Cladribine Tablets: Observational Evaluation of Effectiveness and PROs in Suboptimally Controlled Patients Previously Taking Injectable DMDs for RMS (CLICK-MS)
Conditions: Multiple Sclerosis
Sponsor: EMD Serono Research & Development Institute, Inc.

Company substance code: 
 
700568 
Protocol number: 
 
 
MS700568_0078 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
1/61 
 
 
Non-Interventional Study Protocol 
Study Protocol Number 
MS700568_0078 
 
Title 
CLadribine tablets: Observational evaluation of effectIveness 
and patient-reported outcomes (PROs) in suboptimally 
Controlled 
patients 
previously 
taKing 
injectable 
disease-modifying drugs (DMDs) for relapsing forms of 
Multiple Sclerosis (RMS) (CLICK-MS) 
 
Protocol Version Identifier 7.0 
 
Protocol Date/Version 
14 February 2024 / Version 7.0 
 
Replaces Version 
1 July 2022 / Version 6.0 
 
Active Substance 
Cladribine 
 
Medicinal Product 
Mavenclad® 
 
Marketing Authorization 
Holder(s) 
EMD Serono, Inc., Rockland, MA, USA 
 
Research Question and 
Objectives 
The main research questions are to evaluate the effectiveness 
and safety of cladribine tablets in patients with RMS, 
including relapsing-remitting multiple sclerosis (RRMS) and 
active secondary progressive multiple sclerosis (aSPMS), 
who transition to cladribine tablets after suboptimal response 
to any injectable disease-modifying drugs (DMD) approved 
in the United States (US) for RMS in a real-world setting. 
Primary Objective(s): 
• To estimate the annualized relapse rate (ARR) over a 
24-month period in patients with RMS, including RRMS 
and aSPMS, who are treated with cladribine tablets in a 
real-world setting and after suboptimal response to any 
injectable DMD approved in the US for RMS 
Secondary Objectives: 
• To assess patient-reported outcomes (PROs), treatment 
adherence and treatment satisfaction during treatment 
with cladribine tablets 

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Company substance code: 
 
700568 
Protocol number: 
 
 
MS700568_0078 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
4/61 
 
 
9.7.2 
Derived and Transformed Data ..........................................................44 
9.7.3 
Statistical Methods ..............................................................................44 
9.7.4 
Sequence of Analyses .........................................................................45 
9.8 
Quality Control ...................................................................................46 
9.9 
Limitations of the Research Methods .................................................46 
9.10 
Other Aspects ......................................................................................46 
9.10.1 
Independent Ethics Committee or Institutional Review Board ..........46 
9.10.2 
Monitoring ..........................................................................................47 
9.10.3 
Health Authorities ...............................................................................47 
9.10.4 
Quality Assurance ...............................................................................47 
9.10.5 
Archiving ............................................................................................47 
10 
Protection of Human Patients .............................................................47 
10.1 
Patient Information and Informed Consent ........................................47 
10.2 
Patient Identification and Privacy .......................................................48 
11 
Management and Reporting of Adverse Events .................................48 
11.1 
Adverse Events ...................................................................................48 
11.2 
Severity of Adverse Events ................................................................51 
11.3 
Causality Assessment of Adverse Events ...........................................51 
11.4 
Recording of Adverse Events .............................................................51 
11.5 
Safety Data Collection for Reporting .................................................52 
11.6 
Regulatory Reporting to the Health Authorities .................................55 
12 
Plans for Disseminating and Communicating Study Results .............55 
12.1 
Study Report .......................................................................................55 
12.2 
Publication ..........................................................................................55 
13 
References ...........................................................................................56 
14 
Appendices .........................................................................................58 
14.1 
List of Stand-Alone Documents .........................................................58 
14.2 
Signature Pages and Responsible Persons for the Study ....................59 
Signature Page – Protocol Lead .........................................................................................59 
Signature Page – Principal Investigator .............................................................................60 
Sponsor Responsible Persons not Named on the Cover Page ...........................................61 
 
 

Company substance code: 
 
700568 
Protocol number: 
 
 
MS700568_0078 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
5/61 
 
 
2 
List of Abbreviations 
 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AESI 
Adverse Events of Special Interest 
ALC 
Absolute Lymphocyte Count 
ARR 
Annualized Relapse Rate  
aSPMS 
Active Secondary Progressive Multiple Sclerosis 
BDI-FS 
Beck-Depression Inventory-Fast Screen 
CBC 
Complete Blood Count 
CI 
Confidence Interval 
CNS 
Central Nervous System 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CU 
Combined Unique 
DMD 
Disease-Modifying Drug 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EDSS 
Expanded Disability Status Score 
ePRO 
Electronic Patient-Reported Outcomes 
FSS 
Functional System Scores 
Gd+ 
Gadolinium-Enhancing 
HIV 
Human Immunodeficiency Virus 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
JCV 
John Cunningham Virus 
MFIS-5 
Modified Fatigue Impact Scale – 5-item Version 
MRI 
Magnetic Resonance Imaging 
MS 
Multiple Sclerosis 
MS-TAQ 
Multiple Sclerosis Treatment Adherence Questionnaire  
PDDS 
Patient Determined Disease Steps 

Company substance code: 
 
700568 
Protocol number: 
 
 
MS700568_0078 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
6/61 
 
 
PRO 
Patient-Reported Outcome 
RMS 
Relapsing form of Multiple Sclerosis 
RRMS 
Relapsing-remitting Multiple Sclerosis 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SF-36 
36-Item Short Form Health Survey 
TSQM 
14-Item Treatment Satisfaction Questionnaire for Medication 
US 
United States 
US FDA 
United States Food and Drug Administration 
USPI 
United States Prescribing Information 
WPAI-MS 
Work Productivity Activity Impairment – Multiple Sclerosis 
2-CdA 
2-chloro-2’-deoxyadenosine 

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Company substance code: 
 
700568 
Protocol number: 
 
 
MS700568_0078 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
9/61 
 
 
3.1 
Responsibilities of the Investigator 
The investigator is responsible for the conduct of the study at his/her site. He/She will ensure 
that the study is performed in accordance with the protocol and will ensure the quality and 
integrity of data, following all applicable international and national guidelines. 
This non-interventional study will not interfere with treatment prescription by investigators. 
Accordingly, the investigator will decide in advance the best therapeutic strategy for each 
patient according to current practice, regardless of the potential participation of this patient in 
the study. Subsequently, if the prescribed treatment is in line with the study protocol, the 
investigator will consider the possibility of including the patient in the study. 
The investigator is responsible for adverse reaction and/or laboratory abnormalities recording 
and reporting, as specified in Section 11. 
 

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PPD
PPD

Company substance code: 
 
700568 
Protocol number: 
 
 
MS700568_0078 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
11/61 
 
 
before, during, and after treatment with cladribine tablets in patients 
with suboptimal response to prior injectable DMDs. 
Research question 
and objectives 
The main research questions are to evaluate the effectiveness and 
safety of cladribine tablets in patients with RMS, including RRMS and 
aSPMS, who transition to cladribine tablets after suboptimal response 
to any injectable DMD approved in the US for RMS in a real-world 
setting. 
Primary Objective: 
• To estimate the annualized relapse rate (ARR) over a 24-month 
period in patients with RMS, including RRMS and aSPMS, who 
are treated with cladribine tablets in a real-world setting and after 
suboptimal response to any injectable DMD approved in the US 
for RMS. 
Secondary Objectives: 
• To assess PROs, treatment adherence and treatment satisfaction 
during treatment with cladribine tablets 
• To assess treatment patterns (MS treatment prior to transition to 
cladribine tablets, since MS diagnosis, concomitant treatment for 
MS during the last 2 years before transition to cladribine tablets (or 
since MS diagnosis, if diagnosis <24 months), follow-up treatment 
in case of discontinuation of cladribine tablets) 
• To estimate the ARR over the 24-month period prior to initiation 
of cladribine tablets (or since MS diagnosis, if diagnosis <24 
months) 
• To collect all serious adverse events (SAEs), adverse drug 
reactions (ADRs), adverse events of special interest (AESIs) and 
special situations during treatment with cladribine tablets over a 24 
month period 
Study design 
This is a prospective, observational, multicenter, 30-month, Phase IV 
study. Patients who had decided prior to enrollment to transition from 
any injectable DMD to treatment with cladribine tablets under routine 
clinical care and who meet all eligibility criteria consistent with the 
approved US Prescribing Information (USPI) will receive an initial 
treatment course with cladribine tablets in Year 1 and are planned to 
receive a second course in Year 2, as per the approved USPI. 
Cladribine tablets are being prescribed as part of patients’ standard 
medical care and commercial product will be used. Patients will not be 
provided the cladribine tablets free of charge in connection with their 
participation in the study. It is expected that the investigator considered 
the mode of action and duration of effect of the previous DMD prior 
to initiation of cladribine tablets. It is at the investigator’s discretion to 
define this time period, following respective USPI. All treatment 
decisions are at the discretion of the investigator. Patients will be 

Company substance code: 
 
700568 
Protocol number: 
 
 
MS700568_0078 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
12/61 
 
 
followed up until the end of the observation period, irrespective if they 
discontinue cladribine tablets during follow-up. 
Baseline PROs, MRI, and treatment adherence data will be collected 
before first dose of cladribine is taken. Baseline data on previous MS 
DMD use, relapses during the previous 2 years (or since MS diagnosis, 
if diagnosis <24 months), will be collected retrospectively at the 
Baseline Visit. 
During the observation period, patients will attend visits as per routine 
clinical practice, which are expected to happen approximately at the 
end of Month 2, Month 6 and Month 12 during Year 1, and at the end 
of Month 14, 18, and 24 (i.e. after the second course of treatment 
during Year 2), as clinically indicated. In patients whose lymphocyte 
count has not returned to 800 cells per microliter, Year 2 treatment 
should be delayed as per USPI and, thus, these patients could be 
followed for up to 30 months. 
Detailed clinical data about MS disease relapses, MRI findings, 
hematologic and other laboratory assessments, medications received, 
and adverse events (AEs), as well as PROs, will be prospectively 
collected during the study period. 
 
Population 
Inclusion criteria: 
1. Male or female patients ≥18 years 
2. Signed informed consent 
3. Have diagnosis of RMS, including RRMS and aSPMS, and satisfy 
the approved indication for cladribine tablets as per USPI  
4. Have time since diagnosis of RMS of at least 12 months 
5. In the opinion of the investigator, experienced suboptimal response 
(lack of effectiveness, intolerability, poor adherence) to injectable 
DMD treatment 
6. Had received their last previous injectable DMD for at least 
3 months 
7. Have decided to initiate treatment with cladribine tablets during 
routine clinical care (i.e. before enrollment) 
8. Meet criteria as per the approved USPI 
9. Have access to a valid e-mail address 
Exclusion criteria: 
1. Have been previously treated with cladribine in any dosing form 
(intravenous, subcutaneous, or oral) 
2. Transitioning from previous injectable DMD solely for 
administrative reasons such as relocation 

Company substance code: 
 
700568 
Protocol number: 
 
 
MS700568_0078 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
13/61 
 
 
3. Have any clinical condition or medical history noted as 
contraindication on USPI 
4. Are currently participating in an interventional clinical trial 
5. Pregnant or breastfeeding women, women who plan to become 
pregnant or men whose partner plans to become pregnant during 
the cladribine treatment period 
Outcomes 
Primary Outcome: 
• ARR over 24 months of treatment with cladribine tablets 
(prospectively collected data), accompanied by 95% confidence 
interval (CI). 
For this study, a relapse will be defined as per routine clinical practice 
as determined by the investigator. As a guide, relapse may be defined 
as exacerbation of symptoms that occur over a minimum of 24 hours 
and separated from a previous attack by at least 30 days, in the absence 
of fever or infection. 
Secondary Outcomes: 
• Baseline scores and change in scores from baseline to Month 6, 12 
and 24 for the following PROs (collected via electronic PRO 
[ePRO] at the practice or at the patient’s home): 
o 14-Item Treatment Satisfaction Questionnaire for Medication 
(TSQM) 
o 36-Item Short Form Health Survey (SF-36) 
o Modified Fatigue Impact Scale – 5-item version (MFIS-5) 
o Beck-Depression Inventory – Fast Screen (BDI-FS) [7 items] 
o Work Productivity Activity Impairment – MS (WPAI-MS) 
[6 items] 
o PDDS scale 
• Treatment adherence questions, based on modified versions of the 
Multiple Sclerosis Treatment Adherence Questionnaire (MS-
TAQ); data to be collected via ePRO at baseline (modified for 
self-injectables to assess adherence during last previous injectable 
DMD treatment) and at the end of Months 1, 2, 13, and 14 
(modified for cladribine tablets) 
• Proportion of patients experiencing a relapse 
• Proportion of patients with relapse associated with hospitalization 
• Proportion of patients with relapse associated with glucocorticoid 
use 
• Assessment of previous treatment for MS 
o Previous DMD(s) received for MS prior to study enrollment, 
since MS diagnosis 

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CCI

Company substance code: 
 
700568 
Protocol number: 
 
 
MS700568_0078 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
15/61 
 
 
Data analysis 
All patients starting treatment with cladribine tablets will be included 
in the analyses.  
The primary endpoint will be analyzed at Month 24. All secondary 
endpoints on relapse rates, PROs, MRI, and treatment patterns will be 
analyzed at Month 12 (12-month interim analysis) and Month 24 (final 
analysis). PRO data will be analyzed once the first 30 patients reach 
the 6-month follow-up as well as at Month 6 for all enrolled patients. 
Safety data will also be assessed at Month 6 for the first 30 patients 
enrolled as well as at Months 12 and 24.  
Descriptive statistics will be used to summarize data. If the outcome in 
question is a continuous variable, the number of observations, number 
of missing values, mean, standard deviation (SD), median, first quartile 
and third quartile, minimum and maximum values will be presented; if 
the outcome is categorical, numbers and percentages of patients for 
each of the categories and numbers and percentages of missing values 
will be presented. 
Where appropriate, 95% CIs will be presented. For continuous data, 
CIs for the mean will be calculated assuming a normal distribution of 
the data. CIs for binary endpoints will be presented using the 
Clopper-Pearson method. 
Time to event data will be analyzed both descriptively as continuous 
data and through Kaplan-Meier analysis. 
The primary study outcome of ARR over the 24-month period will be 
accompanied by the respective 95% CI. Sensitivity analyses of the 
ARR will be performed considering the relapses as count data and 
using a negative binomial regression model with time as explanatory 
variables. A zero-inflated negative binomial regression model will also 
be considered. 
Milestones 
First Patient First Visit (first patient to sign Informed Consent Form 
[ICF]): 12-Jun-2019 
30% of Patient consented: 31-Jan-2020 
60% of Patient consented: 31-May-2020 
Last Patient First Visit (last patient to sign ICF): 31-Oct-2021 
Last Patient Last Visit: 30-Mar-2024 
Database Lock: 03-Jun-2024 
Key Stats Available: 15-Aug-2024 
Clinical Study Report: 20-Nov-2024 
 
 

Company substance code: 
 
700568 
Protocol number: 
 
 
MS700568_0078 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
16/61 
 
 
5 
Amendments and Updates 
Amendment 
Number 
Protocol 
Version 
Date 
Section of 
Study 
Protocol 
Amendment or 
Update 
Reason 
1 
Version 2 
02/14/2019 
Header 
Protocol number 
was corrected 
Administrative 
Section 3 
Lead Principal 
investigator was 
added 
Administrative 
Operational Study 
Lead was updated 
Administrative 
Sections 4 and 
6 
Dates for study 
milestones were 
updated 
Administrative 
Section 11.1 
Definition for severe 
lymphopenia was 
added 
For added clarity 
Sections 4 and 
9.2.1 
Added inclusion 
criterion that patient 
must have access to 
a valid e-mail 
address 
To ensure 
patients have a 
means to receive 
link to the PRO 
questionnaires  
Sections 4 and 
9.2.1 
Corrected exclusion 
criterion #1 by 
removing term 
“tablets” 
Administrative 
Corrected exclusion 
criterion #5 by 
removing “other 
than cladribine 
tablets” 
Administrative 
Section 9.1.1 
Updated Figure 1 
For added clarity 
Sections 4 and 
9.1.1 
Added clarification 
that cladribine 
tablets are being 
prescribed as per 
standard of care and 
are not given as part 
of this study 
For added clarity 
Sections 4 and 
9.1.1 
Clarified that time 
between end of 
previous DMD and 
start of cladribine 
tablets is at the 
discretion of the 
investigator who 
should consider 
mode of action and 
duration of effect of 
previous DMD 
when making this 
decision 
For added clarity 

Company substance code: 
 
700568 
Protocol number: 
 
 
MS700568_0078 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
17/61 
 
 
Amendment 
Number 
Protocol 
Version 
Date 
Section of 
Study 
Protocol 
Amendment or 
Update 
Reason 
Sections 
9.1.2.4 and 
9.2.4 
Clarified that MRIs 
collected during the 
study follow-up 
period will be 
assessed by a central 
neuroradiology 
center 
For added clarity 
Section 9.2.2 
Clarified that no 
additional risk to 
patient is expected 
since cladribine 
tablets are 
prescribed as per 
standard of care and 
per USPI 
For added clarity 
Sections 4, 
9.1.1, 9.1.2.2, 
9.2.4, 9.3 and 
9.7.3 
Clarified that 
treatment adherence 
is captured using 
questions that are 
based on MS-TAQ 
For added clarity 
2 
Version 3 
06/19/2019 
Title page, 
Sections 4, 
8.2, 9.1.1, 
9.1.2.2, 9.3 
and 9.7.4 
Clarified that 
retrospective data 
over the 24-month 
period prior to 
enrollment should 
be related to 
patients’ MS 
diagnosis; thus, if a 
patient’s diagnosis 
is <24 months, then 
data since diagnosis 
is collected 
For added clarity 
Sections 4 and 
9.2.1 
Changed inclusion 
criterion “Have time 
since diagnosis of 
RMS of at least 
24 months” to 
“Have time since 
diagnosis of RMS of 
at least 12 months” 
 
This inclusion 
criterion was 
updated based on 
site feedback and 
to expand the 
pool of eligible 
patients as a 
diagnosis of 1 
year was deemed 
sufficient from a 
clinical 
perspective 
Sections 4 and 
9.1.2.2 
Data on all previous 
DMDs since MS 
diagnosis (rather 
than only those 
received within 2 
years prior to 
enrollment) will be 
collected 
Data collection 
on previous 
DMDs has been 
expanded for a 
full picture on 
patients’ 
treatment 
pathway since 
MS diagnosis 

Company substance code: 
 
700568 
Protocol number: 
 
 
MS700568_0078 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
18/61 
 
 
Amendment 
Number 
Protocol 
Version 
Date 
Section of 
Study 
Protocol 
Amendment or 
Update 
Reason 
Title page, 
Sections 4, 
7.4, 8, 8.1 and 
9.2.1 
Clarified that 
indication for 
cladribine tablets is 
RMS, including 
RRMS and active 
SPMS 
For added clarity 
Title page, 
Sections 4, 
7.4, 8.2 and 
9.7.3 
Re-phrased 
“physicians’ 
treatment patterns” 
to “treatment 
patterns” 
To clarify that 
MS treatment 
patterns are 
assessed, not 
comparisons of 
treatment 
patterns across 
physicians 
Section 11.1 
Added further 
definition for severe 
lymphopenia to 
include description 
of Grade 3 and 
Grade 4 
lymphopenia 
For added clarity 
Section 9.1.1 
Added additional 
recommendations 
from the USPI for 
when ALC drops to 
<200 cells per 
microliter 
For added clarity 
Section 9.3 
Clarified that data 
on prior medication 
should be limited to 
MS symptomatic 
specific medications 
For added clarity 
and to reduce site 
burden for data 
entry 
Section 9.1.2.2 
Added information 
that validated 
Spanish translations 
of PROs are 
available for this 
study; except for the 
PDDS for which a 
non-validated 
Spanish translation 
is used 
For added clarity 
and transparency 
regarding the 
PDDS Spanish 
translation not 
being 
linguistically 
validated 
Section 8.3 
The other objective 
on MRI data was 
updated to also refer 
to the fact that the 
impact of cladribine 
tablets on brain 
atrophy will be 
assessed 
To align the 
objective with 
the proposed 
endpoints 
collected in the 
study 

Company substance code: 
 
700568 
Protocol number: 
 
 
MS700568_0078 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
19/61 
 
 
Amendment 
Number 
Protocol 
Version 
Date 
Section of 
Study 
Protocol 
Amendment or 
Update 
Reason 
Section 9.2.4 
In the schedule of 
assessment data 
collection of 
treatment with 
cladribine tablets 
and other MS 
treatment during the 
study was separated 
For added clarity 
since the 
anticipated 
assessments of 
treatment with 
cladribine tablets 
and other MS 
treatment differ 
Section 9.2.4 
The time period for 
pre-baseline 
screening has been 
changed to -30 to 0 
days (from -24 to 0 
days)  
To accommodate 
the current 
insurance 
approval and 
drug shipment 
timelines 
Sections 9.2.4 
and 9.3 
Hepatitis B and C 
screening was added 
prior to initiation of 
the first and second 
course of cladribine 
tablets. A footnote 
was included to 
clarify that hepatitis 
B screening prior to 
the second course of 
treatment with 
cladribine tablets is 
not required as per 
USPI if the patient 
received vaccination 
prior to the first 
course of treatment 
For added clarity 
and for 
consistency with 
the USPI 
Section 9.2.4 
Assessment of JCV 
status was moved 
from the Table 1. 
Schedule of 
Assessments table to 
a footnote 
For added clarity 
since JCV data is 
only collected if 
assessed by the 
investigator as 
per standard of 
care 
Section 9.2.4 
A footnote was 
added to Table 1. 
Schedule of 
Assessments to 
indicate that at PRO 
only time points 
(Month 1 and 
Month 13) patients 
will complete PROs 
at their home; 
patients are not 
asked to come to the 
clinic for PRO 
completion at these 
time points 
For added clarity 
and to indicate 
reduced patient 
burden as PROs 
can be completed 
at home at Month 
1 and Month 13 

Company substance code: 
 
700568 
Protocol number: 
 
 
MS700568_0078 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
20/61 
 
 
Amendment 
Number 
Protocol 
Version 
Date 
Section of 
Study 
Protocol 
Amendment or 
Update 
Reason 
Section 9.2.4 
The column on 
“staff function” was 
removed from the 
Table 1. Schedule of 
Assessments 
For added clarity 
since this column 
initially only 
listed the 
physician as 
being responsible 
for assessments 
at the clinic, but 
some of these 
tasks could be 
delegated to 
other site staff 
Sections 9.2.4 
and 9.3 
It was clarified that 
during study follow-
up sites are asked to 
upload MRI scans as 
available per routine 
practice and scans 
will be read by a 
central 
neuroradiology 
center 
To clarify that 
sites are not 
asked to report 
MRI results 
during follow-up 
3 
Version 4 
10/03/2019 
Section 11.1 
‘Pregnancy’ and 
‘adverse pregnancy’ 
were removed from 
the list of AESIs 
To clarify that 
pregnancy and 
adverse 
pregnancy 
outcomes are not 
AESIs for this 
study 
Sections 4, 
9.2.1, 11.4 
Updated exclusion 
criteria to exclude 
women who plan to 
become pregnant 
during cladribine 
treatment phase 
To clarify that 
pregnancy is 
only a 
contraindication 
during the 
cladribine 
treatment phase 
Section 4 and 
9.2.2 
Updated language 
regarding 
administration of 
cladribine tablets to 
align with the USPI 
To align with the 
USPI 
Section 9.2.4 
The time period for 
pre-baseline 
screening has been 
changed to -45 to 0 
days (from -30 to 0 
days) 
To accommodate 
the current 
insurance 
approval and 
drug shipment 
timelines 

Company substance code: 
 
700568 
Protocol number: 
 
 
MS700568_0078 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
21/61 
 
 
Amendment 
Number 
Protocol 
Version 
Date 
Section of 
Study 
Protocol 
Amendment or 
Update 
Reason 
Section 9.2.4 
Renamed 
Enrollment Visit as 
Baseline Visit and 
clarified that 
Baseline Visit 
should occur 
immediately prior to 
the patient initiating 
treatment with 
cladribine tablets 
and that a Screening 
Visit can be 
performed if the site 
anticipates a delay 
between decision to 
start cladribine and 
access to cladribine 
tablets 
For added clarity 
Section 9.2.4  
Definition of 
enrolled patient was 
added (i.e. once ICF 
is signed) 
For added clarity  
Sections 4, 
7.4, 8.1, 9.2.1 
Abbreviated active 
SPMS as ‘aSPMS’  
Updated for 
consistency 
Section 9.2.5 
Added statement 
that patients who 
never take at least 1 
dose of cladribine 
tablets will be 
withdrawn from the 
study 
For added clarity 
Section 9.1.1 
Updated Figure 1 to 
reflect time since 
diagnosis of at least 
12 months 
Updated for 
consistency to 
reflect prior 
changes to 
inclusion criteria  

Company substance code: 
 
700568 
Protocol number: 
 
 
MS700568_0078 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
22/61 
 
 
Amendment 
Number 
Protocol 
Version 
Date 
Section of 
Study 
Protocol 
Amendment or 
Update 
Reason 
4 
Version 5 
10/21/2021 
Section 9.2.4 
The schedule of 
assessments table 
notes collection of 
MRI documentation 
at the Baseline Visit, 
but further clarifies 
in footnote ‘e’, that 
during follow-up, 
MRIs will be 
assessed by a central 
neuroradiology 
center. MRI 
documentation, at 
baseline and follow-
up should be sent to 
and reviewed by the 
central 
neuroradiology 
center  
Updated for 
clarity 
 
 
 
Figure 1 
Figure 1 updated to 
reflect population 
including patients 
who have been 
diagnosed at least 12 
months prior 
(previously at least 
24 months) 
Updated to align 
with inclusion 
criteria 
 
 
 
Sections 8.2, 
9.1.1, 9.2.3, 
9.2.4 (Table 
1), 9.7, 11.4, 
Figure 1 
Follow-up safety 
collection extended 
by 2-years  
Updated to allow 
for the capture of 
long-term safety 
data (extending 
to 48 months 
post-treatment 
initiation and up 
to 54 months if 
Year 2 treatment 
is delayed) 
 
 
 
Section 7.1 
Updated incidence 
and prevalence 
estimates 
Updated to be 
aligned with 
current literature 
 
 
 
Section 7.3 
Added additional 
medications to the 
treatment and 
management of 
RMS 
Added given new 
MS indicated 
products have 
been recognized  
 
 
 
Section 12.1 
Study report 
schedule updated 
Updated to align 
with 
implementation 
of safety 
extension 

Company substance code: 
 
700568 
Protocol number: 
 
 
MS700568_0078 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
23/61 
 
 
Amendment 
Number 
Protocol 
Version 
Date 
Section of 
Study 
Protocol 
Amendment or 
Update 
Reason 
 
 
 
9.5 
Study size 
Updated the 
expected number 
of enrolled and 
evaluable 
patients  
 
 
 
Section 9.2.4, 
9.3, and 9.7 
Schedule of 
assessments to 
include MRI data 
collection through 
safety extension 
period 
Updated to 
ensure relevant 
assessments are 
collected as 
available during 
the safety 
extension time 
period 
 
 
 
Section 9.1.1, 
9.2.4, 9.3, and 
9.7 
PDDS assessment to 
be collected during 
the safety extension 
(at Month 36 and 
Month 48). 
Frequency of 
assessments table 
and Figure 1 
updated accordingly 
to reflect change 
Updated to 
ensure  relevant 
assessments are 
collected as 
available during 
the safety 
extension time 
period 
 
 
 
Section 9.7.3 
Removed 95% 
confidence interval 
metrics from 
secondary end point 
analysis presentation 
95% confidence 
intervals will not 
be presented for 
secondary 
analyses given 
they can be wide 
with a reduced 
sample size. 
Further, 95% 
confidence 
intervals are not 
presented in the 
study’s tables, 
listings, and 
figures and have 
been removed 
from the protocol 
for consistency 
 
 
 
Sections 9.2.4, 
9.3, and 9.7 
Added relapse data 
collection through 
safety extension 
time period  
Updated to 
ensure  relevant 
assessments are 
collected as 
available during 
the safety 
extension time 
period 

Company substance code: 
 
700568 
Protocol number: 
 
 
MS700568_0078 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
24/61 
 
 
Amendment 
Number 
Protocol 
Version 
Date 
Section of 
Study 
Protocol 
Amendment or 
Update 
Reason 
 
 
 
Sections 9.1, 
9.2.4, 9.3, 
9.7.3, 9.7.4, 
and 12.1 
Added footnote 
throughout to clarify 
that the last follow-
up visit can occur at 
Month 54 if 
treatment is delayed  
Updated for 
consistency  
 
 
 
Sections 5 and 
10 
Updated ‘subjects’ 
to ‘patients’ 
throughout  
Updated for 
consistency  
 
 
 
Section 6 
Added specific 
clinical study report 
addendum dates to 
milestones table 
Added for more 
precision 
 
 
 
Signature page 
Added additional 
context to the 
principal 
investigator 
signature page 
Added to align 
with standard 
signature page 
language 
5 
Version 6 
07/1/2022 
Section 9.1.1, 
Figure 1, 
Section 9.3, 
Table 1, 
Section 9.7 
Removed MRI 
collection from the 
2-year safety 
extension 
Given the low 
volume and 
availability of 
MRI data 
expected during 
the safety 
extension, MRI 
data will no 
longer be 
collected and 
analyzed during 
the extension 
period 
6 
Version 7 
02/13/2024 
Section 8.2 
Section 9.1.1,  
Section 9.1.2, 
Section 
9.1.2.3, 
Figure 1,  
Table 1,  
Section 9.2.4, 
Section 9.3, 
Section 9.7.3 
Section 9.2.3 
Section11.4 
Section 12.1 
Removed 2-year 
safety extension and 
affiliated data 
collection items and 
timepoints 
To accommodate 
early study 
closure as 
determined by 
Sponsor 

Company substance code: 
 
700568 
Protocol number: 
 
 
MS700568_0078 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
25/61 
 
 
Amendment 
Number 
Protocol 
Version 
Date 
Section of 
Study 
Protocol 
Amendment or 
Update 
Reason 
 
 
 
Section 11.4 
Section 11.5 
Reflected the safety 
reporting of non-
serious ADR 
accurately (directly 
to Sponsor GPS and 
not via the Safety 
Check Desk), 
updated the Safety 
Check Desk 
contacts.  
 
To accurately 
describe the 
reporting for 
non-serious ADR 
as well as the 
current contact 
details of the 
CRO Safety 
Check Desk. 

Company substance code: 
 
700568 
Protocol number: 
 
 
MS700568_0078 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
26/61 
 
 
6 
Study Milestones 
 
Milestone 
Planned date 
First Patient First Visit (first patient to sign 
Informed Consent Form [ICF])  
12-Jun-2019* 
30% of Patients Consented 
31-Jan-2020* 
60% of Patients Consented 
31-May-2020* 
Last Patient First Visit (last patient to sign ICF) 
31- Oct-2021 
Last Patient Last Visit 
30-Mar-2024 
Database Lock 
 03-Jun-2024 
Key Stats Available 
15-Aug-2024 
Clinical Study Report 
 
20-Nov-2024 
 
N.b. Timelines are based on estimated date of FDA approval (01-April-2019) 
*Actual recorded dates 
Abbreviations: FDA=Food and Drug Administration 

Company substance code: 
 
700568 
Protocol number: 
 
 
MS700568_0078 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
27/61 
 
 
7 
Rationale and Background 
7.1 
Epidemiology of Multiple Sclerosis 
Multiple sclerosis (MS) is an immune-mediated, chronic inflammatory disease of the central 
nervous system (CNS) characterized by the demyelination and destruction of axons 
(Tullman 2013). With no definite cause established, MS has been hypothesized to result from 
a complex interaction between individual genetic susceptibility and environmental factors that 
act as triggers of a self-sustained auto-immune response (Noseworthy 2000). With a peak of 
onset averaging at the age of 30 years in both genders, MS occurs predominantly in women 
with a female: male ratio of 3:1 (Kingwell 2013). 
Globally, the median estimated prevalence of MS is 35.9 patients per 100,000 population 
(Walton 2020). MS median estimated prevalence varies substantially across regions, with 
North America and Europe presenting the highest prevalence (Multiple Sclerosis International 
Federation 2013). There are approximately 1,000,000 persons in the United States (US) living 
with MS (Wallin 2019). Regarding incidence, globally, the median estimated incidence of MS 
is 2.5 per 100,000 person-years (Dua 2008). In the US, the incidence is estimated to be 3.2 per 
100,000 person-years (Multiple Sclerosis International Federation 2013). 
Studies indicate that MS patients show a nearly 3-fold increase in mortality relative to the 
general population, and about half of them are attributed to MS as the underlying cause of death 
(Scalfari 2013). 
7.2 
Clinical Presentation and Categorization of MS 
MS is not characterized by a singular, well-defined clinical presentation common to all MS 
patients. The symptoms, which include a combination of cognitive, sensory and motor 
manifestations, vary among patients and throughout the disease course according to the CNS 
areas affected and the severity of the demyelinating attacks. 
Approximately 85% of patients with MS initially have a relapsing form of multiple sclerosis 
(RMS) (Multiple Sclerosis International Federation 2013), which is characterized by 
alternating periodic acute exacerbations of disease activity (relapses) and periods of remission, 
consisting of partial or complete recovery (Lublin 2014). The most important features of highly 
active RMS include frequent relapses with incomplete recovery, and/or high radiological 
burden of disease, rapid accrual of disability after disease onset, with otherwise typical features 
of RMS (Lublin 2014). Data on the epidemiology of highly active RMS is lacking and currently 
the proportion of patients that are classified as highly active comes from clinical trials. 
However, data show that around 14.4% to 14.8% of patients who had experienced 
breakthrough disease activity (≥1 relapse in the 12 months prior to randomization) (Rudick 
2006; Gold 2013) and 22.2% of treatment-naïve patients (Polman 2006) met the criteria for 
highly active RMS (≥2 relapses in the year prior to study entry and ≥1 gadolinium-enhancing 
(Gd+) lesion on T1-weighted magnetic resonance imaging [MRI] at study entry) (Polman 
2006; Rudick 2006; Gold 2013). 
7.3 
Treatment and Management of RMS 
Patients with RMS are recommended to receive treatment with disease-modifying drugs 
(DMDs) to decrease the rate of relapse and slow the accumulation of brain lesions on MRI. 
Numerous immunomodulatory agents with differing routes of administration (including 
injectable, oral and infusion) and differing mechanisms of action have been shown to have 
beneficial effects. The medications that have received labels from the US Food and Drug 

Company substance code: 
 
700568 
Protocol number: 
 
 
MS700568_0078 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
28/61 
 
 
Administration (US FDA) for the treatment of RMS include the intravenous medications 
natalizumab, ocrelizumab, alemtuzumab, and mitoxantrone; the injected medications 
interferon beta, glatiramer, ofatumumab, and daclizumab; and the oral medications diroximel 
fumarate, siponimod, ozanimod, monomethyl fumarate, dimethyl fumarate, teriflunomide, 
fingolimod, ponesimod, and cladribine tablets. Because they are not curative, most DMDs are 
typically continued indefinitely unless they are ineffective or not tolerated. There is currently 
no standard protocol to guide the choice of DMDs for patients with MS. Rather, treatment 
decisions and medication choices are the result of a thorough risk-benefit analysis and 
consideration of disease activity, patient-specific factors, and drug-related factors (Pardo 
2017). 
7.4 
Cladribine Tablets 
Cladribine (2-chloro-2'-deoxyadenosine [2-CdA]) is a synthetic anti-neoplastic drug that 
belongs to the subgroup of agents called purine analogs. In 2019, cladribine tablets were 
indicated for the treatment of patients with RMS, including relapsing-remitting multiple 
sclerosis (RRMS) and active secondary progressive multiple sclerosis (aSPMS), by the US 
FDA.  
Three clinical trials for cladribine tablets have been completed (CLARITY, ORACLE MS and 
ONWARD), and data from these trials (Leist 2014; Montalban 2016; Giovannoni 2010), as 
well as the extension phase of the CLARITY trial (Giovannoni 2013) and the interim long-term 
follow-up data from a prospective registry (the PREMIERE registry), have provided 
information on the efficacy and safety of cladribine tablets. In total, the follow-up consisted of 
>10,000 person-years of exposure for both cladribine tablets and placebo, with over 8 years of 
follow-up for some patients. 
In the CLARITY trial, patients with active RMS were randomized to placebo or cladribine 
tablets (3.5 or 5.25 mg/kg body weight) for 2 years; each dose showed significant benefits in 
rate of relapse, disability progression, and MRI measures (Giovannoni 2010). Treatment with 
cladribine tablets in CLARITY produced efficacy improvements that were maintained in 
patients treated with placebo in the extension phase (Giovannoni 2013). 
Approximately 20% to 25% of the patients treated with 3.5 mg/kg as monotherapy developed 
transient Grade ≥3 lymphopenia. Grade 4 lymphopenia was observed in 0.7% of patients. 
Overall, nearly 90% of patients recovered by the end of the trials. The remaining patients 
recovered during long-term follow-up without developing severe or opportunistic infections. 
Herpes zoster infection is considered as an important identified risk of treatment with 
cladribine tablets. The observed incidence rates in the monotherapy oral cohort for herpes 
zoster infection were 0.86 adjusted adverse events (AEs) per 100 person-years for cladribine 
tablets 3.5 mg/kg vs. 0.20 for placebo, and for severe herpes zoster infection 0.9 vs. 0.5, 
respectively. The incidence of herpes zoster infection was higher during periods of Grade 3 or 
4 lymphopenia compared to the time when the patients were not experiencing Grade 3 or 4 
lymphopenia. 
Incidence rates of the most common infections, including the most common severe infections, 
were similar between the placebo and the cladribine tablets exposed groups, with the exception 
of herpes zoster infection as described above. The incidence rates for infections, in general, 
were 24.93 vs. 27.05 adjusted AEs per 100 person-years (cladribine tablets 3.5 mg/kg 
monotherapy vs. placebo), and for severe infections 0.84 vs. 0.86, respectively. There was no 
evidence for an increased risk of opportunistic infections in patients treated with cladribine 
tablets (incidence rates were 1.08 and 1.17 for cladribine tablets 3.5 mg/kg monotherapy and 

Company substance code: 
 
700568 
Protocol number: 
 
 
MS700568_0078 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
29/61 
 
 
placebo, respectively). However, tuberculosis has been defined as an important identified risk, 
with overall 3 cases observed in the cladribine tablets development program. All cases were 
reported prior to the implementation of mandatory pre-screening for tuberculosis; no cases 
occurred thereafter. 
The types of malignancies reported in the cladribine tablets clinical program were in line with 
what is reported in the general population and in patients with MS. No malignancy pattern 
reflective of immunosuppression was observed, and no malignancies were seen in cell types 
most affected by cladribine tablets (e.g., lymphomas). There is no evidence of a dose effect of 
cladribine tablets on malignancy occurrence and with cladribine tablets, there was no change 
in the risk of malignancy over time. The overall malignancy rate with cladribine tablets was 
similar to the rates observed with other DMD approved in MS. In summary, there is no 
conclusive evidence for an increased risk of malignancy with cladribine tablets compared to 
placebo with a risk difference of 0.2033 per 100 person-years (95% confidence interval [CI]: -
0.0785, 0.3947) in the overall exposed cohort. An independent meta-analysis of study results 
from Phase III trials of DMD used in RMS (Pakpoor 2015) showed that the malignancy risk 
profile of cladribine tablets in the CLARITY study was comparable to that observed in similar 
trials with other DMD. 
Data about the safety and effectiveness of cladribine tablets in real-world clinical settings are 
still limited since cladribine tablets were approved for treatment of adult patients with highly 
active RMS in August 2017 in the European Union. The product has recently been approved 
by the Food and Drug Administration (FDA) in the US. Real-world data are also limited about 
patients’ adherence to treatment with cladribine tablets, patient-reported outcomes (PRO), and 
treatment patterns for RMS before, during, and after treatment with cladribine tablets in 
patients with suboptimal response to prior injectable DMDs. 
8 
Research Question and Objectives 
The main research objectives are to evaluate the effectiveness and safety of cladribine tablets 
in patients with RMS, including RRMS and aSPMS, who transition to cladribine tablets after 
suboptimal response to any injectable DMD approved in the US for RMS in a real-world 
setting. 
8.1 
Primary Objective 
To estimate the annualized relapse rate (ARR) over a 24-month period in patients with RMS, 
including RRMS and aSPMS, who are treated with cladribine tablets in a real-world setting 
and after suboptimal response to any injectable DMD approved in the US for RMS. 
8.2 
Secondary Objectives 
• To assess PROs, treatment adherence and treatment satisfaction during treatment with 
cladribine tablets  
• To assess treatment patterns (MS treatment prior to transition to cladribine tablets, since 
MS diagnosis, concomitant treatment for MS during the last 2 years prior to initiation of 
cladribine tablets (or since MS diagnosis, if diagnosis <24 months), follow-up treatment in 
case of discontinuation of cladribine tablets) 
• To estimate the ARR over the 24-month period prior to initiation of cladribine tablets (or 
since MS diagnosis, if diagnosis <24 months) 

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CCI

Company substance code: 
 
700568 
Protocol number: 
 
 
MS700568_0078 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
32/61 
 
 
Figure 1. Study Design Schematic 
 
 
a Duration between stopping previous injectable DMD and start of cladribine tablets is at the discretion of the investigator. 
b Year 2 course may be delayed for some patients, according to the ALC. If Year 2 treatment is delayed, follow-up may continue through Month 30. 
Note. Refer to Table 1 for more data collection details and assessments at each visit. 
Abbreviations: ARR=annualized relapse rate, AEs=adverse events, ALC=absolute lymphocyte count, BDI-FS=Beck-Depression Inventory–Fast Screen, BV=Baseline Visit, 
CBC=complete blood count, DMD=disease-modifying drug, ePRO=electronic Patient-Reported Outcome, MFIS-5=Modified Fatigue Impact Scale – 5-item version, MRI=magnetic 
resonance imaging, MS=multiple sclerosis, MS-TAQ=MS Treatment Adherence Questionnaire, NV=No Visit, PDDS=Patient Determined Disease Steps, PRO=Patient-Reported 
Outcome, RMS=relapsing form of multiple sclerosis, SF36=36-Item Short Form Health Survey, TSQM=14-Item Treatment Satisfaction Questionnaire for Medication, 
Tx=Treatment, USPI=United States Prescribing Information, WPAI-MS=Work Productivity Activity Impairment – MS.

Company substance code: 
 
700568 
Protocol number: 
 
 
MS700568_0078 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
33/61 
 
 
9.1.2 
Outcomes 
9.1.2.1 
Primary 
• ARR over 24 months of treatment with cladribine tablets (prospectively collected data), 
accompanied by 95% CI. 
For this study, a relapse will be defined as per routine clinical practice as determined by the 
investigator. As a guide, relapse may be defined as exacerbation of symptoms that occur over a 
minimum of 24 hours and separated from a previous attack by at least 30 days, in the absence of 
fever or infection. 
9.1.2.2 
Secondary 
• Baseline scores and change in scores from baseline to Month 6, 12 and 24 for the following 
PROs (collected via electronic PRO [ePRO] at the practice or at the patient’s home using 
computer’s URL or device application; validated Spanish translations are available for all 
PROs, except for the patient determined disease steps (PDDS) scale for which a translation is 
used that has not been linguistically validated): 
o 14-Item Treatment Satisfaction Questionnaire for Medication (TSQM). TSQM-14 is an 
instrument to assess patient's satisfaction with medication, providing scores on 4 scales: 
side effects, effectiveness, convenience and global satisfaction. 
o 36-Item Short Form Health Survey (SF-36). SF-36 is a self-administered, generic health 
status questionnaire consisting of 36 questions that measure 8 health concepts: physical 
functioning, role limitations due to physical problems, bodily pain, general health 
perception, vitality, social functioning, role limitations due to emotional problems and 
mental health. 
o Modified Fatigue Impact Scale – 5-item version (MFIS-5). MFIS-5 is a modified form of 
the Fatigue Impact Scale that consists of 5 questions that assess the impact of fatigue on 
physical, cognitive, and psychosocial functioning, with 5 response levels ranging from 0 
("Never") to 4 ("Almost always"). Total scores range from 0 to 20, with higher scores 
representing a greater impact of fatigue. 
o Beck-Depression Inventory-Fast Screen (BDI-FS) [7 items]. The 7 items BDI-FS is a self-
report inventory for measuring the severity of depression on a 7-item scale. 
o Work Productivity Activity Impairment – MS (WPAI-MS) [6 items]. The WPAI-MS 
questionnaire is a validated instrument to measure impairments in work and activities. The 
WPAI yields 4 types of scores: 1. Absenteeism (work time missed); 2. Presenteeism 
(impairment at work / reduced on-the-job effectiveness); 3. Work productivity loss 
(overall work impairment / absenteeism plus presenteeism); 4. Activity Impairment. 
WPAI outcomes are expressed as impairment percentages, with higher numbers indicating 
greater impairment and less productivity. 
o PDDS scale. The PDDS is a patient-reported scale to assess the disability status in patients 
with MS and it focuses mainly on how patients walk. A higher score represents a higher 
level of disability. Scores on the PDDS range from 0 (normal) to 8 (bedridden). 

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Company substance code: 
 
700568 
Protocol number: 
 
 
MS700568_0078 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
36/61 
 
 
9.2.2 
Definition of Study Cohorts and Description of Treatments 
The study will have a single cohort that consists of all patients enrolled in the study who received 
at least 1 dose of cladribine tablets. All treatment and other medical decisions will be made by the 
investigator. 
All study patients are anticipated to receive marketed cladribine tablets as per investigator 
discretion and as per US approved label: 3.5 mg/kg body weight over 2 years, administered as 1 
treatment course of 1.75 mg/kg per year. Each treatment course consists of 2 treatment weeks, 1 
at the beginning of the first month and 1 at the beginning of the second month of the respective 
year. Each treatment week consists of 4 or 5 days on which a patient receives 10 mg or 20 mg (1 
or 2 tablets) as a single daily dose, depending on body weight. Since prescribing is determined by 
the investigator as per standard of care and according to the USPI, the benefits and risks to patients 
in being in the study are not different than the benefits and risks to patients taking cladribine tablets 
as per standard of care and according to the USPI in the general population. 
Following completion of the 2 treatment courses, do not administer treatment during the next 2 
years as stated in the USPI. 
As per USPI, ALC values need to be normal at the initiation of cladribine tablets in Year 1, and 
ALC results need to indicate ≥800 cells per microliter at the start of the Year 2 treatment course. 
If necessary, the Year 2 treatment course should be delayed for up to 6 months to allow for 
recovery of lymphocytes to ≥800 cells per microliter. If this recovery takes more than 6 months, 
the patient should not receive further treatment with cladribine tablets. 
9.2.3 
Observation Period 
Each patient will be followed from the date of first dose of cladribine tablets until loss to follow-up, 
withdrawal of consent, death or the end of the data collection period, whichever comes first. 
Patients will be followed for 24 months from first dose and up to 30 months for those patients who 
may require a delay of initiation of Year 2 treatment for up to 6 months due to low lymphocyte 
counts. Follow-up will continue regardless of cladribine tablets discontinuation. 
9.2.4 
Frequency of Assessments 
Table 1 lists the Schedule of Assessments. Patients are considered enrolled once the informed 
consent form (ICF) has been signed prior to any data collection for this study. The Baseline Visit 
is the visit immediately prior to the patient initiating treatment with cladribine tablets. If the sites 
anticipate a delay between the decision to start cladribine tablets (i.e. prescription) and patient 
access to cladribine tablets (i.e. due to delays in cladribine tablets availability or access), the site 
can perform a Screening Visit first to determine eligibility of the patient and a subsequent Baseline 
Visit closer to the time the patient starts taking cladribine tablets. Data entered during the Baseline 
Visit are considered baseline data for the purposes of analysis. 
Sites are asked to enter patient follow-up data for up to 24 months after a patient received initial 
dose if Year 2 treatment course is not delayed and up to 30 months after initial dose if Year- 2 
treatment course is delayed up to 6 months. Visits will be conducted within the context of routine 
clinical care; thus, the timing of study visits is approximate and not mandated by the study protocol. 

Company substance code: 
 
700568 
Protocol number: 
 
 
MS700568_0078 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
37/61 
 
 
It is anticipated that patients enrolled in the study may not immediately start cladribine tablets after 
the decision to initiate cladribine tablets is made, owing to the need to first discontinue their current 
injectable DMD (for a time period determined by the investigator) and to potential delays in 
obtaining cladribine tablets in the clinical setting. The initial PRO only collection (Month 1) is 
intended to be obtained after the patient has started treatment with cladribine tablets. The timing 
of Visit 1 (Month 2) and the subsequent visits may need to be adjusted based upon the actual start 
date of cladribine tablets, which will be recorded by the investigator. 
In accordance with the USPI, it is anticipated that patients may not receive their second course of 
cladribine tablets precisely 12 months after the initiation of cladribine tablets owing to ALC levels 
<800 cells per microliter or other potential clinical factors. In the event that the second course of 
cladribine tablets is delayed beyond Month 13, the PRO only collection scheduled for Month 13 
should be adjusted to occur during the start of the second course of cladribine tablets. The timing 
of Visit 4 (Month 14) and the subsequent visits may need to be adjusted based upon the actual start 
date of the second course of cladribine tablets, which will be recorded by the investigator. 
 
 

Company substance code: 
 
700568 
Protocol number: 
 
 
MS700568_0078 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
38/61 
 
 
Table 1. Schedule of Assessments 
Assessments 
Data Collection Time Points (As Expected Based on Routine Clinical Practice) 
Pre-baseline 
Screening 
Visit 
(Days -45 to 
0) 
Baseline 
Visit a 
(Baseline) 
Month 0 
PRO 
Only b 
Month  
1 
Visit #1 
Month  
2 
Visit #2 
Month  
6 
Visit #3 
Month  
12 
PRO 
Only b 
Month  
13 
Visit #4 
Month  
14 
Visit 
#5 
Month  
18 
Visit 
#6 
Month  
24 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Medical history, previous relapses, previous DMD 
treatment 
 
X 
 
 
 
 
 
 
 
 
Inclusion / exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
Pregnancy test, HIV, hepatitis B, hepatitis C and 
tuberculosis status 
 
X 
 
 
 
X 
 
 
 
 
Cladribine tablets c 
 
X 
 
X 
 
X 
 
X 
 
 
Other MS DMD during study period, if applicable  
 
 
 
X 
 
X 
 
X 
 
X 
Neurological examination as per standard of care 
 
X 
 
 
X 
X 
 
 
X 
X 
Physical examination as per standard of care 
 
X 
 
 
 
 
 
 
 
 
Relapse count (prospective) d 
 
 
 
 
 
X 
 
 
 
X 
MRI documentation e 
 
X 
 
 
X 
X 
 
 
X 
X 
Hematology assessment (ALC, CBC, lymphocyte 
subsets) f 
 
X 
 
X 
X 
X 
 
X 
X 
X 
Patient-reported outcomes 
 
 
 
 
 
 
 
 
 
 
Treatment adherence g 
 
X h 
X 
X 
 
 
X 
X 
 
 
TSQM 
 
X h 
 
 
X 
X 
 
 
 
X 
SF-36 
 
X h 
 
 
X 
X 
 
 
 
X 
MFIS-5 
 
X h 
 
 
X 
X 
 
 
 
X 
BDI-FS 
 
X h 
 
 
X 
X 
 
 
 
X 
WPAI-MS 
 
X h 
 
 
X 
X 
 
 
 
X 
PDDS 
 
X h 
 
 
X 
X 
 
 
 
X 
Adverse events i 
 
X 
 
X 
X 
X 
 
X 
X 
X 

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Company substance code: 
 
700568 
Protocol number: 
 
 
MS700568_0078 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
40/61 
 
 
9.2.5 
Withdrawal from the Study 
Patients may discontinue from the study at any time. Investigators may choose to discontinue 
patients from the study at any time. Further, enrolled patients who do not take at least 1 dose of 
cladribine tablets will be withdrawn from the study. The reason for any study discontinuations will 
be collected, if available. 
9.3 
Variables 
The following variables will be collected: 
Screening and/or Baseline Visit 
• Patient demographics, including: age, sex, weight, self-reported race/ethnicity 
• Date of diagnosis of MS, date of first symptoms of MS 
• DMD treatments received prior to study enrollment, since MS diagnosis (including medication 
doses and routes of administration, start dates, stop dates, and reasons for discontinuation) 
• Relapse of MS in the 2 years prior to the study period or since MS diagnosis, if diagnosis <24 
months (including dates of onset and resolution of relapse) 
• Most recent MRI results prior to starting cladribine tablets (baseline MRI), which is expected 
to have been taken within the prior 90 days (number of T1 Gd+ lesions; number of new T2 
lesions compared to most recent prior MRI; number of newly enlarging T2 lesions compared 
to most recent prior MRI; number of CU lesions; presence of brain atrophy and segmental 
atrophy) 
• Results of MRI in the 2 years prior to study enrollment or since MS diagnosis, if diagnosis <24 
months (including prior documentation of number of T1 Gd+ lesions; new or newly enlarging 
T2 lesions; number of CU lesions; presence of brain atrophy and segmental atrophy) 
• Results of neurological examination as per standard of care (e.g., Kurtzke Functional System 
Scores (FSS), ambulation up to 500 meters and Expanded Disability Status Score [EDSS]) 
• Results of physical examination as per standard of care 
• Hematology assessment (white blood cell count, hemoglobin, hematocrit, platelet count, 
ALC). If the investigator assesses JCV status, these data should be recorded as well 
• Pregnancy, human immunodeficiency virus (HIV), hepatitis B, hepatitis C and tuberculosis 
test results 
• ePRO assessments (treatment adherence questions based on modified versions of the MS-
TAQ, TSQM, SF-36, MFIS-5, BDI-FS, WPAI-MS, PDDS) 
• Comorbid conditions 
• List of all MS symptomatic specific medications taken in the 2 years prior to study enrollment 
(or since MS diagnosis, if diagnosis <24 months), including medication start and stop dates 
and reasons for discontinuation 

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CCI

Company substance code: 
 
700568 
Protocol number: 
 
 
MS700568_0078 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
43/61 
 
 
9.6 
Data Management 
The main purpose of the eCRF is to obtain data required by the non-interventional study protocol 
in a complete, accurate, legible and timely manner. The data in the eCRF should be consistent with 
the relevant source documents. 
The investigator or designee is responsible for ensuring that the data collected in the course of this 
study is accurate and documented appropriately on all applicable forms. Data will then be 
processed, evaluated, and stored in anonymous form in accordance with applicable data protection 
regulations. The investigator must ensure that the eCRFs and any other associated documents 
forwarded to the Sponsor or its designated organization contain no mention of any patient names. 
The data will be entered into a validated database. The Contract Research Organization (CRO) 
will be responsible for data processing, in accordance with the CRO’s data management 
procedures. Database lock will occur once Quality Control and Quality Assurance procedures 
(including reconciliation of SAEs, ADRs, AESIs and special situations) and coding activities have 
been completed. PDF files of the eCRFs will be provided to the investigators at the completion of 
the study. 
9.7 
Data Analysis 
Further details will be provided in a Statistical Analysis Plan. 
There will be a baseline analysis and 3 interim analyses: The baseline analysis will summarize  
baseline characteristics. In the first interim analysis, mainly for safety purposes, safety, adherence 
and PRO data will be analyzed for the subset of the first 30 patients enrolled into the study at the 
6-month time point. A second interim analysis on the safety, adherence and PRO data will be 
performed as soon as 6-month data are available for all patients. The third and full interim analysis 
will be performed on the 12-month data. The final analysis evaluating the primary and secondary 
objectives will be on the 24-month data at the end of the study. 
All patients enrolled in the study who receive at least 1 dose of cladribine tablets will be included 
in the analyses. The primary endpoint will be analyzed at Month 24. All secondary endpoints on 
relapse rates, PROs, MRI, and treatment patterns will be analyzed at Month 12 (12-month interim 
analysis) and Month 24 (final analysis). PRO data will additionally be analyzed once the first 
30 patients reach the 6-month follow-up as well as at Month 6 for all enrolled patients. Safety data 
will also be assessed at Month 6 for the first 30 patients enrolled as well as at Months 12 and 24, 
unless Year 2 treatment is delayed in which case the final safety assessment would occur at Month 
30.  
9.7.1 
Analysis Sets 
Full Analysis Set 
The Full Analysis Set includes all patients enrolled in the study who received at least 1 dose of 
cladribine tablets.  
Per Protocol Analysis Set 

Company substance code: 
 
700568 
Protocol number: 
 
 
MS700568_0078 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
44/61 
 
 
The Per Protocol Population includes all patients who have completed a full treatment course of 
cladribine tablets (2 weeks of treatment (4-5 doses per week) for years 1 and 2), according to the 
USPI and are compliant with all entry criteria. 
Safety Analysis Set 
The Safety Population includes all patients enrolled in the study who have received at least 1 dose 
of cladribine tablets (same as Full Analysis Set). 
9.7.2 
Derived and Transformed Data 
Data will be transformed if required by the analysis method, e.g. to approximate the normal 
distribution of the data. Details on the eventual derivation/transformation of the analysis variables 
will be given in the Statistical Analysis Plan. For the primary outcome, the patterns of missingness 
will be explored. When the number of missing values is substantial (>5%), multiple imputation 
methodology will be considered for the analysis of the primary objective. 
9.7.3 
Statistical Methods 
Descriptive statistics will be used to summarize data. If the outcome in question is a continuous 
variable, the number of observations, number of missing values, mean, SD, median, first quartile 
and third quartile, minimum and maximum values will be presented; if the outcome is categorical, 
numbers and percentages of patients for each of the categories and numbers and percentages of 
missing values will be presented. 
Where appropriate, 95% CIs will be presented. For continuous data, CIs for the mean will be 
calculated assuming a normal distribution of the data. CIs for binary endpoints will be presented 
using the Clopper-Pearson method. 
Time to event data will be analyzed both descriptively as continuous data and through 
Kaplan-Meier analysis. 
Primary Endpoint Analysis: 
The ARR over the 24-month period will be presented, accompanied by the respective 95% CI. 
Sensitivity analyses of the ARR will be performed considering the relapses as count data and using 
a negative binomial regression model with time as explanatory variables. A zero-inflated negative 
binomial regression model will be also considered. 
Secondary Endpoints Analysis: 
All secondary endpoints will be analyzed at Month 12 (interim analysis) and Month 24 (final 
analysis). Data will be summarized descriptively.  
ARR (prospective assessment): The ARR over the 12-Month and 24-Month follow-up period 
after starting cladribine tablets will be presented, accompanied by the respective 95% CIs. 
Other relapse analyses: The proportion of patients experiencing a relapse, ARR associated with 
hospitalization and associated with glucocorticoid use will be presented together with the 
corresponding 95% CI over the 24-month and over the 12-month period. 
Treatment adherence: Treatment adherence, based on modified versions of the MS-TAQ, will 
be described at baseline (modified for self-injectables to assess adherence during last previous 

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CCI
CCI

Company substance code: 
 
700568 
Protocol number: 
 
 
MS700568_0078 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
46/61 
 
 
9.8 
Quality Control 
This study will be monitored in accordance with the International Council for Harmonization 
(ICH) Note for Guidance on Good Clinical Practice (ICH Topic E6, 1996). The site Monitor will 
perform visits to the study site at regular intervals. Representatives of the Sponsor’s Quality 
Assurance unit or a designated organization, as well as Health Authorities, must be permitted to 
inspect all study-related documents and other materials at the site, including the investigator Site 
File, the completed Case Report Form (CRFs), and the patients’ original medical records/files. The 
protocol, each step of the data capture procedure, and the handling of the data, including the final 
study report, will be subject to independent Quality Assurance activities. Audits may be conducted 
at any time during or after the study to ensure the validity and integrity of the study data. 
9.9 
Limitations of the Research Methods 
As this study is being conducted as an observational study, data will be collected in the context of 
routine clinical care and standard of care rather than with a mandated clinical visit and assessment 
completion schedule. This may lead to inconsistent and variable data collection across patients and 
may result in missing data or information bias. In addition, variability in the treatments received 
may limit interpretation of the results. However, the objectives of this study are to assess real-
world effectiveness, safety and treatment patterns of cladribine tablets and therefore an 
observational design is the appropriate method to achieve the study objectives. 
The patients enrolled in this study may not be generalizable to all patients in the US receiving 
cladribine tablets for RMS. This will be addressed by including a heterogeneous group of study 
sites that are broadly representative of MS care centers in the US. 
9.10 
Other Aspects 
9.10.1 
Independent Ethics Committee or Institutional Review Board 
Prior to commencement of the study at a given site, the protocol will be submitted together with 
its associated documents (e.g. ICF) to the responsible Independent Ethics Committee 
(IEC)/Institutional Review Board (IRB) for its favorable opinion/approval. The written favorable 
opinion/approval of the IEC/IRB will be filed by the investigator and a copy will be sent to the 
Sponsor. 
The study must not start at a site before the Sponsor has obtained written confirmation of favorable 
opinion/approval from the concerned IEC/IRB. The IEC/IRB will be asked to provide 
documentation of the date of the meeting at which the favorable opinion/approval was given, and 
of the members and voting members present at the meeting. Written evidence of favorable 
opinion/approval that clearly identifies the study, the protocol version, and the Patient Information 
and Consent Form version reviewed should be provided. Where possible, copies of the meeting 
minutes should be obtained. 
Amendments to the protocol will also be submitted to the concerned IEC/IRB before 
implementation in case of substantial changes. 

Company substance code: 
 
700568 
Protocol number: 
 
 
MS700568_0078 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
47/61 
 
 
9.10.2 
Monitoring 
A CRO Monitor will perform monitoring both remotely and via visits to the site at intervals. 
Monitoring visits will involve checking of CRFs against original patient records and identification 
of any questions or problems related to study conduct or data collection. Investigators must 
therefore ensure that the Monitor has access to relevant documents during monitoring visits, and 
that they and/or relevant site staff members are available to discuss any issues that may arise. 
The study Monitor will send monitoring reports to the Sponsor. 
9.10.3 
Health Authorities 
Not applicable. 
9.10.4 
Quality Assurance 
In compliance with regulatory requirements, the Sponsor, a third party on behalf of the Sponsor, 
regulatory agencies, or IRB/IECs may conduct Quality Assurance audits/inspections at any time 
during or following a study. The investigator must agree to allow auditors/inspectors direct access 
to all study-related documents, including source documents, and must agree to allocate his or her 
time and the time of his or her study staff to the auditors/inspectors in order to discuss findings 
and issues. 
The protocol, each step of the data capture procedure, and the handling of the data, as well as the 
study report, may be subject to independent Clinical Quality Assurance. Audits may be conducted 
at any time during or after the study to ensure the validity and integrity of the study data. 
9.10.5 
Archiving 
The archive should be maintained for the period specified by local regulations, where applicable. 
All original patient files (medical records) must be stored at the site (hospital, research institute, 
or practice) for the longest possible time permitted by the applicable regulations. In the absence of 
applicable regulations, the archive should be maintained for at least 5 years after the final study 
report or the first publication of study results, whichever comes later. In any case, the investigator 
should ensure that no destruction of medical records is performed without the written approval of 
the Sponsor. 
10 
Protection of Human Patients 
10.1 
Patient Information and Informed Consent 
An unconditional prerequisite for a patient’s participation in the study is his/her written or e-signed 
informed consent. The patient’s written informed consent to participate in the study must be given 
before any study-related activities are carried out. 
Adequate information must therefore be given to the patient by the investigator before informed 
consent is obtained (a person designated by the investigator may give the information, if permitted 
by local regulations). A patient information sheet will be provided by the Sponsor for the purpose 
of obtaining informed consent. In addition to providing this written information to a potential 
patient, the investigator or his/her designee will inform the patient verbally of all pertinent aspects 

Company substance code: 
 
700568 
Protocol number: 
 
 
MS700568_0078 
 
 
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of the study (the language used in doing so will be chosen so that the information can be fully and 
readily understood by laypersons). Depending on national regulations, a person other than the 
investigator may inform the patient and sign the ICF. 
The ICF must be signed and personally dated by the patient and the investigator. The signed and 
dated declaration of informed consent will remain at the investigator’s site and must be safely 
archived by the investigator. A copy of the signed and dated information and consent form should 
be provided to the patient prior to participation. 
Whenever important new information becomes available that may be relevant to the patient’s 
consent, the written patient information sheet and any other written information provided to 
patients will be revised by the Sponsor and be submitted again to the IEC/IRB for review and 
favorable opinion. The agreed, revised information will be forwarded to each patient in the study. 
The investigator will explain the changes to the previous version. 
10.2 
Patient Identification and Privacy 
A unique patient number will be assigned to each patient at inclusion. This number will serve as 
the patient’s identifier in the study as well as in the study database. 
The investigator must ensure that the patients’ anonymity is maintained. On the CRFs or other 
documents submitted to the Sponsor, patients should not be identified by their names, but by their 
assigned identification numbers. If patient names are included on copies of documents submitted 
to the Sponsor, the names (except for initials) must be obliterated and the assigned patient numbers 
added to the documents. 
The investigator should keep a separate log of patients’ identification numbers, names, addresses, 
telephone numbers and hospital numbers (if applicable). Documents not for submission to the 
Sponsor, such as signed ICFs, should be maintained in strict confidence by the investigator. 
Only authorized persons will have access to identifiable personal details, if required for data 
verification. The patient’s original medical data that are reviewed at the site during source data 
verification by the Monitor, audits, and Health Authority inspections will be kept strictly 
confidential. The investigator agrees to provide direct access to these documents to the Sponsor 
and to Health Authority representatives. The investigator is responsible for retrieving information 
from personal medical records. 
Data protection and privacy regulations will be observed in capturing, forwarding, processing, and 
storing patient data. Patients will be informed accordingly and will be requested to give their 
consent on data handling procedures in accordance with national regulations. 
11 
Management and Reporting of Adverse Events 
11.1 
Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical study patient administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 

Company substance code: 
 
700568 
Protocol number: 
 
 
MS700568_0078 
 
 
C O N F I D E N T I A L 
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Adverse Drug Reaction  
An ADR is a response to a medicinal product which is noxious and unintended. 
Response in this context means that a causal relationship between a medicinal product and an AE 
is at least a reasonable possibility. 
ADRs may arise from use of the product within or outside the terms of the marketing authorization 
or from occupational exposure. Conditions of use outside the marketing authorization include 
off-label use, overdose, misuse, abuse and medication errors. 
Reports of Special Situations: Pregnancy, Overdose, Off-label Use, Misuse, Medication 
Error, Occupational Exposure, Lack of Therapeutic Effectiveness and Others 
• Use of a medicinal product during pregnancy or breastfeeding: reports where embryo, fetus or 
child may have been exposed to medicinal products (either through maternal exposure or 
transmission of a medicinal product via semen following paternal exposure) 
• Reports of overdose, abuse, off-label use, misuse, medication error or occupational exposure 
• Lack of therapeutic effectiveness 
• Prescription error/dispensing error, e.g. due to confusion of invented names of the medicinal 
products 
• Drug interaction 
• Suspected transmission of an infectious agent via a medicinal product 
• Product complaints, including falsified product or counterfeit 
Reports of special situation with no associated ADR will not be submitted to the authorities as 
Individual Case Safety Reports. They will be collected and considered in the study report or any 
interim reports, as applicable. 
Serious Adverse Events/Serious Adverse Reactions 
An SAE/Serious Adverse Reaction is any AE/ADR as defined above, which also fulfills at least 
one of the seriousness criteria below: 
• Results in death 
• Is life-threatening1 
• Requires in-patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Is otherwise considered as medically important2 
1 Life threatening in this context refers to a reaction in which the patient 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 more severe.  
2 Medical and scientific judgment should be exercised in deciding whether other situations should be considered as serious 
reactions, such as important medical events that might not be immediately life threatening or result in death or hospitalization but 
might jeopardize the patient or might require an intervention to prevent one of the other outcomes listed above. Such important 
medical events should be considered as serious. 

Company substance code: 
 
700568 
Protocol number: 
 
 
MS700568_0078 
 
 
C O N F I D E N T I A L 
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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. As a guidance, the important medical event terms list is intended to be 
used for assessment of suspected ADRs (see EMA/207865/2017). 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious ADR. 
Adverse Events of Special Interest  
An adverse events of special interest (AESI) is an AE of scientific and medical concern specific 
to the Sponsor’s product or program, for which ongoing monitoring and rapid communication by 
the investigator to the Sponsor can be appropriate. AESIs for monitoring should then be collected 
following the procedure for an SAE described in Section 11.4. The following events will be 
considered AESIs: 
• Severe lymphopenia: defined as Grade 3 (<500 to 200 cells per microliter) or Grade 4 
(<200 cells per microliter) 
• Severe infection 
• Tuberculosis 
• Herpes zoster infection 
• Progressive multifocal leukoencephalopathy 
• Other opportunistic infection 
• Malignancy 
Events that Do Not Meet the Definition of a Serious Adverse Event 
Elective hospitalizations (e.g. an overnight stay to facilitate therapy) are not considered as SAEs. 
However, all events leading to unplanned hospitalizations or unplanned prolongation of an elective 
hospitalization (e.g., undesirable effects of any administered treatment) must be documented and 
reported as SAEs. 
Events Not to Be Considered an Adverse Event 
Medical conditions present and documented at study start, that do not worsen in severity or 
frequency during the study are defined as baseline Medical Conditions and elective procedures 
and are NOT to be considered AEs. 
In this protocol, symptoms and signs of relapse or worsening of MS will be captured in the context 
of the effectiveness assessment and recorded on the relapse module of the eCRF. Therefore, 
symptoms, relapses or worsening of MS will not be considered as AEs nor captured on the AE 
module of the eCRF unless suspected to be related to cladribine tablets (i.e., worsening is not 
consistent with the anticipated natural progression of the disease). 

Company substance code: 
 
700568 
Protocol number: 
 
 
MS700568_0078 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
51/61 
 
 
11.2 
Severity of Adverse Events 
Investigators should assess the severity/intensity of any AE as follows: 
Mild: 
The patient is aware of the event or symptom, but the event or symptom is easily 
tolerated. 
Moderate: 
The patient experiences sufficient discomfort to interfere with or reduce his or 
her usual level of activity. 
Severe: 
Significant impairment of functioning: the patient is unable to carry out usual 
activities. 
11.3 
Causality Assessment of Adverse Events 
Investigators must assess the causal relationship between AEs and study drug (including any other 
non-medicinal product, radiation therapy, etc.) considering temporal relationship between the AE 
onset and study drug administration, safety profile of study drug (known ADRs), the patient's 
condition (medical history, underlying disease), concomitant medication, and study procedures. 
Related: 
Suspected to be reasonably related to any study medication. 
Not related: Not suspected to be reasonably related to any study medication. A reasonable 
alternative explanation must be provided. 
11.4 
Recording of Adverse Events 
The recording period for AEs begins when the patient is initially included in the study (date of 
signature of first informed consent) and continues at least to the end of the mandatory safety 
follow-up period (i.e. up to 24 months in most patients or up to 30 months in patients with delayed 
start of Year 2 treatment). 
All safety data, as specified above, occurring during the study, must be documented by the 
investigator within 24 hours of awareness and recorded in the CRF, including its description, 
seriousness, severity (grading), duration (onset and resolution dates), causal relationship, any other 
potential causal factors, actions taken with the study drug (e.g. dose reduction, withdrawal), 
required treatment and outcome of the AE. 
Note - Event term 'Death', ‘Disability’ and ‘Hospitalization’ 
Death, disability, and hospitalization are considered outcomes in the context of safety reporting 
and not usually considered ADRs/AEs. Therefore, the primary cause of death, disability or 
hospitalization should be recorded and reported as an SAE/ADR, and the outcome should be 
recorded in a separate data field. However, a term for the outcome will be selected if it is the only 
information reported or provides significant clinical information. 
If death occurs, the primary cause of death or event leading to death should be recorded and 
reported as an SAE. “Fatal” will be recorded as the outcome of this respective event and not be as 
separate event. Only if no cause of death can be reported (for example, sudden death, unexplained 
death), the death per se might then be reported as an SAE. 
Reports of Special Situations (see definition in Section 11) are also to be recorded in the CRF 
following the AE procedure, even if occurring without AE. 

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Company substance code: 
 
700568 
Protocol number: 
 
 
MS700568_0078 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
54/61 
 
 
Investigators must actively follow-up, document, and report to the Sponsor on the outcome of all 
these pregnancies and deliveries even if the patient is withdrawn from the study. If an abnormal 
outcome occurs, the respective safety data collection form (Pregnancy Report Form, Parent-
Child/Fetus AE Report Form) is to be completed and sent to the Sponsor. 
Procedure for Follow-up Information 
The investigator must promptly respond to any request by CRO for follow-up information or 
questions from the Sponsor or delegate, as noted above for initial report. Such requests will be sent 
to the investigator via the CRO Safety Check Desk. SAEs/ADRs, special situations and AESIs 
occurring during the study must be monitored and followed up by the investigator until 
stabilization or until the outcome is known, unless the patient has a fatal outcome or is lost to 
follow-up. 
The investigator will ensure any necessary additional therapeutic measures and follow-up 
procedures are recorded and reported via a follow-up report form. For all serious cases/ADRs/fatal 
cases, special situations and AESIs, missing information such as outcome, confounders, and 
causality are to be provided. Additionally, follow-up information of non-serious ADRs may be 
required by the Sponsor for medical assessment. Reasonable attempts to obtain follow-up 
information must be made and documented. 
Reporting of any new information on a previously reported event (follow-up) will follow the 
procedures and timelines of the original report. 
CRO should forward the follow-up information within 24 hours to Global Patient Safety, as noted 
above for initial reports. The Sponsor has to meet strict regulatory timelines associated with 
expedited safety reporting obligations. 
Abnormal Laboratory Findings and Other Abnormal Investigational Findings 
No scheduled laboratory assessments are required by protocol. Nevertheless, laboratory data of 
medical importance, as deemed necessary and requested by the investigator as part of the patient’s 
standard medical care, will be, when available, recorded into the eCRF by the investigator. 
Abnormal laboratory findings and other abnormal investigational findings (e.g. on an 
electrocardiogram trace) should not be reported as AEs unless they are associated with clinical 
signs and symptoms or are considered otherwise medically important by the investigator or general 
practitioner. If an abnormality fulfills these criteria, the identified medical condition (e.g. anemia, 
increased alanine transaminase [ALT]) must be reported as the AE rather than the abnormal value 
itself. 
Vital Signs, Physical Examinations, and Other Assessments 
Weight will be collected at baseline when available. 
Physical examination data will be collected during the course of routine clinical care. Abnormal 
physical examination findings should not be reported as AEs unless they are considered medically 
important by the investigator. If an abnormality fulfills these criteria, the identified medical 
condition must be reported as the AE rather than the abnormal physical examination finding itself. 

Company substance code: 
 
700568 
Protocol number: 
 
 
MS700568_0078 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
55/61 
 
 
11.6 
Regulatory Reporting to the Health Authorities 
Expedited reporting of SAEs and non-serious ADRs to Health Authorities is performed by the 
Sponsor’s Local Patient Safety Officer according to applicable global and local requirements. 
In addition, the investigator will comply with any applicable local pharmacovigilance 
requirements to report appropriate safety data, to national pharmacovigilance systems (e.g. Yellow 
Card Scheme in the United Kingdom), as required by country specific reporting requirements. 
12 
Plans for Disseminating and Communicating Study Results 
12.1 
Study Report 
The first and second interim reports will present the results of analyses of the safety, adherence, 
and PRO data. These reports will allow interim assessment of the safety of cladribine tablets in 
this study. 
The third interim report will present results of the analysis of the safety, adherence, and PRO data, 
as well as the analyses of the primary and secondary outcomes at 12 months. This report will allow 
interim assessment of all relevant aspects of the study. 
The completed study will be summarized in a final clinical study report that accurately and 
completely presents the study objectives, methods, results, limitations of the study, and 
interpretation of the findings from study start through Month 24. 
12.2 
Publication 
The study design as well as yearly interim data will be presented at scientific congresses. The first 
publication will include the results of the analysis of the primary outcome(s) and will include data 
from all study sites. 
The investigator will inform the Sponsor in advance about any plans to publish or present data 
from the study. Any publications and presentations of the results (abstracts in journals or 
newspapers, oral presentations, etc.), either in whole or in part, by investigators or their 
representatives will require pre-submission review and approval by the Sponsor. 
The Sponsor will not suppress or veto publications but maintains the right to delay publication in 
order to protect intellectual property rights. 

Company substance code: 
 
700568 
Protocol number: 
 
 
MS700568_0078 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
56/61 
 
 
13 
References 
Dua T and Rompani P. (2008). Atlas: Multiple sclerosis resources in the world, 2008. Retrieved 
10/15/18, from http://www.who.int/mental_health/neurology/Atlas_MS_WEB.pdf. 
Giovannoni G, Comi G, Cook S, et al. (2010). A placebo-controlled trial of oral cladribine for 
relapsing multiple sclerosis. N Engl J Med 362: 416-26. 
Giovannoni G, Comi G, Cook S, et al. (2013). Safety and Efficacy of Oral Cladribine in Patients 
with Relapsing-Remitting Multiple Sclerosis: Results from the 96 Week Phase IIIb Extension Trial 
to the CLARITY Study. Neurology 80 (suppl 7): P07.119. 
Gold R, Giovannoni G, Selmaj K, et al. (2013). Daclizumab high-yield process in relapsing-
remitting multiple sclerosis (SELECT): a randomised, double-blind, placebo-controlled trial. 
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Kingwell E, Marriott JJ, Jetté N, et al. (2013). Incidence and prevalence of multiple sclerosis in 
Europe: a systematic review. BMC Neurol 1: 128. 
Leist TP, Comi G, Cree BA, et al. (2014). Effect of Oral Cladribine on Time to Conversion to 
Clinically Definite Multiple Sclerosis in Patients with a First Demyelinating Event (ORACLE 
MS): A Phase 3 Randomised Trial. Lancet Neurol 13: 257-67. 
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the 2013 revisions. Neurology 83: 278-86. 
Montalban X, Cohen B, Leist T, et al. (2016). Efficacy of Cladribine Tablets as Add-On to IFN-
beta Therapy in Patients with Active Relapsing MS: Final Results from the Phase II ONWARD 
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Noseworthy JH, Lucchinetti C, Rodriguez M, et al. (2000). Multiple Sclerosis. N Engl J Med 343: 
938-52. 
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with multiple sclerosis taking cladribine. Neuroinflamm 2: e158. 
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with Multiple Sclerosis. Am J Manage Care 19: (S15-20). 

Company substance code: 
 
700568 
Protocol number: 
 
 
MS700568_0078 
 
 
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I N F O R M A T I O N 
57/61 
 
 
Wallin MT, Culpepper WJ, Campbell J, et al. (2019) The prevalence of multiple sclerosis in the 
United States: a population-based estimate using claims data. Neurology. 92 (10): e1029-e1040. 
Walton C, King R, Rechtman L, et al. (2020) Rising prevalence of multiple sclerosis worldwide: 
Insights from the Atlas of MS, third edition. Multiple Sclerosis Journal. 26 (14): 1816-1821. 
 
 

Company substance code: 
 
700568 
Protocol number: 
 
 
MS700568_0078 
 
 
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I N F O R M A T I O N 
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14 
Appendices 
14.1 
List of Stand-Alone Documents 
Not applicable. 
 
 
 

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