Evaluating the Long-Term Outcomes and Durability of Effect Following Treatment With Cladribine Tablets for MS: An Exploratory Phase IV Ambispective Study of Patients Who Previously Participated in the CLARITY/CLARITY-EXT and ORACLE MS Clinical Trials (CLASSIC-MS)
Phase: PHASE4
Conditions: Multiple Sclerosis (MS)
Sponsor: EMD Serono Research & Development Institute, Inc.

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MS700568_0026 
 
 
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Table of Contents 
Title Page 
1 
Table of Contents 4 
Table of Tables 
7 
Table of Figures 
7 
Documentation of Protocol Amendments ............................................................................9 
1 
Protocol Summary ..............................................................................12 
1.1 
Synopsis ..............................................................................................12 
1.2 
Schema ................................................................................................17 
1.3 
Schedule of Activities .........................................................................18 
2 
Introduction .........................................................................................23 
2.1 
Study Rationale ...................................................................................23 
2.2 
Background .........................................................................................23 
2.3 
Benefit/Risk Assessment ....................................................................26 
3 
Objectives and Endpoints ...................................................................27 
4 
Study Design .......................................................................................32 
4.1 
Overall Design ....................................................................................32 
4.2 
Scientific Rationale for Study Design ................................................35 
4.3 
Justification for Dose ..........................................................................36 
4.4 
End of Study Definition ......................................................................36 
5 
Study Population .................................................................................36 
5.1 
Inclusion Criteria ................................................................................37 
5.2 
Exclusion Criteria ...............................................................................37 
5.3 
Lifestyle Considerations .....................................................................37 
5.3.1 
Meals and Dietary Restrictions ...........................................................37 
5.3.2 
Caffeine, Alcohol, Tobacco, and Cannabinoid-containing 
Products ..............................................................................................38 
5.3.3 
Activity ...............................................................................................38 
5.4 
Screen Failures ....................................................................................38 
6 
Study Intervention(s) ..........................................................................38 
6.1 
Study Intervention(s) Administration .................................................38 
6.1.1 
Medical Device(s) Use .......................................................................38 

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6.2 
Study Intervention(s) Preparation, Handling, Storage, and 
Accountability .....................................................................................38 
6.3 
Measures to Minimize Bias: Study Intervention Assignment and 
Blinding ..............................................................................................38 
6.3.1 
Study Intervention Assignment ..........................................................38 
6.3.2 
Blinding ..............................................................................................38 
6.3.3 
Emergency Unblinding .......................................................................39 
6.4 
Study Intervention Compliance ..........................................................39 
6.5 
Concomitant Therapy .........................................................................39 
6.5.1 
Rescue Medicine .................................................................................39 
6.5.2 
Permitted Medicines ...........................................................................39 
6.5.3 
Prohibited Medicines ..........................................................................39 
6.5.4 
Other Interventions .............................................................................39 
6.6 
Dose Selection and Modification ........................................................41 
6.7 
Study Intervention After the End of the Study ...................................41 
6.8 
Special Precautions .............................................................................41 
6.9 
Management of Adverse Events of Interest ........................................41 
7 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal ...............................................................42 
7.1 
Discontinuation of Study Intervention................................................42 
7.1.1 
Temporary Discontinuation ................................................................42 
7.1.2 
Rechallenge .........................................................................................42 
7.2 
Participant Discontinuation/Withdrawal from the Study ...................42 
7.3 
Lost to Follow-Up...............................................................................43 
8 
Study Assessments and Procedures ....................................................43 
8.1 
Efficacy Assessments and Procedures ................................................44 
8.1.1 
Clinical Endpoints ..............................................................................44 
8.1.2 
Other Assessments ..............................................................................49 
8.2 
Safety Assessments and Procedures ...................................................50 
8.2.1 
Physical Examinations ........................................................................50 
8.2.2 
Vital Signs ..........................................................................................50 
8.2.3 
Electrocardiograms .............................................................................51 
8.2.4 
Clinical Safety Laboratory Assessments ............................................51 

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8.2.5 
Suicidal Risk Monitoring ....................................................................51 
8.3 
Adverse Events and Serious Adverse Events .....................................51 
8.3.1 
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information ....................................................51 
8.3.2 
Method of Detecting Adverse Events and Serious Adverse Events ...52 
8.3.3 
Follow-up of Adverse Events and Serious Adverse Events ...............52 
8.3.4 
Regulatory Reporting Requirements for Serious Adverse Events .....52 
8.3.5 
Pregnancy ...........................................................................................53 
8.4 
Treatment of Overdose .......................................................................53 
8.5 
Pharmacokinetics ................................................................................53 
8.6 
Pharmacodynamics .............................................................................53 
8.7 
Pharmacogenetics ...............................................................................54 
8.8 
Biomarkers ..........................................................................................54 
8.9 
Immunogenicity Assessments  ...........................................................54 
8.10 
Health Economics  ..............................................................................54 
9 
Statistical Considerations ....................................................................54 
9.1 
Statistical Hypotheses .........................................................................55 
9.2 
Sample Size Determination ................................................................55 
9.3 
Populations for Analyses ....................................................................55 
9.4 
Statistical Analyses .............................................................................57 
9.4.1 
Handling of Missing Data ...................................................................58 
9.4.2 
Sequence of Analyses .........................................................................59 
10 
References ...........................................................................................60 
11 
Appendices .........................................................................................63 
Appendix 1 
Abbreviations ......................................................................................63 
Appendix 2  
Study Governance ...............................................................................66 
Appendix 3 
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ................................................72 
Appendix 4 
Pharmacogenetics ...............................................................................76 
Appendix 5 
Expanded Disability Status Scale (EDSS) ..........................................77 
Appendix 6 
2017 Mc Donald Criteria (From Thompson, 2018) ............................80 
Appendix 7 
Sponsor Signature Page ......................................................................83 
Appendix 8 
Principal Investigator Signature Page .................................................84 

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Table of Tables 
Table 1 
Schedule of Activities: Assessments Captured at Each Study Visit...19 
Table 2 
The 2017 McDonald criteria for diagnosis of Multiple Sclerosis in 
patients with an attack at onset ...........................................................47 
 
Table of Figures 
Figure 1 
Study Scheme .....................................................................................17 
Figure 2 
Data collection time windows according to relapse status at 
recruitment and for remote visits ........................................................18 
 
 

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Protocol History  
 
Version Number 
Type 
Version Date 
1.0 
Original Protocol 
28 Jan 2019 
2.0 
Amended Protocol 
03 July 2020 
 
Protocol Version 2.0 (03-JUL-2020) 
This amendment is nonsubstantial based on the criteria in Article 10(a) of Directive 2001/20/EC 
of the European Parliament and the Council of the European Union because it neither significantly 
impacts the safety or physical/mental integrity of participants nor the scientific value of the study. 
 
Overall Rationale for the Amendment 
The changes implemented in the protocol have been undertaken in order to improve the quality 
and analytic plans for data collection, by clarifying study endpoints, the time windows for data 
collection, and the definitions of study subgroups. 
 
 

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Documentation of Protocol Amendments 
 
Section # and name  
Description of Change 
Brief Rationale 
Medical Responsible 
and Medical Monitor 
names 
Change in the study physician. 
Study physician has changed since the first 
protocol was written. 
Section 1.1, Synopsis;  
Section 3, Objectives 
and Endpoints;  
Section 4.2, Scientific 
Rationale and Design; 
Section 9.4, Statistical 
Analysis 
 
Updated definition of primary endpoint. 
New definition to clarify and 
minimize ambiguity (per Steering Committee 
recommendation). 
Section 1.1, Synopsis;  
Section 3, Objectives 
and Endpoints;  
Section 9.4, Statistical 
Analysis 
 
Updated definition of secondary 
endpoint. 
New definition to clarify and 
minimize ambiguity (per Steering Committee 
recommendation). 
Section 1.1, Synopsis;  
Section 3, Objectives 
and Endpoints;  
Section 8.1.1.12, 
Cognition Endpoints  
BVMT-R/SDMT: clarification was 
added for these assessments to be 
collected from ORACLE MS subjects 
only in countries where these 
instruments were approved for the use 
in the CLASSIC MS study 
These instruments were only collected in 
countries where they had been previously 
used as part of data collection in the parent 
study; expansion to all participants would 
require additional ethical approval.  
Section 1.1, Synopsis; 
Section 1.3, Schedule 
of Activities;  
Section 3, Objectives 
and Endpoints;  
Section 4.1, Overall 
Design;    
Section 4.2, Scientific 
Rationale and Design 
Time window for collecting MRI and 
pharmacogenetic samples to be 
expanded to up to 3 months and up to 
6 months, respectively. 
Window extended to accommodate patient 
requests to provide samples/complete MRI at 
a later date than planned in first protocol, as 
long as occurring within expected study 
timeframe. 
Section 1.1, Synopsis; 
Section 1.2, Schema;  
Section 1.3, Schedule 
of Activities;  
Section 4.1, Overall 
Design  
 
Updated description of data collection 
windows and included an additional 
study schema (Figure 2) to reflect 
details of the updated time windows for 
3 scenarios: patients without relapse at 
screening, patients with relapse at 
screening, and patients completing a 
remote visit.  Additionally, new text 
was added to specify that it is possible 
to complete all assessments in a 
single day, and that patients 
undergoing relapse or suspected 
relapse could postpone Visit 1 (4 
weeks to 3 months from baseline) as a 
stabilization period.  
Clarify the different time windows that are 
applicable according to relapse status at 
baseline and specify the aim to collect the 
telephone EDSS within a comparable 
timeframe as the in-clinic EDSS among 
patients without relapse. Additionally, 
specification on potential to collect data in a 
single day was added to clarify acceptable 
practice for study sites.   The change in time 
window between screening and visit 1 has 
been expanded to allow additional time for 
stabilization before Study Visit 1 in case of 
suspected relapses. 
Section 1.1, Synopsis;  
Section 3, Objectives 
and Endpoints; 
Section 8.1.1.13, Brain 
Imaging  
The volume of T1 lesions was added 
as a new endpoint among other MRI 
assessments being evaluated. 
T1 lesion volume was omitted from the first 
protocol.   

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Section # and name  
Description of Change 
Brief Rationale 
Section 1.3, Schedule 
of Activities 
Vital signs added in the physical 
examination at Study Visit 1 in 
Schedule of Assessments. 
Measurement was not included in the 
Schedule of Assessment table in first protocol. 
 
Section 1.3, Schedule 
of Activities; 
Section 4.1, Overall 
Design;   
Section 8.1.1.1, 
Expanded Disability 
Status Scale (EDSS) 
Clarify that in-person Expanded 
Disability Status Scale (EDSS) to be 
collected from patients coming to clinic 
for Study Visit 1, and telephone EDSS 
to be collected for patients 
participating remotely; both modes not 
required. 
Reducing burden on patients and possible 
deviations from sites not doing both the 
assessments. 
Section 1.3, Schedule 
of Activities 
Indicate potential for remote screening 
assessment, pending local approval.  
Avoid losing data collection among participants 
unable or unwilling to attend clinic visits.  
Section 1.3, Schedule 
of Activities  
Footnote added to clarify that the end 
of study form completion will occur at 
the last clinical visit (the later of Study 
Visit 1 or Study Visit 2). 
 
Clarification of when this form is to be 
completed, particularly for the expanded data 
collection windows. 
Section 2, Introduction 
Added approval received by US FDA. 
To reflect the updated status of drug’s 
approval. 
Section 4.1, Overall 
Design 
Revision to enrolment dates. 
Dates updated to reflect changes in study 
recruitment projections since first protocol.  
Section 5.2, Exclusion 
criteria;  
Section 5.4, Screen 
Failures 
Adjustment to study time windows in 
the situation of confirmed or suspected 
relapse.  
Expanded data collection window to allow 
patient to stabilize and participate.  
Section 6.5.4.2, MRI 
Sub-study 
Specification that the MRI could be 
postponed among participants, but not 
beyond the time windows specified for 
the overall study. 
Ensure there is no misunderstanding the MRI 
could be collected after the end of study (i.e. 
no later than 4 weeks after the last patient 
enrolled). 
Section 6.5.4.2, MRI 
Sub-study 
The definition of concomitant 
Cladribine (as an exclusion criterion for 
the MRI sub-study) was updated to 
reflect the availability of Cladribine by 
prescription, and to accommodate the 
shelf-life of Cladribine if received 
(through trial participation or 
prescription). 
The timeline for concomitant Cladribine use 
was updated in relation to shelf-life and 
commercial availability (changed since the 
time of protocol version 1). 
Section 8.3.5, 
Pregnancy 
Clarify writing of section on 
pregnancies: information to be 
collected on prospective pregnancies, 
but only expedited reporting for MRI 
sub-study participants. 
Guidance on requirements for collecting and 
reporting pregnancy data in full study versus 
MRI sub-study was not entirely clear in first 
version of protocol. 
Section 9.3, 
Populations for Analysis 
Definition of the subgroups for analysis 
updated: 
1) 
Subgroup Treatment Course 
in Cohort B. 
2) 
Subset Long-term responder 
3) 
Prior use of DMD 
 
 
1) 
Added details to the definition of 
subgroups according to treatment to 
clarify all subcategories are mutually 
exclusive and minimize ambiguity. 
2) 
Clarification on addition details of 
long-term responders will minimize 
ambiguity 
3) 
Prior use of DMD concern only 
CLARITY patients (Cohort B). 
 

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Section # and name  
Description of Change 
Brief Rationale 
Section 9.4.2; 
Sequence of Analysis 
Updated planned number of patients to 
be included in the planned Interim 
Analysis. Specified that 
pharmacogenetics and MRI would not 
be included in the interim analysis. 
Planned final number of patients is unknown 
(enrolment is slow due to COVID-19 
pandemic) and % can’t be determined. 100 
patients are considered minimum number for 
the interim analysis.  The scope of data to be 
included in the IA required clarification to 
reflect the SAP.  
Appendix 2, Study 
Governance 
Additional text on date of study start 
and patient recruitment. 
Updated as per Merck Template 14 (reflecting 
requirements of the TransCelerate and new 
EU-CTR updates). 
Appendix 2, Study 
Governance  
Details of the third-party service 
provider for MRI added. 
These details were not listed in the first 
protocol.  
Appendix 3, Adverse 
Events: Definitions and 
Procedures for 
Recording, Evaluating, 
Follow-up, and 
Reporting 
Removed specification of expedited 
reporting of non-serious adverse 
events of special interest.  
It is not a requirement to report non-serious 
adverse events within 24 hours.  
Appendix 3, Adverse 
Events: Definitions and 
Procedures for 
Recording, Evaluating, 
Follow-up, and 
Reporting 
Specification that a positive test for 
COVID-19 would be considered an 
AE. 
This text was added to provide clarity for the 
sites, and was not applicable at the time of the 
first protocol  
Appendix 3, Adverse 
Events: Definitions and 
Procedures for 
Recording, Evaluating, 
Follow-up, and 
Reporting 
Clarification on which form ADR data 
is to be captured on, according to 
timing of awareness of the event. 
Reiterate guidance given to the sites to ensure 
correct data entry.  
Throughout 
Minor editorial and document 
formatting revisions. 
Minor; therefore, have not been summarized. 
 
 

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Exploratory Objectives 
Endpoints (Outcome Measures) 
• Proportion of study participants diagnosed as 
Secondary Progressive MS (SPMS) without relapses 
in the 3 months prior to SPMS diagnosis 
• Proportion of study participants diagnosed as SPMS 
with relapses in the 3 months prior to SPMS 
diagnosis 
• Proportion of study participants diagnosed as 
Primary Progressive MS (PPMS) (For ORACLE MS 
study participants only) 
To assess impact on quality of life and cognitive 
outcomes after treatment with IMP during the period 
from the last clinical visit in the CLARITY/CLARITY-
EXT/ORACLE MS clinical trials to Study Visit 1 in 
study participants previously treated with IMP as part 
of the Phase III ORACLE MS and 
CLARITY/CLARITY-EXT clinical trials. 
Tertiary endpoints to be evaluated at Study Visit 1: 
• Change in EuroQoL-5 Dimension Questionnaire (3 
level version) (EQ-5D-3L) 
• Change in cognition as measured by the following 
assessments (to be collected for ORACLE MS 
subjects only in countries where these instruments 
were used  in the CLASSIC MS study):  
o 
The Brief Visuospatial Memory Test – Revised 
(BVMT-R) 
o 
Symbol Digit Modality Test (SDMT) 
To assess durability of outcome on brain imaging after 
treatment with IMP from Baseline (i.e. the last MRI 
before first doseb of IMP; if feasible, by year) to within 
3 months after Study Visit 1 in study participants 
previously treated with IMP as part of the Phase III 
ORACLE MS and CLARITY/CLARITY-EXT clinical 
trials. 
ORACLE MS, CLARITY and CLARITY-EXT study 
participants from selected sites will be invited to 
participate in a follow-up study visit (Study Visit 2) to 
take place within 3 months (maximum 4 weeks from 
Visit 1 after last patient enrolled) following 
Study Visit 1, for evaluation of the following:  
Change in MRI assessment from Baseline (i.e. the last 
MRI before first doseb of IMP) to Study Visit 2 in:  
• Total volume of T2 lesions  
• Total number of T2 lesions  
• Number of hypointense lesions on T1-spin echo MRI 
• Volume of hypointense lesions on T1-spin echo MRI 
• Brain volume or surrogate (in cases where brain 
volume is not possible to assess for technical reasons, 
then 3rd ventricle diameter may be evaluated)  
• Ventricular volume 
To determine whether the high-disease activity (HDA) 
patients from the CLARITY/CLARITY-EXT clinical 
trials are more likely to be the long-term responders. 
Comparison of the responder rate in HDA patientse 
versus the responder rate in non-HDA patients from the 
CLARITY/CLARITY-EXT population. 

