germany (a contract research 
organization [CRO] - in the following referred to as sponsor’s designee). Monitoring will be 
done by the following CROs:  
• Bulgaria and Croatia: Resbiomed Ltd, Sofia, Bulgaria  
• Romania and Hungary: Clinical Trial Center SRL, Timisoara, Romania 
• Ukraine and Poland: verum.de GmbH, Germering, Germany  

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Other vendors used in the trial: 
• Nuvisan GmbH, Neu-Ulm, Germany: PK measurement of IMU-838, labeling, 
packaging, and distribution of the IMP 
• PharmaLex, Mont-Saint-Guibert, Belgium: PK (population PK modeling) 
• LKF - Laboratorium für Klinische Forschung GmbH, Schwentinental, Germany: central 
clinical safety laboratory  
• Labor Lademannbogen, Hamburg, Germany: HIV testing based on Nucleic Acid 
Amplification Technology 
• Institut für Translationale Neurologie, Universitätsklinikum Münster, Germany: central 
biomarker laboratory 
• IMGM Laboratories GmbH, Martinsried, Germany: micro ribonucleic acid-122 
(miR-122) assessment and genotyping 
• Siena Imaging S.R.L. Siena, Italy: central MRI quality control and evaluation  
• Keosys Medical Imaging, Saint-Herblain, France: qualification of MRI sites, upload and 
anonymization of MRI examinations, technical quality assessment of MRI image files, 
queries to MRI sites, access of central readers to MRI examinations 
• Trium Analysis Online GmbH, München, Germany: electronic case report form (eCRF) 
and interactive web response system (IWRS)  
• Anju Software Belgium Holdings, Antwerpen, Belgium: eCRF for extended treatment 
period 
• SCRATCH Pharmacovigilance GmbH, Butzbach, Germany: pharmacovigilance 
services 
A steering committee will be established and provide advice on the conduct of the trial, regular 
reviews of safety data, and publications (for more details refer to Section 15.4). All members of 
the steering committee will stay blinded throughout the trial until data base lock and unblinding 
and will only review blinded data until then. 
Addresses and telephone numbers of main responsible parties involved in the conduct of the 
trial are provided in Section 2. 

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7 
Trial objectives and endpoints 
7.1 
Trial objectives 
Primary 
• To evaluate the efficacy of 45 mg/day IMU-838 in the treatment of RRMS based on 
MRI assessments  
Secondary 
• To evaluate the efficacy of 30 mg/day IMU-838 in the treatment of RRMS based on 
MRI assessments  
• To evaluate the safety and tolerability of 30 mg/day and 45 mg/day IMU-838 in RRMS 
patients 
Tertiary 
• To evaluate PD effects of IMU-838 in RRMS patients 
• To evaluate IMU-838 trough values and population PK  
• To evaluate the effects of IMU-838 on treatment satisfaction in patients with RRMS  
7.2 
Trial endpoints 
Primary 
Efficacy 
Difference between 45 mg/day IMU-838 and placebo in the cumulative number of CUA6 
MRI lesions up to Week 24 
Key secondary (hierarchical testing to primary efficacy) 
Efficacy 
Difference between 30 mg/day IMU-838 and placebo in the cumulative number of CUA 
MRI lesions up to Week 24  
Secondary 
Efficacy 
• Difference between 45 mg/day IMU-838 and 30 mg/day IMU-838 in the cumulative 
number of CUA MRI lesions at Week 24  
• Difference between 30 mg/day IMU-838 and placebo, 45 mg/day IMU-838 and placebo, 
and 30 mg/day and 45 mg/day IMU-838 for the following MRI parameters: 
 
6 Sum of the number of all new Gd+ lesions on T1-weighted MRI and the number of all new or substantially 
enlarged lesions on T2-weighted MRI (non-enhancing on T1-weighted MRI), avoiding double counting. 

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o Mean number of CUA lesions per patient per scan at Weeks 6, 12, 18 and 24 
o Cumulative number of CUA MRI lesions up to Weeks 6, 12, and 18  
o Volume changes of T2 lesions at Weeks 6, 12, 18 and 24 compared to Baseline 
o T2-lesion load at Weeks 6, 12, 18 and 24 compared to Baseline 
o T1-lesion load at Weeks 6, 12, 18 and 24 compared to Baseline 
o Cumulative number of new gadolinium enhancing (Gd+) lesions up to Weeks 6, 12, 
18 and 24 
o Cumulative number of new T2 lesions up to Weeks 6, 12, 18 and 24 
o Cumulative number of new T1 lesions up to Weeks 6, 12, 18 and 24 
o Proportion of patients without new Gd+ lesions over 24 weeks  
o Proportion of patients without new or enlarging T2-weighted lesions over 24 weeks 
o Proportion of patients with CUA lesions at Week 24 
o Proportion of patients with Gd+ lesions at Week 24 
o Proportion of patients with T2 lesions at Week 24  
• 
Differences between individual treatments and between the pooled 30 mg/day and 
45 mg/day groups and placebo in the following relapse-related clinical endpoints: 
o Mean annualized relapse rate (during main and extended treatment period)  
o Proportion of relapse-free patients up to Week 24 and at extended periods thereafter 
o Time to relapse at time of final analysis of main part 
• Differences between treatments in changes of disease activity as measured by the 
following clinical parameters: 
o Mean change in the EDSS as compared to Baseline during the main and extended 
period (every 12 weeks starting at Week 12)  
o Proportion of patients with EDSS progression during the main and extended period 
(every 12 weeks starting at Week 12, and cumulatively) 
• Correlation of MRI-based assessments with quartiles of IMU-838 trough levels at Week 
6 and Week 24 
Safety 
• AEs, serious AEs and clinically significant laboratory abnormalities (as assessed by the 
investigator) 
• AESI:  
o RBC urine positive, at least of moderate intensity 
o Hematuria 

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o Retroperitoneal colicky pain with suspected or confirmed nephrolithiasis 
• Proportion of patients treated with 30 mg/day or 45 mg/day IMU-838 as compared to 
placebo who experienced at least one of the following AEs: 
o Neutropenia 
o Lymphopenia 
o Diarrhea 
o Alopecia 
o Hemorrhage 
o Abnormalities in alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
gamma glutamyl transferase (GGT), and total bilirubin with both elevations ˃1.5 x 
ULN and ≥35% elevated compared to Baseline 
• Electrocardiogram (ECG), physical examination, and vital signs 
• MiR-122 expression (Change from Baseline to 4 hours after first dose) 
• Presence of John Cunningham virus (JCV) deoxyribonucleic acid (DNA) in urine in 
patients with detectable JCV-DNA in urine at Screening Visit 1, at Week 24, and at end-
of-study (EoS) 
• Time to treatment discontinuation for any reason 
• Rate of treatment discontinuations up to Week 24 
Pharmacokinetics  
• Population PK at Week 6 (3-10 hours post-dose) 
• Plasma trough levels of IMU-838 at Days 7 and Weeks 6, 12, 18, and 24 
Pharmacodynamics 
• Changes from Baseline in lymphocyte subset parameters as measured by flow cytometry 
at Weeks 6 and 24 (in selected Biomarker Centers only) 
• Changes from Baseline in biased T-cell clonal repertoire based on T-cell receptor deep 
sequencing at Weeks 6 and 24 (in selected Biomarker Centers only) 
• Changes from Baseline in serum neurofilament at Week 24 
Health outcome 
• Treatment Satisfaction Questionnaire for Medication at Week 6, Week 24 and EoS  
 

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8 
Trial design and design rationale 
8.1 
Overall trial design 
8.1.1 
Design overview 
This is a Phase 2, multicenter, randomized, double-blind, placebo-controlled trial in patients 
with RRMS and evidence of active disease. The trial comprises a screening period, a 24-week 
blinded main treatment period evaluating the efficacy of 2 different doses of IMU-838 
compared with placebo, and an (initially blinded then open-label) optional extended treatment 
period for up to 9.5 years, during which patients receive 2 doses of IMU-838.  
Blinding to individual treatment assignments during the main treatment period and during the 
beginning of the extended treatment period will be maintained for patients, investigators, and 
other personnel involved in the conduct of this trial, until results of the data analysis of the main 
treatment period will be available. Once the results are known, the sponsor will unblind all 
involved personnel, except for the evaluating physician (see below) by sending a summary 
report of the results. Depending on the results of the main treatment period, investigators may 
recommend switching to the other dose in agreement with the patient (also see Section 8.1.4). 
An overview of the design is shown in Figure 1. 
At each center, a 2-physician concept will be established i.e. at least 1 treating physician and at 
least 1 evaluating physician (and at least a deputy for each of the 2 physicians). The treating 
physician will be responsible for all aspects of the trial with the exception of neurological 
examinations which will be done by the evaluating physician. This 2-physician concept ensures 
that the EDSS will be assessed blinded to other trial-related assessments (for details on the 2-
physician concept refer to Section 10.2).  
8.1.2 
Screening period and baseline MRI 
Patients with a confirmed diagnosis of RRMS and an MRI confirmation of at least one MS-
related brain lesion in the last 6 months before informed consent will be included in the trial. 
Presence of active disease (through presence of MS relapses in the past years) and other 
eligibility criteria will be confirmed at Screening Visit 1. For patients eligible for the trial 
following Visit 1 and after review of laboratory results, a baseline MRI will be performed 
(Screening Visit 2) that will serve as reference for further MRI assessments. The quality of the 
baseline MRI, as well as the presence of Gd+ and T2 lesions will be evaluated centrally. The 
baseline MRI may be repeated once for each patient, in case of not acceptable imaging quality. 
Randomization must be performed within 14 days following the baseline MRI (if the MRI 
assessment from the central reader is not available within these 14 days, randomization may be 
postponed by up to 7 days), and within 28 days (up to 35 days due to delay of the centralized 

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assessment of baseline MRI; or up to 60 days if the baseline MRI needs to be repeated for quality 
reasons) from Screening Visit 1. Randomization at the beginning of the main treatment period 
will be stratified by the number of Gd+ lesions (either 0 or ≥1 Gd+ lesions) and by the field 
strength of the MRI scanner used for trial MRIs (1.5T or 3.0T). 
If the baseline MRI will be repeated, patients must be randomized within 14 days of the repeated 
baseline MRI. In this case, the Screening Visit 1 assessments will be valid for up to 60 days 
until the day of randomization, but will have to be repeated if 60 days are exceeded.  
8.1.3 
Main treatment period 
On Day 0 of the main treatment period, approximately 195 patients will be randomized 1:1:1 to 
once-daily oral treatment with 30 mg/day or 45 mg/day IMU-838, or placebo (about 65 patients 
each) for 24 weeks. For the first 7 days of the main treatment period, patients will only receive 
half the dose they were randomized to, i.e. 1 tablet of 15 mg/day or 22.5 mg/day IMU-838, or 
placebo. From Day 7 onwards, patients will receive the full dose, i.e. 2 tablets up until Week 24. 
Tablets (either 1 or 2) will always be taken at the same time in the morning 15 to 60 minutes 
before breakfast (please note that on visit days, the patients should take their doses only after 
trough level blood collection at the site). During the main treatment period, symptomatic 
assessments (EDSS, clinical neurological symptoms, MRI), safety, biomarkers, and IMU-838 
plasma trough levels will be evaluated (see Table 1 for details). The analysis of the main 
treatment period will be done after all patients completed the end-of-main treatment (EoMT) 
visit at Week 24.     
If the MR image of a patient shows ≥8 Gd+ per scan (investigator alert criterion) as assessed by 
the central MRI assessment the investigator will be informed. The requirement and the nature 
of measures to be taken are at the investigator’s discretion. 
Patients who completed 24 weeks of main treatment and fulfilling further eligibility criteria (see 
Sections 9.2 and 1), have the option to continue into the extended treatment period. 
8.1.4 
Optional extended treatment period 
All patients who completed the main treatment period, who are eligible, and who chose the 
option to continue treatment will be re-randomized to the following treatment for the initial 
blinded weeks of the extended treatment period: 
• Patients who received placebo during the main treatment period will be randomized 1:1 
to once-daily oral treatment with 30 mg/day or 45 mg/day IMU-838.  
• Patients who were treated with IMU-838 during the main treatment period will be re-
randomized to the same dose they previously received. Patients, investigator and other 
trial personnel will remain blinded and unaware to this continued treatment as these 

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patients will undergo the same randomization procedures and IMP assignments as 
patients who previously received placebo. 
For the first 7 days of the extended treatment period, patients will receive half the dose, i.e. 
1 tablet of 15 mg/day or 22.5 mg/day IMU-838. Thereafter and throughout the extended 
treatment period, patients will take 2 tablets of 15 mg/day or 22.5 mg/day IMU-838. Tablets 
(either 1 or 2) will always be taken at once in the morning 15 to 60 minutes before breakfast.  
For the initial weeks of the extended treatment period, trial participants, treating physicians, 
evaluating physicians, central MRI readers and all other personnel directly involved in the 
conduct of the trial will remain blinded to all treatment assignments, until the results of the main 
treatment period are available. Once the results of the data analysis are available, the sponsor 
will provide summary results for all treatments of the main treatment period to the investigators. 
Investigators and patients currently in the extended treatment period will be unblinded to the 
treatment assignments of the main and the past extended treatment period. From this moment 
forward, the treatment in the remaining extended treatment period will be open label.  
Depending on the results of the main treatment period, investigators may discuss the option of 
a dose switch for the remaining extended treatment period with those patients still participating 
in the extended treatment period. Doses may be switched more than once during the extended 
treatment period but switching should always be done at a clinic visit.  
The decision of a dose switch should be a personal decision based on patient-specific 
circumstances and treatment history with IMU-838. The investigator will discuss any potential 
risks of a dose switch (i.e. the disease management on the current dose and the potentially added 
risk of switching to a higher dose). Patients will not be obliged to switch to another dose, even 
if the higher dose showed beneficial effects during the main treatment period. 
During the extended treatment period, the safety, clinical neurological symptoms, and EDSS 
will be regularly assessed at clinic visits scheduled every 12 weeks (see schedule of assessments 
in Table 1). The extended treatment period will end with the end-of-treatment (EoT) visit after 
9.5 years, unless the patient prematurely terminates the trial participation (for possible reasons 
see Section 17) or the sponsor terminates the trial (for reasons see Section 19).  
All patients discontinuing the trial as scheduled or prematurely will be encouraged to undergo 
an EoS visit 30 days (+14 days) after the last intake of IMP. 
8.2 
Trial design rationale 
This is a placebo-controlled, double-blind, randomized trial. A placebo arm is included due to 
regulatory recommendations to evaluate efficacy and adverse effects in randomized, 
double-blind, placebo-controlled trials. [16] 

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The distribution of male and female patients will be according to the natural distribution within 
the trial population, expecting more female than male patients. No corrective measures will be 
taken.  
The trial uses a 2-physician concept, i.e. a treating physician and an evaluating physician for the 
EDSS, which ensures that neurological examinations will be assessed blinded to other 
trial-related assessments (for details refer to Section 10.2). 
As this is a Phase 2 trial, the MRI based cumulative number of CUA lesions is considered an 
acceptable primary endpoint in line with the European Medicines Agency (EMA) Guideline on 
clinical investigation of medicinal products for the treatment of MS. [16] As recommended, the 
quality of the baseline MRI images will be centrally assessed. The MRI evaluation will be done 
by a central reader blinded to all clinical information and to treatment assignments (besides trial 
center and patient number to ensure the correct comparison with previous MRI scans). 
Investigators will be provided with a detailed MRI Manual to ensure standardized MRI 
procedures.  
To mitigate any ethical concerns that may arise with the use of placebo in RRMS patients, and 
in line with suggestions from the EMA guidelines, the period of treatment with placebo will be 
limited to 24 weeks. To reduce the number of patients randomized to the placebo arm and to 
test 2 doses of IMU-838, a 3-arm design was chosen with 1:1:1 randomization, which will allow 
the treatment of twice the number of patients with IMU-838 than with placebo. Additionally, an 
MRI investigator alert criterion has been defined in this protocol.  
The primary objective of this trial will be to compare the efficacy of 45 mg/day IMU-838 to 
placebo after 24 weeks of treatment. The schedule of MRI testing selected is more frequent 
(every 6 weeks) than usually used in clinical routine, as Gd+ lesions offer the best evidence of 
recent inflammatory white matter lesions. Enhancement is consistently observed in those lesions 
in relapsing remitting disease and usually lasts 2 to 6 weeks. Therefore, the time period between 
MRI scans was chosen to be 6 weeks to have the highest chance of capturing most or all Gd+ 
lesions. 
MRI testing is an accurate and reliable method. The choice of objective MRI-based endpoints 
will allow to reduce both sample size and trial duration, as opposed to a trial with clinical 
endpoints only, which usually require a longer trial duration. Typically, MRI trials have a 
duration of at least 6 months. In this trial, only one treatment arm will be treated for 24 weeks 
with placebo. At the end of this period, eligible patients will be allowed to participate in an 
optional extension period under active treatment, which will last up to an additional 9.5 years. 
Therefore, the overall maximum duration of this trial was chosen to be 516 weeks, to assess all 
patients completing the blinded treatment period and (after unblinding) the open-label extended 
treatment period for long-term safety, tolerability and efficacy.  

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8.3 
Risk-benefit assessment 
Risks 
Based on pre-clinical and clinical studies with the precursor drug 4SC-101 and the single and 
multiple dose Phase 1 studies with IMU-838, no serious adverse reactions are expected with 
IMU-838 at doses of <70 mg once daily. 
In clinical studies with 4SC-101, including 486 subjects of whom 299 received 4SC-101, no 
drug-associated clinically relevant adverse reactions were observed at doses of <70 mg once 
daily. This included the potential target organs liver and kidney identified in animals or during 
early clinical trials. In a large placebo-controlled, randomized clinical trial of 4SC-101 in 
patients with RA, the AE profile of 35 mg/day 4SC-101 was similar to the AE profile of placebo. 
No increased rate of infections and infestations were seen in the treatment arm as compared to 
placebo in the same trial. 
At high 4SC-101 doses (≥70 mg/day or single doses of ≥210 mg) potential drug-related 
decreases in blood uric acid and increases in urine RBC were observed, in very rare cases 
presenting as symptomatic hematuria during the first days of treatment. Laboratory findings 
were consistent with post-renal events and de novo precipitates in the urinary tract. However, 
no cases of symptomatic hematuria were seen at daily doses of 35 mg 4SC-101, the highest 
therapeutic dose used in previous clinical trials.  
Non-significant effects on serum uric acid effects following 50 mg IMU-838 could be further 
reduced in a Phase 1 trial when subjects received half the dose i.e. 25 mg, during the first week 
of treatment confirming that the effect on serum uric acid is a treatment initiation effect. Pre-
dosing with low doses may therefore further limit the potential risk of AEs of the renal and 
urinary system, like elevated RBC levels in urine or hematuria. 
Based on these results, the underlying mechanism leading to increased RBC in urine appears to 
be an increased uric acid elimination during the initial days after drug administration. By 
inhibition of the urate transport system URAT1, IMU-838 may decrease the tubular re-uptake 
of uric acid in kidneys, leading to an increase in the urinary excretion of uric acid. Increased 
urine uric acid may in turn result in microcrystallization of uric acid in acidic urine and may 
lead to the occurrence of RBC in urine. Although this may not regularly lead to clinically 
relevant AEs or laboratory abnormalities at therapeutic doses, it may be important for patients 
with risk factors (including increased serum uric acid or higher propensity for urinary 
concrements) or in patients with a history of gout.  
Thus, several risk mitigation measures for urinary events were implemented in this trial: 
• Patients will be advised to drink sufficient fluid per day to ensure adequate urine flow.  

