A 2-year Extension Study to Evaluate Long-term Effectiveness of Mavenclad® in Participants Who Have Completed Trial MS700568_0022 (MAGNIFY MS) (Magnify MS Extension)
Phase: PHASE4
Conditions: Multiple Sclerosis
Sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

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Substance code: N/A 
 
Extension to the MAGNIFY MS trial on Mavenclad®  
MS700568_0157 
 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
3/82 
 
 
Table of Contents 
Title Page 
 ..............................................................................................................1 
Table of Contents  ..............................................................................................................3 
List of Tables 
 ..............................................................................................................7 
List of Figures 
 ..............................................................................................................8 
1 
Protocol Summary ................................................................................9 
1.1 
Synopsis ................................................................................................9 
1.2 
Schema ................................................................................................12 
1.3 
Schedule of Activities .........................................................................12 
2 
Introduction .........................................................................................16 
2.1 
Study Rationale ...................................................................................16 
2.2 
Background .........................................................................................16 
2.3 
Benefit/Risk Assessment ....................................................................17 
3 
Objectives and Endpoints ...................................................................18 
4 
Study Design .......................................................................................23 
4.1 
Overall Design ....................................................................................23 
4.2 
Scientific Rationale for Study Design ................................................24 
4.3 
Justification for Dose ..........................................................................26 
4.4 
End of Study Definition ......................................................................26 
5 
Study Population .................................................................................26 
5.1 
Inclusion Criteria ................................................................................26 
5.2 
Exclusion Criteria ...............................................................................26 
5.3 
Lifestyle Considerations .....................................................................27 
5.4 
Screen Failures ....................................................................................27 
6 
Study Intervention(s) ..........................................................................27 
6.1 
Study Intervention(s) Administration .................................................27 
6.2 
Study Intervention(s) Preparation, Handling, Storage, and 
Accountability .....................................................................................27 
6.3 
Measures to Minimize Bias: Study Intervention Assignment and 
Blinding ..............................................................................................27 
6.4 
Study Intervention Compliance ..........................................................27 
6.5 
Concomitant Therapy .........................................................................27 
6.6 
Dose Selection and Modification ........................................................28 

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Substance code: N/A 
 
Extension to the MAGNIFY MS trial on Mavenclad®  
MS700568_0157 
 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
6/82 
 
 
Appendix 12 
Coordinating Investigator Signature Page ..........................................80 
Appendix 13 
Principal Investigator Signature Page .................................................82 
 
 

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Substance code: N/A 
 
Extension to the MAGNIFY MS trial on Mavenclad®  
MS700568_0157 
 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
8/82 
 
 
List of Figures 
Figure 1: Study Schema .....................................................................................................12 
 

Substance code: N/A 
 
Extension to the MAGNIFY MS trial on Mavenclad®  
MS700568_0157 
 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
9/82 
 
 
1 
Protocol Summary 
1.1 
Synopsis 
Protocol Title: A 2-year extension study to evaluate long-term effectiveness of Mavenclad® in 
participants who have completed Trial MS700568_0022 (MAGNIFY MS) 
Short Title: Extension to the MAGNIFY MS trial on Mavenclad® 
Rationale: Despite the recent approvals of several newer therapies, the treatment burden of 
multiple sclerosis (MS) remains significant. While the randomized control studies on cladribine 
tablets (Mavenclad®) provide a wealth of information on clinical and safety outcomes, studies 
evaluating its long-term effect (over 2 years after initial treatment) are relatively limited. This 
study is designed to collect long-term efficacy and safety data of participants with highly-active 
relapsing multiple sclerosis (RMS) treated with cladribine tablets. 
Objectives and Endpoints: The primary and secondary objectives and endpoints are provided in 
Table 1. 
Table 1: Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To evaluate the long-term 
disease activity during Year 3 
and 4 after initial dose of 
cladribine tablets 
Proportion of participants with No Evidence of Disease 
Activity (three parameter [NEDA-3]) during Year 3 and 4 after 
the initial dose of cladribine tablets 
Secondary 
To further explore the long-
term treatment effect of 
cladribine tablets 
• Proportion of participants with NEDA-3 during Year 3 
after the initial dose of cladribine tablets 
• Proportion of participants with NEDA-3 during Year 4 
after the initial dose of cladribine tablets 
• Proportion of participants with NEDA-3 after the onset of 
action of cladribine treatment during the parent study until 
the end of Year 3 after the initial dose of cladribine tablets 
• Proportion of participants with NEDA-3 after onset of 
action of cladribine treatment during the parent study until 
the end of Year 4 after the initial dose of cladribine tablets 
• Proportion of participants remaining NEDA-3 during 
Year 3 or 4 after the initial dose of cladribine tablets among 
those with NEDA-3 during Year 1 or 2 after the initial dose 
of cladribine tablets 

Substance code: N/A 
 
Extension to the MAGNIFY MS trial on Mavenclad®  
MS700568_0157 
 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
10/82 
 
 
• Time to first disease activity, deﬁned as the time to ﬁrst 
occurrence of either qualifying relapse, or confirmed 
disability progression (CDP), or new or enlarging T2-
hyperintense lesions, or new T1 gadolinium enhancing 
(Gd+) lesions, during Year 3 and 4 after initial dose of 
cladribine tablets 
• Time to first disease activity, deﬁned as the time to first 
occurrence of either qualifying relapse, or CDP, or new or 
enlarging T2-hyperintense lesions, or new T1 Gd+ lesions, 
over 4 years after the initial dose of cladribine tablets (i.e., 
between initial dose and end of the extension study) 
• Time from the initial dose of cladribine tablets to 
• first new or enlarging T2 lesion 
• first new T1 Gd+ lesion  
• first CDP, as measured by Expanded Disability Status 
Scale (EDSS) 
• first qualifying relapse 
• second qualifying relapse 
• treatment start with other disease modifying drugs 
(DMDs) 
• Time from extension study baseline to  
• first new or enlarging T2 lesion  
• first new T1 Gd+ lesion  
• first CDP, as measured by EDSS 
• first qualifying relapse 
• second qualifying relapse 
• treatment start with other DMDs 
To evaluate long-term safety 
of cladribine tablets 
Occurrences of adverse events (AEs) and serious adverse 
events (SAEs) during Year 3 and 4 after the initial dose of 
cladribine tablets 
AE: Adverse Event; CDP: Confirmed Disability Progression; DMD: Disease Modifying Drug; EDSS: Expanded 
Disability Status Scale; Gd+: Gadolinium Enhancing; NEDA-3: Three parameter No Evidence of Disease Activity; 
SAE: Serious Adverse Event. 
 