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Exploratory Objectives 
Endpoints (Outcome Measures) 
To evaluate differences in genetics between long-term 
responders and study participants requiring alternate 
therapies following treatment with IMP for the 
CLARITY/CLARITY-EXT and ORACLE MS 
populations. 
Correlation of genetic variations with long-term 
responders (defined as study participants who did not 
demonstrate any evidence of disease reactivation based 
on Investigator assessment of clinical and imaging 
outcomes until Year 4 or later following their last doseb 
of IMP and who did not receive disease modifying 
treatment until Year 4 or later following their last doseb 
of IMP) compared to other study participants who 
started on alternate therapy less than 4 years following 
their last doseb of IMP for the CLARITY/CLARITY-
EXT and ORACLE MS populations. 
ARR=Annualized Relapse Rate, BVMT-R=Brief Visuospatial Memory Test Revised, CDMS=Clinically Definite Multiple 
Sclerosis, EDSS=Expanded Disability Status Scale, EQ-5D=EuroQoL-5 Dimension, HDA=High-disease activity, 
IMP=Investigational Medicinal Product, MRI=Magnetic Resonance Imaging, MS=Multiple Sclerosis, PPMS=Primary 
Progressive 
MS, 
RRMS=Relapsing-Remitting 
Multiple 
Sclerosis, 
SDMT=Symbol 
Digit 
Modalities 
Test, 
SPMS=Secondary Progressive Multiple Sclerosis.  
a Specific clinical and demographic characteristics may include gender, age, race, ethnicity, education, disease 
duration, years previous disease modifying treatment (before start of CLARITY/CLARITY-EXT/ORACLE MS) and 
disease classification (RRMS or SPMS). 
b One dose is equivalent to one tablet. One course of IMP is defined as 1 year of treatment with IMP (2 treatment cycles 
[weeks]). A treatment cycle is defined as daily administration of IMP given consecutively over 4-5 days during a 28-day 
period. One treatment week is equivalent to 1 treatment cycle. 
c Total volume of T2 lesions; Total number of T2 lesions; Number of hypointense lesions on T1-spin echo MRI; Volume 
of hypointense lesions on T1-spin echo MRI; Brain volume or surrogate; Ventricular volume. 
d Mobility endpoints may be determined via EDSS scores (if available) or corresponding clinical descriptions in medical 
records. 
e 1. Patients with ≥2 relapses during the year prior to parent study entry, regardless of prior disease modifying drugs 
(DMD) use; 2. Patients with ≥1 relapse in the previous year and ≥1 T1 Gd+ lesions or ≥9 T2 lesions, while on therapy 
with other DMDs. 
Overall Design: This Phase IV, low-interventional, multicenter, ambispective study will include 
study participants treated with Cladribine Tablets or placebo in the previously conducted parent 
studies. Long-term retrospective data will be collected through evaluation of medical 
charts/records (e.g., sociodemographic and clinical characteristics, medical and disease history, 
Secondary Progressive Multiple Sclerosis [SPMS] conversion, Expanded Disability Status Scale 
[EDSS], details of subsequent Disease Modifying Drugs (DMDs), including physician questions 
on treatment decisions, date of first use of an ambulatory device or wheelchair and relapse history 
from end of parent study to Study Visit 1 as well as, for ORACLE MS patients only, Clinically 
Definite MS conversion [CDMS] and Primary Progressive MS [PPMS] diagnosis).  
Additional prospective data will be collected at Study Visit 1 (e.g., physical assessment, EDSS, 
Patient-Reported Outcomes [PRO], cognitive assessments). An optional blood sample for 
pharmacogenetic testing will be taken from patients who consent to the optional testing. A sub-
study at Study Visit 2 involves a magnetic resonance imaging (MRI) scan without gadolinium in 
approximately 150 patients who are willing to participate in this MRI sub-study. 
Number of Participants: No formal sample size calculation has been performed for this 
exploratory study as enrolment is limited to eligible study participants from the parent studies. 
Therefore, as many study participants as feasibly possible will be enrolled from this group. 
Additional considerations on the sample size of the study are included in Section 9.2. 

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Study Intervention Groups and Duration: No investigational medicinal product (IMP) will be 
administered as part of this study. The duration of the study for most patients is no more than 2 
weeks from the time of the Screening Visit to Study Visit 1, except in the case of relapse at 
screening in which case the duration between Screening and Study Visit 1 is between 1 and 3 
months. An optional blood sample will be collected at Study Visit 1from patients who consent to 
the optional pharmacogenetic testing. Pharmacogenetic testing may also occur during a subsequent 
clinical visit up to 6 months after the Screening Visit (unless last patient enrolled has occurred, in 
which case the testing must occur at Study Visit 1). For patients selected to participate in the MRI 
sub-study, an additional visit will be required (Study Visit 2) that will occur within a maximum of 
3 months of Study Visit 1 (maximum 4 weeks from Study Visit 1 if last patient enrolment has 
occurred), and these patients’ total study duration will be no more than 6 months. Sites will be 
asked to enter any retrospective data into the electronic case report form (eCRF) for this study 
within 12 weeks of enrolling the patient. Patients who are eligible will be given the option of 
completing screening, Study Visit 1 and 2 (where facilities for MRI are available) on the same day 
if prefer to do so and meet the eligibility criteria on that day (e.g. abstention from alcohol or 
cannabinoid products in the preceding 24 hours). Patients who are undergoing relapse or suspected 
relapse at the time of screening will be invited for Study Visit 1 after a stabilization period 
determined through consultation with the medical monitor. 
Involvement of Special Committee(s): Yes. 
 
 

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1.2 
Schema 
Figure 1 represents an overall schematic of the exploratory study design. Figure 2 represents the 
different time windows according to subject relapse status at the time of screening, and for 
participants completing the study remotely.  A detailed Schedule of Activities (SoA) is provided 
in Section 1.3. 
Figure 1 
Study Scheme 
 

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Figure 2 
Data collection time windows according to relapse status at recruitment 
and for remote visits 
 
 
1.3 
Schedule of Activities 
Table 1 
Schedule of Activities: Assessments Captured at Each Study Visit 
 provides 
details on the SoA.

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Form, IRB=Institutional Review Board, MS=Multiple Sclerosis, MRI=Magnetic Resonance Imaging, PPMS=Primary Progressive Multiple Sclerosis, SDMT=Symbol 
Digit Modalities Test, SPMS=Secondary Progressive Multiple Sclerosis. 
a Scheduling of Study Visit 2 cannot occur more than 4 weeks from Study Visit 1 if last subject has been recruited 
b The in-person EDSS is a standardized physical neurological examination conducted in-person, including assessment of walking distance, whereas the telephone 
EDSS is a validated tool for telephone administration of the EDSS 
c The Study Termination form will be completed at the date of MRI visit (Study Visit 2), or Study Visit 1, whichever is the last assessment for that patient.  
 

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2 
Introduction 
Despite the recent approvals of several newer therapies, the treatment burden of Multiple 
Sclerosis (MS) remains significant. The evidence of potential beneficial effects of new 
therapies are weak and studies are often of a short-term nature with little follow-up of original 
clinical trial participants (Tramacere, 2015). 
Treatment with Cladribine Tablets in 2 short courses over 2 consecutive years has consistently 
shown robust clinically and statistically significant benefits in patients across the spectrum of 
Relapsing-Remitting Multiple Sclerosis (RRMS), across early to late stage studies as well as 
in treatment-naïve or treatment-experienced patients (Giovannoni, 2010; Leist, 2014; 
Section 2.2).  
Cladribine (2-chloro-2'-deoxyadenosine [2-CdA]) is a synthetic anti-neoplastic drug that 
belongs to the subgroup of agents called purine analogs. Mavenclad® is approved (European 
Medical Agency [EMA] approval on 25th Aug 2017, and United States (US) Food and Drug 
Agency [FDA] on 29th March 2019) for the treatment of adult patients with highly active 
RRMS, as defined by clinical or imaging features, in:  
• patients with 1 relapse in the previous year and at least 1 T1 Gd+ lesion or 9 or more 
T2 lesions, while on therapy with other disease modifying drugs (DMDs), 
• patients with 2 or more relapses in the previous year, whether on DMD treatment or 
not. 
Complete information on the chemistry, pharmacology, efficacy, and safety of Cladribine 
Tablets is in the Summary of Product Characteristics (SmPC) and/or the country specific 
label. 
2.1 
Study Rationale 
The purpose of this study is to explore the long-term outcomes, durability of effect, and real-
world treatment patterns in patients previously participating in the Phase III ORACLE MS 
and CLARITY/CLARITY-EXT clinical trials (i.e. parent studies). The results from this study 
may be of benefit to patients with MS and clinicians by helping to inform future treatment 
approaches and treatment decision-making. For Scientific Rationale for Study Design see 
Section 4.2. 
2.2 
Background 
Epidemiology of Multiple Sclerosis 
MS is a chronic, inflammatory, demyelinating disease of the central nervous system (CNS) 
and is the most common cause of serious neurological disability in young adults (Przybek, 
2015). 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 

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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 33 patients per 100,000 population. MS 
median estimated prevalence varies substantially across regions, with North America and 
Europe presenting the highest prevalence (140 and 108 patients per 100,000 population, 
respectively) (Multiple Sclerosis International Federation, 2013). Within Europe, the 
prevalence is highest in Denmark (227 patients with MS per 100,000 population), and Sweden 
(189 patients with MS per 100,000 population), while in most of the other countries the 
prevalence is under 100 patients with MS per 100,000 population (Multiple Sclerosis 
International Federation, 2013). 
Regarding incidence, globally, the median estimated incidence of MS is 2.5 per 100,000 
person-years (PY) (Dua, 2008). Regionally, the median estimated incidence is greatest in 
Europe (3.8 per 100,000 PY) (Dua, 2008). The highest prevalence in Europe is 189 per 100,000 
people in Sweden, and the lowest is 22 per 100,000 people in Albania (Multiple Sclerosis 
International Federation, 2013). In the United States, the incidence is estimated to be 3.2 per 
100,000 PY (Multiple Sclerosis International Federation, 2013). Based on a recent study by 
the National Multiple Sclerosis Society, an estimated 947,000 people in the US have MS 
(Wallin, 2017). 
Studies indicate that patients with MS 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). 
Clinical Presentation and Categorization of MS 
MS is not characterized by a singular, well-defined clinical presentation common to all 
patients with MS. The symptoms, which include a combination of cognitive, sensory and 
motor manifestations, vary among patients and throughout the disease course according to the 
affected CNS areas and the severity of the demyelinating attacks. Approximately 85% of 
patients with MS have initially RRMS (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 RRMS 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 RRMS (Lublin, 2014). Data on the epidemiology of 
highly active RRMS 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) (Gold, 2013; Rudick, 2006) and 22.2% of treatment-naïve patients 
(Polman, 2006) met the criteria for highly active RRMS (≥2 relapses in the year prior to study 
entry and ≥ 1 Gd+ lesion on T1- weighted MRI at study entry) (Gold, 2013; Rudick, 2006; 
Polman, 2006). 

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Treatment and Management of Relapsing Multiple Sclerosis 
Patients with relapsing MS (RMS) are recommended to receive treatment with DMD to 
decrease the rate of relapse and slow the accumulation of brain lesions on MRI. Numerous 
immunomodulatory agents with differing routes of administration and mechanisms of action 
have been shown to have beneficial effects. Because they are not curative, most DMDs are 
typically continued indefinitely unless they are ineffective or not tolerated. There is currently 
no standard protocol to guide the choice of DMDs for patients with MS. Rather, treatment 
decisions and medication choices are the result of a thorough risk-benefit analysis and 
consideration of disease activity, patient-specific factors, and drug-related factors (Pardo, 
2017).  
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 have been 
approved by the EMA in 2017 for the treatment of adult MS patient with high active disease 
(see Section 2). 
CLARITY Clinical Trial (NCT00213135) 
In the Phase III, multi-center, randomized, double-blind CLARITY clinical trial 
(NCT00213135), treatment with Cladribine Tablets demonstrated a significant reduction in 
the annualized relapse rate (ARR) at 2 years from 0.33 to 0.14 when compared with placebo. 
This corresponded to an ARR risk reduction of 57.4% for the 3.5 mg/kg dose. The reduction 
in ARR was also consistent across various patient subgroups, including those with highly 
active disease. Furthermore, the CLARITY study demonstrated that Cladribine Tablets were 
significantly superior to placebo in the treatment of RRMS across all clinical and MRI 
efficacy outcomes (Giovannoni, 2010).  
The CLARITY-EXT study showed that in patients who followed Cladribine Tablets with 
placebo, a substantial proportion remained free from indicators of disease activity, regardless 
of prior active treatment in CLARITY. Overall rates of (clinical and MRI) disease activity-
free status were consistently high, although a longer treatment gap resulted in lower 
proportions of patients with no new T1 Gd+ lesions compared with those who had a shorter 
treatment gap (Comi, 2018). 
ORACLE MS Clinical Trial (NCT00725985) 
The ORACLE MS clinical trial (NCT00725985) was a Phase III, randomized, double-blind, 
placebo-controlled, multicenter, triple arm trial to evaluate the safety and efficacy of 
Cladribine Tablets in patients with early disease who had experienced a first clinical 
demyelinating event (FCDE) and who were at high risk of converting to CDMS, according to 
Poser criteria. Patients taking Cladribine Tablets (3.5 mg/kg) demonstrated statistically 
significant differences to the placebo group in the time to CDMS conversion during the initial 
treatment period up to the data cut-off (Leist, 2014).  
Additionally, treatment with Cladribine Tablets significantly reduced the number of T1 Gd+ 
-enhanced lesions, new or enlarging T2 lesions, and combined unique active MRI lesions 
compared with placebo (Leist, 2014). Cladribine Tablets were associated with clinical and 

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MRI improvements versus placebo in patients with early RRMS (time to second event), active 
RRMS, and patients who were experiencing relapses despite ongoing interferon therapy 
(Comi, 2013; Comi, 2016; Freedman, 2017; Giovannoni, 2010; Giovannoni, 2016; 
Giovannoni, 2018; Leist, 2014; Montalban, 2016).  
Based on these clinical trial results, Cladribine Tablets were approved for the treatment of 
RRMS in several markets. However, following negative Committee for Medicinal Products 
for Human Use opinion in 2011, Merck voluntarily withdrew further applications for approval 
as some regulatory authorities required more data to fully characterize the drug’s benefit-risk 
profile. Consequently, there are a number of patients who received Cladribine Tablets prior 
to the earlier withdrawal. These patients have been followed in MS registries and 
observational studies for safety outcomes. The PREMIERE (Prospective Observational Long-
term Safety Registry of Multiple Sclerosis Patients Who Have Participated in Cladribine 
Clinical Studies) study evaluated the safety of Cladribine Tablets over 10,000 PY of exposure 
in total, with follow-up in some patients exceeding 8 years at completion.  
In August of 2017, the European Commission granted marketing authorization for 
Mavenclad® (Cladribine Tablets) for the treatment of highly active relapsing MS. The clinical 
program for cladribine in MS included more than 10,000 patient-years of data. This included 
8,650 patient-years of cladribine exposure and more than 2,000 patient-years of placebo 
exposure (Cook , 2016). 
Although the PREMIERE study provides long-term data following treatment with Cladribine 
Tablets, this study primarily evaluated safety outcomes, and thus additional real-world data 
are needed to understand the long-term effects of Cladribine Tablets on key measures of 
disability progression and to address the knowledge gaps around treatment patterns of patients 
with MS in a clinical setting. 
2.3 
Benefit/Risk Assessment 
The primary aim of this study is to generate evidence regarding long-term disability 
progression and treatment sequencing following Cladribine Tablet treatment. Results from 
this study may be of benefit to patients with MS and clinicians by helping to inform future 
treatment approaches and treatment decision-making.  
As this study does not involve administration of any investigational medicinal product  
(IMP), there are minimal risks to the patients involved. Patients who come to the clinic will 
be asked to provide an optional blood sample for pharmacogenetics testing only if they 
consent to this additional sample and testing. Blood draws may cause discomfort, bruising 
and very rarely infection at the site where the skin is punctured by the needle. Patients may 
also experience dizziness, nausea or fainting during blood sampling. However, in general 
these reactions are mild to moderate and will resolve on their own.  
Only a subset of study participants will participate in the MRI (without gadolinium) sub-study 
at Study Visit 2, and steps have been taken to minimize risk to patients participating in the 
MRI assessment by excluding study participants who are pregnant due to the unknown risks 
regarding rare fetal and childhood adverse event (AE) outcomes following exposure to MRI 

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during pregnancy. Any MRI scans will be performed according to a standard protocol detailed 
in a separate MRI user’s manual, with appropriate safety precautions i.e. not including patients 
with MRI-incompatible metal in their body. 
There are no restrictions or instructions for permitted or prohibited medicines for this study. 
Study participants will receive medicines according to their usual care under their treating 
physician. Once study participants have concluded their participation in this study, they will 
continue to be treated according to their usual practice and care and their usual care will not 
be affected by participation in this study. 
Based on the available nonclinical and clinical data to date, the conduct of the study, as 
specified in this protocol, is considered justifiable. 
3 
Objectives and Endpoints 
Data will be collected retrospectively and prospectively to evaluate the long-term outcomes, 
durability of effect, and real-world treatment patterns following treatment with Cladribine 
Tablets or placebo among patients with MS who were part of the parent studies. The 
objectives of this study are all exploratory and for hypothesis generating purposes. 