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• Patients will receive only half of their assigned full dose during the first week of 
treatment as the main changes on uric acid urinary excretion are expected during the 
initial treatment days.  
• Regular urine dipsticks and urine sediment analysis will be performed to monitor 
presence of RBC in urine.  
• Patients with a history of renal diseases, especially those favoring or resulting in 
nephrolithiasis, with serum uric acid levels at Screening Visit 1 >1.2 x upper limit of 
normal (ULN), and/or history of gout or symptoms suggestive of gout will be excluded 
from the trial. 
During clinical trials using the previous formulation 4SC-101, 1 SAE of hepatitis was reported 
in a patient with Gilbert syndrome receiving 35 mg 4SC-101. Gilbert syndrome is a genetic 
disease characterized by a 70–80% reduction in the glucoronidation activity of UDP-
glucuronosyltransferase 1A1 (UGT1A1). IMU-838 is a moderate inhibitor of UGT1A1 which 
may have contributed to this AE. Patients with known or suspected Gilbert syndrome or with 
elevation of indirect (unconjugated) bilirubin above 1.2 x ULN will therefore be excluded from 
this clinical trial. 
A thorough analysis of the clinical data did not confirm a potential adverse effect of 
vidofludimus on liver function tests in patients other than those with Gilbert syndrome. 
However, patients with liver impairment or elevated liver functions tests (˃1.5 x ULN) will be 
excluded from trial participation and liver enzymes and bilirubin will be regularly monitored 
throughout the trial. For more information please refer to the investigator’s brochure.  
Benefits 
Vidofludimus has so far been evaluated in about 230 patients with RA and inflammatory bowel 
disease. A Phase 2 trial for ulcerative colitis is currently ongoing, but results are not available 
yet.  
IMU-838 has currently not been tested for the treatment of RRMS. However beneficial effects 
are expected based on pre-clinical findings. In the rat spinal cord extract-induced EAE model, 
treatment with IMU-838 inhibited motor symptoms and reduced EAE-associated weight loss. 
Further the DHODH inhibitor teriflunomide is already authorized for the treatment of RRMS 
and similar effects can be expected for IMU-838. However, IMU-838 appears to have several 
advantages compared to teriflunomide. IMU-838 is safe and can be easily managed by the 
treating physician for the following reasons:  
• The low intra- and inter-patient variation in IMU-838 plasma trough levels reduce the 
risk of under- or over-dosing of patients compared with teriflunomide. 

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• IMU-838 has a low risk of major safety issues compared with frequent side-effects 
observed with teriflunomide. 
• In case of treatment termination, IMU-838 will be cleared from the body within a few 
days, whereas teriflunomide remains in the body for up to 2 years.  
Risk management 
Risk minimization procedures are implemented for this trial to minimize and assess potential 
risks to participating patients. These include, but are not limited to: 
• specific inclusion and exclusion criteria which ensure that patients who present with 
characteristics that may increase the risk for an adverse outcome are excluded, 
• close monitoring for RBC in urine, 
• regular monitoring of liver enzymes  
• a 1-week initiation dose at half-dose level. 
Risk-benefit assessment 
Considering the safety data, the implemented risk minimization measures, the positive data in 
animal models of MS, the expected benefits in the target population, and the medical need for 
further treatment in MS, the benefit-risk evaluation is considered favorable. 
9 
Patient selection 
9.1 
Sample size 
The planned sample size in this trial is approximately 195 patients, randomized 1:1:1 to once-
daily oral 30 mg/day or 45 mg/day IMU-838, or placebo (about 65 patients each) for 24 weeks 
in the main treatment period. During the extended treatment period, patients previously on 
placebo treatment will be randomized 1:1 to treatment with 30 mg/day or 45 mg/day IMU-838, 
all other patients will continue their previous treatment. For the sample size calculation see 
Section 16.1.  
The maximum numbers of patients enrolled will be 35 per center and 120 per country. 
9.2 
Inclusion criteria  
Main treatment period 
1. Male or female patient (age ≥18 to 55 years, inclusive) 
2. Diagnosis of RRMS according to the revised McDonald criteria (2017) [1] 
Note: The diagnosis of MS (including “dissemination in time”) must have been 
established before the patient is screened for the trial.  

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3. Disease activity evidenced  
o by either at least 2 relapses in the last 24 months, or at least 1 relapse in the last 
12 months before randomization (relapses must have been assessed and documented 
by a physician in the patient files), AND 
o ≥1 documented Gd+ MS-related brain lesion, in the last 6 months before informed 
consent (date of MRI examination as well as copy of MRI report or representative 
image has to be available and accessible as patient source data at the study site) 
4. Expanded Disability Status Scale (EDSS) score between 0 and 4.0 (inclusive) at 
Screening Visit 1 
5. Female patients  
o must be of non-child-bearing potential i.e. surgically sterilized (hysterectomy, 
bilateral salpingectomy, bilateral oophorectomy at least 6 weeks before Screening 
Visit 1) or post-menopausal (where postmenopausal is defined as no menses for 
12 months without an alternative medical cause), or 
o if of child-bearing potential, must have a negative pregnancy test at Screening Visit 1 
(blood test) and before the first IMP intake (Day 0 urine test). They must agree not to 
attempt to become pregnant, must not donate ova, and must use a highly effective 
contraceptive method (see below) together with a barrier method between trial 
consent and 30 days after the last intake of the of the IMP. 
Highly effective forms of birth control are those with a failure rate less than 1% per 
year and include: 
− oral, intravaginal, or transdermal combined (estrogen and progestogen 
containing) hormonal contraceptives associated with inhibition of ovulation 
− oral, injectable, or implantable progestogen-only hormonal contraceptives 
associated with inhibition of ovulation 
− intrauterine device or intrauterine hormone-releasing system 
− bilateral tubal occlusion 
− vasectomized partner (i.e. the patient’s male partner underwent effective surgical 
sterilization before the female patient entered the clinical trial and is the sole 
sexual partner of the female patient during the clinical trial) 
− sexual abstinence (acceptable only if it is the patient’s usual form of birth 
control/lifestyle choice; periodic abstinence [e.g. calendar, ovulation, 
symptothermal, postovulation methods] and withdrawal are no acceptable 
methods of contraception) 
Barrier methods of contraception include: 

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− Condom  
− Occlusive cap (diaphragm or cervical/vault caps) with spermicidal 
gel/film/cream/suppository 
6. Male patients must agree not to father a child or to donate sperm starting at Screening 
Visit 1, throughout the clinical trial and for 30 days after the last intake of the IMP. Male 
patients must also  
o abstain from sexual intercourse with a female partner (acceptable only if it is the 
patient’s usual form of birth control/lifestyle choice), or 
o use adequate barrier contraception during treatment with the IMP and until at least 
30 days after the last intake of the IMP, and 
o if they have a female partner of childbearing potential, the partner should use a highly 
effective contraceptive method as outlined in inclusion criterion 5 
o if they have a pregnant partner, they must use condoms while taking the IMP to avoid 
exposure of the fetus to the IMP 
7. Willingness and ability to comply with the protocol  
8. Written informed consent given prior to any trial-related procedure 
Inclusion criteria for optional extended treatment period 
1. Completed 24 weeks of main treatment  
2. Baseline MRI, a Week 24 MRI as well as 2 additional post-dose MRIs  
Continuation criteria for optional extended treatment period  
1. In case the initial Week 24 MRI was not evaluated at least partially assessable, 
availability of a repeated Week 24 MRI  
2. Week 24 MRI (initial or repeated one, if applicable) evaluated at least partially assessable 
9.3 
Exclusion criteria 
A patient will not be eligible for inclusion if any of the following criteria applies:  
MS-related exclusion criteria 
1. Any disease other than MS that may better explain the signs and symptoms, including 
history of complete transverse myelitis 
2. Signs and symptoms suggestive of transmissible spongiform encephalopathy, or family 
members who suffer(ed) from these 
3. Clinical signs or presence of laboratory findings suggestive for neuromyelitis optica 
(NMO) spectrum disorders or MOG-associated encephalomyelitis (i.e. presence of anti-
NMO [aquaporin-4] antibodies or anti-MOG-antibodies)  

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4. MS types other than RRMS 
5. Any MRI finding, atypical for MS, including but not limited to a longitudinally extensive 
spinal cord lesion 
6. Any active and uncontrolled coexisting autoimmune disease, other than MS (except for 
type 1 diabetes mellitus and inflammatory bowel disease) 
7. An MS relapse within 30 days before Screening Visit 1 and/or during the screening period 
(until Day 0) 
Therapy exclusion criteria 
8. Any previous or current use of the following MS treatments: monoclonal antibodies 
(natalizumab, alemtuzumab, daclizumab, ocrelizumab, anti-CD4, rituximab or 
belimumab, including their biosimilars), total lymphoid irradiation, bone marrow 
transplantation, stem cell transplantation, or any use of DHODH inhibitors, including 
teriflunomide (Aubagio™) or leflunomide (Arava™) 
9. Any use of the following MS treatments within 12 months before the date of 
informed consent: any cytokine (other than interferon) or anti-cytokine therapy, 
intravenous immunoglobulin, mitoxantrone, cytotoxic or immunosuppressive therapy 
(including, but not limited to azathioprine and cyclophosphamide, excluding only 
systemic corticosteroids or adrenocorticotrophic hormone [ACTH]), tofacitinib, 
methotrexate, mycophenolate mofetil, mycophenolate sodium, fingolimod, any 
calcineurin inhibitors (e.g. tacrolimus, cyclosporine, or pimecrolimus) 
10. Any use of the following MS treatments within 30 days before the date of informed 
consent: interferon-β, glatiramer acetate, dimethyl fumarate and plasmapheresis 
11. Within 30 days before the baseline MRI: Use of systemic corticosteroids (intravenous 
or oral) or ACTH 
12. Use of the following concomitant medications is prohibited at Screening Visit 1 and 
throughout the duration of the trial:  
o any medication known to significantly increase urinary elimination of uric acid, in 
particular lesinurad (Zurampic™) as well as uricosuric drugs such as probenecid  
o treatments for any malignancy, in particular irinotecan, paclitaxel, tretinoin, 
bosutinib, sorafinib, enasidenib, erlotinib, regorafenib, pazopanib and nilotinib  
o any drug significantly restricting water diuresis, in particular vasopressin and 
vasopressin analogs  
o use of rosuvastatin at daily doses higher than 10 mg 

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13. Use of any investigational product within 8 weeks or 5 x the respective half-life before 
the date of informed consent, whichever is longer, and throughout the duration of the 
trial 
Immune response exclusion criteria 
14. Conditions negatively affecting the immune response such as previous organ transplant  
15. Clinically significantly low lymphocyte and/or neutrophil count (Common Terminology 
Criteria for AEs Grade of 2 or higher), i.e.  
o lymphocyte count <800/mm³ (0.8 x 109/L), and/or 
o neutrophil count <1,500/mm³ (1.5 x 109/L) 
16. History of chronic systemic infections within 6 months before the date of informed 
consent, including but not limited to tuberculosis, human immunodeficiency virus (HIV), 
hepatitis B or C  
17. Positive IFNγ release assay for Mycobacterium tuberculosis at Screening Visit 1 
18. Positive hepatitis B virus surface antigen (HBsAg), hepatitis B core antibody (HBcAb), 
positive HCV-antibody (HCV-Ab) and/or HIV-antigen-antibody test7 at Screening 
Visit 1 
19. Any live vaccinations within 30 days before the date of informed consent except for the 
influenza vaccine 
Other medical history and concomitant disease exclusion criteria 
20. Presence of the following laboratory values at Screening Visit 1:  
o platelet count <100,000/mm³ (<100 109/L) 
o serum creatinine >1.5 x ULN 
o total bilirubin, ALT, or GGT >1.5 x ULN 
o Serum uric acid levels at Screening Visit 1 >1.2 x ULN (for women >6.8 mg/dL, for 
men >8.4 mg/dL) 
o indirect (unconjugated) bilirubin >1.2 x ULN (i.e. >1.1 mg/dL) 
21. Known history of nephrolithiasis or underlying condition with a strong association of 
nephrolithiasis, including hereditary hyperoxaluria or hereditary hyperuricemia  
22. History or clinical diagnosis of gout 
23. Renal impairment defined as estimated glomerular filtration rate8 ≤60 mL/min/1.73m²  
 
7 A positive HIV-Ag/Ab test will be confirmed by further testing based on Nucleic Acid Amplification 
Technology (NAAT). If the NAAT test is negative, the patient will be considered HIV negative.  
8 Calculated according to the Chronic Kidney Disease Epidemiology Collaboration equation. 

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24. Known or suspected Gilbert syndrome 
25. Diagnosis or suspected liver function impairment which may cause fluctuating liver 
function tests during this trial, as assessed by the investigator  
26. History or presence of serious or acute heart disease such as uncontrolled cardiac 
dysrhythmia or arrhythmia, uncontrolled angina pectoris, cardiomyopathy, or 
uncontrolled congestive heart failure (New York Heart Association [NYHA] class 3 or 
4) 
Note: NYHA class 3: Cardiac disease resulting in marked limitation of physical activity. 
Patients are comfortable at rest. Less than ordinary activity causes fatigue, palpitation, 
dyspnea, or anginal pain. NYHA class 4: Cardiac disease resulting in inability to carry 
on any physical activity without discomfort. Symptoms of heart failure or the anginal 
syndrome may be present even at rest. If any physical activity is undertaken, discomfort 
is increased.  
27. Clinically relevant, severe pulmonary diseases, uncontrolled hypertension, or poorly 
controlled diabetes 
28. Concurrent malignancy or prior malignancy within the previous 10 years except for the 
following: adequately-treated non-melanoma skin cancer and adequately-treated cervical 
cancer 
29. History or presence of any major medical or psychiatric illness (such as severe 
depression, psychosis, bipolar disorder), history of suicide attempt, or current suicidal 
ideation that in the opinion of the investigator could create undue risk to the patient or 
could affect adherence with the trial protocol 
30. Epilepsy or seizures not adequately controlled by treatment 
31. Any other substantial medical condition that in the opinion of the investigator could 
create undue risk to the patient or could affect adherence with the trial protocol 
General exclusion criteria 
32. Current or past (within 12 months of Screening Visit 1) alcohol or drug abuse 
33. Any condition that would prevent the patient from undergoing an MRI scan, including: 
o claustrophobic conditions 
o unable to receive Gd-based MRI-contrast agents due to history of hypersensitivity to 
Gd-based contrast agents, or severe renal insufficiency 
o presence of metallic implants incompatible with brain MRI 
34. Legal incapacity, limited legal capacity, or any other condition that makes the patient 
unable to understand the patient information and informed consent form 
35. Pregnant or breastfeeding 

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36. An employee of an investigator or sponsor or an immediate relative of an investigator 
37. Patients institutionalized due to judicial or administrative order 
Exclusion criteria for optional extended treatment period 
1. Any ongoing, clinically significant (as assessed by the investigator) treatment-emergent 
(started after intake of IMP) AE or laboratory abnormality (including blood chemistry 
and urinalysis)9  
2. Significant treatment or trial non-compliance during the main treatment period (as 
assessed by the investigator), and/or inability or unwillingness to follow instructions by 
trial personnel 
3. Treatment compliance <70% during the main treatment period 
4. Significant protocol deviations during the main treatment period that are assessed by the 
investigator to negatively affect further patient cooperation in this trial 
10 
Randomization, blinding and unblinding procedures 
10.1 
Blinding 
Trial participants, treating and evaluating physicians (see below for details), central MRI readers 
and all other personnel directly involved in the conduct of the trial will be blinded to treatment 
assignments during the main treatment period and for the initial time of the extended treatment 
period. The evaluating physician will also be blinded to any clinical outcome or treatment 
change. 
To maintain the blind, IMU-838 and placebo tablets will have identical appearance, shape and 
color, and will have identical labeling and packaging. To minimize the potential for bias, 
treatment randomization information will be kept confidential by the responsible personnel and 
will not be released to investigators, other trial center personnel, or the sponsor’s designee(s) 
during the main treatment period and the blinded phase of the extended treatment period.  
To maintain the blind during re-randomization for the extended treatment period, all patients 
will be randomized after Week 24 (see Section 10.6), although patients already assigned to 
treatment with IMU-838 will be re-assigned to their previous treatment.  
The MRI evaluation will be blinded by means of the central MRI assessment procedure. 
Once the results of the main treatment period are available, treating physicians, participants, and 
other involved personnel, except for the evaluating physician, will be unblinded. The evaluating 
 
9 If treatment-emergent AEs are the reason for exclusion from the extended treatment period, the eligibility can 
be re-assessed up to 30 days following the last treatment in the main treatment period. 

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physician will remain blinded to patients’ clinical characteristics and treatment assignment 
during the entire clinical trial. 
10.2 
Two-physician concept 
To achieve blinding for the evaluation of clinical endpoints, a 2-physician concept will be 
applied, consisting of a ‘treating physician’ and an ‘evaluating physician’. For each role, one 
deputy must be nominated. Therefore, in total at least 4 staff members have to be involved in 
the treatment and evaluation of patients at each center. Throughout this protocol, references to 
the treating physician and evaluating physician include their respective deputies. 
The investigator responsible for the conduct of the trial and for supervision of the management 
of individual patients at the center should not take the role of evaluating physician. 
10.2.1 
Treating physician 
The treating physician will be responsible for all aspects of treatment and clinical management 
of the patient, including the management of relapses, and will have the same level of blinding 
as the patient. The treating physician will perform the following activities: 
• Physical examinations 
• Evaluation of the patient’s subjective findings 
• Assigning (through IWRS randomization) the IMP and monitoring the trial medication 
• Evaluating and managing (serious) AEs, concomitant medication, laboratory results, and 
relapses 
• Relapse assessment of concurrent fever or infection, assessment of EDSS criteria for a 
relapse based on the current and the previous EDSS scores 
The treating physician can never be involved in evaluating EDSS scores. 
10.2.2 
Evaluating physician 
The evaluating physician will perform all standardized neurological examinations needed for 
the EDSS (see Section 13.3 and A-Table 1).  
Throughout the trial, the evaluating physician will not exchange any treatment-related 
information with the patient or with the treating physician, will not have access to the eCRFs, 
or to any source documents, and will have no access to any MRI scans or laboratory reports. For 
all data recordings, the evaluating physician will use hardcopies of the Neurostatus tool forms 
(see Appendix 1), which will be forwarded to the treating physician after their completion for 
subsequent storage, both as hardcopies and through transcription of the data into the eCRF. 

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The interaction with the patient will be restricted to the neurological evaluation. The evaluating 
physician will not be allowed to talk with the patient about AEs, or any other issue that could 
potentially disclose the patient’s treatment. 
Thus, the evaluating physician will be completely blinded to all aspects related to the patient’s 
treatment.  
10.3 
Patient’s identification card 
Patients will be provided with patient cards during their trial participation. The patient card 
allows the clinical trial patients to identify themselves as clinical trial participants, and thus 
ensures that health care providers (who are not part of this trial) have access to the information 
about this participation that may be needed to determine the course of the patient’s medical 
treatment. 
This may include the possibility of emergency unblinding if needed. In case of an emergency 
the health care provider should first contact the respective clinical trial investigator, whose name 
will be given on the patient card (investigator must agree to this). If the investigator is available, 
he/she will answer any questions. Any subsequent action (e.g. unblinding) will follow the 
standard processes established for the investigators. 
10.4 
Emergency unblinding 
The premature breaking of the blind will be restricted to emergency cases in which knowledge 
of the administered drug is necessary for treatment of clinically significant AEs. Whenever 
possible, the investigator must contact the sponsor or the medical monitor before breaking the 
blind, and evaluate if the knowledge of the administered drug would have any impact on 
treatment decisions for the AE. If the blind is broken, the respective patient will be withdrawn 
from further treatment in this trial and a written explanation must be given by the investigator 
to the sponsor immediately. Emergency unblinding, if necessary, will be conducted via the 
IWRS of the eCRF. 
10.5 
Patient identification 
A 6-digit patient identifier consisting of 2 digits each for country (YY), center (XX) and patient 
(ZZ) i.e. YYXX-ZZ will be assigned to each screened patient.  
10.6 
Randomization 
The trial includes two randomizations, one randomization at the start of the main treatment 
period, and a second randomization at the start of the extended treatment period.  

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Eligible patients will be randomized by an IWRS within the eCRF. The IWRS will assign the 
IMP kits to each patient during the main treatment period and the blinded phase of the extended 
treatment period. The sites will be supplied with user guides for the IWRS in English or the 
national language. 
Data on the presence or absence of Gd+ lesions needed to stratify the randomization in the main 
treatment period, will be forwarded by the central MRI reader. In case this information is not 
available within 14 days after the baseline MRI, the randomization may be delayed by up to an 
additional 7 days. The center will also use a dedicated single MRI machine for all trial-related 
MRI examinations, and the field strength of this MRI scanner (1.5 Tesla vs 3.0 Tesla) will also 
be used as stratification factor for randomization. 
The investigators will be provided with technical options and password information to 
selectively break the code for an individual patient via the IWRS or (as backup) telephone. For 
further information see Section 10.4. 
11 
Treatments 
11.1 
Investigational medicinal product 
All IMPs supplied by the sponsor will be manufactured, tested, and released according to current 
Good Manufacturing Practice guidelines and local requirements.  
11.1.1 
IMU-838  
Name: 
IMU-838  
Manufacturer: 
Immunic AG 
Active ingredient: 
Vidofludimus calcium (IM90838) 
Inactive ingredients: 
Microcrystalline cellulose EP, polyvidon K25, crospovidone EP 
type A, talc, and magnesium stearate 
Formulation: 
Tablets containing a specific polymorph of vidofludimus calcium  
Matrix: 
White uncoated tablets, biconvex shape, diameter of 8 mm 
Dose strengths: 
15 mg and 22.5 mg  
 

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11.1.2 
Placebo  
The placebo tablets will be identical to the IMU-838 tablets in terms of appearance, constitution 
of inactive ingredients, and packaging. 
11.1.3 
Packaging, labeling and dispensing 
All IMP will be packed and labeled according to applicable regulatory requirements.  
The labels will contain at least the following information: route of administration, trial code, 
randomization number, batch number, expiry date, and instructions for storage. 
IMU-838 and placebo tablets will be packaged in 30 mL polyethylene bottles containing 
85 tablets.  
For the main treatment period, one bottle containing IMP will be dispensed at Day 0, then 
2 bottles each at Weeks 6, 12 and 18 (Visits 2-4). For the extended treatment period, 3 bottles 
of IMP will be dispensed at Week 24/EoMT (Visit 5), and every 12 weeks (until EoT or until 
Week 504, whichever comes first).   
11.1.4 
Storage and stability 
The investigator is responsible for the safe and proper handling and storage of the IMP at the 
investigational site. The IMP must be stored in a locked facility with access limited to the 
investigator and authorized personnel. The investigator must ensure that the IMP is administered 
only to patients enrolled in this trial. 
In stability studies, IMP was stable at ambient (25°C/60% relative humidity) and at accelerated 
storage conditions (40°C/75% relative humidity), and does not require any special storage 
conditions. However, the tablets should be protected from direct sun light, moisture, freezing, 
and extended periods of excessive heat (defined as any temperature above 40°C [104 F]). It 
should also be advised to keep the bottle tightly closed to protect tablets from moisture. 
11.1.5 
Treatment dose, dose selection, and administration  
The IMP will be administered once daily as oral tablets. Tablets (1 tablet per day for the initial 
week of treatment, 2 tablets per day thereafter) will be taken once daily in the morning in fasted 
state (no food after midnight, unrestricted intake of water is always allowed) and taken with one 
glass of water approximately 15 minutes to 1 hour before breakfast. If 2 tablets need to be taken, 
these will be taken at the same time. 
The following must be considered for IMP intake: 
• At all trial visit days in the main treatment period, tablets must be taken at the trial center 
to allow for pre-dose assessments (i.e. plasma IMU-838 trough levels). 

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• During the entire trial, patients will not be allowed to have breakfast before they arrive 
at the trial center (to allow for blood chemistry). Intake of water is always allowed and 
will not be restricted.  
• The patient will be encouraged to drink sufficiently (approximately 1.5 liters per day 
throughout the trial).  
Doses of 30 and 45 mg once daily were chosen based on 4SC-101 data where a daily dose 
around 35 mg/day was safe, and based on the results of the Phase 1 studies with IMU-838 
showing comparable serum exposure of the free acid and calcium salt formulation of 
vidofludimus. Additionally, the Phase 1 trial of IMU-838 investigating multiple doses over a 
14-day period found doses of 30 to 50 mg IMU-838 to be safe. The highest dose used in this 
trial will be 45 mg/day IMU-838. The area under the concentration time curve of this dose is 
expected to be far lower than that of 70 mg/day 4SC-101, which was associated with increased 
RBC in urine. To further reduce the risk of increased urine RBC, patients will receive only half 
the dose during the first week of treatment as the mechanism of increased uric acid excretion is 
thought to be more pronounced during treatment initiation. 
An elimination half-life of 30-40 hours allows a once daily administration with minimal 
accumulation (accumulation factor of 2). 
11.1.6 
Drug accountability and patient compliance 
The IMP must not be used outside the context of this trial protocol. The investigator must ask 
the patient to return excess IMP and all packaging materials (including empty containers) at all 
applicable visits (see Table 1) for drug accountability. Unused IMP cannot be used outside the 
context of this trial protocol. Dispensed and returned IMP cannot be re-used for any other 
patients. 
The investigator or authorized staff must document the receipt, dispensing, and return of all IMP 
received during this trial. These records will include but are not limited to dates, quantities, 
batch numbers, patient identifiers, and unique interactive response technology codes, as 
applicable. The investigators must maintain records documenting that patients were provided 
with the IMP as outlined in the protocol. Furthermore, investigators will reconcile all IMP 
received from the sponsor and returned from the patient. It is the responsibility of the 
investigator to reason any discrepancies in IMP accountability. Forms will be provided to ease 
accountability. 
At the end of the clinical trial, or as directed, all remaining and unused IMP must be accurately 
counted (final drug accountability) and destroyed according to the sponsor’s instructions, i.e. to 
e.g. return all remaining and unused IMP to the sponsor or sponsor’s designee.  

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11.2 
Prior and concomitant medications 
All medications administered within 1 month before the day of informed consent and until EoS 
must be documented in the corresponding section of the eCRF. In addition, all MS-related 
therapies since MS diagnosis will be documented in the eCRF. 
All medications taken by the patients after giving informed consent and all treatments given in 
addition to the IMP during the trial are regarded as concomitant treatments and must be 
documented in the eCRF. 
11.2.1 
Permitted therapies 
11.2.1.1 
Corticosteroid treatment of MS relapses 
In case of MS-related neurological events, whether or not they meet the protocol’s clinical 
relapse criteria (Section 13.2), corticosteroid treatment will be provided at the discretion of the 
investigator. 
It will be allowed to treat a clinical attack by a 3 to 5-day course of methylprednisolone 500 to 
1000 mg/day intravenous (i.v.) without tapering-out. 
Note: As corticosteroid treatment may affect the results of MRI scans, specific restrictions will 
be applied with respect to timing of corticosteroid treatment and planned MRI assessments (see 
Section 13.4). 
11.2.1.2 
Plasma exchange due to MS relapses 
Only during the extended treatment period and only if with the corticosteroid treatment 
described above (Section 11.2.1.1) the patient remains non-responsive (and after assessing the 
risk-benefit ratio as well as treatment options outside of the trial), plasma exchange is allowed 
for a total of 5 sessions within 2 weeks. 
If (in the assessment of the investigator) none of the above-mentioned rescue therapies 
(corticosteroid treatment and plasma exchange) are sufficiently able to treat the MS relapse, the 
patient must be discontinued from the trial immediately and other treatment options outside this 
trial should be considered (see Section 17). 
11.2.1.3 
Patient’s self-medication 
As this is an out-patient trial, special care will be taken in questioning the patients on any self-
medication. All concomitant medications taken by the patient during the trial from the date of 
signature of informed consent must be reported in the appropriate section of the eCRF along 
with dosage information, dates of administration, and reasons for use. If the IMP is discontinued, 
all remaining medications taken must be recorded in the eCRF until the end of the trial. The 

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following conditions should be particularly addressed, documenting the reasons why the 
concomitant medication was administered: 
• supportive therapy for MS-related conditions (e.g. pain, fatigue or weakness, 
incoordination, bladder dysfunction, spasticity etc.) 
• medication and/or therapy for MS relapse (as allowed in this trial) 
• for a medical condition already reported in the patient’s medical history (e.g. any form 
of pain, especially lumbar pain and headache, depression, etc.)  
• for prophylactic use 
• as treatment of an AE 
11.2.2 
Prohibited medication 
The use of the following medications and treatments will be prohibited during the trial: 
• Monoclonal antibodies (including, but not limited to natalizumab, alemtuzumab, 
daclizumab, ocrelizumab, anti-CD4, rituximab or belimumab, including their 
biosimilars) 
• Total lymphoid irradiation 
• Bone marrow transplantation 
• Stem cell transplantation 
• Teriflunomide (Aubagio™)  
• Leflunomide (Arava™) 
• Any cytokine (other than interferon) or anti-cytokine therapy 
• I.v. immunoglobulin 
• Mitoxantrone 
• Cytotoxic or immunosuppressive therapy, including, but not limited to azathioprine and 
cyclophosphamide 
• Any chemotherapy treatment for malignancies, in particular irinotecan, paclitaxel, 
tretinoin, bosutinib, sorafinib, enasidenib, erlotinib, regorafenib, pazopanib, and 
nilotinib 
• Tofacitinib 
• Methotrexate 
• Mycophenolate mofetil (CellCept™) or mycophenolate sodium (Myfortic™) 
• Fingolimod 

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• Dimethyl fumarate (DMF, Tecfidera™) 
• Any calcineurin inhibitors (e.g. tacrolimus, cyclosporine, or pimecrolimus) 
• Interferon-β  
• Glatiramer acetate 
• ACTH 
• Any uricosuric drugs, in particular lesinurad (Zurampic™) as well as probenecid 
• Vasopressin of vasopressin analogues 
• Rosuvastatin at daily doses higher than 10 mg 
• Live vaccines 
• Corticosteroid therapy other than for MS-relapses, as defined above (see Section 
11.2.1.1) during the main treatment period; during the extended treatment corticosteroid 
therapy will be allowed also to treat conditions other than MS relapses 
• Plasma exchange during the main treatment period; in the extended treatment period it 
is allowed as defined above (see Section 11.2.1.2) 
• Any other IMP 
Every treatment with oral or systemic corticosteroids must be reported. Furthermore, specific 
restrictions will be applied for the timing of MRI assessment relative to corticosteroid treatment 
(see Section 13.4). 
11.2.3 
Restricted medications 
The concomitant administration of drugs metabolized for more than 70% by CYP2C8 (although 
not prohibited) should be carefully considered since it cannot be excluded that IMU-838 
potentially increases their blood levels. Major substrates of CYP2C8 include  
• amodiaquine (anti-malarial) 
• dasabuvir (anti-viral), enzalutamide (anti-cancer) 
• montelukast (anti-asthmatic), and 
• pioglitazone and repaglinide (anti-diabetics) 
In addition, concomitant administration of drugs being intermediate or minor CYP2C8 
substrates (metabolized for 20-70% or <20% by CYP2C8, respectively) known to have a 
clinically relevant association with impaired CYP2C8 functionality such as paclitaxel, 
chloroquine, loperamide, ibuprofen and possibly diclofenac will also be considered with 
reasonable care. The use of these CYP2C8 substrates as concomitant medication is not 
prohibited during this trial. However, their use will be restricted in terms of dose and treatment 

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duration (if possible), alternatives to these drugs will be considered, and patients will be 
carefully monitored for any indication of toxicity. Given the narrow therapeutic window of 
ibuprofen, the use of ibuprofen should be carefully considered or, if possible, therapeutic 
alternatives should be used. 
Care should be exercised when using medications that are substrates of the BCRP transport 
system, especially where the elimination of the medication depends on the BCRP transport 
system. Patients should be closely monitored for signs and symptoms of excessive exposure to 
the medicinal products and dosing of these medicinal products should be carefully considered. 
This is particularly true for statins, and their dose should be lowered to the lowest possible dose. 
Specifically, doses of rosuvastatin are not to exceed 10 mg daily. 
11.3 
Precautions and restrictions 
Female patients: 
• must be of non-child-bearing potential i.e. surgically sterilized (hysterectomy, bilateral 
salpingectomy, bilateral oophorectomy at least 6 weeks before Screening Visit 1) or 
post-menopausal (where postmenopausal is defined as no menses for 12 months without 
an alternative medical cause), or 
• if of child-bearing potential, must have a negative pregnancy test at Screening Visit 1 
(blood test) and before the first IMP intake (Day 0 urine test). They must agree not to 
attempt to become pregnant, must not donate ova, and must use a highly effective 
contraceptive method (see below) together with a barrier method between trial consent 
and 30 days after the last intake of the IMP. 
Highly effective forms of birth control are those with a failure rate less than 1% per year 
and include: 
o 
oral, intravaginal, or transdermal combined (estrogen and progestogen containing) 
hormonal contraceptives associated with inhibition of ovulation 
o 
oral, injectable, or implantable progestogen-only hormonal contraceptives 
associated with inhibition of ovulation 
o 
intrauterine device or intrauterine hormone-releasing system 
o 
bilateral tubal occlusion 
o 
vasectomized partner (i.e. the patient’s male partner underwent effective surgical 
sterilization before the female patient entered the clinical trial and is the sole sexual 
partner of the female patient during the clinical trial) 
o 
sexual abstinence (acceptable only if it is the patient’s usual form of birth 
control/lifestyle 
choice; 
periodic 
abstinence 
[e.g. 
calendar, 
ovulation, 

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symptothermal, postovulation methods] and withdrawal are no acceptable methods 
of contraception) 
Barrier methods of contraception include: 
o 
Condom  
o 
Occlusive 
cap 
(diaphragm 
or 
cervical/vault 
caps) 
with 
spermicidal 
gel/film/cream/suppository 
Male patients: 
• must agree not to father a child or to donate sperm starting at Screening Visit 1 and 
throughout the clinical trial and for 3 months after the last intake of the IMP.  
• must abstain from sexual intercourse with a female partner (acceptable only if it is the 
patient’s usual form of birth control/lifestyle choice), or 
• use adequate barrier contraception during treatment with the IMP and for at least 
3 months after the last intake of the IMP, and 
• if they have a pregnant partner, they must use condoms while taking the IMP to avoid 
exposure of the fetus to the IMP. 
If male patients do have a female partner of childbearing potential, the female partner must use 
a highly effective contraceptive or other effective birth control method (see above) throughout 
the trial and for 30 days after the last intake of the IMP.  
For restrictions concerning the administration of the IMP see Section 11.1.5. 
12 
Trial schedule 
12.1 
Trial conduct 
An overview of the trial conduct is provided in Table 1. Patients will be given a patient’s 
identification card at Screening Visit 1 stating the patient’s name, that the patient is participating 
in a clinical trial, and the name, address and telephone number of the investigator. Patients must 
be advised to carry this identification card at all times during their participation in the trial (see 
also Section 10.3). 
Patients will be advised to bring the IMP (including empty bottles) to specified visits. At each 
visit, patients will be advised to drink a generous amount of fluid per day (approximately 
1.5 liters per day throughout the trial are recommended) to ensure adequate urine flow. 
Patients will be asked to withhold IMP intake on days of clinic visits, because they will take the 
IMP at the clinic after all scheduled pre-dose assessments were completed. Patients will also be 

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asked to fast overnight before all clinic visits as specified in Section 11.1.5, but not to restrict 
their water intake.  
Patients will rest for at least 5 min before any blood is drawn (if applicable) or vital signs are 
measured. 
At all visits (except the EoS visit), patients will be reminded to return to the trial site for their 
next scheduled visit (see Table 1). However, patients will also be instructed to contact the trial 
site at any time if they experience a pronounced deterioration of their disease. Patients must be 
advised to inform the investigator in case of any emergency.   
12.2 
Screening  
Screening Visit 1 (Day -28 to Day -9) 
Patients for whom written informed consent (for consent procedures see Section 18.3) was 
obtained will undergo the assessments shown in Table 1. Patients will be screened for eligibility 
based on the trial’s inclusion and exclusion criteria. The presence of active MS will be confirmed 
based on the review of previous MRI (performed locally no longer than 6 months before the 
Screening Visit 1).  
Screening Visit 2 (Baseline MRI; Day -14 to Day -3) 
A baseline MRI will be performed to serve as reference for all future MRI assessments during 
the trial. The quality of the baseline MRI will be assessed centrally and may be repeated as soon 
as possible, if considered necessary by the independent MRI reader. If then acceptable, the 
repeated MRI will serve as baseline MRI. The screening period may be extended by the time 
from initial MRI to repeat MRI. However, randomization must occur within 14 days of the 
repeated MRI. Assessments from Screening Visit 1 will be valid for up to 60 days between 
Screening Visit 1 and randomization. If 60 days are exceeded, Screening Visit 1-assessments 
must be repeated.   
Re-screening 
If the patient experiences a relapse during the screening period, the patient can be re-screened 
earliest 30 days after the onset of the MS attack. 
12.3 
Main treatment period 
Randomization visit (Visit 0; Day 0) 
Patients will undergo the assessments and procedures detailed in Table 1 and will be randomized 
to treatment with the IMP. Randomization must be performed within 14 days after the baseline 
MRI (if the baseline MRI was repeated, within 14 days of the repeated MRI) and within 28 days 

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from obtaining informed consent. Blood samples for assessing IMU-838 trough levels will be 
collected before IMP intake. 
For female patients, the result of the local urine pregnancy test must be available and negative 
before the first IMP intake.  
Visits 1 to 4 (Day 7, Weeks 6, 12 and 18) 
Patients will undergo the assessments and procedures detailed in Table 1. 
At each visit, blood samples will be taken pre-dose to assess IMU-838 trough levels. At Week 6, 
an additional plasma sample will be taken 3 to 10 hours post-dose for assessing IMU-838 
population PK. Hence, the patient will be asked to remain at the trial site for at least 3 hours, or 
to return to the site 3 to 10 hours after IMP intake.  
In case of premature discontinuation during the main treatment period, patients will undergo all 
assessments scheduled for the EoMT visit (Table 1).  
Visit 5/EoMT (Week 24) 
Patients will undergo the assessments and procedures detailed in Table 1 and, if they chose to 
continue into the optional extended treatment period, will be randomized for treatment in the 
extended treatment period. All patients who completed the assessments scheduled for this visit 
and fulfil the eligibility criteria for the extended treatment period have the option to continue 
into the extended treatment period.  
If the Week 24 MRI turns out to be not at least partially assessable it can be repeated as soon as 
possible. If the repeated MRI is still not at least partially assessable, the patient must be 
withdrawn from the extended treatment period. 
Patients prematurely discontinuing during the main treatment period will undergo the 
assessments scheduled for this visit (Table 1). 
12.4 
Extended treatment period 
Visits 6 to 45 (Week 36 to Week 504; every 12 weeks)10 
Patients will undergo the assessments and procedures shown in Table 1. Patients will be 
assessed every 12 weeks during the extended treatment period.  
 
10 For patients in the Cohort 2 sub-trial the extended treatment period will be terminated the day the last patient 
of the Cohort 1 main trial has completed or discontinued the extended treatment period. The extended treatment 
period for Cohort 2 patients may thus be shorter. 

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Visit 46/EoT (Week 516)11  
Patients will undergo the assessments and procedures shown in Table 1 and will be asked to 
return all remaining IMP and its packaging (including empty bottles) to the trial center for IMP 
accountability checks.  
Patients prematurely discontinuing during the extended treatment period will undergo the 
assessments scheduled for this visit (Table 1). 
12.5 
Unscheduled visit  
A patient may return for an unscheduled visit at the discretion of investigator to undergo 
additional safety evaluations (i.e. laboratory re-testing, AE assessments), or for additional 
neurological evaluations, particularly in the case of neurological symptoms indicative of a 
potential MS relapse (see Section 13.2).   
The data from unscheduled visits will be collected in the eCRF. 
12.5.1 
Unscheduled visit due to symptoms indicative for an MS relapse 
Patients who experience symptoms indicating a potential MS relapse (in the absence of fever, 
as defined in Section 13.2) will undergo the assessments of an unscheduled visit as shown in 
Table 1. For allowed treatments of MS relapse, please refer to Section 11.2.1. 
If the patient experiences fever, the unscheduled visit should be planned after fever has subsided 
and if neurological symptoms are still present. 
12.5.2 
Unscheduled visit due to safety 
Patients who experience AEs of clinical relevance, i.e. AEs that in the investigator’s opinion 
require additional safety assessments, or require laboratory re-testing will undergo the 
assessments of an unscheduled visit as shown in Table 1. 
For follow-up of AEs including clinically relevant laboratory events please refer to 
Section 15.1.6. 
12.6 
Premature termination 
If a patient prematurely discontinues the trial (for possible reasons, please see Section 17)  
• during the main treatment period, i.e. before Week 24, all assessments scheduled for the 
EoMT visit should be performed; 
 
11 For patients in the Cohort 2 sub-trial the extended treatment period will be terminated the day the last patient 
of the Cohort 1 main trial has completed or discontinued the extended treatment period. The extended treatment 
period for Cohort 2 patients may thus be shorter. 

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• during the extended treatment period, i.e. before Week 516,10 all assessments scheduled 
for the EoT visit should be performed. 
All patients who prematurely discontinue the trial will be encouraged to complete the EoMT or 
EoT visit, as described above, as well as the EoS assessments at 30 days (+14 days) after the 
last IMP intake.  
In case of premature withdrawal from the trial, reasons, circumstances and findings will be fully 
described on the corresponding page in the eCRF respecting the patient’s rights.  
12.7 
End of study visit (EoS; 30 days +14 days after the EoT) 
Patients who discontinue the treatment (at any time during the trial or as scheduled) will be 
asked to return for an EoS visit 30 days (+14 days) after their last IMP intake with assessments 
as shown in Table 1. For the follow-up of ongoing AEs at EoS, please refer to Section 15.1.6. 
For patients who have had the EoS visit but who have still ongoing AEs which need to be 
followed up (see Section 15.1.6) and thus require additional clinic visits, these visits should be 
documented as an unscheduled visit due to safety. 
13 
Efficacy assessments and procedures  
13.1 
Demographics and other baseline assessments 
During Screening Visit 1, demographics (including sex, age, and race), a complete medical 
history including a detailed MS history and previous therapy will be collected. A previous MRI 
scan (not older than 6 months) will be used to assess the eligibility.  
13.2 
Neurological assessments and MS relapse 
MS clinical events occurring during any of the trial periods must be evaluated to determine 
whether they qualify as “MS relapse” as defined in this protocol for efficacy assessment. 
All of the following criteria must be met for a clinical event to qualify as a relapse: 
1. Neurological deficit, either newly appearing or re-appearing, with abnormality specified 
by both 
o Neurological abnormality separated by at least 30 days from onset of a preceding 
relapse 
AND 
o Neurological abnormality lasting for at least 24 hours 

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2. Absence of fever or known infection (i.e. temperature [axillary, oral, or intra-auricular] 
≤37.5ºC) 
3. Neurological impairment, defined as either 
o Increase in at least one of the functional systems of the EDSS 
OR 
o Increase of the total EDSS score. 
In both cases, the increase in EDSS must correlate with the patient’s reported 
symptoms. 
The occurrence of fatigue, mental symptoms, and/or vegetative symptoms without any 
additional symptom will not classify as a relapse (please see Section 15.1.7 if and when such 
symptoms must be recorded as an AE). 
To maintain blinding, the treating and evaluating physicians must fulfil different tasks in 
neurological and MS relapse assessments. Whereas the evaluating physician will perform the 
standardized EDSS assessment (as outlined in Section 13.3), the treating physician will assess 
neurological symptoms and confirm the presence of MS relapse based on all available data. 
At each scheduled visit, the treating physician will ask the patient if any new MS-related 
neurological symptoms have occurred. If the treating physician expects that a protocol-defined 
MS relapse has occurred, the evaluating physician will be asked to do an EDSS assessment even 
if not planned according to the schedule of assessments. When the treating physician receives 
the EDSS score, he/she will also determine whether the EDSS criterion for an MS relapse is 
met. 
In-between scheduled visits, the patient will be instructed to contact the treating physician 
immediately if he/she develops new, recurring, or worsening neurological (including visual) 
symptoms. If symptoms indicative of an MS relapse are reported by the patient, the treating 
physician will assess whether the symptoms occur in the presence of fever or infection (in case 
of an unscheduled phone contact, the treating physician may simply ask the patient). 
If fever or infection is excluded, the evaluating physician must arrange for a neurological 
examination (assessment of EDSS) as soon as possible, at the latest within 7 days following the 
reporting of the event. If fever or infection cannot be excluded, the neurological examination by 
the evaluating physician will have to be postponed until the fever or the infection has ceased 
(provided that the symptoms indicative of an MS relapse are still present). Treatment of the MS 
event with corticosteroids should not begin prior to the assessment by the evaluating physician. 
For allowed MS relapse treatments in this trial, please refer to Section 11.2.1. 

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Based on the EDSS scores, in conjunction with the results from previous examinations, the 
treating physician will determine whether the EDSS criterion for an MS relapse is fulfilled. 
Since corticosteroid treatment of MS relapses may affect the results of MRI scans, the 
occurrence of an MS relapse may result in the postponement of a scheduled MRI scan. 
Neurological symptoms characteristic of MS that are captured as new MS related neurological 
symptoms in the EDSS and/or as MS relapse are efficacy measures and must generally not be 
documented as AEs. However neurological symptoms which are abnormally severe, not 
anticipated for the disease or are judged to be related to IMP treatment must be reported as AE 
(for more details please refer to Section 15.1.7).  
13.3 
Expanded Disability Status Scale  
The EDSS [17] is a widely used and validated instrument evaluating the functional systems of 
the CNS to describe disease progression and the efficacy of MS therapy. The composite rating 
system ranges from 0 (normal neurological status) to 10 (death due to MS) in 0.5-unit 
increments.  
The EDSS measures the impairment in 8 functional systems: 
• pyramidal - weakness or difficulty moving limbs 
• cerebellar - ataxia, loss of coordination or tremor 
• brainstem - problems with speech, swallowing and nystagmus 
• sensory - numbness or loss of sensations 
• bowel and bladder function 
• visual function 
• cerebral (or mental) functions 
• other 
Each functional system is scored independently. The combination of findings from the 
functional system scores allows to establish the final EDSS score. 
EDSS steps 1.0 to 4.5 refer to a functional status of patients with MS with some limitations 
within at least one functional system, but still able to walk without any aid. EDSS steps 5.0 to 
9.5 are defined by the impairment to walk. Refer to A-Table 1 (Appendix 1) for details on the 
EDSS scores.  
The EDSS will be assessed by the evaluating physician as scheduled in Table 1, and if possible, 
before any other assessments scheduled for that visit will be performed. To standardize the 
EDSS assessment, a paper-based Neurostatus tool set (provided by Neurostatus Systems AG, 
University Hospital Basel, Neurology, Switzerland) will be used (see Appendix 1) for the 

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scoring of the impairment within each functional system based on which the EDSS scores will 
be automatically calculated upon data entry into the eCRF. 
To maximize data consistency, the same physician should perform the same assessments for a 
given patient at approximately the same time of day, whenever possible. The assessments must 
be performed without consulting the results from previous visits.  
The Neurostatus tool should always be retained as a source document and the resulting scores 
(7 functional systems and 1 ambulatory) and final EDSS score be entered into the eCRF.  
To ensure consistency of EDSS scoring across all sites, investigators will receive a standardized 
manual on scoring EDSS using the Neurostatus tool, which will be supplied to sites by the 
sponsor.  
All evaluating physicians should be familiar with the Neurostatus tool, however no specific 
qualification level will be required. The qualification level previously obtained by the evaluating 
physicians participating in this trial will be collected and documented. 
13.4 
Magnetic resonance imaging 
MRI assessments will be performed before the treatment with the IMP (baseline MRI, Section 
12.2) and regularly during the main treatment period as scheduled in Table 1.  
For central assessment, it is of vital importance that all scans adhere to the standardized MRI 
protocol (complying with the MRI manual) which will be provided separately. The same 
dedicated MRI machine (field strength of ≥1.5 Tesla) will be used for all patients at each trial 
site. The only contrast agents allowed in this trial are macrocyclic gadolinium-containing agents. 
Details on MRI protocol are described in the MRI Manual. 
The baseline MRI and all following scans during the main treatment period will be assessed 
centrally and no local assessments will be done for trial endpoints. No MRI finding will be 
communicated to the treating and evaluating investigators involved in this trial as they need to 
remain blinded to MRI scans results of this trial (except for the investigator alert criteria as 
defined below). However, the local site needs to assure that every MRI scan is reviewed for any 
unexpected non-MS findings that would be important for the patient’s health. Such important 
non-MS findings need to be communicated to the treating physician. 
A local previously taken MRI scan will only be used to confirm presence of MS-related brain 
MRI lesions, which is an inclusion criterion (see Section 12.2).  
The treating physician at the site will only be informed about the results of the central MRI 
assessment if the investigator alert criterion was met (i.e. ≥8 Gd+ lesions, observed at a single 

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post-treatment MRI scan performed at Weeks 6, 12, or 18) or in case of any unexpected finding 
on the MRI likely not related to the underlying MS disease. 
MRI restriction rules 
To reduce the impact of corticosteroid treatment on the MRI read-out, the following restrictions 
for the timing of MRI scans will be applied: 
1. No MRI scan is to be performed while a patient is receiving i.v. corticosteroid therapy or 
for 30 days thereafter (counting from the date of treatment end). 
2. Whenever possible, any planned MRI scan should be performed before corticosteroid 
treatment is initiated. Any post-randomization MRI scan may be prematurely performed 
for up to 2 weeks if a corticosteroid treatment needs to be initiated. 
3. No further MRI scans will be performed until the following criteria has been met: 
a. If the baseline MRI scan at Screening Visit 2 (S2) cannot be performed due to 
corticosteroid treatment of a relapse, the patient may be fully re-screened earliest 
30 days after the onset of the MS attack (including all local and central laboratory 
assessment, and baseline MRI).  
b. If any post-dose MRI scan after Day 0 cannot be performed due to corticosteroid 
treatment, the MRI scan for this timepoint will be postponed to fulfill the above 
mentioned criteria of 30 days following end of corticosteroid therapy. 
14 
Pharmacokinetics, pharmacodynamics, and health outcome 
assessments 
14.1 
Pharmacokinetics 
IMU-838 plasma trough level concentrations will be determined by validated direct liquid 
chromatography tandem-mass spectrometry. This method determines the concentration of the 
active moiety vidofludimus contained in IMU-838. Details of the assay will be described in a 
separate bioanalytical report.  
Plasma samples for IMU-838 trough levels will be assessed centrally at Nuvisan. Samples will 
be collected and subsequently stored at -20°C at the site, and shipped to the central laboratory 
as frozen samples, as appropriate. Investigators will be provided with detailed written 
instructions how to collect, handle, store, and ship the samples.  
Plasma trough levels of IMU-838  
Blood samples to assess IMU-838 serum trough values will be collected in all patients as 
specified in the schedule of assessments during the main treatment period (Table 1).  

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Patients are required to withhold intake of the IMP at each visit until after the blood sample 
collection. If the patient inadvertently took the IMP on those days, blood samples for trough 
levels will only be taken within 1.5 hours of IMP intake. If 1.5 hours are exceeded, no blood 
sample for trough levels will be collected. Both cases will be recorded as protocol deviations. 
Trough levels of IMU-838 (trough level quartiles) will be correlated with selected safety and 
efficacy variables. 
Population PK 
Blood samples for population PK will only be collected at Week 6 (Visit 2) pre-dose, and a 
second sample at 3 to 10 hours post dose.  
The first blood draw will be a trough level draw as on other study visits during the main 
treatment period. 15 minutes after patients have taken IMP, they are allowed to eat and drink. 
For the second post-dose blood sample on the same day, the patient may remain at the trial 
center for at least 3 hours or leave the center and return to the trial center any time between 3 
and 10 hours of the morning blood draw. If feasible, these PK data will be evaluated (in 
combination with PK data from other trials) using a non-linear mixed effects modeling. A 
correlation with safety and efficacy may be evaluated if warranted by the data.  
Plasma PK samples will be stored at -20°C at the site until the next scheduled dry ice shipment 
to the central laboratory (see Table 1). 
14.2 
Pharmacodynamics 
14.2.1 
Neurofilament 
Neurofilaments light chain are an emerging serum biomarker for acute and chronic neuronal 
damage and will be assessed as detailed in Table 1. Samples will be centrally analyzed using 
Lab Kit NFL. 
14.2.2 
Peripheral blood mononuclear cell-based biomarkers 
Peripheral blood mononuclear cell (PBMC)-based biomarkers will be assessed in a subset of 
patients only at selected Biomarker centers and will include lymphocyte subset analysis and T-
cell clonal repertoire assessment (see Table 1). The lymphocyte subset will be analyzed by 
immunophenotyping and flow cytometry. The T-cell clonal repertoire will be analyzed by deep 
sequencing of T-cell receptors.  
PBMC-based biomarkers will be assessed centrally using Lab Kit PD.  

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14.2.3 
Blood genotyping 
At Day 0 before dosing, a single blood sample per patient will be collected for genotyping. This 
includes assessment of gene and single nucleotide mutations for genes coding for metabolizing 
enzymes, transporter proteins, and for the target protein DHODH.  
Samples for genotyping (Lab Kit G) will be collected and stored at -20°C at the center until the 
next scheduled dry ice shipment to the central laboratory for analysis. Investigators will be 
provided with detailed written instructions how to collect, handle, store, and ship the respective 
samples. Samples will be evaluated centrally. 
14.3 
Health outcome assessment 
The patient rated outcome will be assessed based on answering questions of the Treatment 
Satisfaction Questionnaire for Medication (TSQM).  
The TSQM is a reliable and valid instrument to assess patients’ satisfaction with medication, 
providing scores on 4 scales: side effects, performance, convenience and global satisfaction. 
[18] Patients will be asked to indicate their level of satisfaction with the treatment by answering 
the 14 questions of the TSQM (refer to Appendix 2) as scheduled in Table 1. Patients will 
complete the TSQM during respective clinic visits and results will then be transferred to the 
eCRF. 
15 
Safety assessments 
15.1 
Adverse events documentation and reporting 
15.1.1 
Definitions 
15.1.1.1 
Adverse events 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product, which does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of the 
IMP, whether or not related to the IMP. 
Overdosing, defined as intake of more than twice the intended dose, will not be considered an 
AE but must be documented as protocol deviation. However, symptoms associated with 
overdose are considered adverse drug reactions (ADR, for definition see below).  

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Untoward medical experiences occurring during pre-treatment periods do not meet the above-
mentioned definition of AE. Nevertheless, they have to be documented in the same way as AEs, 
if they occur in the safety monitoring period, i.e. between signing the informed consent form 
and completion of the EoS visit. Should they already be present at the Screening Visit 1 and 
don’t worsen later on, they will only be documented as medical history. 
A surgery or procedure scheduled to occur during the trial will not be considered an AE if the 
surgery or procedure will be performed for a pre-existing condition and the surgery or procedure 
was planned prior to trial entry. However, if the pre-existing condition deteriorates unexpectedly 
during the trial (e.g. surgery performed earlier than planned), then the deterioration of the 
condition for which the surgery or procedure is being done will be considered an AE. 
Diagnostic medical or non-surgical procedures, including MRI will not be considered as AEs. 
Hospital admission for social or convenience reasons will also not be recorded as AE. 
AEs that occur between signing the informed consent form and the time when the patient first 
administers the IMP (Day 0) are defined as pre-treatment AEs. 
Treatment-emergent adverse events are defined as any event not present prior to the first 
intake of IMP or any event already present that worsens in either intensity or frequency 
following exposure to the IMP. 
A continuous event with changing intensities will be considered as one event of the most severe 
intensity documented. A continuous event with a changing seriousness will also be considered 
as one event, but the start and stop date of the time the event is serious must be separately 
documented. Clearly separated episodes of an event will be considered as separate events. 
For AESIs see Section 15.1.3. 
15.1.1.2 
Adverse drug reactions and unexpected adverse drug reactions 
All adverse events judged by either the reporting investigator or the sponsor as having a 
reasonable causal relationship to the IMP qualify as ADR. The expression reasonable causal 
relationship means to convey in general that there is evidence or argument to suggest a causal 
relationship. 
An unexpected ADR is an adverse reaction, the nature or severity of which is not consistent 
with the applicable product information (e.g. investigator’s brochure for an unapproved 
investigational product or package insert or summary of product characteristics for an approved 
product). Reports that add significant information on specificity or severity of a known, already 
documented AE constitute unexpected AEs, too. For example, an event more specific or more 
severe than described in the reference document would be considered ‘unexpected’. Specific 

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examples would be: acute renal failure as a labeled AE with a subsequent new report of 
interstitial nephritis or hepatitis with a subsequent report of autoimmune hepatitis. 
15.1.1.3 
Serious adverse events 
An SAE is any untoward medical occurrence that, at any dose: 
• results in death 
• is life-threatening 
• requires in-patient hospitalization or prolongation of existing hospitalization 
• results in persistent or significant disability or incapacity 
• results in a congenital abnormality or birth defect 
NOTE: The term "life-threatening" in the definition of "serious" refers to an event in which the 
patient was at risk of death at the time of the event; it does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
Medical and scientific judgment will be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the patient or may 
require intervention to prevent one of the other outcomes listed in the definition above. These 
will usually also be considered serious. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or 
development of drug dependency or drug abuse. In addition, new malignancies that occur during 
the participation in the trial are defined as important medical events and must be reported as 
SAEs.  
An SAE requires that the underlying event is considered an AE as defined in Section 15.1.1.1. 
Hospitalizations due to a surgery or procedure during the trial will not be considered an SAE if 
the surgery or procedure will be performed for a pre-existing condition and the surgery or 
procedure was planned prior to trial entry. However, if the pre-existing condition deteriorates 
unexpectedly during the trial (e.g. surgery performed earlier than planned), then the 
deterioration of the condition leading to hospitalization will be considered an SAE. Hospital 
admission for social or convenience reasons will not be recorded as SAE. 
15.1.1.4 
Suspected unexpected serious adverse reaction  
A suspected unexpected serious adverse reaction (SUSAR) is a serious adverse reaction 
(SAR) that is unexpected or for which the development is uncommonly (unexpected issue) 

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observed during a clinical trial and for which there is at least a reasonable possibility of a causal 
relationship with the IMP. 
15.1.2 
Classification of adverse events 
Classification of AEs will be performed by the investigator. 
Causality 
The causal relationship between the AE and the administration of the IMP or trial procedure 
will be assessed as follows: 
• Related: 
Implies a reasonable possibility of a causal relationship between the 
event and the IMP or procedure. This means that there are facts 
(evidence) or arguments to suggest a causal relationship. 
• Not 
related: 
Implies no reasonable possibility of a causal relationship between the 
event and the IMP or procedure. This means that there are neither facts 
(evidence) nor arguments to suggest a causal relationship. 
Severity 
Severity is a clinical observation and describes the intensity of the event. 
• Mild: 
Any symptom, of which the patient is aware, but which is easily tolerated 
• Moderate: 
Any symptom, which is discomforting enough to cause interference with 
a patient’s usual activity 
• Severe: 
Any symptom, which causes a patient’s inability to perform usual 
activity 
For the severity classification of hematuria see Section 15.1.3. 
Outcome categories 
Recovered: 
The patient has fully recovered from the event or the condition has 
returned to the level observed at Baseline 
Recovering: 
The patient has recovered from the event, but the condition has not 
returned to the level observed at Baseline; 
Not recovered: 
The event is ongoing at the time of reporting and the patient has 
still not recovered 
Recovered 
with sequelae: 
As a result of the AE, the patient suffered persistent and significant 
disability/incapacity (e.g. became blind, deaf or paralyzed) 

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Fatal: 
The patient died due to the event. If the patient died due to other 
circumstances than the event, the outcome should be stated 
otherwise (e.g. not recovered or recovering) 
Unknown: 
If the outcome is not known or not reported 
15.1.3 
Adverse events of special interest 
The following AEs are defined as AESIs, if these events are different from any pre-existing 
conditions or a result from known conditions: 
• RBC urine positive (as defined below), at least of moderate intensity 
• Hematuria (as defined below) 
• Retroperitoneal colicky pain with suspected or confirmed nephrolithiasis 
Evaluation and assessments of RBC in urine 
The evaluation of RBC in urine will be solely based on findings from microscopic examinations 
of urinary sediment and not from dipstick reading only. [19] Therefore all conspicuous dipstick 
readings will be followed up by a microscopic examination of urinary sediment. All findings of 
RBC in urine per high-powered field (HPF) will be listed as urinalysis abnormalities but not as 
an AE, if assessed by the investigator as not clinically significant. The investigator will also 
assess any increased RBC in urine as not clinically significant, if there are more likely 
alternatives to explain this finding. The following alternative explanations of RBC in urine high 
will be considered:  
• The urine sample was not properly collected (random midstream clean-catch collection) 
or evidence of contamination (e.g. presence of bacteria or an unusual number of 
epithelial cells in urine sediment not explained by other conditions).  
• Evidence of infection not considered secondary to a drug-induced damage.  
• Likely benign causes, such as menstruation, vigorous exercise, viral illness, trauma, and 
infection. 
If any finding of “RBC in urine high” is assessed by the investigator as clinically significant, 
this finding will be reported as the AE “RBC urine positive”.  
Evaluation and assessment of hematuria 
Any occurrence of RBC urine positive will only be defined as the AE “hematuria” if at least one 
of the following 2 conditions are met:  
• ≥5 RBCs per HPF were found in at least 2 consecutive, properly collected urinalysis 
specimens, [20] and/or 

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• the finding of RBC urine positive had diagnostic or therapeutic consequences. 
Severity assessment of hematuria 
Severity is a clinical observation and describes the intensity of the event. The severity of 
hematuria is classified as follows:  
• Mild: 
Asymptomatic hematuria; clinical or diagnostic observations only 
• Moderate: 
Symptomatic hematuria; e.g. with moderate flank pain (and including 
short-term*, standard-dose therapy with oral nonsteroidal anti-
inflammatory drugs, oral acetaminophen or oral aspirin), interfering with 
but not limiting activities of daily living 
• Severe: 
Gross or macrohematuria 
Any hematuria with severe flank pain limiting activities of daily living. 
Any hematuria requiring additional treatment (e.g. oral anti-emetics or 
muscle relaxants, around the clock narcotic analgesics, use of narcotics or 
any intravenous treatment) or procedures for maintaining adequate urinary 
flow (e.g. urinary catheter or bladder irrigation). 
* For less than 24 hours. 
15.1.4 
Documentation of adverse events 
All AEs occurring between the date written informed consent was obtained and 30 days after 
the patient’s last IMP intake (observation period) must be recorded. Information on AEs will be 
derived by non-directive questioning of the patients in general terms at each visit (e.g. "How do 
you feel?” or “How have you been since the last questioning?"), by patients’ spontaneous 
reports, or by observation. Adverse events also may be detected when they are volunteered by 
the patient during or between visits or through physical examination, laboratory test, or other 
assessments. 
All AEs that occur during the observation period of the trial as described above will be recorded 
in the patient’s AE section of the eCRF and will include the following information: a description 
of the AE, date of onset and resolution, severity, relationship to the IMP, relationship to trial 
procedure, action taken, and outcome. For SAEs, the SAE form must be completed (see Section 
15.1.5). 
15.1.5 
Documentation and reporting of immediately reportable adverse events 
Any AESI (see Section 15.1.3), any unexpected AE that could adversely affect the safety of the 
patient or the conduct of the trial, and any SAE that occurs during this trial will be reported (via 
the "Adverse Event of Special Interest Form" or the "Serious Adverse Event Form") to the 

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sponsor immediately (i.e. within 24 hours). The information will include at least the following 
data: 
• Name, address, and telephone number of the reporting investigator 
• Investigational product(s) 
• Trial code 
• Patient identification number, sex, and date of birth 
• Description of the AE, measures taken and outcome (at the time of reporting) 
• Assessment of causality to the IMP by the investigator 
Reports will be addressed to:  
SCRATCH Pharmacovigilance GmbH 
Schlossstrasse 25, 35510 Butzbach, Germany 
E-mail: 
safety-immunic@scratch-pv.com 
Telephone: +49 6033 74535 50 
Fax: 
+49 6033 74535 59 
The sponsor ensures that all relevant information about SUSARs that are fatal or life threatening 
is recorded. Reporting of SUSARs to the independent ethics committee (IEC) and regulatory 
authorities will follow pertinent national legislation. 
The sponsor will inform as soon as possible and following national pertinent national legislation 
the regulatory authorities and the IECs about any event that necessitates reconsideration of the 
benefit-risk-ratio of the IMP. These events are in particular: 
• single cases of expected SARs with an unexpected outcome, 
• an increased incidence of expected SARs considered clinically significant, 
• SUSARs occurring after a concerned person has completed the trial, 
• events related to the conduct of the trial or the development of the tested IMP possibly 
affecting the safety of the concerned persons. 
All additional measures deemed necessary through new findings and taken by the sponsor or 
the investigator to protect the safety of the persons concerned and their triggering circumstances 
will be reported as soon as possible to the concerned regulatory authorities and the IECs, if 
applicable. 
Periodic safety reporting to regulatory authorities and the IECs will follow pertinent national 
legislation. 

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In the event of a fatality, the "Trial participant’s insurer" will be informed by the sponsor’s 
designee within 24 hours of gaining knowledge of the event. In case of other SAEs, the "Trial 
participant’s insurer" will be informed promptly. 
15.1.6 
Follow-up of adverse events 
All SAEs judged to be related to the IMP must be followed by the investigator until the patient 
has recovered, recovered with sequelae, died, or until the investigator determines that the 
patient’s condition is stable, whichever occurs first. All other AEs must be followed by the 
investigator until the conditions mentioned above are met or until the EoS visit (30 days after 
the last IMP intake), whichever comes first, and until all AE-related queries for the patient have 
been resolved. The investigator will take all appropriate and necessary therapeutic measures 
required for resolution of the AE, if applicable. All efforts to collect follow-up information must 
be documented in the source data. 
Follow-up information should be supplied on the respective forms of the eCRF.  
During and following a patient’s participation in this trial, the investigator must ensure that 
adequate medical care is provided to a patient for any AEs related to the trial, including clinically 
significant laboratory values. 
15.1.7 
Handling of events typical for MS 
The disease characteristics, in particular those neurological symptoms that are characteristic for 
MS and neurological functional systems scores during the EDSS assessment, will be regularly 
captured throughout the trial and are classified as efficacy assessments. For this reason, any MS-
related symptoms should not be collected as AE, if any one of the following criteria applies: 
• These MS-related symptoms were already present at Screening (and their fluctuations in 
pattern and intensity throughout the trial are considered anticipated based on the 
individual patient’s disease history), or 
• These MS-related symptoms had already occurred during the disease history of the 
patient prior to the trial and their pattern and intensity during the course of the clinical 
trial is consistent with the individual course of the disease, or 
• These MS-symptoms are in close temporal correlation to an acute exacerbation of MS 
in this patient and (in the assessment of the investigator) have a clear relationship to this 
exacerbation event and have an anticipated intensity for such exacerbation event. 
The terms “MS relapse”, “MS attack”, “MS exacerbation” or “worsening of MS” will not be 
considered as AEs, since MS relapse or worsening of EDSS score will be collected as efficacy 
parameters in this trial. 

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However, neurological symptoms should be collected as an AE (even if those symptoms are 
characteristic for patients with MS), if any of the following conditions applies: 
• Any new or worsened neurological symptom if its course is abnormally severe or 
abnormal in its temporal pattern (even if any of the above-mentioned criteria for an 
exclusion from AE collection applies), or 
• Any new neurological symptom that does not have a close temporal relationship to an 
exacerbation event and (in the assessment of the investigator) is not anticipated for the 
course of the disease, or 
• Any new neurological symptoms that (in the assessment of the investigator) is correlated 
to start or change of IMP in this trial. 
Only those neurological symptoms which qualify as AEs according to the definition above may 
potentially be reportable as SAEs. In these cases, the seriousness criterion (e.g. hospitalization) 
must be assessed and an SAE report completed and sent to the sponsor.  
The terms “MS relapse”, “MS attack”, “MS exacerbation”, “worsening of MS” or other MS-
related symptoms which should not be collected as AEs according to the description above, can 
per definition not qualify as SAE, even if they fulfill a seriousness criterion such as 
hospitalization. 
15.1.8 
Pregnancies 
Should a pregnancy occur in a female patient, or in a female partner of a male patient, it must 
be reported to the sponsor within 24 hours of the first awareness of the event and be recorded 
on the appropriate pregnancy form. The trial participation of patients who become pregnant 
during the trial after signing the informed consent will be discontinued immediately. 
A pregnancy is not regarded an AE unless there is a suspicion that the IMP may have interfered 
with the effectiveness of a contraceptive method. Whenever possible, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, normal birth or congenital 
abnormality, maternal and/or new-born complications) must be followed up and documented 
even if the patient was discontinued from the trial. All reports of congenital abnormalities or 
birth defects are SAEs. Spontaneous miscarriages will also be reported and handled as SAEs. 
Elective abortions without complications will not be handled as AEs. 
Pregnancy follow-up will be recorded on the pregnancy form and will include an assessment of 
the possible relationship of the IMP to any pregnancy outcome. 

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15.2 
Laboratory investigations 
Clinical laboratory tests will be performed at the times indicated in the schedule of assessments 
(Table 1).  
All laboratory samples must be clearly and fully labeled according to the central laboratory 
manual. The laboratory reports received from the central laboratory via email or fax will be 
printed, reviewed, signed, and dated by the investigator, and filed at the center. The laboratory 
results will be additionally imported into the eCRF.  
Abnormal results will be assessed by the investigator and classified as clinically significant 
(yes/no). Clinically significantly abnormal values must be reported as AE, if not already 
clinically significantly abnormal at Baseline (i.e. pre-dose on Day 0) or Screening Visit 1 or if 
there are known circumstances unrelated to a disease or the medication (such as patient activities 
or sample handling) that are a likely explanations for the abnormal value. 
Persistent clinically significant abnormal values must be followed up using local laboratory 
values until the cause is determined or until they returned to normal or to the level observed at 
Baseline (for follow-up of clinically significant laboratory values reported as AEs, see Section 
15.1.6). 
15.2.1 
Pregnancy tests 
Female patients of childbearing potential, i.e. not postmenopausal (where postmenopausal state 
is defined as no menses for 12 months without an alternative medical cause) or not surgically 
sterile, must have a negative pregnancy test before the first intake of the IMP. A blood pregnancy 
test is required at Screening Visit 1. Any local urine pregnancy test that shows a positive result 
must be followed up with a confirmatory local blood pregnancy test. 
Additional urine pregnancy testing will be performed locally as scheduled in Table 1 for all 
female patients of childbearing potential. For follow-up procedures in case of pregnancy see 
Section 15.1.8. 
15.2.2 
Blood chemistry, hematology, and coagulation 
15.2.2.1 
Assessments 
Blood chemistry, hematology and coagulation assessments will be performed using Lab Kits A, 
B and C as scheduled in Table 1. The following parameters will be tested: 
Lab Kits A and B 
• Hematology: 
Erythrocytes, 
leucocytes, 
differential 
leucocyte 
count 
(neutrophils, eosinophils, basophils, lymphocytes, monocytes), 

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hemoglobin, hematocrit, mean corpuscular volume (MCV), 
mean corpuscular hemoglobin (MCH), platelets. 
• Biochemistry: 
Liver function monitoring: AST, ALT, alkaline phosphatase, 
GGT, total bilirubin, unconjugated (indirect) and conjugated 
(direct) bilirubin.  
 
Renal function monitoring: creatinine, uric acid, blood urea 
nitrogen (BUN). eGFR will be calculated according to the 
Chronic 
Kidney 
Disease 
Epidemiology 
Collaboration 
(CKD-EPI) equation. 
 
Other parameters: Sodium (Na), potassium (K), magnesium, 
chloride (Cl), inorganic phosphate (P), calcium (Ca), creatine 
phosphokinase, 
lactate 
dehydrogenase, 
amylase, 
lipase, 
C-reactive protein (CRP), total protein, albumin, glucose, 
hemoglobin A1c, triglycerides, cholesterol 
• Coagulation (only in Lab Kit A): 
 
 
Prothrombin time, activated partial thromboplastin time, and 
 
 
international normalized ratio (INR)  
Lab Kit C 
• Hematology: 
Erythrocytes, leucocytes, hemoglobin, hematocrit, MCV, MCH, 
platelets 
• Biochemistry: 
Liver function monitoring: AST, ALT, AP, GGT, total 
bilirubin, unconjugated (indirect) and conjugated (direct) 
bilirubin.  
Renal function monitoring: 
creatinine, uric acid, BUN. eGFR 
clearance will be calculated according to the CKD-EPI equation. 
Other parameters: Na, K, Cl, P, Ca, CRP, total protein, amylase, 
lipase, albumin, glucose, triglycerides, cholesterol 
Blood chemistry, hematology, and coagulation analyses will be done centrally (see Section 6). 
Abnormal results will be classified as clinically significant (yes/no). Clinically significantly 
abnormal values, which were not clinically significantly abnormal at Baseline, must be reported 
as AE. 
Blood samples will be collected, handled and stored according to the instructions provided by 
the central laboratory. Coagulation samples will be collected and stored at -20°C at the site until 
the next scheduled shipment to the central laboratory for analysis. Dry ice shipments may be 
delayed for up to 2 weeks if another patient is expected to finish the respective visit. 

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Samples collected at Baseline, stored but not used for the primary analysis (“B-sample”), may 
be used in future research to evaluate other serum markers (e.g. Epstein-Barr Virus) and address 
research questions that may arise after trial completion. 
15.2.2.2 
Monitoring of hepatotoxicity 
Patients will be monitored throughout the trial for evidence of hepatotoxicity with regular 
assessments (every 6 weeks during the main treatment period and every 12 weeks during the 
extended treatment period) of liver enzymes e.g. AST, ALT, AP, GGT and total and indirect 
bilirubin. In addition, the exploratory biomarker Micro ribonucleic acid-122 (miR-122) of drug-
induced liver injury will be assessed pre-dose and at 4 hours after the first dose of the IMP in 
the main treatment period.  
In case of an increase in ALT, GGT or AST to >3 x ULN, or indirect or total bilirubin >2 x ULN 
during dosing with the IMP, testing of all liver parameters (ALT, AST, GGT, total and indirect 
bilirubin) will be repeated as soon as possible (to be documented as unscheduled visit due to 
safety). Patients will also be asked about symptoms. Concomitant medication will be checked 
for hepatotoxic medications and possible drug-drug interactions. 
If repeat testing still shows ALT or AST to be >3 x ULN, or bilirubin >2 x ULN close 
monitoring of the respective patient will be initiated (including but not limited to repeating liver 
enzymes and serum bilirubin tests 2 or 3 times weekly, detailed evaluation of medical history 
and concomitant drug use, ruling out any other cause of liver enzyme increases, and further liver 
function tests as considered appropriate by the investigator). 
Treatment with the IMP will be discontinued if at least one of the following applies 
(hepatoxicity-related stopping rules): 
• ALT or AST >8 x ULN 
• ALT or AST >5 x ULN for more than 2 weeks 
• ALT or AST >3 x ULN, and total bilirubin >2 x ULN or INR >1.5 x ULN 
• ALT or AST >3 x ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia 
• Indirect bilirubin >3 x ULN 
15.2.3 
Urinalysis 
15.2.3.1 
Assessments 
Urine assessments will be performed using Lab Kits A, B, and C as scheduled in Table 1, 
including the following parameters: 

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Lab Kits A and B 
• pH, nitrites, hemoglobin, protein, albumin, glucose, ketones, uric acid, creatinine 
• microscopic examination of the urine sediment: RBC, white blood cells, epithelial cells, 
bacteria, casts, crystals (including identification of crystals, if possible) 
Lab Kit C 
• pH, nitrites, hemoglobin, protein, albumin, glucose, ketones, uric acid, creatinine 
• a dipstick analysis, including the assessment of RBC in urine, performed and read 
centrally12 
• if the dipstick is positive for RBC in urine, a urine sediment analysis will be performed: 
RBC, white blood cells, epithelial cells, bacteria, casts, crystals (including identification 
of crystals, if possible) 
Urinalysis will be done centrally (see Section 6). Abnormal results will be classified as clinically 
significant (yes/no). Clinically significantly abnormal values must be reported as AE, if not 
already clinically significantly abnormal at Baseline. 
The handling and collection of urine samples will be detailed in the Laboratory Manual. 
15.2.3.2 
Monitoring of red blood cells in urine 
Urinalysis for presence of RBC in urine (microscopic examination of urinary sediment) will be 
regularly assessed throughout the main treatment period. Urinary screening during the extended 
treatment period will be performed with urine dipstick assessments for RBC in urine. A positive 
dipstick assessment will trigger a full urine sediment analysis. In addition, plasma uric acid will 
be regularly monitored throughout the entire trial. Assessment of RBC in urine and hematuria 
as laboratory abnormality and/or AE should be based solely on findings from the microscopic 
examination of urinary sediment and not on dipstick readings only. [19]  For further information 
see Section 15.1.3. 
15.2.4 
miR-122 expression and John Cunningham virus DNA 
The biomarker miR-122 is an early indicator of drug-induced liver injury. At Day 0, before 
dosing and 4 hours after dosing, a blood sample per patient will be collected for miR-122 
expression. Samples will be centrally analyzed using Lab Kit BM. Samples for miR-122 
quantification will be collected and stored at -20°C at the site until the next scheduled dry ice 
shipment to the central laboratory for analysis. Dry ice shipments may be delayed for up to 
2 weeks if another patient is expected to finish the respective visit. 
 
12 The dipstick as well as the urine sample (to be included for potential urine sediment analysis) will be shipped 
to the central laboratory. 

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Detection of urinary JCV-DNA: at time points given in Table 1, urine samples will be used to 
determine whether the patient is an active secretor of the JCV-DNA in urine, and if this secretion 
is influenced by administration of IMU-838. Samples will be centrally analyzed using Lab Kit 
JCV. 
Investigators will be provided with detailed written instructions how to collect, handle, store, 
and ship the respective samples. 
15.2.5 
Serology  
Tests for HBsAg, HBcAb, HCV-Ab, and HIV-Ag/Ab combined test, and a Mycobacterium 
tuberculosis IFNγ-release assay (Tbc-IGRA) will be performed during Screening Visit 1. The 
HBcAb assay will be a combined IgG and IgM test. In case of a positive result, IgM will be 
evaluated separately.  
A positive HIV-Ag/Ab test will be followed up by further HIV testing based on Nucleic Acid 
Amplification Technology. A patient will only be considered HIV positive, and must be 
excluded from the trial, when both tests are positive. 
The Tbc-IGRA will be done locally, all other Screening Visit 1 tests will be done centrally using 
Lab Kit S. 
15.2.6 
Screening laboratory 
The screening laboratory tests include:  
• Blood pregnancy test 
• Hematology and blood biochemistry: Neutrophils, lymphocytes, platelets, serum 
creatinine, ALT, AST, and GGT, total, direct and indirect bilirubin, uric acid, eGFR 
(CKD-EPI) 
• Serology: Tbc-IGRA, HCV-Ab, HIV-Ag/Ab, HBsAg, HBcAb (IgG/IgM) 
The screening tests for Tbc-IGRA will be done locally at the trial site. All other tests will be 
done centrally using Lab Kit S. 
15.3 
Vital signs, physical examination, and ECG  
Vital signs, routine physical examinations, and ECG will be performed as scheduled in Table 1. 
Vital signs 
Vital signs will include: height (only at Screening), weight, body temperature (ºC), respiratory 
rate, pulse rates, systolic and diastolic blood pressures. Height in centimeters and weight in 
kilograms will be recorded without shoes. 

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Blood pressure (systolic and diastolic), and pulse must be measured with the patient in a seated 
position, after at least 5 minutes at rest. 
Changes in vital signs judged by the investigator as clinically significant will be reported as an 
AE. 
Physical examination 
Physical examinations will cover the following body systems: general appearance, skin, neck 
(including thyroid), throat, lungs, heart, abdomen, back, lymph nodes, extremities, vascular, 
neurological systems, and, if applicable, others.  
Any new clinically significant finding compared to Screening Visit 1 must be documented as 
AE. 
Any clinically significant finding at Screening Visit 1 must be documented in the medical 
history section of the eCRF. 
12-lead electrocardiogram 
The 12-lead ECG (I, II, III, aVR, aVL, aVF, V1-V6) will be recorded in supine position after at 
least 5 minutes at rest using the local standard ECG machine. The ECG will be analyzed 
qualitatively (normal or abnormal, if abnormal clinically significant [yes/no]). The heart rate, 
PQ-, QRS-, and QT-intervals, as well as the heart rate-corrected QTc interval (according to 
Bazett’s formula) will be determined. All procedures will be done according to local practice. 
Any findings from ECGs collected after the IMP administration will be captured as AEs if, in 
the opinion of the investigator, there was a clinically significant change from Screening Visit 1. 
15.4 
Steering committee 
A steering committee will provide advice on the conduct of the trial, the review of safety data 
and for publications of trial results. The steering committee will include at least 5 members: the 
coordinating investigator, an independent clinical neurologist (with experience in MS clinical 
trials), an independent pharmacovigilance and safety expert, an MRI expert and at least one 
representative of the sponsor. All members of the steering committee will stay blinded 
throughout the trial until data base lock and unblinding, and will only review blinded data until 
then. 
The first formal safety review will occur after about 60 patients have received the IMP for at 
least 3 months. Subsequently, periodic safety reviews will occur on regular intervals, at least 
once per year. 
Recruitment will not be interrupted due to the scheduled safety reviews by the steering 
committee. The sponsor or any member of the steering committee may request an ad-hoc 
meeting for any reason, including a significant unexpected safety event, unplanned unblinding 

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of trial results, or a report external to the trial, such as results from a different trial. At each 
review, patient incidence rates of AEs (including all SAEs, serious treatment-related events, 
AESIs, and events leading the discontinuation of the IMP) will be tabulated by system organ 
class, preferred term, and severity grade. Listings and/or narratives of deaths and other serious 
AEs as well as reasons for discontinuations, stopping criteria regarding liver enzymes, and 
clinically significant laboratory abnormalities occurring during the trial will be provided. 
Records of all meetings will be archived. The steering committee will recommend modification 
or termination of the trial to the sponsor, if considered necessary. Further details will be provided 
in a separate steering committee charter. 
16 
Biostatistical methods 
16.1 
Sample size calculation 
The sample size calculation is based on the primary endpoint assessed at Week 24 after the main 
treatment period: the difference between 45 mg/day IMU-838 and placebo in the cumulative 
number of CUA MRI lesions at Week 24. In this early stage development trial, a higher α, i.e. 
0.1, than the standard 0.025 level is considered appropriate. The assumptions for the effect size 
for this trial using IMU-838 are derived from a Phase 2 trial of teriflunomide, a drug that shares 
the mechanism of action with IMU-838. [21] For a sample size calculation based on a test for 
the ratio of two negative binomial rates, the negative binomial dispersion parameter has to be 
assumed, which is difficult without data of previous similar studies being available for analysis. 
Publications containing results of modeling the number of new enhancing lesions in MS using 
a negative binomial model were used to get an impression of the magnitude of the negative 
binomial dispersion parameter. [22,23] The values for the parameter ϑ reported in these two 
publications ranged from 0.6 to 0.75. Since the binomial dispersion parameter used in PASS 
15.0.4 equals 1/ϑ, dispersion parameter values of 1.3 and 1.7 correspond to the published 
modeling results. To be conservative, the higher value of 1.7 was used for the sample size 
calculation. Additionally, medical experts generally agree that the overall activity status of 
patients suffering from MS declines secondary to improved diagnostic criteria, which allows 
early imaging-based diagnosis and early treatment start with broadly available effective 
treatment options in the countries selected for this trial. We believe that for these reasons the 
mean event rate for the placebo arm is likely lower than that observed in the historical Phase 2 
trial of teriflunomide, and therefore slightly more conservative assumptions were made for the 
placebo event rate. 

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Underlying assumptions:  
Primary endpoint: cumulative number of CUA MRI lesions up to   Week 24  
Randomization ratio: 
 
 
1:1 (45 mg/day IMU-838:placebo) 
Power:  
 
 
80% 
Significance level:  
 
 
0.1, 1-sided 
Average exposure time: 
 
 
24 weeks 
Mean event rate per 24 weeks for 45 mg/day IMU-838: 
4.5 
Mean event rate per 24 weeks for placebo:  
8.0 
Negative binomial dispersion parameter:  
1.7 
 
Based on these assumptions the necessary sample size per group is 51. Assuming a drop-out 
rate of 25%, about 65 patients will be randomized to each of the dose groups. 
16.2 
Analysis sets and types of analyses 
Safety analysis set 
The safety analysis set (SAF) will consist of all randomized patients who received at least one 
dose of IMP, i.e. any dose of IMU-838 or placebo. If it is uncertain if the patient has received 
any IMP, the patient will be included in the SAF. The analyses based on the SAF will be 
conducted on an “as treated” basis, i.e. all patients will be analyzed by the treatment they 
received. 
Full analysis set 
The full analysis set (FAS) will consist of all randomized patients who received at least one dose 
of IMP, i.e. any dose of IMU-838 or placebo. The analyses based on the FAS will be conducted 
on an intention-to-treat procedure, i.e. all patients will be analyzed by the groups to which they 
were randomized to. 
Per-protocol set 
All patients of the FAS will also be included in a per-protocol (PP) set if they did not violate 
any major protocol criteria. Protocol deviations will be identified and classified for each patient 
during a blind data review. 
Assignment of analysis sets to analyses and allocation of patients 
All efficacy analyses will be based on the FAS. The primary and the key secondary efficacy 
endpoint only will be additionally analyzed for the PP set. The analysis of the primary and the 
key secondary efficacy endpoint using the FAS will be considered confirmatory according to 

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the rules of the hierarchical testing procedure. All other analyses will be exploratory. Safety 
analyses will be based on the SAF. 
The allocation of patients to the analysis sets for the final analysis of the main treatment period 
will be done during a blind data review meeting. The analysis sets to be used for the analysis of 
the extended treatment period will be defined in the corresponding statistical analysis plan 
(SAP). 
16.3 
Statistical analyses 
For qualitative variables, the frequencies (absolute and relative) will be calculated. Quantitative 
parameters will be described by declaring the mean value, standard deviation, minimum, first 
quartile, median, third quartile, and maximum. The different treatment groups will be separately 
tabulated. A detailed description of the statistical analyses for all scheduled analyses (i.e. final 
analysis of the main treatment period and analyses for the extended treatment period) will be 
provided in an SAP and will be finalized before any data will be analyzed, i.e. before the final 
analysis of the main treatment period. 
16.4 
Primary and key secondary efficacy analyses 
Since the primary and key secondary endpoint data (cumulative number of CUA MRI lesions 
at Week 24) represent count data, it is planned to analyze the primary and key secondary 
endpoint using a generalized linear model with a negative binomial distribution and a 
logarithmic link function. The following independent effects will be included in the models 
• Treatment group 
• Baseline volume of T2 lesions 
• MRI field strength of 1.5 or 3.0 Tesla (factor groups used for stratification) 
• Number of Gd+ lesions (factor groups used for stratification) 
A hierarchical testing procedure will be applied for the primary and the key secondary efficacy 
endpoint. Both tests will be performed at a significance level of 0.1 (1-sided). In case of a 
non-significant result for the primary endpoint, the hierarchical testing procedure will be 
stopped and the analysis of the key secondary endpoint will be considered exploratory. 
17 
Patient withdrawal from trial participation 
Participation in the trial is voluntary and patients may withdraw from the trial at any time and 
for any reason. However, all patients will be encouraged to complete the trial. All patients 
withdrawing from the trial will be encouraged to complete the EoS assessment 30 days 
(+14 days) after the last intake of the IMP (also refer to Section 12.7).  

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Patients will be withdrawn from the study for any of the following reasons (the primary reason 
leading to patient withdrawal will be documented):  
• Patient withdraws consent due to 
o 
AE(s) 
o 
MS related clinical events  
o 
other reason (to be specified) 
• Investigator decision due to  
o 
AE(s), which in the opinion of the investigator may jeopardize the patient’s health 
or may compromise the trial objectives 
o 
relevant non-compliance with the protocol, which in the opinion of the investigator 
may jeopardize the trial integrity or scientific goals of the trial 
o 
reasons other than AE or non-compliance (to be specified) 
• Pregnancy 
• Fulfilling hepatoxicity-related stopping rules (see Section 15.2.2.2) 
• Treatment with prohibited concomitant medication (see Section 11.2.2) 
• Violation of inclusion or exclusion criteria noted only after randomization 
• The trial is terminated by the sponsor 
 
The primary reason for discontinuation from the trial is to be recorded in the source documents 
and on the early termination page of the eCRF. 
If the patient withdraws consent, no further evaluations should be performed and no attempts 
should be made to collect additional data. 
Patients who prematurely discontinue the trial will be treated according to the investigator’s 
discretion and standard treatment guidelines, irrespective of the reason for withdrawal, and will 
not be replaced. 
Reasonable efforts will be made to contact any patient lost to follow up, to complete assessments 
(including an EoS assessment) and to retrieve any outstanding data and IMP and supplies. 
If the IMP will be prematurely discontinued, the primary reason for discontinuation is to be 
recorded in the appropriate section of the eCRF. Patients who discontinue therapy with study 
drug will be encouraged to continue with study-related assessments (including EoS visit) until 
their trial completion. 

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18 
Ethical and legal requirements 
18.1 
Ethical conduct of the trial 
The trial will be conducted in a manner consistent with all applicable regulatory authority and 
IEC regulations (e.g. International Council for Harmonisation [ICH] Guideline for Good 
Clinical Practice [GCP, CPMP/ICH/135/95] and the Declaration of Helsinki [version of 1996]) 
as well as in keeping with applicable local law(s) and regulation(s). The investigator must also 
comply with all applicable privacy regulations (for EU: General Data Protection Regulation 
[24]). 
18.2 
Independent ethics committee  
Before the initiation of the clinical trial, the final protocol, any amendments if applicable, the 
patient information sheet and consent form, as well as any additional documents which are 
required by national regulations and the IEC will be submitted to the competent IEC for review. 
A favorable opinion for the clinical trial must be obtained from the IEC before any patient is 
enrolled at a center.  
If appropriate, any additional requirements imposed by the IEC will be followed. Amendments 
to the trial documents will be notified to, or approved by, the IEC before implementation, if 
applicable. 
18.3 
Patient information and consent procedure 
Before any clinical trial-related activities are performed, the investigator (or authorized 
designee) must review the informed consent form and explain the trial to potential trial 
participants. The investigator must ensure that the patient is fully informed about the aims, 
procedures, potential risks, any discomforts, and expected benefits of the clinical trial. Before 
consenting, the patient must be left with ample time to consider and ask questions. It must be 
emphasized that participation is voluntary and that the patient has the right to withdraw from 
the clinical trial at any time without prejudice. The patient and the investigator must then sign 
and date the consent form before the conduct of any trial procedures.  
A copy of the patient information and informed consent form will be given to the patients for 
their records. The rights and welfare of the patients will be protected by emphasizing to them 
that the quality of their medical care will not be adversely affected if they decline to participate 
in this clinical trial. 
If amendments to the final trial protocol affect the patient’s participation in the clinical trial (e.g. 
a change in any procedure), the patient information and informed consent form must be updated 

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to incorporate this modification, and patients must agree to sign the amended form indicating 
that they re-consent to participate in the clinical trial. 
18.4 
Insurance coverage 
Insurance coverage for damages emerging from the clinical trial will be provided according to 
applicable legal requirements. During the informed consent procedure, the investigator must 
inform the patient accordingly. Insurance details will be provided to the patient within the 
patient information sheet. 
18.5 
Submission to authorities 
Documents required for the trial application will be submitted to the responsible competent 
authority (CA). The trial will not start until this authority has authorized the trial. Amendments 
to the trial protocol or to any other documents that must be reviewed by the CA will also be 
submitted to the CA in accordance with the regulatory requirements. If applicable, approval of 
the amendment must be awaited before implementing any changes. 
18.6 
Patient confidentiality 
The trial protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the clinical trial or the data will be released to any 
unauthorized third party without prior written approval of the sponsor. 
Personal patient data will be kept confidential in compliance with the General Data Protection 
Regulation [24], and other applicable international and national requirements.  
The investigator must ensure that the confidentiality and anonymity of trial participants will be 
maintained and that their identities are protected from unauthorized parties. In eCRFs, 
compensation documentation, or any other documents submitted to the sponsor or sponsor’s 
designee, patients must be identified only by their identification codes; it is not allowed to use 
their names, addresses, telephone numbers, or similar information. The investigator will keep 
the original of the Patient Identification Log (including complete name and date of birth of each 
patient) in his/her file. The investigator must maintain these documents in strict confidence. 
To allow compliance with GCP, all patients will be asked for consent regarding the access to 
their personal clinical trial-related data for monitoring, audits, and inspections as well as 
regarding transmission and storage of their pseudonymous data; a respective statement will be 
part of the informed consent form. Professionals getting access to source data for monitoring, 
audits and inspections are bound to preserve strict confidentiality. 

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19 
Criteria for premature termination of the trial and criteria for 
initializing and closing a trial center 
19.1 
Criteria for halting or terminating the trial 
The sponsor reserves the right to halt or terminate the trial at any time. Reasons for termination 
include but are not limited to: 
• Potential health risk for the patients 
• High withdrawal rate 
• New scientific knowledge becomes available that makes the objectives of the trial no 
longer feasible or valid 
• Insufficient enrollment of patients 
19.2 
Criteria for closing a trial center 
A trial center may be closed for the following reasons: 
• The center is unable to recruit sufficient patients within the agreed time frame 
• The center does not respond to trial management requests 
• Multiple significant protocol deviations or substantial non-compliance 
• The approval of the IEC in charge of the clinical trial is permanently revoked 
• Additional local criteria might be established by written agreements between the sponsor 
and the trial center 
The sponsor will notify the relevant CA, IEC(s), and investigator(s) in writing about the 
termination of individual centers or the whole trial. 
The investigator may terminate his/her participation prematurely. If the investigator decides to 
terminate his/her participation before the trial is completed, he/she will notify the sponsor in 
writing stating the reasons for the early termination. In terminating the trial, the sponsor and the 
investigator will ensure that adequate consideration is given to the protection of the patients’ 
interests.  
The investigator will notify the relevant CAs and IEC(s) in writing, if required, submit a copy 
of that notification to the sponsor and return all IMPs and all related trial material, as applicable, 
to the sponsor. Concerned eCRFs will be archived at the site. Authorization to access and edit 
the eCRF will be removed from the investigator and all authorized delegates. 

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20 
Trial protocol, documentation and archiving of data 
20.1 
Amendments to the protocol 
Any change to the protocol concerning the purpose of the trial, the trial design, or the patient’s 
eligibility can only be made in the form of a written amendment to the trial protocol. Such 
amendments must be discussed and signed by the sponsor and the investigator before 
implementation.  
Substantial amendments, i.e. amendments likely affecting to a significant degree 
• the safety or physical or mental integrity of the patients of the trial 
• the scientific value of the trial 
• the conduct or management of the trial, or 
• the quality or safety of any IMP used in the trial 
will be submitted to the CA and IEC for approval and favorable opinion as required by 
applicable regulations. If such amendments affect the patient’s participation in the clinical trial 
(e.g. a change in any procedure), the patient information and informed consent form must be 
updated to incorporate this modification, and patients enrolled at the time of implementation of 
the amendment must re-consent to their participation in the clinical trial. 
Non-substantial changes, e.g. minor corrections of administrative nature and/or rephrasing, 
which do not meet the above criteria for being substantial, are considered editorial changes. The 
IEC and CA do not need to be notified of such minor corrections. Non-substantial amendments 
will be signed by the sponsor only. 
If new events occur related to the conduct of the trial or the development of the tested IMP that 
may affect the safety of the patients, the sponsor and the investigator will take appropriate safety 
measures to protect the patients against any immediate hazard. The sponsor will immediately 
inform the CA and IEC of the new events and the measures taken. 
20.2 
Protocol deviations 
A protocol deviation is a failure to follow, intentionally or unintentionally, the requirements of 
the protocol. As required by national regulation or guidelines, reports of deviations will be 
provided to the IEC. 
In emergency circumstances, deviations from the protocol may proceed without prior 
consultation with the sponsor and favorable opinion of the IEC, if the rights, safety and well-
being of the patients need to be protected. Such deviations will be documented and reported to 
the sponsor and the IEC as soon as possible in accordance with national regulations. 

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All protocol deviations will be listed. If concerned patients are evaluable for data analysis will 
be discussed in a data review meeting prior to statistical analyses. 
20.3 
Data retention 
The trial center and the sponsor or sponsor’s designee(s) will maintain all trial records according 
to ICH GCP and applicable regulatory requirement(s). Records will be retained until at least 2 
years after the last approval of a marketing application in an ICH region, until there are no 
pending or contemplated marketing applications in an ICH region, until at least 2 years have 
elapsed since the formal discontinuation of clinical development of the tested IMP, and at least 
15 years after the end of the trial, whichever period is longer. The final report will be kept for 
another 5 years after the tested IMP was taken off the market according to legal stipulations. 
The documents will be archived for a longer period, if required by the applicable regulatory 
authorities or if agreed with the sponsor. It is the responsibility of the sponsor to inform the 
investigators when these documents need not to be retained any longer. 
The medical files of trial patients must be retained in accordance with local legislation and in 
accordance with the maximum period of time permitted by the hospital, institution or private 
practice. 

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21 
Data collection, monitoring and quality assurance 
21.1 
Data collection 
All data will be collected on an eCRF separately for each patient. eCRFs will be provided as a 
regulatory compliant, electronically secure and protected web-based database, and will be 
handled in accordance with the instructions provided. An audit trail will record all entries and 
corresponding changes. 
The trial sites will be provided with secure access to and training on the eCRF.  
All data generated after the patient provided informed consent must be recorded in the eCRF. 
The treating investigator is responsible for ensuring accurate and proper completion of the 
eCRF. 
Only treating physician and authorized designees will enter and edit data via a secure network 
and a secure access system. Completed data for each visit will be approved by the investigator 
or authorized designee using an electronic signature to confirm the accuracy of the data. Any 
change or addition will be recorded by an electronic audit trail system. 
The investigator or designee has to carefully answer queries issued by data management. 
21.2 
Source data 
Source data are defined as all data in original records and certified copies of original records of 
clinical findings, observations, or other activities in a clinical trial that are necessary for the 
reconstruction and evaluation of the trial (see ICH E3 GCP, 1.51). Source records should be 
stored for a time period as defined by local regulations. 
The investigator must keep a patient file (medical file, original medical records) on paper or 
electronically for every patient included in the trial.  
It must be possible to identify each patient by using this patient file. Dates and authors of all 
source data entry and changes must be clearly identifiable. 
Documents and data to be considered source data will be identified and agreed with the 
investigator in advance of the first screening visit. The location of all source data will be 
documented and filed in the Investigator Site File (source data location form). 
Electronic patient files will be printed whenever the monitor performs source data verification. 
Printouts must be signed and dated by the investigator, countersigned by the monitor, and filled 
at the center as required for other source data documents.  

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21.3 
Monitoring 
The extent and details of monitoring including source data verification will be specified in the 
monitoring plan. 
The trial center must not enroll any patient before the initiation visit was performed and final 
eligibility of the center is confirmed by the monitor and Sponsor. During the trial, further 
monitoring visits will be performed according to ICH GCP, the sponsor’s designee’s or local 
CRO’s standard operating procedures, and local regulations. eCRFs will be reviewed against 
source data for adherence to the trial protocol and ICH GCP, as well as for completeness, 
accuracy, and consistency of data. Additionally, the monitor will check the progress of 
enrolment, and will ensure that the IMP is being stored, dispensed and accounted for according 
to specifications. Key trial personnel must be available to assist the monitor during these visits. 
The investigators must permit the monitor`s access to the patient’s medical records and all 
applicable source documents. Throughout the trial, all data captured in the eCRF will only be 
identified by patient number. The data will be blinded correspondingly in all data analyses. 
It is the investigators’ obligation to assure documentation of all relevant data in the patient’s 
file, such as medical history and concomitant diseases, date of trial enrolment, visit dates, results 
of examinations, administrations of IMP and any concomitant medication, and AEs. 
21.4 
Audits and inspections 
During the trial, audits may be performed by independent auditors. Audits of clinical research 
activities will be performed in accordance with corresponding standard operating procedures to 
ensure compliance with the principles of GCP. 
Regulatory authorities may wish to conduct an inspection. If an inspection is requested, the 
investigator must inform the sponsor or sponsor’s designee immediately. 
The investigator must allow auditors or inspectors access to source data and documents and will 
answer any questions. 
21.5 
Data management procedures 
All data management activities will be conducted by the sponsor’s designee following their 
standard operating procedures. 
Details on data handling will be described in the data management plan. Data entered into the 
eCRF will be validated through online edit checks and offline checks run by the data manager 
according to the data validation plan. For all identified discrepancies, the data manager will raise 
a query in the electronic data capture application. The appropriate investigational personnel will 

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answer the queries in the eCRF, which will be audit trailed by the electronic data capture 
application. 
The sponsor’s designee will handle the data cleaning process, query process, and coding. 
For the main analysis, the respective database will be locked when it is considered complete and 
accurate and after all changes following the data review meeting (if applicable) are included 
(i.e. all data cleaning activities performed). All changes will be tracked (audit trail). Sponsor 
approval prior to database lock is mandatory.  
21.6 
Trial report and publications 
The results of the main treatment period will be summarized in a clinical trial report according 
to the ICH E3 Note for guidance on structure and content of clinical trial reports. Results of the 
extended treatment period will be reported in an addendum to the clinical trial report. 
Regular safety update reports will be submitted to investigators as well as to regulatory 
authorities and IECs, as appropriate, within the timeframes defined per national regulation or 
by the IEC.  
The preparation and submission of abstracts or manuscripts including the trial results will be 
coordinated by the steering committee. The publication or presentation of any trial results shall 
comply with all applicable privacy laws. 
22 
Trial periods 
Cohort 1:  
Actual start: 
February 2019 (first patient in) 
Actual recruitment period: 
8 months 
Actual end main treatment period: 
April 2020 (main part: last patient out)  
Estimated end extended treatment period: 
December 2029 (last patient EoS visit) 
Cohort 2 (Planned):  
Estimated start: 
October 2020 (first patient in) 
Estimated recruitment period: 
3 months 
Estimated interim analysis: 
March 2021 (main part: last patient completing 
Week 12) 
Estimated end main treatment period: 
May 2021 (main part: last patient out)  
Estimated end extended treatment period: 
December 2029 (last patient EoS visit) 
The end of the trial is defined as last patient visit, i.e. the EoS visit, in any participating center. 
 

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Principal investigator agreement page for the protocol 
I agree: 
o To assume responsibility for the proper conduct of the clinical trial at this site, and to 
conduct the trial in compliance with national law, the valid version of the Declaration 
of Helsinki, the GCP-guidelines, the present trial protocol including its amendments, 
and with any other trial conduct procedures provided by the sponsor or authorized 
representatives. 
o Not to implement any deviations from or changes to the protocol (including protocol 
amendments) without agreement from the sponsor and prior review and favorable 
opinion from the ethics committee and approval from the competent authority, if 
applicable, except where necessary to eliminate an immediate hazard to the patient(s), 
or for administrative aspects of the clinical trial (where permitted by all applicable 
regulatory requirements). 
o That I am familiar with the appropriate use of the investigational medicinal product as 
described in this protocol and any other information provided by the sponsor including, 
but not limited to, the current investigator’s brochure or equivalent document provided 
by the sponsor. 
o To ensure that all persons assisting me with the clinical trial are adequately informed 
about the investigational medicinal product and of their trial-related duties and 
functions. 
o That I have been informed that certain regulatory authorities require the sponsor to 
obtain and supply details about the investigator’s ownership interest in the sponsor or 
the trial product, and more generally about his/her financial ties with the sponsor. The 
sponsor will use and disclose the information solely for the purpose of complying with 
regulatory requirements. 
 
 
 
 
 
Principal investigator name (print) 
 
 
 
 
 
 
 
 
Principal investigator signature 
 
Date 

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25 
Appendices 
Appendix 1 Expanded Disability Status Scale and Neurostatus form 

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A-Table 1: 
Expanded Disability Status Scale (EDSS) 
Score 
Description 
0.0 
Normal neurological exam – (all Grade 0 in Functional Systems [FS*]) 
1.0 
No disability, minimal signs in one FS (i.e., Grade 1) 
1.5 
No disability, minimal signs in more than one FS (more than one Grade 1) 
2.0 
Minimal disability in one FS (one FS Grade 2, others 0 or 1) 
2.5 
Mild disability in one FS or minimal disability in two FS (two FS Grade 2, others 0 or 1) 
3.0 
Moderate disability in one FS (one FS grade 3, others 0 or 1) though fully ambulatory; or mild 
disability in three or four FS (three / four FS grade 2, others 0 or 1) though fully ambulatory 
3.5 
Fully ambulatory but with moderate disability in one FS (one FS grade 3) and mild  
disability in one or two FS (one / two FS grade 2) and others 0 or 1; or fully ambulatory with two 
FS grade 3 (others 0 or 1); or fully ambulatory with five FS grade 2 (others 0 or 1) 
4.0 
Ambulatory without aid or rest for ≥500 meters; up and about some 12 hours a day despite relatively 
severe disability consisting of one FS grade 4 (others 0 or 1) or combinations of lesser grades 
exceeding limits of previous steps 
4.5 
Ambulatory without aid or rest for ≥300 meters; up and about much of the day, characterized by 
relatively severe disability usually consisting of one FS grade 4 and combination of lesser grades 
exceeding limits of previous steps 
5.0 
Ambulatory without aid or rest for ≥ 200 meters (usual FS equivalents include at least one FS grade 
5, or combinations of lesser grades usually exceeding specifications for step 
5.5 
Ambulatory without aid or rest for ≥ 100 meters 
6.0 
Unilateral assistance (cane or crutch) required to walk at least 100 meters with or without resting 
(see chapter 8, ambulation)  
6.5 
Constant bilateral assistance (canes or crutches) required to walk at least 20 meters without resting  
7.0 
Unable to walk 5 meters even with aid, essentially restricted to wheelchair; wheels self and transfers 
alone; up and about in wheelchair some 12 hours a day 
7.5 
unable to take more than a few steps; restricted to wheelchair; may need some help in transferring 
and in wheeling self 
8.0 
Essentially restricted to bed or chair or pushed in wheelchair. May be out of bed itself much of the 
day. Retains many self-care functions. Generally, has effective use of arms 
8.5 
Essentially restricted to bed much of day. Has some effective use of arms retains some self-care 
functions 
9.0 
Confined to bed. Can still communicate and eat 
9.5 
Confined to bed and totally dependent. Unable to communicate effectively or eat/swallow 
10.0 
Death due to MS 
 
Note: EDSS steps of 4 and below refer to patients who are fully ambulatory (able to walk 
500 m without aid or rest), and the precise steps are defined by the Functional System 
score(s).  EDSS steps from 4.5 up are based entirely on ambulation capabilities.  
For the Functional System Visual Function Grades, the following conversions should be made 
for the calculation of the EDSS:  6 = 4, 5 = 3, 4 = 3, 3 = 2, 2 = 2, 1 = 1, and 0 = 0.  
 *An Functional System Mental Function Grade of 1 does not count towards EDSS.  

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A-Table 2: 
Neurostatus form 
 

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Appendix 2 Treatment satisfaction questionnaire for medication 
 

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Appendix 3 Dose response Cohort 2 sub-trial (not valid in Romania)   
 
1. 
BACKGROUND AND RATIONALE ...................................................................... 122 
2. 
TRIAL DESIGN .......................................................................................................... 124 
2.1 
Overall trial design ................................................................................... 124 
2.2 
Treatments ................................................................................................ 126 
2.3 
Randomization, blinding and unblinding procedures .......................... 127 
2.4 
Trial patients ............................................................................................. 128 
2.5 
Objectives and endpoints ......................................................................... 128 
2.6 
Study schedule .......................................................................................... 130 
2.7 
Efficacy and safety assessments .............................................................. 133 
3. 
BIOSTATISTICAL METHODS AND REPORTING ............................................ 133 
 
 
1. 
Background and rationale 
In the Cohort 1 main analysis of this trial the primary and key secondary endpoints have been 
met with high statistical significance i.e. both IMU-838 doses statistically significantly reduced 
the number of CUA MRI lesions up to Week 24 as compared to placebo. The reduction was 
62% with 45 mg IMU-838 (p = 0.0002, 1-sided, primary endpoint) and 70% with 30 mg 
IMU-838 (p <0.0001, 1-sided, key secondary endpoint). All other secondary endpoints, 
including other MRI parameters, clinical endpoints such as relapses and biomarkers such as 
neurofilament light chain, also provided a noticeable and numerical benefit for IMU-838 as 
compared to placebo. IMU-838 in this trial was safe and well-tolerated in patients with RRMS. 
The rate of TEAEs was similar in IMU-838 and placebo-treated patients (30 mg: 45.1%, 45 mg: 
40.6%, placebo: 43.5%). Serious TEAEs were rare and only observed in 3 out of 140 IMU-838-
treated patients, and in 1 out of 69 placebo-treated patients. The rate of treatment withdrawals 
in the 24-week blinded treatment period was only 4.3% in the pooled IMU-838 treatment arms 
versus 7.2% in the placebo group. 
Based on these results both doses, 30 and 45 mg/day IMU-838, appear to be equally safe and 
effective in patients with RRMS. Although there was no safety signal in the Cohort 1 main 
analysis for either doses, the lowest effective dose 30 mg/day IMU-838 may be proposed to be 
investigated in further trials in RRMS, including the planned Phase 3 trial. However, and given 
the relative equal performance of the 2 doses in Cohort 1 and to allow for pharmacodynamic 

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modeling of the dose-response relationship, data from a lower dose in the effective dose range 
will be required. The objective of the Cohort 2 sub-trial is thus to obtain exploratory data on the 
dose response of IMU-838 by evaluating a lower IMU-838 dose i.e. 10 mg/day to provide 
additional data for pharmacodynamic modelling.  
The 10 mg IMU-838 dose was selected since it is more than 50% lower than the lowest effective 
dose of Cohort 1 (30 mg IMU 838) and avoids undesired overlap in serum trough levels for 
pharmacodynamic modelling of the pooled Cohort 1 and 2 data. 
The 10 mg/day dose is expected to show noticeable efficacy in the Cohort 2 sub-study as an 
interim analysis of the ongoing Trial P2-IMU-838-UC in patients with ulcerative colitis, 
confirmed that the 10 mg dose lies within the potential effective dose range of IMU-838 i.e. this 
interim analysis showed that none of the doses used (10 mg, 30 mg, or 45 mg IMU-838) was 
either likely ineffective or intolerable expanding the expected effective dose range of IMU-838 
in immunological diseases. In summary, the dose of 10 mg/day IMU-838 is expected to be an 
effective dose in this Cohort 2 sub-trial. A small placebo arm is included to provide blinding of 
patients and to relate Cohort 2 treatment effects. 
Assessments and procedures will mostly follow those described for the main treatment period 
in the Cohort 1 main trial. However, some assessments not necessary for pharmacodynamic 
modelling from Cohort 2 data will not be performed as well as few new exploratory biomarker 
data are added. Additionally, only MRI machines with a field strength of 1.5 Tesla will be 
allowed to provide more homogeneous MRI data for pharmacodynamic modelling. The 
Cohort 1 main trial allowed MRI assessments of 1.5 and 3 Tesla. As there was a strong 
imbalance of cases between 1.5 Tesla and 3 Tesla, the uncertainty of statistical estimators for 
adjustment of means for the 3 Tesla MRI cases was very high. 
In addition, an unblinded interim analysis of selected MRI data is planned after all Cohort 2 
patients have completed Week 12 assessments. In the Cohort 1 main analysis a recognizable 
reduction of the number of CUA and Gd+ lesions by IMU-838 as compared to placebo was 
already observed at Week 12. This interim analysis will therefore provide an early assessment 
of dose-response of the 10 mg/day dose and will facilitate expeditious regulatory discussions 
for Phase 3 execution. The interim analysis after Week 12 would be performed without revealing 
individual treatment assignments to the Sponsor, however the interim analysis will provide very 
selected group-level MRI data. As all or almost all Cohort 2 patients may have already 
completed the final Week 24 assessment of the main treatment period of Cohort 2 when the 
interim analysis is performed, the impact for the conduct of the Cohort 2 sub-trial may be 
minimal, if any. 
PBMC-based pharmacodynamic biomarkers, PRO questionnaires (TSQM), coagulation 
assessments, miR-122, JCV-DNA, and genotyping parameters are not necessary for 

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pharmacodynamic modelling and were already assessed in the Cohort 1 main trial. Thus, such 
assessments are unnecessary for the objectives of Cohort 2 and will not be performed in this 
Cohort 2 sub-trial. Additional assessments in Cohort 2 that were not performed in the Cohort 1 
include fibroblast growth factor 19 (FGF-19), 7α-Hydroxy-4-cholesten-3-one (C4), and high-
density lipoprotein cholesterol as indicated in Table 2. 
7α-Hydroxy-4-cholesten-3-one (C4) is an intermediate in the biochemical synthesis of bile acids 
from cholesterol. The FGF-19 is a protein that in humans functions as a hormone, regulating 
bile acid synthesis. High-density lipoprotein (HDL) cholesterol is a commonly performed 
surrogate value for hepatic reverse cholesterol transport. Change in serum C4, FGF-19 and HDL 
cholesterol concentrations may be indicative for activation of certain nuclear receptors by 
medications. 
2. 
Trial design 
2.1 
Overall trial design  
This is a double-blind, placebo-controlled, randomized, parallel-group sub-trial of 
P2-IMU-838-MS to assess the efficacy and safety of once-daily oral 10 mg/day IMU-838 
compared to placebo in patients with RRMS and evidence of active disease. 
The design generally follows the design of the main trial. However, only MRI machines with a 
field strength of 1.5 Tesla will be allowed (the main trial allowed ≥1.5 Tesla, for reasons see 
Section 1 of this Appendix). An overview is given in Figure 2 below. Screening (12.2) and 
eligibility (Section 9) will be the same as in the Cohort 1 main trial.  
Before any clinical activities for the sub-trial are performed, patients will be informed by the 
investigator (or authorized designee, see Section 18) about this trial and the risk profile of 
IMU-838 and patients will have to sign an informed consent form specific to this Cohort 2 sub-
trial. 
Main treatment period 
Patients in the Cohort 2 sub-trial main treatment part will be randomized 1:4 to placebo and 
10 mg IMU-838 for 24 weeks. All patients will receive half the assigned dose during the first 
7 days of the main treatment period (1 tablet per day) and the full assigned dose from Day 7 
onwards (2 tablets once daily). Clinic visits after Day 0 during the double-blind Cohort 2 main 
treatment period will be scheduled at Day 7, and at Weeks 6, 12, 18 and 24, with MRI 
assessments at Weeks 6, 12, 18 and 24. At Week 24 (EoMT), patients will have the option to 
continue into the extended treatment period if they meet respective eligibility criteria as 
described in Sections 9.2 and 9.3 of this protocol. An unblinded interim analysis evaluating 
selected MRI parameters will be performed at Week 12 (see Section 2.3 below). 

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Extended treatment period 
Treatment during the extended period will be open label. The recommended dose for the 
extended treatment period will be 30 mg/day. However, based on discussion between 
investigator and patient 45 mg/day IMU-838/day may also be used as this dose was also found 
to be safe and effective in the Cohort 1 main analysis. Switching between open-label doses will 
be allowed in the extended treatment period, as described for patients in Cohort 1. Although the 
treatment in the extended treatment period will be always open, the treatment assignment during 
the main treatment period for patients and investigators will be kept blinded until after database 
lock of the main treatment period of the sub-trial. Identical to the start of the main treatment 
period, all patients will receive half the assigned dose during the first 7 days of the extended 
treatment period and will then continue with the full assigned dose.  
The extended treatment period will be terminated for patients in the Cohort 2 sub-trial at the day 
the last patient of the Cohort 1 main trial has completed the respective extended treatment 
period, prematurely or as scheduled. 
End-of-study visit 
All patients discontinuing treatment, as scheduled or prematurely, will undergo an EoS visit 
30 days (+14 days) after last IMP administration. 
 

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Figure 2: 
Trial flow chart - Cohort 2 sub-trial 
 
 
 
a Can be interrupted/extended, if the baseline MRI must be repeated due to poor quality (to be done as soon as possible). If 
results of the central MRI assessment are not available in time for randomization, the screening period can be extended by up 
to 7 days, if needed. 
b 30 mg/day IMU-838 is recommended. However, based on discussion between investigator and patient 45 mg/day IMU-
838/day may also be used. Switching between open-label doses will be allowed. 
c The extended treatment period will be terminated for patients in the Cohort 2 sub-trial, at the day the last patient of the 
Cohort 1 main trial has completed, prematurely or as scheduled, the extended treatment period. 
 
BL = baseline, D = day, EoMT = end-of-main treatment, EoS = end-of-study, EoT = end-of-treatment, exam = examination, 
FAMT = final analysis of main treatment period, IA = interim analysis, MRI = magnetic resonance imaging, MT =main 
treatment, R = randomization, Scr. = screening, W = Week. 
 
Investigators and trial sites: centers who participated in the Cohort 1 main trial from Bulgaria, 
Ukraine, and Poland, that use an MRI machine with a field strength of 1.5 Tesla. 
Assessments and procedures not specifically described in this Appendix will be done as 
described for the main trial.  
2.2 
Treatments 
Test product 
Main treatment period: tablets with 5 mg; administration as in the main trial (Section 11.1) i.e. 
1 tablet once daily (Days 0 to 6) and 2 tablets once daily (Days 7 to EoM).  
Extended treatment period: 1 tablet once daily, i.e. 15 mg/day (or 22.5 mg/day) IMU 838 for 
Days 0 to 6, and 2 tablets once daily Day 7 to EoT.  
Blinded 
Screening up to 28 
Sub-trial MT period 24 weeks 
Extend. treatment up to ~8.5 yearsc (optional) 
Open-label 
Scr. exam BL MRI 
R 
10 mg IMU-838 
EoMT 
EoMT 
30 (or 45 mg) IMU-838b 
EoS 
EoT 
EoT 
30 (or 45 mg) IMU-838b 
Placebo 
D-28                 D-14      D0                               W12                  W24/EoMT                                                              EoT           EOS  
 -9                       -3                                              IA                  FAMT of sub-trial                                                                        (EoT+30d)    

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Reference product (only applicable during main treatment period) 
Matching placebo, once-daily oral administration of 1 or 2 tablets, as described for the test 
product and Section 11.1 
Prior and concomitant medications; precautions and restrictions  
Will be applied as in main trial (Section 11.3) 
2.3 
Randomization, blinding and unblinding procedures 
Randomization will be done either by a voice-interactive system or manually by an unblinded 
designee. At randomization, all IMP kits for the entire 24-week main treatment duration will be 
assigned to each patient; however IMP kits will be handed out to patients only during visits as 
outlined in Table 2. Since only 1.5 Tesla MRI machines will be used, stratification of 
randomization for MRI field strength is not necessary and stratification will only consider 
number of Gd+ lesions in baseline MRI (0 Gd+ lesion; ≥1 Gd+ lesion). 
Other procedures will be applied as in the main study (Section 10), however there will be no re-
randomization at the start of the extended treatment period as the extended treatment period of 
the Cohort 2 sub-trial will be open right from the start of the extended treatment period (while 
in Cohort 1 it was blinded until the main results for the main treatment were available). 
Blinding during the interim analysis of the main treatment period 
An interim analysis will be performed after all Cohort 2 patients have completed the Week 12 
assessments. Care will be taken to maintain the blind regarding individual treatment assignments 
for the Sponsor, patients, investigators and other study personnel during this analysis to avoid 
introducing any biases. This will include that only very selected group-level data are provided 
to the Sponsor, that any reference to individual patients or of potentially unblinding information  
in footnotes and listing will be avoided and that investigators will not be informed about the 
data of the interim analysis. 
After all patients have completed their Week 12 assessments the respective data base will be 
locked, data unblinded and analyzed.  
Access to interim individual patient data will be restricted to an independent data manager and 
an independent biostatistician performing the interim analysis. The following selected data will 
be analyzed and respective group level averages without minimum and maximum values will 
be made available to the Sponsor: 
• cumulative CUA MRI lesions until Week 12 
• cumulative Gd+ lesions until Week 12  
• number of patients without CUA MRI lesions until Week 12  

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• number of patients without Gd+ lesions until Week 12 
In order to provide sufficient data points in the placebo arm, Cohort 1 placebo patients from the 
same sites that contributed to the Cohort 2 Week 12 data and investigated using 1.5 Tesla MRI 
examinations will be allowed to enrich the Cohort 2 placebo arm. In addition, summary data 
from Cohort 1 30 mg/day and 45 mg/day data may be shown as comparison to Cohort 2 data 
from 10 mg/day IMU-838, however the same restriction for sites and 1.5 Tesla MRI as for 
placebo will apply. Details will be described in the SAP for Cohort 2. To minimize bias, the 
SAP for the interim analysis will be finalized before any data will be analyzed. 
Aggregate data on accrual and drop-out rates, and reasons for ineligibility and discontinuation 
will also be made available for the Sponsor. 
2.4 
Trial patients 
Number of patients (total and for each treatment) planned 
Approximately 60 patients are planned to be randomized 1:4 to treatment with placebo or 
10 mg/day (12:48 patients) in the main treatment period. 
No formal sample size calculation was performed for this sub-trial but N = 60 randomized 
patients are considered sufficient for a robust estimation of the dose response and 
pharmacodynamic modelling. 
The maximum numbers of Cohort 2 patients randomized will be 30 per center and 50 per 
country. 
Eligibility criteria and withdrawal of patients 
For the main treatment and extended treatment periods eligibility will be applied as in the main 
study (Sections 9 and 17). 
2.5 
Objectives and endpoints 
Objective 
The objective of this sub-trial is to obtain more efficacy and safety data of IMU-838 in patients 
with RRMS and to allow pharmacodynamic modelling of the dose response. 
Endpoints 
Efficacy 
• Between-treatment differences in the cumulative number of CUA MRI and Gd+ lesions 
up to Week 24 (will be of primary interest). 
• Between-treatment differences in the following MRI parameters: 
o Mean number of CUA lesions at Weeks 6, 12, 18 and 24 
o Cumulative number of CUA MRI lesions up to Weeks 6, 12, 18 and 24  

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o T2-lesion load at Weeks 6, 12, 18 and 24 compared to Baseline 
o T1-lesion load at Weeks 6, 12, 18 and 24 compared to Baseline 
o Cumulative number of new Gd+ lesions up to Weeks 6, 12, 18 and 24   
o Cumulative number of new T2 lesions up to Weeks 6, 12, 18 and 24 
o Cumulative number of new T1 lesions up to Weeks 6, 12, 18 and 24 
o Proportion of patients without new Gd+ lesions over 24 weeks  
o Proportion of patients without new or enlarging T2-weighted lesions over 24 weeks 
o Correlation of MRI-based assessments with quartiles of IMU-838 trough levels at 
Week 24 
• Clinical endpoints: 
o Number of relapses in each treatment arm 
o Change of EDSS from Baseline to Weeks 12 and 24 
o Biomarkers: 
o 
Changes from Baseline in serum neurofilament at Week 24 
o 
Changes in serum C4 (7α-hydroxy-4-cholesten-3-one) 
o 
Changes in serum fibroblast growth factor 19 (FGF-19) 
Safety 
• AEs, serious AEs and clinically significant laboratory abnormalities (as assessed by the 
investigator) 
• AEs of special interest:  
o Red blood cell urine positive, at least of moderate intensity 
o Hematuria 
o Retroperitoneal colicky pain with suspected or confirmed nephrolithiasis 
• Proportion of patients treated with 10 mg/day as compared to placebo who experienced 
at least one of the following AEs: 
o Neutropenia 
o Lymphopenia 
o Diarrhea 
o Alopecia 
o Hemorrhage 

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o Abnormalities in alanine aminotransferase, aspartate aminotransferase, gamma 
glutamyl transferase, and total bilirubin with both elevations ˃1.5 x ULN and ≥35% 
elevated compared to Baseline 
• ECG, physical examination, and vital signs 
• Time to treatment discontinuation for any reason 
• Rate of treatment discontinuations up to Week 24 
Pharmacokinetics  
• Population PK at Week 6 (3-10 hours post-dose) 
• Plasma trough levels of IMU-838 at Days 7, and Weeks 6, 12, 18, and 24 
 
2.6 
Study schedule 
A schedule of assessments of the main treatment part for the Cohort 2 sub-trial is provided in 
Table 2.  
The assessment and procedures for patients who will continue into the extended period will 
follow those describe for the Cohort 1 main trial (Table 1). However, the extended treatment 
period will be terminated for patients in the Cohort 2 sub-trial, at the day the last patient of the 
Cohort 1 main trial has completed or discontinued the extended treatment period. The extended 
treatment period in this sub-trial will thus be shorter and the EoT will be before V46 (W516) as 
indicated in Table 1. 
For more details on procedures (except for FGF-19 and C4) to be performed at the visits 
described in Table 2 please refer to the main trial (Section 12).  
If a patient prematurely discontinues this Cohort 2 sub-trial before Week 24 (for possible 
reasons, please see Section 17), all assessments scheduled for the EoMT visit should be 
performed. All patients who prematurely discontinue the Cohort 2 sub-trial will be encouraged 
to complete the EoMT visit, and the EoS assessments at 30 days (+14 days) after the last IMP 
intake.  
 

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Table 2: 
Schedule of assessments - Cohort 2 sub-trial (main treatment period) 
 
Screening 
Blinded treatment 
 
Unscheduled 
visit 
 
EoS  
 
BL 
MRI 
Main treatment (MT) period 
 
 
due to 
MS-
related 
symp 
toms 
due to 
safety 
(end of 
study 
visit) 
S1a 
S2k 
V0 V1 
V2 
V3 
V4 
V5/ 
EoMT 
D-28 
- D-9 
D-14 
- D-3 
D0 D7 
W6 
W12 W18 
W24 
 
 
 30 d after 
last IMP  
Assessments 
 
±1 d -7/+4 d ±7 d ±7 d 
±7 d 
 
 
 
 
+14 d 
Informed consent 
• 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
• 
 
 
 
 
 
 
 
 
 
 
 
 
In-/exclusion criteria 
• 
 
• 
 
 
 
 
(•)j 
 
 
 
 
 
Randomization 
 
 
• 
 
 
 
 
 
 
 
 
 
 
Medical historyb 
• 
 
 
 
 
 
 
 
 
 
 
 
 
Previous therapy 
• 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medications/procedures 
• 
• 
• 
• 
• 
• 
• 
• 
 
• 
• 
 
• 
MS disease history 
• 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
• 
 
• 
 
 
 
 
• 
 
• 
• 
 
• 
New MS related 
neurological symptoms 
(treating physician) 
• 
 
• 
• 
• 
• 
• 
• 
 
• 
 
 
 
EDSS  
(evaluating physician) 
• 
 
• 
(•)m 
(•)m 
• 
(•)m 
• 
 
(•)m 
 
 
 
MS relapse  
(treating physician) 
 
 
• 
(•)m 
(•)m 
• 
(•)m 
• 
 
(•)m 
 
 
 
MRI scan 
 
• 
 
 
• 
• 
• 
•e 
 
 
 
 
 
Central MRI quality & 
eligibility assessment as 
well as BL stratification 
variables 
 
• 
 
 
 
 
 
 
 
 
 
 
 
Central MRI assessment 
of efficacy variables 
 
 
 
 
• 
• 
• 
• 
 
 
 
 
 
Laboratory assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central screening labs, 
incl. blood pregnancy 
testf 
• 
 
 
 
 
 
 
 
 
 
 
 
 
Local screening lab (Tbc-
IGRA) 
• 
 
 
 
 
 
 
 
 
 
 
 
 
Blood biochemistry 
(including HDL 
cholesterol) 
 
 
• 
• 
• 
• 
• 
• 
 
• 
• 
 
• 
Hematology 
 
 
• 
• 
• 
• 
• 
• 
 
• 
• 
 
• 
continued 
 

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Table 2: 
Schedule of assessments - Cohort 2 sub-trial (main treatment period) 
(continued) 
 
Screening 
Blinded treatment 
 Unscheduled 
visit 
 
EoS  
 
BL 
MRI 
Main treatment (MT) period 
 
 
due to 
MS-
related 
symp-
toms 
due 
to 
safety 
(end of 
study 
visit) 
S1a 
S2k 
V0 V1 
V2 
V3 
V4 
V5/ 
EoMT 
D-28 - 
D-9 
D-14 
- D-3 
D0 D7 
W6 
W12 W18 
W24 
 
 
 30 d after 
last IMP  
Assessments 
 
±1 d -7/+4 d ±7 d ±7 d 
±7 d 
 
 
 
 
+14 d 
Urinalysis 
 
 
• 
• 
• 
• 
• 
• 
 
• 
• 
 
• 
IMU-838 trough levelg 
 
 
• 
• 
• 
 
• 
• 
• 
 
 
 
 
•p 
Population PKg   
 
 
 
 
 
•l 
 
 
 
 
 
 
 
 
C4s 
 
 
• 
• 
• 
• 
• 
• 
 
 
 
 
•p 
Local urine pregnancy 
testd 
 
 
•i 
 
• 
• 
• 
• 
 
 
 
 
• 
Neurofilamentg 
 
 
• 
 
• 
 
 
• 
 
 
 
 
 
FGF-19r 
 
 
• 
 
•q 
•q 
 
 
• 
 
 
 
 
 
Lab kits used 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening lab kit 
S 
 
 
 
 
 
 
 
 
 
 
 
 
Trial lab kit 
 
 
B 
B 
B 
B 
B 
B 
 
C 
C 
 
C 
Neurofilament  
 
 
NFL 
 
2xNFL 
 
 
NFL 
 
 
 
 
 
PK kit  
 
 
PK PK 2xPK 
PK 
PK 
PK 
 
 
 
 
PKp 
Shipment to central lab 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ambient temperature 
• 
 
• 
• 
• 
• 
• 
• 
 
• 
• 
 
• 
Dry ice 
 
 
 
 
 
 
 
•o 
 
 
 
 
•n 
Safety 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE assessment 
• 
• 
• 
• 
• 
• 
• 
• 
 
• 
• 
 
• 
12-lead ECG 
• 
 
 
 
• 
 
 
• 
 
 
• 
 
 
Vital signs 
•c 
 
•c 
•c 
 
•c 
 
•c 
 
 
 
 
•c 
IMP 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP administrationh 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP dispensing 
 
 
• 
 
• 
• 
• 
• 
 
 
 
 
 
No. of bottles disp. 
 
 
1 
 
1-2t 
1-2t 
1-2t 
3 
 
 
 
 
 
IMP accountability 
 
 
 
 
 
 
 
• 
 
 
 
 
 
Assessments in brackets (•) indicate assessments which must not always be performed. Refer to the respective footnote. 
a 
Within 28 days from Baseline (Day 0). If the baseline MRI is repeated, the screening period maybe extended. However, 
patients must be randomized within 14 days of the repeated baseline MRI. Screening Visit 1 assessments will be valid for 
up to 60 days until the day of randomization, but will have to be repeated if exceeding 60 days. If results of the baseline 
MRI assessments are not available within 14 days (either after the first or, if applicable, after the repeated MRI) 
randomization can be delayed by up to 7 days, which may also result in an extension of the screening period. 
b 
Including the history of autoimmune diseases (other than MS). 
c 
Including height (only at Screening), respiratory rate, weight, blood pressure, pulse rate, and body temperature. 

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d 
Any positive local urine pregnancy test has to be followed up with a confirmatory local blood pregnancy test. 
e 
Can be repeated if initial MRI scan is not at least partially assessable. 
f 
Serum pregnancy test at central laboratory. 
g 
Samples to be stored at -20°C until next scheduled dry-ice shipment to central laboratory. 
h 
During the first week of treatment: 1 tablet once daily; other weeks: 2 tablets once daily. 
i 
The result of this local pregnancy test must be available and negative before the first IMP can be taken. 
j 
Only for patients who continue into the extended treatment phase. 
k 
If the central reader evaluates the quality of the baseline MRI as not sufficient, the MRI must be repeated as soon as 
possible. 
l 
Taken at 3 to 10 hours post-dose (in addition to the sample which is collected pre-dose at the same day for IMU-838 
trough values). 
m 
If, based on new neurological symptoms of the patient, the treating physician suspects that the patient may have an MS 
relapse (as defined in this protocol), an EDSS assessment by the evaluating physician and an assessment of MS relapse by 
the treating physician (based on the EDSS) must be performed at this visit. 
n 
The sample can be stored at -20°C for up to 1 year and dry ice shipment can be combined with another dry ice shipment. 
However, the last dry ice shipment should be done when the last Cohort 2 patient has completed the MT period. 
o 
The dry ice shipment should be generally done immediately after Week 24 visit. However, it may be delayed by up to 
4 weeks if the dry ice shipment can be combined with the dry ice shipment for another patient at the same site.  
p 
To be performed only up to the time of last patient last visit of the main treatment period in the Cohort 2 sub-trial 
(Week 12). Investigators will be notified immediately. 
q 
Taken pre-dose and at 3 to 6 hours post-dose. 
r 
Will be measured out of neurofilament lab kit (NFL lab kit), requires second NFL kit at Week 6 at 3 to 6 hours post-dose. 
s 
Will be measured out of IMU-838 trough level samples (PK lab kit). 
t 
Depending on amount of tablets patients still have from the previous visit. 
 
AE = adverse event, BL = baseline, C4 = 7α-Hydroxy-4-cholesten-3-one, D = day, disp. = dispensed, 
DNA = deoxyribonucleic acid, ECG = electrocardiogram, EDSS = Expanded Disability Status Scale, EoMT = end-of-main 
treatment, EoS = end-of-study, EoT = end-of-treatment, ET = extended treatment, FGF = fibroblast growth factor, HDL-high 
density lipoprotein, IMP = investigational medicinal product, incl. = including, MRI = magnetic resonance imaging, 
MS = multiple sclerosis, MT = main treatment, No = number,  PD = pharmacodynamic, PK= pharmacokinetic, S = screening, 
Tbc-IGRA = Tuberculosis interferon gamma release assay, V = Visit; W = Week. 
 
2.7 
Efficacy and safety assessments 
Details on efficacy and safety assessments are described in Sections 14 and 15. 
MRI assessments will be done using an MRI machine with a field strength of 1.5 Tesla. 3 Tesla 
machines as in the main trial are not allowed. For this reason, the Cohort 2 will only allow 
inclusion and assessments of patients at sites using 1.5 Tesla MRI. 
The assessments performed will mostly include those described for the Cohort 1 main trial with 
few exceptions (for details see Section 1 of this Appendix). 
3. 
Biostatistical methods and reporting 
The Cohort 2 sub-trial will be analyzed after the last patient has terminated the sub-trial and the 
data base for the sub-trial has been locked (for data collection, monitoring and quality assurance 
see Section 21. However, for data collection during the Cohort 2 main treatment period no eCRF 
but paper CRF will be used. For the extended treatment period an eCRF, as in the Cohort 1 main 
trial, will be used. 

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All data will be analyzed descriptively as described in an SAP. The primary analysis set will be 
the FAS (for definition see Section 16.2). No formal statistical testing will be performed. 
The cumulative number of CUA and cumulative number of new Gd+ lesions up to Week 24 
will be analyzed with a negative binomial regression model with logarithmic link function with 
treatment group, Baseline volume of T2 lesions, and number of Gd+ lesions at Baseline as 
independent factor.  
The main analysis of Cohort 2 will be done using Cohort 2 data, however an additional analysis 
of pooled Cohort 1 and 2 data will be performed. In order to allow pooling of data with an 
identical patient population, Cohort 1 placebo patients from the same sites that contributed to 
the Cohort 2 Week 12 data and investigated using 1.5 Tesla MRI examinations will be allowed 
to enrich the Cohort 2 placebo arm. In addition, Cohort 1 data of 30 mg/day and 45mg/day may 
be listed as comparison to Cohort 2 data of 10 mg/day IMU-838, however the same restriction 
for sites and 1.5 Tesla MRI as for placebo will apply. Details will be described in the SAP for 
Cohort 2.  
All safety analyses will be done descriptively. Some limited pooled safety assessments of 
Cohorts 1 and 2 will also be provided. 
The results of the Cohort 2 sub-study will be summarized in an addendum to the clinical trial 
report.