 

Substance code: N/A 
 
Extension to the MAGNIFY MS trial on Mavenclad®  
MS700568_0157 
 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
11/82 
 
 
Overall Design: This will be an extension study to the 2-year MAGNIFY MS trial (i.e., parent 
study) to observe participants in Year 3 and 4 after the 2-year treatment with cladribine tablets; no 
cladribine tablets will be administered during the extension study period. Participants will attend 
visits for assessments at extension study Baseline, which is planned to coincide with the last visit 
of the parent study at 12 months after initiation of the second year cladribine treatment (or 24 
months after initiation of first year treatment if the participant did not initiate the second year 
treatment); for participants who complete the parent study before the recruitment is open for the 
extension study, the extension study Baseline visit may be planned later, after the parent study last 
visit and before Visit 1. For these patients, data will be collected retrospectively from the potential 
gap period between the parent study last visit and the extension study Baseline. In addition, 
participants will attend Visit 1 (at Month 12/Year 1 since parent study last visit) and Visit 2 (at 
Month 24/Year 2 since parent study last visit). The study includes 3 sub-studies, which include 
additional sample collection from participants who agree to participate. 
Disclosure Statement: This will be an open label, single arm, exploratory, multicenter, 2-year, 
retrospective and prospective, Phase IV extension study. The primary purpose is the evaluation of 
long-term disease activity after treatment with cladribine tablets in adults with highly-active RMS. 
No cladribine tablets will be administered during the study, but the study has an interventional 
nature due to mandated visits and assessments (including MRIs and blood draws). 
Number of Arms: 1. 
Blinding: Not applicable. 
Number of Participants: A maximum of 256 participants are planned to be enrolled to obtain 
200 to 220 evaluable participants.   
Study Intervention Groups and Duration: The extension study will cover a 2-year period in 
which the participants will not be administered cladribine tablets, which was administered during 
the parent study. Participants will be followed up for 2 years. 
Involvement of Special Committee(s): Yes. 
 
 

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Substance code: N/A 
 
Extension to the MAGNIFY MS trial on Mavenclad®  
MS700568_0157 
 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
16/82 
 
 
2 
Introduction 
Mavenclad® (cladribine tablets) was approved (European Medicines Agency approval on 
25 August 2017) for the treatment of highly-active relapsing multiple sclerosis (RMS) in adults. 
Detailed information on the chemistry, pharmacology, efficacy, and safety of Mavenclad is in the 
Summary of Product Characteristics (SmPC). 
2.1 
Study Rationale 
Despite the recent approvals of several newer therapies, the treatment burden of multiple sclerosis 
(MS) remains significant. While the randomized control studies on cladribine tablets provide a 
wealth of information on clinical and safety outcomes, there is a call for Phase IV studies to 
monitor long-term effects of sequential disease-modifying therapies (Derfuss 2020). This study 
adds to the evidence by investigating the long-term efficacy and safety effects (over the third and 
fourth year after initiation of treatment) among adults with highly-active RMS. 
This extension study will collect follow-up data from the MAGNIFY MS trial (i.e., the parent 
study) until 4 years after the initial dose of cladribine tablets to explore the long-term effects of 
cladribine tablet administration. 
See Section 4.2 for further details on the study rationale. 
2.2 
Background 
Multiple sclerosis is a chronic, inflammatory, progressive, demyelinating disease of the central 
nervous system and is the most common cause of serious neurological disability in young adults 
(Przybek 2015). The disease course of MS is heterogeneous and unpredictable requiring chronic 
treatment and regular medical monitoring by numerous methods such as magnetic resonance 
imaging (MRI) that was designed for the investigation, diagnosis, and management of patients 
with MS (Oreja-Guevara 2015). 
Eight percent of patients with MS experience a highly-active disease course with a rapid disability 
often heralded by high relapse rates and early motor, cerebellar and/or cognitive dysfunction (Hirst 
2008). Early initiation of effective immunotherapy is considered to be important in this group of 
patients in order to prevent aggressive disease progression and severe disability accumulation 
(Dubey 2015). 
It has been demonstrated that 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 MS (RRMS) (early to late stages, treatment naïve, or 
experienced patients) (Giovannoni 2010; Leist 2014). In particular, it was found that treatment 
with cladribine tablets resulted in significant improvements in clinical and radiological efficacy 
outcomes, with significantly more patients remaining free from relapse, free from 3-month 
sustained Expanded Disability Status Scale (EDSS) progression, and free from MRI lesion activity 
over 96 weeks compared to placebo (Giovannoni 2010). 
Cladribine tablets are indicated for the treatment of adult patients with highly-active RMS as 
defined by clinical or imaging features:  

Substance code: N/A 
 
Extension to the MAGNIFY MS trial on Mavenclad®  
MS700568_0157 
 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
17/82 
 
 
• 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. 
Efficacy data from the CLARITY trial, a Phase III, placebo-controlled, double-blind study, 
showed a statistically significant lower annualized relapse rate (ARR), higher proportion of 
participants relapse-free over 96 weeks, higher proportion of participants free of sustained 
disability over 96 weeks, and increased time to 3-month EDSS progression in participants 
receiving cladribine 3.5 mg/kg compared to participants on placebo (Giovannoni 2010). In 
addition, cladribine was statistically significantly superior to placebo with regard to the number 
and relative reduction of T1 Gd+ lesions, active T2 lesions, and combined unique active (CUA) 
lesions as demonstrated in brain MRI over the entire 96 weeks of the study (Comi 2013). 
2.3 
Benefit/Risk Assessment 
The purpose of this study is to assess the long-term effectiveness of cladribine tablets over the 
third and fourth year after the initial administration of cladribine tablets. 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. The benefits of increased potential convenience and 
compliance with the unique posology of cladribine tablets will fill an unmet medical need in 
treating subjects with MS. 
Cladribine tablets is an oral drug approved in the treatment of highly-active RMS. Data from the 
CLARITY trial results suggest a clear benefit over placebo underlining the rationale for earlier 
treatment with cladribine tablets. In addition, data from CLARITY extension study indicates that 
treatment with cladribine tablets over 2 years, followed by 2 years of a placebo, produces a durable 
clinical response (as measured from the end of CLARITY to the end of the extension period). 
Importantly, there was no evidence of increased clinical activity (i.e., disease rebound) after 
treatment discontinuation (e.g. in the cladribine 3.5 mg/kg switched to the placebo group), as 
reported for other therapies in MS with a direct effect on lymphocytes (Giovannoni 2018; 
Giovannoni 2019). The 2-year CLARITY trial and CLARITY extension study also demonstrated 
the safety and tolerability of cladribine tablets in RRMS (Cook 2016). More detailed information 
about the known and expected benefits and risks and reasonably expected adverse events of 
cladribine tablets may be found in Section 4.2 and the SmPC. 
The risk-benefit relationship was carefully considered in the planning of this extension study. 
Minimal risk to patients is expected since patients enrolled in this study will not be receiving 
cladribine tablets; the cladribine treatment course is to be completed under the study protocol of 
the parent study, and the participants will receive routine clinical care over the extension study 
period. This extension study will involve mandated visits and assessments as per the study 
protocol. Although most assessments are also part of routine monitoring of MS disease progression 
and treatment outcomes, this extension study will be of an interventional nature due to the 
mandated assessments including MRIs and blood draws. These additional diagnostic or monitoring 
procedures do not pose more than minimal risk or burden to the safety of the participants compared 
to normal clinical practice. 
The MRI scans are part of the study assessments. The MRI scanning with gadolinium enhancing 
contrast agents is routinely used for the identification and characterization of MS lesions 