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Exploratory Objectives 
Endpoints (Outcome Measures) 
To assess durability of clinical outcomes 
after treatment with IMP from Baseline (i.e. 
first doseb of IMP) to Study Visit 1 in study 
participants previously treated with IMP as 
part of the Phase III ORACLE MS and 
CLARITY/CLARITY-EXT clinical trials. 
Tertiary endpoints to be evaluated via 
retrospective data collection from medical 
records or at Study Visit 1:  
• Proportion of study participants being 
bedriddend  
• Time from first doseb of IMP to first use of 
an ambulatory deviced 
• Time from first doseb of IMP to first use of 
a wheelchaird 
• Annualized Relapse Rate (ARR) from time 
of first doseb of IMP to Study Visit 1, and 
by 2-year intervals 
• Time to conversion to Clinically Definite 
MS (CDMS) (For ORACLE MS study 
participants only) 
• Proportion of study participants diagnosed 
as Secondary Progressive MS (SPMS) 
without relapses in the 3 months prior to 
SPMS diagnosis 
• Proportion of study participants diagnosed 
as SPMS with relapses in the 3 months 
prior to SPMS diagnosis 
• Proportion of study participants diagnosed 
as Primary Progressive MS (PPMS) (For 
ORACLE MS study participants only) 

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Exploratory Objectives 
Endpoints (Outcome Measures) 
To assess impact on quality of life and 
cognitive outcomes after treatment with 
IMP during the period from the last clinical 
visit in the CLARITY/CLARITY-
EXT/ORACLE MS clinical trials to 
Study Visit 1 in study participants 
previously treated with IMP as part of the 
Phase III ORACLE MS and 
CLARITY/CLARITY-EXT clinical trials. 
Tertiary endpoints to be evaluated at 
Study Visit 1:  
• Change 
in 
EuroQoL-5 
Dimension 
Questionnaire (3 level version) (EQ-5D-
3L) 
• Change in cognition as measured by the 
following assessments (to be collected for 
ORACLE MS subjects only in countries 
where these instruments were used in the 
CLASSIC MS study):  
o The Brief Visuospatial Memory Test – 
Revised (BVMT-R) 
o Symbol Digit Modality Test (SDMT) 
To assess durability of outcome on brain 
imaging after treatment with IMP from 
Baseline (i.e. the last MRI before first doseb 
of IMP; if feasible, by year) to within 3 
months after Study Visit 1 in study 
participants previously treated with IMP as 
part of the Phase III ORACLE MS and 
CLARITY/CLARITY-EXT clinical trials. 
ORACLE MS, CLARITY and CLARITY-
EXT study participants from selected sites 
will be invited to participate in a follow-up 
study visit (Study Visit 2) to take place 
within 3 months (maximum 4 weeks from 
Study Visit 1 after last patient enrolled) 
following Study Visit 1, for evaluation of the 
following: 
Change in MRI assessment from Baseline 
(i.e. the last MRI before first doseb of IMP) 
to Study Visit 2 in:  
• Total volume of T2 lesions 
• Total number of T2 lesions 
• Number of hypointense lesions on T1-spin 
echo MRI 
• Volume of hypointense lesions on T1-spin 
echo MRI 
• Brain volume or surrogate (in cases where 
brain volume is not possible to assess for 
technical reasons, then 3rd ventricle 
diameter may be evaluated)  
• Ventricular volume 

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Exploratory Objectives 
Endpoints (Outcome Measures) 
To determine whether the high-disease 
activity (HDA) patients from the 
CLARITY/CLARITY-EXT clinical trials 
are more likely to be the long-term 
responders. 
Comparison of the responder rate in HDA 
patientse versus the responder rate in non-
HDA patients from the 
CLARITY/CLARITY-EXT population. 
To evaluate differences in genetics between 
long-term responders and study participants 
requiring alternate therapies following 
treatment with IMP for the 
CLARITY/CLARITY-EXT and ORACLE 
MS populations. 
Correlation of genetic variations with long-
term responders (defined as study 
participants who did not demonstrate any 
evidence of disease reactivation based on 
Investigator assessment of clinical and 
imaging outcomes until Year 4 or later 
following their last doseb of IMP and who 
did not receive disease modifying treatment 
until Year 4 or later following their last doseb 
of IMP) compared to other study participants 
who started on alternate therapy less than 4 
years following their last doseb of IMP for 
the CLARITY/CLARITY-EXT and 
ORACLE MS populations. 
ARR=Annualized Relapse Rate, BVMT-R=Brief Visuospatial Memory Test Revised, CDMS=Clinically Definite 
Multiple Sclerosis, EDSS=Expanded Disability Status Scale, EQ-5D=EuroQoL-5 Dimension, HDA=High-disease 
activity, IMP=Investigational Medicinal Product, MRI=Magnetic Resonance Imaging, MS=Multiple Sclerosis, 
PPMS=Primary Progressive MS, RRMS=Relapsing-Remitting Multiple Sclerosis, SDMT=Symbol Digit Modalities 
Test, SPMS=Secondary Progressive Multiple Sclerosis.  
a Specific clinical and demographic characteristics may include gender, age, race, ethnicity, education, disease 
duration, years previous disease modifying treatment (before start of CLARITY/CLARITY-EXT/ORACLE MS) and 
disease classification (RRMS or SPMS). 
b One dose is equivalent to one tablet. One course of IMP is defined as 1 year of treatment with IMP (2 treatment 
cycles [weeks]). A treatment cycle is defined as daily administration of IMP given consecutively over 4-5 days 
during a 28-day period. One treatment week is equivalent to 1 treatment cycle. 
c Total volume of T2 lesions; Total number of T2 lesions; Number of hypointense lesions on T1-spin echo MRI; 
Brain volume or surrogate; Ventricular volume. 
d Mobility endpoints may be determined via EDSS scores (if available) or corresponding clinical descriptions in 
medical records. 
e 1. Patients with ≥2 relapses during the year prior to parent study entry, regardless of prior disease modifying 
drugs (DMD) use; 2. Patients with ≥1 relapse in the previous year and ≥1 T1 Gd+ lesions or ≥9 T2 lesions, while 
on therapy with other DMDs. 
 
 
4 
Study Design 
4.1 
Overall Design 
This Phase IV, low-interventional, multicenter, ambispective study will involve the evaluation 
of medical records of study participants treated with Cladribine Tablets or placebo (IMP) in 
the previously conducted parent studies. Long-term retrospective data will be collected 
through evaluation of medical charts/records, and additional prospective data will be 

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collected. No IMP will be administered as part of this study. An interim analysis is planned 
when data from approximately 100 patients are collected (see Section 9 for further details on 
analyses).  
This study will collect data from study participants with MS who participated in the 
CLARITY/CLARITY-EXT clinical trial(s) and who received ≥ 1 course of IMP, or study 
participants with their FCDE who were randomized in the ORACLE MS study and received 
≥ 1 course of IMP.  
An overall Study Schema is depicted in Section 1.2.   Additionally, details of the different 
timelines according to subject relapse status at the time of screening, and for participants 
completing the study remotely are presented in Section 1.2, and a detailed SoA is provided in 
Section 1.3.  
Participants are invited to up to 3 clinic visits for this study. The first visit is the Screening 
Visit. The following screening activities may be administered by telephone if the patient is 
unable and/or not willing to attend clinic for the visit, depending on approval by Ethics 
Committees (ECs), Institutional Review Boards (IRBs), and/or local regulations: Informed 
consent (for patients participating in retrospective data collection only, local requirements for 
patient consent will be observed, which may include informed consent form [ICF] waiver), 
sociodemographic and clinical characteristics, medical and disease history, and study 
inclusion/exclusion determination.  
Retrospective data for deceased or lost to follow-up patients will be collected in case an ICF 
waiver is granted, or proxy/caregiver/legal representative consent is obtained, depending on 
approval by ECs, IRBs, and/or local regulations. 
The second visit is Study Visit 1, which could be combined with the Screening Visit. At this 
visit retrospective data (from medical chart review) and current data will be collected. For 
patients who are able to attend the visit at the clinic data on a physical assessment, Expanded 
Disability Status Scale (EDSS), Patient-Reported Outcomes (PROs), cognitive assessments, 
AEs and concomitant medications will be collected. For all patients the following 
retrospective data will be collected: EDSS, Secondary Progressive MS (SPMS) conversion, 
details of subsequent DMDs, including physician questions on treatment decisions, date of 
first use of an ambulatory device or wheelchair, date of first time bedridden and relapse history 
from end of parent study to Study Visit 1. In ORACLE MS patients, CDMS conversion and 
PPMS diagnosis will be assessed as well. An optional blood sample for pharmacogenetic 
testing will be taken from patients who consent to the optional sampling at the clinic and who 
are seen at a site with available capabilities to store and ship these samples. Patients will also 
have the opportunity to provide pharmacogenetic samples after Study Visit 1 and up to 
6 months from Screening (unless last patient enrolment has occurred, in which case the 
sample can only be collected at Study Visit 1). 
For patients from whom in-person EDSS at clinic visit was not planned to be collected, a 
telephone EDSS questionnaire will be administered. Attempts should be made to administer 
the telephone EDSS within 14 days after informed consent was received for patients not 
attending the clinic visit.  

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Study data will be supplemented with information from the past clinical trial(s), which will 
be integrated for milestones such as interim analyses and, if needed, on a regular basis. It is 
the Sponsor, not the site, that is responsible for obtaining the information from the past clinical 
trial(s) study databases. However, the sites will be requested to provide some patient 
identifiers (e.g. patient number, parent study patient participated in, year of birth and gender) 
to match data being collected with previous data sets.  
The third potential clinic visit is Study Visit 2, which involves an MRI scan without 
gadolinium in approximately 150 patients who are willing to participate in this MRI sub-
study. The sites that participate in the MRI sub-study will be selected primarily based on their 
technical capabilities to perform the required MRI assessments and the availability of the 
original MRI machine from the parent studies. The patients at these sites will be selected 
based on being able to fulfill the eligibility criteria (see Section 6.5.4.2), including the 
availability/consent of the patient to perform a new MRI and the provision of a urine 
pregnancy test within a week prior to the MRI assessment (for female patients of childbearing 
age). A serum pregnancy test is also acceptable if available as per standard of care (SOC). 
Verbal reporting of pregnancy status by the female patient is not acceptable. AEs and 
concomitant medications will also be reviewed and recorded during this visit. For patients 
who are not experiencing relapse at the time of screening, the duration between  Screening 
Visit to Study Visit 1 is no more than 2 weeks, including for patients who are participating 
remotely and who are completing a telephone EDSS assessment only.  For patients 
experiencing relapse, the duration between Screening and Study Visit 1 is between 4 weeks 
and 3 months. For patients selected to participate in the MRI sub-study, an additional visit 
will be required that will occur within a maximum of 3 months of Study Visit 1 (maximum 4 
weeks from Study Visit 1 if last patient recruitment has occurred), and these patients’ total 
study duration will likely be no more than 3.5 months if the patient was not experiencing 
relapse at Screening, or up to 6 months maximum in the case of relapse.  For patients 
providing samples for pharmacogenetic testing, the time window for sample collection is up 
to a maximum of 6 months from Screening (unless last patient enrolled has occurred, in which 
case the testing must occur at Study Visit 1).    Sites will be asked to enter any retrospective 
data into the electronic case report form (eCRF) for this study within 12 weeks of enrolling 
the patient. Participants who are eligible will be given the option of completing the screening, 
Study Visit 1, and 2 (where facilities for MRI are available) on the same day if prefer to do 
so and meet the eligibility criteria on that day (e.g. abstention from alcohol or cannabinoid 
products in the preceding 24 hours). Participants who are undergoing relapse or suspected 
relapse at the time of screening will be invited for Study Visit 1 after a stabilization period 
determined through consultation with the medical monitor. 
The study aims to enroll patients from approximately Q3 2019 to Q1 2021. Last Patient Last 
Visit is expected in Q1 2021 (see Section 4.4 End of Study Definition). 
Patient selection bias will be addressed through specific statistical methods (see Section 9 for 
further details on statistical considerations). Site selection bias will be addressed by robust 
site feasibility open to all sites that participated in the parent studies.  

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4.2 
Scientific Rationale for Study Design 
The purpose of this study is to explore the long-term outcomes, durability of effect, and real-
world treatment patterns in patients previously participating in the parent studies. This 
exploratory Phase IV study includes retrospective and prospective assessments. It will involve 
the collection of long-term retrospective data through abstraction of medical charts/records. 
For patients participating in the prospective assessment of the study, additional data will be 
collected at Study Visit 1 and patients will be asked for an optional blood sample. For a subset 
of patients, an MRI assessment will be performed at Study Visit 2, which will occur within a 
maximum of 3 months after completing Study Visit 1 (maximum 4 weeks from Visit 1 if  last 
patient recruitment has occurred). No IMP will be administered as part of this study.  
The primary objective of this study is to evaluate long-term mobility after treatment with 
Cladribine Tablets or placebo in the parent studies. This will be evaluated by the primary 
endpoint, the proportion of study participants using a wheelchair (defined as unable to walk 
beyond approximately 5 meters even with aid, essentially restricted to wheelchair; wheels self 
in standard wheelchair and transfers alone; up and about in wheelchair some 12 hours a day) 
the majority of the time in the 3 months prior to Study Visit 1 or participants are bedridden 
any time prior to Study Visit 1, determined via EDSS score of 7.0 or higher, or alternative 
clinical description data in medical records. This primary endpoint was selected as a reliable 
and valid measure of long-term mobility following treatment with IMP in the parent studies. 
This endpoint was agreed upon by the Steering Committee members as one that is practical 
for this ambispective study design, as use of a wheelchair or being bedridden is a disability 
milestone for patients with MS and will likely be recorded in medical charts, either as a 
clinical description or via an EDSS score of 7.0 or higher. This endpoint is also practical to 
evaluate at Study Visit 1, thus maximizing the amount of data that can be collected for the 
primary endpoint in this study.  
The secondary objective is the comparison of clinical characteristics between long-term 
responders (defined as study participants who did not demonstrate any evidence of disease 
reactivation based on Investigator assessment of clinical and imaging outcomes until Year 4 
or later following their last dose of IMP and who did not receive disease modifying treatment 
until Year 4 or later following their last dose of IMP) compared to those who started on 
alternate therapy less than 4 years following their last dose of IMP for the combined parent 
study populations. This secondary objective helps to fill an important data gap, which is 
understanding treatment sequencing following Cladribine Tablets and specifically 
understanding if there are differences in clinical characteristics (gender, age/year of birth, 
race, ethnicity, education, employment status, disease duration [years], current disease 
modifying treatment, time since last relapse [months], and disease classification [RRMS or 
SPMS]) between study participants who did and did not start on an alternative therapy within 
4 years of their last dose of IMP in the parent studies. 
The study will enroll study participants with MS who participated in the 
CLARITY/CLARITY-EXT clinical trials and who received ≥ 1 course of IMP (Cladribine 
Tablets or placebo), or with their FCDE who were randomized in the ORACLE MS study and 
received ≥ 1 course of IMP (Cladribine Tablets or placebo). Data collection for this study is 
based on study participants recruited into previously conducted clinical trials which had 

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defined inclusion and exclusion criteria. Therefore, the chosen inclusion criteria (Section 5.1) 
aim to be as inclusive as possible to maximize the number of study participants from the 
parent studies who can be enrolled, while allowing for the patient or their 
proxy/caregiver/legal representative (in cases where an ICF waiver will not apply) to consent 
to allow the collection of retrospective data and/or prospective data in order to maximize the 
data that can be collected in this exploratory study. The chosen exclusion criteria (Section 5.2) 
will protect the safety of study participants by excluding particularly vulnerable individuals. 
4.3 
Justification for Dose 
Not Applicable. 
4.4 
End of Study Definition 
A participant has completed the study if he/she has completed all study parts, including the 
last visit and/or the last scheduled procedure shown in Section 1.3 (Schedule of Activities). 
The end of the study is defined as the date of the last patient’s last visit. For study participants 
taking part in the main study only (i.e. for participants not participating in the MRI sub-study), 
a participant has completed the study if he/she has completed all study parts, including the 
Study Visit 1, which will be the last patient’s last visit collected for the study. For those also 
taking part in the MRI sub-study, the Study Visit 2 will be the last study participant’s last 
visit.  
A clinical study protocol may not be considered closed as long as:  
• Visits specified by the protocol are still taking place, or  
• Procedures according to the protocol are still being undertaken in any patient. 
During study participation and once patients have concluded their participation in this study, 
they will continue to be treated as part of their usual practice and care.  
5 
Study Population 
The study population will be patients with MS randomized in the CLARITY or CLARITY-
EXT study who have received ≥ 1 course of IMP (Cladribine Tablets or placebo) or patients 
with their FCDE randomized in the ORACLE MS study who have received ≥ 1 course of 
IMP.  
The criteria in Sections 5.1 (Inclusion Criteria) and 5.2 (Exclusion Criteria) are designed to 
enroll only participants who are appropriate for the study; thereby, ensuring the study fulfills 
its objectives. All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a participant is suitable for this study. 
Prospective approval of protocol deviations to inclusion and exclusion criteria, also known as 
protocol waivers or exemptions, is not permitted. 

