Conditions: Multiple Sclerosis
Keywords: Multiple Sclerosis Mavenclad ® Cladribine Relapsing Multiple Sclerosis Immune cell kinetics
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 219
Healthy volunteers: no

Brief summary:
The primary purpose of this study was to evaluate the long-term effectiveness of Mavenclad® tablets, in terms of disease activity and safety, in participants with highly-active relapsing multiple sclerosis (RMS) previously participating in the MAGNIFY MS trial MS700568\_0022 (NCT03364036).

Detailed description:

Arms:
arm 1: None

Interventions: intervention 1: Mavenclad®
Intervention descriptions: intervention 1: No intervention was administered as a part of this study. Participants who had received Mavenclad® up to 2 years (Year 1 and 2) in the parent study MS700568\_0022 (NCT03364036) were enrolled into this extension study and will be assessed up to 2 years follow-up (Year 3 and 4).

Protocol document:
Prot_000.pdf: 
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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 
 
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 
47/82 
 
 
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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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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11 
Appendices 
 
 
 


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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 
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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. 


Substance code: N/A 
 
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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. 


Substance code: N/A 
 
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MS700568_0157 
 
 
 
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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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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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• 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. 


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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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• 
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 
 
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MS700568_0157 
 
 
 
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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 
 
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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 11 Sponsor Signature Page 
 
 


 
PPD
PPD


Substance code: N/A 
 
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MS700568_0157 
 
 
 
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Appendix 12 Coordinating Investigator Signature Page 
 
 


PPD
PPD
PPD


Substance code: N/A 
 
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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: 
 
 

SAP_001.pdf: 
Mavenclad® 
MAGNIFY Extension 
MS700568_0157  
Version 2.0 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
1/86 
 
 
 
Integrated Analysis Plan  
Study Number: 
MS700568_0157 
Clinical Study Protocol 
Title: 
A 2-year extension study to evaluate long-term effectiveness of 
Mavenclad® in participants who have completed Trial 
MS700568_0022 (MAGNIFY MS) 
Study Phase: 
IV 
Merck Compound: 
Mavenclad® 
Protocol Version: 
20 August 2020 / Version 1.0 
Integrated Analysis Plan 
Author: 
 
Coordinating Author 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Integrated Analysis Plan 
Date and Version: 
 05 October 2023 / Version 2.0 (Final) 
Integrated Analysis Plan 
Reviewers: 
 
Function 
Name 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confidential 
This document is the property of Merck Healthcare KGaA, Darmstadt, Germany, or one of its affiliated companies. 
It is intended for restricted use only and may not - in full or part - be passed on, reproduced, published or used without 
express permission of Merck Healthcare KGaA, Darmstadt, Germany or its affiliate.  
Copyright © 2023 by Merck Healthcare KGaA, Darmstadt, Germany or its affiliate. All rights reserved. 
*OREDO9HUVLRQ,'CCI
PPD
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PPD


Mavenclad® 
MAGNIFY Extension 
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Version 2.0 
 
 
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I N F O R M A T I O N 
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Approval Page  
 
Integrated Analysis Plan: MS700568_0157  
A 2-year extension study to evaluate long-term effectiveness of Mavenclad® in participants who 
have completed Trial MS700568_0022 (MAGNIFY MS) 
 
Approval of the IAP by all Merck Data Analysis Responsible has to be documented within EDMS 
via eSignature. With the approval, the Merck responsible for each of the analysis also takes 
responsibility that all reviewers’ comments are addressed adequately. 
By using eSignature, the signature will appear at the end of the document. 
*OREDO9HUVLRQ,'CCI


Mavenclad® 
MAGNIFY Extension 
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I N F O R M A T I O N 
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1 
Table of Contents  
Approval Page 
2 
1 
Table of Contents ..................................................................................3 
2 
List of Abbreviations and Definition of Terms ....................................6 
3 
Modification History ............................................................................9 
4 
Purpose of the Integrated Analysis Plan .............................................10 
5 
Objectives and Endpoints ...................................................................12 
6 
Overview of Planned Analyses ...........................................................14 
6.1 
Interim Analysis ..................................................................................15 
6.1.1 
Cut-off Date ........................................................................................17 
6.1.2 
Data Handling after Cut-off Date .......................................................18 
6.2 
Final Analysis .....................................................................................18 
7 
Changes to the Planned Analyses in the Clinical Study Protocol ......18 
8 
Analysis Sets and Subgroups ..............................................................20 
8.1 
Definition of Analysis Sets .................................................................20 
8.2 
Subgroup Definition and Parameterization ........................................21 
9 
General Specifications for Data Analyses ..........................................21 
9.1 
Definition of Baseline and Change from Baseline .............................22 
9.2 
Definition of Visit Dates .....................................................................22 
9.3 
Definition of Duration ........................................................................22 
9.4 
Conversion Factors .............................................................................23 
9.5 
Time Window .....................................................................................23 
9.6 
Study Period........................................................................................24 
9.7 
Imputation of Missing Data ................................................................26 
9.8 
Data Handling for MRI data ...............................................................27 
9.9 
Data Handling in Case of PDs ............................................................29 
9.10 
Covariates and Stratification Factors ..................................................29 
9.11 
Definition of Start of COVID-19 Pandemic .......................................30 
9.12 
Visit timing with respect to COVID-19 pandemic .............................31 
10 
Study Participants ...............................................................................31 
10.1 
Disposition of Participants and Discontinuations ...............................31 
10.2 
Protocol Deviations / Exclusion from Analysis Sets ..........................32 
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10.2.1 
Important Protocol Deviations ............................................................32 
10.2.2 
Reasons Leading to the Exclusion from an Analysis Set ...................33 
11 
Demographics and Other Baseline Characteristics .............................34 
11.1 
Demographics .....................................................................................34 
11.2 
Medical History ..................................................................................34 
11.3 
Other Baseline Characteristics ............................................................34 
12 
Previous or Concomitant Therapies/Procedures .................................34 
13 
Study Intervention: Compliance and Exposure ..................................35 
14 
Efficacy Analyses ...............................................................................35 
14.1 
Primary Endpoint: Proportion of participants with No Evidence of 
Disease Activity (three parameter [NEDA-3]) during Year 3 Visit 
and Year 4 Visit Period after the initial dose of cladribine tablets .....36 
14.1.1 
Primary Objective: Derivation and analysis of the primary 
endpoint ..............................................................................................36 
14.1.2 
Primary Objective: Sensitivity Analyses of the Primary Endpoints ...38 
14.2 
Secondary Endpoints ..........................................................................39 
14.2.1 
No Evidence of Disease Activity ........................................................39 
14.2.2 
Time to First Disease Activity ............................................................43 
14.2.3 
Time to MRI Activities, 6MCDP, Qualifying Relapse and 
Treatment Start with Other DMDs .....................................................45 
 
50 
..50 
..54 
..55 
..56 
..57 
..58 
..59 
..62 
..63 
..63 
..63 
..67 
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..67 
..68 
..69 
 
..71 
..73 
15 
Safety Analyses ..................................................................................76 
15.1 
Adverse Events ...................................................................................76 
15.1.1 
All Adverse Events .............................................................................76 
15.1.2 
Adverse Events Leading to Discontinuation of Study Intervention ...78 
15.2 
Deaths, Other Serious Adverse Events, and Other Significant 
Adverse Events ...................................................................................78 
15.2.1 
Deaths .................................................................................................78 
15.2.2 
Serious Adverse Events ......................................................................78 
15.2.3 
Other Significant Adverse Events ......................................................78 
15.3 
Clinical Laboratory Evaluation ...........................................................79 
15.4 
Vital Signs ..........................................................................................79 
15.5 
Other Safety or Tolerability Evaluations ............................................79 
16 
Analyses of Other Endpoints ..............................................................80 
16.1 
Baseline Characteristics Compared to Parent Study ..........................80 
17 
References ...........................................................................................81 
18 
Appendices .........................................................................................82 
18.1 
Appendix 1: List of DMDs for MAGNIFY MS Extension Study ......82 
 
 ............84 
18.3 
Appendix 3: Preferred terms for selection of AEs associated to 
Lymphopenia ......................................................................................86 
 
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2 
List of Abbreviations and Definition of Terms  
 
 
 
AE 
Adverse Event 
 
 
ATC 
Anatomical Therapeutic Chemical classification  
 
 
CDISC 
Clinical Data Interchange Standards Consortium 
CDP 
Confirmed Disability Progression 
CI 
Confidence Interval 
(e)CRF 
(electronic) Case Report Form 
CAR 
Censoring at Random 
CNAR 
Censoring not at Random 
 
 
CSP 
Clinical Study Protocol 
CSR 
Clinical Study Report 
 
 
CV 
Coefficient of Variation 
 
 
DMD 
Disease Modifying Drug 
DTS 
Data Transfer Specification 
EAIR 
Exposure Adjusted Incidence Rate 
EDMS 
Electronic Document Management System 
EDSS 
Expanded Disability Status Scale 
ES 
Enrolled Set 
EW 
Early Withdrawal 
FAS 
Full Analysis Set 
 
 
HRA 
High-relapse Activity 
IA 
Interim Analysis 
IAP 
Integrated Analysis Plan 
ICH 
International Conference on Harmonization 
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IPD 
Important Protocol Deviation 
KM 
Kaplan-Meier 
LLOQ 
Lower Limit of Quantification 
LS 
Least Square 
M 
Month 
MAR 
Missing At Random 
MCF 
Mean Cumulative Function 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed-effects Linear Model with Repeated Measure 
MRI 
Magnetic Resonance Imaging 
MS 
Multiple Sclerosis 
 
 
NA 
Not Applicable 
NE 
Not Evaluable 
NEDA 
No Evidence of Disease Activity 
 
 
 
 
 
 
PD 
Protocol Deviation 
 
 
PT 
Preferred Term 
RNA 
Ribonucleic Acid 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Population  
SD 
Standard Deviation 
 
 
SDTM 
Study Data Tabulation Model 
SE 
Standard Error 
SMC 
Safety Monitoring Committee 
 
 
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SOC 
System Organ Class 
T1 Gd+ 
T1 gadolinium-enhancing 
 
 
TCS 
Treatment Completer Set  
TLF 
Tables, Listings, and Figures 
WHO-DD 
World Health Organization Drug Dictionary 
 
 
 
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3 
Modification History  
Unique 
Identifier for 
Version 
Date of 
IAP Version 
Author 
Changes from the Previous Version 
1.0 
17 Aug 2022 
 
 
New Document 
2.0 
05 Oct 2023 
 
 
x 
Author and reviewers list updated 
x 
Editorial changes to harmonize terminology 
x 
References to parent study IAP added where 
applicable 
x 
Section 4: Explanation added regarding use of 
parent study data 
x 
 
 
x 
Section 6.1, Interim Analysis: NEDA-3 analysis to 
be performed on subgroups (subset analyses 
removed) 
x 
Section 6.1, Interim Analysis: Relapse Report 
analysis added 
x 
Section 6.1, Interim Analysis: Artefact to analyze 
“Annex 2” in Interim Analysis to be removed 
x 
Section 7: Explanation added regarding use of 
“new” vs. “all” T1-Gd+ lesions in Extension Study 
Period 
x 
Section 8.1: Previous and concomitant 
medications to be summarized on the FAS 
x 
Section 8.2: Definition of subset analyses updated 
x 
Section 9: Definition of percentage calculation for 
by visit summaries updated 
x 
Section 9.7: Missing data imputation rules 
corrected 
x 
Section 9.9: Reference to section 10.2 added 
x 
Section 9.10: Clarification added  
x 
Section 9.11: Link corrected 
x 
Section 10.1: Duration of gap period to be 
presented separately 
x 
Sections 10.1, 11.1, 11.2, 12: Summaries updated 
consistent to CLARIFY MS Extension study 
x 
Section 11.2: Summary for medical history in 
parent study added 
x 
Sections 14.1.1, 14.2.1, 14.2.2, 
: The start 
date for the time to event analyses during the 
Extension Study Period will be Visit end date of 
M24 Visit + 1, instead of the NEDA-3 assessment 
date at M24 Visit + 1. 
x 
Section 14.1.1: Detailed definitions for NEDA 
components added 
x 
Sections 14.1.2, 14.2.2: Log-rank test and 
resulting p-values removed for subgroup analyses 
by “Previous treatment with DMDs” 
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Unique 
Identifier for 
Version 
Date of 
IAP Version 
Author 
Changes from the Previous Version 
x 
Section 14.1.2, 14.2.1: Summary for crude 
percentages of NEDA components added 
x 
Section 14.2.1: Definition of event date corrected 
x 
Section 14.2.2: Percentile summary added 
x 
Section 14.2.3: Clarification for definition of 
recurrent qualifying relapses added 
x 
 
 
 
x 
 
 
x 
Section 14.3.2: Summary for “Level of Education” 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Section 15.1.1: Summaries for AEs and study 
treatment related AEs leading to discontinuation 
added consistent to CLARIFY MS Extension 
study (MS700568_0158) 
x 
Section 15.2.3: Summaries for “AEs associated to 
Lymphopenia” added 
x 
Section 16.1: minor wording update 
x 
Section 18.1: Updated list of DMDs in Appendix 1 
x 
Section 18.3: List of terms for Lymphopenia 
added as Appendix 3 
4 
Purpose of the Integrated Analysis Plan  
The purpose of this Integrated Analysis Plan (IAP) is to document technical and detailed 
specifications for the analysis of data collected for protocol MS700568_0157. Results of the 
analyses described in this IAP will be included in the Clinical Study Report (CSR). Additionally, 
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the planned analyses identified in this IAP may be included in regulatory submissions or future 
manuscripts. Any post-hoc, or unplanned analyses performed to provide results for inclusion in 
the CSR but not identified in this prospective IAP will be clearly identified in the CSR. 
The IAP is based upon Section 9 (Statistical considerations) of the study protocol and protocol 
amendments and is prepared in compliance with ICH E9. 
 
 
 
 
The analyses described in this IAP will also include data from the MAGNIFY MS trial 
(MAGNIFY MS study MS700568_0022, referred to as the parent study in the current document). 
Therefore, the study protocol and protocol amendments of the MAGNIFY MS trial, as well as the 
MAGNIFY MS IAP version 3.0, will also be referenced, where applicable. When analysis datasets 
from parent study will be utilized, no separate removal of data, not specifically required for the 
analysis of the MAGNIFY MS Extension Study, will be done. 
The wording used in this IAP is chosen to best match the respective wording in the study protocol 
template, the CSR template, CDISC requirements and special requirements for table layouts. 
Therefore, the following approach is used: 
Generally, the term ‘participant’ will be used instead of ‘subject’ or ‘patient’. However, in tables 
and listings the term ‘subject’ will be used to match CDISC requirements, except for in-text tables 
where ‘participant’ will be used to match the CSR and protocol templates. Similarly, the term 
‘study intervention’ will be used in this document instead of ‘treatment’ to match protocol and 
CSR templates, however, tables and listings will use ‘treatment’ for brevity reasons. Exceptions 
from this rule are commonly used terms like “on-treatment”, “treatment-emergent”, “treatment 
policy”, “subject-years”, “by-subject”, or names of eCRF pages like “Treatment Termination” 
page. 
 
 
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5 
Objectives and Endpoints 
Objectives 
Endpoints 
IAP section 
Primary 
To evaluate the long-term disease 
activity during Year 3 and 4 after 
initial dose of cladribine tablets 
x 
Proportion of participants with No Evidence of Disease 
Activity (three parameter [NEDA-3]) during Year 3 Visit 
and Year 4 Visit Period after the initial dose of 
cladribine tablets 
14.1 
Secondary 
To further explore the long-term 
treatment effect of cladribine tablets 
x 
Proportion of participants with NEDA-3 during Year 3 
Visit Period after the initial dose of cladribine tablets 
x 
Proportion of participants with NEDA-3 during Year 4 
Visit Period after the initial dose of cladribine tablets 
x 
Proportion of participants with NEDA-3 after start of 
study medication during the parent study until the end 
of Year 3 Visit after the initial dose of cladribine tablets 
x 
Proportion of participants with NEDA-3 after start of 
study medication during the parent study until the end 
of Year 4 Visit after the initial dose of cladribine tablets 
x 
Proportion of participants remaining NEDA-3 during 
Year 3 Visit Period or Year 4 Visit Period after the 
initial dose of cladribine tablets among those with 
NEDA-3 during Course 1 Treatment Period or Course 
2 Treatment Period in the parent study 
x 
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 Visit and Year 4 Visit 
Period after initial dose of cladribine tablets 
x 
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, during the parent study until the end of Year 4 
Visit after the initial dose of cladribine tablets (i.e., 
between initial dose and end of the extension study) 
x 
Time from the initial dose of cladribine tablets to 
x 
first new or enlarging T2 lesion 
x 
first new T1 Gd+ lesion 
x 
first CDP, as measured by Expanded Disability 
Status Scale (EDSS) 
x 
first qualifying relapse 
x 
recurrent qualifying relapses 
x 
Time from M24 Visit in the parent study to 
x 
first new or enlarging T2 lesion 
x 
first new T1 Gd+ lesion 
x 
first CDP, as measured by EDSS 
x 
first qualifying relapse 
x 
recurrent qualifying relapses 
x 
treatment start with other DMDs 
14.2 
To evaluate long-term safety of 
cladribine tablets 
x 
Occurrences of adverse events (AEs) and serious 
adverse events (SAEs) during Year 3 Visit and Year 4 
Visit Period after the initial dose of cladribine tablets 
15 
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6 
Overview of Planned Analyses  
The following analyses are planned for the study: 
x Interim analysis (IA) at the end of Year 3 Visit (i.e., Visit 1 of the MAGNIFY MS 
Extension Study) after the initial dose of cladribine tablets (i.e., after all participants have 
completed the Year 3 Visit assessment). 
x Final analysis at the end of the MAGNIFY MS Extension Study. 
The following bioinformatic analyses of the main study are described in the Clinical Study 
Protocol (CSP), version 1.0: 
 
 
 
 
 
 
 
The analyses for the protocol endpoint “Explore the association between genetic variants, clinical 
efficacy, 
 and MRI endpoints” (see Section 5) will be specified in these Annexes. 
 
 
 
 
 
 
 
 
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6.1 
Interim Analysis  
The IA will be exploratory in nature. There will be no stopping criteria or any other planned 
adaptations to the study associated with this IA. Due to the exploratory nature of the study, no 
alpha spending was planned to control for overall type-I-error inflation. 
The IA will be performed when all participants have completed Visit 1 or have discontinued from 
the study prior to Visit 1. 
The IA will describe the following characteristics of the study population (overall and by “Previous 
treatment with DMDs” subgroup as defined in Section 8.2): 
x Disposition of participants and discontinuations including and up to the cut-off point 
(Section 10.1) 
x Demographics, Medical History, and Other Baseline Characteristics including MS Disease 
Characteristics, MRI Baseline Characteristics and Vital Signs (Section 11) 
x Previous or concomitant medications including and up to the cut-off point (Section 12) 
and will include analyses of the following secondary, 
 and safety endpoints as 
described in the respective referenced sections up to Visit 1 or the cut-off point: 
x NEDA-3 (Section 14.2.1 including subgroup analyses) 
o Proportion of participants with NEDA-3 during Year 3 Visit Period after the initial 
dose of cladribine tablets 
o Proportion of participants with NEDA-3 after the start of study medication during 
the parent study until the end of Year 3 Visit after the initial dose of cladribine 
tablets  
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x Time from M24 Visit to treatment start with other DMDs (Section 14.2.3 including 
subgroup analysis) 
 
 
 
x Relapse Report: The number of participants with (qualifying) relapses, the number of 
(qualifying) relapses, 
 will be presented 
for the Extension Study Period and the Parent and Extension Study Period. Also, the 
number of participants with relapses and number of relapses which were treated with 
steroids or leading to hospitalization will be presented separately.  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x Occurrences of AEs and SAEs during Year 3 Visit Period after initial dose of cladribine 
tablets, overall and by “Previous treatment with DMDs” subgroup as defined in Section 
8.2, including and up to the cut-off point of IA (Section 15) 
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The following table lists all assessments which will be included in the IA. 
 
Assessments 
MAGNIFY 
MS 
Screening 
MAGNIFY 
MS 
Baseline 
MAGNIFY MS M24 
Visit$ 
MAGNIFY 
Extension 
Baseline 
MAGNIFY 
Extension 
Visit 1 +/- 
30 days 
Informed Consent 
 
 
 
X 
 
Inclusion/exclusion criteria 
 
 
 
X 
 
Demography 
X 
 
 
X 
 
Vital Sign 
X 
X 
 
 
 
Concomitant medications and 
procedures 
 
 
 
 X* 
X 
MRI 
 
 
 
 
 
MRI 
X 
X 
X 
 
X 
Disability 
 
 
 
 
 
EDSS 
X 
X 
X 
X* 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Relapse reporting 
 
X 
X 
X* 
X 
Safety Assessments 
 
 
 
 
 
Adverse event reporting 
X 
X 
X 
X* 
X 
Medical history 
 
 
 
 X** 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
$All Visits (up to the M24 Visit) where the assessment is available in MAGNIFY MS trial will be included if checked.  
*Baseline data will be collected retrospectively from the gap period between MAGNIFY MS Final Visit (M24) and 
MAGNIFY MS Extension Baseline. 
** Ongoing SAEs and events of lymphopenia (also if not serious) with an onset date prior to the parent study exit date 
will be recorded as medical history in the extension study. 
6.1.1 
Cut-off Date 
Only data up to and including Visit 1 of each participant will be analyzed in the IA. Therefore, the 
cut-off date is defined as the maximum Visit 1 date (i.e., date of the last assessment for Visit 1). 
For participants with a missing Visit 1, the cut-off date will be 1 year (360 days) after end date of 
M24 Visit in the MAGNIFY MS trial. This includes participants of the MAGNIFY MS Extension 
Study who discontinued before Visit 1. 
Cut-off date (Visit 1 done) = Visit 1 end date (i.e., Maximum Visit 1 date) 
Cut-off date (Visit 1 not done) = 1 year (360 days) after end date of M24 Visit in the MAGNIFY 
MS trial 
Any assessments from later than Visit 1 will not be included in the IA, however, any events or 
concomitant medications reported during these visits that have an onset/start date before or at the 
cut-off date will be included. 
All data included in the IA will undergo a data cleaning process, however, as no decisions on 
further study conduct are based on this IA, it is not required to have all data 100% cleaned. 
Details and level of data cleaning will be documented in data management plans. The quality of 
the data will be reviewed during the Data Review Meeting. 
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6.1.2 
Data Handling after Cut-off Date 
Data not included in the IA do not undergo the cleaning process. 
Data other than the date of death obtained after the cut-off will not be displayed in any listings or 
used for summary statistics. If the stop date for an AE is after the date of cut-off, the AE will be 
considered as ongoing during the IA. 
6.2 
Final Analysis 
The final analysis will be performed at the end of study, i.e., when all participants have completed 
Visit 2 or have discontinued from the study prior to Visit 2 and will include all described analyses 
of this IAP. The final analysis will be based on all data available in the database at the time of the 
final database lock. 
7 
Changes to the Planned Analyses in the Clinical Study 
Protocol  
Below changes are made in the IAP compared to the planned analyses in the CSP. 
x Visits (Year 3 Visit [Visit 1] and Year 4 Visit [Visit 2]) in the Extension Study were not 
scheduled in calendar years from initial dose of cladribine tablets in parent study. Instead, 
these visits were scheduled relative to the final visit (M24 Visit) of parent study (see 
Section 9.5). Since there was potentially substantial delay in parent study visit schedule 
(could be more than 6 months), Year 3 Visit (or Year 4 Visit) would not reflect Year 3 (or 
Year 4) after initial dose of cladribine tablets. Therefore, the below text replacement for 
protocol endpoints is implemented in the IAP Section 5 for clarification.   
o “during Year 3 / Year 4 / Year 3 and 4 after initial dose of cladribine tablets” is 
replaced with “during Year 3 Visit Period / Year 4 Visit Period / Year 3 Visit and 
Year 4 Visit Period after initial dose of cladribine tablets”, respectively. 
o “at the end of Year 3 / Year 4 after initial dose of cladribine tablets” is replaced 
with “at the end of Year 3 Visit / Year 4 Visit after initial dose of cladribine tablets”, 
respectively. 
o “over the 2-year extension study period (Year 3 and 4 after initial dose of cladribine 
tablets” and “during the first and second year of extension study (Year 3 and 4 after 
the initial dose of cladribine tablets)” are replaced with “over the extension study 
period”. 
o “over the 4-year study period of the parent and extension study (Year 1 to 4 after 
initial dose of cladribine tablets)” is replaced with “over the study period of the 
parent and extension study”. 
x It was described in the CSP that “In addition, interim analysis at extension study Baseline 
or at the end of Year 3 after the initial dose of cladribine tablets may be performed”. Due 
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to the same reason as above, it is decided during IAP development that the IA will be 
performed at the end of Year 3 Visit (Visit 1). See detailed description in Section 6.1. 
x The protocol endpoint “Proportion of participants remaining NEDA-3 during Year 3 Visit 
Period or Year 4 Visit Period after the initial dose of cladribine tablets among those with 
NEDA-3 during Year 1 or 2 after initial dose of cladribine tablets” is replaced with 
“Proportion of participants remaining NEDA-3 … among those with NEDA-3 during 
Course 1 Treatment Period or Course 2 Treatment Period in the parent study”, as Study 
Periods in parent study were not defined in calendar years relative to initial dose of 
cladribine tablets. 
x The text “the onset of action of cladribine treatment” in protocol endpoints is replaced with 
“start of study medication”, as these refer to the same day (Day 1 as defined in Section 9.5) 
and the latter is chosen to keep consistent with parent study Day 1 definition. 
x The protocol endpoint “Time from the initial dose of cladribine tablets to treatment start 
with other DMDs” is removed. This is because in the parent study, a participant receiving 
any rescue medication with any other DMD would not participate further in any trial 
assessments and should instead complete the early termination visit for final assessment. 
Such participants would not have EDSS or MRI assessment at M24 Visit and therefore 
would not be included in the Extension Study as per inclusion criteria. Hence, the Extension 
Study population have excluded potentially a subgroup of participants who started DMDs 
earlier during the parent study. The analysis of “time from initial dose of cladribine to 
treatment start with other DMDs” conducted on the Extension Study population would be 
biased and, therefore, would not be performed. 
x The protocol endpoints “time from extension study baseline to …” are replaced with “Time 
from M24 Visit in the parent study to …”. This is because the Extension Study baseline is 
planned to coincide with the parent study last visit (M24 Visit), while in practice it can 
occur after the parent study last visit and before Visit 1, resulting in incomparable starting 
dates across participants for the planned time-to-event analyses in protocol. These time-to-
event analyses will be more meaningful to start from the intended Extension Study 
baseline, i.e., M24 Visit in the parent study. 
x The protocol endpoints, “time from … to second qualifying relapse” are replaced with 
“time from … to recurrent qualifying relapses”. Correspondingly, a recurrent event 
analysis will be implemented as specified in Section 14.2.3. 
 
 
 
x
 
 
  
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x 6-months confirmed disability progression (6MCDP), is used in the IAP to keep consistent 
with the parent study IAP, although 3 months confirmed disability progression, 3MCDP, 
is defined in the CSP. 
x As data provided from MRI vendor only contains absolute values for (all) T1-Gd+ lesions 
per assessment (no new T1-Gd+ lesions), in consequence (all) T1-Gd+ lesions per 
assessment will be used for definition of disease activity and for calculation of Combined 
Unique Active (CUA) lesions during MAGNIFY MS Extension Study. However, as 
MAGNIFY MS Extension Study only has yearly MRI assessments the number of “new” 
and “all“ T1-Gd+ lesions can be considered identical (see also explanation in Section 9.8). 
 
 
 
 
8 
Analysis Sets and Subgroups  
8.1 
Definition of Analysis Sets  
Enrolled Set (ES) 
All participants who provided informed consent. 
Full Analysis Set (FAS) 
The FAS will include all enrolled, eligible participants. 
Safety Analysis Population (SAF) 
All participants treated with at least one dose of cladribine tablets during the parent study. 
Treatment Completer Set (TCS) 
All participants from the FAS who completed the full treatment course of the first and second year 
in the parent study (i.e., participants who were in TCS-2 as defined in MAGNIFY MS IAP version 
3.0). 
Analyses per Analysis Set 
Unless otherwise specified, all efficacy analyses will be performed on the FAS and all safety 
analyses will be performed on the SAF. The primary analysis will also be repeated on the TCS as 
a sensitivity analysis. 
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If not stated otherwise, disposition of participants will be summarized on the ES, previous and 
concomitant medications will be summarized on the FAS, and the analyses on demographics and 
other baseline characteristics will be based on the FAS. 
8.2 
Subgroup Definition and Parameterization  
Subgroup analyses will be performed on subgroups as defined below. 
x Previous (prior to parent study Baseline) treatment with DMDs: 
o DMD pre-treated: Participants will be categorized as DMD pre-treated if they have 
taken DMDs any time before start of study medication. 
o Pre-treatment naïve: all participants not classified as DMD pre-treated.  
Details of the definition of DMDs used for subgroups classification are specified in MAGNIFY 
MS IAP version 3.0. The updated list of DMDs (Appendix 18.1) will be used to identify DMD in 
concomitant medications in the Extension Study.  
All descriptive statistical analyses will be presented separately for the DMD subgroups. The 
primary analysis, secondary analyses and selected exploratory analyses will also be repeated for 
this subgroup.  
Subset analyses will be performed on the subsets defined as follows: 
x Participants with NEDA-3 during Course 1 Treatment Period 
x Participants with NEDA-3 during Course 2 Treatment Period 
Secondary analyses of NEDA-3 during Year 3 Visit Period and during Year 4 Visit Period (see 
Section 14.2.1) will be repeated on these subsets. Definition of NEDA-3 during Course 1 
Treatment Period and Course 2 Treatment Period is described in Section 14.2.1. 
9 
General Specifications for Data Analyses  
Unless otherwise specified, continuous variables will be summarized using descriptive statistics, 
i.e., the number of participants with non-missing values (n), mean, standard deviation, median, 
25th percentile (Q1) and 75th percentile (Q3), minimum, and maximum.  
Qualitative variables will be summarized by frequency counts and percentages. Unless otherwise 
stated the calculation of proportions will be based on the number of participants of the analysis set 
of interest. Therefore, counts of missing observations will be included in the denominator and 
presented as a separate category.  
Descriptive statistics by nominal visit or time point will include only data from scheduled visits. 
Unscheduled visits will be included in the derivation of baseline or worst on-treatment values. 
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All statistical tests mentioned in this IAP are to be regarded as descriptive and exploratory, and 
differences with a p-value of 0.05 or less will be considered nominally statistically significant. No 
correction for multiple testing will be applied for any of the analyses. If confidence intervals (CI) 
are to be calculated, these will be two-sided with a confidence probability of 95%, unless otherwise 
specified in this IAP. 
Study data will be integrated with study data from the MAGNIFY MS trial as required to perform 
the statistical analyses, i.e., study data up to M24 visit is integrated from the MAGNIFY MS trial. 
If not specified otherwise, all listings will only include data collected in the Extension Study, 
including the gap period between the MAGNIFY MS trial and MAGNIFY MS Extension Study. 
Listings regarding demographic and other Baseline characteristics will include data from 
MAGNIFY MS Baseline. 
If data from parent study are used, all rules from parent study IAP still apply for the analysis of 
these data, except alternative rules are explicitly specified in this IAP. 
All analyses will be performed using SAS® Software version 9.4 or higher or R (http://www.r-
project.org/), Version 3.6.3 or higher as applicable. 
9.1 
Definition of Baseline and Change from Baseline  
The Baseline is defined as the MAGNIFY MS Baseline (parent study Baseline) that is specified in 
Section 9 of MAGNIFY MS IAP version 3.0, unless otherwise specified.  
Absolute and percent changes from baseline are defined as: 
x Absolute change = Visit value – Baseline value 
x Percent change = 100 * (Visit value – Baseline value) / Baseline value 
The Percentage Change from Baseline will be set to missing for participants with a zero at 
Baseline. 
All changes that are defined as comparing to prior initial dose of cladribine tablets will use the 
MAGNIFY MS Baseline as reference. 
9.2 
Definition of Visit Dates 
The visit start date is the date of the first assessment which belongs to the corresponding visit. 
The visit end date is the date of the last assessment which belongs to the corresponding visit. 
9.3 
Definition of Duration  
Durations in days will be calculated by the difference of start and stop date + 1 if not otherwise 
specified. 
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9.4 
Conversion Factors  
The following conversion factors will be used to convert days into months or years for all 
observations except Visit related dates:  
x 1 month = 30.4375 days,  
x 1 year = 365.25 days. 
9.5 
Time Window  
x Day 1 is the day of start of study medication at MAGNIFY MS Baseline Visit, the day 
before is Day -1 (no Day 0 is defined). 
x Study day is defined relative to Day 1. 
The visit schedule in the Extension Study is defined as follows: 
x 1 month = 30 days,  
x 1 year = 360 days,  
relative to the M24 Visit in the parent study. 
x MAGNIFY Extension Baseline Visit: The visit is planned to coincide with or be as near to 
M24 as possible to minimize the transition gap period, it may also be the same visit as 
M24. 
x Visit 1: 1 year ((360 days) after M24 Visit (± 30 days) 
x Visit 2: 2 years (720 days) after M24 Visit (± 30 days) 
Visit 1 and Visit 2 will also be referred to as the M36 Visit and the M48 Visit, respectively, in the 
following sections of this IAP as well as in the Tables, Listings, and Figures (TLF) outputs, for 
consistent presentation of analyses and results over time. Footnotes will be added in the TLF 
outputs to clarify that these Visits are to be understood as nominal Visits. 
In each analysis, should an assessment be delayed, participants’ assessment data will be treated as 
though it occurred at the nominal time point specified (i.e., data collected out of visit windows will 
not be excluded or adjusted in any analysis) and inferences will be conducted accordingly. Thus, 
further time windows will not be specified. The MRI assessment will be the only exception to this 
rule. Handling of out-of-window MRI assessments is discussed in Section 9.8. 
All observations from unscheduled visits will be included only in the analyses of visit 
independent summaries (e.g., counts of AEs, concomitant medications and procedures, relapse 
reporting and EDSS) unless for the last assessment available. In this case the missing Early 
Withdrawal (EW) visit will be imputed by the unscheduled visit. 
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The assessments of the EW visit will be mapped to the nearest planned post-baseline visit with a 
missing assessment before or after the EW visit of the individual assessment for all statistical 
analyses and descriptive summaries. As not all assessments of the EW are performed at each visit, 
the different assessments of the EW can be assigned to different visits. If the duration (in days) 
between the EW visits and two missing planned visits are equal, then the assessment will be 
assigned to the later visit. 
9.6 
Study Period 
Study Periods 
The following study periods are defined: 
Treatment Period (i.e., Parent Study Period): see MAGNIFY MS IAP version 3.0 for definition. 
Course 1 Treatment Period: see MAGNIFY MS IAP version 3.0 for definition. 
Course 2 Treatment Period: see MAGNIFY MS IAP version 3.0 for definition. 
Gap Period:  
x Start = Visit end date of M24 Visit + 1  
x End = Extension Study Baseline Visit start date  
Year 3 Visit Period:  
x Start = Visit end date of M24 Visit + 1 
x End = Visit end date of M36 Visit 
Year 4 Visit Period:  
x Start = Visit end date of M36 Visit + 1 
x End = Visit end date of M48 Visit 
Year 3 Visit and Year 4 Visit Period (i.e., Extension Study Period): 
x Start = Visit end date of M24 Visit + 1 
x End = Visit end date of M48 Visit 
After start of study medication until end of Year 3 Visit Period: 
x Start = Start of study medication (see MAGNIFY MS IAP version 3.0 for definition) 
x End = Visit end date of M36 Visit 
After start of study medication until end of Year 4 Visit Period (i.e., Parent and Extension Study 
Period): 
x Start = Start of study medication (see MAGNIFY MS IAP version 3.0 for definition) 
x End = Visit end date of M48 Visit 
In case of missing M48 Visit or early discontinuation before an End of Period defined above, the 
Visit end date of EW Visit will be used to replace the corresponding End date, or the study 
discontinuation date will be used if the EW visit was not performed.  
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In case of missing M36 Visit, the Visit end date of M36 Visit in the above definitions (including 
Start and End) will be replaced by MAGNIFY MS M24 Visit date + 480 days (which is obtained 
by 360 (12 months) + 90 (3 months delay allowed for FAS) + 30 (Visit window)), or the Visit end 
date of EW Visit if earlier, or date of discontinuation if earlier and the EW Visit was not performed. 
Study Periods for MRI Assessments 
The MRI scans in the parent study were reconciled during central MRI review process. Therefore, 
MRIs were considered as Baseline MRIs if assigned to the Baseline Visit by the central imaging 
review. 
The following study periods for MRI assessments are defined as per MAGNIFY MS IAP version 
3.0 with extension to Month 36 Visit and Month 48 Visit MRI scans: 
Baseline Period (p0): The Baseline Period is defined as the Period between the Screening and the 
Baseline MRI scan in MAGNIFY MS trial. 
Post-Baseline Periods (ppost-Baseline): 
Yearly Periods: 
Period 12.1 (p12.1) is defined as the Period between Baseline to Month 12 MRI scans, 
Period 12.2 (p12.2) is defined as the Period between Month 12 to Month 24 MRI scans, 
Period 12.3 (p12.3) is defined as the Period between Month 24 to Month 36 MRI scans, 
Period 12.4 (p12.4) is defined as the Period between Month 36 to Month 48 MRI scans. 
2-Year Period: 
Period 24.1 (p24.1) is defined as the Period between Baseline to Month 24 MRI scans. 
3-Year Period: 
Period 36.1 (p36.1) is defined as the Period between Baseline to Month 36 MRI scans. 
4-Year Period: 
Period 48.1 (p48.1) is defined as the Period between Baseline to Month 48 MRI scans. 
Sequential Visit Periods: 
For p100.0, p100.1, p100.2, p100.3, p100.6, p100.12, p100.15, p100.18, p100.24, see Section 9 of MAGNIFY MS 
IAP version 3.0. 
Period 100.36 (p100.36) is defined as the Period between Month 24 to Month 36 (equivalent to p12.3) 
MRI scans. 
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Period 100.48 (p100.48) is defined as the Period between Month 36 to Month 48 (equivalent to p12.4) 
MRI scans. 
9.7 
Imputation of Missing Data  
Unless otherwise specified, all data will be evaluated as observed, and no imputation method for 
missing values will be used. 
In all participant data listings, imputed values will be presented, and imputed information will be 
flagged. 
Missing statistics, e.g., when they cannot be calculated, should be presented as “nd”. For example, 
if n=1, the measure of variability (SD) cannot be computed and should be presented as “nd”. 
Where tables are presented over time, the total number of participants with missing and non-
missing observations at each time point should reflect the complete population. 
Incomplete or missing start dates of DMDs reported during the Extension Study Period will be 
imputed as follows: 
x In cases where the start date is completely missing the start date will be replaced by M24 
Visit + 1 
x if start date is partially missing but the start month and year, or the start year are equal to 
the M24 Visit date then the onset date will be replaced by M24 Visit + 1. 
x In all other cases the missing onset day or missing onset month will be replaced by 1st day 
of the known month or 1st day of the known year. 
Incomplete or missing onset dates of relapses reported at Extension Study Baseline Visit (i.e., 
relapses experienced during gap period) will be imputed as follows: 
x In cases where the onset date is completely missing the onset date will be replaced by M24 
Visit + 1 
x if onset date is partially missing but the onset month and year, or the onset year are equal 
to the M24 Visit date then the onset date will be replaced by M24 Visit + 1. 
x In all other cases the missing onset day or missing onset month will be replaced by 1st day 
of the known month or 1st day of the known year. 
Incomplete or missing onset dates of relapses reported after Extension Study Baseline Visit will 
be imputed as follows: 
x In cases where the onset date is completely missing the onset date will be replaced by the 
Extension Study Baseline Visit date + 1. 
x if onset date is partially missing but the onset month and year, or the onset year are equal 
to the Extension Study Baseline Visit, then the onset date will be replaced by the Extension 
Study Baseline Visit date + 1. 
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x In all other cases the missing onset day or missing onset month will be replaced by 1st day 
of the known month or 1st day of the known year. 
Incomplete or missing onset dates of AE-associated dates during the Extension Study Period will 
be imputed as follows:  
x In case the onset date is missing completely or missing partially but the onset month and 
year, or the onset year are equal to the M24 Visit date then the onset date will be replaced 
by the M24 Visit + 1.  
x In all other cases the missing onset day or missing onset month will be replaced by 1st 
day of the known month or 1st day of the known year.  
x Incomplete stop dates will be replaced by the last day of the month (if day is missing 
only), if not resulting in a date later than the date of participant's death. In the latter case 
the date of death will be used to impute the incomplete stop date.  
x In all other cases the incomplete stop date will not be imputed.  
9.8 
Data Handling for MRI data 
MRI data will be integrated with MRI data from the MAGNIFY MS trial, which will be handled 
according to “Data Handling for MRI data – Data handling of Tertiary endpoints” in Section 9 of 
the MAGNIFY MS IAP version 3.0.  
The MRIs will be evaluated by independent central review. The assignment of MRIs to the 
respective Visits in the parent study was ensured by the central reading process, while this process 
is not adopted in the Extension Study. Therefore, the statistical analysis will be based on the MRI 
Visit assignments as provided by central reading for parent study data and MRI Visit assignments 
as reported in the eCRF for Extension Study data. A 6-months window will be allowed for the 
Extension Study MRI data. An MRI assessment will be excluded from all analyses if the absolute 
value of (MRI assessment date – Visit date) > 185 days (which is obtained by 180 [6 months] + 5 
[window allowed by protocol]).  
All derived lesion counts (except for the Mean T1 Gd+ lesion count) as specified below will be 
classified as Not Evaluable (NE) if one of the components required for the calculation has been 
classified as NE by the central reading. The Mean T1 Gd+ lesion count will be set to NE only, if 
all T1 Gd+ lesion counts that correspond to the respective Period are classified as NE. In all other 
cases the mean will be calculated based on the available counts during the respective Period. 
For definition of Period see Section 9.6 “Study Periods for MRI Assessments”. 
T1 Gd+ lesion count 
x The T1 Gd+ are defined as follow: T1 Gd+ lesion count (by Visit) = T1 Gd+ lesions count 
from the MRI at the respective Visit. 
x Mean T1 Gd+ lesion count (by Period) = sum of all T1 Gd+ lesion counts during the Period 
/ # of scans belonging to the respective Period with non-missing T1 Gd+ lesion count. 
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All MRI scans belonging to a Period are MRI scans that have been performed during the 
Period including start and end Visits. For post-Baseline periods starting at Baseline, the 
Baseline Visit will not be included. For example, Period 48.1 will include all MRI scans 
during both MAGNIFY MS trial and Extension Study except Screening and Baseline Visit. 
x New T1 Gd+ lesion count (by Period)  
o For Periods including up to Month 24 Visit, refer to “Data handling for MRI data: 
Data handling of Tertiary endpoints” in Section 9 of MAGNIFY MS IAP version 
3.0 
o For other Periods ending at Month 36 / Month 48 Visit, 
New T1 Gd+ lesion count = T1 Gd+ lesions count from the MRI at Month 36 / 
Month 48 Visit due to longer periods 
For example: New T1 Gd+ lesion count of the Period between Month 24 and 
Month 36 (p12.3) is equal to T1 Gd+ lesion count from the MRI at Month 36 
Visit. 
Active T2 lesion count  
As the active (i.e., the new or enlarging) T2 lesion count depends on the length of the Period, it 
will be presented as reported (non-standardized) and annualized (standardized to 1 years (365.25 
days)): 
x Period length (days) = MRI date at end of Period – MRI date at start of Period +1, 
x Annualized active T2 lesion count (by Period) = Total number of active T2 lesions per 
Period * 365.25/ Period length. 
The following types of T2 lesions are defined per Period (standardized and non-standardized):  
x Total new T2 lesion count =  
 
Total number of new T2 lesions with T1 Gd+  
 
+ Total number of new T2 lesions without T1 Gd+  
x Total enlarging T2 lesion count =  
 
Total number of enlarging T2 lesions with T1 Gd+  
 
+ Total number of enlarging T2 lesions without T1 Gd+ 
x Total active T2 lesion count =  
 
Total new T2 lesion count  
 
+ Total enlarging T2 lesion count  
Note: the number of new or enlarging T2 (with and without T1 Gd+) will be provided by central 
reading for each of the Periods including the Sequential Visit Periods. 
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9.9 
Data Handling in Case of PDs 
Protocol Deviations (PDs) in the Extension Study will not be considered in the planned statistical 
analyses (i.e., all data will be analyzed independent from any reported PD). Further details on a 
subset of protocol deviations are described in Section 10.2. 
9.10 
Covariates and Stratification Factors 
The following covariates are defined:  
Unless otherwise specified, these factors will be obtained from the baseline information of the 
MAGNIFY MS Baseline. 
Age 
See MAGNIFY MS IAP version 3.0. 
EDSS at Baseline 
see MAGNIFY MS IAP version 3.0. 
Pooled centers 
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Some centers will have few eligible participants only. Therefore, the centers will be pooled 
together by country except for  
x sites that have more than 12 participants in the FAS (i.e., these sites will not be pooled with 
any other site). 
Some countries will have few eligible participants only. Therefore, countries will be pooled as 
follows: 
o Scandinavia = Finland and Sweden 
o Mediterranean = Italy and Spain 
o France-UK = France and UK 
o Austria-Hungary-Czech = Austria, Hungary, and Czech Republic 
o Australia-Canada = Australia and Canada 
The following MRI specific covariate is defined: 
Time between scans: in Years 
Time between scans (in Years) is calculated as follows: 
x Time between scans (in Years) = (MRI date of the Visit - MRI of the previous Visit + 1) 
/365.25, i.e.: 
o If (Visit= Month 36) then Time between scans (in Years) = (MRI date at Month 36 
- MRI date at Month 24 + 1)/ 365.25 
o If (Visit= Month 48) then Time between scans (in Years) = (MRI date at Month 48 
- MRI date at Month 36 + 1)/ 365.25 
If the corresponding MRI is available and the time between scans is missing (due to preceding 
MRI being missing) it will be replaced by expected time as follows: 
x Month 36 Visit = 1 year 
x Month 48 Visit = 1 year 
For calculations for Month 1, 2, 3, 6, 12, 15, 18, 24 Visits, see MAGNIFY MS IAP version 3.0 
Section 9. 
9.11 
Definition of Start of COVID-19 Pandemic 
The start of COVID-19 pandemic will be defined by country as the earliest date of either the date 
of the first death from COVID-19 occurred in each country according to the published data by 
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European 
Center 
for 
Disease 
Prevention 
and 
Control 
on 
26th 
June 
2020 
(https:/www.ecdc.europa.eu/en/publications-data/download-todays-data-geographic-distribution-
covid-19-cases-worldwide) or 11th March 2020 (when the WHO declared COVID-19 pandemic). 
9.12 
Visit timing with respect to COVID-19 pandemic 
A visit is defined to be performed after the start of COVID-19 pandemic if the visit end date is 
greater than the start of COVID-19 pandemic date. 
10 
Study Participants  
The subsections in this section include specifications for reporting participant disposition and 
study intervention/study discontinuations. Additionally, procedures for reporting PDs are 
provided. 
10.1 
Disposition of Participants and Discontinuations  
This section describes participant disposition in the extension study.  
Participant disposition in this Extension Study will be presented for the ES: 
x Total number of participants enrolled in the MAGNIFY MS Extension Study (i.e., 
participants who gave informed consent for the Extension Study) 
x Number of participants who discontinued in the Screening phase by the main reason: 
o Subject did not meet all eligibility criteria 
o Withdrawal by subject 
o Progressive Disease 
o Adverse Event 
o Lost to Follow-up 
o Death 
o Other 
x Number of eligible participants in the Extension Study, overall and by the following 
categories: 
o Number and percentage of eligible participants enrolled before the start of COVID-
19 
o Number and percentage of eligible participants ongoing at data cut-off (applicable 
to IAs only) 
o Number and percentage of eligible participants who completed the study 
o Number and percentage of eligible participants who discontinued the study, with 
the primary reason of discontinuation: 
 Withdrawal by subject 
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 Progressive disease 
 Adverse event 
 Lost to follow-up 
 Death 
 Protocol non-compliance 
 Other 
The duration of gap period between MAGNIFY MS Trial and MAGNIFY Extension Study 
Baseline will be summarized using the following classes: 
o No gap (i.e., Month 24 Visit and Extension Baseline coincide) 
o Duration of gap period < 1 month 
o 'XUDWLRQRIJDSSHULRGPRQWKDQG 3 months 
o 'XUDWLRQRIJDSSHULRGPRQWKVDQG 6 months 
o 'XUDWLRQRIJDSSHULRGPRQWKVDQG 9 months  
o 'XUDWLRQRIJDSSHULRGPRQWKVDQG 12 months 
o Duration of gap period > 12 months 
Additionally, duration of gap period will be summarized using descriptive statistics. 
Percentages will be presented with respect to the number of eligible participants. 
The number of participants in each analysis set will be provided overall, by region, by country 
within region and by site. 
The following participant data listings will be provided: 
x Listing of discontinued participants for the FAS, 
x Listing of participants excluded from the Analysis Sets. 
 
10.2 
Protocol Deviations / Exclusion from Analysis Sets  
10.2.1 
Important Protocol Deviations  
Important protocol deviations (IPDs) are a subset of protocol deviations that might significantly 
affect the completeness, accuracy, and/or reliability of the study data or that might significantly 
affect a participant's rights, safety, or well-being. 
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Important protocol deviations will be identified for all participants by either site monitoring, 
medical review processes or programming and confirmed prior to or at the Data Review Meeting 
at the latest. 
Any IPD is documented in SDTM datasets whether identified through site monitoring, medical 
review or programming. The management of protocol deviations is outside of this IAP document.  
The following summary tables and listings of IPDs will be provided for the FAS:  
x Number and proportion of participants with IPDs by classification of IPDs (overall and 
based on relationship to COVID-19 pandemic),  
x Listing of IPDs (including information regarding relationship to COVID-19 pandemic). 
10.2.2 
Reasons Leading to the Exclusion from an Analysis Set  
A frequency table, as well as a listing, organized according to reasons for exclusion from the FAS 
and TCS, respectively, will be provided, if applicable.  
Possible reasons for exclusion from the FAS include: 
x Not fulfill any of the inclusion criteria 
o Participants of the MAGNIFY MS trial who received at least a single dose of 
cladribine tablets during the MAGNIFY MS trial 
o Data on MRI is available/acquired from at least parent study Month 18 or Month 
24 visit 
o Data on EDSS and relapse is available/acquired from parent study Month 24 visit 
o Capable of giving signed informed consent 
x Meet any of the exclusion criteria 
o Participant is considered by the Investigator, for any reason, to be an unsuitable 
candidate for the study 
o Participation in other studies/trials 
Possible reasons for exclusion from the TCS include: 
x Participants are not included in the FAS 
x Participants did not complete the full treatment course of the first and second year in the 
parent study 
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11 
Demographics and Other Baseline Characteristics  
If not stated otherwise, the following analyses will be performed based on the FAS. 
11.1 
Demographics  
Demographic characteristics will be summarized descriptively using the information from the 
Screening/Baseline Visit eCRF pages in the MAGNIFY MS trial. The data will be presented in a 
summary table as well as a listing as specified in MAGNIFY MS IAP version 3.0. In addition, age 
at time of informed consent as collected from the “Demographics” eCRF page in the MAGNIFY 
MS Extension Study will be added in both the summary table and the listing. 
11.2 
Medical History  
The medical history will be summarized from the “Medical History” eCRF page of the MAGNIFY 
MS Extension Baseline, using the most recent Medical Dictionary for Regulatory Activities 
(MedDRA) version at time of database lock, preferred term (PT) as event category and system 
organ class (SOC) body term as Body System category. Each participant will be counted only once 
within each PT or SOC. 
Additionally, also the medical history from the “Medical History” eCRF page of the MAGNIFY 
MS Baseline, using the MedDRA version that has been applied for coding of Medical History in 
the parent study, will be summarized as well. 
Medical history will be displayed in terms of frequency tables: ordered by primary SOC and PT 
in alphabetical order. 
11.3 
Other Baseline Characteristics  
Other baseline characteristics at MAGNIFY MS Baseline, including MS Disease Characteristics, 
MRI Baseline Characteristics and Vital Signs, will be presented as specified in MAGNIFY MS 
IAP version 3.0.  
EDSS assessment at Extension Baseline Visit was performed for almost all participants, regardless 
of whether they had a gap period, and will be listed only. The EDSS scores of participants who 
had a gap period will still be considered for determining disease progression, as planned in the 
CSP. 
12 
Previous or Concomitant Therapies/Procedures  
Relevant previous medications at MAGNIFY MS Baseline will be summarized as specified in 
MAGNIFY MS IAP version 3.0.  
Concomitant medications are medications, other than study medications, which are taken by 
participants after the initial dose of cladribine tablets (including the study period of the MAGNIFY 
MS trial and the Extension Study which is including the gap period between the MAGNIFY MS 
trial and MAGNIFY MS Extension Study). 
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Concomitant medications will be summarized separately for the study period of the MAGNIFY 
MS trial and the Extension Study Period. 
Data will be used from the “Concomitant medication” eCRF page of the MAGNIFY MS trial and 
the Extension Study. All medications entered into the “Concomitant medication” eCRF page will 
be assumed to be “concomitant” irrespective of the actual start and end dates. 
Anatomical Therapeutic Chemical classification (ATC)-1st level and PT will be tabulated as given 
from the World Health Organization Drug Dictionary (WHO-DD) dictionary. In case multiple 
ATCs are assigned to a drug, all ATC-1st level will be used for reporting. 
The most current WHO-DD dictionary version at time of MAGNIFY Extension Study analysis 
data base lock will be used only for MAGNIFY MS Extension Study. For MAGNIFY MS parent 
study, the version of that has been used for coding of concomitant medications will apply. The 
WHO-DD dictionary used for coding will be listed as a footnote of corresponding table or listing.  
Additionally, all DMDs which have been reported for the study period of the MAGNIFY MS trial 
and the MAGNIFY MS Extension Study will be presented together by PT. The updated list of 
DMDs (see Appendix 18.1) will be used to identify DMD in concomitant medications in 
MAGNIFY MS Extension Study instead of the parent study DMD list (see MAGNIFY MS IAP 
version 3.0). List could further be updated before database lock. 
Concomitant procedures which were undertaken any time during the Extension Study Period 
will be listed by participant for the SAF. 
13 
Study Intervention: Compliance and Exposure  
As no treatment is provided in the Extension Study, participants’ compliance and exposure in the 
MAGNIFY MS trial will be presented for the Extension Study SAF as defined in MAGNIFY MS 
IAP version 3.0. 
14 
Efficacy Analyses  
The following analyses will be performed based on the FAS except when otherwise stated. 
For the detailed definition of covariates and stratification factors that are used in the statistical 
models see Section 9.10. Details about the derived MRI endpoints and general handling of MRI 
data is described in Section 9.8.  
Descriptive summary statistics will be presented for the absolute values and the changes from 
Baseline as applicable by Visit [Protocol Scheduled Visits except for Baseline (defined in Section 
9.1)] for all efficacy endpoints (and the components, where applicable) for the FAS and respective 
subgroups for which the variables are analyzed. Details about the presentation of continuous and 
categorical variables are given in Section 9. 
Wherever possible, all estimated results from the statistical models will be calculated with the 
same observed margin which reflects the population of the whole corresponding analysis set, 
regardless of missing data (as described in MAGNIFY MS IAP version 3.0). 
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14.1 
Primary Endpoint: Proportion of participants with No 
Evidence of Disease Activity (three parameter [NEDA-3]) 
during Year 3 Visit and Year 4 Visit Period after the initial 
dose of cladribine tablets 
The primary endpoint for the Extension Study is defined as the proportion of participants with 
NEDA-3 during Year 3 Visit and Year 4 Visit Period after the initial dose of cladribine tablets, 
i.e., NEDA-3 during the following period will be evaluated: 
x Year 3 Visit and Year 4 Visit Period (i.e., Extension Study Period) 
For the detailed definition of Periods, see Section 9.6. 
14.1.1 
Primary Objective: Derivation and analysis of the primary 
endpoint 
No Evidence of Disease activity (NEDA), also referred to as freedom from disease activity, is a 
new goal that is emerging in MS treatment. NEDA is a composite measure of disease activity, 
including relapses, cognition and disability progression, and MRI activity. 
NEDA-3 during the Extension Study Period is defined as absence of the following three events 
during the Period: 
x Qualifying Relapses 
x 6-months Confirmed Disability Progression (6MCDP, see definition below) 
x MRI Activity (i.e., presence of T1 Gd+ lesions and/or active T2 lesions) 
NEDA-3 will be analyzed with the Kaplan-Meier (KM) time-to-event method to reduce the impact 
of unknown/missing information.  
The start date will be the end date of M24 Visit + 1. 
The event date will be defined as the minimum of  
x the onset date of the first qualifying relapses during the Extension Study Period 
x the start date of the first 6MCDP during the Extension Study Period (see definition below) 
x the scan date of the first MRI during the Extension Study Period where at least one T1 Gd+ 
lesion or at least one active T2 lesion (see Section 9.8 for definition) is identified.  
Imputation of partial onset dates of relapses is described in Section 9.7. Since full dates of MRI 
scan and EDSS assessment are mandatory, partial dates of 6MCDP, or MRI Activity are not 
expected. 
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If the participant did not experience any of the three events described above during the Extension 
Study Period, the minimum of the scan date of the last available MRI, the assessment date of the 
last available EDSS, and the Extension Study completion/discontinuation date will be used as the 
censoring date. 
The time to disease activity (in months) will be calculated as [event date or censoring date as 
applicable – start date + 1]/30.4375. The number of participants at risk, failed, and survival rate 
(i.e., the proportion of participants with NEDA-3) along with the 95% CI will be estimated as per 
the KM method and reported at 6-months intervals. The KM survival curve will be plotted as well. 
A descriptive summary of number and proportion of participants with event (overall and by type 
of event, i.e., qualifying relapse, 6MCDP, or MRI activity as the earliest event) and censored will 
be also presented.  
6MCDP 
The 6MCDP during Extension Study Period is defined as sustained increase in EDSS score that 
started during the Period. A Sustained Increase in EDSS score is defined by an increase of: 
x at least 1.5 points if the Baseline EDSS score was 0, or 
x at least 1 point if Baseline EDSS score was between 0.5 and 4.5 inclusively, or 
x at least 0.5 point if the Baseline EDSS score was at least 5, 
that occurs over a 6-months’ time-period. 
The increase will be defined as sustained when it occurs on two post-Baseline Visits during the 
Extension Study Period that are at least 166 days apart (to be consistent with the parent study 
minimum visit gap) and no observations at any other visits (including unscheduled visits) in 
between are less than the defined increase. The assessment date of the earlier of the two EDSS 
assessments with the defined increase will be defined as the start date of 6MCDP. 
For descriptive summaries the following rules will be defined: 
Qualifying Relapse 
x Yes: any qualifying relapse reported during the Extension Study Period, 
x No: Extension study period completed, and no qualifying relapse reported during the 
Extension Study Period, 
x Unknown: otherwise. 
6MCDP 
x Yes: sustained increase in EDSS score that started during the Extension Study Period, 
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x No: at least 2 post-Baseline EDSS assessments that are 166 (or more) apart and no 
sustained EDSS progression that started during the Extension Study Period, 
x Unknown: Otherwise. 
MRI activity 
x Yes: any T1-Gd+ or active T2 observed during the Extension Study Period, 
x No: at least one post-Baseline MRI and no T1-Gd+ or active T2 observed during the 
Extension Study Period, 
x Unknown: otherwise. 
 
Analysis 
(Analysis 
Set) 
Derivation 
Statistical Analysis 
Methods 
 Missing data handling 
Primary endpoint: Proportion of participants with NEDA-3 during Year 3 Visit and Year 4 Visit Period after 
the initial dose of cladribine tablets 
Primary 
(FAS) 
 
Time to event: [event date or 
censoring date as applicable 
– start date + 1]/30.4375 
KM time-to-event: 
The number of participants at 
risk, failed, and survival rate 
(i.e., the proportion of 
participants with NEDA-3) 
along with the 95% CI will be 
estimated as per the KM 
method and reported at 6-
months intervals. The KM 
survival curve will be plotted 
as well. 
Imputation for partial dates is 
described in Section 9.7. 
 
Participants experienced no event 
will be censored as defined above 
(minimum of the scan date of the 
last available MRI scan, the 
assessment date of the last 
available EDSS, and the study 
completion/discontinuation date). 
 
14.1.2 
Primary Objective: Sensitivity Analyses of the Primary 
Endpoints 
The robustness of the results of the primary analysis will be evaluated by the following: 
x The primary analysis will be repeated on the TCS 
x The primary analysis will be repeated by subgroup “Previous treatment with DMDs” on 
the FAS. 
 
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Analysis 
(Analysis 
Set) 
Derivation 
Statistical Analysis Methods 
 Missing data handling 
Primary endpoint: Proportion of participants with NEDA-3 during Year 3 Visit and Year 4 Visit Period after 
the initial dose of cladribine tablets 
Sensitivity 
(TCS) 
Same as in the Primary 
Analysis (see Section 14.1.1) 
Same as in the Primary Analysis 
(see Section 14.1.1) 
Same as in the Primary 
Analysis (see Section 14.1.1) 
Sensitivity 
(FAS by 
subgroup 
“Previous 
treatment 
with DMDs”) 
Same as in the Primary 
Analysis (see Section 14.1.1) 
Same as in the Primary Analysis 
(see Section 14.1.1) with KM 
estimates reported by subgroup. 
Same as in the Primary 
Analysis (see Section 14.1.1) 
Sensitivity 
(FAS) 
Crude percentages and time to 
event with descriptive 
summaries for qualifying 
relapse, 6MCDP, or MRI 
activity and NEDA 
A descriptive summary of 
number and proportion of 
participants with event  
A descriptive summary of time to 
earliest event (overall and by 
type of event, i.e., qualifying 
relapse, 6MCDP, or MRI 
activity). 
Missings will be presented in 
a separate category 
14.2 
Secondary Endpoints  
14.2.1 
No Evidence of Disease Activity 
As a secondary analysis, NEDA-3 during the following Periods (see definition in Section 9.6) will 
be analyzed similarly as in the primary analysis using the KM method: 
Year 3 Visit Period 
x Start date: end date of M24 Visit (see definition in Section 14.1.1) + 1 
x Event date: same as in Section 14.1.1 accounting for events started during Year 3 Visit 
Period only 
x Censoring date: the minimum of the scan date of the last available MRI during Year 3 Visit 
Period, the assessment date of the last available EDSS during Year 3 Visit Period, and the 
end date of Year 3 Visit Period (see definition in Section 9.6) 
Year 4 Visit Period 
x Start date: end date of M36 Visit  + 1  
x Event date: same as in Section 14.1.1 accounting for events started during Year 4 Visit 
Period only 
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x Censoring date: the minimum of the scan date of the last available MRI during Year 4 Visit 
Period, the assessment date of the last available EDSS during Year 4 Visit Period, and the 
Extension Study completion/discontinuation date 
After start of study medication until end of Year 3 Visit Period 
x Start date: date of Day 1 as defined in Section 9.5 
x Event date: The event date will be defined as the minimum of  
o the onset date of the first qualifying relapses during the Parent and Extension Study 
Period 
o the start date of the first 6MCDP during the Parent and Extension Study Period 
o the scan date of the first MRI during the Parent and Extension Study Period where 
at least one T1 Gd+ lesion or at least one active T2 lesion (see Section 9.8 for 
definition) is identified, 
accounting for events started during “After start of study medication until end of Year 3 
Visit Period” only. 
x Censoring date: the minimum of the scan date of the last available MRI during “After start 
of study medication until end of Year 3 Visit Period”, the assessment date of the last 
available EDSS during “After start of study medication until end of Year 3 Visit Period”, 
and the end date of “After start of study medication until end of Year 3 Visit Period” (see 
definition in Section 9.6) 
After start of study medication until end of Year 4 Visit Period (i.e. Parent and Extension 
Study Period) 
x Start date: date of Day 1 as defined in Section 9.5 
x Event date: same as for “After start of study medication until end of Year 3 Visit Period” 
accounting for events started during “After start of study medication until end of Year 4 
Visit Period” 
x Censoring date: the minimum of the scan date of the last available MRI during “After start 
of study medication until end of Year 4 Visit Period”, the assessment date of the last 
available EDSS during “After start of study medication until end of Year 4 Visit Period”, 
and the Extension Study completion/discontinuation date 
Year 3 Visit Period (or Year 4 Visit Period) among participants with NEDA-3 during Course 
1 Treatment Period (or Course 2 Treatment Period)  
Analysis of NEDA-3 during the Year 3 Visit Period and analysis of NEDA-3 during the Year 4 
Visit Period as defined above will be repeated, respectively, on the subset of participants with 
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NEDA-3 during Course 1 Treatment Period and on the subset of participants with NEDA-3 during 
Course 2 Treatment Period. 
NEDA-3 during Course 1 Treatment Period is defined similarly as in Section 14.3.12 of 
MAGNIFY MS IAP version 3.0 with just Treatment Period replaced by Course 1 Treatment Period 
and the following definition for MRI activity: 
x Yes: At least one T1 Gd+ at any scan assigned to Month 6, Month 12 Visit, or at least one 
active T2 during any of the following Periods: Baseline - Month 6, Month 6 - Month 12. 
x No: T1 Gd+ = 0 at all scans assigned to Month 6, Month 12 Visit that have a value and at 
least one T1 Gd+ value from Month 6 or Month 12 Visit is available, and all active T2 = 0 
during any of the following Periods: Baseline - Month 6, Month 6 - Month 12 that have a 
value and at least one active T2 value from Periods Baseline – Month 6 or Month 6 – Month 
12 is available. 
x Unknown: Otherwise. 
NEDA-3 during Course 2 Treatment Period is defined similarly as in Section 14.3.12 of 
MAGNIFY MS IAP version 3.0 with just Treatment Period replaced by Course 2 Treatment Period 
and the following definition for MRI activity: 
x Yes: At least one T1 Gd+ at any scan assigned to Month 18, Month 24 Visit, or at least one 
active T2 during any of the following Periods: Month 12 - Month 18, Month 18 - Month 
24. 
x No: T1 Gd+ = 0 at all scans assigned to Month 18, Month 24 Visit that have a value and at 
least one T1 Gd+ value from Month 18 or Month 24 Visit is available, and all active T2 = 
0 during any of the following Periods: Month 12 - Month 18, Month 18 - Month 24 that 
have a value and at least one active T2 value from Periods Month 12 - Month 18, Month 
18 - Month 24 is available. 
x Unknown: Otherwise. 
 
Analysis 
(Analysis Set) 
Derivation 
Statistical Analysis 
Methods 
 Missing data handling 
Secondary endpoint: Proportion of participants with NEDA-3 during Year 3 Visit Period 
Secondary 
(FAS) 
 
Time to event: [event date or 
censoring date as applicable – 
start date + 1]/30.4375 for 
NEDA-3 events started during 
the Year 3 Visit Period 
 
Same as in the primary 
analysis (see Section 14.1.1 
and for subgroup analysis 
see Section 14.1.2)  
Same as in the primary 
analysis (see Section 14.1.1) 
Secondary 
(FAS by 
subgroup 
“Previous 
treatment with 
DMDs”) 
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Analysis 
(Analysis Set) 
Derivation 
Statistical Analysis 
Methods 
 Missing data handling 
Secondary 
(FAS for 
subset 
“participants 
with NEDA-3 
during Course 
1 Treatment 
Period”) 
Secondary 
(FAS for 
subset 
“participants 
with NEDA-3 
during Course 
2 Treatment 
Period”) 
Secondary endpoint: Proportion of participants with NEDA-3 during Year 4 Visit Period 
Secondary 
(FAS) 
 
Time to event: [event date or 
censoring date as applicable – 
start date + 1]/30.4375 for 
NEDA-3 events started during 
the Year 4 Visit Period 
 
Same as in the primary 
analysis (see Section 14.1.1 
and for subgroup analysis 
see Section 14.1.2) 
Same as in the primary 
analysis (see Section 14.1.1) 
Secondary 
(FAS by 
subgroup 
“Previous 
treatment with 
DMDs”) 
Secondary 
(FAS for 
subset 
“participants 
with NEDA-3 
during Course 
1 Treatment 
Period”) 
Secondary 
(FAS for 
subset 
“participants 
with NEDA-3 
during Course 
2 Treatment 
Period”) 
Secondary endpoint: Proportion of participants with NEDA-3 during “After start of study medication until 
end of Year 3 Visit Period” 
Secondary 
(FAS) 
 
Same as in the primary 
analysis (see Section 14.1.1) 
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Analysis 
(Analysis Set) 
Derivation 
Statistical Analysis 
Methods 
 Missing data handling 
Secondary 
(FAS by 
subgroup 
“Previous 
treatment with 
DMDs”) 
Time to event: [event date or 
censoring date as applicable – 
start date + 1]/30.4375 for 
NEDA-3 events started during 
the “After start of study 
medication until end of Year 3 
Visit Period” 
Same as in the primary 
analysis (see Section 14.1.1 
and for subgroup analysis 
see Section 14.1.2) 
Secondary 
(FAS) 
Crude percentages and time to 
event with descriptive 
summaries for qualifying 
relapse, 6MCDP, or MRI 
activity and NEDA 
A descriptive summary of 
number and proportion of 
participants with event  
A descriptive summary of 
time to earliest event (overall 
and by type of event, i.e., 
qualifying relapse, 6MCDP, 
or MRI activity). 
Missings will be presented in a 
separate category 
Secondary endpoint: Proportion of participants with NEDA-3 during “After start of study medication until 
end of Year 4 Visit Period” 
Secondary 
(FAS) 
 
Time to event: [event date or 
censoring date as applicable – 
start date + 1]/30.4375 for 
NEDA-3 events started during 
the “After start of study 
medication until end of Year 4 
Visit Period” 
Same as in the primary 
analysis (see Section 14.1.1 
and for subgroup analysis 
see Section 14.1.2) 
Same as in the primary 
analysis (see Section 14.1.1) 
Secondary 
(FAS by 
subgroup 
“Previous 
treatment with 
DMDs”) 
Secondary 
(FAS) 
Crude percentages and time to 
event with descriptive 
summaries for qualifying 
relapse, 6MCDP, or MRI 
activity and NEDA 
A descriptive summary of 
number and proportion of 
participants with event  
A descriptive summary of 
time to earliest event (overall 
and by type of event, i.e., 
qualifying relapse, 6MCDP, 
or MRI activity). 
Missings will be presented in a 
separate category 
14.2.2 
Time to First Disease Activity 
Time to first disease activity is defined as the time to first occurrence of either qualifying relapse, 
or 6MCDP, or new or enlarging T2-hyperintense lesions (active T2 lesions), or new T1 Gd+ 
lesions. This will be evaluated for the following Periods with corresponding start dates defined 
below: 
x Extension Study Period 
o Start date for time to first disease activity: end date of M24 Visit + 1 (as defined in 
Section 14.1.1) 
x Parent and Extension Study Period 
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o Start date for time to first disease activity: date of Day 1 (as defined in Section 9.5) 
Since events described above are the same events as in NEDA-3 definition, the event date will be 
defined the same as in Sections 14.1.1 or 14.2.1, accounting for only events started during the 
above Periods, respectively. If the participant did not experience any disease event during a Period, 
the minimum of the scan date of the last available MRI during this Period, the assessment date of 
the last available EDSS during this Period, and the Extension Study completion/discontinuation 
date will be used as the censoring date. 
Time to first disease activity (in months) will be calculated as [event date or censoring date as 
applicable – start date of the Period + 1]/30.4375 and the 5%, 10%, 15%, 25% percentile and 
median time to first disease activity will be estimated using the KM method along with the 95% 
CI. 
 
Analysis 
(Analysis 
Set) 
Derivation 
Statistical Analysis Methods 
 Missing data handling 
Secondary endpoint: Time from M24 Visit to first disease activity 
Secondary 
(FAS) 
 
Time to event: [event date or 
censoring date as applicable 
– start date + 1]/30.4375 for 
disease activities started 
during Extension Study 
Period 
KM time-to-event: 
5%, 10%, 15%, 25% percentiles 
and Median time to disease 
activity will be estimated as per 
the KM method and reported 
along with the corresponding 95% 
CI. 
Same as Section 14.1.1 
Secondary 
(FAS by 
subgroup 
“Previous 
treatment 
with DMDs”) 
Same as above 
Same as above with KM estimates 
reported by subgroup. 
Same as Section 14.1.1 
Secondary endpoint: Time from initial dose of cladribine tablets to first disease activity 
Secondary 
(FAS) 
 
Time to event: [event date or 
censoring date as applicable 
– start date + 1]/30.4375 for 
disease activities started 
during Parent and Extension 
Study Period 
Same as above. 
Same as above. 
 
Secondary 
(FAS by 
subgroup 
“Previous 
treatment 
with DMDs”) 
 
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14.2.3 
Time to MRI Activities, 6MCDP, Qualifying Relapse and 
Treatment Start with Other DMDs 
Time (in months) from the initial dose of cladribine tablets (i.e. start date = date of Day 1 as defined 
in Section 9.5) to the following events will be calculated as [event date or censoring date as 
applicable – start date + 1]/30.4375, and analyzed similarly as in Section 14.2.2 using the KM 
method. 
x first new or enlarging T2 lesion 
o Event date: the scan date of the first MRI during the Parent and Extension Study 
Period where at least one active T2 lesion (see Section 9.8 for definition) is 
identified 
o Censoring date: participants with no active T2 lesion identified at any scans during 
the Parent and Extension Study Period will be censored at the scan date of the last 
available MRI during this Period 
x first new T1 Gd+ lesion 
o Event date: the scan date of the first MRI during the Parent and Extension Study 
Period where at least one new T1 Gd+ lesion (see Section 9.8 for definition) is 
identified 
o Censoring date: participants with no new T1 Gd+ lesion identified at any scans 
during the Parent and Extension Study Period will be censored at the scan date of 
the last available MRI during this Period 
x first 6MCDP, as measured by EDSS 
o Event date: the start date of the first 6MCDP during the Parent and Extension Study 
Period 
6MCDP during the Parent and Extension Study Period will be defined similarly as 
in Section 14.1.1 with just Extension Study Period replaced by Parent and 
Extension Study Period. 
o Censoring date: participants with no 6MCDP started during the Parent and 
Extension Study Period will be censored at the assessment date of the last available 
EDSS during this Period 
x first qualifying relapse 
o Event date: the onset date of the first qualifying relapse during the Parent and 
Extension Study Period 
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o Censoring date: participants with no qualifying relapse reported during the Parent 
and Extension Study Period will be censored at the Extension Study 
completion/discontinuation date 
Time (in months) from M24 Visit (i.e. start date = end date of M24 Visit + 1) to the following 
events will be calculated as (event date or censoring date as applicable – start date + 1)/30.4375, 
and analyzed similarly as in Section 14.2.2 using the KM method. 
x first new or enlarging T2 lesion 
o Event date: the scan date of the first MRI during the Extension Study Period where 
at least one active T2 lesion (see Section 9.8 for definition) is identified 
o Censoring date: participants with no active T2 lesion identified at any scans during 
the Extension Study Period will be censored at the scan date of the last available 
MRI during this Period 
x first new T1 Gd+ lesion 
o Event date: the scan date of the first MRI during the Extension Study Period where 
at least one new T1 Gd+ lesion (see Section 9.8 for definition) is identified 
o Censoring date: participants with no new T1 Gd+ lesion identified at any scans 
during the Extension Study Period will be censored at the scan date of the last 
available MRI during this Period 
x first 6MCDP, as measured by EDSS 
o Event date: the start date of the first 6MCDP during the Extension Study Period 
(see definition in Section 14.1.1) 
o Censoring date: participants with no 6MCDP started during the Extension Study 
Period will be censored at the assessment date of the last available EDSS during 
this Period 
x first qualifying relapse 
o Event date: the onset date of the first qualifying relapse during the Extension Study 
Period 
o Censoring date: participants with no qualifying relapse reported during the 
Extension 
Study 
Period 
will 
be 
censored 
at 
the 
Extension 
Study 
completion/discontinuation date 
x treatment start with other DMDs 
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o Event date: the start date of the first other DMDs used during the Extension Study 
Period 
o Censoring date: participants who did not use any other DMDs during the Extension 
Study Period will be censored at the Extension Study completion/discontinuation 
date 
A recurrent event analysis will be performed on all qualifying relapses using the Mean Cumulative 
Function (MCF) method, where MCF(t) represents the mean cumulative number of relapses up to 
time t. The MCF estimate for recurrent events will be calculated and plotted for all qualifying 
relapses. The MCF Nelson estimates will be presented for every month along with their 95% CIs. 
The increase in MCF in each month, defined as MCF(t) - MCF(t-1) will also be displayed. 
Time (in months) from the initial dose of cladribine tablets (i.e. start date = date of Day 1 as defined 
in Section 9.5) to each event and to censoring (as defined below) will be calculated as [event date 
or censoring date – start date + 1]/30.4375, and analyzed using the MCF method. 
x recurrent qualifying relapse 
o Event date: the onset date of each qualifying relapse during the Parent and 
Extension Study Period 
o Censoring date: all participants with no qualifying relapse reported during the 
Parent and Extension Study Period will be censored at the Extension Study 
completion/discontinuation date 
Time (in months) from M24 Visit (i.e. start date = end date of M24 Visit + 1) to each event and to 
censoring (as defined below) will be calculated as [event date or censoring date – start date + 
1]/30.4375, and analyzed using the MCF method. 
x recurrent qualifying relapse 
o Event date: the onset date of each qualifying relapse during the Extension Study 
Period 
o Censoring date: all participants with no qualifying relapse reported during the 
Extension 
Study 
Period 
will 
be 
censored 
at 
the 
Extension 
Study 
completion/discontinuation date 
 
Analysis 
(Analysis 
Set) 
Derivation 
Statistical Analysis Methods 
 Missing data handling 
Secondary endpoint: Time from the initial dose of cladribine tablets to MRI activities, 6MCDP, and 
qualifying relapse 
Secondary 
(FAS) 
Same as in Section 14.2.2 
 
Same as in Section 14.2.2 
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Analysis 
(Analysis 
Set) 
Derivation 
Statistical Analysis Methods 
 Missing data handling 
 
Time to event: [event date or 
censoring date as applicable – 
start date + 1]/30.4375 for first 
active T2 lesion identified during 
the Parent and Extension Study 
Period 
Secondary 
(FAS by 
subgroup 
“Previous 
treatment 
with 
DMDs”) 
Secondary 
(FAS) 
 
Time to event: [event date or 
censoring date as applicable – 
start date + 1]/30.4375 for first T1 
Gd+ lesion identified during the 
Parent and Extension Study 
Period 
Secondary 
(FAS by 
subgroup 
“Previous 
treatment 
with 
DMDs”) 
Secondary 
(FAS) 
 
Time to event: [event date or 
censoring date as applicable – 
start date + 1]/30.4375 for first 
6MCDP started during the Parent 
and Extension Study Period 
Secondary 
(FAS by 
subgroup 
“Previous 
treatment 
with 
DMDs”) 
Secondary 
(FAS) 
 
Time to event: [event date or 
censoring date as applicable – 
start date + 1]/30.4375 for first 
qualifying relapse reported during 
the Parent and Extension Study 
Period 
Secondary 
(FAS by 
subgroup 
“Previous 
treatment 
with 
DMDs”) 
Secondary 
(FAS) 
 
Same as Section 14.2.2 
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Analysis 
(Analysis 
Set) 
Derivation 
Statistical Analysis Methods 
 Missing data handling 
Secondary 
(FAS by 
subgroup 
“Previous 
treatment 
with 
DMDs”) 
Time to event:  
[event date – start date + 
1]/30.4375 for each qualifying 
relapse reported during the Parent 
and Extension Study Period 
and 
[censoring date – start date + 
1]/30.4375 with censoring at 
Extension Study 
completion/discontinuation date 
for all participants 
The MCF estimate for 
recurrent events will be 
calculated and plotted for all 
qualifying relapses. The MCF 
Nelson estimates will be 
presented for every month 
along with their 95% CIs. The 
increase in MCF in each 
month, defined as MCF(t) - 
MCF(t-1) will also be 
displayed. 
Secondary endpoint: Time from M24 Visit to MRI activities, 6MCDP, qualifying relapse, and treatment start 
with other DMDs 
Secondary 
(FAS) 
 
Time to event: [event date or 
censoring date as applicable – 
start date + 1]/30.4375 for first 
active T2 lesion identified during 
the Extension Study Period 
Same as in Section 14.2.2 
 
Same as in Section 14.2.2 
Secondary 
(FAS by 
subgroup 
“Previous 
treatment 
with 
DMDs”) 
Secondary 
(FAS) 
 
Time to event: [event date or 
censoring date as applicable – 
start date + 1]/30.4375 for first T1 
Gd+ lesion identified during the 
Extension Study Period 
Secondary 
(FAS by 
subgroup 
“Previous 
treatment 
with 
DMDs”) 
Secondary 
(FAS) 
 
Time to event: [event date or 
censoring date as applicable – 
start date + 1]/30.4375 for first 
6MCDP started during the 
Extension Study Period 
Secondary 
(FAS by 
subgroup 
“Previous 
treatment 
with 
DMDs”) 
Secondary 
(FAS) 
 
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Analysis 
(Analysis 
Set) 
Derivation 
Statistical Analysis Methods 
 Missing data handling 
Secondary 
(FAS by 
subgroup 
“Previous 
treatment 
with 
DMDs”) 
Time to event: [event date or 
censoring date as applicable – 
start date + 1]/30.4375 for first 
qualifying relapse reported during 
the Parent and Extension Study 
Period 
Secondary 
(FAS) 
 
Time to event: [event date or 
censoring date as applicable – 
start date + 1]/30.4375 for other 
DMDs started during the 
Extension Study Period 
Secondary 
(FAS by 
subgroup 
“Previous 
treatment 
with 
DMDs”) 
Secondary 
(FAS) 
 
Time to event:  
[event date – start date + 
1]/30.4375 for each qualifying 
relapse reported during the 
Extension Study Period 
and 
[censoring date – start date + 
1]/30.4375 with censoring at 
Extension Study 
completion/discontinuation date 
for all participants 
The MCF estimate for 
recurrent events will be 
calculated and plotted for all 
qualifying relapses. The MCF 
Nelson estimates will be 
presented for every month 
along with their 95% CIs. The 
increase in MCF in each 
month, defined as MCF(t) - 
MCF(t-1) will also be 
displayed. 
Same as Section 14.2.2 
Secondary 
(FAS by 
subgroup 
“Previous 
treatment 
with 
DMDs”) 
 
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15 
Safety Analyses  
This section includes specifications for summarizing safety endpoints that are common across 
clinical studies such as adverse events, laboratory tests and vital signs. 
Safety analyses will be done on the SAF and reflect data collected during the Extension Study 
Period. 
15.1 
Adverse Events  
The definition of AE has been described in Appendix 7 of the CSP. All analyses described in this 
Section will be based on reported AEs during the Extension Study Period.  
SAEs and events of lymphopenia (also if not serious) with an onset date prior to the MAGNIFY 
MS exit date and are ongoing on the MAGNIFY MS Extension enrollment date will be recorded 
on the “Medical History” CRF. A listing comprising all ongoing SAEs and events of lymphopenia 
(also if not serious) from the MAGNIFY MS trial will be presented.  
Each participant will be counted only once within each SOC or PT. If a participant experiences 
more than one AE within a SOC or PT for the same summary period, only the AE with the 
strongest relationship or the worst severity, as appropriate, will be included in the summaries of 
relationship and severity.  
Incomplete AE-associated dates will be imputed as described in Section 9.7. 
15.1.1 
All Adverse Events  
All AEs reported during the Extension Study Period will be summarized using MedDRA (latest 
version available) PT as event category and MedDRA primary SOC body term as Body System 
category overall and by DMD subgroups as defined in Section 8.2. 
Unless otherwise stated, adverse events will be displayed in terms of frequency tables: PT and 
primary SOC in alphabetical order. 
Adverse events related to study treatment are those events with relationship missing, unknown or 
related. 
The following overall frequencies of participants with the corresponding AEs will be prepared. In 
addition, the tables will be provided by PT and primary SOC in alphabetical order: 
x Any AE, 
x Any study treatment related AEs, 
x Any serious AEs, 
x Any non-serious AEs,  
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x Any study treatment related serious AEs, 
x Any AE by severity (mild, moderate, severe), 
x Any study treatment related AE by severity (mild, moderate, severe), 
x Any AEs leading to death (AEs with outcome “fatal”), 
x Any study treatment related AEs leading to death (AEs with outcome “fatal”). 
x Any AEs leading to study discontinuation, 
x Any study treatment related AEs leading to study discontinuation. 
Summary table for non-SAEs applying frequency threshold of 5% will be provided by SOC and 
PT. 
Summary tables for serious and non-SAEs applying frequency threshold of 5% sorted by 
decreasing frequency will be provided by PT. 
All AEs by worst severity will be presented by SOC and PT. Missing severity will be presented in 
all severity groups. 
All AEs collected during the Extension Study Period will be listed by participant for the SAF. 
Exposure Adjusted Incidence Rate 
Exposure adjusted incidence rates (EAIR) are calculated as number of participants with AE 
divided by the total time at risk, which is defined as a sum of the individual times in years of all 
participants in the safety population from start of Extension Study Period to first onset of AE or 
end of the Extension Study Period, whichever occurs first.  
The exact Poisson 95% confidence intervals for the EAIR are calculated using the relationship 
between the Poisson and the Chi-square distribution (Ulm, 1990): 
ܮܥܫ=
߯ଶ௡,௔
ଶ
ଶ
2 × ݐ, 
ܷܥܫ=
߯ଶ(௡ାଵ),ଵି௔
ଶ
ଶ
2 × ݐ
, 
where t is the sum of the individual times in years of all participants and n is the number of 
participants with a specific AE for the EAIR, which will be the basis for the number of the degrees 
of freedom for the chi-VTXDUHTXDQWLOHIRUWKHXSSHUWDLOSUREDELOLW\Ȥ2.  
The incidence rate multiplied with 100 would give the number of AEs expected in 100 participants 
within 1 year. 
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EAIR of AEs will be presented overall, and by SOC and PT. 
The following table will be provided: 
x Exposure adjusted incidence rates of AEs by SOC and PT. 
15.1.2 
Adverse Events Leading to Discontinuation of Study 
Intervention  
Not applicable. 
15.2 
Deaths, Other Serious Adverse Events, and Other Significant 
Adverse Events  
15.2.1 
Deaths  
Any discontinuations due to death (see Section 10.1) and any AEs leading to death will be 
tabulated (see Section 15.1.1). 
A summary table of observed Deaths (from “Study Termination” eCRF page) will be provided 
together with AEs with fatal outcome by PT. 
15.2.2 
Serious Adverse Events  
The statistical analysis and reporting of SAEs are defined in Section 15.1.1. In addition, all SAEs 
will be listed. 
15.2.3 
Other Significant Adverse Events  
AEs associated to COVID-19  
The frequency of AEs associated to COVID-19 will be presented. The relevant events will be 
identified based on the SMQ COVID-19 (narrow scope) and will be presented by SOC and PT. 
A listing comprising all COVID-19 related AE terms will be presented. 
AEs associated to COVID-19 vaccines 
The frequency of AEs associated to COVID-19 vaccines will be presented. 
The safety profile of the investigational treatment and vaccine may overlap. Investigators are asked 
to provide all AEs with potential COVID-19 vaccine related causality AEs as part of information 
on “Causality factors other than study treatment” and to enter “COVID19 vaccination” as free text 
on the AEDT eCRF page. Per this classification a focused analysis will be possible for potential 
vaccination associated AEs. 
A listing comprising all COVID-19 vaccines related AE terms will be presented. 
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AEs associated to Lymphopenia 
The frequency of AEs associated to Lymphopenia will be presented. The relevant events will be 
identified based on the list of PTs in Appendix 18.3 and will be presented by SOC and PT. 
A listing comprising all Lymphopenia related AE terms will be presented.  
 
15.3 
Clinical Laboratory Evaluation  
Not applicable. 
15.4 
Vital Signs  
The maximum changes of vital sign measurements from MAGNIFY MS Baseline during 
Extension Study Period will be grouped as follows: 
Heart rate increase from baseline  
ESPESP 
d20 bpm, >20 – 40 bpm, >40 bpm 
Heart rate decrease from baseline  
ESPESP 
d20 bpm, >20 – 40 bpm, >40 bpm 
SBP increase from baseline  
PP+JPP+J 
d20 mmHg, >20 – 40 mmHg, >40 mmHg 
SBP decrease from baseline  
PP+JPP+J 
d20 mmHg, >20 – 40 mmHg, >40 mmHg 
DBP increase from baseline  
PP+JPP+J 
d20 mmHg, >20 – 40 mmHg, >40 mmHg 
DBP decrease from baseline  
PP+JPP+J 
d20 mmHg, >20 – 40 mmHg, >40 mmHg 
For each participant, the worst change during the Extension Study Period will be considered. 
Missing values will be presented as a separate category. 
The following summaries will be prepared for vital sign parameters as grouped above considering 
only participants with post-Baseline values: 
x Summary of Maximal Shifts (changes in categories), 
x Listing of highest change per participant. 
15.5 
Other Safety or Tolerability Evaluations  
The results of the physical examination will not be presented in any statistical analysis or listing. 
Abnormalities occurring, or worsening, during the study will be reported as AE. 
Pregnancies reported as AEs or SAEs will be listed for the SAF. 
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16 
Analyses of Other Endpoints  
16.1 
Baseline Characteristics Compared to Parent Study 
A comparison of participant baseline and background characteristics from population of the 
CLARIFY MS trial with population of the CLARIFY MS EXTENSION trial will be done by 
visual comparison. No special statistical analysis will be planned in this IAP. 
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17 
References  
Ulm, K. “A simple method to calculate the confidence interval of a standardized mortality ratio 
(SMR).” 
American 
journal 
of 
epidemiology 
vol. 
131,2 
(1990): 
373-5. 
doi:10.1093/oxfordjournals.aje.a115507  
Parmenter, Brett A. et al. “The utility of regression-based norms in interpreting the minimal 
assessment of cognitive function in multiple sclerosis (MACFIMS).” Journal of the International 
Neuropsychological Society: JINS vol. 16,1 (2010): 6-16. doi:10.1017/S1355617709990750  
Lipkovich, I., Ratitch, B., O'Kelly, M. “Sensitivity to censored-at-random assumption in the 
analysis of time-to-event endpoints.” Pharm Stat vol.15, 3 (2016): 216-29. doi:10.1002/pst.1738. 
Zhao, Y., Herring, A.H., Zhou, H., Ali, M.W., Koch, G.G. “A multiple imputation method for 
sensitivity analyses of time-to-event data with possibly informative censoring.” J Biopharm Stat 
vol. 24, 2 (2014): 229-53. doi:10.1080/10543406.2013.860769. 
Data Transfer Specification - MS700568_0157 - MRI-based endpoint values, Version 1.0, 02 April 
2022 (specification provided by SIENA imaging)  
 
 
Clinical Study Protocol, A 2-year extension study to evaluate long-term effectiveness of 
Mavenclad® in participants who have completed Trial MS700568_0022 (MAGNIFY MS); 
Version 1.0, 20 August 2020. 
Clinical Study Protocol, A 2-year prospective study to evaluate the onset of action of Mavenclad 
® in participants with highly active relapsing multiple sclerosis; Version 2.0, 12 February 2019. 
Integrated Analysis Plan, A 2-year prospective study to evaluate the onset of action of Mavenclad® 
in subjects with highly active relapsing multiple sclerosis; Version 3.0. 
 
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18 
Appendices  
18.1 
Appendix 1: List of DMDs for MAGNIFY MS Extension 
Study 
DMDs 
Preferred Term 
Alemtuzumab* (Campath, MabCampath, 
Lemtrada)  
ALEMTUZUMAB  
Cladribine (Mavenclad) 
CLADRIBINE 
Daclizumab* (Zinbryta)  
DACLIZUMAB  
Dimethyl fumarate (Tecfidera)  
DIMETHYL FUMARATE  
Diroximel fumarate (Vumerity) 
DIROXIMEL FUMARATE 
Fingolimod* (Gilenya)  
FINGOLIMOD  
FINGOLIMOD HYDROCHLORIDE  
Glatiramer Acetate (Copaxone)  
GLATIRAMER  
GLATIRAMER ACETATE  
Immunoglobulins  
IMMUNOGLOBULIN HUMAN NORMAL  
IMMUNOGLOBULINS  
IMMUNOGLOBULINS NOS  
Interferon beta (Avonex, Rebif, Betaferon, 
Extavia, Plegridy)  
INTERFERON  
INTERFERON BETA  
INTERFERON BETA-1A  
INTERFERON BETA-1B  
PEGINTERFERON  
PEGINTERFERON BETA-1A  
Mitoxantrone (Novantrone)  
MITOXANTRONE  
MITOXANTRONE HYDROCHLORIDE  
Natalizumab* (Tysabri)  
NATALIZUMAB  
Non-approved investigational DMDs* 
(monoclonal antibodies, antiS1PR, 
laquinimod etc)  
INVESTIGATIONAL DRUG  
LAQUINIMOD  
OPICINUMAB  
OTHER ANTINEOPLASTIC AGENTS  
 
Ocrelizumab* (Ocrevus)  
OCRELIZUMAB  
Ofatumumab (Kesimpta) 
OFATUMUMAB 
Off-label immunosuppressants 
(azathioprine, mycophenolate, 
cyclophosphamide)  
AZATHIOPRINE  
CYCLOPHOSPHAMIDE  
METHOTREXATE  
Ozanimod (Zeposia) 
OZANIMOD 
Ponesimod (Ponvory) 
PONESIMOD 
Rituximab 
RITUXIMAB 
Siponimod (Mayzent)* 
SIPONIMOD 
SIPONIMOD FUMARATE 
Teriflunomide (Aubagio) 
TERIFLUNOMIDE 
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Version 2.0 
 
 
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DMDs marked with a * are second line DMDs, which were not allowed as a previous 
medication in the parent study according to the study protocol. 
 
The list may be extended during medical review in case that new or other DMDs will be applied 
during the study.  
For categorization into DMD pre-treated group, the DMDs listed in MAGNIFY MS IAP V3.0 
was used. Participants who have taken any of the listed DMDs according to the “Relevant 
Previous Medication” eCRF page of the parent study Baseline visit will be categorized as DMD 
pre-treated. All other participants will be considered as pre-treatment naïve. 
 
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MS700568_0157  
Version 2.0 
 
 
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MS700568_0157  
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C O N F I D E N T I A L 
I N F O R M A T I O N 
85/86 
 
 
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I N F O R M A T I O N 
86/86 
 
 
18.3 
Appendix 3: Preferred terms for selection of AEs associated to 
Lymphopenia 
All PTs given are based on MedDRA version 25.1 and might be subject to change in future 
MedDRA version. 
PTs for selection of “Lymphopenia” 
Preferred Code 
Preferred Term 
10025327 
Lymphopenia 
10007839 
CD4 lymphocytes decreased 
10007843 
CD4/CD8 ratio decreased 
10012785 
Differential white blood cell count abnormal 
10025252 
Lymphocyte count abnormal 
10025256 
Lymphocyte count decreased 
10051313 
B-lymphocyte count decreased 
10051318 
T-lymphocyte count decreased 
10052231 
Lymphocyte percentage decreased 
10056283 
CD8 lymphocytes decreased 
10057284 
T-lymphocyte count abnormal 
10063293 
CD4 lymphocytes abnormal 
10063337 
Lymphocyte percentage abnormal 
10068497 
Natural killer cell count decreased 
10068500 
Natural killer T cell count decreased 
10071543 
CD8 lymphocytes abnormal 
10072798 
CD4 lymphocyte percentage decreased 
10078384 
CD8 lymphocyte percentage decreased 
10078589 
B-lymphocyte count abnormal 
10080721 
B-cell aplasia 
10083934 
Idiopathic CD4 lymphocytopenia 
 
 
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