Substance code: N/A 
 
Extension to the MAGNIFY MS trial on Mavenclad®  
MS700568_0157 
 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
18/82 
 
 
(Rovira 2012). A recent assessment by European Medicines Agency’s Pharmacovigilance Risk 
Assessment Committee (PRAC) concluded on the positive benefit risk outcome on gadolinium 
agents (gadobutrol, gadoteric acid and gadoteridol) with a recommendation to continue the use of 
such agents as per their current indications (EMA/424715/2017). 
The study assessments include the analysis of blood samples. Blood draws may cause discomfort, 
bruising and very rarely infection at the site where the skin is punctured by the needle. Participants 
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. 
Based on the available clinical and safety data to date, the conduct of the study, as specified in this 
protocol, is considered justifiable. 
This extension study will be conducted in compliance with the clinical study protocol, 
International Council for Harmonization (ICH) Good Clinical Practice (GCP) and any additional 
applicable regulatory requirements. 
 
3 
Objectives and Endpoints 
The study objectives and their linked endpoints are described in Table 3. Statistical analyses of the 
endpoints are described in Section 9.4. 
 

Substance code: N/A 
 
Extension to the MAGNIFY MS trial on Mavenclad®  
MS700568_0157 
 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
19/82 
 
 
Table 3: Study Objectives 
Objectives 
Endpoints 
Primary 
To evaluate the long-term disease activity 
during Year 3 and 4 after initial dose of 
cladribine tablets 
Proportion of participants with No Evidence of Disease Activity (three parameter 
[NEDA-3]) during Year 3 and 4 after the initial dose of cladribine tablets 
Secondary 
To further explore the long-term treatment 
effect of cladribine tablets 
• Proportion of participants with NEDA-3 during Year 3 after the initial dose of 
cladribine tablets 
• Proportion of participants with NEDA-3 during Year 4 after the initial dose of 
cladribine tablets 
• Proportion of participants with NEDA-3 after the onset of action of cladribine 
treatment during the parent study until the end of Year 3 after initial dose of 
cladribine tablets 
• Proportion of participants with NEDA-3 after onset of action of cladribine 
treatment during the parent study until the end of Year 4 after the initial dose of 
cladribine tablets 
• Proportion of participants remaining NEDA-3 during Year 3 or 4 after the initial 
dose of cladribine tablets among those with NEDA-3 during Year 1 or 2 after the 
initial dose of cladribine tablets 
• Time to first disease activity, deﬁned as time to ﬁrst occurrence of either qualifying 
relapse, or confirmed disability progression (CDP), or new or enlarging T2-
hyperintense lesions, or new T1 gadolinium enhancing (Gd+) lesions, during 
Year 3 and 4 after the initial dose of cladribine tablets 
• Time to first disease activity, deﬁned as time to first occurrence of either qualifying 
relapse, or CDP, or new or enlarging T2-hyperintense lesions, or new T1 Gd+ 
lesions, over 4 years after the initial dose of cladribine (i.e., between the initial dose 
of cladribine tablets and end of the extension study) 

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Substance code: N/A 
 
Extension to the MAGNIFY MS trial on Mavenclad®  
MS700568_0157 
 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
23/82 
 
 
4 
Study Design 
4.1 
Overall Design 
This will be an open label, single arm, multicenter, retrospective and prospective, 2-year Phase 
IV extension study of the MAGNIFY MS trial (EudraCT no.: 2017-002631-42). 
The parent study (MAGNIFY MS trial) is a single arm, open label, multicenter, 2-year Phase IV 
study of participants who received treatment with cladribine tablets for 2 years, with one 
treatment course of 2 weeks each year. Baseline is defined as the day on which the first dose of 
cladribine tablets was administered. 
This extension study involves a 2-year follow-up of participants who completed the parent study. 
Participants who early withdrew or were withdrawn from treatment with cladribine tablets in the 
parent study may participate in the extension study. The follow-up period will cover Year 3 and 
4 after initial administration of cladribine tablets. During this follow-up period, participants will 
not be treated with cladribine tablets. 
Extension Baseline: The extension Baseline is planned such that it coincides with the last study 
visit of the parent study (i.e., Month 24 Visit of the parent study). The parent study last visit is 
planned at 12 months after initiation of the second-year treatment with cladribine tablets (or 24 
months after initiation of first year treatment if the participant did not initiate the second-year 
treatment). For participants who complete the parent study before recruitment is open for the 
extension study, the extension Baseline visit will be planned later, after the parent study last visit 
and before Visit 1. For these participants, there will be a gap period between the parent study 
last visit and extension Baseline. Extension Baseline will involve retrospective data collection 
for the participants with a gap period between the parent study last visit and extension Baseline, 
to record any EDSS assessments, relapses, any adverse events (AEs) and serious adverse events 
(SAEs) (see Section 8.3.1), and concomitant medications (see Section 6.5) that may have been 
performed/initiated in that time period. 
Visit 1 and Visit 2: Visit 1 is planned 12 months (Year 1) after the parent study last visit and 
Visit 2 is planned 24 months (Year 2) after the parent study last visit. The visits should be planned 
as close to the yearly date as possible, but as a maximum, fall within a window of ±30 days. Visit 
1 and 2 are planned relative to parent study last visit; therefore, participants with a gap period 
between the parent study last visit and extension Baseline will have less than 12 months between 
the extension Baseline and Visit 1 and less than 24 months between extension Baseline and 
Visit 2.  
Early Withdrawal: In the event of early discontinuation from the extension study, the 
participants will be invited for an Early Withdrawal visit as soon as possible. Visit schedules for 
efficacy and safety assessments are detailed in the Schedule of Activities (Section 1.3). In case 
the participant is not willing or cannot return to the site for the Early Withdrawal visit, a 
telephone call will be organized to obtain the reason for withdrawal and AEs reporting. 
Unscheduled visits: A participant may return for an unscheduled visit at the discretion of the 
Investigator and these visits may include assessments as described in the Schedule of Activities 
(Section 1.3). If a participant experiences a relapse requiring treatment with steroids or switching 
to other DMD, a blood sample will be taken before administration of these drugs, irrespective of 

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CCI

Substance code: N/A 
 
Extension to the MAGNIFY MS trial on Mavenclad®  
MS700568_0157 
 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
27/82 
 
 
Prior/Concurrent Clinical Study Experience 
2. Participation in other studies/trials. 
5.3 
Lifestyle Considerations 
Not applicable. 
5.4 
Screen Failures 
Individuals who do not meet the criteria for participation in this study (screen failure) may not 
be rescreened. 
6 
Study Intervention(s) 
Not applicable. 
6.1 
Study Intervention(s) Administration 
Not applicable. 
6.2 
Study Intervention(s) Preparation, Handling, Storage, and 
Accountability 
Not applicable. 
6.3 
Measures to Minimize Bias: Study Intervention Assignment 
and Blinding 
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. In addition, the following concomitant therapies will be recorded in the CRF 
as well: 
• Concomitant therapies that are linked to a SAE, which were initiated during the parent study, 
and are ongoing at the time of enrolling (i.e., signing the informed consent) for the extension 
study 
• Concomitant therapies that were initiated during the potential gap period between the parent 
study last visit and enrollment (i.e., signing the informed consent) in the extension study 

Substance code: N/A 
 
Extension to the MAGNIFY MS trial on Mavenclad®  
MS700568_0157 
 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
28/82 
 
 
Contact the Medical Monitor for any questions on concomitant or prior therapy. 
The protocol does not provide any restrictions regarding the therapies that a patient can be on 
during the extension study period. Decisions regarding concomitant therapies are at the 
Investigator's discretion. 
• Disease-related: All concomitant medications used for conditions/symptoms related to MS 
(for example, pain, fatigue or weakness, incoordination, bladder dysfunction, spasticity). In 
addition, participants who switch to any other DMD, appropriate safety and contraception 
measures will be followed as per the new DMD’s SmPC and local clinical practice. 
• Medical history related: All concomitant medications used for a medical condition already 
reported in the participant's medical history (for instance, any form of pain, especially low 
back pain, headache, and depression) or family history (primary headache, insomnia, etc.). 
• Self-medication: As this is an outpatient study, special care will be taken to question 
participants on any self-medication, and they will be asked to respond about the details of the 
administration of the doses and the concomitant medications in a diary. The use of any herbal 
or natural products, or other "home remedies" is allowed. However, the use of these products, 
and the use of vitamins, nutritional supplements and all other concomitant medicinal products 
should also be noted in a diary. 
• Relapse management: In case of neurological events related to MS, with relapse criteria 
(Section 8.1.3.1), treatment will be at the discretion of the Investigator, following local good 
medical practice and international guidelines. 
6.6 
Dose Selection and Modification 
Not applicable. 
6.7 
Study Intervention after the End of the Study 
Not applicable. 
 

Substance code: N/A 
 
Extension to the MAGNIFY MS trial on Mavenclad®  
MS700568_0157 
 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
29/82 
 
 
7 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal 
7.1 
Discontinuation of Study Intervention 
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 or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, compliance, 
or administrative reasons. 
• A participant will be withdrawn from the study if the participant enrolls in another study. 
• At the time of discontinuing from the study, if possible, a discontinuation visit will be 
conducted, as listed in the Schedule of Activities (Section 1.3). The Schedule of Activities 
specifies the data to collect at study discontinuation and follow-up, and any additional 
evaluations that need to be completed. If a physical visit is not possible, a telephone call option 
is provided, to obtain a reason for discontinuation and the safety assessment. 
• If the participant withdraws consent for future involvement in the study, any data collected 
up to that point may still be used, but no future data can be generated, and any biological 
samples collected will be destroyed, unless the Investigator obtains permission to retain and 
further evaluate the samples. 
• A participant has the right at any time to request destruction of any biological samples taken. 
The investigator will document this in the site study records. 
• Participants who are discontinued/withdrawn from the study will not be replaced. 
• The Investigator will secure the safety of the study participants and make every attempt to 
collect data. 
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 will be taken if a participant fails to return to the clinic for a required study 
visit:  
• The site will 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 will 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 will be documented 
in the participant’s medical record. 

Substance code: N/A 
 
Extension to the MAGNIFY MS trial on Mavenclad®  
MS700568_0157 
 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
30/82 
 
 
• If the participant continues to be unreachable, he/she will be deemed as “lost to follow-up”. 
8 
Study Assessments and Procedures 
• Study assessments and procedures and their timing are summarized in the Schedule of 
Activities (Section 1.3). 
• No protocol waivers or exemptions are allowed. 
• Immediate safety concerns are discussed with the Sponsor immediately upon occurrence or 
awareness.    
• Adherence to the study design requirements, including those specified in the Schedule of 
Activities, is essential and required for study conduct. 
• All screening evaluations will 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, the Investigator will obtain written informed consent as specified in Appendix 2. 
• Procedures conducted as part of the participant’s routine medical care (e.g., blood count) 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 Schedule of Activities. 
• Once the participant has provided informed consent for the extension study, they will be 
assigned a Participant ID Number (the same as or linked to the Participant ID Number used 
in the parent study). 
• Among data obtained from the parent study are baseline information including demography, 
medical history, concomitant medications, and disease (MS) status and history.  
• The results of the assessments and procedures will be stored in the extension study electronic 
data capture (EDC). Further details regarding the data collection are provided in Appendix 2 
and the eCRF Completion Instructions.  
• The Investigator or designee is responsible for ensuring that the data collected in the course 
of this study is accurate and documented appropriately on all applicable forms. They will then 
be processed, evaluated, and stored in anonymous form in accordance with applicable data 
protection regulations. 
• The Investigator must ensure that the eCRFs and any other associated documents forwarded 
to Sponsor or its designated organization contain no mention of any participants’ names. 
• This extension study will be monitored in accordance with the ICH GCP, and any other 
applicable regulations. The site Monitor will perform visits to the study site at regular 
intervals. Further information regarding monitoring is provided in the Study Monitoring Plan. 
• A maximum of 25 mL of blood will be collected in any one-month period from each 
participant in the study, including any extra assessments that may be required (Appendix 9). 

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Substance code: N/A 
 
Extension to the MAGNIFY MS trial on Mavenclad®  
MS700568_0157 
 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
38/82 
 
 
The incidence of AEs will be summarized overall, by severity, and by relationship to cladribine 
tablets. The summary tables will include incidence rates of AEs for overall system organ classes 
and by preferred term within each system organ class. 
More information can be found in Appendix 7 and in the CRF Completion and Monitoring 
Conventions provided by the Sponsor. 
8.2.1 
Physical Examinations  
• A complete physical examination will include, at a minimum, assessments of the 
Cardiovascular, Respiratory, Gastrointestinal, and Neurological systems. 
• A brief physical examination will include, at a minimum, assessments of the skin, lungs, 
cardiovascular system, and abdomen (liver and spleen). 
• Abnormal results will be documented in the CRF.  
• Investigators will pay special attention to clinical signs related to previous serious illnesses. 
8.2.2 
Vital Signs 
Vital signs will be measured in a semi-supine position after 5 minutes rest and will include body 
temperature, systolic and diastolic blood pressure, and pulse. 
8.3 
Adverse Events and Serious Adverse Events 
In this section, “study intervention” refers to cladribine tablets (i.e., the study intervention of the 
MAGNIFY MS parent trial) since no study intervention is administered in this study. 
• The definitions of an AE and a SAE are in Appendix 7. 
• The Investigator and any qualified designees (e.g., Sub-Investigators) are responsible for 
detecting, documenting, and recording events that meet the definition of an AE or SAE. 
The Investigator remains responsible for following up AEs that are serious or that caused 
the participant to discontinue the study, as specified in Section 8.3.3. 
• Requests for follow-up will usually be made via the Study Monitor, although in 
exceptional circumstances the global patient safety department may contact the 
Investigator directly to obtain further information or to discuss the event. 
8.3.1 
Time Period and Frequency for Collecting Adverse Event 
and Serious Adverse Event Information 
• 
All SAEs will be collected from the signing of the ICF until the last study visit at the time 
points specified in the Schedule of Activities (Section 1.3). Beyond this reporting period, 
any new unsolicited SAEs that the Investigator spontaneously reports to the Sponsor will 
be collected and processed. 
• 
All AEs will be collected from the signing of the ICF until the last study visit at the time 
points specified in the Schedule of Activities. 

Substance code: N/A 
 
Extension to the MAGNIFY MS trial on Mavenclad®  
MS700568_0157 
 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
39/82 
 
 
• 
The date of the last procedure according to the parent study protocol (i.e., the parent study 
exit date) and the date of signing informed consent for the extension study (i.e., the 
extension study enrollment date) is important to determine how AEs/SAEs should be 
recorded and reported:  
• Ongoing SAEs and events of lymphopenia (also if not serious) with an onset date 
prior to the parent study exit date will be recorded on the Medical History/Current 
Medical Conditions CRF. If the condition worsens, a new SAE will be recorded on 
the AE CRF page and reported as specified in Appendix 7. Other non-serious AEs 
which are ongoing at the parent study exit date will not be recorded in the extension 
study. 
• AEs/SAEs with an onset date after the parent study exit date and before the extension 
study enrollment date will be collected retrospectively (after obtaining informed 
consent) and recorded on the AE CRF page for the extension study.  
• AEs/SAEs with an onset date after the extension study enrollment date will be 
recorded on the AE CRF page for the extension study. 
• 
All SAEs will be recorded and reported to the Sponsor or designee immediately and 
under no circumstance will this exceed 24 hours, as indicated in Appendix 7. The 
Investigator will submit any updated SAE data to the Sponsor within 24 hours of it being 
available using the same procedure that was used for the initial report. 
• 
Investigators are not obligated to actively solicit AEs or SAEs after the end of study 
participation. However, if the investigator learns of any SAE, including a death, 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. 
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. In addition, 
the participants will be asked to record AEs in a continuous manner in their patient diary. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-
leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences. 
It is important that each AE report include a description of the event, its duration (onset and 
resolution dates and times when it is important to assess the time of AE onset relative to the 
recorded treatment administration time), its severity, its causal relationship with cladribine 
tablets, any other potential causal factors, any treatment given or other action taken, and its 
outcome. In addition, serious cases should be identified, and the appropriate seriousness criteria 
documented. 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are in Appendix 7. 

Substance code: N/A 
 
Extension to the MAGNIFY MS trial on Mavenclad®  
MS700568_0157 
 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
40/82 
 
 
8.3.3 
Follow-up of Adverse Events and Serious Adverse Events 
After the initial AE/SAE report, the Investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event 
is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). 
Reasonable attempts to obtain this information will be made and documented. It is also the 
Investigator’s responsibility to ensure that any necessary additional therapeutic measures and 
follow-up procedures are performed. Further information on follow-up procedures is in 
Appendix 7. 
8.3.4 
Regulatory Reporting Requirements for Serious Adverse 
Events 
Prompt notification by the Investigator to the Sponsor of an SAE (particularly life-threatening 
and deaths) is essential so that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study intervention under clinical investigation are met. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting 
to the regulatory authority, Institutional Review Boards (IRB)/Independent Ethics Committees 
(IEC), and Investigators. 
Individual Case Safety Reports will be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators, as necessary. 
An Investigator who receives an Individual Case Safety Report describing a SUSAR or other 
specific safety information (e.g., Emerging Safety Issue Report, summary or listing of 
SAEs/SUSARs) from the Sponsor will review and then file it along with the SmPC in the 
Investigator’s Site File and will notify the IRB/IEC, if appropriate according to local 
requirements. 
8.3.5 
Pregnancy 
• Details of all pregnancies in female participants will be collected from the signing of the ICF 
until the last study visit at the time points specified in the Schedule of Activities (Section 1.3). 
• If a pregnancy is reported, the Investigator will inform the Sponsor within 24 hours of learning 
of the pregnancy and will follow the procedures specified below for collection of pregnancy 
information. 
• Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
Collection of Pregnancy Information 
Pregnancy relevant information on male participants with female partners will not be collected 
due to lapse of more than 6 months since the last dose of cladribine tablets.  
Female Participants who become pregnant 

Substance code: N/A 
 
Extension to the MAGNIFY MS trial on Mavenclad®  
MS700568_0157 
 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
41/82 
 
 
• The Investigator will collect pregnancy information on any female participant who becomes 
pregnant while she is in the study. The initial information will be recorded on the appropriate 
form and submitted to the Sponsor within 24 hours of learning of the pregnancy.  
• The participant will be followed to determine the outcome of the pregnancy. The Investigator 
will collect follow-up information on the participant and the neonate, and the information will 
be forwarded to the Sponsor. Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date. Any termination of pregnancy will be reported, 
regardless of fetal status (presence or absence of anomalies) or indication for the procedure. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be reported as an AE or SAE and 
recorded in the eCRF. 
• A spontaneous abortion (occurring at <22 weeks gestational age) or stillbirth (occurring at 
>22 weeks gestational age) is always considered to be an SAE and will be reported as such. 
• Any post-study pregnancy related SAE considered reasonably related to cladribine tablets by 
the Investigator will be reported to the Sponsor as specified in Section 8.3.4. While the 
Investigator is not obligated to actively seek this information in former study participants, he 
or she may learn of an SAE through spontaneous reporting. 
• Any female participant who becomes pregnant while participating in the study may continue 
in the study, as no study intervention is involved, and the assessments are largely part of 
routine medical care for MS.  
8.3.6 
Disease-Related Events and/or Disease-Related Outcomes 
Not Qualifying as AEs or SAEs 
The following disease-related events are common in participants with highly-active RMS and 
can be serious/life threatening:  
• Symptoms and signs of relapse or worsening of MS 
Because these events are typically associated with the disease under study, they will not be 
reported according to the standard process for expedited reporting of AEs and SAEs even though 
the event may meet the definition of an AE or SAE. These events will be recorded on the relapse 
module of the eCRF page within 15 days after the visit. 
However, if either of the following conditions applies, then the event will be recorded and 
reported as an SAE (instead of a disease-related event):  
• The event is, in the Investigator’s opinion, of greater intensity, frequency, or duration than 
expected for the individual participant (i.e. worsening not consistent with the anticipated 
natural progression of the disease). 
OR 
• The Investigator considers that there is a reasonable possibility that the event was related to 
study intervention. 