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Before performing any study assessments that are not part of the participant’s routine medical 
care, the Investigator 
will 
confirm that 
the participant or the participant’s 
proxy/caregiver/legal representative has provided written informed consent, or an ICF waiver 
is in place, if permitted by local regulation and approved by the relevant EC/IRB. 
5.1 
Inclusion Criteria 
Participants are eligible to be included in the study only if all the following criteria apply: 
1. Patients with MS randomized in CLARITY/CLARITY-EXT clinical trial(s) who have 
received ≥ 1 course of IMP (Cladribine Tablets or placebo). 
or 
Patients with their FCDE randomized in ORACLE MS clinical trial who have received 
≥ 1 course of IMP (Cladribine Tablets or placebo). 
Informed Consent 
2. Can give signed informed consent, as indicated in Appendix 2 (Study Governance), 
which includes compliance with the requirements and restrictions listed in the ICF 
and this protocol. Data will be collected from the medical records of deceased or lost 
to follow-up patients if consent is obtained by participant’s proxy/caregiver/legal 
representative or if an ICF waiver is in place, if permitted by local regulation and 
approved by the relevant EC/IRB. 
5.2 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:  
Medical Conditions 
Any condition, including any uncontrolled disease state other than MS, that in the 
Investigator’s opinion, constitutes an inappropriate risk or a contraindication for participation 
in the study or that could interfere with the study objectives, conduct, or evaluation. If a patient 
is experiencing a confirmed or suspected relapse at the time of screening, the Medical Monitor 
is to be consulted to agree on a stabilization period (estimated to be between 4 weeks and 3 
months) before Study Visit 1. 
For specific exclusion criteria for the MRI sub-study please see Section 6.5.4.2 (MRI Sub-
Study). 
5.3 
Lifestyle Considerations 
5.3.1 
Meals and Dietary Restrictions 
Not applicable. This study does not have any meal/dietary restrictions to specify. 

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5.3.2 
Caffeine, Alcohol, Tobacco, and Cannabinoid-containing 
Products 
Twenty-four hours prior to Study Visits 1 and Study Visit 2, when cognitive assessments or 
MRI procedures may be performed, participants will abstain from alcohol and cannabinoid-
containing products.  
5.3.3 
Activity 
Not applicable. This study does not have any restrictions on participant activity level to 
specify. 
5.4 
Screen Failures 
Individuals who do not meet the criteria for participation in this study (screen failure) may 
not be rescreened. Patients with confirmed or suspected relapses can remain in the study, 
and Study Visit 1 will be postponed until the patient has stabilized. 
6 
Study Intervention(s) 
Study intervention is any investigational intervention(s), marketed product(s), placebo, or 
medical device(s) intended to be administered to a study participant per the study protocol. 
6.1 
Study Intervention(s) Administration 
This study does not involve administration of any IMP. Participants enrolled will have 
participated in CLARITY/CLARITY-EXT and ORACLE MS clinical trials, where they 
received Cladribine Tablets or placebo according to those study protocols.  
6.1.1 
Medical Device(s) Use 
Not Applicable. No medical devices are provided for use in this study. 
6.2 
Study Intervention(s) Preparation, Handling, Storage, and 
Accountability 
Not Applicable.  
6.3 
Measures 
to 
Minimize 
Bias: 
Study 
Intervention 
Assignment and Blinding 
6.3.1 
Study Intervention Assignment 
Not Applicable. 
6.3.2 
Blinding 
Not Applicable. 

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6.3.3 
Emergency Unblinding 
Not Applicable. 
6.4 
Study Intervention Compliance 
Not Applicable. 
6.5 
Concomitant Therapy 
Record in the case report form (CRF) all concomitant therapies (e.g., medicines or nondrug 
interventions) used from the time the participant signs the informed consent until completion 
of the study, including any changes. For prescription and over-the-counter medicines, 
vaccines, vitamins, and herbal supplements, record the name, reason for use, dates 
administered, and dosing information. 
The use of concomitant medications and therapies is not controlled as part of this study. The 
first sequential disease modifying MS therapy that was taken following treatment with 
Cladribine Tablets, and the categorization of the second sequential treatment following 
Cladribine Tablets (categorized by platform injectable therapies, monoclonal antibody disease 
modifying treatments, oral disease modifying treatments, other, and unknown treatments) will 
be assessed through retrospective review of the patient’s medical records and captured as part 
of the CRF. 
Contact the Medical Monitor for any questions on concomitant or prior therapy. 
6.5.1 
Rescue Medicine 
There are no restrictions or instructions for rescue medicines for participants in this study. 
Participants will receive medicines as part of their usual care by their treating physician.  
6.5.2 
Permitted Medicines 
There are no restrictions or instructions for permitted medicines for participants in this study. 
Participants will receive medicines as part of their usual care under their treating physician. 
6.5.3 
Prohibited Medicines 
There are no prohibited medicines in this study. Study participants will receive medicines as 
part of their usual care under their treating physician. 
6.5.4 
Other Interventions 
6.5.4.1 
Optional Blood Sampling for Pharmacogenetics Testing 
Patients willing to consent to provide an optional blood sample and who are seen at a site with 
available capabilities to store and ship samples will have a blood draw taken at Study Visit 1 
for pharmacogenetics testing.  

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6.5.4.2 
MRI Sub-Study 
The population to be included in the MRI sub-study will be based on the availability/consent 
of the patient to perform a new MRI, availability of the original machine and other technical 
site capabilities that will be defined following assessment of site feasibility to conduct the 
MRI sub-study. 
For study participants at selected sites where MRI assessments will be conducted, the 
following exclusion criteria will apply to the MRI assessment only:1  
a. Female study participants who are pregnant2  
b. Patients were administered Cladribine Tablets through prescription or as part of 
another study within 6 month period before enrolment in the MRI Sub-study (i.e. 
patients participating in a clinical trial or observational study within the 6 month 
period before enrolment in the MRI Sub-study, but do not receive Cladribine Tablets 
as part of these studies, are allowed to participate in the sub-study). 
Patients willing to provide their consent to participate in the MRI sub-study and who do not 
meet any of the above exclusion criteria will have an MRI without gadolinium taken. Any 
MRI scan will be performed according to a standard protocol detailed in a separate MRI scan 
user’s manual. A central neuroradiology center will perform the analysis of all MRI scans. As 
with other laboratory tests and clinical measures, strict adherence to the MRI scanning 
protocol and prompt handling of the scans is essential in obtaining a meaningful result. A 
urine pregnancy test will be conducted in female patients of childbearing potential 
participating in the MRI sub-study within a week prior to the MRI assessment. A serum 
pregnancy test is also acceptable if available as per SOC. Verbal reporting of pregnancy status 
by the female patient is not acceptable. For pregnant female patients the MRI visit may be 
rescheduled for a later date (within the timeframes specified in Section 4.1) following 
pregnancy outcome. 
Prior to patient assessment, each study site will be asked to send a ‘test’ or ‘dry-run’ scan to 
assess image quality and shipment procedures, to evaluate the accessibility of the electronic 
data carrier, and to assess the ability to correctly reposition patients to get comparable brain 
images. Only upon final approval of this test scan, sites will be allowed to begin assessing 
patients. Once patients are enrolled, the quality of the scans will be assessed as soon as 
possible, as part of an ongoing quality control procedure. Investigators will be informed about 
the acceptance of scans and the need for scans to be repeated due to protocol deviations. 
                                                 
 
 
1 If patient is not eligible for MRI, MRI will not be performed but clinical data for other objectives may be 
collected. 
2 Due to unknown risks regarding rare foetal and childhood adverse event outcomes following exposure to MRI 
during pregnancy (Ray, 2016), MRI procedures will not be performed for female patients who are pregnant, but 
may be scheduled for a later follow up date following pregnancy outcome. 

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6.6 
Dose Selection and Modification 
Not Applicable.  
6.7 
Study Intervention After the End of the Study 
Throughout the duration of the study, participants will continue to receive their SOC 
treatment. Once participants have concluded their participation in this study, they will 
continue to be treated as part of their usual practice and care.  
6.8 
Special Precautions 
Subject to the applicable local laws and regulations, patients who cannot participate or 
complete the SoA due to cognitive impairment or relapsing episode and are thus not able to 
give informed consent will be given the opportunity to participate by their 
proxy/caregiver/legal representative providing consent on their behalf.  
Study visits for participants who are relapsing can be postponed until it is appropriate for them 
to complete study visit assessments. The decision to postpone the study visit will be made at 
the discretion of the physician based on the ability of the patient to attend the clinic and 
complete the assessments without causing discomfort or harm to the patient.  
6.9 
Management of Adverse Events of Interest 
Adverse events of special interest (AESIs) for this study as defined in the SmPC should be 
considered as a medically significant AE and reported to the Sponsor using a Serious Adverse 
Event (SAE) Report Form with all related information. 
Three main categories of AEs were defined as AESI: 
• Severe (≥ Grade 3) lymphopenia: Lymphopenia is an expected event based on the 
mechanism of action of cladribine, an adenosine deaminase-resistant analog of 
deoxyadenosine, that after conversion to its active triphosphate form (2-Cd-ATP), 
decreases peripheral lymphocyte counts; grading should be performed according 
Common Terminology Criteria for Adverse Events where Grade 3 is defined as 
< 500/mm3- 200/mm3. 
• Infections: Defects in cell-mediated immunity and immunosuppressive conditions 
may predispose patients to infectious diseases. 
• Malignancies: Immunodeficiency could lead to an increased risk for the development 
of malignancies; however, this is generally seen where immunosuppression is 
profound and long-lasting. Malignancy cases have been reported in MS patients 
treated with other DMDs. In view of these considerations the potential risk of 
malignancy for Cladribine Tablets has been thoroughly evaluated. 
 

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7 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal 
7.1 
Discontinuation of Study Intervention 
Not Applicable. 
7.1.1 
Temporary Discontinuation 
Not Applicable. 
7.1.2 
Rechallenge 
Not Applicable. 
7.2 
Participant Discontinuation/Withdrawal from the Study 
• A participant may withdraw from the study at any time, at his/her own request (i.e., 
withdrawal of consent), and without giving a reason. 
• Patients’ proxy/caregiver/legal representative may withdraw consent at any time as well, 
without giving a reason. 
• For the MRI sub-study, the participant may be withdrawn by the Investigator due to 
participation in another clinical study if the participant receives Cladribine Tablets in the 
other clinical study. 
• The participant may be withdrawn at any time at the discretion of the Investigator for 
safety, behavioral, or administrative reasons. 
• The SoA specifies the data to collect at each follow-up visit, and any additional evaluations 
that need to be completed. These assessments are not mandatory, and patients can remain 
in the study if certain assessments (e.g. PROs) are not completed.  
• Participants can withdraw consent for the optional pharmacogenetic testing any time; this 
does not preclude them from continuing in the study and complete other assessments. 
The patient will be informed that any data collected from the signature of the informed consent 
until the point of withdrawal will be maintained and included in the analysis (pending review 
and approval by ECs, IRBs and/or local regulations and patient consent). The Investigator 
should make every attempt to clarify the level of withdrawal: e.g., if the participant can still 
be contacted by phone for checking his/her status (e.g., alive or not). In case of withdrawal 
from the study, the appropriate CRF section must be completed.  
If a participant withdraws consent from the optional pharmacogenetic testing before the 
samples have been analyzed, the participant’s samples will be destroyed without being 
analyzed. In addition, data collected will be excluded from the analysis. If a participant 
withdraws from the pharmacogenetic testing after the participant’s sample has been analyzed, 
any information learned from the analysis will remain part of the study database and may not 
be removed. 

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Participants or their proxy/caregiver/legal representative will be informed that they have the 
right to withdraw from the study at any time, without prejudice to their medical care, and that 
they are not obliged to state their reasons. Any withdrawal must be fully documented in the 
eCRF and source documents and should be followed up by the Investigator. The Investigator 
may withdraw a patient at any time if this is considered to be in the patient’s best interest. 
Participants who are discontinued/withdrawn from the study will not be replaced.  
7.3 
Lost to Follow-Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon 
as possible, counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain if the participant wants to or should continue in the study. 
• Before a participant is deemed “lost to follow-up”, the Investigator or designee must 
make every effort to regain contact with the participant: 1) where possible, make 
3 telephone calls; 2) if necessary, send a certified letter (or an equivalent local method) 
to the participant’s last known mailing address, and 3) if a participant has given the 
appropriate consent, contact the participant’s general practitioner for information. These 
contact attempts should be documented in the participant’s medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
8 
Study Assessments and Procedures 
• Study assessments and procedures and their timing are summarized in Section 1.3 
(Schedule of Activities). 
• No protocol waivers or exemptions are allowed. 
• Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue the study. 
• Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log 
to record details of all participants screened, to confirm eligibility, and if applicable, 
record reasons for screening failure.  
• Prior to performing any study assessments that are not part of the participant’s routine 
medical care or before entering data in the study electronic data capture (EDC) system, 
the 
Investigator 
will 
confirm 
that 
the 
participant 
or 
the 
participant’s 
proxy/caregiver/legal representative has provided informed consent. Data will be 
collected from the medical records of deceased or lost to follow-up patients if consent 

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is obtained by participant’s proxy/caregiver/legal representative or an ICF waiver is in 
place, if permitted by local regulation and approved by the relevant EC/IRB.  
• Procedures conducted as part of the participant’s routine medical care (e.g., pregnancy 
test for MRI sub-study) and obtained before signing of the ICF may be used for 
screening or baseline purposes provided the procedures met the protocol-specified 
criteria and were performed within the time frame defined in the SoA. 
8.1 
Efficacy Assessments and Procedures 
A detailed schedule of study procedures/assessments is provided in the SoA (Section 1.3). 
During the Screening Visit, the patient or their proxy/caregiver/legal representative will be 
informed of the study objectives and overall requirements, and informed consent will be 
obtained prior to any study specific assessments, unless an ICF waiver is in place (see 
Appendix 2  
Study Governance for details on informed consent process). The site will 
also confirm that patients meet the Inclusion/Exclusion Criteria. During this visit, a complete 
Screening Evaluation will be performed, which will capture sociodemographic and clinical 
characteristics (including gender, age/year of birth, race and ethnicity where permitted, 
employment status and education level attained), medical history, and disease history 
(including classification of disease and diagnosis date). These screening activities may be 
administered by telephone if the patient is unable to attend the clinic for study visits, 
dependent on approval by ECs, IRBs, and/or local regulations. For patients participating only 
in retrospective data collection, local requirements for patient consent will be observed, which 
may include informed consent waiver.  
PRO questionnaires, followed by cognition assessments (for ORACLE MS patients only), 
should be performed prior to any other assessments.  
For patients participating in the MRI assessment, attempts should be made to perform 
Study Visit 2 within 3 months (maximum) after completing Study Visit 1 (maximum 4 weeks 
from Study Visit 1 after the last patient has been recruited). A urine pregnancy test will be 
performed within a week prior to the MRI assessment in female patients of childbearing 
potential. A serum pregnancy test is also acceptable if available as per SOC. Verbal reporting 
of pregnancy status by the patient is not acceptable. The Investigator will ensure that the 
patient or the patient’s proxy/caregiver/legal representative has provided specific informed 
consent to participate in MRI assessments. 
8.1.1 
Clinical Endpoints 
8.1.1.1 
Expanded Disability Status Scale (EDSS) 
The EDSS is a neurological assessment that will be used to assess the long-term disability 
progression following treatment with IMP in the parent studies (Appendix 5Expanded 
Disability Status Scale (EDSS)). EDSS is a scale from 0-10 that evaluates a person with MS’s 
disability/neurologic function level with 6 being the critical point at which a patient requires 
ambulatory assistance. The primary endpoint of proportion of study participants using a 
wheelchair (defined as unable to walk beyond approximately 5 meters even with aid, 

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essentially restricted to wheelchair; wheels self in standard wheelchair and transfers alone; up 
and about in wheelchair some 12 hours a day) the majority of the time in the 3 months prior 
to Study Visit 1 or participants are bedridden any time prior to Study Visit 1 determined via 
an EDSS score of 7.0 or higher (if available), or alternative clinical description data in medical 
records. The secondary endpoint will be determined as the proportion of study participants 
with EDSS of 6.0 or higher by EDSS documentation or alternative clinical description in 
medical records after last IMP from parent study. 
Sustained disease progression is important because transient increases in the EDSS may also 
be due to relapses, which reflect disease activity rather than disease progression (Healy, 
2013); an EDSS measurement taken at a single point in time may be subject to measurement 
error (Goodkin, 1992). As such, confirmation of sustained EDSS score is needed to mitigate 
against measurement error and EDSS fluctuation (Kalincik, 2015).  
Furthermore, while EDSS scores at any timepoint, regardless of their relationship to relapses, 
may serve as evidence of EDSS progression, it is generally recommended that only EDSS 
scores that are recorded more than 30 days from the onset of a preceding relapse be used in 
order to confirm progression events (Kalincik, 2015). As such, Investigators in this study will 
be instructed to exclude any EDSS score recorded within 30 days of a previous relapse. 
The in-person EDSS will be completed by the evaluating physician for those study 
participants who can come to the clinic for Study Visit 1. Alternatively, a telephone EDSS 
score can be determined by telephone interview in which trained clinical site staff member to 
administer the EDSS telephone questionnaire (Lechner-Scott, 2003). The telephone EDSS 
will be collected only from patients not attending clinic visits, and will be collected within 14 
days of obtaining informed consent. Only one mode of the collection (in-person during a clinic 
visit, or by telephone) is required per patient. Retrospective EDSS scores will be ascertained 
from medical records for the time period between end of parent study to Study Visit 1 (when 
available).  
Reasons for inability to come to the clinic for Study Visit 1 may include travel/migration, or 
limited mobility (bedridden), or clinical site restrictions due to COVID-19. In addition, 
patients may not want to come to the clinic for Study Visit 1 due to a lack of interest.. 
8.1.1.2 
EDSS Confidence Scale 
For each EDSS score that is obtained retrospectively from medical charts and at the time of 
Study Visit 1, the evaluating physician will be asked to complete the EDSS Confidence Scale 
which is a single question indicating their confidence in that score’s accuracy. This will be 
based on a non-validated 4-point Likert scale where 0 = not at all confident and 3 = highly 
confident.  
8.1.1.3 
Bedridden Status  
A patient’s status as being bedridden will be determined by EDSS scores of 8.0 or higher 
(“essentially restricted to bed or chair or perambulated in wheelchair but may be out of bed 
itself much of the day”), if available, or by clinical descriptions in medical records.  

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8.1.1.4 
Subsequent Disease Modifying Drugs and Treatment 
Decisions 
Details of subsequent DMDs, including physician questions on treatment decisions will be 
captured in the eCRF, based on chart review to determine the time, type, and reason for the 
first sequential treatment after the first course of Cladribine Tablets and the categorization of 
the second sequential treatment (categorized by platform injectable therapies, monoclonal 
antibody disease modifying treatments, oral disease modifying treatments, other, and 
unknown treatments).  
8.1.1.5 
First Use of Ambulatory Device  
The date of first use of ambulatory device will be determined through retrospective chart 
review, based on an EDSS score of 6.0 or higher (score of 6.0 is defined as “intermittent or 
unilateral constant assistance [cane, crutch, brace] required to walk about 100 meters with or 
without resting”) or clinical descriptions if EDSS scores are not available. 
8.1.1.6 
First Use of Wheelchair 
The date of first use of a wheelchair will be determined through retrospective chart review, 
based on an EDSS score of 7.0 or higher (score of 7.0 is defined as unable to walk beyond 
approximately 5 meters even with aid, essentially restricted to wheelchair; wheels self in 
standard wheelchair and transfers alone; up and about in wheelchair some 12 hours a day) or 
clinical descriptions if EDSS scores are not available. 
8.1.1.7 
Relapse Count  
The following information on relapses will be recorded on the relapse module of the eCRF, 
if available: the number of relapses from end of parent study to Study Visit 1; relapse onset 
date and stabilization/resolution date; estimated relapse duration; maximal EDSS at time of 
relapse (if known); major systems affected; treatment required for relapse; patient 
hospitalization for relapse; outcome of relapse (i.e. increase in disability). A relapse will be 
defined as patient-reported symptoms and objectively observed signs typical of an acute 
inflammatory demyelinating event in the CNS, developing acutely or sub-acutely, with 
duration of at least 24 hours, in the absence of fever or infection (Thompson, 2018). 
8.1.1.8 
Conversion to Clinically Definite Multiple Sclerosis 
(ORACLE MS Participants Only)  
Conversion to CDMS will be determined according to the McDonald 2017 criteria 
(Thompson, 2018; Table 2). For more details please see Appendix 6 2017 Mc Donald 
Criteria (From Thompson, 2018)). 

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Table 2 
The 2017 McDonald criteria for diagnosis of Multiple Sclerosis in 
patients with an attack at onset  
Clinical Presentation 
Additional Data Needed to Make MS Diagnosis 
• ≥2 attacks and objective 
clinical evidence of ≥2 
lesions 
• ≥2 attacks and objective 
clinical evidence of 1 
lesion with historical 
evidence of prior attack 
involving lesion in 
different location  
None. Dissemination in space (DIS) and dissemination in 
time (DIT) have been met. 
• ≥2 attacks and objective 
clinical evidence of 1 
lesion 
 
One of these criteria: 
• DIS: additional clinical attack implicating different CNS 
site 
• DIS: ≥1 symptomatic or asymptomatic MS-typical T2 
lesions in ≥2 areas of CNS: periventricular, 
juxtacortical/cortical, infratentorial or spinal cord 
 
• 1 attack and objective 
clinical evidence of ≥2 
lesions 
One of these criteria: 
• DIT: additional clinical attack  
• DIT: simultaneous presence of both enhancing and non-
enhancing symptomatic or asymptomatic MS-typical 
MRI lesions 
• DIT: new T2 or enhancing MRI lesion compared to 
baseline scan (without regard to timing of baseline scan) 
• Cerebrospinal fluid (CSF)-specific (i.e. not in serum) 
oligoclonal bands 
• 1 attack and objective 
clinical evidence of 1 
lesion 
One of these criteria: 
• DIS: additional attack implicating different CNS site 
• DIS: ≥1 MS-typical symptomatic or asymptomatic T2 
lesions in ≥2 areas of CNS: periventricular, 
juxtacortical/cortical, infratentorial or spinal cord 
AND 
One of these criteria: 
• DIT: additional clinical attack  
• DIT: simultaneous presence of both enhancing and non-
enhancing symptomatic or asymptomatic MS-typical 
MRI lesions 
• DIT: new T2 or enhancing MRI lesion compared to 
baseline scan (without regard to timing of baseline scan) 
• CSF-specific (i.e. not in serum) oligoclonal bands 

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8.1.1.9 
Diagnosis of Secondary Progressive Multiple Sclerosis 
Without Relapses 
SPMS without relapses will be defined as follows (Lublin, 2014; Kappos, 2018): 
• Documented moderate-to-advanced disability indicated by EDSS score of 3.0–6.5 at 
time of diagnosis of SPMS 
• A history of RMS diagnosis 
• Documented at least 6 months sustained EDSS progression based on clinical 
judgment 
• Without evidence of relapses in the 3 months before SPMS diagnosis 
Conversion to SPMS will be ascertained by the evaluating physician retrospectively from 
medical records or determined at Study Visit 1 (for study participants who may have 
converted to SPMS between last regular clinic visit and Study Visit 1). 
8.1.1.10 
Diagnosis of Secondary Progressive Multiple Sclerosis 
With Relapses 
SPMS with relapses will be defined as follows (Lublin, 2014; Kappos, 2018): 
• Documented moderate-to-advanced disability indicated by EDSS score of 3.0–6.5 at 
time of diagnosis of SPMS 
• A history of RMS diagnosis 
• Documented at least 6 months sustained EDSS progression based on clinical 
judgment 
• With evidence of relapses in the 3 months before SPMS diagnosis 
Conversion to SPMS will be ascertained by the evaluating physician retrospectively from 
medical records or determined at Study Visit 1 (for study participants who may have 
converted to SPMS between last regular clinic visit and Study Visit 1). 
8.1.1.11 
Diagnosis of Primary Progressive Multiple Sclerosis 
(ORACLE MS Participants Only) 
As per the McDonald 2017 criteria (Thompson, 2018), PPMS can be diagnosed in patients 
with: 
• One year of disability progression (retrospectively or prospectively determined) 
independent of clinical relapse 
 
Plus 2 of the following criteria: 

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• One or more T2-hyperintense lesions3 characteristic of multiple sclerosis in one or 
more of the following brain regions: periventricular, cortical or juxtacortical, or 
infratentorial 
• Two or more T2-hyperintense lesions3 in the spinal cord 
• Presence of cerebrospinal fluid (CSF) -specific oligoclonal bands 
8.1.1.12 
Cognition Endpoints (ORACLE MS Participants Only) 
Cognition measures to be administered at Study Visit 1 are as follows: 
• The Brief Visuospatial Memory Test – Revised (BVMT-R) 
• Symbol Digit Modality Test (SDMT) 
Note that the BVMT-R and SDMT assessments are to be collected for ORACLE MS subjects 
only in countries where these instruments were used in the CLASSIC MS study.  
8.1.1.13 
Brain Imaging 
A subset of study participants from the parent studies will be invited to participate in a follow-
up study visit (Study Visit 2) for an MRI assessment without gadolinium, to evaluate the 
following parameters associated with chronic disease activity in MS patients:  
o Total volume of T2 lesions  
o Total number of T2 lesions  
o Number of hypointense lesions on T1-spin echo MRI 
o Volume of hypointense lesions on T1-spin echo MRI 
o Brain volume or surrogate (In cases where brain volume is not possible to assess 
for technical reasons, then 3rd ventricle diameter may be evaluated) 
o Ventricular volume 
8.1.2 
Other Assessments 
8.1.2.1 
Patient-reported Outcomes/Quality of Life: EQ-5D-3L 
The 3-level version of the EuroQoL-5 Dimension questionnaire (EQ-5D-3L) will be 
administered at Study Visit 1. The EQ-5D-3L is a validated, self-administered, generic, utility 
instrument that includes 5 single-item dimensions: mobility, self-care, usual activities, 
                                                 
 
 
3 Unlike the 2010 McDonald criteria, no distinction between symptomatic and asymptomatic MRI lesions is 
required. 

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pain/discomfort, and anxiety/depression (EuroQoL Group, 1990). Study participants must 
choose between 3 levels of difficulty in accomplishing tasks in each dimension. The 
questionnaire also contains a Visual Analog Scale for the study participants to rate their 
current health state from 0 (worst imaginable health state) to 100 (best imaginable health 
state). 
8.1.2.2 
Frequency of Stable Patient Monitoring Questions  
Each evaluating physician at the clinical sites will be asked to complete questions assessing 
how frequently the study patients with MS are monitored and evaluated at their site in regular 
clinical practice. These questions ask about frequency of follow-up visits and follow-up MRI 
assessments if the study patients with MS are considered stable.  
8.2 
Safety Assessments and Procedures 
The safety profile of this study’s interventions will be assessed through the recording, 
reporting and analysis of medical conditions, AEs, physical examination findings, and vital 
signs as specified in the SoA (Section 1.3). A comprehensive assessment of any potential AE 
experienced by each participant will be conducted starting when the participants give 
informed consent and throughout the study. The Investigator will report any AE, whether 
observed by the Investigator or reported by the participant; the reporting period is specified 
in Section 8.3.1 (Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information).  
All clinically significant abnormalities occurring before signature of informed consent should 
be recorded in the Medical History section and/or Disease History; all abnormalities occurring 
or worsening after signature of informed consent should be recorded in the AE section unless 
otherwise stated by the protocol. 
There are no specific safety endpoints included in this study. 
8.2.1 
Physical Examinations 
• A complete physical examination will include, at a minimum, assessments of the 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. Height and 
weight will also be measured and recorded. 
• A brief physical examination will include, at a minimum, assessments of the skin, lungs, 
cardiovascular system, and abdomen (liver and spleen). 
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
8.2.2 
Vital Signs 
Vital signs will be assessed and interpreted as per SOC. 
• Oral temperature, pulse rate, respiratory rate, and blood pressure will be assessed. 
• Blood pressure and pulse measurements will be assessed with a completely automated 
device. Manual techniques will be used only if an automated device is not available. 

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• Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest 
for the participant in a quiet setting without distractions (e.g., television, cell phones). 
• Vital signs will be measured in a semi-supine position after 5 minutes rest and will 
include temperature, systolic and diastolic blood pressure, and pulse and respiratory 
rate. Three readings of blood pressure and pulse will be taken. The first reading should 
be rejected. The second and third readings should be averaged to give the measurement 
to be recorded in the CRF. 
8.2.3 
Electrocardiograms 
Not Applicable. 
8.2.4 
Clinical Safety Laboratory Assessments 
Not Applicable.  
8.2.5 
Suicidal Risk Monitoring 
Not Applicable. 
8.3 
Adverse Events and Serious Adverse Events 
The definitions of an AE and a SAE are in Appendix 3 (Adverse Events: Definitions and 
Procedures for Recording, Evaluating, Follow-up, and Reporting). 
8.3.1 
Time Period and Frequency for Collecting Adverse Event 
and Serious Adverse Event Information 
The AE reporting period for safety surveillance begins when the participant is initially 
included in the study (i.e. date of first signature of informed consent) and continues until Study 
Visit 1 or, if applicable, Study Visit 2. 
All SAEs will be collected and reported as indicated in Appendix 3 from the signing of the 
informed consent form until study Visit 1 or, if applicable, Study Visit 2. Beyond this 
reporting period if investigator learns of any SAE at any time after a participant has been 
discharged from the study, and he/she considers the event to be reasonably related to the study 
intervention or study participation, the Investigator will promptly notify the Sponsor.   
Please note, in addition to any AE/SAE which occurs after informed consent, any adverse 
drug reaction (ADR) that occurred after the End of Trial Visit in the parent study and is 
assessed as related to Cladribine Tablets by the Investigator must be recorded in the eCRF as 
well. 
The method of recording, evaluating, and assessing causality of AEs (including SAEs) and 
the procedures for completing and transmitting SAE reports are in Appendix 3. 

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8.3.2 
Method of Detecting Adverse Events and Serious Adverse 
Events 
At each study visit, the participant will be queried on changes in his or her condition. During 
the reporting period, any unfavorable changes in the participant’s condition will be recorded 
as AEs, regardless if reported by the participant or their caregiver/legal representative or 
observed by the Investigator. 
Complete, accurate and consistent data on all AEs experienced for the duration of the 
reporting period (defined above) will be reported on an ongoing basis in the appropriate 
section of the CRF. All SAEs must be additionally documented and reported using the 
appropriate Report Form as specified in Appendix 3. 
Due to the interventional nature of the MRI examination that is done specifically for the 
purpose of this study, the study specific procedure of AEs and SAEs data collection and 
reporting will be followed. The Sponsor’s responsibilities regarding safety reporting will be 
carried out in accordance to the European Directive 2001/20/EC and with the related detailed 
guidance documents.  
8.3.3 
Follow-up of Adverse Events and Serious Adverse Events 
AEs are recorded and assessed continuously throughout the study, as specified in Section 
8.3.1 (Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event 
Information) and are assessed for their outcome at the patient’s last visit (i.e. Study Visit 1 for 
patients not participating in the MRI sub-study or Study Visit 2 for patients participating in 
the MRI sub-study). All SAEs ongoing at the patient’s last visit must be monitored and 
followed up by the Investigator until stabilization or until the outcome is known, unless the 
participant is documented as “lost to follow-up”. Reasonable attempts to obtain this 
information must be made and documented. It is also the responsibility of the Investigator to 
ensure that any necessary additional therapeutic measures and follow-up procedures are 
performed. Further information on follow-up procedures is given in Appendix 3 (Adverse 
Events: Definitions and Procedures for Recording, Evaluating, Follow-up, and Reports). 
8.3.4 
Regulatory Reporting Requirements for Serious Adverse 
Events 
The Sponsor will send appropriate safety notifications to Health Authorities in accordance 
with applicable laws and regulations. 
The Investigator must comply with any applicable site-specific requirements related to the 
reporting of SAEs (particularly deaths) involving study participants to the Independent Ethics 
Committee (IEC)/IRB that approved the study. 
In accordance with International Conference on Harmonisation (ICH) Good Clinical Practice 
(GCP), the Sponsor/designee will inform the Investigator of findings that could adversely 
affect the safety of participants, impact the conduct of the study or alter the IEC’s/IRB’s 
approval/favorable opinion to continue the study. In line with respective regulations, the 
Sponsor/designee will inform the Investigator of AEs that are both serious and unexpected 
and considered to be related to the administered product (“suspected unexpected serious 

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adverse reactions” or SUSARs). The Investigator should place copies of Safety Reports in the 
Investigator Site File. National regulations regarding Safety Report notifications to 
Investigators will be considered. 
When specifically required by regulations and guidelines, the Sponsor/designee will provide 
appropriate Safety Reports directly to the concerned lead IEC/IRB and will maintain records 
of these notifications. When direct reporting is not clearly defined by national or site-specific 
regulations, the Investigator will be responsible for promptly notifying the concerned 
IEC/IRB of any Safety Reports provided by the Sponsor/designee and of filing copies of all 
related correspondence in the Investigator Site File. 
For studies covered by the European Directive 2001/20/EC, the Sponsor’s responsibilities 
regarding the reporting of SAEs/SUSARs/Safety Issues will be carried out in accordance with 
that Directive and with the related detailed guidance documents. 
8.3.5 
Pregnancy 
All pregnancies of female participants occurring during the Adverse Event Reporting Period, 
defined in Section 8.3.1 (Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information), must be recorded in the AE page/section of the CRF.  
For female participants in the MRI sub-study with an estimated conception date during the 
safety surveillance period (Section 8.3.1), the Investigator must notify the Sponsor/designee 
in an expedited manner of any pregnancy using the Pregnancy Report Form, which must be 
transmitted by the same process specified for SAE reporting in Appendix 3, section on 
Reporting Serious Adverse Events and AESIs. Investigators must actively follow up, 
document and report on the outcome of all these pregnancies (among MRI sub-study 
participants, as described above), even if the participants are withdrawn from the study. The 
Investigator must notify the Sponsor/designee of the outcomes of pregnancies among MRI 
sub-study participants using the Pregnancy Report Form. If an abnormal outcome occurs, the 
SAE Report Form will be used if the participant sustains an event and the Parent-Child/Fetus 
Adverse Event Report Form if the child/fetus sustains an event. Any abnormal outcome (e.g., 
spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) must 
be reported in an expedited manner, as specified in Section 8.3.1, while normal outcomes 
must be reported within 45 days after delivery. 
8.4 
Treatment of Overdose 
Not Applicable.  
8.5 
Pharmacokinetics 
Not Applicable.  
8.6 
Pharmacodynamics 
Not Applicable.  

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8.7 
Pharmacogenetics 
Optional blood samples for pharmacogenetics testing will be collected at Study Visit 1 or 
during following clinic visits as per SoA (Section 1.3). 
• Where local regulations and IRB/IEC allow, an 8ml blood sample will be collected for 
DNA analysis from consenting participants. Participation in pharmacogenetic research is 
optional. Participants who do not wish to participate in the pharmacogenetic research 
may still participate in the study. 
• In the event of DNA extraction failure, a replacement for pharmacogenetic testing may 
be requested from the participant. Additional informed consent will not be required to 
obtain a replacement sample. 
• Appendix 4 provides further information on pharmacogenetic research. 
8.8 
Biomarkers 
Not Applicable.  
8.9 
Immunogenicity Assessments  
No Applicable.  
8.10 
Health Economics  
Not Applicable.  
9 
Statistical Considerations 
One interim and 1 final analysis are planned for this study. 
Study data will be integrated with study data from the parent studies as required to perform 
the statistical analyses. 
Generally, data will be analyzed descriptively with the following measures: mean with 
standard deviation, median with interquartile range, minimum and maximum for continuous 
variables and counts with percentages for categorical variables. Missing data will also be 
summarized. Patients’ demographic factors and clinical characteristics at enrolment will be 
summarized descriptively as detailed above.  
As the study visits are around 10 years after the initial treatment with IMP in the parent 
studies, it is likely that only a specific type of participants from these trials is available for 
follow-up. A potential selection bias will be evaluated by comparing the characteristics of 
those patients randomized to the parent studies and those patients included in this study.  
Methodological approaches which evaluate and address this potential selection bias will be 
further detailed in the Statistical Analysis Plan (SAP). Differences in study populations will 
be considered when making inferences based upon study results. With this in mind, analyses 

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will generally be exploratory and for hypothesis generating purposes. Parameter estimates 
with associated 95% confidence intervals (CIs) will be reported for the study endpoints, as 
appropriate 
The analytical approach for all endpoints is described below and will be further detailed in 
the integrated Analysis Plan (iAP).  
All procedures outlined within this section will be undertaken using a SAS statistical analysis 
software (version 9.4 or higher). 
9.1 
Statistical Hypotheses 
No formal statistical hypothesis will be tested, as the study is designed to be exploratory.  
9.2 
Sample Size Determination 
No formal sample size calculation has been made for this exploratory study as enrolment is 
limited to eligible study participants from the parent studies (N=1,958). Therefore, as many 
study participants as feasibly possible will be enrolled from this group.  
Using East Version 6, based on proportions of study participants that could be expected to be 
in a wheelchair (5%, 10% and 15%), and a range of sample size (30%, 40%, 50% and 60% 
participants recruited from the 1,958 participants in the parent studies), the following 
precision (half-width) could be achieved for the 95% CI: 
% recruited 
Sample Size 
Proportion (π) 
95% CI 
Half-width 
30 
587 
5% 
[3.52 ; 6.48] 
1.48% 
30 
587 
10% 
[7.97 ; 12.03] 
2.03% 
30 
587 
15% 
[12.58 ; 17.42] 
2.42% 
40 
783 
5% 
[3.82 ; 6.18] 
1.18% 
40 
783 
10% 
[8.37 ; 11.63] 
1.63% 
40 
783 
15% 
[13.06 ; 16.94] 
1.94% 
50 
979 
5% 
[4.03 ; 5.97] 
0.97% 
50 
979 
10% 
[8.67 ; 11.33] 
1.33% 
50 
979 
15% 
[13.42 ; 16.58] 
1.58% 
60 
1175 
5% 
[4.21 ; 5.79] 
0.79% 
60 
1175 
10% 
[8.92 ; 11.08] 
1.08% 
60 
1175 
15% 
[13.71 ; 16.29] 
1.29% 
9.3 
Populations for Analyses 
The analysis populations are specified below. Four patient cohorts will be used for the purpose 
of exploring all objectives of the study protocol. These will include: 
• 
Cohort A: Patients who meet both the protocol inclusion and exclusion criteria and are 
drawn from the pooled CLARITY, CLARITY-EXT and ORACLE MS clinical trials 
• 
Cohort B: Patients who meet both the protocol inclusion and exclusion criteria and are 
drawn from the CLARITY or CLARITY-EXT study only 

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• 
Cohort C: Patients who meet both the protocol inclusion and exclusion criteria and are 
drawn from the CLARITY-EXT study only  
• 
Cohort D: Patients who meet both the protocol inclusion and exclusion criteria and are 
drawn from the ORACLE MS study only 
The statistical analyses will generally be performed for Cohort A except for the secondary 
and tertiary endpoints unique to the parent studies, which will be analyzed using study 
participants from these parent studies only. The primary and selected secondary or tertiary 
analyses may be repeated by Cohort B, C and D in order to evaluate consistency of results 
across clinical trials. 
The following subgroups will be defined: 
Subgroup/Subset 
Description 
Subgroup Treatment 
Course in Cohort B 
• Study participants who received placebo only (i.e. study 
participants that received placebo in CLARITY who did 
not enter CLARITY-EXT or received placebo in both 
CLARITY and CLARITY-EXT) 
• Study participants who received at least 1 dosea of 
Cladribine Tablets during either CLARITY or CLARITY -
EXT but did not start the 2nd year treatment coursea of 
Cladribine Tablets 
• Study participants who received at least 1 dosea of 
Cladribine Tablets during either CLARITY or CLARITY 
-EXT that started the 2nd year treatment coursesa of 
Cladribine Tablets but did not start a third-year treatment 
course of Cladribine treatment 
• Study participants who received at least 1 dosea of 
Cladribine Tablets during CLARITY and CLARITY -
EXT that started > 2 treatment coursesa of Cladribine 
Tablets (i.e. patients who completed CLARITY and 
started at least the 1st year treatment coursea in 
CLARITY-EXT). This corresponds to completing 
2 courses of Cladribine treatment and start the third 
course of Cladribine treatment. 

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Subgroup/Subset 
Description 
Subset Long-term 
Responder 
Study participants  
• not requiring DMD until Year 4 or later following their last 
dosea of IMP, and who did not demonstrate any evidence of 
disease reactivation based on Investigator assessment of 
clinical and imaging outcomes 
• who started on alternate therapy (DMD) less than 4 years 
following their last dosea of IMP or who demonstrate any 
evidence of disease reactivation based on Investigator 
assessment of clinical and imaging outcomes. 
Subset Types of 
Subsequent DMDs 
• Platform injectable therapy (Interferon-β [Avonex®, Rebif®, 
Betaferon®, Extavia®, Plegridy®] or glatiramer acetate 
[Copaxone®]) 
• Monoclonal antibody disease modifying treatment 
• Oral disease modifying treatment 
• Other subsequent treatment 
• Off-label treatments (drugs not approved by regulatory 
agencies to treat MS) 
• No subsequent treatment 
Subgroup Prior Use 
of DMD 
• Prior use of DMD at any time in the patient's history before 
enrolment into CLARITY  
• Complementary subgroup 
Subgroup HDA for 
Cohort B 
• HDA study participants 
• Non-HDA study participants 
DMD=disease-modifying drug, HDA=high disease activity, MS=multiple sclerosis. 
a One dose is equivalent to one tablet. One course of IMP is defined as 1 year of treatment with IMP (2 
treatment cycles [weeks]. A treatment cycle is defined as daily administration of IMP given consecutively 
over 4-5 days during a 28-day period. One treatment week is equivalent to 1 treatment cycle. 
The primary and selected secondary or tertiary analyses may be repeated by these 
subgroups/subsets in order to evaluate the pattern of response.  
It should be noted that the subgroup analyses on the subgroups’ treatment courses and 
subsequent DMD do not support the comparison of any treatment effect as the definition of 
subgroups already is not independent from randomized treatment.  
9.4 
Statistical Analyses 
The primary endpoint of this study will be evaluated by determining the percentage and 
95% CI of patients using a wheelchair the majority of the time in the 3 months prior to 
Study Visit 1 or patients bedridden any time prior to Visit 1 (as defined in Section 8.1.1.1) 
for each Cohort and the appropriate subgroups/subsets as defined above in Section 9.3. 
Forest plots will also be used to display these results. 

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In addition, proportions adjusted for participation in previous parent studies, as well as other 
patient characteristics which are deemed to be prognostic for the primary endpoint will be 
determined applying a logistic regression model. Variables with multiple levels of discrete 
values will be modeled as categorical variables, and variables with continuous scales (e.g. 
age) may be modeled as a continuous covariate or categorized where appropriate. 
The secondary endpoint, the proportion of patients with EDSS of 6.0 or higher as determined 
by EDSS documentation or alternative clinical description in medical records after last IMP 
from parent study. will be presented together with the corresponding 95% CI for each Cohort 
and appropriate subgroups/subsets as defined above. The results of the confidence scale of 
EDSS values will be presented descriptively and may be used to interpret EDSS results.  
The clinical and MRI characteristics of study participants will be evaluated descriptively by 
the subgroup long-term responders for Cohort A. 
Tertiary endpoints collected retrospectively or at Study Visit 1 will be analyzed descriptively.  
Analyses of the change in EQ-5D-3L and change in cognition from the last clinical visit in 
the parent studies to Study Visit 1 in study participants previously treated with IMP as part of 
the parent studies will also be performed according to instrument developer instructions and 
analyzed descriptively to assess the durability of treatment effect.  
Similarly, changes in MRI assessment from the last clinical visit in the parent studies to Study 
Visit 2 will be analyzed descriptively. 
In addition, responder rates in high-disease activity (HDA) patients versus the responder rate 
in non-HDA patients from the CLARITY/CLARITY-EXT population will be analyzed 
descriptively. 
Time-to-event data will be calculated from first dose of IMP in the parent study and will be 
presented using Kaplan-Meier estimates or cumulative incidence curves as appropriate. The 
analytical approach will be further detailed in the SAP. 
Genetic variations will be analyzed descriptively. In addition, association of genetic variations 
with patients experiencing long-term response will be analyzed. 
Adverse events will be summarized by number and frequency of patients with events. 
 
Endpoint 
Statistical Analysis Methods 
Primary 
Percentage and 95% CI 
Secondary 
Percentage and 95% CI 
Tertiary/Exploratory 
Descriptive statistics and time-to-event analyses as described above 
9.4.1 
Handling of Missing Data 
It is anticipated that missing data will feature within the available dataset for the many of the 
endpoints, particularly those that are collected through retrospective medical chart review. 
Subsequently, should missing values constitute a substantial proportion of the endpoint data 

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then multiple imputation may be used in addition to the complete case approach. The multiple 
imputation may be repeated applying different assumptions (missing at random, missing not 
at random). 
9.4.2 
Sequence of Analyses 
An interim analysis is planned to publish results when data from a minimum of 100 of patients 
is available from Cohort A. This data includes the primary and key secondary endpoints as 
well as the EQ-5D-3L; pharmacogenetics and MRI will not be included in the interim 
analysis. Specifics will be detailed in the iAP. Due to the exploratory nature of the study, an 
adjustment for multiple comparisons is not required. 
The final analysis will be performed after final database lock. 
 
 

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10 
References  
Cook S, Leist T, Comi G, et al. Cladribine tablets in the treatment of patients with multiple 
sclerosis: an integrated analysis of infections in association with severe lymphopenia. 
ECTRIMS Online Library, n. 146475, 2016. 
Comi G, Cook SD, Giovannoni G, et al. MRI outcomes with cladribine tablets for multiple 
sclerosis in the CLARITY study. 2013. J Neurol; 260 (4): 1136-46. 
Comi G, Giovannoni G, Cook S, et al. Magnetic resonance imaging (MRI) outcomes in 
patients with relapsing-remitting multiple sclerosis (RRMS) treated with cladribine tablets: 
results from the 120-week phase IIIb extension of the CLARITY study. Poster presented at: 
68th American Academy of Neurology Annual Meeting; April 15-21, 2016; Vancouver, BC, 
Canada. Poster P2.114. 
Comi G, Cook S, Rammohan K, et al. Long-term effects of cladribine tablets on MRI activity 
outcomes in patients with relapsing-remitting multiple sclerosis: the CLARITY Extension 
study. Ther Adv Neurol Disord. Jan 2018; 11.  
Dua T, Rompani P. Atlas: Multiple sclerosis resources in the world, 2008. Retrieved 10/15/18, 
from http://www.who.int/mental_health/neurology/Atlas_MS_WEB.pdf. 
EuroQol Group. EuroQol-a new facility for the measurement of health-related quality of life. 
Health Policy. 1990; 16(3): 199-208. 
Freedman MS, Leist T, Comi G, et al. The efficacy of cladribine tablets in CIS patients 
retrospectively assigned the diagnosis of MS using modern criteria: Results from the 
ORACLE-MS study. Mult Scler J Exp Transl Clin. 2017; 3(4): 1-4. 
Giovannoni G, Comi G, Cook S, et al. A placebo-controlled trial of oral cladribine for 
relapsing multiple sclerosis. N Engl J Med. 2010; 362(5): 416-26. 
Giovannoni G, Comi G, Cook S, et al. Benefits of cladribine tablets on the proportion of 
patients with multiple sclerosis free from clinical and radiological indicators of disease 
activity in the CLARITY EXTENSION study. ECTRIMIS Online Library, n. 146476, 2016. 
Giovannoni G, Sorensen P, Cook S, et al. Safety and efficacy of cladribine tablets in patients 
with relapsing-remitting multiple sclerosis: Results from the randomized extension trial of the 
CLARITY study. Mult Scler. 2018; 24(12): 1594-1604. 
Gold R, Giovannoni G, Selmaj K, et al. Daclizumab high-yield process in relapsing-remitting 
multiple sclerosis (SELECT): a randomised, double-blind, placebo-controlled trial. Lancet. 
2013; 381(9884):2167-75.  
Goodkin D, Cookfair D, Wende K, et al. Inter- and intrarater scoring agreement using grades 
1.0 to 3.5 of the Kurtzke Expanded Disability Status Scale (EDSS). Multiple Sclerosis 
Collaborative Research Group. Neurology.1992;; 42(4): 859-63.  

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Healy B, Engler D, Glanz B, et al. Assessment of Definitions of Sustained Disease 
Progression in Relapsing-Remitting Multiple Sclerosis. Multiple Sclerosis International. 
2013; 2013: 9.  
Kalincik T, Cutter G, Spelman T, et al. Defining reliable disability outcomes in multiple 
sclerosis. Brain Nov 2015; 138(11): 3287-98.  
Kappos L, Bar-Or A, Cree B, et al. Siponimod versus placebo in secondary progressive 
multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet. 2018; 
391(10127): 1263-1273.  
Kingwell E, Marriott J, Jette N, et al. Incidence and prevalence of multiple sclerosis in Europe: 
a systematic review. BMC Neurol. Sep 2013; 13:128. 
Lechner-Scott J, Kappos L, Hofman M, et al. Can the Expanded Disability Status Scale be 
assessed by telephone? Mult Scler. 2003; 9(2): 154-9. 
Leist T, Comi G, Cree B, et al. 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 Neurology. 2014 ; 13(3): 257-267.  
Lublin F, Reingold S, Cohen J, et al. Defining the clinical course of multiple sclerosis: the 
2013 revisions. Neurology. 2014; 83(3): 278-86. 
Montalban X, Cohen B, Leist T, et al. 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. 
Poster presented at: 68th American Academy of Neurology Annual Meeting; April 15-21, 
2016; Vancouver, BC, Canada. Poster P3.029. 
Multiple Sclerosis International Federation. Atlas of MS 2013. Mapping Multiple Sclerosis 
around 
the 
world. 
Retrieved 
1/25/19, 
from 
https://www.msif.org/wp-
content/uploads/2014/09/Atlas-of-MS.pdf 
Noseworthy J, Lucchinetti C, Rodriguez M, et al. Multiple Sclerosis. N Engl J Med. Sep 2000; 
343(13): 938-52. 
Pardo G, Jones DE. The sequence of disease-modifying therapies in relapsing multiple 
sclerosis: safety and immunologic considerations. J Neurol. 2017 ; 264(2): 2351-74. 
Polman C, O’Connor P, Havrdova E, et al. A randomized, placebo-controlled trial of 
natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006; 354: 899-910. 
Przybek J, Gniatkowska I, Mirowska-Guzel D, et al. Evolution of diagnostic criteria for 
multiple sclerosis. Neurol Neurochir Pol. 2015; 45(5):  313-21. 
Ray J, Vermeulen M, Bharatha A, et al. Association between MRI exposure during pregnancy 
and fetal and childhood outcomes. JAMA. 2016; 316(9): 952-61.  

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Rudick R, Stuart W, Calabresi P, et al. Natalizumab plus interferon beta-1a for relapsing 
multiple sclerosis. N Engl J Med. Mar 2006; 354(9): 911-23. 
Scalfari A, Knappertz V, Cutter G, et al. Mortality in patients with multiple sclerosis. 
Neurology. Jul 2013; 81(2): 184-192. 
Thompson A, Banwell B, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of 
the McDonald criteria. Lancet Neurol. 2018; 17(2):162-173. 
Tramacere I, Giovane C, Salanti G, et al. Immunomodulators and immunosuppressants for 
relapsing-remitting multiple sclerosis: a network meta-analysis. Cochrane Database Syst Rev. 
2015; 9: CD011381. 
Wallin M, Culpepper W, Campbell J, et al. The prevalence of multiple sclerosis in the United 
States: a population-based healthcare database approach. Multiple Sclerosis Journal. 2017; 
23(S3): 85-426. 

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11 
Appendices 
Appendix 1 
Abbreviations 
 
ADR 
Adverse Drug Reaction 
AEs 
Adverse Events 
AESI 
Adverse Event of Special Interest 
ARR 
Annualized Relapse Rate 
BVMT-R 
Brief Visuospatial Memory Test – Revised 
CDMS 
Clinically Definite Multiple Sclerosis 
CI 
Confidence Intervals 
CNS 
Central Nervous System 
CRF 
Case Report Form 
CSF 
Cerebrospinal Fluid 
CUA 
Combined Unique Active 
DIS 
Dissemination in space 
DIT 
Dissemination in time 
DMD 
Disease Modifying Drug 
EC 
Ethics Committees 
ECG 
Electrocardiography 
EDC 
Electronic Data Capture 
EDSS 
Expanded Disability Status Scale 
eCRF 
Electronic Case Report Form 
EDSS 
Expanded Disability Status Scale 
EMA 
European Medical Agency 
EQ-5D-3L 
EuroQoL-5 Dimension Questionnaire (3 level version) 

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FCDE 
First Clinical Demyelinating Event 
FS 
Functional System 
GCP 
Good Clinical Practice 
HDA 
High-Disease Activity 
iAP 
Integrated Analysis Plan 
ICF 
Informed Consent Form 
ICH 
International Council for  Harmonisation 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
MRI 
Magnetic Resonance Imaging  
MS 
Multiple Sclerosis 
PPMS 
Primary Progressive Multiple Sclerosis 
PRO 
Patient-Reported Outcomes 
PY 
Person-years 
RMS 
Relapsing Multiple Sclerosis 
RRMS 
Relapsing-Remitting Multiple Sclerosis 
SAP 
Statistical Analysis Plan  
SAE 
Serious Adverse Event 
SDMT 
Symbol Digit Modalities Test 
SmPC 
Summary of Product Characteristics 
SoA 
Schedule of Activities 
SOC 
Standard of Care 
SPMS 
Secondary Progressive Multiple Sclerosis  

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SUSAR 
Suspected Unexpected Serious Adverse Reactions 
 
 
 
 
 

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Appendix 2  
Study Governance 
Financial Disclosure 
Investigators and Sub-Investigators will provide the Sponsor with sufficient, accurate 
financial information, as requested, for the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
This information is required during the study and for 1 year after completion of the study. 
Informed Consent Process 
• A study main informed consent will be provided to patients or their 
proxy/caregiver/legal representative and this will cover both Screening and study 
participation. The informed consent requires a wet ink signature.  
o For deceased or lost to follow-up patients, the informed consent may be obtained 
from proxy/caregiver/legal representative, or an informed consent form (ICF) 
waiver will apply, dependent on approval by Ethics Committees, Institutional 
Review Boards, and/or local regulations. 
• A separate informed consent will be provided for optional pharmacogenetic testing, 
including collection and storage of an optional blood sample. This informed consent 
will need to be completed at the site.  
• Patients participating in the MRI sub-study will be provided with a separate informed 
consent for the sub-study. This informed consent will need to be completed at the site.  
• The Investigator or his/her representative will explain the nature of the study to the 
participant or his/her proxy/caregiver/legal representative and answer all questions on 
the study. 
• Participants must be informed that their participation is voluntary. 
• Participants or their legally-authorized representative (defined as proxy or caregiver) 
will be required to sign a statement of informed consent that meets the requirements of 
local regulations; International Council for Harmonisation (ICH) guidelines; Health 
Insurance Portability and Accountability Act (HIPAA) requirements, where applicable; 
and the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) or study 
center.  
• The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written consent 
was obtained. For written informed consent, the authorized person obtaining the 
informed consent must also sign the ICF. 
• If the ICF is updated during their participation in the study, participants must be re-
consented to the most current, approved version, if still on the study. 
• A copy of the ICF(s) (or an original, signed ICF in applicable countries) must be 
provided to the participant or the participant’s proxy/caregiver/legal representative. 

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• The third-party service provider tasked for Biostatistical services on the study is Cytel Inc. 
(675 Massachusetts Avenue, Cambridge, MA 02139, USA).  
• Responsibilities regarding safety and medical monitoring are described in the Safety 
Monitoring Plan and the Medical Monitoring Plan, respectively. Details of structures and 
associated procedures will be defined in a separate Study Reference Manual. 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and the following: 
o Consensus ethical principles derived from international guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines 
o Applicable ICH GCP Guidelines 
o Applicable laws and regulations 
• The Investigator must submit the protocol, protocol amendments (if applicable), ICF, 
summary of product characteristics (SmPC), and other relevant documents (e.g., 
advertisements) to an IRB/IEC and the IRB/IEC must review and approve them before 
the study is initiated. 
• Any protocol amendments (i.e., changes to the protocol) will be documented in writing 
and require IRB/IEC approval before implementation of changes, except for changes 
necessary to eliminate an immediate hazard to study participants. When applicable, 
amendments will be submitted to the appropriate Health Authorities. 
• The Investigator will be responsible for the following: 
o Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently per the IRB’s/IEC’s requirements, policies, and procedures 
o Notifying the IRB/IEC of serious adverse events (SAEs) or other significant safety 
findings, as required by IRB/IEC procedures 
o Providing oversight of the study conduct at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical 
studies (if applicable), and all other applicable local regulations 
• The protocol and any applicable documentation will be submitted or notified to the 
Health Authorities in accordance with all local and national regulations for each site. 
Clinical Study Insurance and Compensation to Participants 
Insurance coverage will be provided for each country participating in the study. Insurance 
conditions shall meet good local standards, as applicable. 
Clinical Study Report 
After study completion, the Sponsor or delegate will write a clinical study report in 
consultation with the Steering Committee or other relevant study-appointed committees or 
groups. 

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Publication 
• The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission. This allows Merck to protect proprietary information and to provide 
comments.  
• The Sponsor will comply with the requirements for publication of study results. Per 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
Coordinating Investigator will be designated by agreement. 
• Authorship will be determined by agreement and in line with International Committee 
of Medical Journal Editors authorship requirements. 
Dissemination of Clinical Study Data 
• After completion of the study, a Clinical Study Report (including results on all study 
objectives except, in case not available in time, results of the pharmacogenetic testing) 
according to ICH Topic E3 will be written by the Sponsor or the designated CRO. 
• Analyses of pharmacogenetics testing will be completed approximately 2 years after 
study completion and will be presented in a clinical study report addendum, if not 
reported in the Clinical Study Report. 
• The Investigators will inform the Sponsor in advance of 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 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. 
• The study will be posted on clinicaltrials.gov. 
Data Quality Assurance 
• All participant study data will be recorded on electronic case report form (eCRFs) or 
transmitted to the Sponsor or designee electronically (e.g., laboratory data). The 
Investigator is responsible for verifying that data entries are complete, accurate, legible, 
and timely by physically or electronically signing the case report form (CRF). Details 
for managing CRFs are in the Study Reference Manual. 
• For PRO data (e.g., QoL and cognitive assessments), paper PRO will be used. 
• The Investigator must maintain accurate documentation (source data) that supports the 
information in the CRF. 
• The Investigator must permit study-related monitoring, quality assurance audits, 
IRB/IEC review, and regulatory agency inspections and provide direct access to the 
study file and source data. 

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• Monitoring details describing strategy (e.g., risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are in the Monitoring Plan. 
• The Sponsor or designee is responsible for data management of this study, including 
quality checking of the data and maintaining a validated database. Database lock will 
occur once quality control and quality assurance procedures have been completed.  
• Study monitors will perform ongoing source data verification to confirm that data in the 
CRF are accurate, complete, and verifiable; that the safety and rights of participants are 
being protected; and that the study is being conducted per the currently approved 
protocol and any other study agreements, ICH GCP, and all applicable regulatory 
requirements. 
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for 15 years after study completion, unless local 
regulations, institutional policies, or the Sponsor requires a longer retention. No records 
may be destroyed during the retention period without the Sponsor’s written approval. 
No records may be transferred to another location or party without the Sponsor’s written 
notification. 
Source Documents 
• Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. 
• The Investigator must keep a paper or electronic file (medical file and original medical 
records) at the site for each study participant. The file must identify each participant, 
contain the following demographic and medical information for the participant, and 
should be as complete as possible: 
• Participant’s full name, date of birth, sex, height, and weight 
• Medical history and concomitant diseases 
• Prior and concomitant therapies (including changes during the study) 
• Study identifier (i.e., the Sponsor’s study number) and participant’s study number 
• Dates of entry into the study (i.e., signature date on the informed consent) and each 
visit to the site 
• Any medical examinations and clinical findings predefined in the protocol 
• All AEs 
• Date that the participant left the study, including any reason for early withdrawal 
from the study or study intervention, if applicable 
• All source data must be filed (e.g., CT or MRI scan images, ECG recordings, and 
laboratory results). Each document must have the participant number and the procedure 
date; ideally, printed by the instrument used for the procedure. As necessary, medical 

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evaluation of these records should be performed, documented, signed and dated by the 
Investigator.  
• Data recorded on printed or electronic CRFs that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. 
The Investigator may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available. 
• The study monitors will use printouts of electronic files for source data verification. 
These printouts must be signed and dated by the Investigator and kept in the study file. 
• Source documents are stored at the site for the longest possible time permitted by the 
applicable regulations, and/or as per ICH GCP guidelines, whichever is longer. The 
Investigator ensures that no destruction of medical records is performed without the 
Sponsor’s written approval. 
• Definition of what constitutes source data is found in the Monitoring Plan. 
Study and Site Start and Closure 
• The study start date is the date when the clinical study will be open for recruitment. 
• The first act of recruitment is when the site first activated and opened to recruitment, and 
will be the study start date. 
• The Sponsor reserves the right to close the study site or terminate the study at any time 
and for any reason. Study sites will be closed upon study completion. A study site is 
considered closed when all required documents and study supplies have been collected 
and a site closure visit has been completed. 
• The Investigator may initiate site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
• Reasons for the early closure of a study site by the Sponsor or Investigator may include: 
• Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local Health Authorities, the Sponsor's procedures, or GCP guidelines 
• Inadequate recruitment of participants by the Investigator 
• Discontinuation of further development of the Sponsor’s compound 

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Appendix 3 
Adverse 
Events: 
Definitions 
and 
Procedures 
for 
Recording, Evaluating, Follow-up, and Reporting 
Definitions 
Adverse Event 
An AE is any untoward medical occurrence in a participant administered a pharmaceutical 
product, regardless of causal relationship with this treatment. Therefore, an AE can be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal product, regardless if it is 
considered related to the medicinal product. 
For surgical or diagnostic procedures, the condition/illness leading to such a procedure is 
considered as the AE rather than the procedure itself. 
The Investigator is required to grade the severity or toxicity of each AE. 
Investigators must assess the severity of AEs per the Qualitative Toxicity Scale, as follows: 
Mild: 
The participant is aware of the event or symptom, but the event or symptom 
is easily tolerated. 
Moderate: 
The participant experiences sufficient discomfort to interfere with or reduce 
his or her usual level of activity. 
Severe: 
Significant impairment of functioning: the participant is unable to carry out 
his or her usual activities. 
Investigators must also systematically assess the causal relationship of AEs to study 
intervention (including any other non-study interventions, radiation therapy, etc.) using the 
following definitions. Decisive factors for the assessment of causal relationship of an AE 
to the investigational medicinal product (IMP) treatment received in the parent study 
include, but may not be limited to, temporal relationship between the AE and the IMP 
treatment received in the parent study, known side effects of the IMP treatment received 
in the parent study, medical history, concomitant medication, course of the underlying 
disease, and the MRI procedure (if applicable). 
Unrelated: 
Not reasonably related to the study intervention. AE could not medically 
(pharmacologically/clinically) be attributed to the study intervention under 
study in this clinical study protocol. A reasonable alternative explanation 
must be available. 
Related: 
Reasonably related to the study intervention. AE could medically 
(pharmacologically/clinically) be attributed to the study intervention under 
study in this clinical study protocol.  
Abnormal Laboratory Findings and Other Abnormal Investigational Findings 
Abnormal laboratory findings and other abnormal investigational findings (e.g., on an ECG 
trace) should not be reported as AEs unless they are associated with clinical signs and 
symptoms, lead to study intervention discontinuation or are considered otherwise 
medically important by the Investigator. A positive test for COVID-19, with or without the 
presence of symptoms, would be considered an AE. If a laboratory abnormality fulfills 

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these criteria, the identified medical condition (e.g., anemia or increased alanine amino 
transferase) must be reported as the AE rather than the abnormal value itself. 
Serious Adverse Events 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death 
• Is life-threatening. Life-threatening refers to an event in which the participant is at risk 
of death at the time of the event, not an event that hypothetically might have caused 
death if it was more severe 
• Requires inpatient hospitalization or prolongs an existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Is a congenital anomaly or birth defect 
• Is otherwise considered to be medically important. Important medical events that may 
not result in death, be life-threatening, or require hospitalization may be considered as 
SAEs when, based upon appropriate medical judgment, they may jeopardize the 
participant or may require medical or surgical intervention to prevent one of the 
outcomes listed above. Examples of such events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse 
For the purposes of reporting, any suspected transmission of an infectious agent via a study 
intervention is also considered an SAE, as specified below for reporting SAEs and adverse 
events of special interest (AESIs). 
Events that Do Not Meet the Definition of an SAE 
Elective hospitalizations are not considered SAEs. However, all events leading to 
unplanned hospitalizations or unplanned prolongation of an elective hospitalization (i.e., 
undesirable effects of any administered treatment) must be documented and reported as 
SAEs. 
Events Not to Be Considered as AEs/SAEs 
Medical conditions present at the initial study visit that do not worsen in severity or 
frequency during the study are defined as Baseline Medical Conditions and are not to be 
considered AEs. 
MS Relapses  
In this protocol, symptoms and signs of relapse or worsening of MS will usually be 
captured in the context of the efficacy 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 considered possibly or probably 
related to the IMP (i.e. worsening is not consistent with the anticipated natural progression 
of the disease). 
 

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Adverse Events of Special Interest 
AEs of interest for this study defined in the Section 6.9 should be considered as medically 
significant AEs. 
Recording and Follow-Up of AE and/or SAE 
It is important that each AE report include a description of the event, its duration (onset 
and resolution dates and also onset and resolution times, when it is important to assess the 
time of AE onset relative to the recorded study intervention administration time), its 
severity, its causal relationship with the study intervention, any other potential causal 
factors, any treatment given or other action taken, including dose modification or 
discontinuation of the study intervention, and its outcome. In addition, serious cases should 
be identified, and the appropriate seriousness criteria documented.  
Specific guidance is in the CRF Completion and Monitoring Conventions provided by the 
Sponsor. 
Reporting Serious Adverse Events and Adverse Events of Special Interest  
Serious Adverse Events 
In the event of any new SAE occurring during the reporting period, the Investigator must 
immediately (within a maximum of 24 HOURS after becoming aware of the event) inform 
the Sponsor or its designee using the electronic SAE report form in the electronic data 
capture (EDC) system. Any ADRs (assessed as related to cladribine by the Investigator 
after the End of Trial Visit in the parent study CLARITY/ORACLE/CLARITY-EXT) must 
be recorded in the eCRF as well. If the ADR information is captured in the subject’s 
medical chart already at the time of enrolment then the event is not considered to be of new 
awareness and it is expected to be reported in the Medical History page (e.g. awareness 
date prior to ICF date). If the ADR is reported by the patient at the time of enrolment or 
after that then the event is considered of new awareness, and it is expected to be reported 
in the ADR page (e.g. awareness date is after ICF date).Reporting of SAEs using a paper 
report form is required as a back-up method only for an EDC system failure. Names, 
addresses, and telephone and fax numbers will be included on the paper form. All 
information from the paper form must be transcribed into the electronic form as soon as 
the system becomes available. 
In exceptional circumstances, an SAE (or follow-up information) may be reported by 
telephone; in these cases, an electronic SAE report form must be completed immediately 
thereafter. 
Relevant pages from the CRF may be provided in parallel (e.g., medical history, 
concomitant drugs). Additional documents may be provided by the Investigator, if 
available (e.g., laboratory results, hospital report, autopsy report).  
The Investigator must respond to any request for follow-up information (e.g., additional 
information, outcome, final evaluation, other records where needed) or to any question the 
Sponsor/designee may have on the AE within the same timelines as those noted above for 
initial reports. This is necessary to ensure prompt assessment of the event by the Sponsor 

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or designee and (as applicable) to allow the Sponsor to meet strict regulatory timelines 
associated with expedited safety reporting obligations. 
Requests for follow-up will usually be made via the study monitor, although in exceptional 
circumstances the drug safety department may contact the Investigator directly to obtain 
further information or to discuss the event. 
Adverse Events of Special Interest 
In the event of a non-serious AESI, the Investigator will notify the Sponsor/designee by 
completing the electronic AESI Report Form in the EDC system. Serious AESIs must be 
reported in an expedited manner as SAEs, as outlined above. Reporting of non-serious 
AESIs using a paper report form is required as a back-up method only for an EDC system 
failure. Names, addresses, and telephone and fax numbers will be included on the paper 
report form. All information from the paper form must be transcribed into the electronic 
form as soon as the system becomes available. 
 
 

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Appendix 4 
Pharmacogenetics 
Use/Analysis of DNA  
• Genetic variation may impact a participant’s response to therapy, susceptibility to, 
and severity and progression of disease. Variable response to therapy may be due to 
genetic determinants that impact study intervention absorption, distribution, 
metabolism, and excretion; mechanism of action of the study intervention; disease 
etiology; and/or molecular subtype of the disease being treated. 
• DNA samples will be analyzed for association of genetic variations with clinical 
outcome measures. Additional analyses may be conducted if it is hypothesized that 
this may help further understand the clinical data. 
• In addition, DNA samples will be used for research related to mechanism of action, 
and related diseases. They may also be used to develop tests or assays, including 
diagnostic tests related to mechanism of action and indication. Pharmacogenetic 
research may consist of the analysis of one or more candidate genes or the analysis 
of genetic markers throughout the genome or analysis of the entire genome (as 
appropriate).  
• The results of pharmacogenetic analyses will be reported in the Clinical Study 
Report or a separate study summary within approximately 2 years after the end of 
the study. 
• Details on processes for collection and shipment of these samples can be found in 
the Q2 Solutions Laboratory manual and flow chart. Post-study, the Sponsor will 
store the DNA samples in a secure storage space with adequate measures to protect 
confidentiality. 
• Retention time and possible analysis of DNA sample after the study ends are 
specified in the respective ICF. 
 
 
 

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Appendix 5 
Expanded Disability Status Scale (EDSS) 
 
General  
• The Evaluating Physician will complete the Expanded Disability Status Scale (EDSS).  
• The same individual should remain as the Evaluating Physician for each patient, except 
when exceptional circumstances make this impossible.  
• Prior to each neurological assessment, the Evaluating Physician should not refer to any 
previous neurological assessments carried out on that patient.  
• The current EDSS will be recorded (i.e. the EDSS as assessed during the visit).  
EDSS SCORING  
• 0.0 Normal neurological exam [all grade 0 in all Functional System (FS) scores*]  
• 1.0 No disability, minimal signs in one FS* (i.e., grade 1)  
• 1.5 No disability, minimal signs in more than one FS* (more than 1 FS grade 1)  
• 2.0 Minimal disability in one FS (one FS grade 2, others 0 or 1)  
• 2.5 Minimal disability in 2 FS (2 FS grade 2, others 0 or 1)  
• 3.0 Moderate disability in one FS (one FS grade 3, others 0 or 1) or mild disability in 3 or 
4 FS (3 or 4 FS grade 2, others 0 or 1) though fully ambulatory  
• 3.5 Fully ambulatory but with moderate disability in one FS (one grade 3) and one or 2 FS 
grade 2; or 2 FS grade 3 (others 0 or 1) or 5 grade 2 (others 0 or 1)  
• 4.0 Fully ambulatory without aid, self-sufficient, up and about some 12 hours a day despite 
relatively severe disability consisting of one FS grade 4 (others 0 or 1), or combination of 
lesser grades exceeding limits of previous steps; able to walk without aid or rest some 500 
meters  
• 4.5 Fully ambulatory without aid, up and about much of the day, able to work a full day, 
may otherwise have some limitation of full activity or require minimal assistance; 
characterized by relatively severe disability usually consisting of one FS grade 4 (others 0 
or 1) or combinations of lesser grades exceeding limits of previous steps; able to walk 
without aid or rest some 300 meters  
• 5.0 Ambulatory without aid or rest for about 200 meters; disability severe enough to impair 
full daily activities (e.g., to work a full day without special provisions); (Usual FS 
equivalents are one grade 5 alone, others 0 or 1; or combinations of lesser grades usually 
exceeding specifications for step 4.0)  
• 5.5 Ambulatory without aid for about 100 meters; disability severe enough to preclude full 
daily activities; (Usual FS equivalents are one grade 5 alone, others 0 or 1; or combination 
of lesser grades usually exceeding those for step 4.0)  
• 6.0 Intermittent or unilateral constant assistance (cane, crutch, brace) required to walk 
about 100 meters with or without resting; (Usual FS equivalents are combinations with 
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• 6.5 Constant bilateral assistance (canes, crutches, braces) required to walk about 20 meters 
without resting; (Usual FS equivalents are combinations with more than 2 FS grade 3+)  
• 7.0 Unable to walk beyond approximately 5 meters even with aid, essentially restricted to 
wheelchair; wheels self in standard wheelchair and transfers alone; up and about in 
wheelchair some 12 hours a day; (Usual FS equivalents are combinations with more than 
one FS grade 4+; very rarely pyramidal grade 5 alone)  
• 7.5 Unable to take more than a few steps; restricted to wheelchair; may need aid in transfer; 
wheels self but cannot carry on in standard wheelchair a full day; May require motorized 
wheelchair; (Usual FS equivalents are combinations with more than one FS grade 4+)  
• 8.0 Essentially restricted to bed or chair or perambulated in wheelchair, but may be out of 
bed itself much of the day; retains many self-care functions; generally has effective use of 
arms; (Usual FS equivalents are combinations, generally grade 4+ in several systems)  
• 8.5 Essentially restricted to bed much of day; has some effective use of arms(s); retains 
some self-care functions; (Usual FS equivalents are combinations, generally 4+ in several 
systems)  
• 9.0 Helpless bed patient; can communicate and eat; (Usual FS equivalents are 
combinations, mostly grade 4+)  
• 9.5 Totally helpless bed patient; unable to communicate effectively or eat/swallow; (Usual 
FS equivalents are combinations, mostly grade 4+)  
• 10.0 Death due to MS 
*Excludes cerebral function grade 1  
Note 1: EDSS steps 1.0 to 4.5 refer to patients who are fully ambulatory and the precise step 
number is defined by the FS score(s). EDSS steps 5.0 to 9.5 are defined by the impairment to 
ambulation and usual equivalents in FS scores are provided.  
Note 2: EDSS should not change by 1.0 step unless there is a change in the same direction of 
at least one step in at least one FS. 
 
Scores of 4.5 and above are determined by ambulation distances as follows:  
4.0 Able to walk at least 500 meters without aid  
4.5 Able to walk 300-499 meters without aid  
5.0 Able to walk 200-299 meters without aid  
5.5 Able to walk 100-199 meters without aid  
6.0 Able to walk 5-99 meters without aid or with unilateral assistance is able to walk at least 
100 meters  
6.5 Bilateral assistance required to walk but able to walk at least 20 meters; or unilateral 
assistance needed but able to walk between 5-99 meters  
7.0 Only able to walk between 1- 5 meters even with assistance  
7.5 Unable to walk more than a few steps (i.e., not able to walk at all or able to walk a 
maximum of about 1 meter)  
8.0-9.5 Investigator judgment  

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The guiding principle: if a patient fails to meet the criteria of a given level, they are 
automatically assigned to the next higher level. If a patient does not need aids to walk (i.e., 
walks unassisted) but can only walk 50 meters, they are to be considered EDSS 6.0 since they 
do not satisfy the criteria for EDSS 5.5. 
 
 
 

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Appendix 6 
2017 Mc Donald Criteria (From Thompson, 2018) 
Table: The 2017 McDonald criteria for diagnosis of multiple sclerosis in patients with 
an attack at onset  
 
 
Number 
of 
lesions 
with 
objective clinical evidence 
Additional data needed for a 
diagnosis of multiple sclerosis 
≥2 clinical attacks 
≥2 
None* 
≥2 clinical attacks 
1 (as well as clear-cut historical 
evidence of a previous attack 
involving a lesion in a distinct 
anatomical location†) 
None* 
≥2 clinical attacks 
1 
Dissemination 
in 
space 
demonstrated by an additional 
clinical attack implicating a 
different CNS site or by MRI‡ 
1 clinical attack 
≥2 
Dissemination 
in 
time 
demonstrated by an additional 
clinical attack or by MRI§ OR 
demonstration of CSF-specific 
oligoclonal bands¶ 
1 clinical attack 
1 
Dissemination 
in 
space 
demonstrated by an additional 
clinical attack implicating a 
different CNS site or by MRI‡  
AND  
Dissemination 
in 
time 
demonstrated by an additional 
clinical attack or by MRI§ OR 
demonstration of CSF-specific 
oligoclonal bands¶ 
  
If the 2017 McDonald Criteria are fulfilled and there is no better explanation for the clinical 
presentation, the diagnosis is multiple sclerosis. If multiple sclerosis is suspected by virtue of a 
clinically isolated syndrome but the 2017 McDonald Criteria are not completely met, the diagnosis is 
possible multiple sclerosis. If another diagnosis arises during the evaluation that better explains the 
clinical presentation, the diagnosis is not multiple sclerosis. An attack is defined in panel 1. *No 
additional tests are required to demonstrate dissemination in space and time. However, unless MRI is 
not possible, brain MRI should be obtained in all patients in whom the diagnosis of multiple sclerosis 
is being considered. In addition, spinal cord MRI or cerebrospinal fluid (CSF) examination should be 
considered in patients with insufficient clinical and MRI evidence supporting multiple sclerosis, with 
a presentation other than a typical clinically isolated syndrome, or with atypical features. If imaging 
or other tests (e.g., CSF) are undertaken and are negative, caution needs to be taken before making a 
diagnosis of multiple sclerosis, and alternative diagnoses should be considered. †Clinical diagnosis 
based on objective clinical findings for 2 attacks is most secure. Reasonable historical evidence for 
one past attack, in the absence of documented objective neurological findings, can include historical 
events with symptoms and evolution characteristic for a previous inflammatory demyelinating attack; 

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at least one attack, however, must be supported by objective findings. In the absence of residual 
objective evidence, caution is needed. ‡The MRI criteria for dissemination in space are described in 
panel 5. §The MRI criteria for dissemination in time are described in panel 5. 
¶The presence of CSF-specific oligoclonal bands does not demonstrate dissemination in time per se 
but can substitute for the requirement for demonstration of this measure. 
Panel 3: Considerations to help avoid misdiagnosis of multiple sclerosis 
• Recognize that the McDonald criteria were not developed to differentiate multiple sclerosis 
from other conditions but to identify multiple sclerosis or a high likelihood of the disease 
in patients with a typical clinically isolated syndrome once other diagnoses have been 
deemed unlikely. 
• Integration of the history, examination, imaging, and laboratory evidence by a clinician 
with multiple sclerosis-related expertise remains fundamental in making a reliable 
diagnosis of multiple sclerosis or an alternative diagnosis. In addition to confirming 
dissemination in space and time, diagnostic rigor in the interpretation of clinical data, 
imaging findings, and test results is necessary. 
• In the absence of a clear-cut typical clinically isolated syndrome (panel 1), caution should 
be exercised in making the diagnosis of multiple sclerosis, and the diagnosis should be 
confirmed by further clinical and radiological follow-up. In such cases, the clinician should 
consider postponing making a definitive diagnosis and initiation of long-term disease-
modifying therapies, pending longer follow-up to accumulate additional evidence 
supporting the diagnosis. 
• Caution should be taken in accepting a historical event as an attack in the absence of 
contemporaneous or current objective evidence providing corroboration. 
• The threshold for additional testing should be low, including for spinal cord MRI or CSF 
examination in the following situations: when clinical and brain MRI evidence supporting 
a diagnosis of multiple sclerosis is insufficient, particularly if initiation of long-term 
disease-modifying therapies are being considered; when there is a presentation other than 
a typical clinically isolated syndrome, including patients with a progressive course at onset 
(primary progressive multiple sclerosis); when there are clinical, imaging, or laboratory 
features atypical of multiple sclerosis; and in populations in which multiple sclerosis is less 
common (e.g., children, older individuals, or non-white populations). 
Panel 4: 2017 revisions to the McDonald diagnostic criteria for multiple sclerosis 
• In a patient with a typical clinically isolated syndrome and fulfillment of clinical or MRI 
criteria for dissemination in space and no better explanation for the clinical presentation, 
demonstration of CSF-specific oligoclonal bands in the absence of other CSF findings 
atypical of multiple sclerosis allows a diagnosis of this disease to be made. This 
recommendation is an addition to the 2010 McDonald criteria. 

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• Symptomatic and asymptomatic MRI lesions can be considered in the determination of 
dissemination in space or time. MRI lesions in the optic nerve in a patient presenting with 
optic neuritis remain an exception and, owing to insufficient evidence, cannot be used in 
fulfilling the McDonald criteria. In the 2010 McDonald criteria, the symptomatic lesion in 
a patient presenting with brainstem or spinal cord syndrome could not be included as MRI 
evidence of dissemination in space or time. 
• Cortical and juxtacortical lesions can be used in fulfilling MRI criteria for dissemination 
in space. Cortical lesions could not be used in fulfilling MRI criteria for dissemination in 
space in the 2010 McDonald criteria. 
• The diagnostic criteria for primary progressive multiple sclerosis in the 2017 McDonald 
criteria remain the same as those outlined in the 2010 McDonald criteria, aside from 
removal of the distinction between symptomatic and asymptomatic MRI lesions and that 
cortical lesions can be used. 
• At the time of diagnosis, a provisional disease course should be specified (relapsing-
remitting, primary progressive, or secondary progressive) and whether the course is active 
or not, and progressive or not based on the previous year’s history. The phenotype should 
be periodically re-evaluated based on accumulated information. This recommendation is 
an addition to the 2010 McDonald criteria. 
Panel 5: 2017 McDonald criteria for demonstration of dissemination in space and time 
by MRI in a patient with a clinically isolated syndrome 
• Dissemination in space can be demonstrated by one or more T2-hyperintense lesions* that 
are characteristic of multiple sclerosis in 2 or more of 4 areas of the central nervous system 
(CNS): periventricular,† cortical or juxtacortical, and infratentorial brain regions, and the 
spinal cord 
• Dissemination in time can be demonstrated by the simultaneous presence of gadolinium-
enhancing and non-enhancing lesions* at any time or by a new T2-hyperintense or 
gadolinium-enhancing lesion on follow-up MRI, with reference to a baseline scan, 
irrespective of the timing of the baseline MRI 
*Unlike the 2010 McDonald criteria, no distinction between symptomatic and asymptomatic MRI lesions is 
required. †For some patients—e.g., individuals older than 50 years or those with vascular risk factors—it might 
be prudent for the clinician to seek a higher number of periventricular lesions. 

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Appendix 8 
Principal Investigator Signature Page 
 
Study Title: 
Evaluating the Long-Term Outcomes and Durability of 
Effect Following Treatment with Cladribine Tablets for 
Multiple Sclerosis: An Exploratory Phase IV 
Ambispective Study of Patients Who Previously 
Participated in the CLARITY/CLARITY-EXT and 
ORACLE Trials 
Regulatory Agency Identifying 
Numbers: 
EudraCT number: 2019-000069-19 
Clinical 
Study 
Protocol 
Version: 
03 July 2020/Version 2 
Site Number: 
 
I am responsible for the conduct of the study at this site, and understand and will conduct it 
per the clinical study protocol, any approved protocol amendments, International Council for 
Harmonisation Good Clinical Practice (Topic E6) and all applicable Health Authority 
requirements and national laws. 
 
____________________________________ 
____________________________ 
Signature 
 
Date of Signature 
 
Name, academic degree: 
[Insert Name and highest degree or for a single center study, 
insert from Title Page] 
Function/Title: 
 
Institution: 
[Insert Name of Institution or for a single center study, insert 
from Title Page] 
Address: 
[Insert Full Mailing Address (e.g., Street, City, postal code, 
and Country)] 
Telephone number: 
[Insert Full number, including country code] 
Fax number: 
[Insert Full number, including country code or “Not 
Applicable”] 
E-mail address: