Cladribine Tablets: Observational Evaluation of Effectiveness and PROs in Suboptimally Controlled Patients Previously Taking Oral or Infusion DMDs for RMS (MASTER-2)
Conditions: Multiple Sclerosis
Sponsor: EMD Serono Research & Development Institute, Inc.

Company substance code: 
700568 
Protocol number: 
 
MS700568_0079 
 
 
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Non-Interventional Study Protocol 
Study Protocol Number 
MS700568_0079 
 
Title 
Cladribine tablets: Observational evaluation of effectiveness 
and patient-reported outcomes (PROs) in suboptiMAlly 
controlled patientS previously Taking oral or infusion 
disEase-modifying dRugs (DMDs) for relapsing forms of 
multiple sclerosis (RMS) (MASTER-2) 
 
Protocol Version Identifier 11.0 
 
Protocol Date/Version 
21 October 2024 / Version 11.0 
 
Replaces Version 
19 September 2024 / Version 10.0 
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 other oral or infusion disease-modifying drugs 
(DMDs) approved in the United States (US) for RMS in a 
real-world setting. Additionally, this study will separately 
describe real-world clinical and demographic characteristics 
among a sub-cohort of patients who transition from 
ocrelizumab to cladribine. 
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 
other oral or infusion DMDs approved in the US for RMS 

Company substance code: 
700568 
Protocol number: 
 
MS700568_0079 
 
 
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Secondary Objectives: 
 To assess patient-reported outcome (PROs), treatment 
adherence and treatment satisfaction during treatment 
with cladribine tablets 
 To assess treatment patterns (multiple sclerosis [MS] 
treatment prior to transition to cladribine tablets since MS 
diagnosis, concomitant treatment for MS during the last 
2 years prior to transition to cladribine tablets (or since 
MS diagnosis, if diagnosis <24 months), follow-up 
treatment in case of discontinuation of cladribine tablets); 
and in particular, to assess the clinical and demographic 
characteristics related to the sequential use of ocrelizumab 
and cladribine 
 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 and following 
treatment with cladribine tablets over a 24-month period 
 
Country of Study 
United States 
 
Author 
 
EMD Serono, Inc. 
A business of Merck KGaA, Darmstadt, Germany 
One Technology Place Rockland, MA 02370 
 
 
- Confidential – 
This document is the property of Merck KGaA, Darmstadt, Germany, or one of its subsidiaries. It is intended 
for restricted use only and may not – in full or part – be passed on, reproduced, published or used without 
express permission of Merck KGaA, Darmstadt, Germany, or its subsidiary. Copyright © 2018 by Merck 
KGaA, Darmstadt, Germany, or its subsidiary. All rights reserved. 
 
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Company substance code: 
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Protocol number: 
 
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1 
Table of Contents 
1 
Table of Contents .............................................................................. 3 
2 
List of Abbreviations......................................................................... 5 
3 
Responsible Parties ........................................................................... 7 
3.1 
Responsibilities of the Investigator .................................................... 8 
4 
Abstract ............................................................................................ 9 
5 
Amendments and Updates ............................................................... 16 
6 
Study Milestones ............................................................................. 28 
7 
Rationale and Background .............................................................. 29 
7.1 
Epidemiology of Multiple Sclerosis ................................................ 29 
7.2 
Clinical Presentation and Categorization of MS............................... 29 
7.3 
Treatment and Management of RMS ............................................... 29 
7.4 
Cladribine Tablets ........................................................................... 30 
8 
Research Question and Objectives ................................................... 31 
8.1 
Primary Objective ........................................................................... 32 
8.2 
Secondary Objectives ...................................................................... 32 
 
 
9 
Research Methods ........................................................................... 32 
9.1 
Study Design ................................................................................... 32 
9.1.1 
Design Overview ............................................................................ 32 
9.1.2 
Outcomes ........................................................................................ 36 
9.2 
Setting............................................................................................. 38 
9.2.1 
Study Population ............................................................................. 38 
9.2.2 
Definition of Study Cohorts and Description of Treatments............. 39 
9.2.3 
Observation Period .......................................................................... 39 
9.2.4 
Frequency of Assessments .............................................................. 39 
9.2.5 
Withdrawal from the Study ............................................................. 43 
9.3 
Variables ......................................................................................... 43 
9.4 
Data Source..................................................................................... 45 
 
 
9.6 
Data Management ........................................................................... 46 
9.7 
Data Analysis .................................................................................. 46 
9.7.1 
Analysis Sets ................................................................................... 47 
9.7.2 
Derived and Transformed Data........................................................ 47 
9.7.3 
Statistical Methods .......................................................................... 47 
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9.7.4 
Sequence of Analyses...................................................................... 48 
9.8 
Quality Control ............................................................................... 49 
9.9 
Limitations of the Research Methods .............................................. 49 
9.10 
Other Aspects.................................................................................. 49 
9.10.1 
Independent Ethics Committee or Institutional Review Board ......... 49 
9.10.2 
Monitoring ...................................................................................... 50 
9.10.3 
Health Authorities ........................................................................... 50 
9.10.4 
Quality Assurance ........................................................................... 50 
9.10.5 
Archiving ........................................................................................ 50 
10 
Protection of Human Patients .......................................................... 51 
10.1 
Patient Information and Informed Consent ...................................... 51 
10.2 
Patient Identification and Privacy .................................................... 51 
11 
Management and Reporting of Adverse Events ............................... 52 
11.1 
Adverse Events ............................................................................... 52 
11.2 
Severity of Adverse Events ............................................................. 54 
11.3 
Causality Assessment of Adverse Events ........................................ 54 
11.4 
Recording of Adverse Events .......................................................... 54 
11.5 
Safety Data Collection for Reporting ............................................... 55 
11.6 
Regulatory Reporting to the Health Authorities ............................... 58 
12 
Plans for Disseminating and Communicating Study Results ............ 58 
12.1 
Study Report ................................................................................... 58 
12.2 
Publication ...................................................................................... 58 
13 
References ...................................................................................... 59 
14 
Appendices ..................................................................................... 61 
14.1 
List of Stand-Alone Documents ...................................................... 61 
14.2 
Signature Pages and Responsible Persons for the Study................... 62 
Signature Page – Protocol Lead ..................................................................................... 62 
Signature Page – Principal Investigator ......................................................................... 63 
Sponsor Responsible Persons not Named on the Cover Page ......................................... 64 

Company substance code: 
700568 
Protocol number: 
 
MS700568_0079 
 
 
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2 
List of Abbreviations 
 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AESI 
Adverse Event 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 
CSR 
Clinical Study Report 
CU 
Combined Unique 
DMD 
Disease-Modifying Drug 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EDSS 
Expanded Disability Status Score 
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 
 
 
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 
CCI

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Protocol number: 
 
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PRO 
Patient-Reported Outcome 
RMS 
Relapsing forms 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 

Company substance code: 
700568 
Protocol number: 
 
MS700568_0079 
 
 
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3 
Responsible Parties 
Responsible Parties 
Contact details 
Investigators 
The name and contact information of all investigators will be 
maintained by the MAH/MAH’s representative(s) in a separate 
document. 
 
Operational Study Lead 
 
 
  
 
EMD Serono, Inc. 
A business of Merck KGaA, Darmstadt, Germany 
One Technology Place Rockland, MA 02370, USA 
 
  
 
Protocol Medical Lead 
 
 
 
EMD Serono, Inc. 
A business of Merck KGaA, Darmstadt, Germany 
One Technology Place Rockland, MA 02370, USA 
 
 
 
Contract Research 
Organization 
 
 
 
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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. 
 

Company substance code: 
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Protocol number: 
 
MS700568_0079 
 
 
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4 
Abstract 
Title 
Cladribine tablets: Observational evaluation of effectiveness and 
patient-reported outcomes (PROs) in suboptiMAlly controlled 
patientS previously Taking oral or infusion disEase-modifying dRugs 
(DMDs) for relapsing forms of multiple sclerosis (RMS) (MASTER-
2) 
Protocol Version 11.0, 21 October 2024 
 
EMD Serono, Inc. 
A business of Merck KGaA, Darmstadt, Germany 
One Technology Place Rockland, MA 02370, USA 
E-mail:
 
Rationale and 
background 
Multiple sclerosis (MS) is an immune-mediated, chronic inflammatory 
disease of the central nervous system (CNS) characterized by the 
demyelination and destruction of axons. According to a recent study 
by the National Multiple Sclerosis Society, there are approximately 
1,000,000 persons in the United States (US) living with MS. 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. Approximately 85% of patients 
with MS initially have RMS which is characterized by alternating 
periodic acute exacerbations of disease activity (relapses) and periods 
of remission, consisting of partial or complete recovery. 
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 magnetic resonance imaging 
(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. 
Because they are not curative, most DMDs are generally 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. 
Cladribine (2-chloro-2'-deoxyadenosine [2-CdA]) is a synthetic 
anti-neoplastic drug that belongs to the subgroup of agents called 
purine analogs. 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 Food and Drug Administration (US FDA) in 2019. Data 
about the safety and effectiveness of cladribine tablets in real-world 
clinical settings are currently limited. Real-world data are also limited 
about patients’ adherence to treatment with cladribine tablets, 
patient-reported outcomes (PROs), and treatment patterns for RMS 
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Company substance code: 
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Protocol number: 
 
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before, during, and after treatment with cladribine tablets in patients 
with suboptimal response to prior oral or infusion 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 other oral DMDs or any infusion DMDs approved in the US for 
RMS in a real-world setting. Additionally, this study will separately 
describe real-world clinical and demographic characteristics that 
contribute to sequential treatment patterns among a sub-cohort of 
patients who transition from ocrelizumab to cladribine. 
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 other oral DMDs or any infusion 
DMDs 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); and in particular, 
to assess the clinical and demographic characteristics related to the 
sequential use of ocrelizumab and cladribine 
 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 and following 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 
an oral DMD or an infusion 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 

Company substance code: 
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Protocol number: 
 
MS700568_0079 
 
 
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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 followed up until the end of the observation period, irrespective 
if they discontinue cladribine tablets during follow-up. 
Baseline data on previous MS DMD use, relapses during the previous 
2 years (or since MS diagnosis, if diagnosis <24 months), and available 
baseline MRI data will be collected 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 Months 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 oral DMD 
treatment other than cladribine tablets or infusion DMD treatment 
6. Had received their last previous oral DMD for at least 1 month or 
at least 1 dose of their last previous infusion DMD 
7. Have decided to initiate treatment with cladribine tablets during 
routine clinical care (i.e. before enrollment) 
1. Meet criteria as per the approved USPI 
2. 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 oral or infusion DMD solely for 
administrative reasons such as relocation 

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MS700568_0079 
 
 
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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 Months 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 Patient Determined Disease Steps (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 
once or twice daily oral dosing to assess adherence during last 
previous oral DMD treatment or modified for infusion dosing to 
assess adherence to last previous infusion 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: 

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o Previous DMD(s) received for MS prior to study enrollment, 
since MS diagnosis 
o Reasons for discontinuation of previous DMD(s) 
 Assessment of clinical and demographic characteristics of patients 
who transition from ocrelizumab to oral cladribine tablets 
o Reasons for discontinuation of ocrelizumab 
 Proportion of patients who discontinue oral cladribine tablets 
o Reason for discontinuation of cladribine tablets 
o Elapsed time to discontinuation after first dose 
o Number of doses and % of planned doses (as per USPI) 
received 
o Subsequent treatment chosen following discontinuation of 
cladribine tablets 
 Assessment of concomitant MS medications used during study 
period 
 The ARR based on the last 24 months (or since MS diagnosis, if 
diagnosis <24 months) prior to the start of treatment with 
cladribine tablets (retrospective data) 
 All SAEs, ADRs, AESIs and special situations over a 24-month 
period 
 Absolute lymphocyte count (ALC) assessed as per USPI 
 Complete blood count (CBC) and lymphocyte subset information 
as assessed per routine clinical practice 
Variables 
 Baseline characteristics of patients initiating cladribine tablets: 
age, sex, weight, race/ethnicity, elapsed time since diagnosis of 
MS, elapsed time since first symptoms of MS 
 Medical history (including prior medications for MS) 
 Physical and neurological examinations 
 MRI results 
 Hematological assessments 
 ePRO assessments results 
 Relapse information 
Data sources 
Data sources for this study will include data extracts from patients’ 
medical records performed by site personnel as well as questionnaires 
directly filled out by patients. 
The data to be collected in the study will be obtained by means of 
electronic Case Report Forms (eCRFs).  

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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., for all patients, unless Year 
2 treatment is delayed in which case the final safety assessment would 
occur at Month 30.  
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]): 31-July-2019 
75 Patients Consented: 28 Feb 2020 
150 Patients Consented: 30-Nov-2020 
Last Patient First Visit (last patient to sign ICF): 28-Nov-2022 
Last Patient Last Visit: 03-Jan-2025 
CCI

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Database Lock: 17-Feb-2025 
Key Stats Available: 14-Jul-2025 
Clinical Study Report: 19-Sep-2025 
 

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5 
Amendments and Updates 
 
Amendment 
Number 
Protocol 
Version 
Date 
Section of 
Study 
Protocol 
Amendment or 
Update 
Reason 
1 
Version 2 
12/11/2018 
Section 3 
Operational 
Study Lead was 
updated 
Administrative 
Sections 4 and 
9  
MS-TEQ was 
replaced by MS-
TAQ, modified 
versions 
To adequately assess 
treatment adherence 
2 
Version 3 
02/14/2019 
Section 3 
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 
Section 9.1.1 
Updated Figure 1 
For added clarity 
Sections 4 and 
9.1.1 
Clarified 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 

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Protocol number: 
 
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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 
3 
Version 4 
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 

Company substance code: 
700568 
Protocol number: 
 
MS700568_0079 
 
 
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Amendment 
Number 
Protocol 
Version 
Date 
Section of 
Study 
Protocol 
Amendment or 
Update 
Reason 
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 
Title page, 
Sections 4, 
7.4, 8, 8.1 and 
9.2.1 
Clarified that 
indication for 
cladribine tablets 
is RMS, 
including RRMS 
and aSPMS 
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 9.2.4 
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 
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 

Company substance code: 
700568 
Protocol number: 
 
MS700568_0079 
 
 
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Amendment 
Number 
Protocol 
Version 
Date 
Section of 
Study 
Protocol 
Amendment or 
Update 
Reason 
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 
 
 
 
 
 
 
 
 
 
To align the objective 
with the proposed 
endpoints collected in 
the study 
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 
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 
CCI

Company substance code: 
700568 
Protocol number: 
 
MS700568_0079 
 
 
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Amendment 
Number 
Protocol 
Version 
Date 
Section of 
Study 
Protocol 
Amendment or 
Update 
Reason 
Section 9.2.4 
Assessment of 
 was 
moved from the 
Table 1. 
Schedule of 
Assessments 
table to a 
footnote 
For added clarity since 
 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 
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 
4 
Version 5 
8/19/2019 
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 
CCI
CCI

Company substance code: 
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Protocol number: 
 
MS700568_0079 
 
 
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Amendment 
Number 
Protocol 
Version 
Date 
Section of 
Study 
Protocol 
Amendment or 
Update 
Reason 
Sections 4, 
9.2.1, and 11.4 
Updated 
inclusion criteria 
regarding 
treatment period 
of prior oral 
DMD to at least 
1 month 
(changed from at 
least 3 months) 
To allow enrollment of 
patients who might 
have discontinued 
previous oral DMD due 
to intolerability within 
less than 3 months 
Sections 4, 
9.2.1, and 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 
Title page and 
Sections 4, 
8.1, 9.1.1, and 
9.2.1 
Clarified that 
enrollment 
includes patients 
who are 
switching from 
infusion 
treatment to 
cladribine in 
addition to those 
previously 
treated with other 
oral DMDs 
To allow enrollment of 
patients who are 
transitioning from an 
infusion DMD to 
cladribine tablets as it 
was observed that a 
substantial proportion 
of patients who are 
initiating cladribine 
tablets are transitioning 
from an infusion DMD 
Sections 4, 
9.1.2.2, 9.2.4, 
and 9.7.3 
Updated 
description of 
MS-TAQ which 
was also 
modified to 
assess adherence 
to previous 
infusion DMD 
Since 
inclusion/exclusion 
criteria were expanded 
to also allow 
enrollment of patients 
transitioning from 
infusion DMD to 
cladribine tablets, the 
MS-TAQ had to be 
modified accordingly 
as well 
Sections 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 
Clarified that 
pregnancy, HIV, 
and Hep B & C 
assessments will 
be collected at 
Month 12 
To align with the USPI 

Company substance code: 
700568 
Protocol number: 
 
MS700568_0079 
 
 
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Amendment 
Number 
Protocol 
Version 
Date 
Section of 
Study 
Protocol 
Amendment or 
Update 
Reason 
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 
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 

Company substance code: 
700568 
Protocol number: 
 
MS700568_0079 
 
 
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Amendment 
Number 
Protocol 
Version 
Date 
Section of 
Study 
Protocol 
Amendment or 
Update 
Reason 
5 
 
Version 6 
7/13/2021 
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  
Section 9.1.1 
Figure 1 
Figure 1 updated 
to reflect 
population 
including 
patients who 
have been 
diagnosed at least 
12 months prior 
(previously at 
least 24 months). 
Additionally, 
Figure 1 was 
updated to reflect 
Table 1 
(Schedule of 
Assessments) 
Updated to align with 
inclusion criteria and 
Schedule of 
Assessments 
Sections 8.2, 
9.2.3, 9.2.4 
(Table 1), 9.7, 
11.4, Section 
9.1.1 (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) 

Company substance code: 
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Protocol number: 
 
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Amendment 
Number 
Protocol 
Version 
Date 
Section of 
Study 
Protocol 
Amendment or 
Update 
Reason 
Sections 7.1, 
7.3, 8, 8.2, 
9.1.2.2, 9.2.2, 
9.3, and 13  
Added language 
incorporating 
patients who 
switch from 
ocrelizumab to 
cladribine tablets  
Additional patients are 
being introduced to the 
study as a sub cohort in 
order to better 
understand clinical 
and/or demographic 
characteristics that may 
potentially influence 
the patient decision to 
switch from 
ocrelizumab to 
cladribine  
Sections 9.3 
and 9.2.4 
(Table 1) 
Added capture of 
immunoglobulin 
levels (if 
assessed by the 
investigator) 
Immunoglobulin levels 
will be collected (if 
monitored by 
investigator during 
routine clinical 
practice) for additional 
clinical context of the 
ocrelizumab cohort  
Sections 6 and 
12.1 
Updated study 
report delivery 
schedule and 
associated 
milestones table 
Updated given safety 
extension 
6 
Version 7 
7/13/2021 
Sections 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 
Sections 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 

Company substance code: 
700568 
Protocol number: 
 
MS700568_0079 
 
 
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Amendment 
Number 
Protocol 
Version 
Date 
Section of 
Study 
Protocol 
Amendment or 
Update 
Reason 
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 
Section 9.1.1 
Updated figure 
text to reference 
transition from 
oral/infusion 
medications, not 
injectables 
Corrected from prior 
error 
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 
CSR addendum 
dates to study 
milestones table 
Added for more 
precision 
Signature page 
Added additional 
context to the PI 
signature page 
Added to align with 
standard signature page 
language 
7 
Version 8 
7/1/2022 
Section 9.2.4: 
Table 1, 
Figure 1 
Increased pre-
baseline 
screening 
window to 60 
days from 45 
To accommodate the 
current insurance 
approval and drug 
shipment timelines 

Company substance code: 
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Protocol number: 
 
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Amendment 
Number 
Protocol 
Version 
Date 
Section of 
Study 
Protocol 
Amendment or 
Update 
Reason 
8 
Version 9 
9/10/2024 
Section 4, 
Section 8.2, 
Section 9.1.1, 
Figure 1,  
Section 
9.1.2.2, 
Section 
9.1.2.3,  
Section 9.2.3,  
Section 9.2.4,  
Table 1,  
Section 9.3, 
Section 9.7,  
Section 9.7.3,  
Section 9.7.4,  
Section 11.4, 
Section 12.1 
Removed 2-year 
safety extension 
and affiliated 
data collections 
items and 
timepoints 
To accommodate early 
study closure as 
determined by Sponsor 
Section 4, 
Section 6 
Updates to study 
milestones: 
removing safety 
extension period; 
LPI updated to 
actual date (28 
Nov 2022) and 
LPO updated to 
3rd Jan 2025. All 
subsequent 
milestones 
updated 
accordingly 
As per Sponsors 
request 
Section 4 
ePRO 
assessments and 
relapse 
information 
added to 
variables section 
in the protocol 
abstract 
To provide a more 
comprehensive 
summary of variables 
to address the primary 
and secondary 
objectives of the study 
in the protocol abstract 
Cover page, 
Section 3, 
Section 4, 
Section 14.2 
Updated to 
Angela Chandler, 
MD 
As per Sponsors 
request 
Section 3, 
Section 14.2 
Removed Lead 
PI 
As per Sponsors 
request / Addendum 
provided 

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Protocol number: 
 
MS700568_0079 
 
 
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Amendment 
Number 
Protocol 
Version 
Date 
Section of 
Study 
Protocol 
Amendment or 
Update 
Reason 
9 
Version 10 
9/19/2024 
Section 11.5 
Contacts of the 
Safety Check 
Desk and 
Sponsor Safety 
department 
updated;  
Reporting events 
via Safety Check 
Desk clarified. 
To align with the 
Safety Management 
Plan as the main 
operational document 
for safety reporting. 
10 
Version 11 
10/21/2024 
Section 14.2 
Signature Page 
Reinstated PI 
signature page 
erroneously 
removed from 
protocol v9.0 and 
subsequently 
missing from 
v10.0. 
Administrative. Whilst 
Lead PI and 
requirement for Lead 
PI signature was 
removed in v9.0 
onwards (see protocol 
addendum dated 
September 10, 2024), 
the PI protocol 
signature page in its 
entirety was 
erroneously removed 
from v9.0 and 
subsequently missing 
form v10.0.  
This page is still 
required for Site PI 
approval/signature of 
the protocol as also 
stated in the 
aforementioned 
addendum. 

Company substance code: 
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Protocol number: 
 
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6 
Study Milestones 
Milestones 
Planned date 
First Patient First Visit (first patient to sign 
Informed Consent Form [ICF])  
31-July-2019* 
75 patients consented 
28-Feb-2020* 
150 patients consented 
30-Nov-2020* 
Last Patient First Visit (last patient to sign ICF) 
28-Nov-2022* 
Last Patient Last Visit 
03-Jan-2025 
Database Lock 
17-Feb-2025 
Key Stats Available 
14-Jul-2025 
Clinical Study Report  
19-Sep-2025 
 
 
n.b. Timelines are based on estimated date of FDA approval (01-April-2019) 
*Actual recorded dates 

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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 most recent 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 forms 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 mechanisms of action have been shown to have beneficial 

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effects. The medications that have received labels from the US Food and Drug 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. Patients with relapsing-remitting multiple sclerosis (RRMS) 
typically require more than one DMD during their clinical course. Because they are not 
curative, most DMDs are generally continued indefinitely unless they are ineffective or not 
tolerated. There is currently no standard protocol to guide the choice of DMD 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 
indicted for the treatment of patients with RMS, including 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 
CCI

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zoster infection were 0.86 adjusted 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 
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 FDA in the US. Real-world data are also limited about patients’ adherence to treatment 
with cladribine tablets, patient-reported outcomes (PROs), and treatment patterns for RMS 
before, during, and after treatment with cladribine tablets in patients with suboptimal response 
to prior oral or infusion 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 other oral DMDs or any infusion DMDs approved in the US for 
RMS in a real-world setting. Additionally, this study will separately describe real-world 
clinical and demographic characteristics among a sub-cohort of patients who transition from 
ocrelizumab to cladribine. 

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MS700568_0079 
 
 
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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 other oral or infusion DMDs 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); and in particular, to assess the clinical and 
demographic characteristics related to the sequential use of ocrelizumab and cladribine 
 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 (AESI) and special situations during and following treatment with 
cladribine tablets over a 24-month period 
 
 
 
 
 
 
 
 
 
 
9 
Research Methods 
9.1 
Study Design 
9.1.1 
Design Overview 
This is a prospective, observational, multicenter, 30-month, Phase IV study. Sites in the US 
who are known to treat patients with MS will be targeted for enrollment. Patients who had 
decided prior to enrollment to transition from an oral DMD or an infusion 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. 
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Baseline PROs, MRI and treatment adherence data will be collected before the first dose of 
cladribine tablets is taken. Baseline data on previous MS DMD use and relapses during the 
previous 2 years (or since MS diagnosis, if diagnosis <24 months) will be collected 
retrospectively at the Baseline Visit. All treatment decisions are at the discretion of the 
investigator. Patients will be followed up until the end of the observation period, irrespective 
if they discontinue cladribine tablets during follow-up. 
During the observation period, patients will attend visits as per routine clinical practice, which 
are expected to happen approximately at the end of Months 2, 6 and 12 during Year 1, and at 
the end of Months 14, 18, and 24 during (i.e. after the second course of treatment during 
Year 2), as clinically indicated. 
Post-enrollment relapse count data will be collected at Month 12 (end of Year 1) and Month 24 
(end of Year 2) only. Treatment adherence data during treatment with cladribine tablets will 
be collected at the end of Months 1, 2, 13, and 14, while other PROs will be collected at the 
end of Months 6, 12 and 241.
Investigators are expected to assess patients’ absolute lymphocyte count (ALC) in accordance 
with the USPI and to follow any other recommended monitoring and guidance as specified in 
the USPI. Based on this, investigators are expected to assess the ALC before initiating 
cladribine tablets in Year 1, before initiating cladribine tablets in Year 2, as well as 2 
and 6 months after start of treatment in each treatment year or as clinically indicated. It is 
assumed that investigators will not exclusively assess the ALC, but rather the complete blood 
count (CBC) and, at some of these time points, also lymphocyte subsets and certain 
 
 These data will be collected as 
available. 
Patients with lymphopenia resulting in delay of the scheduled Year 2 treatment course are 
expected to receive the second treatment course once the lymphocyte count is appropriate 
(≥800 cells per microliter) consistent with USPI labeling and will be followed up until the end 
of the observation period. If the ALC drops to <500 cells per microliter, the patient should be 
actively monitored until values increase as per USPI. If the ALC drops to <200 cells per 
microliter, anti-herpes prophylaxis should be administered, and the patient should be monitored 
for infections. Such unscheduled additional hematology assessments as per clinical 
requirements should be documented as well. 
An overview of the study design is shown in Figure 1. 
Visits and assessments are detailed in the Schedule of Assessments (see Section 9.2.4). 
 
                                               
1 If Year 2 treatment is delayed, final follow up visit may occur at Month 30 
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Figure 1. Study Design Schematic 
 
a Duration between stopping previous oral or infusion 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. 

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Abbreviations: AEs=adverse events, ALC=absolute lymphocyte count, ARR=Annualized Relapse Rate, BV=Baseline Visit, BDI-FS=Beck-Depression Inventory – Fast Screen, 
CBC=complete blood count, DMD=disease-modifying drug, ePRO=electronic Patient-Reported Outcome, m=month, 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, pts=patients, SF-36=36-Item Short Form Health Survey, TSQM=14-Item Treatment Satisfaction Questionnaire for Medication, Tx=Treatment, 
US=United States, USPI=United States Prescribing Information, V=visit, WPAI-MS=Work Productivity Activity Impairment – MS.

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Protocol number: 
 
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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 Months 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. 

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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). 
 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 once or twice daily oral dosing to assess adherence during last previous oral 
DMD treatment or modified for infusion dosing to assess adherence to last previous infusion 
DMD treatment) and at the end of Months 1, 2, 13, and 14 (modified for cladribine tablets); a 
Spanish translation is available to patients. 
 Proportion of patients experiencing a relapse. For this study, a relapse will be defined as 
determined and recorded by the investigator and information on the definition used by the 
investigator will be collected (see Section 9.1.2.1 for a guide on definition). 
 Proportion of patients with relapse associated with hospitalization (relapse as primary 
diagnosis or reason for hospitalization). For this study, a relapse will be defined as determined 
by the investigator (see Section 9.1.2.1 for a guide on definition). 
 Proportion of patients with relapse associated with glucocorticoid use. For this study, a relapse 
will be defined as determined by the investigator (see Section 9.1.2.1 for a guide on definition). 
 Assessment of previous treatment for MS:  
o Previous DMD(s) received for MS prior to study enrollment, since MS diagnosis 
o Reasons for discontinuation of previous DMD(s) 
 Assessment of clinical and demographic characteristics of patients who switch from 
ocrelizumab to oral cladribine tablets 
o Reasons for discontinuation of ocrelizumab 
 Proportion of patients who discontinue oral cladribine tablets 
o Reason for discontinuation of cladribine tablets 
o Elapsed time to discontinuation after first dose 
o Number of doses and % of planned doses (as per USPI) received 
o Subsequent treatment chosen following discontinuation of cladribine tablets 
 Assessment of concomitant MS medications used during study period 
 The ARR based on the last 24 months (or since MS diagnosis, if diagnosis <24 months) prior 
to the start of treatment with cladribine tablets (retrospective data). For this study, a relapse 
will be defined as determined by the investigator (see Section 9.1.2.1 for a guide on definition). 
9.1.2.3 
Safety 
 All SAEs, ADRs, AESIs and special situations over a 24-month period 
 ALC assessed as per USPI 
 CBC and lymphocyte subset information as assessed per routine clinical practice 

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9.2 
Setting 
9.2.1 
Study Population 
The study population will be identified according to the below inclusion and exclusion criteria. 
For inclusion in the study, all of the following inclusion criteria must be fulfilled: 
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 oral DMD treatment other than cladribine tablets or 
infusion DMD treatment 
6. Had received their last previous oral DMD for at least 1 month or at least 1 dose of their 
last previous infusion DMD 
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 
 
Patients are not eligible for this study if they fulfill any of the following exclusion criteria: 
1. Have been previously treated with cladribine in any dosing form (intravenous, 
subcutaneous, or oral) 
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2. Transitioning from previous oral or infusion DMD solely for administrative reasons such 
as relocation 
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 
9.2.2 
Definition of Study Cohorts and Description of Treatments 
The study will have a single primary cohort that consists of all patients enrolled in the study who 
received at least 1 dose of cladribine tablets. Additionally, a sub-cohort of approximately 100 
patients that directly switched from ocrelizumab to cladribine tablets will be prospectively 
enrolled. All treatment and other medical decisions will be made by the investigator, with no 
directives mandated by this study protocol. 
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 additional cladribine tablet 
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 and patient access to cladribine 

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MS700568_0079 
 
 
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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 the initial 
month dose of cladribine tablets 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. 
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 
oral or infusion 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. 
 
 

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Table 1. Schedule of Assessments 
Assessments 
Data collection time points (as expected based on routine clinical practice) 
Pre-baseline 
Screening 
Visit 
Baseline 
Visit a 
PRO 
Only b 
Visit 
#1 
Visit 
#2 
Visit 
#3 
PRO 
Only b 
Visit 
#4 
Visit 
#5 
Visit 
#6 
(Days -60 to 
0) 
Month 0 
Month 
1 
Month 
2 
Month 
6 
Month 
12 
Month 
13 
Month 
14 
Month 
18 
Month 
24j 
Informed consent 
X 
  
  
  
  
  
  
  
  
  
Medical history, previous 
relapses, previous DMD 
treatment 
  
X 
  
  
  
  
  
  
  
  
Inclusion / exclusion criteria 
X 
  
  
  
  
  
  
  
  
  
Demographic data 
X 
  
  
  
  
  
  
  
  
  
Pregnancy test, HIV, hepatitis 
B and 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, immunoglobulins) 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 

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Assessments 
Data collection time points (as expected based on routine clinical practice) 
Pre-baseline 
Screening 
Visit 
Baseline 
Visit a 
PRO 
Only b 
Visit 
#1 
Visit 
#2 
Visit 
#3 
PRO 
Only b 
Visit 
#4 
Visit 
#5 
Visit 
#6 
(Days -60 to 
0) 
Month 0 
Month 
1 
Month 
2 
Month 
6 
Month 
12 
Month 
13 
Month 
14 
Month 
18 
Month 
24j 
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 
 
  
 
  
 
 
 
  
 
 
 
a Duration between end of previous treatment and start of cladribine tablets is at the discretion of the investigator. 
b At the PRO only time point, patients fill out the PROs at their home; patients do not come to the clinic for filling out PROs at these time points. 
c Cladribine tablets are expected to be taken according to the USPI. If cladribine tablets are discontinued, reasons for discontinuation and follow-up MS treatment will be collected. 
d Relapse count includes relapses associated with hospitalization and/or glucocorticoid use.  
e For baseline MRI documentation sites are asked to record patients’ most recent MRI results prior to starting cladribine tablets, which is expected to have been taken within the prior 90 days. During 
follow-up, MRI scans are provided as available per routine practice. MRI documentation collected at baseline and follow-up are assessed by a central neuroradiology center. Specific instructions for 
transfer of the MRIs to the central neuroradiology center will be provided in a separate manual. 
f Investigators are expected to assess patients’ ALC in accordance with the USPI, that is, before initiating cladribine tablets in Year 1, before initiating cladribine tablets in Year 2, and 2 and 6 months 
after start of treatment in each treatment year or as clinically indicated. It is assumed that investigators will not exclusively assess the ALC, but rather the CBC and, at some of these time points, also 
lymphocyte subsets. These data will be reported as available from routine practice. If the investigator assesses 
, these data should be recorded as well. 
g Treatment adherence questions, based on modified versions of the MS-TAQ, will be completed by patients via ePRO: at Baseline Visit (modified for once or twice daily oral dosing to assess adherence 
during last previous oral DMD treatment or modified for infusion dosing to assess adherence during last previous infusion DMD treatment) as well as at the end of Month 1, Month 2, Month 13, and 
Month 14 (modified for cladribine tablets). 
h Baseline PRO scales will be completed before first cladribine tablet dose is taken. 
i Adverse events,
, relapse count, PDDS score and MRI data will be collected as per running page and will be recorded on an ongoing basis as new information is collected 
for up to 24 months (or 30 months if treatment is delayed).  
j If Year 2 treatment is delayed, final follow-up visit may occur at Month 30. 
Abbreviations: ALC=absolute lymphocyte count, BDI-FS=Beck-Depression Inventory-Fast Screen, CBC=complete blood count, DMD=disease-modifying drug, ePRO = electronic Patient-Reported 
Outcome, HIV=human immunodeficiency 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, PRO=Patient-Reported Outcome, SF-36=36-Item Short Form Health Survey; 
TSQM=14-Item Treatment Satisfaction Questionnaire for Medication, USPI=US Prescribing Information; WPAI-MS=Work Productivity Activity Impairment – MS. 
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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 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
 
 
 
 
 Results of MRI in the 2 years prior to study enrollment or since MS diagnosis, if diagnosis <24 
months 
 
 
 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
 or immunoglobulin levels, 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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Follow-Up Visits 
The anticipated timing of assessments is presented in Table 1: Schedule of Assessments. 
 Medication log of cladribine tablets treatment during the study period, including medication 
start dates, medication stop dates, medication dose (mg), number of dose and reasons for 
discontinuation 
 Medication log containing other MS DMD treatments (if applicable) during the study period, 
including medication doses and routes of administration, start dates, stop dates and reasons for 
discontinuation 
 Relapse of MS during the study period as determined by the investigator (see Section 9.1.2.1 
for a guide on definition) including date of onset, resolution of relapse and definition for relapse 
used  
 Relapse of MS associated with hospitalization (relapse as primary diagnosis or reason for 
hospitalization) during the study period as determined by the investigator (see Section 9.1.2.1 
for a guide on definition) including date of onset, resolution of relapse and definition for relapse 
used 
 Relapse of MS associated with glucocorticoid use during the study period as determined by 
the investigator (see Section 9.1.2.1 for a guide on definition) including date of onset, 
resolution of relapse and definition for relapse used 
 MRI scans from all MRIs performed during the study period; MRI scans are assessed by a 
central neuroradiology center; data includes: 
 
 
 
 
 Results of neurological examination as per standard of care (Kurtzke FSS, ambulation up to 
5000 meters and EDSS) 
 Hematology assessment (white blood cell count, hemoglobin, hematocrit, platelet count, 
ALC). If the investigator assesses 
 or immunoglobulin levels, these data should be 
recorded as well 
 Pregnancy, HIV, hepatitis B, hepatitis C and tuberculosis test results 
 Comorbid conditions 
 
 
 
 AEs as a continuous log 
 ePRO assessments (treatment adherence questions based on modified versions of the 
MS-TAQ, TSQM, SF-36, MFIS-5, BDI-FS, WPAI-MS, PDDS) 
Derived and transformed data needed for the analysis are described in Section 9.7.2. 
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9.4 
Data Source 
Data sources for this study will include data extracts from patients’ medical records performed by 
site personnel as well as questionnaires directly filled out by patients. The data to be collected in 
the study will be obtained by means of an Electronic Data Capture (EDC) system. The data in the 
electronic Case Report Form (eCRF) should be consistent with the relevant source documents. 
Further details are provided in Section 9.6. 
Each patient will be able to be identified from their patient file. Additionally, any other 
documents containing source data must be filed (e.g., laboratory value listings, etc.). Such 
documents must bear at least the patient number and the date when the procedure was performed. 
Information should be printed by the instrument used to perform the assessment or measurement, 
if possible. Information that cannot be printed by an automated instrument will be entered 
manually. Medical evaluation of such records should be documented as necessary and the 
documentation signed and dated by the investigator. 
Patient questionnaire data will be recorded directly via EDC rather than entered into the patient’s 
original medical file. In such cases there will be no record in the original patient file (either on 
paper or electronically) that corresponds to the entries. For all PROs, the patient will enter data 
directly with a validated ePRO. 
 
 
 
 
 
 
 
 
 
 
 
 
 
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will also be assessed at Month 6 for the first 30 patients enrolled as well as at Months 12 and 24, 
for all patients, 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 
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. 

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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 once or twice daily oral dosing to assess adherence during 
last previous oral DMD treatment or modified for infusion dosing to assess adherence during last 
previous infusion DMD treatment), and for the first and second course of treatment with cladribine 
tablets during the first and second treatment year (modified for cladribine tablets). 
Other PROs: For each ePRO score (TSQM-14, SF-36, MFIS-5, BDI-7, WPAI-MS, and PDDS), 
the actual value at each visit and change in scores from Baseline to Month 6, 12 and 242 will be 
described. 
Treatment patterns: Prior treatment patterns will be described at baseline (previous DMD 
treatment(s) and baseline characteristics of patients initiating cladribine tablets). Treatment 
discontinuation of cladribine tablets and the reasons for discontinuation will be described, as will 
be the follow-up treatments. 
Annualized Relapse Rate (retrospective assessment): The ARR during the last 24 months before 
starting cladribine tablets (or since MS diagnosis, if diagnosis <24 months) will be presented, 
accompanied by the respective 95% CIs. 
 
 
 
 
 
 
Safety: All safety data (AEs and hematology data, including lymphocyte subtype data, as 
available) will be evaluated descriptively. 
9.7.4 
Sequence of Analyses 
There will be a baseline analysis, 3 interim analyses and a final analysis. Interim analyses are 
mainly descriptive and for monitoring purposes. Multiplicity corrections will not be considered. 
 Baseline analysis: baseline characteristics of patients initiating cladribine tablets, baseline PRO 
data, baseline laboratory data, baseline data on previous MS DMD use, relapses during the 
previous 2 years (or since MS diagnosis if diagnosis <24 months), baseline MRI data and past 
treatment adherence will be analyzed. 
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 First interim analysis: 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. This will be conducted 
primarily for evaluation of safety. 
 Second interim analysis: safety, adherence and PRO data will be analyzed as soon as 6-month 
data are available for all patients. 
 Third interim analysis: full data analyses will be performed on the 12-month data for all 
patients. 
 Final analysis: full data analyses will be performed on the 24-month data for all patients at the 
end of the study. The final analysis will include the endpoint analyses illustrated in 
Section 9.7.3 as well as a comparison of characteristics of patients completing the study vs. 
those who drop out. 
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 

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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. 
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. 

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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 
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 
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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. 
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 Reaction 
An SAE/ Serious Adverse Reaction (SAR) is any AE/ADR as defined above, which also fulfills 
at least one of the seriousness criteria below: 

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 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 
1Life 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. 
2Medical 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. 
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 Event of Special Interest 
An 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 as Adverse Events 

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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). 
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),
, 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  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 (SAEs and AESI), 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 
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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. 
Pregnancy and Breastfeeding. Pregnancy or breastfeeding must be recorded in the CRF and 
additionally be reported to the Sponsor immediately (within 24 hours of awareness) by using 
separate data collection forms for pregnancy, independent if an AE was reported or not (this 
includes male patients whose partner becomes pregnant during the cladribine treatment period). 
The outcome of the pregnancy should be followed up and reported to the Sponsor until delivery. 
In the event of a pregnancy occurring during the cladribine treatment period, the female patient 
must be discontinued from cladribine tablets immediately. 
Request for immediate discontinuation of study drug. In accordance with the USPI, patients 
should discontinue cladribine tablets if they become pregnant during the cladribine treatment 
period, become infected with HIV, develop an active chronic infection (hepatitis or tuberculosis) 
or develop moderate or severe renal impairment (creatinine clearance <60 milliliter per minute). 
11.5 
Safety Data Collection for Reporting 
Safety Data Collection Forms: 
The following safety data collection forms are used in this study: 
 (S)AE Report Form 
 Pregnancy Report Form 
 Parent-Child/Fetus AE Report Form 
 AESI Report Form 
Reportable Events 
The following events are reportable to the 
 
 
(Safety Check Desk) (via Fax: 
 or E-
 within 24 hours of awareness: 
 All SAEs (related or unrelated) are to be reported independent of their relationship to the study 
drug by entering the event onto the eCRF or via the SAE paper report form in the event of 
eCRF outage 
 AESIs should be reported if non-serious via the eCRF or via the AESI paper reporting form in 
the case of an eCRF outage and if serious following the procedure for an SAE, as described 
 Non-serious ADRs are to be reported within 4 calendar days via the eCRF directly to the 
Sponsor Global Patient Safety (contact below), or via the ADR paper reporting form in the 
case of an eCRF outage 
PPD
PPD
PPD
PPD
PPD

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 Pregnancy or lactation is to be reported by entering the event of pregnancy on to the relevant 
eCRF pages in conjunction with completing and sending the Pregnancy Report Form 
 All events that occur in a Child/Fetus of a pregnant woman who was exposed to the study drug 
are to be reported via the eCRF or via the paper reporting form in the case of an eCRF outage 
 Special situations (see definition in Section 11, including pregnancy, overdose, off-label use, 
misuse, medication error, occupational exposure, lack of therapeutic effectiveness) should be 
reported on the (S)AE Report Form by indicating whether serious or not 
All reportable events shall be reported via the Safety Check Desk, except for NSADRs that shall 
be reported directly to GPS. 
 
Procedure for Safety Data Reporting (Completion and Forwarding) 
For any new events that are serious, fatal or related to a special situation the investigator/healthcare 
provider must immediately (within 24 hours after becoming aware of the event) report the event 
via the eCRF or via the paper reporting form in the case of an eCRF outage. For all events that are 
non-serious an electronic data transfer (or paper form in case of eCRF outage) must be transmitted 
within 4 calendar days to Sponsor, including the 
 
 
 if applicable. The 
investigator must respond to any request by CRO for follow-up information, as noted above for 
initial 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. 
 Lifecycle Safety (Safety Check Desk): 
 E-mail:
 
 Fax: 
 
Global Patient Safety: 
 E-mail: 
 
 Fax: 
 
The data entered on the safety data collection forms must be consistent with the information 
recorded in the CRF. If some data are missing, the form should be completed with the available 
data and a follow-up report will be sent as soon as possible. The minimum information to be 
included in the initial report is the following: 
 Investigator name and contact details 
 Patient identification (e.g., ID number, gender, age) 
 Product (including lot/ batch number) 
 Description of SAE/ADR/fatal case/special situation 
The report should contain causality and seriousness information (for AEs) and must be signed off 
by the investigator. 
PPD
PPD
PPD
PPD
PPD
PPD
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When AE information is communicated via telephone, a written/EDC report must be sent 
immediately within 24 hours thereafter by fax or e-mail. In such cases the “clock start” for case 
reporting to Health Authorities is the date and time of the telephone communication. 
Exposure During Pregnancy 
All pregnancies with an estimated conception date in the period from the date of informed consent 
signature (where applicable) until the last post-treatment safety visit, or as defined in the protocol, 
must be recorded by convention in the AE page/section of the CRF. The same rule applies to 
pregnancies in female patients and to pregnancies in female partners of male patients. The 
investigator must notify the Sponsor in an expedited manner of any pregnancy using the Pregnancy 
Report Form, which must be transmitted according to the same process as described for SAE 
reporting. The Sponsor must be notified about any pregnancy independent whether the pregnancy 
is associated with an AE related to cladribine tablets or not. 
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 

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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. 
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 (LPSO) 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 UK), 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 (CSR) 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_0079 
 
 
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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. 
Lancet 381: 2167-75. 
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. 
Lublin FD, Reingold SC, Cohen JA, et al. (2014). Defining the clinical course of multiple sclerosis: 
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 
Study. Neurology 86 (suppl 16): P3.029. 
Multiple Sclerosis International Federation. (2013). Atlas of MS. Retrieved 10/15/18, from 
https://www.msif.org/about-us/who-we-are-and-what-we-do/advocacy/atlas/. 
Noseworthy JH, Lucchinetti C, Rodriguez M, et al. (2000). Multiple Sclerosis. N Engl J Med 343: 
938-52. 
Pakpoor J, Disanto G, Altmann DR, et al. (2015). No evidence for higher risk of cancer in patients 
with multiple sclerosis taking cladribine. Neuroinflamm 2: e158. 
Pardo G and Jones DE. (2017). The sequence of disease-modifying therapies in relapsing multiple 
sclerosis: safety and immunologic considerations. J Neurol 264(2): 2351-74. 
Polman CH, O'Connor PW, Havrdova E, et al. (2006). A randomized, placebo-controlled trial of 
natalizumab for relapsing multiple sclerosis. N Engl J Med 354: 899-910. 
Rudick RA, Stuart WH, Calabresi PA, et al. (2006). Natalizumab plus interferon beta-1a for 
relapsing multiple sclerosis. N Engl J Med 354: 911-23. 
Scalfari A, Knappertz V, Cutter G, et al. (2013). Mortality in patients with multiple sclerosis. 
Neurology 81: 184-92. 
Tullman MJ. (2013). Overview of the epidemiology, diagnosis, and disease progression associated 
with Multiple Sclerosis. Am J Manage Care 19: (S15-20). 

Company substance code: 
700568 
Protocol number: 
 
MS700568_0079 
 
 
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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.  
Faissner S and Gold R. (2019). Progressive multiple sclerosis: latest therapeutic developments and 
future direction. Ther Adv Neurol Disord 12: 1-11. 
Mulero P, Midaglia L, and Montalban X. (2018). Ocrelizumab: a new milestone in multiple 
sclerosis therapy. Ther Adv Neurol Disord 11: 1-6. 
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_0079 
 
 
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14 
Appendices 
14.1 
List of Stand-Alone Documents 
Not applicable. 
 
 
 

Company substance code: 
700568 
Protocol number: 
 
MS700568_0079 
 
 
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14.2 
Signature Pages and Responsible Persons for the Study 
 
Signature Page – Protocol Lead 
Study Title: 
Cladribine tablets: Observational evaluation of 
effectiveness and patient-reported outcomes (PROs) 
in suboptiMAlly controlled patientS previously 
Taking oral or infusion disEase-modifying dRugs 
(DMDs) for relapsing forms of multiple sclerosis 
(RMS) (MASTER-2) 
Study Protocol Date / Version: 
21 October 2024 / Version 11.0  
Protocol Lead Responsible for 
Designing the Non-interventional 
Study: 
 
 
I approve the design of the non-interventional study: 
 
_____________________________________ 
____________________________ 
Signature 
Date of Signature 
 
Name, academic degree: 
 
Function / Title: 
 
  
Institution: 
EMD Serono, Inc. 
A business of Merck KGaA, Darmstadt, Germany 
Address: 
One Technology Place Rockland, MA 02370, USA 
Telephone number: 
 
Fax number: 
n/a 
E-mail address: 
 
PPD
PPD
PPD
PPD
PPD

Company substance code: 
700568 
Protocol number: 
 
MS700568_0079 
 
 
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Signature Page – Principal Investigator 
Study Title 
Cladribine tablets: Observational evaluation of 
effectiveness and patient reported outcomes (PROs) 
in suboptiMAlly controlled patientS previously 
Taking oral or infusion disEase-modifying dRugs 
(DMDs) for relapsing forms of multiple sclerosis 
(RMS) (MASTER-2) 
Study Protocol Date / Version 
21 October 2024 / Version 11.0  
Center Number 
 
Principal Investigator 
 
I, the undersigned, am responsible for the conduct of the study at this site. I approve the design of 
the non-interventional study and I understand and will conduct the study according to the study 
protocol, any approved protocol amendments, Good Pharmaco-epidemiology Practices (GPP) and 
all applicable Health Authority requirements and national laws. 
 
_____________________________________ 
____________________________ 
Signature 
Date of Signature 
 
Name, highest academic degree: 
 
Function / Title: 
 
Institution: 
 
Address: 
 
Telephone number: 
 
E-mail address: 
 
 
 

Company substance code: 
700568 
Protocol number: 
 
MS700568_0079 
 
 
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Sponsor Responsible Persons not Named on the Cover Page 
 
Name, academic degree: 
 
Function / Title: 
 
 
Institution: 
EMD Serono R&D Center, Inc 
Address: 
821 
Telephone number: 
 
E-mail address: 
 
 
 
PPD
PPD
PPD
PPD
PPD