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Substance code: N/A 
 
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MS700568_0157 
 
 
 
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10 
References  
Benedict RHB, DeLuca J, Phillips G et al. Validity of the Symbol Digit Modalities Test as a 
cognition performance outcome measure for multiple sclerosis. Mult Scler. 2017;23(5):721-33. 
Derfuss T, Mehling M, Papadopoulou A, et al. Advances in Oral Immunomodulating Therapies 
in Relapsing Multiple Sclerosis. Lancet Neurol. 2020;19(4):336-47. 
Dubey D, Cano CA, Stuve O. Intractable and highly active relapsing multiple sclerosis - role of 
alemtuzumab. Neuropsychiatr Dis Treat. 2015;11:2405–14. 
EMA/424715/2017. PRAC confirms restrictions on the use of linear gadolinium agents. Benefit-
risk balance of certain linear gadolinium agents no longer favourable. 7 July 2017. 
Comi G, Cook SD, Giovannoni G et al. MRI outcomes with cladribine tablets for multiple 
sclerosis in the CLARITY study. J Neurol. 2013;260:1136-46. 
Cook S, Comi G, Rieckmann P et al. Safety and Tolerability of Cladribine Tablets in Patients 
with Relapsing-Remitting Multiple Sclerosis (RRMS): Final Results from the 120-Week Phase 
IIIb Extension Trial to the CLARITY Study (P3.095). Neurology Apr 2016, 86 (16 Supplement) 
P3.095. 
Giovannoni G, Comi G, Cook S et al. A placebo-controlled trial of oral cladribine for relapsing 
multiple sclerosis. NEJM. 2010 Feb 4;362(5):416-26. 
Giovannoni G, Cook S, Rammohan K et al. Sustained disease-activity-free status in patients with 
relapsing- remitting multiple sclerosis treated with cladribine tablets in the CLARITY study: a 
post-hoc and subgroup analysis. Lancet Neurol. 2011;10(4):329-37. 
Giovannoni G, Soelberg 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 
Oct;24(12):1594-1604. 
doi: 
10.1177/1352458517727603. Epub 2017 Sep 5. 
Giovannoni G, Keller B, Jack D. Durability of NEDA-3 status in patients with relapsing multiple 
sclerosis receiving cladribine tablets: CLARITY Extension (P3. 2-100). 2019. 
Hirst CL, Pace A, Pickersgill TP et al. Campath 1-H treatment in patients with aggressive 
relapsing remitting multiple sclerosis. Journal of neurology. 2008 Feb 1;255(2):231-8. 
Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status 
scale (EDSS). Neurology. 1983 Nov 1;33(11):1444-52. 
Leist TP, Comi G, Cree BA 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 Neurol. 2014 Mar 1;13(3):257-67. 
Lucchetta RC, Leonart LP, Gonçalves MVM et al. Reliability in long-term clinical studies of 
disease-modifying therapies for relapsing-remitting multiple sclerosis: A systematic review. 
PLoS One. 2020;15(6): e0231722. 
Mavenclad 10 mg tablets. Summary of Product Characteristics. Merck Europe B.V. 22 August 
2017. 

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MS700568_0157 
 
 
 
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11 
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Substance code: N/A 
 
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MS700568_0157 
 
 
 
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Appendix 2 
Study Governance 
Financial Disclosure 
Investigators and Sub-Investigators will provide the Sponsor with enough, 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 
• The Investigator or his/her representative will explain the nature of the study to the participant 
or his/her legally authorized representative and answer all questions on the study.  
• Participants will be informed that their participation is voluntary. 
• Participants or their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50; 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 will 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. The 
authorized person obtaining the informed consent will also sign the ICF. 
• If the ICF is updated during their participation in the study, participants will be re-consented 
to the most current, approved version. 
• A copy of the ICF(s) will be provided to the participant or the participant’s legally authorized 
representative. 
• The original signed and dated consent will remain at the Investigator’s site and will be safely 
archived so that it can be retrieved at any time for monitoring, auditing and inspection 
purposes. 
Data Protection 
• The Sponsor will assign a unique identifier to participants after obtaining their informed 
consent. Any participant records or datasets that are transferred to the Sponsor will contain 
the identifier only; participant names or any identifiable information will not be transferred. 
• The Sponsor will inform participants that their personal study-related data will be used per 
local data protection and privacy laws. The level of disclosure will also be explained to the 
participant and pregnant partners (if applicable), who will be required to give consent for their 
data to be used, as specified in the informed consent. 
• The participants will be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other Sponsor-appointed, authorized personnel, by appropriate 
IRB/IEC members, and by regulatory authority inspectors. All such persons will strictly 
maintain participants’ confidentiality. 

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Study Administrative 
Sponsor 
• The Sponsor of this extension study is Merck KGaA, Frankfurter Strasse 250, 64293 
Darmstadt, Germany. 
• Sites, that participated in the parent study (MAGNIFY MS trial), from Europe (including the 
following countries: Austria, Czech Republic, Finland, France, Germany, Hungary, Italy, 
Spain, Sweden, and the United Kingdom), Australia, Canada, and Israel will be approached 
for participation in this study. About 80 sites are expected to participate. 
• The Coordinating Investigator listed on the title page represents all Investigators for decisions 
and discussions on this study, per ICH GCP. The Coordinating Investigator will provide 
expert medical input and advice on the study design and execution and is responsible for the 
review and signoff of the clinical study report (CSR). 
The study will appear in the following clinical studies registries: EU Clinical Trials Register, 
ClinicalTrials.gov, and national registries as per local regulations. 
Scientific Steering Committee 
• A Steering Committee (SC) will be established to ensure that the study meets scientific 
standards. The SC Charter will be in the place that describes the SC responsibilities. The SC 
is a multidisciplinary group of lead study Investigators, medical experts, and Sponsor’s 
personnel, who, collectively, have the scientific, medical, and clinical study management 
experience to design, conduct and evaluate the study. The SC provides advice and 
recommendations with regard to the design, the conduct, and the evaluation of the study. The 
SC is responsible for safeguarding the interests of participating participants and for the 
conduct of the study. 
Contract research organization 
• A contract research organization (CRO), IQVIA, will undertake the operational aspects of 
this study with oversight by the Sponsor. Details of such structures and associated procedures 
will be defined in a separate Integrated Study Management Plan (ISMP). 
• The ISMP will be prepared by the CRO. Clinical quality assurance will be performed under 
the responsibility of the Development Quality Assurance department at Merck KGaA. 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and the following: 
• Consensus ethical principles derived from international guidelines, including the 
Declaration of Helsinki and the Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
• Applicable ICH GCP Guidelines 
• Applicable laws and regulations 

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• The Investigator will submit the protocol, protocol amendments (if applicable), ICF, 
Investigator Brochure, and other relevant documents (e.g., advertisements) to an IRB/IEC and 
the IRB/IEC will 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: 
• 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 
• Notifying the IRB/IEC of serious adverse events (SAEs) or other significant safety 
findings, as required by IRB/IEC procedures 
• 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 will meet good local standards, as applicable. 
Clinical Study Report 
• After study completion, the Sponsor will write a CSR in consultation with the Coordinating 
Investigator, Principal Investigator (for single center studies), and any SC or other relevant 
study-appointed committees or groups. 
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 the 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 
• The Sponsor will not suppress publication, but maintains the right to delay the publication in 
order to protect intellectual property rights. 

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• Disclosure of CSRs, periodic safety reports, and clinical study summary reports is only 
required, if applicable by local law and regulations. 
• Posting of data on the European Clinical Trials Register and ClinicalTrials.gov is planned and 
will occur 12 months after the last clinic visit of the final study participant or another 
appropriate date to meet applicable requirements. 
Data Quality Assurance 
• All participant study data will be recorded on printed or electronic case report forms (CRFs) 
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 CRF. Details for managing CRFs are in the 
Data Management Plan and Data Validation Plan. 
• For patient reported outcome (PRO) data (e.g., quality of life and pain assessments), ePRO 
will be used. 
• The Investigator will maintain accurate documentation (source data) that supports the 
information in the CRF. 
• The Investigator will 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. 
• 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 or 
contracts. 
• 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. Details will be 
outlined in Data Management documents and procedures. 
• 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. 
• The Investigator will retain records and documents, including signed ICFs, pertaining to the 
conduct of this study 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. 

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• The Investigator will keep a paper or electronic file (medical file and original medical records) 
at the site for each study participant. The file will identify each participant, contain the 
following demographic and medical information for the participant, and will 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. 
• All source data will be filed (e.g., CT or MRI scan images, ECG recordings, and laboratory 
results). Each document will have the participant number and the procedure date; ideally, 
printed by the instrument used for the procedure. As necessary, medical evaluation of these 
records will be performed, documented, signed and dated by the Investigator. 
• Data recorded on printed or electronic CRFs that are transcribed from source documents will 
be consistent with the source documents or the discrepancies will be explained. The 
Investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records will be available. 
• The Study Monitors will use printouts of electronic files for source data verification. These 
printouts will 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 ISMP. 
Study and Site Start and Closure 
First Act of Recruitment 
• 
The study start date is the date when the clinical study will be open for recruitment. 
• 
The first act of recruitment is when the first site is opened and will be the study start date. 
Study Closure and Site Termination 
• 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 

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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 
enough 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 
• If the study is prematurely terminated or suspended, the Sponsor will promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The Investigator will promptly inform the participants and assure appropriate 
participant therapy and/or follow-up. 
 
 

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CCI

Substance code: N/A 
 
Extension to the MAGNIFY MS trial on Mavenclad®  
MS700568_0157 
 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
68/82 
 
 
Appendix 6 
Example of Patient Diary 
 
Patient Diary Card: Month ___ to ____ 
 
Patient initials: 
 
 
Patient number: 
 
 
Dear participant, 
 
Please complete this diary card (with a pen) between study visits and always take it with you to the 
hospital when you visit. 
 
This diary has been designed to help us follow your general health and any problem or discomfort you 
may experience between the study visits and to record all medication you take.  
 
 
Medication record 
Start Date 
Stop Date 
List any new medications 
for changes in the 
medications 
Specify reason for taking any specific medication. All 
medications should be listed here, e.g. painkillers, …, 
as well. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Symptom record 
Start Date 
Stop Date 
Briefly list any problem or discomfort you experienced 
(use as many lines as necessary) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Substance code: N/A 
 
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MS700568_0157 
 
 
 
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I N F O R M A T I O N 
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Appendix 7 
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
In this section, “study intervention” refers to cladribine tablets (i.e., the study intervention of the 
MAGNIFY MS parent study) since no study intervention is administered in this study. 
AE Definition 
AE Definition 
• An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether considered related to 
the study intervention or not.  
• An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated 
with the use of study intervention. For surgical or diagnostic procedures, the 
condition/illness leading to such a procedure is considered as the AE rather than the 
procedure itself. 
Events Meeting the AE Definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the Investigator (i.e., not related to progression of 
underlying disease). 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. However, as the study 
intervention (cladribine tablets) was administered during the parent study, only new 
conditions not detected/diagnosed during the parent study need to be collected. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. 
• “Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or a SAE. However, the signs, symptoms, and/or clinical sequelae 
resulting from lack of efficacy will be reported as an AE or a SAE if they fulfill the 
definition of an AE or SAE. 
Events NOT Meeting the AE Definition 
• Unless judged by the Investigator to be more severe than expected for the participant’s 
condition, any clinically significant abnormal laboratory findings, other abnormal safety 
assessments that are associated with the underlying disease, the disease/disorder being 
studied, or expected progression, signs, or symptoms of the disease/disorder being 
studied. 

Substance code: N/A 
 
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MS700568_0157 
 
 
 
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• Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads 
to the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
AE/SAEs Observed in Association with Disease Progression 
Progression of the disease/disorder being studied assessed by measurement of lesions on 
radiographs or other methods as well as associated clinical signs or symptoms (including 
laboratory abnormalities) will not be reported as AEs/SAEs, unless the participant’s general 
condition is more severe than expected for the his/her condition and/or unless the outcome 
is fatal within the AE reporting period, as defined in Section 8.3.1. 
Symptoms and signs of relapse or worsening of MS since the previous visit 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 
unless considered possibly or probably related to cladribine tablets (i.e. worsening is not 
consistent with the anticipated natural progression of the disease). 
SAE Definition 
If an event is not an AE per the definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, death 
due to progression of disease). 
 
A SAE is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE will be considered serious. 

Substance code: N/A 
 
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• Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
• 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. 
d. Results in persistent disability/incapacity 
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (e.g., sprained ankle) which may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Other situations: 
• Medical or scientific judgment will be exercised in deciding whether SAE reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events are usually considered as serious. 
• 
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization, or development of drug dependency or drug abuse. 
Any suspected transmission of an infectious agent via a diagnostic procedure is also 
considered an SAE for reporting purposes, as specified below for reporting SAEs. 
Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
• 
The Investigator will then record all relevant AE/SAE information in the CRF. 
• 
As needed, the Sponsor may ask for copies of certain medical records (e.g., autopsy 
reports, supplemental lab reports, documents on medical history/concomitant 
medications, discharge letters), as supporting source documentation. All participant 
identifiers, except the participant number, will be redacted on these copies before 
submission to the Sponsor. 

Substance code: N/A 
 
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• 
The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
• 
Specific guidance is in the CRF Completion and Monitoring Conventions. 
 
Assessment of Intensity 
The Investigator will assess the intensity of each AE and SAE reported during the study and 
assign it to 1 of the following categories: 
• Mild: An event that is easily tolerated by the participant, causing minimal discomfort and 
not interfering with everyday activities. 
• Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities. 
• Severe: An event that prevents normal everyday activities. Do not confuse an AE that is 
assessed as severe with a SAE. Severe is a category used to rate the intensity of an event; 
both AEs and SAEs can be assessed as severe. 
An event is defined as “serious” when it meets at least 1 of the predefined criteria specified 
in the definition of an SAE, NOT when it is rated as severe. 
 
Assessment of Causality 
• 
The Investigator will assess the relationship between study intervention and each 
AE/SAE occurrence: 
• 
Unrelated: Not reasonably related to study intervention. AE could not medically 
(pharmacologically/clinically) be attributed to study intervention. A reasonable 
alternative explanation will be available. 
• 
Related: Reasonably related to study intervention. AE could medically 
(pharmacologically/clinically) be attributed to study intervention. 
• 
A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot be 
ruled out. 
• 
The Investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• 
The Investigator will also consult the Investigator Brochure and/or Product Information, 
for marketed products, in his/her assessment. 
• 
For each AE/SAE, the Investigator will document in the medical notes that he/she has 
reviewed the AE/SAE and assessed causality. 
• 
There may be situations when an SAE has occurred, and the Investigator has minimal 
information to include in the initial report to the Sponsor or its designee. To meet the 
reporting timeline, the causality assessment is not required for the initial report. 

Substance code: N/A 
 
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MS700568_0157 
 
 
 
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• 
The Investigator may change his/her causality assessment after considering follow-up 
information and send a SAE follow-up report with the updated causality assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-up of AEs and SAEs 
• The Investigator will perform or arrange for the conduct of supplemental measurements 
and/or evaluations, as medically indicated or as requested by the Sponsor to elucidate the 
nature and/or causality of the AE or SAE, as fully as possible. This may include 
additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals. 
• New or updated information will be recorded in the originally completed CRF. 
• The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information. 
 
Reporting of SAEs 
SAE Reporting by an Electronic Data Collection Tool 
• 
The primary mechanism for reporting an SAE to the Sponsor or its designee will be the 
electronic data collection tool. 
• 
If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool, specified below, to report the event within 24 hours. 
• 
The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• 
After the study is completed at a site, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data. 
• 
If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form or to the 
Sponsor’s safety department. 
• 
By exception, an SAE (or follow-up information) may be reported by telephone. The 
site will complete the electronic SAE data entry immediately thereafter. 
SAE Reporting by a Paper Form 
• 
SAE reporting on a paper report form is used as a back-up method for an EDC system 
failure. The form includes completion instructions for the Investigator, names, 
addresses, and telephone and fax numbers. All information from the paper form will be 
transcribed into the electronic form as soon as the system becomes available. 
• 
Facsimile transmission (fax to mail) of the paper form or any follow-up information is 
the preferred method for transmission and will be done within 24 hours to the Sponsor 
or its designee. 

Substance code: N/A 
 
Extension to the MAGNIFY MS trial on Mavenclad®  
MS700568_0157 
 
 
 
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I N F O R M A T I O N 
74/82 
 
 
• 
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the form sent by overnight mail or courier 
service. 
• 
Initial notification via telephone does not replace the need for the Investigator to 
complete and sign the form within 24 hours after becoming aware of the event. 
• 
Additional documents (e.g. laboratory reports, autopsy report, hospital discharge letter) 
and relevant pages from the CRF may be required in addition (e.g. medical history, 
concomitant medication). The data provided will be consistent with the information in 
the CRF. 
Reporting of Pregnancies 
• Pregnancy will be reported whether related to the study intervention using the applicable 
paper form. 
• The applicable form will be used to report if an abnormal outcome of the pregnancy 
occurs and the child/fetus sustains an event. 
• Facsimile transmission (fax to mail) of the paper form or any follow-up information is 
the preferred method for transmission and will be done within 24 hours to the Sponsor or 
its designee. 
 
 
 

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Substance code: N/A 
 
Extension to the MAGNIFY MS trial on Mavenclad®  
MS700568_0157 
 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
77/82 
 
 
Appendix 10 Contraception 
According to cladribine tablets (Mavenclad®) SmPC, there are no requirements regarding 
contraception that apply after 6 months since the last dose. At the time of enrollment in the 
MAGNIFY MS Extension study, participants will have completed treatment. The treatment start 
was since minimally 2 years, with minimally 12 months since starting the second year treatment. 
 

Substance code: N/A 
 
Extension to the MAGNIFY MS trial on Mavenclad®  
MS700568_0157 
 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
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Appendix 11 Sponsor Signature Page 
 
 

 
PPD
PPD

Substance code: N/A 
 
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Appendix 12 Coordinating Investigator Signature Page 
 
 

PPD
PPD
PPD

Substance code: N/A 
 
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MS700568_0157 
 
 
 
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Appendix 13 Principal Investigator Signature Page 
Study Title: 
A 2-year extension study to evaluate long-term 
effectiveness of Mavenclad® in participants who have 
completed Trial MS700568_0022 (MAGNIFY MS) 
Regulatory Agency Identifying 
Numbers: 
2020-003995-42 
Clinical Study Protocol Version: 20 August 2020/Version 1.0 
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 on 
Harmonisation Good Clinical Practice (Topic E6) and all applicable Health Authority 
requirements and national laws. 
I also understand that Health Authorities may require the Sponsors of clinical studies to obtain 
and supply details about ownership interests in the Sponsor or Investigational Medicinal Product 
and any other financial ties with the Sponsor. The Sponsor will use any such information solely 
for complying with the regulatory requirements. Therefore, I agree to supply the Sponsor with 
any necessary information regarding ownership interest and financial ties including those of my 
spouse and dependent children, and to provide updates as necessary to meet Health Authority 
requirements. 
 
____________________________________ 
____________________________ 
Signature 
Date of Signature 
 
Name, academic degree: 
 
Function/Title: 
 
Institution: 
 
Address: 
 
Telephone number: 
 
Fax number: 
 
E-mail address: