Conditions: Secondary Progressive Multiple Sclerosis
Keywords: COVID-19 SARS-CoV-2 mRNA vaccine Siponimod Secondary Progressive Multiple Sclerosis SPMS adult MS
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 41
Healthy volunteers: no

Brief summary:
The purpose of this study was to understand whether participants could mount an immune response to SARS-CoV-2 modRNA vaccines administered either during continuous siponimod treatment or during a treatment break versus while on treatment with first-line DMTS or no current MS treatment..

Detailed description:
This was a three cohort, multicenter, open-label, study of 60 planned (optionally up to 90) multiple sclerosis (MS) patients who were on treatment with siponimod or a first-line disease modifying therapy (DMT) or without MS treatment planning to undergo a SARS-CoV-2 modRNA vaccination as part of clinical routine.

* The first cohort enrolled participants who did not interrupt their siponimod therapy for the purpose of a SARS-CoV-2 modRNA vaccination.
* The second cohort enrolled participants who interrupted their siponimod therapy for the purpose of a SARS-CoV-2 modRNA vaccination for approximately 2-3 months
* The third cohort enrollled participants who received modRNA vaccination while on treatment with the following first-line DMTs (dimethylfumarate, glatirameracetate, interferons, teriflunomide) or no current treatment in clinical routine.

The study consists of a screening period, vaccination period and investigational period. During the screening period of up to one month eligibility and SARS-CoV-2 antibodies at baseline were assessed. The 3-4 week vaccination period started with first dose of modRNA vaccine on Day 1 and ended with second dose of modRNA vaccine 3-4 weeks after first dose depending on EU SmPC.

The investigational period lasted 12 months, during which blood samples for primary and secondary endpoint analyses were drawn at 1 week (Visit 1), 1 Month (Visit 2) and 6 months (Visit 3) after completion of vaccination (i.e. second dose of vaccine). 12 months after completion of vaccination a COVID-19 follow-up call was scheduled.

As patients were treated according to clinical routine, the start of treatment was defined as the date the informed consent was signed.

Booster vaccinations were allowed as per local regulations, physician's discretion and as part of clinical routine. This booster may have been any type of SARS-CoV2 vaccine and introduction of a treatment break for the purpose of booster vaccination was at the discretion of the treating physician or patient for all three cohorts. In case of booster vaccinations an additional blood sample was collected 1 month after the booster vaccination (booster Visit).

The planned study duration for each participant was 56-64 weeks, depending on the length of the screening period.

The study investigated the development of functional anti-SARS-CoV-2 antibodies and T-cell titers for six months after the participants' vaccination.

Arms:
arm 1: Continuous treatment with siponimod (oral, daily, dose depending on CYP2C9 genotype: 2mg or 1 mg) during SARS-CoV-2 mRNA vaccination arm 2: Siponimod (oral, daily, dose depending on CYP2C9 genotype: 2mg or 1 mg) with treatment interruption (for approx. 2-3 months) for the purpose of a SARS-CoV-2 mRNA vaccination arm 3: Baseline DMTs or no treatment during SARS-CoV-2 mRNA vaccination

Interventions: intervention 1: BAF312 intervention 2: Baseline disease modifying therapies (DMTs) intervention 3: BNT162 intervention 4: mRNA-1273
Intervention descriptions: intervention 1: taken orally once per day (dose depends on CYP2C9 genotype) intervention 2: DMTs: Dimethylfumarate, glatirameracetate, interferon, teriflunomode according to respective SmPC intervention 3: Administerd according to the respective EU SmPC at the discretion of the treating physician independent of AMA-VACC. If suggested by local regulations and performed as part of clinical routine any type of booster/refresher vaccination (e.g. mRNA, vector, peptide) was allowed in this study. intervention 4: Administerd according to the respective EU SmPC at the discretion of the treating physician independent of AMA-VACC. If suggested by local regulations and performed as part of clinical routine any type of booster/refresher vaccination (e.g. mRNA, vector, peptide) was allowed in this study

Protocol document:
Prot_000.pdf: 
Novartis 
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Clinical trial protocol (Version No. 02) 
Protocol No. CBAF312ADE03 
Novartis Research and Development 
Mayzent (siponimod) 
Synopsis/Clinical Trial Protocol CBAF312ADE03 / NCT04792567
An open-label multicenter study to assess response to 
SARS-CoV-2 modRNA vaccines in participants with 
secondary progressive multiple sclerosis treated with 
Mayzent (siponimod) (AMA-VACC) 
Document type: 
Amended Protocol Version 
EUDRACT number: 
2020-005752-38 
Version number: 
02 
Clinical Trial Phase: 
IV 
Release date: 
25-Sep-2021
Property of Novartis Pharma GmbH  
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 3.0 dated 31-Jan-2020 


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Clinical trial protocol (Version No. 02) 
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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 4 
List of figures ...................................................................................................................... 4 
List of abbreviations ............................................................................................................ 5 
Protocol summary ................................................................................................................ 6 
1 
Introduction ....................................................................................................................... 16 
1.1 
Background ............................................................................................................ 16 
1.2 
Purpose .................................................................................................................. 17 
2 
Objectives and endpoints ................................................................................................... 18 
2.1 
Primary estimands ................................................................................................. 18 
3 
Study design ...................................................................................................................... 19 
4 
Rationale ............................................................................................................................ 22 
4.1 
Rationale for study design ..................................................................................... 22 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 23 
Siponimod.......................................................................................................................... 23 
Vaccination ........................................................................................................................ 23 
4.3 
Rationale for choice of control drugs (reference) .................................................. 24 
4.4 
Purpose and timing of interim analyses ................................................................. 24 
4.5 
Risks and benefits .................................................................................................. 24 
4.5.1 
Blood sample volume ............................................................................ 25 
5 
Study Population ............................................................................................................... 25 
5.1 
Inclusion criteria .................................................................................................... 25 
5.2 
Exclusion criteria ................................................................................................... 26 
6 
Treatment ........................................................................................................................... 27 
6.1 
Study treatment ...................................................................................................... 27 
6.1.1 
Investigational and control drugs .......................................................... 27 
6.1.2 
Supply of study treatment ..................................................................... 28 
6.1.3 
Treatment arms ..................................................................................... 28 
6.2 
Other treatment(s) .................................................................................................. 28 
6.2.1 
Concomitant therapy ............................................................................. 29 
6.3 
Participant numbering, treatment assignment, randomization .............................. 33 
6.3.1 
Participant numbering ........................................................................... 33 
6.3.2 
Treatment assignment, randomization .................................................. 33 
7 
Informed consent procedures ............................................................................................ 34 
8 
Visit schedule and assessments ......................................................................................... 35 


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Clinical trial protocol (Version No. 02) 
Protocol No. CBAF312ADE03 
 
 
 
8.1 
Participant demographics/other baseline characteristics ....................................... 36 
8.2 
Screening ............................................................................................................... 37 
8.2.1 
Eligibility screening .............................................................................. 37 
8.2.2 
Information to be collected on screening failures ................................. 37 
8.3 
Efficacy .................................................................................................................. 39 
8.3.1 
Efficacy assessment 1 ........................................................................... 39 
8.3.2 
Efficacy assessment 2 ........................................................................... 39 
8.3.3 
Appropriateness of efficacy assessments .............................................. 39 
8.4 
Safety ..................................................................................................................... 39 
9 
Study discontinuation and completion .............................................................................. 40 
9.1 
Discontinuation and completion ............................................................................ 40 
9.1.1 
Study treatment discontinuation and study discontinuation ................. 40 
9.1.2 
Withdrawal of informed consent ........................................................... 42 
9.1.3 
Lost to follow-up ................................................................................... 42 
9.1.4 
Early study termination by the sponsor ................................................. 42 
9.2 
Study completion and post-study treatment .......................................................... 43 
10 Safety monitoring and reporting ........................................................................................ 43 
10.1 
Definition of adverse events and reporting requirements ...................................... 43 
10.1.1 
Adverse events ...................................................................................... 43 
10.1.2 
Serious adverse events .......................................................................... 45 
10.1.3 
SAE reporting ....................................................................................... 45 
10.1.4 
Pregnancy reporting .............................................................................. 46 
10.1.5 
Reporting of study treatment errors including misuse/abuse ................ 46 
11 Data Collection and Database management ...................................................................... 47 
11.1 
Data collection ....................................................................................................... 47 
11.2 
Database management and quality control ............................................................ 47 
11.3 
Site monitoring ...................................................................................................... 48 
12 Data analysis and statistical methods ................................................................................ 48 
12.1 
Analysis sets .......................................................................................................... 49 
12.2 
Participant demographics and other baseline characteristics................................. 49 
12.3 
Analysis of the primary endpoint .......................................................................... 49 
12.3.1 
Definition of primary endpoint(s)/estimand(s) ..................................... 49 
12.3.2 
Statistical model, hypothesis, and method of analysis .......................... 49 
12.3.3 
Handling of remaining intercurrent events of primary estimand .......... 50 
12.3.4 
Supportive analyses ............................................................................... 50 
12.4 
Analysis of secondary endpoints ........................................................................... 50 


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12.4.1 
Safety endpoints .................................................................................... 50 
12.5 
Interim analyses ..................................................................................................... 51 
12.6 
Sample size calculation ......................................................................................... 51 
12.6.1 
Primary endpoint(s) ............................................................................... 51 
13 Ethical considerations and administrative procedures ...................................................... 51 
13.1 
Regulatory and ethical compliance ........................................................................ 51 
13.2 
Responsibilities of the investigator and IRB/IEC .................................................. 52 
13.3 
Publication of study protocol and results .............................................................. 52 
13.4 
Quality Control and Quality Assurance ................................................................. 52 
14 Protocol adherence ............................................................................................................ 52 
14.1 
Protocol amendments ............................................................................................ 53 
15 References ......................................................................................................................... 54 
List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 18 
Table 8-1 
Assessment schedule ............................................................................. 38 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse ......................................................................................... 47 
List of figures 
Figure 3-1 
Study design .......................................................................................... 21 
 
 


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List of abbreviations 
 
AE 
Adverse Event 
CDP 
Clinical Development Plan 
CDS 
Core Data Sheet 
CRO 
Contract Research Organization 
CSR 
Clinical study report 
CTC 
Common Terminology Criteria 
eSource 
Electronic Source 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GCS 
Global Clinical Supply 
i.v. 
intravenous 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
IEC 
Independent Ethics Committee 
PK 
Pharmacokinetic(s) 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
s.c. 
subcutaneous 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SmPC 
Summary of Product Characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
WoC 
Withdrawal of Consent 


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Amendment 2 (released 25-Sep-2021) 
 
Amendment summary 
The main changes introduced in this protocol amendment are a) termination of recruitment, b) 
optional treatment interruption according to SmPC also in cohort 1 in case of a booster 
vaccination and c) an additional study visit in case of a SARS-CoV-2 booster vaccination. 
 
a) Termination of recruitment 
With the advancement of the vaccination efforts in Germany participating centers of this study 
report that there are no more suitable MS patients for this study that have not yet received their 
initial SARS-CoV-2 vaccination cycle. Therefore, recruitment will be officially stopped with 
the approval of this amendment. 
 
b) Optional treatment interruption for booster vaccination in cohort 1 
The underlying study protocol already allows patients to receive a SARS-CoV-2 vaccination 
booster with any approved type of vaccination including but not limited to mRNA or vector 
based vaccines as part of clinical routine. Furthermore, according to SmPC all siponimod 
patients in cohort 1 and 2 will now be able to introduce a voluntary treatment break for the 
purpose of the booster vaccination e.g. if the immune response to the initial vaccination cycle 
was low or not detectable. The decision of a possible treatment break is at the discretion of the 
treating physician and patient. 
 
c) Additional study visit after SARS-CoV-2 booster vaccination 
At this point it is unclear if and at which point MS patients will be eligible for such a booster 
vaccination. In order to enable the assessment of the immune system to such a potential booster 
vaccination an additional study visit will be scheduled by the treating physician at one month 
after a potential booster vaccination. This additional visit will be termed ‘booster visit’ and will 
only be performed in a subgroup of patients receiving a booster vaccination. The additional 
booster visit includes all assessments conducted in the regular visit 3. If this additional visit 
would fall within +/-1 week of the regular visit 3, then the booster visit will not be performed 
as all required assessments are already part of the regular study visit 3. If the booster visit would 
be later than end of study at month 12 after the initial vaccination cycle then it will not be 
performed.   
 
 
 


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Clinical trial protocol (Version No. 02) 
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Changes to the protocol 
Protocol summary 
Sections ‘study treatment’ and ‘study design’: a sentence was added, that patients in cohort 1 
and cohort 2 may also choose to conduct a treatment break for the purpose of a potential booster 
vaccination. 
Section 2: Objectives and endpoints 
A sentence was added to secondary endpoints that SARS-CoV-2 antibody levels and T-cell 
response will be assessed after a potential booster vaccination. 
Section 3: study design 
Explanations were added explaining that according to the EU SmPC all siponimod patients in 
cohort 1 and cohort 2 may introduce a treatment break for the purpose of the booster 
vaccination. 
Section 4.2: Rationale for dose/regimen and duration of treatment 
A sentence was added explaining that according to the EU SmPC all siponimod patients in 
cohort 1 and cohort 2 may introduce a treatment break for the purpose of the booster 
vaccination. 
Table 6-1: Table 6-1 Investigational and control drug 
Vector based SARS-CoV-2 vaccines were added to the list of IMPs in all treatment arms which 
are now allowed for booster vaccination as an alternative to mRNA vaccines 
Section 6.1.3: Treatment arms 
A sentence was added explaining that according to the EU SmPC patients in cohort 1 may 
introduce a treatment break for the purpose of the booster vaccination. 
Section 6.3.2: Treatment assignment, randomization 
A sentence was added that patients in cohort 1 may introduce a treatment break for the purpose 
of the booster vaccination. 
Section 8: Visit schedule and assessments 
An explanation was added during which time frame of the study a “booster visit” shall be 
performed to analyze the immune response to a potential booster vaccination.   
Section 8.1: Documentation of IMPs 
For the purpose of analyzing potential booster vaccinations the investigational period and end 
of study was extended to month 12 meaning that the study ends with the COVID-19 follow-up 
call in month 12. For individual patients the study duration therefore does not change. 
 
Figure 3-1: Study design 
The figure was amended to include a telephone contact in case of a booster vaccination and an 
additional study visit 1 month after a potential booster vaccination. A sentence was added to 


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the figure footer explaining during which time frame of the study a “booster visit” shall be 
performed to analyze the immune response. 
Table 8-1: Assessment schedule 
A sentence was added to the table footer explaining during which time frame of the study a 
“booster visit” shall be performed to analyze the immune. 


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Clinical trial protocol (Version No. 02) 
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Amendment 1 (released 25-May-2021) 
 
Amendment summary 
The main changes introduced in this protocol amendment are: a) prolongation of the visit 
window for investigational visit 1, b) classification of adverse events according to the Common 
Toxicity Criteria (CTC) AE grade (version 5 or higher) c) start and optional prolongation of 
screening period and d) optional booster/refresher SARS-CoV-2 vaccinations if suggested by 
local regulations e) more detailed description of IMP documentation. 
 
Visit window: In this study, investigational visits will only be possible from Monday to 
Wednesday due to organizational reasons in the central laboratory. In order to still allow 
vaccinations on all weekdays, the visit window for investigational visit 1 will be extended from 
“7 +/- 1 days” to “8 +/-2 days after second dose of vaccination”. 
 
Adverse events: Severity assessment of (serious) adverse events was changed to CTCAE 
scale as this scale is more common in clinical trial setting and participating physicians are more 
accustomed to this kind of severity scale. Therefore, severity assessment of adverse events 
would be more comparable between different physicians resulting in more valuable data. 
 
Screening period:  In order to avoid screening failures and replacement of patients due to 
changes in the German vaccination regulation, guidance for physicians has been included in 
the protocol to contact the Novartis Medical Advisor in case a patient is not eligible for SARS-
CoV-2 vaccination within one month after screening by local regulation to discuss further 
proceeding including re-evaluation of anti-SARS-CoV-2 antibody level and PCR test. 
Furthermore, length of the screening period was adjusted from 1-30 days to 3-30 days prior 
SARS-CoV-2 vaccination to ensure availability of SARS-CoV-2 PCR results before 
vaccination.  
 
Booster/refresher SARS-CoV-2 vaccinations 
It is currently under discussion to offer booster/refresher SARS-CoV-2 vaccinations to the 
population in general and patients under immune modulatory treatments especially. As AMA-
VACC follows clinical routine it shall be possible for participants to receive such a 
booster/refresher vaccination if recommended by local regulations and conducted as part of 
clinical routine. 
 
Detailed description of IMP documentation 
A more detailed description of the required documentation of all IMPs (MS DMTs, SARS-CoV-
2 vaccinations) was added to provide participating centers with an even clearer documentation 
guidance. 
 
 
 


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Changes to the protocol 
Protocol Summary 
Typos were corrected 
 
Section 3: Study design 
• 
Sentence has been added to clarify that PCR test results need to be available before 
a patient receives SARS-CoV-2 vaccination in this study. 
• 
During COVID-19 follow up call, all confirmed COVID-19 infections will be recorded. 
• 
Individual study duration will be 56-60 weeks (1-4 weeks between screening and 
vaccination 1, 3-4 weeks between vaccination 1 and 2 and 52 weeks until follow-up 
phone call) 
• 
It is currently under debate that patients with immunosuppressive treatment may 
require additional booster/refresher SARS-CoV-2 vaccinations. Guidance was 
therefore added that booster/refresher SARS-CoV-2 vaccinations are allowed if 
performed according to local regulations and as part of clinical routine independent of 
the type of vaccination used. 
• 
Guidance was included to contact the Novartis Medical Advisor in case a patient is not 
eligible for SARS-CoV-2 vaccination within one month after screening by local 
regulation to discuss further proceeding including re-evaluation of anti-SARS-CoV-2 
antibody level and PCR test. 
• 
Visit window for visit 1 was adapted to 6-10 days in section “3. Investigational period” 
and Figure 3-1 
 
Section 4.5: Risks and benefits 
Typo was corrected 
 
Section 5.1: Inclusion criteria 
Typo was corrected 
 
Section 6.2.1: Concomitant therapy 
Reference was corrected 
Wording of updated Siponimod Investigators Brochure version 19 was included regarding 
vaccination guidance. 
 
Section 6.3.1: Treatment arms 
Typo was corrected 
 


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Section 8 Visiting schedule  
An explanation regarding the possibility of unscheduled on-site (repeated sampling, safety) or 
telephone visits (booster/refresher vaccination) was added. 
Section 8.1 Documentation of IMPs 
This section was added for improved clarity on the parameters that need to be documented for 
all IMPs in this study (SARS-CoV-2 vaccine and all MS DMTs) 
 
Table 8-1 assessment Schedule 
Examination of vital signs, height and weight was included in the description of the full physical 
exam. Information on allowed booster/refresher SARS-CoV-2 vaccinations was added as well 
as the requirement of a negative SARS-CoV-2 PCR result prior to vaccination and guidance 
that information on MS relapses of the previous 2 years shall be collected. 
 
 
Section 8.4: Safety 
Examination of vital signs, height and weight was included in the description of the full physical 
exam. 
 
Section 9.1.1: Study treatment discontinuation and study discontinuation 
Visit window for visit 1 was adjusted to 6-10 days 
 
Section 9.1.1.1 Replacement policy 
Guidance was included to contact Novartis Medical Advisor in case a patient is not eligible for 
SARS-CoV-2 vaccination within one month after screening by local regulation to discuss 
further proceeding. 
 
Section 10.1.1: Adverse events 
Assessment and grading of adverse events will be done according to Common Terminology 
Criteria for Adverse Events (CTCAE) version 5 or higher. 
 
Section 12.1: Analysis sets 
Sentence was deleted because a more detailed description is given in the following paragraph. 
 
Table 6-1: Investigational and control drug 
Route of administration for vaccine will be i.m. according to EU SmPC 
 
 


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Table 8-1: Assessment schedule 
• 
The visit window for investigational visit 1 has been adapted to 8 +/- 2 days. 
• 
Screening period has been adapted to -30 to -3 days to make sure that PCR results 
will be available before vaccination (results will be available within 2 days). 
• 
It was specified that at screening, all MS relapses within the last 2 years should be 
recorded. 
• 
Assessment of current MS medication and concomitant medication should also be 
performed during telephone contacts after vaccination 1 and 2. 
• 
Footnote regarding PCR test was amended with the statement that patients are only 
allowed to continue the study and receive SARS-CoV-2 vaccination within the study 
context after they received a negative PCR test result. 
• 
Footnote was amended to allow possible booster/refresher vaccinations if they are 
suggested by local regulations and performed as part of clinical routine. 
 
Section 12.5: Interim Analysis 
To match the wording of section 4.4, a sentence was added to section 12.5 regarding additional 
interim analyses to support decision making concerning the current clinical study including an 
increase in participants (from 60 to 90), the sponsor’s clinical development projects in general, 
or in case of any safety concerns. 
 


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Protocol summary 
 
Protocol 
number 
CBAF312ADE03 
Full Title 
An open-label multicenter study to assess response to SARS-CoV-2 modRNA 
vaccines in participants with secondary progressive multiple sclerosis treated with 
Mayzent (siponimod) (AMA-VACC) 
Brief title 
Study to assess SARS-CoV-2 vaccination response in siponimod treated SPMS 
patients  
Sponsor and 
Clinical Phase 
Novartis Pharma GmbH / clinical phase IV 
Investigation 
type 
Drug (Siponimod (BAF312)) 
Study type 
Low-intervention, 3 cohorts 
Purpose and 
rationale 
MS disease modifying treatments generally target the immune system and may 
therefore interfere with vaccination responses. The purpose of this study is to 
understand whether participants can mount an immune response to SARS-CoV-2 
modRNA vaccines administered either during continuous siponimod treatment or 
during a treatment break. Furthermore, the study will investigate the development 
of anti-SARS-CoV-2 antibody and T-cell titers over six months after participants’ 
vaccination.  
Primary 
Objective(s)  
To estimate the proportion of those achieving seroconversion (i.e. having SARS-
CoV-2 serum functional antibodies) after receiving a modRNA vaccine in 
participants treated concomitantly with siponimod and siponimod treatment break. 
Secondary 
Objectives 
• 
Describing SARS-CoV-2 serum functional antibody levels in participants 
treated concomitantly with siponimod versus siponimod treatment break 
versus first-line DMTs and in patients currently not on a DMT  
• 
Describing the T cell response to modRNA vaccines in participants treated 
concomitantly with siponimod versus siponimod treatment break versus first-
line DMTs and in patients currently not on a DMT  
• 
Describing safety, incl. AEs related to discontinuation and new onset of 
siponimod treatment and patients developing COVID-19 
Study design 
This is a three cohort, multicenter, open-label, prospective study of 60 (optionally 
up to 90) MS patients currently treated with siponimod or a first-line DMT or without 
MS treatment in clinical routine planning to undergo a SARS-CoV-2 modRNA 
vaccination as part of clinical routine.  
• 
The first cohort will be participants not interrupting their current siponimod 
therapy for the purpose of a SARS-CoV-2 modRNA vaccination. In case of a 
booster vaccination, patients in this cohort may also undergo a treatment 
break which is also covered by the EU SmPC. 
• 
The second cohort will be participants interrupting their current siponimod 
therapy for the purpose of a SARS-CoV-2 modRNA vaccination (treatment 
interruption for about 2-3 months).  
• 
The third cohort will be participants receiving modRNA vaccine while on 
treatment 
with 
the 
following 
first-lineDMTs 
(dimethylfumarate, 


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glatirameracetate, interferons, teriflunomide) or no current treatment in clinical 
routine. 
Study 
population 
The study population will consist of females and males at risk for SPMS or with 
SPMS diagnosis treated in clinical routine with either siponimod, a first line MS 
DMT or no current therapy. 
Key Inclusion 
criteria 
1. Signed informed consent must be obtained prior to participation in the study. 
2. One of the following MS treatments as part of clinical routine:  
a. Cohort 1: Siponimod treatment according to EU SmPC without 
interrupting daily dosing for the purpose of vaccination with 
SARS-CoV-2 modRNA  
b. Cohort 2: Siponimod treatment according to EU SmPC 
interrupting daily dosing for the purpose of vaccination with 
SARS-CoV-2 modRNA  
c. Cohort 3: Dimethylfumarate, glatirameracetate, interferon, 
teriflunomide as per respective EU SmPC or no current 
treatment with diagnosis of SPMS or with RRMS at risk to 
develop SPMS (at the discretion of the treating physician) 
3. Planning to receive a SARS-CoV-2 modRNA vaccination as part of clinical 
routine 
4. No change regarding DMT within 4 weeks prior to inclusion to AMA-VACC, 
i.e. stable on current DMT according to dosing within label, no interruption, 
start or withdrawal of DMT in this period of time and no planned switch of 
DMT within following 2 months 
5. Patients willing and eligible to receive a modRNA vaccine against COVID-19 
as part of clinical routine 
Key Exclusion 
criteria 
1. History of COVID-19 
2. SARS-CoV-2 antibodies at screening 
3. Patients likely not being able or willing to complete the study 
4. Use of other investigational drugs within 5 half-lives of enrollment/initiation of 
study treatment (e.g. small molecules) or until the expected 
pharmacodynamic effect has returned to baseline (e.g., biologics), whichever 
is longer 
5. Patients with any medical or psychological condition that, in the investigators 
opinion, renders the patient unable to understand the nature, scope, and 
possible consequences of the study and who are therefore not able to 
comply with the requirements of the study and capable of giving informed 
consent 
6. No person directly associated with the administration of the study is allowed 
to participate as a study subject  
7. No family member of the investigational study staff is allowed to participate in 
this study 
8. Known or suspected clinically relevant allergy, intolerance or hypersensitivity 
to peanuts, soya (only cohort 1 and 2) or to any of the study treatments 
designated for the individual subject (DMTs or mRNA vaccines) or drugs of 
similar chemical classes (active substance or excipients) 
9. Women of child-bearing potential, defined as all women physiologically 
capable of becoming pregnant, unless they are using highly effective 
methods of contraception while taking study treatment and for 10 days of 
study treatment after stopping medication. 
10. For cohort 3: patients with contraindications for their current MS medication 
according to the respective EU SmPC 


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Study 
treatment 
• 
Cohort 1: Siponimod (BAF312) treatment according to EU SmPC without 
interrupting daily dosing for the purpose of a SARS-CoV-2 modRNA 
vaccination In case of a booster vaccination, patients in this cohort may also 
undergo a treatment break which is also covered by the EU SmPC. 
• 
Cohort 2: Siponimod (BAF312) treatment according to EU SmPC 
interrupting daily dosing for the purpose of a SARS-CoV-2 modRNA 
vaccination (treatment interruption for about 2-3 months) 
• 
Cohort 3: Dimethylfumarate, glatirameracetate, interferon, teriflunomide as 
per respective EU SmPC or no current treatment without a change in 
treatment for the purpose of a SARS-CoV-2 modRNA vaccination 
Treatment of 
interest 
Siponimod (BAF312) / SARS-CoV-2 modRNA vaccine 
Efficacy 
assessments 
• 
Detection of SARS-CoV-2 serum functional antibodies  
• 
Detection of SARS-CoV-2 specific T-cells 
Key safety 
assessments 
• 
Patients developing COVID-19 
Data analysis 
The primary analysis will not use any statistical testing or modelling. The absolute 
numbers and the proportion of participants achieving seroconversion within each 
cohort will be calculated. It will be augmented by a (descriptive) 95% confidence 
interval (exact Clopper-Pearson). All secondary endpoints will be summarized 
descriptively as frequencies and percentages, or, for continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented.  
Key words 
COVID-19, SARS-CoV-2, RNA vaccine, siponimod, secondary progressive 
multiple sclerosis 
 


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1 
Introduction 
1.1 
Background 
Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) infection was first observed in Wuhan, China, in December 2019. 
Since then, pandemic illness spread around the globe and currently affects millions of people, 
not only their health, but also their entire social and economic life. COVID-19 is associated 
with an increased risk of severe and potentially lethal disease especially among the elderly and 
among persons with preexisting medical conditions. Tremendous efforts are undertaken to 
develop a vaccine to SARS-CoV-2. The first promising data have recently been reported by 
BioNTech, Moderna and others using nucleoside-modified RNA (modRNA) vaccines 
encapsulated in lipid nanoparticles (Sahin et al, 2020; Jackson et al, 2020; press release 
BioNTech). Furthermore, the BioNTech and Moderna vaccines have just been granted 
marketing authorization by the European Medicines Agency (EMA). 
Multiple sclerosis (MS) is a common cause of neurologic disability in young adults. In this 
disease, damage is caused by an autoimmune attack of the central nervous system. The majority 
of relapsing remitting multiple sclerosis (RRMS) patients convert to secondary progressive 
multiple sclerosis (SPMS) in their lifetime. Siponimod is indicated by the EMA for the 
treatment of SPMS patients with active disease as evidenced by relapse or MRI activity. 
Siponimod selectively targets S1P1 and S1P5 receptors present on lymphocytes inducing 
receptor internalization and therefore preventing egress of these cells from secondary lymphoid 
tissues (Behrangi et al, 2019).  
In general, MS disease modifying treatments target the immune system and in doing so may 
diminish vaccine efficacy (Farez et al 2019). In a double-blind, placebo controlled study with 
siponimod in healthy volunteers, it was observed that concomitant siponimod was associated 
with no relevant effect on antibody response to pneumococcal polysaccharide vaccine and most 
of the patients met the EMA criteria of seroconversion for a T-cell dependent influenza vaccine 
although titers were lower (Ufer et al, 2017). 
The current guidance for vaccination of siponimod patients is based on the findings by Ufer et 
al., reflected in section 4.4 Special warnings and precautions for use in the EMA SmPC 
(product information siponimod):  
• The use of live attenuated vaccines should be avoided while patients are taking 
siponimod and for 4 weeks after stopping treatment.  
• Vaccinations may be less effective if administered during siponimod treatment. 
Discontinuation of treatment 1 week prior to planned vaccination until 4 weeks after is 
recommended. When stopping siponimod therapy for vaccination, the possible return of 
disease activity should be considered  
The modRNA vaccine BNT162b2 was shown to not only trigger a vaccine-induced antibody 
response against the receptor binding domain (RBD) of the SARS-CoV-2 spike protein but also 
a functional and proinflammatory CD4+ and CD8+ T-cell response in a phase I/II trial 
(NCT04380701) (Sahin et al, 2020). In the following phase III trial with 43,548 participants 
(NCT04368728), BNT162b2 mRNA vaccine has further been shown to be 95% effective in 


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preventing COVID-19 (Polack et al, 2020). Similar results were also shown for the mRNA 
vaccine developed my Moderna: the efficacy of mRNA-1273 in preventing COVID-19 in a 
phase III trial with 30,420 participants was 94.1% (NCT04470427) (Lindsay et al, 2021).  
It is therefore essential to understand the immune response to the novel class of modRNA 
vaccines in siponimod treated patients where S1P1 expressing Th17 cells are retained in lymph 
nodes (Behrangi et al, 2019) to develop a guidance for SARS-CoV-2 vaccination strategies in 
the vulnerable population of SPMS patients. This becomes even more important when 
considering that SARS-CoV-2 vaccination needs to be boosted after 3 or 4 weeks, resulting in 
a possible treatment interruption of about 2-3 months.  
The detection of SARS-CoV-2 serum functional antibodies after vaccination in patients 
negative for this parameter at baseline is defined as seroconversion according to World Health 
Organization guidelines (WHO guideline, 2020). In this study, we will test for functional 
antibodies, i.e. antibodies that inhibit the binding of the viral spike protein to the human 
angiotensin-converting enzyme 2 (ACE2) receptor, which is the first and necessarily required 
step during SARS-CoV-2 infection (Yang et al, 2020). Vaccination response will be analyzed 
during continued siponimod treatment (cohort 1) or a short treatment interruption (cohort 2) in 
accordance with label recommendations / upon discretion of the treating physician to cover both 
scenarios taking place in clinical practice.  
In order to set findings into relation to MS patients on disease modifying treatments (DMTs) 
with potentially less immunomodulatory effects, data will also be compared to cohort 3 with 
RRMS patients at risk of SPMS and SPMS patients either without treatment or on first-line 
therapies dimethylfumarate, glatirameracetate, interferons or teriflunomide. 
These data are needed in a very timely manner to help physicians make an educated decision 
about vaccination in siponimod treated patients in the upcoming months. Therefore, the present 
study will be conducted in parallel to currently ongoing studies AMASIA (CBAF312ADE01) 
and PANGAEA 2.0 EVOLUTION (CFTY720DDE26), thereby leveraging established 
operational structures without influencing the non-interventional character of these trials. In 
case patients participating in AMASIA consider participation in AMA-VACC, for regulatory 
and safety reporting reasons, documentation in AMASIA needs to be paused for the time 
patients are participating in AMA-VACC.   
1.2 
Purpose 
MS disease modifying treatments generally target the immune system and may therefore 
interfere with vaccination responses. The purpose of this study is to understand whether 
participants can mount an immune response to SARS-CoV-2 modRNA vaccines administered 
either during continuous siponimod treatment or during a treatment break. Furthermore, the 
study will investigate the development of anti-SARS-CoV-2 antibody and T-cell titers over six 
months after participants’ vaccination. 


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2 
Objectives and endpoints 
Table 2-1 
Objectives and related endpoints  
Objective(s) 
Endpoint(s) 
Primary Objective(s) 
• 
To estimate the proportion of those 
achieving seroconversion (i.e. having SARS-
CoV-2 serum functional antibodies) after 
receiving a modRNA vaccine in participants 
treated concomitantly with siponimod and 
siponimod treatment break. 
 
Endpoint(s) for primary objective(s)  
Proportion of participants achieving 
seroconversion as defined by detection of 
SARS-CoV-2 serum functional antibodies one 
week after second dose of vaccine in 
participants treated concomitantly with 
siponimod and siponimod treatment break 
(yes/no) 
 
Secondary Objective(s) 
• 
Describing SARS-CoV-2 serum functional 
antibody 
levels 
in 
participants 
treated 
concomitantly 
with 
siponimod 
versus 
siponimod treatment break versus first-line 
DMTs and in patients currently not on a DMT  
• 
Describing the T-cell response to modRNA 
vaccines 
in 
participants 
treated 
concomitantly 
with 
siponimod 
versus 
siponimod treatment break versus first-line 
DMTs and in patients currently not on a DMT  
• 
Describing safety, incl. AEs related to 
discontinuation and new onset of siponimod 
treatment and patients developing COVID-19 
 
Endpoint(s) for secondary objective(s) 
• 
SARS-CoV-2 serum functional antibody 
levels one week, one month and six months 
after second dose of vaccine and additionally 
one 
month 
after 
an 
optional booster 
vaccination 
in 
participants 
treated 
concomitantly 
with 
siponimod 
versus 
siponimod treatment break versus first-line 
DMTs and in patients currently not on a DMT  
• 
SARS-CoV-2 specific T-cell levels one week, 
one month and six months after second dose 
of vaccine and additionally one month after 
an 
optional 
booster 
vaccination 
in 
participants 
treated 
concomitantly 
with 
siponimod versus siponimod treatment break 
versus first-line DMTs and in patients 
currently not on a DMT measured by e.g. 
enzyme-linked 
immunosorbent 
spot 
(ELIspot) assay from peripheral blood 
mononuclear cells  that were stimulated with 
SARS-CoV-2 peptide mix 
• 
AEs, SAEs, incl. patients with clinical 
confirmed COVID-19, events leading to 
discontinuation 
in 
participants 
treated 
concomitantly 
with 
siponimod 
versus 
siponimod treatment break versus first-line 
DMTs and in patients currently not on a DMT  
 
2.1 
Primary estimands 
The primary clinical question in this trial is: What is the proportion of SPMS patients treated 
with siponimod within the three cohorts defined below which develop an immune response to 
a SARS-CoV-2 modRNA vaccine?  
Of note, this is not a randomized trial, therefore no randomization needs to be preserved and 
the ITT-principle and the associated estimands framework do not apply. However, this protocol 


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will keep as close as appropriate to the terminology and the definitions established within that 
framework. 
The justification for the primary estimand is that it will capture whether siponimod treated 
participants generate functional antibodies to SARS-CoV-2 vaccine as assessed by geometric 
mean titers. 
The following attributes describe the primary estimand: 
• 
Population: MS patients divided in three cohorts, each receiving a SARS-CoV-2 
vaccination as part of clinical routine: (1) vaccination during continued siponimod 
treatment; (2) vaccination during a siponimod treatment interruption (of approx. 2-3 
months); (3) vaccination in MS patients during continued treatment with first-line 
DMTs or no DMT. Patients who fail to receive their second dose of vaccine for whatever 
reason will be included in the analysis as non-responders. Patients who did receive their 
second dose of vaccine and do not have a valid determination of functional antibodies 
to SARS-CoV-2 for whatever reason will be excluded from the analysis of vaccine 
efficacy. 
• 
Variable: Receiving the second dose of vaccine and achieving seroconversion as 
defined by detection of SARS-CoV-2 functional antibodies one week after second dose 
of vaccine (yes/no) 
• 
Treatment of interest: siponimod either continuously applied or with a treatment break 
for the purpose of the vaccination, or first line DMTs or no treatment as part of clinical 
routine 
• Intercurrent events: Failure to receive the second dose of vaccine: These patients 
will be counted as non-responders. 
Missing or invalid determination of functional antibodies to SARS-CoV-2: These 
patients will be excluded from the efficacy analyses (if they received their 2nd dose of 
vaccine) 
• 
Summary measure: n.a., there will be no formal comparison between cohorts. 
Response rates will only be calculated within each cohort. 
3 
Study design 
This is a three cohort, multicenter, open-label, prospective study of 60 (optional increase to 90) 
MS patients currently treated with siponimod or a first-line DMT (as per EU SmPC) or without 
MS treatment planning to undergo a SARS-CoV-2 modRNA vaccination as part of clinical 
routine and according to the respective EU SmPC. For each participant, total expected duration 
of the trial is 56-60 weeks. 
• The first cohort will be participants not interrupting their current siponimod therapy for the 
purpose of a SARS-CoV-2 modRNA vaccination. In case of a booster vaccination, patients 
in this cohort may also undergo a treatment break which is also covered by the EU SmPC. 
• The second cohort will be participants interrupting their current siponimod therapy for the 
purpose of a SARS-CoV-2 modRNA vaccination (treatment interruption of about 2-3 
months).  


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• The third cohort will be participants receiving modRNA vaccine while on treatment with 
first-line DMTs (dimethylfumarate, glatirameracetate, interferons, teriflunomide) or no 
current treatment in clinical routine.  
The interventional part of AMA-VACC is limited to the collection of blood samples at specified 
time-points to analyze levels of SARS-CoV-2 specific antibodies and T-cells as response to the 
modRNA vaccination in clinical routine. 
 
There are 3 study periods: 
1. Screening period: 
Participants enter a screening period of up to 1 month to assess eligibility requirements 
including a blood draw and assessment of SARS-CoV-2 specific antibodies at baseline to 
exclude any prior exposure to the virus or a vaccination. In case the patient is not eligible for 
SARS-CoV-2 vaccination by local regulation within this time, the Novartis Medical Advisor 
should be contacted to discuss further proceeding including re-evaluation of anti-SARS-CoV-2 
antibody level and PCR test. Furthermore, a SARS-CoV-2 PCR test will be performed at 
screening to exclude current COVID-19 infection. In case of a positive test result, the patient 
has to go into quarantine immediately. Patients are only allowed to continue within the study 
and receive SARS-CoV-2 vaccination once they received a negative PCR test result. 
 
2. Vaccination period 
Patients are vaccinated with a complete cycle of modRNA based SARS-CoV-2 vaccine at the 
discretion of the treating physician outside the study as part of clinical routine. 
• Participants in cohort 1: vaccination will be administered according to EU SmPC under 
continued siponimod treatment. In case of a booster vaccination, patients in this cohort 
may also undergo a treatment break which is also covered by the EU SmPC. 
• Participants in cohort 2: vaccination will be administered according to EU SmPC after 
start of the siponimod treatment break.  
• Participants in cohort 3: vaccination will be administered according to EU SmPC during 
continued treatment with first-line MS DMTs or no current treatment.  
If suggested by local regulations, patients will be allowed to receive additional SARS-CoV-2 
vaccinations (booster or refresher) during the study according to the physician’s discretion and 
as part of the clinical routine. This booster may be any type of SARS-CoV-2 vaccine, depending 
on local regulations. According to SmPC, siponimod patients in Cohort 1 and Cohort 2 may 
introduce a treatment break for the purpose of the booster vaccination e.g. in case there was no 
measurable immune response during the initial vaccination cycle. The decision for such a 
treatment break is at the discretion of the treating physician and patient. 
 
3. Investigational period 
Blood samples for SARS-CoV-2 functional antibody titers and T-cells for primary and 
secondary endpoints will be drawn from all patients 1 week (day 6 - 10), 1 month (day 28 - 35) 


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and 6 months (week 25 - 27) after completion of vaccination. In case of booster vaccinations 
an additional blood sample will be collected one month (+/- 1 week after the booster 
vaccination). 
12 months (week 50 – 54) after completion of the vaccination a COVID-19 follow-up call is 
scheduled to inquire about a possible confirmed COVID-19 disease after the end of the study. 
In total, the study duration for each participant is 56-60 weeks, depending on the length of the 
screening period. 
Figure 3-1 
Study design  
 
 
PEP: primary endpoint; d= day, w=week, m=month, vacc= vaccination independent of study site. # vaccination as part of clinical 
routine. * Number of Vaccinations required and interval depends on SmPC of respective modRNA vaccines. Any kind of SARS-
CoV-2 booster/refresher vaccination is allowed in this study, if this is suggested by local regulations and applied as part of clinical 
routine. ΩIf booster vaccinations are performed as part of clinical routine an additional telephone contact (booster vacc) is 
scheduled. Furthermore, an additional study visit (booster visit) will be performed one month (+/- 1 week) after the booster 
vaccination matching all assessments of investigational visit 3. If this booster visit falls within +/-1 week of the regular visit 3 or 
later than the telephone contact in month 12, it will not be performed. Timing of visits 1-3: 1 week (day 6 - 10), 1 month (day 28 - 
35) and 6 months (week 25 - 27) after completion of vaccination. COVID-19 follow-up call: 50-54 weeks after completion of 
vaccination 
 


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4 
Rationale 
4.1 
Rationale for study design 
A multicenter, multi-cohort, open-label, comparator design has been selected to enable feasible 
recruitment in a timely manner that allows fast generation of data in order to provide a guidance 
to physicians and patients how to apply SARS-CoV-2 vaccination in siponimod patients. The 
study therefore addresses two main questions: 
• Can participants continuously treated with siponimod develop SARS-CoV-2 serum 
functional antibodies after receiving a modRNA vaccine? 
• Can participants undergoing a siponimod treatment interruption for the purpose of a 
SARS-CoV-2 vaccination develop serum functional antibodies? 
The third cohort comprising MS patients treated with first-line DMTs according to respective 
SmPC or no current MS therapy serves as a reference on the development of an immune 
response in MS patients. 
As SPMS patients may be considered a vulnerable COVID-19 group these patients may be 
given access to the modRNA vaccines as one of the first groups in Germany (German ministry 
of health statement). In order to provide a guidance for vaccination of siponimod patients as 
early as possible a study design allowing fast implementation and execution was chosen. 
Therefore, immune responses to vaccination will be analyzed in patients receiving both MS 
treatment and modRNA vaccine in clinical routine. The intervention of AMA-VACC is limited 
to blood sampling and analysis of the immune response. 
When considering possible randomization of siponimod patients into cohort 1 (continued 
treatment) and cohort 2 (treatment interruption) for the purpose of SARS-CoV-2 vaccination 
two perspectives are important: the SPMS disease and the possible vaccination response. 
The siponimod SmPC suggests that patients may undergo vaccination with inactive agents 
either during continued siponimod treatment or during a treatment break. It is however also 
stated, that a return of disease activity has to be considered when interrupting the treatment. 
Therefore, physicians need to take the individual MS history into consideration when deciding 
about the most beneficial vaccination approach together with the patient. Randomization would 
overrule this decision process and may not lead to the most suitable result for the individual 
patient. One limitation of this approach however is that patient characteristics e.g. regarding 
age or MS parameters may not be completely matched in the two cohorts. 
From a vaccination point of view two factors may influence the immune response: co-treatment 
with siponimod and patient characteristics. Interestingly, during clinical development of 
BNT162b2 which has recently been submitted to EMA and FDA, no impact of age was 
observed regarding the antibody response (Welch et al, 2020). Here, similar levels of S1-
binding IgG antibodies were found in patients aged 18-55 and 65-85. With such a large range 
of ages studied it is not expected that these patient characteristics may lead to a strong bias in 
the development of an adequate immune response to modRNA vaccines in cohort 1 vs 2. The 
second possible impact factor – continued vs interrupted siponimod treatment – is part of the 
objectives of this study. 


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Therefore, randomization is not performed in AMA-VACC to allow patients and physicians to 
decide about the most suitable vaccination approach for the individual situation which also 
reflects the guidance of the siponimod SmPC. 
 
Rationale for study population 
In order to reflect the clinical routine of siponimod patients in Germany as close as possible 
no inclusion/ exclusion criteria regarding age or disease severity were implemented. This 
means, any siponimod patient willing to undergo a SARS-CoV-2 vaccination in clinical 
routine may be suitable for AMA-VACC as long as all other inclusion/exclusion criteria are 
met. During screening patients will be excluded if detectable levels of SARS-CoV-2 specific 
antibodies can be detected or if patients have a positive SARS-CoV-2 PCR test result at 
screening in order to ensure participants did not have previous contact to the virus or 
vaccination. This is necessary to assess whether siponimod patients can mount a response 
after vaccination. 
Rationale for chosen endpoints 
The primary endpoint was chosen in analogy to recently completed and ongoing clinical trials 
of the modRNA vaccine BNT162b2 (Walsh et al, 2020; ClinicalTrials.gov Identifier: 
NCT04368728). The endpoints will provide evidence addressing whether siponimod treated 
patients can mount an immune response to a SARS-CoV-2 modRNA vaccine. 
 
4.2 
Rationale for dose/regimen and duration of treatment 
Siponimod 
Patients in cohort 1 and cohort 2 are treated with siponimod as part of clinical routine with 2 mg 
or 1 mg siponimod daily depending on CYP2C9 metabolisation status. The siponimod SmPC 
allows vaccination with non-live or attenuated substances both during continued daily intake of 
siponimod (cohort 1) or a treatment break for the purpose of the vaccination (cohort 2, duration 
of treatment break will be around 2-3 months)). In case of a booster vaccination, patients in 
both cohorts may undergo a treatment break according to SmPC. The decision to continue 
siponimod treatment or to interrupt the treatment is at the discretion of the treating physician 
together with the patient independent of AMA-VACC and as part of clinical routine.  
Vaccination 
Several pharmaceutical companies have received or are awaiting approval of modRNA 
vaccines including but not limited to BNT162 (Biontech/Pfizer) and mRNA-1273 (Moderna). 
AMA-VACC participants will be vaccinated with any modRNA vaccine according to the 
respective EU SmPC at the discretion of the treating physician independent of AMA-VACC. If 
suggested by local regulations and performed as part of clinical routine any type of 
booster/refresher vaccination (e.g. mRNA, vector, peptide) is allowed in this study. 


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4.3 
Rationale for choice of reference treatment 
First-line DMTs 
Dimethyl fumarate, glatiramer acetate, interferons and teriflunomide applied as per respective 
EU SmPC were chosen as reference therapy as these drugs are routinely used as first line MS 
treatments and negative effects on vaccination outcomes are not expected according to 
respective SmPCs. An interruption of treatment for the purpose of a SARS-CoV-2 vaccination 
is not indicated in the respective SmPCs.  
 
4.4 
Purpose and timing of interim analyses 
An interim analysis is planned after all participants have completed the study visit at one week 
after the end of the SARS-CoV-2 vaccination cycle in the study. The week +1 data regarding 
antibody and T-cell response (along with relevant safety data) will be examined as a preliminary 
evaluation of proof of concept and are the basis for the primary endpoint of the study. 
Additional interim analyses may be conducted to support decision making concerning the 
current clinical study including an increase in participants (from 60 to 90), the sponsor’s clinical 
development projects in general, or in case of any safety concerns. 
Additional information is presented in the interim analysis section. 
4.5 
Risks and benefits 
This study does not interfere with clinical routine treatment of MS patients regarding DMTs or 
SARS-CoV2 vaccinations. The only intervention is the blood sampling at specific time-points 
in the course of this trial. In the case that a blood sampling for antibody and T-cell response 
measurement is not related to a clinical routine blood draw, during patient’s regular 
consultation, this blood draw could bear some minimal risk for the patient, associated with the 
sampling procedure (venous puncture). As of February 2021, for the currently EU approved 
mRNA vaccines (COMIRNATY® by BioNTech/Pfizer, COVID 19 Vaccine Moderna by 
Moderna), no data 
on 
safety 
and 
efficacy 
are 
available 
for patients 
with 
immunomodulating/immunosuppressive treatment as this condition was excluded from 
pivotal phase III clinical trials. However, as vaccines based on nucleoside modified RNA do 
not contain living viral particles, the risk to experience adverse events is considered similar as 
for 
healthy 
individuals. Thus, the 
risk 
evaluation 
for 
patients 
with 
immunomodulatory/immunosuppressive treatment is the same as for any other individual and 
the risks of the vaccine are considered much lower than the risks of suffering from (a severe 
course of) COVID-19 in the future.  
However, this study involves the risk to reveal a reduced or insufficient immune response after 
vaccination in patients with immunomodulatory/immunosuppressive treatment. Although no 
data and recommendations are available for these circumstances, such a situation might 
require additional booster vaccination. Furthermore, the vaccine itself might have an effect 
on MS 
disease 
activity 
or 
on 
the 
anti-MS 
effect 
of 
the 
concomitant 


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immunosuppressing/immunomodulating therapy. However, no increased disease activity has 
been reported in MS patients in Israel that have received SARS-CoV-2 mRNA vaccination 
(DMSG statement, February 2021).  
 
It is unlikely that there will be a direct benefit to the patient as a result of the participation in 
this study other than receiving the information whether measurable SARS-CoV-2 antibody and 
T-cell levels are reached after the vaccination. This information can then be used to decide 
whether an additional booster vaccination might be necessary in MS patients with/without 
concomitant immunosuppressing/immunomodulating therapy. Furthermore, the results of the 
study will contribute to a better understanding of immune responses to modRNA vaccines in 
siponimod treated SPMS patients. Findings can inform physicians and patients if risk factor 
management may need to be reviewed and potentially give additional guidance for vaccination 
with the novel class of modRNA vaccines in MS patients. 
4.5.1 
Blood sample volume 
A volume smaller than a typical blood donation is planned to be collected over a period of up 
to 9 months, from each participant as part of the study. Additional samples may be required for 
safety monitoring. 
Timings of blood sample collection are outlined in the assessment schedule (Table 8-1). 
A summary blood log is provided in the laboratory manual. Instructions for sample collection, 
processing, storage and shipment information are also available in the laboratory manual. 
Blood samples will be stored until the end of the study in case measurements need to be 
repeated. 
5 
Study Population 
The study population will consist of 60 (optional increase to 90 after first interim analysis) 
females and males at risk for SPMS or with SPMS diagnosis treated in clinical routine with 
either siponimod, a first line MS DMT or no current therapy. 
 
5.1 
Inclusion criteria 
Participants eligible for inclusion in this study must meet all of the following criteria: 
 
1. Signed informed consent must be obtained prior to participation in the study. 
2. One of the following MS treatments as part of clinical routine (according to respective 
SmPC):  
a. Cohort 1: Siponimod treatment according to EU SmPC without interrupting 
daily dosing for the purpose of vaccination with SARS-CoV-2 modRNA  
b. Cohort 2: Siponimod treatment according to EU SmPC interrupting daily 
dosing for the purpose of vaccination with SARS-CoV-2 modRNA  


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c. Cohort 3: Dimethylfumarate, glatirameracetate, interferon, teriflunomide as 
per respective EU SmPC or no current treatment with diagnosis of SPMS or 
with RRMS at risk to develop SPMS (at the discretion of the treating 
physician) 
3. Planning to receive a SARS-CoV-2 modRNA vaccination as part of clinical routine 
4. No change regarding DMT within 4 weeks prior to inclusion to AMA-VACC, i.e. stable 
on current DMT according to dosing within label, no interruption, start or withdrawal of 
DMT in this period of time and no planned switch of DMT within following 2 months 
5. Patients willing and eligible to receive a modRNA vaccine against COVID-19 as part of 
clinical routine 
 
5.2 
Exclusion criteria 
Participants meeting any of the following criteria are not eligible for inclusion in this study. 
 
1. History of COVID-19 
2. SARS-CoV-2 antibodies at screening 
3. Patients likely not being able or willing to complete the study 
4. Use of other investigational drugs within 5 half-lives of enrollment/initiation of study 
treatment (e.g. small molecules) or until the expected pharmacodynamic effect has 
returned to baseline (e.g., biologics), whichever is longer 
5. Patients with any medical or psychological condition that, in the investigators opinion, 
renders the patient unable to understand the nature, scope, and possible consequences of 
the study and who are therefore not able to comply with the requirements of the study and 
capable of giving informed consent 
6. No person directly associated with the administration of the study is allowed to participate 
as a study subject  
7. No family member of the investigational study staff is allowed to participate in this study 
8. Known or suspected clinically relevant allergy, intolerance or hypersensitivity to peanuts, 
soya (only cohort 1 and 2) or to any of the study treatments designated for the individual 
subject (DMTs or mRNA vaccines) or drugs of similar chemical classes (active substance 
or excipients) 
9. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception while 
taking study treatment and for 10 days of study treatment after stopping medication. Highly 
effective contraception methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
participant. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception. 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking study 
treatment. In case of oophorectomy alone, only when the reproductive status of the woman 
has been confirmed by follow up hormone level assessment. 


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• Male sterilization (at least 6 months prior to screening). For female participants on the 
study, the vasectomized male partner should be the sole partner for that participant 
• Use of oral, (estrogen and progesterone), injected, or implanted hormonal methods of 
contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), 
or other forms of hormonal contraception that have comparable efficacy (failure rate 
< 1%), for example hormone vaginal ring or transdermal hormone contraception. 
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment. 
Women are considered post-menopausal and not of child bearing potential if they have had 12 
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with 
or without hysterectomy), total hysterectomy or bilateral tubal ligation at least six weeks ago. 
In the case of oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment is she considered not of child bearing 
potential. 
If local regulations deviate from the contraception methods listed above to prevent pregnancy, 
local regulations apply and will be described in the ICF. 
10. For cohort 3: patients with contraindications for their current MS medication according to 
the respective EU SmPC: 
• Teriflunomide: Patients with severe hepatic impairment (Child-Pugh class C), severe 
immunodeficiency states (e.g. acquired immunodeficiency syndrome), significantly 
impaired bone marrow function or significant anemia, leucopenia, neutropenia or 
thrombocytopenia, severe active infection until resolution, severe renal impairment 
undergoing dialysis or severe hypoproteinaemia (e.g. nephrotic syndrome)  
• Dimethylfumarate: Patients with suspected or confirmed Progressive Multifocal 
Leukoencephalopathy (PML) 
• Interferons: Patients with current severe depression and/or suicidal ideation and 
patients with decompensated liver disease 
 
6 
Treatment 
6.1 
Study treatment 
All study treatment is part of clinical routine. This trial does not interfere with the treatment of 
individual patients. All treatments will be performed according to respective EU SmPCs. 
6.1.1 
Investigational and control drugs 
Table 6-1 merely serves as overview on the different treatments investigated in individual 
cohorts. This is not a guidance for treatment as all treatments are performed as part of clinical 
routine and according to respective EU SmPCs. 
 


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Table 6-1 
Investigational and control drug 
Treatment 
Arm 
Type of Study 
Drug 
Compound 
Min Dose 
Max Dose 
Frequency 
Admin. Route 
Cohort 1 
investigational 
modRNA 
Clinical routine 
(EU SmPC) 
Clinical routine 
(EU SmPC) 
Clinical routine 
(EU SmPC) 
i.m. (EU 
SmPC) 
investigational 
vector vaccine 
Clinical routine 
(EU SmPC) 
Clinical routine 
(EU SmPC) 
Clinical routine 
(EU SmPC) 
i.m. (EU 
SmPC) 
investigational 
siponimod 
1 mg (EU 
SmPC) 
2 mg (EU 
SmPC) 
Daily (EU 
SmPC) 
Oral (EU 
SmPC) 
Cohort 2 
investigational 
modRNA 
Clinical routine 
(EU SmPC) 
Clinical routine 
(EU SmPC) 
Clinical routine 
(EU SmPC) 
i.m. (EU 
SmPC) 
investigational 
vector vaccine 
Clinical routine 
(EU SmPC) 
Clinical routine 
(EU SmPC) 
Clinical routine 
(EU SmPC) 
i.m. (EU 
SmPC) 
investigational 
Siponimod 
treatment 
interrupted 
1 mg 
(treatment 
interruption for 
vaccination) 
(EU SmPC) 
2 mg 
(treatment 
interruption for 
vaccination) 
(EU SmPC) 
Daily (EU 
SmPC) 
Oral (EU 
SmPC) 
 
Cohort 3 
investigational 
modRNA 
Clinical routine 
(EU SmPC) 
Clinical routine 
(EU SmPC) 
Clinical routine 
(EU SmPC) 
i.m. (EU 
SmPC) 
investigational 
vector vaccine 
Clinical routine 
(EU SmPC) 
Clinical routine 
(EU SmPC) 
Clinical routine 
(EU SmPC) 
i.m. (EU 
SmPC) 
investigational 
no treatment or 
first-line 
according 
to 
label 
Clinical routine 
(EU SmPC) 
Clinical routine 
(EU SmPC) 
Clinical routine 
(EU SmPC) 
Clinical routine 
(EU SmPC) 
 
6.1.2 
Supply of study treatment 
All study treatment is part of clinical routine. There will be no supply. 
6.1.3 
Treatment arms 
Participants will be assigned at screening to one of the following “3” treatment arms in a ratio 
of “1:1:1” based on the MS treatment received in clinical routine at this point. There is no 
randomization and no distribution of study drug within the trial. 
• Cohort 1: Siponimod treatment without interrupting daily dosing for the purpose of a 
SARS-CoV-2 modRNA vaccination. In case of a booster vaccination, patients in this cohort 
may undergo a treatment break according to SmPC. 
• Cohort 2: Siponimod treatment interrupting daily dosing (for approximately 2-3 months) 
for the purpose of a SARS-CoV-2 modRNA vaccination  
• Cohort 3: Dimethylfumarate, glatirameracetate, interferon, teriflunomide according to 
respective EU SmPC or no current treatment without a change in treatment for the purpose 
of a SARS-CoV-2 modRNA vaccination 
6.2 
Other treatment(s) 
Not applicable. 


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6.2.1 
Concomitant therapy 
All medications, procedures, and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the participant was enrolled into the study must be 
recorded on the appropriate Case Report Forms. 
No studies have been performed to assess interactions of mRNA vaccines with other drugs or 
other vaccines. 
 
6.2.1.1 
Permitted concomitant therapy requiring caution and/or action 
a) For cohort 1 and 2: 
Antineoplastic, immune-modulating or immunosuppressive therapies 
Siponimod has not been studied in combination with antineoplastic, immune-modulating or 
immunosuppressive therapies. Caution should be exercised during concomitant administration 
due to the risk of additive immune effects during such therapy and in the weeks after 
administration of any of these medicinal products. 
Due to the characteristics and duration of alemtuzumab immune suppressive effects described 
in its product information, initiating treatment with siponimod after alemtuzmab is not 
recommended unless the benefits of treatment clearly outweigh the risks for the individual 
patient. 
Anti-arrhythmic medicinal products, QT-prolonging medicinal products, medicinal products 
that may decrease heart rate 
During treatment initiation siponimod should not be concomitantly used in patients receiving 
class Ia (e.g. quinidine, procainamide) or class III (e.g. amiodarone, sotalol) anti-arrhythmic 
medicinal products, QT-prolonging medicinal products with known arrhythmogenic properties, 
heart-rate-lowering calcium channel blockers (such as verapamil or diltiazem) or other 
substances that may decrease heart rate (e.g. ivabradine or digoxin) because of the potential 
additive effects on heart rate (see section 4.4 of Siponimod SmPC). No data are available for 
concomitant use of these medicinal products with siponimod. Concomitant use of these 
substances during treatment initiation may be associated with severe bradycardia and heart 
block. Because of the potential additive effect on heart rate, treatment with siponimod should 
generally not be initiated in patients who are concurrently treated with these substances (see 
section 4.4 of Siponimod SmPC). If treatment with siponimod is considered, advice from a 
cardiologist should be sought regarding the switch to non-heart-rate-lowering medicinal 
products or appropriate monitoring for treatment initiation. 
Beta blockers 
Caution should be exercised when siponimod is initiated in patients receiving beta blockers due 
to the additive effects on lowering heart rate (see section 4.4 of Siponimod SmPC). Beta-blocker 
treatment can be initiated in patients receiving stable doses of siponimod. The negative 
chronotropic effect of co-administration of siponimod and propranolol was evaluated in a 
dedicated pharmacodynamic/safety study. The addition of propranolol on top of siponimod 
pharmacokinetic/pharmacodynamic steady state had less pronounced negative chronotropic 


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effects (less than additive) in comparison to addition of siponimod on top of propranolol 
pharmacokinetic/pharmacodynamic steady state (additive HR effect). 
Vaccination 
According to the IB the administration of any live or live-attenuated vaccine (including for 
measles) is prohibited while patients are receiving siponimod and for 4 weeks after siponimod 
discontinuation. They may be administered thereafter once there is confirmation that 
lymphocyte levels are in the normal range. 
According to the IB non-live attenuated vaccines may be less effective if administered during 
siponimod treatment (Ufer et al., 2017). The decision whether to continue or pause the treatment 
with siponimod should be based on the benefit-risk assessment of the individual patient. The 
efficacy of vaccination is not considered to be compromised if siponimod treatment is paused 1 
week prior to vaccination until 4 weeks after (see section 4.4 of Siponimod SmPC). 
Potential of other medicinal products to affect siponimod pharmacokinetics  
Siponimod is metabolised primarily by cytochrome P450 2C9 (CYP2C9) (79.3%) and to a 
lesser extent by cytochrome P450 3A4 (CYP3A4) (18.5%). CYP2C9 is a polymorphic enzyme 
and the drug-drug interaction (DDI) effect in the presence of CYP3A or CYP2C9 perpetrator 
drugs is predicted to be dependent on the CYP2C9 genotype.  
CYP2C9 and CYP3A4 inhibitors  
Because of a significant increase in exposure to siponimod, concomitant use of siponimod and 
medicinal products that cause moderate CYP2C9 and moderate or strong CYP3A4 inhibition is 
not recommended. This concomitant drug regimen can consist of a moderate CYP2C9/CYP3A4 
dual inhibitor (e.g. fluconazole) or a moderate CYP2C9 inhibitor in combination with a separate 
moderate or strong CYP3A4 inhibitor.  
The co-administration of fluconazole (moderate CYP2C9/strongCYP3A4 inhibitor) 200 mg 
daily at steady state and a single dose of siponimod 4 mg in healthy volunteers with a 
CYP2C9*1*1 genotype led to a 2-fold increase in the area under the curve (AUC) of siponimod. 
According to evaluation of the drug interaction potential using physiologically based 
pharmacokinetic (PBPK) modelling, a maximum of a 2-fold increase in the AUC of siponimod 
is predicted across genotypes with any type of CYP3A4 and CYP2C9 inhibitors except for 
patients with a CYP2C9*2*2 genotype. In CYP2C9*2*2 patients, a 2.7-fold increase in the 
AUC of siponimod is expected in the presence of moderate CYP2C9/CYP3A4 inhibitors.  
CYP2C9 and CYP3A4 inducers  
Siponimod may be combined with most types of CYP2C9 and CYP3A4 inducers. However, 
because of an expected reduction in siponimod exposure, the appropriateness and possible 
benefit of the treatment should be considered when siponimod is combined:  
- 
with strong CYP3A4/moderate CYP2C9 inducers (e.g. carbamazepine) in all patients 
regardless of genotype.  
- 
with moderate CYP3A4 inducers (e.g. modafinil) in patients with a CYP2C9*1*3 or 
*2*3 genotype.  
A significant reduction of siponimod exposure (by up to 76% and 51%, respectively) is expected 
under these conditions according to evaluation of the drug interaction potential using PBPK 
modelling. The co-administration of siponimod 2 mg daily in the presence of 600 mg daily 


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doses of rifampin (strong CYP3A4 and moderate CYP2C9 inducer) decreased siponimod 
AUCtau,ss and Cmax,ss by 57% and 45%, respectively, in CY2C9*1*1 subjects. 
 
b) For cohort 3:  
Dimethylfumarate 
Tecfidera has not been studied in combination with anti-neoplastic or immunosuppressive 
therapies and caution should, therefore, be used during concomitant administration. In multiple 
sclerosis clinical studies, the concomitant treatment of relapses with a short course of 
intravenous corticosteroids was not associated with a clinically relevant increase of infection. 
Concomitant administration of non-live vaccines according to national vaccination schedules 
may be considered during Tecfidera therapy. In a clinical study involving a total of 71 patients 
with relapsing remitting multiple sclerosis, patients on Tecfidera 240 mg twice daily for at least 
6 months (n=38) or non-pegylated interferon for at least 3 months (n=33), mounted a 
comparable immune response (defined as ≥2-fold increase from pre- to post-vaccination titer) 
to tetanus toxoid (recall antigen) and a conjugated meningococcal C polysaccharide vaccine 
(neoantigen), while the immune response to different serotypes of an unconjugated 23-valent 
pneumococcal polysaccharide vaccine (T-cell independent antigen) varied in both treatment 
groups. A positive immune response defined as a ≥4-fold increase in antibody titer to the three 
vaccines, was achieved by fewer subjects in both treatment groups. Small numerical differences 
in the response to tetanus toxoid and pneumococcal serotype 3 polysaccharide were noted in 
favour of non-pegylated interferon. 
No clinical data are available on the efficacy and safety of live attenuated vaccines in patients 
taking Tecfidera. Live vaccines might carry an increased risk of clinical infection and should 
not be given to patients treated with Tecfidera unless, in exceptional cases, this potential risk is 
considered to be outweighed by the risk to the individual of not vaccinating. 
During treatment with Tecfidera, simultaneous use of other fumaric acid derivatives (topical or 
systemic) should be avoided. 
 
Glatiramer acetate 
Interaction between Copaxone and other medicinal products have not been formally evaluated. 
There are no data on interaction with interferon beta. 
An increased incidence of injection site reactions has been seen in Copaxone patients receiving 
concurrent administration of corticosteroids. 
 
Interferons 
No interaction studies have been performed with interferon beta-1a in humans. 
Interferons have been reported to reduce the activity of hepatic cytochrome P450-dependent 
enzymes in humans and animals. Caution should be exercised when administering e.g. Rebif in 
combination with medicinal products that have a narrow therapeutic index and are largely 


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dependent on the hepatic cytochrome P450 system for clearance, e.g. antiepileptics and some 
classes of antidepressants. 
 
Teriflunomide 
The primary biotransformation pathway for teriflunomide is hydrolysis, with oxidation being a 
minor pathway.  
Potent cytochrome P450 (CYP) and transporter inducers  
Co-administration of repeated doses (600 mg once daily for 22 days) of rifampicin (a CYP2B6, 
2C8, 2C9, 2C19, 3A inducer), as well as an inducer of the efflux transporters P-glycoprotein 
[P-gp] and breast cancer resistant protein [BCRP] with teriflunomide (70 mg single dose) 
resulted in an approximately 40% decrease in teriflunomide exposure. Rifampicin and other 
known potent CYP and transporter inducers such as carbamazepine, phenobarbital, phenytoin 
and St John’s Wort should be used with caution during the treatment with teriflunomide.  
Cholestyramine or activated charcoal  
It is recommended that patients receiving teriflunomide are not treated with cholestyramine or 
activated charcoal because this leads to a rapid and significant decrease in plasma concentration 
unless an accelerated elimination is desired. The mechanism is thought to be by interruption of 
enterohepatic recycling and/or gastrointestinal dialysis of teriflunomide. 
Pharmacokinetic interactions of teriflunomide on other substances  
Effect of teriflunomide on CYP2C8 substrate: repaglinide  
There was an increase in mean repaglinide Cmax and AUC (1.7- and 2.4-fold, respectively), 
following repeated doses of teriflunomide, suggesting that teriflunomide is an inhibitor of 
CYP2C8 in vivo. Therefore, medicinal products metabolised by CYP2C8, such as repaglinide, 
paclitaxel, pioglitazone or rosiglitazone, should be used with caution during treatment with 
teriflunomide.  
Effect of teriflunomide on oral contraceptives: 0.03 mg ethinylestradiol and 0.15 mg 
levonorgestrel  
There was an increase in mean ethinylestradiol Cmax and AUC0-24 (1.58- and 1.54-fold, 
respectively) and levonorgestrel Cmax and AUC0-24 (1.33- and 1.41-fold, respectively) 
following repeated doses of teriflunomide. While this interaction of teriflunomide is not 
expected to adversely impact the efficacy of oral contraceptives, it should be considered when 
selecting or adjusting oral contraceptive treatment used in combination with teriflunomide.  
Effect of teriflunomide on CYP1A2 substrate: caffeine  
Repeated doses of teriflunomide decreased mean Cmax and AUC of caffeine (CYP1A2 
substrate) by 18% and 55%, respectively, suggesting that teriflunomide may be a weak inducer 
of CYP1A2 in vivo. Therefore, medicinal products metabolised by CYP1A2 (such as duloxetin, 
alosetron, theophylline and tizanidine) should be used with caution during treatment with 
teriflunomide, as it could lead to the reduction of the efficacy of these medicinal products.  
Effect of teriflunomide on warfarin  
Repeated doses of teriflunomide had no effect on the pharmacokinetics of S-warfarin, indicating 
that teriflunomide is not an inhibitor or an inducer of CYP2C9. However, a 25% decrease in 


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peak international normalised ratio (INR) was observed when teriflunomide was 
coadministered with warfarin as compared with warfarin alone. Therefore, when warfarin is co-
administered with teriflunomide, close INR follow-up and monitoring is recommended.  
Effect of teriflunomide on organic anion transporter 3 (OAT3) substrates  
There was an increase in mean cefaclor Cmax and AUC (1.43- and 1.54-fold, respectively), 
following repeated doses of teriflunomide, suggesting that teriflunomide is an inhibitor of 
OAT3 in vivo. Therefore, when teriflunomide is coadministered with substrates of OAT3, such 
as cefaclor, benzylpenicillin, ciprofloxacin, indometacin, ketoprofen, furosemide, cimetidine, 
methotrexate, zidovudine, caution is recommended.  
Effect of teriflunomide on BCRP and /or organic anion transporting polypeptide B1 and B3 
(OATP1B1/B3) substrates  
There was an increase in mean rosuvastatin Cmax and AUC (2.65- and 2.51-fold, respectively), 
following repeated doses of teriflunomide. However, there was no apparent impact of this 
increase in plasma rosuvastatin exposure on the HMG-CoA reductase activity. For rosuvastatin, 
a dose reduction by 50% is recommended for coadministration with teriflunomide. For other 
substrates of BCRP (e.g., methotrexate, topotecan, sulfasalazine, daunorubicin, doxorubicin) 
and the OATP family especially HMG-Co reductase inhibitors (e.g., simvastatin, atorvastatin, 
pravastatin, methotrexate, nateglinide, repaglinide, rifampicin) concomitant administration of 
teriflunomide should also be undertaken with caution. Patients should be closely monitored for 
signs and symptoms of excessive exposure to the medicinal products and reduction of the dose 
of these medicinal products should be considered. 
 
6.3 
Participant numbering, treatment assignment, randomization 
6.3.1 
Participant numbering 
Each participant is identified in the study by a Participant Number (Participant No.), that is 
assigned when the participant is enrolled for screening and is retained for the participant 
throughout his/her participation in the trial. The Participant No. consists of the Center Number 
(Center No.) (as assigned by Novartis/Sponsor to the investigative site) with a sequential 
participant number suffixed to it, so that each participant’s participation is numbered uniquely 
across the entire database. Upon signing the informed consent form, the participant is assigned 
to the next sequential Participant No. available. 
6.3.2 
Treatment assignment, randomization 
No randomization will be performed in this study. The assignment of a participant to a particular 
cohort will be coordinated by the sponsor depending on the current MS treatment in clinical 
routine: Cohort 1: continued siponimod treatment without interruption for the purpose of a 
SARS-CoV-2 vaccination (except for a booster vaccination). Cohort 2: interruption of 
siponimod treatment for the purpose of a SARS-CoV-2 vaccination. Cohort 3: first-line MS 
treatment other than siponimod or no current treatment. 


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7 
Informed consent procedures 
Eligible participants may only be included in the study after providing, IRB/IEC-approved 
informed consent. 
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the participant source documents. 
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH GCP guidelines and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed by Novartis before submission to the IRB/IEC. 
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval. 
 
 


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8 
Visit schedule and assessments 
The Assessment Schedule (Table 8-1) lists all of the assessments when they are performed. All 
data obtained from these assessments must be supported in the participant’s source 
documentation. 
Participants should be seen for all visits/assessments as outlined in the assessment schedule 
(Table 8-1) or as close to the designated day/time as possible. Missed or rescheduled visits 
should not lead to automatic discontinuation. Participants who prematurely discontinue the 
study for any reason should be scheduled for a visit as soon as possible, at which time all of the 
assessments listed for the final visit will be performed. At this final visit, the adverse event and 
concomitant medications should be recorded on the CRF. Unscheduled on-site visits are 
possible e.g. to repeat sampling in case of lost or unusable samples, in case of suspected safety 
issues.  Additional telephone visits shall be scheduled in case of booster/refresher SARS-CoV-
2 vaccinations to document type and date of the booster vaccination. Additionally, 1 month (+/-
1 week) after a potential booster vaccination a booster visit will be scheduled that includes all 
assessments performed in the regular study visit 3 including the drawing of blood samples. If 
this booster visit falls within +/-1 week of the regular visit 3 or later than the telephone contact 
in month 12, it will not be performed. 
8.1 
Documentation of IMPs 
Both MS DMTs and SARS-CoV-2 vaccinations are considered as IMPs in this study. As part 
of drug accountability the following documentation of IMP treatment is required to allow a 
valid analysis of immune responses to vaccinations in combination with MS treatment.   
Documentation of MS DMTs 
• At screening 
o Documentation of the current prescription and lot number (Ch-B) of the 
currently applied MS DMT and number of remaining doses in the package. This 
information may also be obtained via telephone. 
• Investigational epoch (Month 1-12 after vaccination) 
o Documentation of all re-newed MS-DMT prescriptions including lot numbers 
(Ch-B) of the medication packages. For this purpose, patients should bring any 
new and empty MS DMT packages (including empty blisters) to the next 
possible study visit for documentation purposes. Ch-B numbers may also be 
obtained via telephone contacts. 
Should patients fail to bring new or empty MS DMT packages and blisters to the study center 
even after documented reminders it is also allowed to calculate the compliance from the interval 
of prescriptions. The compliance as judged by the treating physician shall be documented in the 
eCRF. 
Documentation of SARS-CoV-2 vaccinations 
• Vaccination at external site 
o A scan/copy of the “Impfpass” document  


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o Documentation timepoint of vaccination (date and hour) 
o Documentation which external site performed vaccination 
• Vaccination within clinic but outside study site 
o A scan/copy of the “Impfpass” document  
o Documentation timepoint of vaccination (date and hour) 
o Documentation of department and responsible person for vaccination  
o Confirmation that vaccination was performed according to clinical routine 
o Confirmation that temperature log cannot be obtained 
• Vaccination at study site 
o Preparation of syringes directly after delivery to study site 
▪ Documentation DSL authorization 
▪ Documentation timepoint syringe preparation (to make sure 6h at room 
temperature is not exceeded) 
▪ Documentation temperature log of refrigerator (if used for storage) 
▪ A scan/copy of the “Impfpass” document  
▪ Documentation timepoint of vaccination (date and hour) 
o Preparation of syringes NOT directly after delivery to study site 
▪ Documentation DSL authorization 
▪ Documentation temperature log of refrigerator  
▪ Documentation timepoint syringe preparation (to make sure 6h at room 
temperature is not exceeded) 
▪ A scan/copy of the “Impfpass” document  
▪ Documentation timepoint of vaccination (date and hour) 
 
 
8.2 
Participant demographics/other baseline characteristics 
Anamnesis, participant demographics (year of birth, sex, race) and relevant medical 
history/current medical conditions including MS disease and current treatment will be 
documented. 
All prescription medications, over-the-counter drugs and significant non-drug therapies prior to 
the start and during the study must be documented. See the protocol Section 6.2.1 Concomitant 
Therapy for further details on what information must be recorded on the appropriate page of the 
eCRF. 


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8.3 
Screening 
Re-screening is not permitted. 
8.3.1 
Eligibility screening 
At screening blood sampling and analysis is performed to check for pre-existing SARS-CoV-2 
functional antibodies. If detectable levels are present, the patient is not eligible to further 
participate in the study. Furthermore, SARS-CoV-2 PCR testing will be performed at screening 
to exclude current COVID-19 infection. In case of a positive test result, the patient is sent to 
quarantine and is not eligible to further participate in the study. 
8.3.2 
Information to be collected on screening failures 
Participants who sign an informed consent form and subsequently found to be ineligible will be 
considered a screen failure. The reason for screen failure should be entered on the applicable 
Case Report Form. The demographic information, informed consent, and Inclusion/Exclusion 
pages must also be completed for screen failure participants. No other data will be entered into 
the clinical database for participants who are screen failures, unless the participant experienced 
a serious adverse event during the screening phase (see SAE section for reporting details). 
 


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Table 8-1 
Assessment schedule  
Period 
Screening 
Vaccination# 
Investigational 
COVID-19 
follow-up 
call 
Visit 
Screen 
Vaccination 
1# 
Vaccination 
2# 
1 
2 
3  
 
booster 
vaccinationΩ 
booster 
visitΩ 
Call  
(end of 
study) 
Day/Week/Month 
 Day  
-30 to -3 
Day 1* 
Week 3/4* 
Week +1 
(day 8 +/- 2) 
Month +1 
(day 28-35) 
Month +6 
(week 25-
27) 
any time 
Month +1  
(+/- 1 week) 
after booster 
vaccination 
Month +12 
(week 50-
54) 
Obtain informed consent 
 X 
  
  
  
  
  
 
 
  
Inclusion/exclusion 
criteria 
 X 
  
  
  
  
  
 
 
  
Demography, Relevant 
medical and MS history 
 X 
  
  
  
  
  
 
 
  
Physical exam including 
vital signs, height weight 
 F 
  
  
 S 
S 
 F 
 
 F 
 
SARS-CoV-2 PCR test**  
X 
 
 
 
 
 
 
 
 
Urine pregnancy test*** 
X 
 
 
 
 
X 
 
X 
 
Blood sampling 
 X 
  
  
X 
X 
X 
 
X 
 
MS relapse 
X**** 
X 
X 
X 
X 
X 
X 
X 
 
Status MS- and 
concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Documentation SARS-
CoV-2 vaccination 
 
X 
X 
 
 
 
X 
 
 
Telephone contact 
  
 X 
 X 
  
  
  
 X 
 
 X 
AE/SAE 
X  
 X 
 X 
 X 
 X 
 X 
 X 
 X 
X 
X = assessment to be recorded in the clinical database or received electronically from a vendor 
F = full physical exam, S = short medical exam 
# modRNA vaccination using the same type of compound in both vaccinations independent of study site at designated vaccination centers as part of clinical routine and depending on federal 
regulations; vaccination will be performed according to respective EU SmPC. Booster/refresher vaccinations are allowed in this study, if suggested by local regulations and performed as part 
of clinical routine. ΩIf booster/refresher vaccinations are performed an additional telephone contact is required matching documentation parameters shown above for vaccination 1 and 2. 
ΩFurthermore, an additional study visit will be performed one month (+/- 1 week) after the booster vaccination matching all assessments of investigational visit 3. If this unscheduled visit falls 
within +/-1 week of the regular visit 3 or later than the telephone contact in month 12, it will not be performed. * Number of required vaccinations and interval depends on the SmPC of the 
respective modRNA vaccination. ** Patients need to be sent into quarantine immediately in case of positive test results. Patients in this study are only allowed to continue the study and receive 
SARS-CoV-2 vaccination after they received a negative PCR test result. *** Required minimum of sensitivity of the pregnancy test is HCG 25 mlU/mL. **** MS relapses within the last two 
years should be recorded. 
 


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8.4 
Efficacy 
Pharmacodynamic samples will be collected at the time-points defined in the Assessment 
Schedule (Table 8-1). Follow instructions outlined in the Laboratory manual regarding sample 
collection, numbering, processing, and shipment. 
8.4.1 
Efficacy assessment 1 
SARS-CoV-2 vaccination efficacy is defined as seroconversion i.e. detection of SARS-CoV-2 
serum functional antibodies one week after completion of the vaccination cycle.  
8.4.2 
Efficacy assessment 2 
Additional efficacy assessments are: 
• Longitudinal follow-up of SARS-CoV-2 serum functional antibody levels one week, 
one month and six months after second dose of vaccine and additionally 1 month after 
a potential booster vaccination 
• Longitudinal follow-up of SARS-CoV-2 specific T-cell levels one week, one month and 
six months after second dose of vaccine and additionally 1 month after a potential 
booster vaccination 
8.4.3 
Appropriateness of efficacy assessments 
Efficacy assessments in AMA-VACC are based on the study set up of the phase II clinical trial 
NCT04380701 (EudraCT: 2020-001038-36) for the SARS-COV-2 vaccination candidate 
BNT162b1 (Sahin et al., 2020). This study reports SARS-CoV-2 specific IgG antibodies one 
week after completion of the vaccination cycle at a stable level comparable to a later time-point. 
Similar results were also reported for mRNA-1273 by Jackson et al, 2020. The detection of 
specific antibody levels at one week post completion of the vaccination cycle was therefore 
chosen as primary endpoint.  
Furthermore, BNT162b1 was shown to induce a CD4+ and CD8+ T-cell response (Sahin et al., 
2020). Given the mode of action of siponimod targeting TH17 lymphocytes – a subset of CD4+ 
T-cells - it is of importance to understand the T-cell response to a SARS-CoV-2 vaccination in 
siponimod treated patients. This T-cell response was measured utilizing ex vivo IFNγ enzyme-
linked immunosorbent spot (ELISpot) assays in the clinical development of BNT162b1 (Sahin 
et al., 2020) and was therefore also chosen to assess efficacy in the underlying trial. 
8.5 
Safety 
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed. 
For details on AE collection and reporting, refer to AE section. 
 
 
 


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Assessment 
Specification 
Physical examination 
A complete physical examination will include the examination of 
vital signs (blood pressure [SBP and DBP] and pulse), height, 
weight, general appearance, skin, neck (including thyroid), eyes, 
ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, vascular, and neurological. If indicated based on 
medical history and/or symptoms, rectal, external genitalia, breast, 
and pelvic exams will be performed. 
A short physical exam will include the examination of general 
appearance and vital signs (blood pressure [SBP and DBP] and 
pulse). A short physical exam will be at all visits starting from visit 
3 except where a complete physical examination is required (see 
above).  
Information for all physical examinations must be included in the 
source documentation at the study site. Clinically relevant findings 
that are present prior to signing informed consent must be 
recorded on the appropriate CRF that captures medical history. 
Significant findings made after signing informed consent which 
meet the definition of an Adverse Event must be recorded as an 
adverse event. 
Special clinical laboratory evaluations 
All abnormal lab results must be evaluated for criteria defining an adverse event and reported 
as such if the criteria are met. For those lab adverse events, repeated evaluations are mandatory 
until normalization of the result(s) or until the result is no longer considered to be clinically 
significant. 
 
Test Category 
Test Name 
SARS-CoV-2 vaccination 
antibody response 
Serum functional SARS-CoV-2 antibodies 
SARS-CoV-2 vaccination 
T-cell response 
Ex vivo IFNγ enzyme-linked immunosorbent spot (ELISpot)  
9 
Study discontinuation and completion 
9.1 
Discontinuation and completion 
9.1.1 
Study treatment discontinuation and study discontinuation 
All medication is part of clinical routine.  
Discontinuation of study treatment for a participant occurs when study treatment is stopped 
earlier than the protocol planned duration and can be initiated by either the participant or the 
investigator. 
The investigator must discontinue study treatment for a given participant if, he/she believes that 
continuation would negatively impact the participant's well-being. 


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Study treatment must be discontinued under the following circumstances: 
• Participant/guardian decision 
• Pregnancy 
• Use of prohibited treatment as per recommendations in the prohibited treatment section 
• New medical condition not allowing for continuation of study treatment 
• Any situation in which study participation might result in a safety risk to the participant 
• Adverse events, abnormal laboratory values or abnormal test result that indicate a safety 
risk to the participant. 
 
Study discontinuation of a participants occurs under the following circumstances: 
• Significant non-compliance 
• Retroactive failure to fulfil inclusion/exclusion criteria 
• Enrolment in any other clinical trial involving an investigational product or enrolment in 
any other type of medical research judged not to be scientifically or medically compatible 
with this study 
Participants who decide they do not wish to participate in the study further should NOT be 
considered withdrawn from the study UNLESS they withdraw their consent (see Section 9.1.2 
'Withdrawal of Informed Consent' section). Where possible, they should return for the 
assessments indicated in the Assessment Schedule. If they fail to return for these assessments 
for unknown reasons, every effort (e.g. telephone, e-mail, letter) should be made to contact the 
participant/pre-designated contact as specified in the lost to follow-up section. This contact 
should preferably be done according to the study visit schedule. 
Patients completing the vaccination cycle but do not come to the center for the blood draw one 
week later (6-10 days after second vaccination) will be excluded from the study. 
9.1.1.1 
Replacement policy 
Patients failing the screening visit (detectable levels of SARS-CoV-2 serum functional 
antibodies) will be replaced. Patients successfully screened who do not receive a mod-RNA 
SARS-CoV-2 vaccination according to EU SmPC within 1 month after screening will be 
excluded from the study and replaced unless the patient is currently not eligible for SARS-CoV-
2 vaccination by local regulation. In this case, the Novartis Medical Advisor should be contacted 
to discuss further proceeding including re-evaluation of anti-SARS-CoV-2 antibody level and 
PCR test. Patients developing symptoms of COVID-19 or have a SARS-CoV-2 infection 
(positive test result) between screening and first vaccination will be excluded from the study 
and will be replaced. 
 
 


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9.1.2 
Withdrawal of informed consent 
Participants may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a participant: 
• Does not want to participate in the study anymore, 
and 
• Does not want any further visits or assessments 
and 
• Does not want any further study related contacts 
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the participant’s decision to withdraw his/her consent and 
record this information. 
Where consent to the use of personal and coded data is not required, participant therefore cannot 
withdraw consent. They still retain the right to object to the further use of personal data. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the participant are not allowed unless safety findings require 
communicating or follow-up. 
All efforts should be made to complete the assessments prior to study discontinuation. A final 
evaluation at the time of the participant’s study discontinuation should be made as detailed in 
the assessment table. 
Novartis will continue to retain and use all research results (data) that have already been 
collected for the study evaluation. 
9.1.3 
Lost to follow-up 
For participants whose status is unclear because they fail to appear for study visits without 
stating an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the participant, e.g. dates of 
telephone calls, registered letters, etc. A participant should not be considered as lost to follow-
up until due diligence has been completed. 
9.1.4 
Early study termination by the sponsor 
The study can be terminated by Novartis at any time. 
Reasons for early termination: 
• Unexpected, significant, or unacceptable safety risk to participants enrolled in the study 
• Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data 
In taking the decision to terminate, Novartis will always consider participant welfare and safety. 
Should early termination be necessary, participants must be seen as soon as possible and treated 
as a prematurely withdrawn participant. The investigator may be informed of additional 


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procedures to be followed in order to ensure that adequate consideration is given to the 
protection of the participant’s interests. The investigator or sponsor depending on local 
regulation will be responsible for informing IRBs/IECs of the early termination of the trial.  
9.2 
Study completion and post-study treatment 
Study completion is defined as when the last participant finishes their Study Completion visit 
and any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator or, in the event of an early study termination decision, the date 
of that decision.  
All patients in the present study are treated as part of the clinical routine. The interventional 
character of the study is limited to collection and analysis of blood samples.  
There is no plan for further treatment and medical care for the study participants after the end 
of the clinical trial. After completion, all study participants regardless of the reasons will 
continue to be cared for as part of the clinical routine and further treatment will be discussed 
individually with investigator. 
10 
Safety monitoring and reporting 
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical 
investigation participant after providing written informed consent for participation in the study. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 
The investigator has the responsibility for managing the safety of individual participant and 
identifying adverse events. 
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 
The occurrence of adverse events must be sought by non-directive questioning of the participant 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the participant during or between visits or through physical examination findings, laboratory 
test findings, or other assessments. 
Adverse events must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2): 
1. The Common Toxicity Criteria (CTC) AE grade (version 5 or higher):  
Adverse events will be assessed and graded according to the Common Terminology Criteria for 
Adverse Events (CTCAE) version. CTCAE grade 5 will be used to capture death information 
within the eCRF.  


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2. Its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e. progression of the study indication) the assessment of causality 
will usually be ‘Not suspected.’ The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single participant 
3. Its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported 
4. Whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met 
5. Action taken regarding with study treatment.  
All adverse events must be treated appropriately. Treatment may include one or more of the 
following: 
• Dose not changed 
• Dose Reduced/increased 
• Drug interrupted/withdrawn 
6. Its outcome (i.e. recovery status or whether it was fatal) 
 
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the participant. 
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. 
Adverse event monitoring should be continued for at least 30 days following the last study visit 
(Covid-19 follow-up call). 
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g. continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome. 
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator's Brochure (IB). 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
• they induce clinical signs or symptoms 
• they are considered clinically significant 
• they require therapy 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in participant 
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10.1.2 
Serious adverse events 
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s), or medical conditions(s) which meets any one of the following 
criteria: 
• fatal 
• life-threatening 
Life-threatening in the context of a SAE refers to a reaction in which the participant was at risk 
of death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines). 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:  
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition  
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• social reasons and respite care in the absence of any deterioration in the participant’s 
general condition 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• is medically significant, e.g. defined as an event that jeopardizes the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the participant or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” 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 dependency or abuse (please refer to the ICH-
E2D Guidelines). 
All new malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.  
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred.  
10.1.3 
SAE reporting 
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until 30 days after the last study visit must be reported to 


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Novartis safety immediately, without undue delay but not later than within 24 hours of learning 
of its occurrence. Detailed instructions regarding the submission process and requirements are 
to be found in the investigator folder provided to each site. 
 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
immediately, without undue delay but not later than within 24 hours of the investigator 
receiving the follow-up information. An SAE occurring at a different time interval or otherwise 
considered completely unrelated to a previously reported one must be reported separately as a 
new event. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a CMO & PS Department 
associate may urgently require further information from the investigator for health authority 
reporting.  Novartis may need to issue an Investigator Notification (IN) to inform all 
investigators involved in any study with the same study treatment that this SAE has been 
reported. 
Every SAE occurring to a subject after completion of the clinical trial has to be reported to the 
sponsor by the investigator if it is suspected to be causally related to the investigation product. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries. 
 
10.1.4 
Pregnancy reporting 
Pregnancies 
If a female trial participant becomes pregnant, the study treatment should be stopped, and the 
trial participant must be asked to read and sign pregnancy consent form to allow the Study 
Doctor ask about her pregnancy. To ensure participant safety, each pregnancy occurring after 
signing the informed consent must be reported to Novartis within 24 hours of learning of its 
occurrence. The pregnancy should be followed up to determine outcome, including spontaneous 
or voluntary termination, details of the birth, and the presence or absence of any birth defects, 
congenital abnormalities, or maternal and/or newborn complications. 
Pregnancy should be recorded and reported by the investigator to the Novartis Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to the investigational study 
treatmentany pregnancy outcome. Any SAE experienced during pregnancy must be reported. 
10.1.5 
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, participant or 
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Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects. 
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE and reported to 
Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
Investigator’s awareness. 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse 
Treatment error type 
Document in Dosing 
CRF (Yes/No) 
Document in AE 
eCRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes 
Only if associated with 
an AE 
Only if associated with 
an SAE 
Misuse/Abuse 
Yes 
Yes 
Yes, even if not 
associated with a SAE 
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections. 
11 
Data Collection and Database management 
11.1 
Data collection 
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements, Investigator site staff will not 
be given access to the EDC system until they have been trained. Automatic validation programs 
check for data discrepancies in the eCRFs, allow modification and/or verification of the entered 
data by the investigator staff. 
The investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate. 
After final database lock, the investigator will receive copies of the participant data for 
archiving at the investigational site. 
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification. 
11.2 
Database management and quality control 
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 


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investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. 
11.3 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e. eSource DDE or 
eCRFs) with the investigators and their staff. During the study, Novartis employs will apply 
several methods of ensuring protocol and GCP compliance and the quality/integrity of the sites’ 
data. The field monitor will visit the site to check the completeness of participant records, the 
accuracy of data capture / data entry, the adherence to the protocol and to Good Clinical 
Practice, the progress of enrollment. For this clinical trial, it will specifically be verified that 
patients have received a permitted SARS-CoV-2 mRNA vaccine during initial vaccination 
cycle by checking the patient’s vaccination certificate. As this study aims at resembling the 
clinical routine as closely as possible, field monitors will confirm the patients’ treatment 
adherence during on site monitoring visits by verifying the continuous prescription of the 
respective MS drug (prescription records or equivalent sources). Key study personnel must be 
available to assist the field monitor during these visits.  Additionally, a central analytics 
organization may analyze data & identify risks & trends for site operational parameters, and 
provide reports to Novartis clinical teams to assist with trial oversight. 
The investigator must maintain source documents for each participant in the study, consisting 
of case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
participant's file.  The investigator must also keep the original informed consent form signed by 
the participant (a signed copy is given to the participant). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
participants will be disclosed. 
12 
Data analysis and statistical methods 
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation. 


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12.1 
Analysis sets 
For all analysis sets, participants will be analyzed according to the study treatment(s) received.  
The safety analysis set will include all participants that received any study drug. 
The efficacy analysis sets at one week, one month and six month and additionally after a 
potential booster vaccination respectively will include all participants who have a valid 
determination of functional antibodies to SARS-CoV-2 at that time point plus those who failed 
to receive their second dose of vaccine for whatever reason. The latter will be counted as non-
responders. Patients completing vaccination but fail to provide a blood sample at one week after 
the second vaccination will be excluded from the study and analysis. 
12.2 
Participant demographics and other baseline characteristics 
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively by treatment group (Cohort 1-3) for the FAS. 
The Safety set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation, median, minimum, 
and maximum will be presented. 
For Cohort 1, the continued siponimod intake after vaccination will be presented. For Cohort 2 
the duration of discontinuation (time between last prior to vaccination and first dose after 
vaccination will be summarized. For Cohort 3, the various base DMTs will be summarized 
(type, doses and duration) as appropriate.  
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system, by cohort. 
12.3 
Analysis of the primary endpoint 
The primary clinical question in this trial is: what is the proportion of SPMS patients treated 
with siponimod within the tree cohorts defined below which mount an immune response to a 
SARS-CoV-2 modRNA vaccine? 
12.3.1 
Definition of primary endpoint(s)/estimand(s) 
The primary endpoint of the study is the proportion of participants achieving seroconversion as 
defined by detection of SARS-CoV-2 serum functional antibodies one week after second dose 
of vaccine in participants treated concomitantly with siponimod and siponimod treatment break 
(yes/no). 
12.3.2 
Statistical model, hypothesis, and method of analysis 
The primary analysis will not use any statistical testing or modelling. The absolute numbers and 
the proportion of participants achieving seroconversion within each cohort will be calculated. 
It will be augmented by a (descriptive) 95% confidence interval (exact Clopper-Pearson). 


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12.3.3 
Handling of remaining intercurrent events of primary estimand 
Patients who fail to receive their second dose of vaccine for whatever reason will be included 
in the analysis as non-responders. Patients who did receive their second dose of vaccine and do 
not have a valid determination of functional antibodies to SARS-CoV-2 for whatever reason 
will be excluded from the analysis of vaccine efficacy. 
12.3.4 
Supportive analyses 
Patient demographics and baseline characteristics among 3 cohorts will be compared in the data 
analysis. Also the treatment interruption time of the selected cohort 2 patients will be compared 
to that of other siponimod treated patients in AMASIA interrupting daily dosing as per label for 
the purpose of vaccination with SARS-CoV-2 modRNA as part of clinical routine. If major 
imbalance is discovered, the study results will be interpreted with more caution and post-hoc 
supportive analyses may be conducted to adjust for the imbalance. 
12.4 
Analysis of secondary endpoints 
All secondary endpoints will be summarized descriptively as frequencies and percentages, or, 
for continuous data, mean, standard deviation, median, minimum, and maximum will be 
presented. 
 
12.4.1 
Safety endpoints 
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
cohort. 
Safety summaries (tables, figures) include only data from the on-treatment period which will 
also be summarized where appropriate (e.g. change from baseline summaries). In addition, a 
separate summary for death including on treatment and post treatment deaths will be provided. 
In particular, summary tables for adverse events (AEs) will summarize only on-treatment 
events, with a start date during the on-treatment period (treatment-emergent AEs). 
The on-treatment period lasts from the date of first administration of study treatment to 30 days 
after the month 12 COVID-19 follow-up call. 
Adverse events 
All information obtained on adverse events will be displayed by cohort. 
The number (and percentage) of participants with treatment emergent adverse events (events 
started after the first dose of study medication or events present prior to start of double-blind 
treatment but increased in severity based on preferred term) will be summarized in the following 
ways: 
• by cohort, primary system organ class and preferred term. 
• by treatment, primary system organ class, preferred term and maximum severity. 


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Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events, other significant adverse events leading to discontinuation, and adverse events 
leading to dose adjustment. 
A participant with multiple adverse events within a primary system organ class is only counted 
once towards the total of the primary system organ class. 
Vital signs 
All vital signs data will be listed by treatment group, participant, and visit/time and if ranges 
are available, abnormalities (and relevant orthostatic changes) will be flagged. Summary 
statistics will be provided by treatment and visit/time. 
Clinical laboratory evaluations 
All laboratory data will be listed by treatment group (cohort 1-3), participant, and visit/time and 
if normal ranges are available abnormalities will be flagged. Summary statistics will be 
provided by treatment and visit/time.  
12.5 
Interim analyses 
An interim analysis will be performed when all participants have completed study visit 1 (one 
week after SARS-CoV-2 vaccination cycle completion) as this reflects the primary endpoint. 
As all analyses in this study are purely descriptive, there is no need for any statistical 
adjustments. Additional interim analyses may be conducted to support decision making 
concerning the current clinical study including an increase in participants (from 60 to 90), the 
sponsor’s clinical development projects in general, or in case of any safety concerns. 
12.6 
Sample size calculation 
12.6.1 
Primary endpoint(s) 
The sample size of 20 participants per arm is selected based on need for early availability of 
results for the current covid-19 pandemic and the feasibility to recruit sufficient participants 
from AMASIA and PANGAEA 2.0 EVOLUTION. This sample size of 20 subjects will provide 
estimates of proportion responded with margin of error (half-width of a 95% confidence 
interval) of 20.1%, 19%, and 17.5% corresponding to response rates of 70%, 75%, and 80%, 
respectively. Adjusting for 10% drop-out, 22 subjects will be enrolled in each arm. In case of 
fast recruitment the sponsor is allowed to increase sample size in each arm by up to 10 additional 
patients to support the generation of meaningful data in a larger sample size.   
13 
Ethical considerations and administrative procedures 
13.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki. 


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13.2 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, participant recruitment procedures (e.g., 
advertisements) and any other written information to be provided to participants. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made. 
13.3 
Publication of study protocol and results 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT 
etc.). 
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings. 
13.4 
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines. 
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach. 
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes. 
14 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of participants should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 


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Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC and Health Authorities, where required, it cannot be 
implemented. 
14.1 
Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. 
Only amendments that are required for participant safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any participant included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations. 


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15 
References 
References are available upon request 
Behrangi et al (2019) Mechanism of Siponimod: Anti-Inflammatory and Neuroprotective 
Mode of Action, Cells. 8(1): 24 
Farez MF, Correale J, Armstrong MJ, et al. (2019) Practice guideline update summary: 
Vaccine-preventable infections and immunization in multiple sclerosis: Report of the 
Guideline Development, Dissemination, and Implementation Subcommittee of the American 
Academy of Neurology. Neurology 93(13):584-594 
German ministry of health, 
https://www.bundesgesundheitsministerium.de/fileadmin/Dateien/3_Downloads/C/Coronavir
us/Impfstoff/Nationale_Impfstrategie.pdf ; last accessed on November 17th, 2020 
Jackson et al., (2020) An mRNA Vaccine against SARS-CoV-2 - Preliminary Report, N Eng J 
Med. p383(20):1920-1931. 
Lindsey R. Baden, M.D., Hana M. El Sahly, M.D., Brandon Essink, M.D., Karen Kotloff, 
M.D., Sharon Frey, M.D., Rick Novak, M.D., David Diemert, M.D., Stephen A. Spector, 
M.D., Nadine Rouphael, M.D., C. Buddy Creech, M.D., John McGettigan, M.D., Shishir 
Khetan, M.D., et al. for the COVE Study Group (2021). “Efficacy and Safety of the mRNA-
1273 SARS-CoV-2 Vaccine” N Engl J Med. DOI: 10.1056/NEJMoa2035389 
Sahin et al (2020) COVID-19 vaccine BNT162b1 elicits human antibody and TH1 T cell 
responses, Nature volume 586, pages594–599 
Ufer et al (2017) Impact of siponimod on vaccinationresponse in a randomized,placebo-
controlled study, Neurol Neuroimmunol Neuroinflamm 13;4(6):e398. 
Polack, F. P., S. J. Thomas, N. Kitchin, J. Absalon, A. Gurtman, S. Lockhart, J. L. Perez, G. 
Perez Marc, E. D. Moreira, C. Zerbini, R. Bailey, K. A. Swanson, S. Roychoudhury, K. Koury, 
P. Li, W. V. Kalina, D. Cooper, R. W. Frenck, Jr., L. L. Hammitt, O. Tureci, H. Nell, A. 
Schaefer, S. Unal, D. B. Tresnan, S. Mather, P. R. Dormitzer, U. Sahin, K. U. Jansen, W. C. 
Gruber and C. C. T. Group (2020). "Safety and Efficacy of the BNT162b2 mRNA Covid-19 
Vaccine." N Engl J Med. 
Press 
release 
BioNTech: 
https://investors.biontech.de/news-releases/news-release-
details/pfizer-and-biontech-announce-vaccine-candidate-against-covid-19; last accessed on 
Nov 17th, 2020 
Product information Siponimod: https://www.ema.europa.eu/en/documents/product-
information/mayzent-epar-product-information_en.pdf ; last accessed 30-Nov-2020 
Walsh EE, Frenck RW, et al., Safety and Immunogenicity of Two RNA-Based Covid-19 
Vaccine Candidates. New Eng J Med. 2020. DOI: 10.1056/NEJMoa2027906 
WHO guideline: 
https://www.who.int/biologicals/expert_committee/Clinical_changes_IK_final.pdf; last 
accessed on Dec 7th, 2020 


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Yang et al (2020) Molecular interaction and inhibition of SARS-CoV-2 binding to the ACE2 
receptor, Nature communications, Article number: 4541 (2020) 
 

SAP_001.pdf: 
Clinical Development 
Mayzent® 
CBAF312ADE03 / NCT04792567 
An open-label multicenter study to assess response to 
SARS-CoV-2 modRNA vaccines in participants with 
secondary progressive multiple sclerosis treated with 
Mayzent (siponimod) (AMA-VACC)  
Statistical Analysis Plan (SAP) 
Author: 
Trial Statistician, 
 
Clinical Trial Head, Dr.
CRO Statistician,
 
Document type: 
SAP Documentation 
Document status: 
Final 3.0 
Release date: 
26-SEP-2022
Number of pages: 
16 
Property of Novartis 
For business use only 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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Document History – Changes compared to previous final version of SAP 
 
Date 
Time point 
Reason for 
update 
Outcome for update 
Section and 
title impacted 
(Current) 
12-
APR-
2021 
Prior to 
FPFV 
Creation of 1st 
draft version 
(0.1) 
For Sponsor review 
NA 
20-
APR-
2021 
Prior to 
FPFV 
Creation of 
2ndt draft 
version (0.2) 
After Sponsor review 
NA 
29-
APR-
2021 
Prior to first 
patient first 
vaccination 
First final 
version 
Finalization 
NA 
09-
FEB-
2022 
After data 
review for 2nd 
interim 
analysis 
CSP 
Amendment  
Data Review 
Analyses of FACS data (CD4+ and 
CD8+ cell etc) added 
Subgroup analysis for patients 
with/without booster vaccination added 
 
26-
SEP-
2026 
After final 
data review  
Modification 
of Efficacy 
Analysis Set 
To avoid that patients with non-
missing secondary efficacy parameters 
are excluded from efficacy analysi set 
 
Signature Page 
 
 
 
 
Clinical Trial Leader) 
 
 
 
 
 
 
 
Trial Statistican 
 
 
 
 
 
 
 
CRO Statistican 


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Table of contents 
Signature Page ............................................................................................................................ 2 
Table of contents ................................................................................................................. 3 
List of abbreviations ............................................................................................................ 5 
1 
Introduction ......................................................................................................................... 6 
1.1 
Study design............................................................................................................. 6 
1.2 
Study objectives and endpoints ............................................................................... 6 
2 
Statistical methods ............................................................................................................... 7 
2.1 
Data analysis general information ........................................................................... 7 
2.1.1 
General definitions .................................................................................. 7 
2.2 
Analysis sets ............................................................................................................ 8 
2.2.1 
Subgroup of interest ................................................................................ 8 
2.3 
Patient disposition, demographics and other baseline characteristics ..................... 8 
2.3.1 
Patient disposition ................................................................................... 8 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance) .............................................................................................................. 9 
2.4.1 
Study treatment / compliance .................................................................. 9 
2.4.2 
Prior, concomitant and post therapies ..................................................... 9 
2.5 
Analysis of the primary objective ............................................................................ 9 
2.5.1 
Primary endpoint ..................................................................................... 9 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 10 
2.5.3 
Handling of missing values/censoring/discontinuations ....................... 10 
2.5.4 
Supportive analyses ............................................................................... 11 
2.6 
Analysis of the key secondary objective ............................................................... 11 
2.7 
Analysis of secondary efficacy objective(s) .......................................................... 11 
2.7.1 
Secondary endpoints ............................................................................. 11 
2.7.2 
Statistical hypothesis, model, and method of analysis .......................... 12 
2.7.3 
Handling of missing values/censoring/discontinuations ....................... 12 
2.8 
Safety analyses ....................................................................................................... 12 
2.8.1 
Adverse events (AEs) ............................................................................ 12 
2.8.2 
Deaths .................................................................................................... 13 
2.8.3 
Laboratory data ..................................................................................... 13 
2.8.4 
Other safety data ................................................................................... 13 
2.9 
Pharmacokinetic endpoints .................................................................................... 13 
2.10 
PD and PK/PD analyses......................................................................................... 13 
2.11 
Patient-reported outcomes ..................................................................................... 13 
2.12 
Biomarkers ............................................................................................................. 13 


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2.13 
Other Exploratory analyses .................................................................................... 13 
2.14 
Interim analysis ...................................................................................................... 13 
3 
Sample size calculation ..................................................................................................... 13 
4 
Change to protocol specified analyses .............................................................................. 14 
5 
Appendix ........................................................................................................................... 14 
5.1 
Imputation rules ..................................................................................................... 14 
5.2 
Treatment-emergent adverse events ...................................................................... 14 
5.3 
Statistical models ................................................................................................... 15 
5.3.1 
Primary analysis .................................................................................... 15 
5.3.2 
Key secondary analysis ......................................................................... 15 
5.4 
Rule of exclusion criteria of analysis sets.............................................................. 15 
6 
Reference ........................................................................................................................... 16 


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List of abbreviations 
AE 
Adverse event 
ATC 
Anatomical Therapeutic Classification 
CI 
Confidence interval 
CSP 
Clinical Study Protocol 
CSR 
Clinical Study Report 
CV 
Coefficient of variation 
eCRF 
Electronic Case Report Form 
DMT 
Disease modifying therapy 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
MS 
Multiple sclerosis 
RAP 
Report and Analysis Process 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
SmPC 
Summary of Procduc Characteristics 
TFLs 
Tables, Figures, Listings 
WHO 
World Health Organization 
 


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1 
Introduction 
This Statistical Analysis Plan (SAP) describes how the statistical analyses of this study will be 
implemented. Based on the tables/listings/figures (TFL) of resulting from this SAP the Clinical 
Study Report (CSR) will be written. The TFLs will be attached in section 14 of the CSR. 
In addition this SAP describes which patient Data Listings to be attached in section 16.2.1 of 
the CSR will be generated. 
This SAP is not used for other analyses or studies. 
It is based on the Study Protocol (CSP), version 02, dated 25th Sep 2021 (2nd Amendment) 
1.1 
Study design 
This is a three-cohort, multicenter, open-label, prospective study of 60 patients suffering from 
multiple sclerosis (MS) currently treated with siponimod or a first-line disease modifying drug 
(DMT) or without MS treatment planning to undergo a SARS-CoV-2 modRNA vaccination as 
part of clinical routine and according to the respective SmPC.  
MS treatments as part of clinical routine: 
• Cohort 1: Siponimod treatment according to EU SmPC without interrupting daily dosing 
for the purpose of vaccination with SARS-CoV-2 modRNA 
• Cohort 2: Siponimod treatment according to EU SmPC interrupting daily dosing for the 
purpose of vaccination with SARS-CoV-2 modRNA 
• Cohort 3: Dimethylfumarate, glatirameracetate, interferon, teriflunomode as per 
respective EU SmPC or no current treatment with diagnosis of SPMS or with RRMS at 
risk to develop SPMS (at the discretion of the treating physician) 
An interim analysis is planned after all participants have completed the study at one week after the 
end of the SARS-CoV-2 vaccination cycle in the study. The week +1 data regarding antibody and 
T-cell response (along with relevant safety data) will be examined as a preliminary evaluation of 
proof of concept and are the basis for the primary endpoint of the study. 
The primary analysis time point is when all participants have completed the study visit 6 months 
after the end of the SARS-CoV-2 vaccination cycle in the study. 
A follow-up analysis is planned after all participants have completed the follow-up visit 12 
months.  
1.2 
Study objectives and endpoints 
 
Objective(s)  
 
Endpoint(s)  
Primary Objective(s)  
• To estimate the proportion of those 
achieving seroconversion (i.e. having 
SARS-CoV-2 serum functional 
antibodies) after receiving a modRNA 
Endpoint(s) for primary objective(s)  
Proportion of participants achieving 
seroconversion as defined by detection of SARS-
CoV-2 serum functional antibodies one week after 
second dose of vaccine in participants treated 


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vaccine in participants treated 
concomitantly with siponimod and 
siponimod treatment break.  
 
concomitantly with siponimod and siponimod 
treatment break (yes/no)  
Secondary Objective(s)  
• Describing SARS-CoV-2 serum 
functional antibody levels in 
participants treated concomitantly with 
siponimod versus siponimod treatment 
break versus first-line DMTs and in 
patients currently not on a DMT  
• Describing the T-cell response to 
modRNA vaccines in participants 
treated concomitantly with siponimod 
versus siponimod treatment break 
versus first-line DMTs and in patients 
currently not on a DMT  
• Describing safety, incl. AEs related to 
discontinuation and new onset of 
siponimod treatment and patients 
developing COVID-19  
 
Endpoint(s) for secondary objective(s)  
• SARS-CoV-2 serum functional antibody levels 
one week, one month and six months after second 
dose of vaccine in participants treated 
concomitantly with siponimod versus siponimod 
treatment break versus first-line DMTs and in 
patients currently not on a DMT  
• SARS-CoV-2 specific T-cell levels one week, 
one month and six months after second dose of 
vaccine in participants treated concomitantly with 
siponimod versus siponimod treatment break 
versus first-line DMTs and in patients currently 
not on a DMT measured by e.g. enzyme-linked 
immunosorbent spot (ELIspot) assay from 
peripheral blood mononuclear cells that were 
stimulated with SARS-CoV-2 peptide mix  
• AEs, SAEs, incl. patients with clinical 
confirmed COVID-19, events leading to 
discontinuation in participants treated 
concomitantly with siponimod versus siponimod 
treatment break versus first-line DMTs and in 
patients currently not on a DMT.  
2 
Statistical methods 
2.1 
Data analysis general information 
Data analysis will be performed by the CRO 
. The software SAS, 
version 9.2 or higher is used. 
According to the small sample size of this study, percentages are presented without decimal 
places, i.e. as integers without digits. 
2.1.1 
General definitions  
Study treatments 
The modRNA vaccine and the treatment for MS are defined both as study treatments. More 
specifically, the MS treatment is established as study treatment from the time of informed 
consent. 


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Screening failure 
A screening failure is a patient not eligible for the study. Screening failures are identified by:  
- any inclusion criterion is violated or 
- 
Any exclusion criterion applies or 
- 
Patient was not vaccinated with a mRNA-vaccine or different mRNA-vaccines. 
2.2 
Analysis sets 
For all analysis sets, participants will be analyzed according to the study treatment(s) received. 
The safety analysis set (SAF) will include all participants that received any study drug. 
The efficacy analysis set will include all participants who have a valid primary endpoint (i. e. 
determination of functional antibodies to SARS-CoV-2 at Visit 2 / Week 1) plus those who 
failed to receive their second dose of vaccine for whatever reason1. 
2.2.1 
Subgroup of interest 
Not applicable, no subgroup will be investigated. 
2.3 
Patient disposition, demographics and other baseline 
characteristics 
Demographic and other baseline data including disease characteristics will be summarized 
descriptively by treatment group (Cohort 1-3) for the SAF and efficacy analysis set at Week 1. 
If major imbalance in relevant demographic or other baseline charateristics are discovered, the 
study results will be interpreted with more caution and post-hoc supportive analyses may be 
conducted to adjust for the imbalance. 
2.3.1 
Patient disposition 
Patient disposition displays the absolute and relative frequency of screening failures, the 
number of patients included in the different analysis sets.  
The reasons for screening failure, for missed study visits, for exclusion from analysis 
populations and for prematurely drop-out are described by frequency tables as well as protocol 
deviations. 
The duration of intervals between study visits are displayed by sample statistics. The interval 
from screening to first vaccination is analyzed by a frequency table for ≤30 days versus >30 
days. 
 
Not applicable, because all patients received their second dose of study vaccine 


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2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.4.1 
Study treatment / compliance 
The absolute and relative frequency of performed study visits and performed vaccinations are 
presented. Sample statistics for the duration of intervals between screening and date of 1st 
vaccination, date of 1st and 2nd vaccination and date 2nd vaccination to Visit 1/Week 1 are 
displayed. The interval from the 2nd Vaccination to Visit 1/Week 1, Visit2 /Month 1 and 
Visit 3/Month 6 are also displayed by sample statistics. Here always the exact date of the 
respective vaccination is used but not the date of study visit called “Vaccination 1” or 
“Vaccination 2” which displays the date of phone contact with the patient. 
Two types of investigational study drugs are used in this study: 
1. Study medication for treatment of MS 
2. Study medication for vaccination 
The study medication for treatment of MS is displayed by frequencies for type of medication 
(cohort 3 only), sample statistics for duration of treatment prior to screening (cohort 1 and 3) 
and frequencies of dose changes, interruptions, or discontinuation until Visit 1, 2, and 3 
respectively (cohort1 and 3). For cohort 2 the duration of siponimod interruption (i. e. the time 
between last dose prior to vaccination and the fist dose after vaccination) is displayed by sample 
statistics.   
The different vaccines are displayed by a frequency table separately for 1st and 2nd vaccination. 
2.4.2 
Prior, concomitant and post therapies 
The number and types of all pretreatments for MS prior to screening are displayed. Here, the 
current MS-therapy (i. e. starting before screening and ongoing after screening) is not included 
into counts. 
The last disease modifying drug before siponimod (cohort 1 and 2) or the last study medication 
of cohort 3 is displayed in a frequency table.  
Concomitant medications are coded by WHO Drug-dictionary. Frequencies of Anatomic 
Therapeutical Chemical (ATC) categories and Preferred Names are presented. Here, a 
medication with multiple entries is counted only once in a ATC category respectively a 
preferred name category. 
2.5 
Analysis of the primary objective 
2.5.1 
Primary endpoint 
The primary clinical question in this trial is: what is the proportion of SPMS patients treated with 
siponimod within the three cohorts which mount an immune response to a SARS-CoV-2 modRNA 
vaccine?  
The primary endpoint of the study is the proportion of participants achieving seroconversion as 
defined by detection of SARS-CoV-2 serum functional antibodies one week after second dose of 


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vaccine in participants treated concomitantly with siponimod and siponimod treatment break 
(yes/no). 
Of note, this is not a randomized trial, therefore no randomization needs to be preserved and the 
ITT-principle and the associated estimands framework do not apply. However, this protocol will 
keep as close as appropriate to the terminology and the definitions established within that 
framework. 
The justification for the primary estimand is that it will capture whether siponimod treated 
participants generate functional antibodies to SARS-CoV-2 vaccine as assessed by geometric mean 
titers and arithmetic mean for percent inhibition (semiquantitative).  
The following attributes describe the primary estimand:  
• Population: MS patients divided in three cohorts, each receiving a SARS-CoV-2 vaccination 
as part of clinical routine: (1) vaccination during continued siponimod treatment; (2) 
vaccination during a siponimod treatment interruption (of approx. 2-3 months); (3) vaccination 
in MS patients during continued treatment with first-line DMTs or no DMT. Patients who fail 
to receive their second dose of vaccine for whatever reason will be included in the analysis as 
non-responders. Patients who did receive their second dose of vaccine and do not have a valid 
determination of functional antibodies to SARS-CoV-2 for whatever reason will be excluded 
from the analysis of vaccine efficacy.  
• Variable: Receiving the second dose of vaccine and achieving seroconversion as defined by 
detection of SARS-CoV-2 functional antibodies one week after second dose of vaccine (yes/no)  
• Treatment of interest: siponimod either continuously applied or with a treatment break for the 
purpose of the vaccination, or first line DMTs or no treatment as part of clinical routine 
• Intercurrent events. Failure to receive the second dose of vaccine: These patients will be 
counted as non-responders. Missing or invalid determination of functional antibodies to SARS-
CoV-2: These patients will be excluded from the efficacy analyses (if they received their 2nd 
dose of vaccine)  
• Summary measure: n.a., there will be no formal comparison between cohorts. Response rates 
will only be calculated within each cohort. 
2.5.2 
Statistical hypothesis, model, and method of analysis 
The efficacy analysis set at Week 1 is used for all analyses of the primary parameter. 
The primary analysis will not use any statistical testing or modelling. The absolute numbers and the 
proportion of participants achieving seroconversion within each cohort will be calculated. It will be 
augmented by a (descriptive) two-sided 95% confidence interval (exact Clopper-Pearson). 
2.5.3 
Handling of missing values/censoring/discontinuations 
Patients who fail to receive their first dose of vaccine for whatever reason are excluded from the 
efficacy analysis Set(s). The number of these patients is displayed in the patient disposition table. 
Patients who fail to receive their second dose of vaccine for whatever reason will be included in the 
analysis as non-responders. The number of these patients is displayed in the analysis table. 
Patients who did receive their second dose of vaccine and do not have a valid determination of 
functional antibodies to SARS-CoV-2 for whatever reason will be excluded from the analysis of 
vaccine efficacy. The number of these patients is displayed in the analysis table. 


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2.5.4 
Supportive analyses 
If relevant differences in demographic or other baseline chracteristics are observed post-hoc 
analysis will be performed to adjust the primary endpoint for theses inhomogeneities. A logistic 
regression model would be applied. 
The qualitative and (semi)quantitative antibody results towards coronaviridae are analyzed in 
addition. The first by frequency tables, the latter by sample statistics. 
In several patients the booster vaccination was performed before Visit 3 at Months 6, so that 
the efficacy results were expected to be influenced by this booster vaccination. Therefore, the 
analyses of seroconversion in SARS-CoV-2 functional antibodies and reactivity to IFNg and 
IL-2 SARS-CoV-2 were presented for both subgroup of patient who received / did not receive 
a booster vaccination before Visit 3 at Month 3.  
2.6 
Analysis of the key secondary objective 
Not applicable, because no key secondary objectives are specified. 
2.7 
Analysis of secondary efficacy objective(s) 
2.7.1 
Secondary endpoints 
The secondary endpoints are analyzed descriptively within each cohort. The efficacy analysis 
set is used for all analyses of the secondary parameters. 
The semiquantitative SARS-CoV-2 serum functional antibody titer (percent inhibitation) is 
summarized by arithmetic mean, standard deviation, minimum, median and maximum by visit. 
A boxplot graph will be presented. 
The SARS-CoV-2 serum functional antibody titer is summarized by geometric mean, geometric 
coefficient of variation (CV) and 95% confidence intervals for the (geometric) mean. The Visits 
Screening, Visit 1/Week 1, Visit 2 /Month 1 and Visit3 /Month 6 are displayed separately in 
this summary table and a boxplot graph with logarithmic y-axis (log base 10). 
The same summary table and boxplot will be provided for the following secondary parameters: 
a) Qualitative and quantitative result of IFNg towards SARS-CoV-2 and towards 
coronaviridae 
b) Qualitative and quantitative result of IL-2 towards SARS-CoV-2 and towards 
coronaviridae 
c) Combined response in qualitative INFg or IL-s towards SARS-CoV-2 and towards 
coronaviridae, i. e. reactive to INFg or IL-2 or to both. 
d) Cell viability, CD3 lymphocytes, CD4 and CD8 cells, percentage of CD4+ and CD8+ 
cell in peripheral blood mononuclear cells 
The percent inhibition values for INFg at screening will be displayed for the subset of patients 
who are reactive at Week 1 versus non-reactive. The same analysis is provided for IL-2. 
All other laboratory data (e. g. number of basal/background spots, spots, quality, comments, 
mutations) are listed only. 


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The MS activity is measured by relapses. The crude annual relapse rate until end of study and 
underlying sums (of relapses and patient-years) will be presented. 
2.7.2 
Statistical hypothesis, model, and method of analysis 
Not applicable. 
2.7.3 
Handling of missing values/censoring/discontinuations 
Missing values are not replaced. 
2.8 
Safety analyses 
All safety analyses are presented for the Safety Set (SAF). Descriptive statistics are presented 
within study treatment groups (cohorts 1-3).  
It should be mentioned that the follow-up analysis amends all analyses of adverse events. The 
CSR is planned to be finalized after this follow-up analysis. 
 
2.8.1 
Adverse events (AEs) 
According to the CSP all adverse events starting in the on-treatment period, i. e. the treatment 
emergent AEs, are analyzed.  
The on-treatment period lasts from the date of first administration of study treatment after informed 
consent to 30 days after the month 12 COVID-19 follow-up call. 
The number (and percentage) of subjects with treatment-emergent adverse events will be 
summarized in the following ways: 
• by treatment group (cohort 1-3), primary system organ class and preferred term. 
• by treatment group (cohort 1-3), primary system organ class, preferred term and maximum 
severity 
A subject with multiple AEs within a MedDRA primary system organ class is only counted 
once towards the total of the primary system organ class. 
A subject with multiple AEs within a preferred term is only counted once towards the total of 
the preferred term class. 
Separate summaries will be provided for study medication related AEs, death, SAEs, AEs 
leading to discontinuation and adverse events leading to dose adjustment. 
The absolute and relative frequency of COVID-19 infections is presented. 
Deaths and serious adverse events are listied in addition. 
2.8.1.1 
Adverse events of special interest / grouping of AEs 
Adverse events related to COVID-19 are listed. 


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2.8.2 
Deaths 
Deaths are listed. A frequency table with absolute numbers, percentages and 95% confidence 
interval is presented. 
2.8.3 
Laboratory data 
Not applicable. 
2.8.4 
Other safety data 
2.8.4.1 
Physical examination 
Clinically significant findings which were not present at screening but at any later visits are 
displayed by a frequency table. 
2.8.4.2 
Vital signs 
The changes from screening to Visit 1/Week 1, to Visit 2/Month 1, to Visit 3/Months 6 as well 
as differences between last and first value are displayed for pulse, systolic/diastolic blood 
pressure and body weight. 
2.9 
Pharmacokinetic endpoints   
Not applicable.  
2.10 
PD and PK/PD analyses 
Not applicable.  
2.11 
Patient-reported outcomes 
Not applicable. 
2.12 
Biomarkers 
Not applicable.  
2.13 
Other Exploratory analyses 
Not applicable.   
2.14 
Interim analysis 
See section 1.1 Study design. 
3 
Sample size calculation 
The sample size of 20 participants per arm is selected based on need for early availability of results 
for the current covid-19 pandemic and the feasibility to recruit sufficient participants from AMASIA 
and PANGAEA 2.0 EVOLUTION. This sample size of 20 subjects will provide estimates of 
proportion responded with margin of error (half-width of a 95% confidence interval) of 20.1%, 19%, 
and 17.5% corresponding to response rates of 70%, 75%, and 80%, respectively. Adjusting for 10% 


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drop-out, 22 subjects will be enrolled in each arm. In case of fast recruitment the sponsor is allowed 
to increase sample size in each arm by up to 10 additional patients to support the generation of 
meaningful data in a larger sample size.  
4 
Change to protocol specified analyses 
The definition for the Efficacy analysis Set was adapted to avoid that non-missing secondary 
endpoints would be excluded from the efficacy analysis set. For the rate of seroconversion 
(primary parameter) the patients with missing data are already excluded from the denominator. 
5 
Appendix 
5.1 
Imputation rules 
No imputations will be done except: 
If differences between dates are calculated, partial dates are replaced by 15/6 for days/month. 
If negative date differences result from this replacement, the value is set to 0. 
5.2 
Treatment-emergent adverse events 
Treatment emergent AEs are those which start in the on-treatment period. The on-treatment 
period lasts from the date of first administration of study medication after informed consent to 
30 days after the month 12 COVID-19 follow up call. 
The date of first administration of study medication is derived as follows: 
Cohort 1 (continued siponimod treatment): Because patients eligible for cohort 1 should 
have stable siponimod treatment before the study, the date of informed consent is used 
as date of first study medication. Deviations against this assumption will be detected 
during the data review meeting and monitoring of protocol deviations. If, necessary this 
derivation will be adapted. 
Cohort 2 (interrupted siponimod treatment): Siponimod treatment can be interrupted 
before or after the informed consent. For patients who interrupted siponimod before 
informed consent, the date of first study medication is the first siponimod dose after 
informed consent or the date of first vaccination, whatever is earlier. For patients who 
interrupted siponimod after informed consent the date of informed consent is the date 
of first study medication. 
Cohort 3: For patients who are treated with a first-line DMT the date of first study 
medication is derived like in cohort 1. For patients who do not receive any DMT the 
date of first study medication is the date of first vaccination. 
If no month 12 COVID-19 follow-up call is available, the on-treatment period lasts to the date 
of last visit plus 30 days.  


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5.3 
Statistical models 
5.3.1 
Primary analysis 
The primary parameter “seroconversion” is derived from the laboratory data as follows: 
Seroconversion is achieved, when SARS-CoV-2 neutralizing antibodies were not found 
(“negative”) at the time of screening but SARS-CoV-2 neutralizing antibodies are found 
(“positive”) at visit 1, visit 2 respectively visit 3. 
5.3.2 
Key secondary analysis 
Not applicable  
5.4 
Rule of exclusion criteria of analysis sets  
 
Deviation 
ID 
Description of Deviation 
Exclusion in Analyses 
I01 
Incl. crit. no. 1 (IFC) violated 
Excluded from all analysis 
Sets 
O05 
Primary parameter (SARS-2-CoV-2 
antibodies at Week 1) is missing 
Excluded from denominator to 
calculate 
the 
rate 
of 
seroconversion 
 
Table 2 
Subject Classification 
Analysis Set 
PD ID that 
    
cause subjects to be excluded 
Non-PD criteria that cause  
subjects to be excluded 
all 
NA 
Not having informed consent; 
SAF/Efficacy 
Analysis Set 
NA 
Not having any study treatment 
Efficacy 
Analysis 
Set(s) 
NA 
Vaccination 1 not done  
or 
Vaccination not done with mRNA 
or 
Different vaccines at first and 2nd vaccination 
or 
Positive neutralizing SARS-Cov-2  
antibodies at screening 
 


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6 
Reference 
None.