A Multi-center, Open-label, Single-arm, Before and After Switch Study to Evaluate the Efficacy, Safety and Tolerability of Alemtuzumab in Paediatric Patients With Relapsing Remitting Multiple Sclerosis (RRMS) With Disease Activity on Prior Disease Modifying Therapy (DMT)
Phase: PHASE3
Conditions: Multiple Sclerosis
Sponsor: Genzyme, a Sanofi Company

 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to template: QSD-002579 VERSION N°14.0 (04-FEB-2016) 
Page 1 
 
AMENDED CLINICAL TRIAL PROTOCOL NO. 05  
 
COMPOUND: GZ402673 (Alemtuzumab) 
A multi-center, open-label, single-arm, before and after switch study to evaluate 
the efficacy, safety and tolerability of alemtuzumab in paediatric patients with 
relapsing remitting multiple sclerosis (RRMS) with disease activity on prior 
disease modifying therapy (DMT)  
STUDY NUMBER: EFC13429 
STUDY NAME: LemKids 
VERSION DATE/STATUS: 15-Dec-2021/Approved 
 
Version Number: 
1  
EudraCT Number 
2016-003100-30 
IND Number: 
10717 
WHO Universal Trial Number: 
NCT Number: 
U1111-1180-6352 
03368664 
Date: 
15-Dec-2021  
Total number of pages: 
154 
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Page 2 
PROTOCOL AMENDMENT CHANGES TABLE  
DOCUMENT HISTORY 
 
Document 
Country/countries 
impacted by 
amendment 
Date, version 
Amended Clinical Trial Protocol 05 
All 
15 December 2021, version 1 (electronic 5.0) 
Amended Clinical Trial Protocol 04 
All 
09 March 2020, version 1 (electronic 4.0) 
Amended Clinical Trial Protocol 03 
All 
21 June 2019, version 1 (electronic 3.0) 
Amended Clinical Trial Protocol 02 
All 
04 January 2019, version 1 (electronic 2.0) 
Amended Clinical Trial Protocol 03 (GB) 
Great Britain only 
21 May 2018, version 1 (electronic 4.0) 
Amended Clinical Trial Protocol 02 (FR) 
France only 
21 May 2018, version 1 (electronic 1.0) 
Protocol Amendment 06 (FR) 
France only 
21 May 2018, version 1 (electronic 1.0) 
Protocol Amendment 05 (GB) 
Great Britain only 
21 May 2018, version 1 (electronic 1.0) 
Amended Clinical Trial Protocol 02 (IT) 
Italy only 
12 March 2018, version 1 (electronic 1.0) 
Protocol Amendment 04 (IT) 
Italy only 
12 March 2018, version 1 (electronic 1.0) 
Amended Clinical Trial Protocol 02 (GB) 
Great Britain only 
08 November 2017, version 1 (electronic 3.0) 
Amended Clinical Trial Protocol 02 (RU) 
Russia only 
08 November 2017, version 1 (electronic 3.0) 
Amended Clinical Trial Protocol 01 
All 
08 November 2017, version 1 (electronic 1.0) 
Protocol Amendment 03 
All 
08 November 2017, version 1 (electronic 1.0) 
Amended Clinical Trial Protocol 01 (GB) 
Great Britain only 
05 May 2017, version 1 (electronic 2.0) 
Protocol Amendment 02 (GB) 
Great Britain only 
05 May 2017, version 1 (electronic 1.0) 
Amended Clinical Trial Protocol 01 (RU) 
Russia only 
23 January 2017, version 1 (electronic 2.0) 
Protocol Amendment 01 (RU) 
Russia only 
23 January 2017, version 1 (electronic 1.0) 
Clinical Trial Protocol 
All 
21 November 2016, version 1 (electronic 1.0) 
Amended protocol 05 (13 December 2021) 
This amended protocol (amendment 05) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
OVERALL RATIONALE FOR THE AMENDMENT 
This amendment provides an updated list of adverse events of special interest based on the most 
recent update of the safety information from post marketing experience in adults with multiple 
sclerosis.  
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Protocol amendment summary of changes table 
Section No. and name 
Description of change 
Brief rationale 
Section 4 - Introduction 
Added the following adverse events of special interest 
(AESIs) to ‘Alemtuzumab Post-Marketing Updates in 
Adult’: 
- 
Autoimmune encephalitis  
- 
Thrombotic thrombocytopenic purpura 
Update of safety information based 
on post marketing experience in 
adults with multiple sclerosis (MS). 
Section 10.4.1.3 – Adverse 
events of special interest 
Added the following AESIs: 
- 
Autoimmune encephalitis 
- 
Thrombotic thrombocytopenic purpura 
Update of the safety information 
based on post marketing experience 
in adults with MS. 
Section 10.4.6 - Table 9 - 
Summary of adverse event 
reporting instructions 
Added the following AESIs: 
- 
Autoimmune encephalitis 
- 
Thrombotic thrombocytopenic purpura 
Update of the safety information 
based on post marketing experience 
in adults with MS. 
 
 
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Page 4 
NAMES AND ADDRESSES OF 
COORDINATING 
INVESTIGATOR 
Name: 
Address: 
 
 
Tel: 
Fax: 
E-mail: 
 
 
MONITORING TEAM’S 
REPRESENTATIVE  
Name: 
Address: 
 
 
 
Tel: 
Fax: 
E-mail: 
 
 
SPONSOR  
Company: 
Address: 
Sanofi Genzyme 
50 Binney St 
Cambridge, MA 02142 USA 
 
OTHER EMERGENCY 
TELEPHONE NUMBERS 
 
 
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CLINICAL TRIAL SUMMARY 
 
COMPOUND: GZ402673 (Alemtuzumab) 
STUDY No.: EFC13429 
TITLE 
A multi-center, open-label, single-arm, before and after switch study to 
evaluate the efficacy, safety and tolerability of alemtuzumab in 
paediatric patients with relapsing remitting multiple sclerosis (RRMS) 
with disease activity on prior disease modifying therapy (DMT) 
INVESTIGATOR/TRIAL LOCATION 
Multinational 
PHASE OF DEVELOPMENT 
3 
STUDY OBJECTIVES 
 
Primary objective: 
• 
To evaluate the efficacy, safety and tolerability of 
alemtuzumab intravenously (IV) in paediatric patients from 
10 to <18 years of age with RRMS who have disease activity 
on prior DMT. 
Secondary objective: 
• 
To assess the pharmacokinetics (PK), pharmacodynamics 
(PD), antidrug antibody (ADA) formation, and potential effects 
of alemtuzumab on other multiple sclerosis (MS) disease 
characteristics such as cognition and quality of life (QoL). 
STUDY DESIGN 
Open-label, rater-blinded, single-arm, before and after switch study of 
efficacy, safety and tolerability of alemtuzumab in paediatric patients 
from 10 to <18 years of age with RRMS with disease activity on prior 
DMT. 
The study will consist  of: 
• 
Screening period (0-28 days prior to M-4) - This phase 
consists of the screening assessments for study eligibility of 
patients on current DMT.  
• 
Prior DMT phase (approximately 4 months) - This phase 
consists of the efficacy measurements on current DMT, which 
will be used as comparator group in the study. Subjects will 
continue the use of their current DMT (limited to beta 
interferon therapy [IFNB] or glatiramer acetate [GA]) during 
this period until 7 days prior to administration of first dose of 
alemtuzumab at M0.  
• 
Alemtuzumab treatment phase (approximately 2 years) - This 
phase starts with administration of first dose of alemtuzumab 
at M0, after discontinuation of current DMT, and ends at M24. 
The second dose of alemtuzumab will be administered at 
M12. The MRI based primary efficacy endpoint will be 
assessed over a 4 month period during the treatment phase 
compared to an equal period during the prior DMT phase. 
Note: EOTP refers to the end of the Alemtuzumab Treatment 
Phase. 
• 
Safety monitoring phase (approximately 3 years) - Additional 
safety follow-up and monitoring for all patients treated with 
alemtuzumab will be conducted during this phase to yield a 
total of 5 years of follow-up since first alemtuzumab 
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treatment, including 4 years post last treatment with 
alemtuzumab.  
• 
Note: EOS refers to the end of the safety monitoring phase. 
STUDY POPULATION  
Main selection criteria 
Inclusion criteria: 
• 
Patients with RRMS aged from 10 years (12 years in the 
Russian Federation) to less than 18 years at study entry are 
eligible. Patients must meet the criteria of diagnosis of MS as 
defined by the International Paediatric Multiple Sclerosis 
Study Group criteria for paediatric MS, and the criteria of MS 
based on McDonald criteria 2010. 
• 
Signed written informed consent/assent obtained from patient 
and patient’s legal representative (parent or guardian) 
according to local regulations. 
• 
Expanded Disability Status Scale (EDSS) score 0.0 to 5.0 
(inclusive) at screening. 
• 
At least 2 recorded MS attacks, and at least 1 MS attack 
(relapse) in the last year during treatment with a IFNB or GA 
after having been on that therapy for at least 6 months, and is 
currently still taking the same therapy. 
• 
At least 1 of the following: 
- 
≥1 new or enlarging T2 hyperintense lesion or 
gadolinium enhancing lesion while on that same prior 
therapy (IFNB or GA), OR 
- 
2 or more relapses in the prior year, OR 
- 
tried at least 2 MS DMTs. 
Main exclusion criteria: 
• 
Any prior exposure to alemtuzumab. 
• 
Any progressive or nonrelapsing form of MS. 
• 
Treatment with natalizumab, daclizumab, fingolimod, 
methotrexate, azathioprine, cyclosporine, or mycophenolate 
mofetil in the last 6 months, or as determined by the treating 
physician to have residual immune suppression from these or 
other MS treatments. 
• 
Treatment with teriflunomide in the last 12 months except if 
the patient underwent the accelerated elimination procedure 
as per local teriflunomide label. Previous treatment with 
mitoxantrone, cyclophosphamide, cladribine, rituximab, 
ocrelizumab, leflunomide or any cytotoxic therapy. 
• 
CD4+, CD8+, or CD19+ absolute cell count in blood at 
screening below lower limit of normal (LLN). 
• 
Prior documented history of thrombocytopenia, or platelet 
count at screening <LLN. In case of borderline results, one 
retest is allowed. 
• 
NOTE: Prior to initiation of any alemtuzumab treatment 
course, contraindications should be reviewed as pre-
treatment verification of eligibility. 
Total expected number of patients 
At least 50 evaluable patients  
Expected number of sites: 
Approximately 50 sites 
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STUDY TREATMENT 
 
Investigational medicinal product 
Alemtuzumab 
Formulation: 
Concentrate for solution for infusion (sterile concentrate). Each 
single-use vial contains 12 mg alemtuzumab (10 mg/mL; total 
extractable volume 1.2 mL). 
Route(s) of administration: 
Intravenous (IV) infusion in a supervised medical setting 
Dose regimen: 
Alemtuzumab administered as daily IV infusion for 5 consecutive days 
at Month 0 and for 3 consecutive days at Month 12. Calculation of the 
dose used will be determined based on patient weight: 
• 
For patients ≥50 kg: 12 mg/day. 
• 
For patients <50 kg: 0.24 mg/kg/day (this equates to 
12 mg/day for a 50 kg patient). 
Non Investigational medicinal product(s)  
 
Formulation: 
Premedications: 
• 
Day -1 (day before first IV infusion at each course) in the 
morning: 
- 
Oral prednisone/prednisolone,1 mg/kg or 50 mg one 
dose, whichever is lower or equivalent, 
- 
H2 antagonist according to the local label (eg, ranitidine). 
• 
Day -1 (day before first IV infusion at each course) in the 
evening: 
- 
H1 antagonist according to the local label (eg, cetirizine), 
- 
H2 antagonist according to the local label (eg, ranitidine). 
• 
On days of IV infusions (1 hour prior to infusion): 
- 
H2 antagonist: eg, ranitidine or equivalent, 
- 
NSAID/antipyretic: Paracetamol or equivalent, 
- 
H1 antagonist IV diphenhydramine (25 mg or appropriate 
weight based dosing based on local health authority 
recommendation), immediately followed by: 
- 
IV methylprednisolone: administer 30 mg/kg or 1000 mg 
(whichever is lower) on infusion Days 1, 2, 3 (all 
courses) and ≥500 mg on infusion Days 4 and 5 (if 5 
days of infusion). 
• 
Notes: 
a) 
If diphenhydramine IV is not available, an equivalent  H1 
antagonist can be used at an equivalent dosing, via 
IV route. 
b) 
If no H1 antagonist is available in IV formulation, an oral 
formulation of an equivalent compound can be used at 
an equivalent dosing, 2 hours prior to infusion. 
• 
Day 4 and Day 5 of the first course: 
- 
H1 antagonist, H2 antagonist, and antipyretics as 
needed, 
- 
Fluid intake will be encouraged. 
Concomitant medications: 
• 
Acyclovir 200 mg oral twice daily (or therapeutic equivalent) 
will also be provided at the beginning on the first day of each 
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treatment course and continuing for a minimum of 1 month 
following treatment with alemtuzumab. 
Route(s) of administration: 
Methylprednisolone: IV 
Acyclovir: Oral 
Prednisone/Prednisolone: Oral 
Long-acting, nonsedating, nonselective antihistamine: Oral and/or IV 
H2-receptor antagonist: Oral 
Dose regimen: 
See above 
ENDPOINTS 
Primary endpoint: 
• 
The number of new or enlarging T2 lesions on brain MRI, 
during continuation of prior DMT (Period 1) compared to an 
equal period after the first course of alemtuzumab treatment 
(Period 2). 
Secondary endpoints: 
Efficacy: 
• 
The number of patients with new or enlarging T2 lesions 
during continuation of prior DMT (Period 1) compared to an 
equal period after the first course of alemtuzumab treatment 
(Period 2). 
• 
EDSS (descriptive statistics, eg, percentages of 
stable/improved/worsened since the end of Period 1).  
• 
Annualized relapse rate (ARR) at Year 2. 
• 
Cognition test scores: Brief Visuospatial Memory 
Test - Revised (BVMT-R) and Symbol Digit Modality Test 
(SDMT); administered at least every 6 months over 2 years. 
QoL: 
• 
Established generic paediatric QoL measures administered 
every 6 months over 2 years. 
Pharmacokinetics/Pharmacodynamics: 
• 
PK serum concentration and PK parameters (Cmax, Tmax, AUC, 
AUClast, T1/2z) calculated where possible. 
• 
PD assessment including lymphocyte subsets. 
Safety endpoints: 
• 
Safety and tolerability of alemtuzumab for up to 4 years after 
last dose of alemtuzumab. 
• 
Assessment of development of antialemtuzumab antibodies 
at baseline, and post dose Months 1, 3, 12 (prenext dose), 
13, 15, and 24/at EOTP; and annually in the Safety 
Monitoring Phase. 
Exploratory endpoint 
• 
T1 weighted lesions and brain volume will be assessed on 
MRI as an exploratory endpoint throughout the study period. 
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ASSESSMENT SCHEDULE 
Efficacy 
• 
EDSS: Screening, D-14 to D-7, M4, M8, M12, M15, M18, 
M21, M24/at end of treatment phase (EOTP); every 6 months 
in Safety Monitoring Phase, and at every relapse visit. 
• 
Brain MRI: Screening, D-14 to D-7, M4, M8, M12, M24/at 
EOTP; annually in Safety Monitoring Phase. 
• 
SDMT: Screening, D-14 to D-7, M4, M8, M12, M18, M24/at 
EOTP; annually in Safety Monitoring Phase. 
• 
BVMT-R: Screening, D-7, M4, M8, M12, M18, M24/at EOTP; 
annually in Safety Monitoring Phase. 
• 
QoL Questionnaires: Screening, D-7, M4, M8, M12, M18, 
M24/at EOTP; annually in Safety Monitoring Phase. 
 
Safety 
• 
Adverse event (AE) reporting at each visit. 
• 
Physical examination and vital signs: Screening, D-14 to D-7, 
M0/D1, M4, M8, M12, M15, M18, M21, M24/at EOTP; every 
6 months safety monitoring phase, and at every relapse visit, 
if applicable. 
• 
Additionally, vital signs will be collected hourly during 
alemtuzumab infusion and post infusion observation for 
2 hours. 
• 
Clinical chemistry laboratories: Screening, D-14 to D-7, M4, 
M8, M12, M15, M18, M21, M24/at EOTP; quarterly in safety 
monitoring phase. In addition, serum creatinine and alanine 
aminotransferase will be assessed at M0/D1, monthly in 
alemtuzumab treatment phase (Year 1 and 2); monthly in the 
safety monitoring phase (inclusive of chemistry panel). 
• 
Hematology: Screening, D-14 to D-7, M0/D1, and monthly in 
alemtuzumab treatment phase (Year 1 and 2); EOTP and 
monthly in safety monitoring phase. 
• 
Urinalysis: Screening, D-14 to D-7, monthly in alemtuzumab 
treatment phase (Year 1 and 2); EOTP and monthly in safety 
monitoring phase.  
• 
Thyroid function tests: Screening, D-14 to D-7, quarterly in 
both Alemtuzumab Treatment Phase (Year 1 and 2); EOTP, 
and in safety monitoring phase. 
• 
Tanner staging: Screening, M12, M24/at EOTP; annually in 
safety monitoring phase. 
• 
Pregnancy testing (females only): Screening (blood test), D-
14 to D-7 and M12 (urine test). 
• 
Assessment of ADA: M0/D1 (baseline), M1, M3, M12 (prior to 
second course being administered), M13, M15, and M24/at 
EOTP; annually in safety monitoring phase. 
Pharmacodynamics 
• 
Lymphocyte phenotyping: Screening, D-14 to D-7, M1, M4, 
M8, M12, M13, M15, M18, M21, M24/at EOTP; annually in 
Safety Monitoring Phase. 
Pharmacokinetics 
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• 
For patients receiving alemtuzumab, serum concentrations 
and PK parameters will be studied. 
Immune Markers (optional) 
• 
Immune Markers (optional): M0/D1 (baseline), M4, M12, M18 
and M24/at EOTP. 
STATISTICAL CONSIDERATIONS 
 
Sample size determination: 
At least 60 patients will be screened in this study to ensure 
50 evaluable patients to receive alemtuzumab treatment. This sample 
size will provide at least 85% power to detect a 50% reduction in the 
number of new or enlarging T2 lesions during continuation of prior DMT 
(Period 1) with their number in an equal period after the first course of 
alemtuzumab (Period 2), assuming 10% dropout and a two-tailed 
significance level of 0.05. These sample size calculations were 
simulated using a correlated repeated measures negative binomial 
regression model with generalized estimating equations (GEE) with 
robust variance estimation to account for the within-patient correlation in 
lesion counts between treatment Period 1 (prior DMT) and Period 2 
(alemtuzumab).  
The sample size calculations also assume an overdispersion parameter 
of 0.7 for both study periods, which is consistent with the variability 
reported in other paediatric MS studies.  
Analysis population: 
Modified ITT (mITT): The primary analysis will be conducted on the 
population of patients who have received at least 1 dose of 
alemtuzumab and also have evaluable data for both Period 1 and 
Period 2. 
Safety: Safety and tolerability analyses will be conducted on all patients. 
Primary analysis: 
The number of new or enlarging T2 lesions during continuation of prior 
DMT (Period 1) and in an equal length period after the first course of 
alemtuzumab treatment (Period 2) will be analyzed and compared using 
a repeated measures negative binomial regression model with GEE. 
Analysis of secondary endpoints: 
• 
Safety and tolerability will be assessed using descriptive 
statistics and evaluated in comparison to the adult data for the 
treatment of MS using alemtuzumab. 
• 
EDSS (descriptive statistics, eg, percentages of 
stable/improved/worsened since the end of Period 1). 
• 
The ARR at Year 2 will be estimated using a negative 
binomial model with robust variance estimation. 
• 
The change from baseline in cognitive outcomes will be 
analyzed descriptively.  
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• 
The change from baseline in QoL measures will be analyzed 
descriptively.  
• 
PK serum concentrations and PK parameters will be analyzed 
descriptively. 
• 
PD parameters including lymphocyte subsets will be analyzed 
descriptively. 
• 
Antialemtuzumab antibody results will be analyzed 
descriptively. 
• 
The number and proportion of patients with new or enlarging 
T2 lesions during Period 1 and Period 2 will be analyzed and 
compared using a repeated measures logistic regression 
model. 
Planned Database lock date: 
A partial database lock will be done after the last patient has completed 
efficacy assessments including MRI at the end of Period 2. This 
database lock will allow comparing lesion counts between Period 1 
(M-4 to M0) and Period 2 (M4-M8).  No formal interim analysis will be 
performed.  
The second database lock will be after the last patient has completed 
the safety monitoring phase (M60).  
DURATION OF STUDY PERIOD (per 
patient)  
Approximately 5 years 5 months: 
• 
Screening period: maximum 28 days prior to M 4. 
• 
Prior DMT phase: approximately 4 months. 
• 
Alemtuzumab treatment phase: approximately 2 years. 
• 
Safety follow-up period: approximately 3 years. 
STUDY COMMITTEES 
Scientific Advisory Committee: 
 Yes   
 No 
The Scientific Advisory Committee (SAC) is composed of field experts 
and Sponsor-based scientists with clinical and methodological 
expertise. This Committee, led by a Chairperson, is selected by the 
Sponsor for advice regarding scientific issues and operational conduct 
of the study. The SAC will also review any amendments, and provide 
input regarding interpretation of study results.  
Among its responsibilities, the SAC will receive study status reports 
from the Sponsor, and will review the recommendations from the data 
monitoring committee (DMC) throughout the study. 
Moreover, the SAC will be responsible for the primary publication(s) 
emanating from the study. The Principal Investigator (PI) of the study 
will be selected by the Sponsor and will be the first author for the 
primary publication(s). PIs at the 3 sites enrolling the most patients will 
also be included as authors for the primary publication, in addition to the 
SAC members. 
Detailed activities and responsibilities of the SAC are provided in the 
SAC charter. 
Data Monitoring Committee: 
 Yes    
 No 
A DMC, operating independently from the Sponsor and clinical 
Investigators, will be responsible for overseeing the safety of patients 
and the risk/benefit ratio throughout the study. This committee is 
composed of externally-based individuals with expertise in the disease 
under study, biostatistics and/or clinical research. The primary 
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responsibilities of the DMC are to ensure the patients welfare as well as 
to evaluate and review safety and other applicable data throughout the 
course of the study and make appropriate recommendations to the 
Sponsor regarding the conduct of the clinical trial. The specific 
responsibilities of the DMC will be described in the DMC charter. 
Adjudication Committee:  
 Yes    
 No 
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1 
FLOW CHARTS  
1.1 
GRAPHICAL STUDY DESIGN  
 
Abbreviations: DMT: disease modifying therapy; EOS: end of study; EOTP: end of treatment phase; M: month(s); MRI: magnetic resonance imaging. 
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1.2 
STUDY FLOW CHART  
1.2.1 Schedule of events Part 1 (Year 1)  
Table 1 - Schedule of events in Year 1  
 
DMT Phase  
Alemtuzumab treatment phase 
Unscheduled 
visits 
Visita 
Scrn. 
visitb 
Period 1/ Prior DMT 
phase 
M0/ 
D1u 
M1 
M2 
M3 
M4 
Period 2 
M9 
M10 
M11 
M12 
Relapse visitd 
Eligibility 
confirmation 
on M-4 
D-14 to 
D-7c 
M5 
M6 
M7 
M8 
Visit number 
V1 
V2 
V3 
V4v 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16v 
 
Entry procedures 
 
Informed consent & assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
review 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient demographye 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Surgical historyf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior Medication history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility confirmation 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Phone callg 
 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B/C Serology testing  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tuberculosis test (eg, Quanticore)h 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other Serology tests as requiredi 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HPVj(yearly) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm eligibility for alemtuzumab Rx 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Alemtuzumab administration 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Premedication administration  
 
 
 
Xc 
 
 
 
 
 
 
 
 
 
 
 
Xc 
 
Acyclovir administrationk 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Compliance 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Concomitant medications 
 
Prior DMT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discontinue prior DMT 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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DMT Phase  
Alemtuzumab treatment phase 
Unscheduled 
visits 
Visita 
Scrn. 
visitb 
Period 1/ Prior DMT 
phase 
M0/ 
D1u 
M1 
M2 
M3 
M4 
Period 2 
M9 
M10 
M11 
M12 
Relapse visitd 
Eligibility 
confirmation 
on M-4 
D-14 to 
D-7c 
M5 
M6 
M7 
M8 
Visit number 
V1 
V2 
V3 
V4v 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16v 
 
Efficacy: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EDSS  
X 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Brain MRIl 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
SDMT 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
BVMT-R test 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
PedsQL (QoL Questionnaire)/Ped. Neuro-QoL 
(sub-comp.)m 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Safety: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationn 
X 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Clinical chemistry laboratorieso 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Hematology (Differential CBC)o 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Thyroid Function Testsp 
X 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Urinalysisq 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum Creatinine and alanine aminotransferase  
 
 
 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
 
Lymphocyte phenotyping 
X 
 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Samples for antibodies to Study Drug 
 
 
 
X 
X 
 
X 
 
 
 
 
 
 
 
 
X 
 
Tanner Stagingr 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
AE/SAE recording (if any) 
 
Vital Signs 
X 
 
X 
Xs 
 
 
 
X 
 
 
 
X 
 
 
 
Xs 
X 
Laboratory testing: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (for female patients of 
childbearing potentialt 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
PK samplingu 
 
 
 
Xu 
Xu 
Xu 
 
 
 
 
 
 
 
 
 
Xu 
 
Immune Marker Sampling (optional)  
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Abbreviations: AE: adverse event; BVMT-R: brief visuospatial memory test-revised, CBC: complete blood count; D: day; DMT: disease modifying therapy; EDSS: Expanded Disability Status Scale; M  month(s); 
MRI: magnetic resonance imaging; Neuro-QoL: quality of life in neurological disorders; Ped: paediatric; PK: pharmacokinetics; QoL: quality of life; SAE: serious adverse event; Scrn: screening; SDMT: symbol digit 
modality test 
a Recommended windows: The window for obtaining samples and performing assessments at any given visit will be ±7 days, except for the D-14 to D-7 day visit which should occur between -7 to -1 days prior to 
M0/D1and for Visit 16 (M12) which can occur within -7 days or +30 days of the scheduled visit. All post M0/D1 treatment period assessments should be completed within ±7 days of the scheduled visit date relative 
to the M0/D1 visit.  
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b Screening visit should be a maximum of 28 days prior to eligibility confirmation (M-4). If needed, the assessments can be performed over multiple days as long as the window is observed.  
c Some premedications should have been taken prior to Day 1. All lab results/assessments should be available prior to D-7 to confirm patient eligibility. If patient is eligible to receive alemtuzumab a follow-up call 
should be performed and INF/copaxone should be stopped at D-7. 
d This visit is only required for subjects who have a suspected relapse, and should occur within 7 days following the occurrence of the clinical event. 
e Subject race will be collected in this study because these data are required by several regulatory authorities. 
f 
Information on alcohol habits will be collected along with medical history at Visit 1 and in case of alanine aminotransferase (ALT) increase. 
g Phone calls to remind patients and parents about continuation of DMT and participation in study will be utilized at monthly intervals (between V2 and V3) in prior DMT period (Period 1). The phone calls will be 
captured in the e-CRF. 
h Screening tuberculosis test should be performed as per local health care authority recommendations and during the study if deemed clinically indicated. Blood testing (QuantiFERON®-TB Gold test) or skin testing 
on site (purified protein derivative [PPD] skin test) will be allowed only if the Quantiferon TB Gold test is used. Blood testing is preferred where available. . If Quantiferon test results are indeterminate, confirmation 
via skin testing is required. 
i 
Serological testing for Herpes zoster is recommended, in accordance with local public health authority recommendations. Herpes zoster (varicella zoster) vaccination (VZV) of antibody-negative patients should be 
considered prior to treatment with alemtuzumab. In addition if patient receives any vaccination during screening or Alemtuzumab Treatment Phase, relevant antibody titers will be assessed before and 
approximately 6 weeks after completing vaccination course (inactivated vaccines only).   
j 
Testing will be conducted for human papillomavirus (HPV) infection as and when recommended by local public health authorities. If the testing is positive, the patient may be eligible after the condition has resolved 
as per the Investigator opinion (eg, follow-up HPV test is negative or cervical abnormality has been effectively treated). An annual follow-up is recommended. 
k Acyclovir 200 mg twice daily (or a therapeutic equivalent) starting on the first day of each alemtuzumab course and continuing for a minimum of 1 month following treatment with alemtuzumab. 
l 
The MRI assessment will be 4 months (±7 days) apart in Year 1. The MRI assessments will be available to investigators to assess safety. 
m PedsQL questionnaire (Paediatric Quality of Life Inventory) will be completed by patients/parents based on recommendations. Peds NeuroQoL is a quality of life measurement developed for neurological disorders 
and consists of short form questions for multiple domains. Specific subdomains will be utilized. 
n The date of first menarche should be captured if applicable. 'A standard physical examination for clinical and neurological assessments includes examination of major body systems, height and body weight. 
o Hematology and differential panel (hemoglobin, hematocrit, red blood cell count, mean corpuscular hemoglobin, white blood cell count, neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelets) 
Complete chemistry panel (glucose, creatinine, blood urea nitrogen (BUN), sodium, potassium, chloride, bicarbonate, magnesium, calcium uric acid, aspartate aminotransferase (AST), ALT, gamma-glutamyl 
transpeptidase (GGT), lactate dehydrogenase (LDH), total bilirubin, direct/indirect bilirubin, alkaline phosphatase, inorganic phosphorus, total protein, albumin, globulin, albumin/globulin ratio, triglycerides, 
cholesterol and creatine phosphokinase (CPK). It is preferred that CBCs with platelet count, and monitoring for any cytopenia as well as serum creatinine, and urinalysis with microscopy be analyzed at the central 
laboratory, but under special circumstances (eg, if patient is unable to visit the study center weekly or monthly, or results are needed urgently), the assay may be performed at a local laboratory provided that test 
results are entered into the e-CRF in a timely manner. However for study visits that only require laboratory sampling, home nursing or local laboratories may be used for sample collection and shipment to the 
central laboratory, as per local regulations. These visits are to be followed by telephone calls from the study site to assess AEs.  
p Thyroid stimulating hormone (TSH) & if abnormal T3 & T4 performed on the existing samples. However for study visits that only require laboratory sampling, home nursing or local laboratories may be used for 
sample collection and shipment to the central laboratory, as per local regulations. These visits are to be followed by telephone calls from the study site to assess AEs and concomitant medications. 
q Urinalysis (pH, ketones, cells, protein, glucose, blood, urobilinogen, bilirubin, microscopic sediment, specific gravity). However for study visits that only require laboratory sampling, home nursing or local 
laboratories may be used for sample collection and shipment to the central laboratory, as per local regulations. These visits are to be followed by telephone calls from the study site to assess AEs and concomitant 
medications. 
r 
Tanner stage to be assessed as noted until complete sexual maturity. 
s The following vital signs will be recorded before methylprednisolone infusion, at a time after methylprednisolone infusion and prior to alemtuzumab infusion; and 1 hour after the start of alemtuzumab infusion and 
hourly during and after infusion, until  2 hours after infusion has ended or longer until stabilization: systolic and diastolic blood pressure (millimeters of mercury [mm Hg]), heart rate (beats/minute), respiratory rate 
(breaths/minute), and temperature (degrees Celsius [°C] or degrees Fahrenheit [°F]). 
t 
β-human chorionic gonadotropin test will be performed at Screening. Pregnancy test after Screening will be done by urine dipstick and must be conducted prior to methylprednisolone administration; pregnancy 
testing is required for all female patients capable of bearing children and who have commenced menstruating. Those female patients who commence initial menstruation during the study will be similarly monitored 
with urine dipstick pregnancy tests for the duration of the study. Pregnancy testing to be repeated as permitted by national law. 
u For details on PK sampling, refer Section 1.2.4. 
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v Contraindications, including the following must be checked before infusion: severe active infection, uncontrolled hypertension, history of arterial dissection of the cervicocephalic arteries, history of stroke, history of 
angina pectoris or myocardial infarction, known coagulopathy or on concomitant anti-coagulant therapy 
1.2.2 Schedule of events Part 2 (Year 2)  
Table 2 - Schedule of events in Year 2  
Visit Daya 
M13 
M14 
M15 
M16 
M17 
M18 
M19 
M20 
M21 
M22 
M23 
M24 (EOTP) 
Relapse 
Visitb 
Visit number 
V17 
V18 
V19 
V20 
V21 
V22 
V23 
V24 
V25 
V26 
V27 
V28 
 
Treatment: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy: 
 
 
 
 
 
 
 
 
 
 
 
 
 
EDSS 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Brain MRIc 
 
 
 
 
 
 
 
 
 
 
 
X 
 
SDMT 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
BVMT-R Test 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
PedsQL (QoL Questionnaire)/ 
Ped. NeuroQoL (subcomp.)d  
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Safety: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinatione  
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Clinical chemistry laboratoriesf 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Hematology (Differential CBCf) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Thyroid Function Testsg 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Urinalysish  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum Creatinine and alanine aminotransferase 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
 
Lymphocyte phenotyping 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Samples for antibodies to Study Drug  
X 
 
X 
 
 
 
 
 
 
 
 
X 
 
Tanner Stagingi 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Concommitant medications 
 
AE/SAE recording (if any) 
 
Vital Signs 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
HPVj (yearly) 
 
Laboratory testing: 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK samplingk  
Xk 
Xk 
 
 
 
 
 
 
 
 
 
 
 
Immune Marker Sampling (optional)  
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Abbreviations: AE: adverse event; BVMT-R: brief visuospatial memory test-revised, CBC: complete blood count; EDSS: Expanded Disability Status Scale; EOTP: end of treatment phase; M: month(s); MRI: magnetic 
resonance imaging; Neuro-QoL: quality of life in neurological disorders; Ped: pediatric; PK: pharmacokinetics; QoL: quality of life; SAE: serious adverse event; SDMT: symbol digit modality test. 
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a Recommended windows: The window for obtaining samples and performing assessments at any given visit will be ±7 days, except for the D-14 to D-7 visit which should occur between -7 to -1 days prior to M0/D1. 
All post M0/D1 treatment period assessments should be completed within ±7 days of the scheduled visit date relative to the M0/D1 visit. 
b This visit is only required for subjects that have a suspected relapse, and should occur within 7 days following the occurrence of the clinical event. 
c The MRI assessments will be available to investigators to assess safety. 
d PedsQL questionnaire (Paediatric Quality of Life Inventory) will be completed by patients/parents based on questionnaire recommendations. Peds NeuroQoL is a quality of life measurement developed for 
neurological disorders and consists of short form questions for multiple domains. Specific sub-domains will be utilized. 
e The date of first menarche should be captured if applicable. 'A standard physical examination for clinical and neurological assessments which includes examination of major body systems, height and body weight. 
f 
Hematology and differential panel (hemoglobin, hematocrit, red blood cell count, mean corpuscular hemoglobin, white blood cell count, neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelets) 
Complete chemistry panel (glucose, creatinine, blood urea nitrogen (BUN), sodium, potassium, chloride, bicarbonate, magnesium, calcium uric acid, aspartate aminotransferase (AST), ALT, gamma-glutamyl 
transpeptidase (GGT), lactate dehydrogenase (LDH), total bilirubin, direct/indirect bilirubin, alkaline phosphatase, inorganic phosphorus, total protein, albumin, globulin, albumin/globulin ratio, triglycerides, 
cholesterol and creatine phosphokinase (CPK). It is preferred that CBCs with platelet count, and monitoring for any cytopenia as well as serum creatinine, and urinalysis with microscopy be analyzed at the central 
laboratory, but under special circumstances (eg, if patient is unable to visit the study center weekly or monthly, or results are needed urgently), the assay may be performed at a local laboratory provided that test 
results are entered into the e-CRF in a timely manner. However for study visits that only require laboratory sampling, home nursing or local laboratories may be used for sample collection and shipment to the 
central laboratory, as per local regulations. These visits are to be followed by telephone calls from the study site to assess AEs and concomitant medications. 
g Thyroid stimulating hormone (TSH) & if abnormal T3 & T4 performed on the existing samples. However for study visits that only require laboratory sampling, home nursing or local laboratories may be used for 
sample collection and shipment to the central laboratory, as per local regulations. These visits are to be followed by telephone calls from the study site to assess AEs and concomitant medications. 
h Urinalysis (pH, ketones, cells, protein, glucose, blood, urobilinogen, bilirubin, microscopic sediment, specific gravity).However for study visits that only require laboratory sampling, home nursing or local 
laboratories may be used for sample collection and shipment to the central laboratory, as per local regulations. These visits are to be followed by telephone calls from the study site to assess AEs and 
concomitant medications. 
i 
Tanner stage to be assessed as noted until complete sexual maturity. 
j 
Testing will be conducted for human papillomavirus (HPV) infection as and when recommended by local public health authorities. If the testing is positive, the patient may be eligible after the condition has resolved 
as per the Investigator opinion (eg, follow-up HPV test is negative or cervical abnormality has been effectively treated). An annual follow-up is recommended. 
k For details on PK sampling, refer to Section 1.2.5.
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1.2.3 Schedule of events Part 3 (Safety monitoring phase Year 3 - Year 5)  
Table 3 - Safety monitoring phase Year 3-5  
 
Safety monitoring phase 
 
Visit Daya  
M25 
M26 
M27 
M28 
M29 
M30 
M31 
M32 
M33 
M34 
M35 
M36b 
Relapse Visit 
 
M37 
M38 
M39 
M40 
M41 
M42 
M43 
M44 
M45 
M46 
M47 
M48b 
 
 
M49 
M50 
M51 
M52 
M53 
M54 
M55 
M56 
M57 
M58 
M59 
M60b 
 
Visit number 
V29 
V30 
V31 
V32 
V33 
V34 
V35 
V36 
V37 
V38 
V39 
V40 
 
V41 
V42 
V43 
V44 
V45 
V46 
V47 
V48 
V49 
V50 
V51 
V52 
 
V53 
V54 
V55 
V56 
V57 
V58 
V59 
V60 
V61 
V62 
V63 
V64 
 
Efficacy: 
 
EDSS 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Brain MRIc 
 
 
 
 
 
 
 
 
 
 
 
X 
 
SDMT 
 
 
 
 
 
 
 
 
 
 
 
X 
 
BVMT-R Test 
 
 
 
 
 
 
 
 
 
 
 
X 
 
PedsQL (QoL Questionnaire)/ 
Ped. NeuroQoL (sub-comp.) 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Safety: 
 
Physical examination  
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Clinical chemistry laboratoriesd,e 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Hematology (Differential CBC)d,f  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Thyroid Function Testsd 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Urinalysisg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum Creatinineh and alanine 
aminotransferased 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
 
Lymphocyte phenotyping 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Samples for antibodies to Study Drug  
 
 
 
 
 
 
 
 
 
 
 
X 
 
Tanner Staging 
 
 
 
 
 
 
 
 
 
 
 
X 
 
AE/SAE recording (if any) 
 
Concommitant medications 
 
Vital Signs 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
HPVi (yearly) 
 
Abbreviations: AE: adverse event; BVMT-R: brief visuospatial memory test-revised, CBC: complete blood count; EDSS: Expanded Disability Status Scale; M: month(s); 
MRI: magnetic resonance imaging; Neuro-QoL: quality of life in neurological disorders; Ped: paediatric; QoL: quality of life; SAE: serious adverse event; SDMT: symbol digit modality test. 
a All study visits during safety monitoring phase except the M36,M48 and M60 visits can be performed within ±7 days. 
b M36, M48 and M60 Study visits can be performed within ±4 weeks for these visits, to allow for scheduling of assessments. 
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c The MRI assessments will be available to investigators to assess safety. 
d At these visits, in some countries, there is an option for the nurse to obtain samples for clinical chemistry laboratories, hematology, thyroid function tests, urinalysis and serum creatinine at the patient’s home. This 
will therefore be considered a home visit. In this case, a phone call from the Investigator to review AE and concomitant medication is allowed. If home nursing cannot be implemented, local laboratories may be 
used for sample collection and shipment to the central laboratory, as per local regulations. These visits are to be followed by telephone calls from the study site to assess AEs and concomitant medications. 
e Complete chemistry panel (glucose, creatinine, blood urea nitrogen (BUN), sodium, potassium, chloride, bicarbonate, magnesium, calcium uric acid, aspartate aminotransferase (AST), alanine aminotransferase 
(ALT), gamma-glutamyl transpeptidase (GGT), lactate dehydrogenase (LDH), total bilirubin, direct/indirect bilirubin, alkaline phosphatase, inorganic phosphorus, total protein, albumin, globulin, albumin/globulin 
ratio, triglycerides, cholesterol and creatine phosphokinase (CPK). It is preferred that CBCs with platelet count, and monitoring for any cytopenia as well as serum creatinine, and urinalysis with microscopy be 
analyzed at the central laboratory, but under special circumstances (eg, if patient is unable to visit the study center weekly or monthly, or results are needed urgently), the assay may be performed at a local 
laboratory provided that test results are entered into the e-CRF in a timely manner. 
f 
Hematology and differential panel (hemoglobin, hematocrit, red blood cell count, mean corpuscular hemoglobin, white blood cell count, neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelets).  It is 
preferred that CBCs with platelet count, and monitoring for any cytopenia as well as serum creatinine, and urinalysis with microscopy be analyzed at the central laboratory, but under special circumstances (eg, if 
patient is unable to visit the study center weekly or monthly, or results are needed urgently), the assay may be performed at a local laboratory provided that test results are entered into the e-CRF in a timely 
manner.  
g Urinalysis (pH, ketones, protein, glucose, blood, urobilinogen, bilirubin, microscopic sediment, specific gravity). However for study visits that only require laboratory sampling, home nursing or local laboratories may 
be used for sample collection and shipment to the central laboratory, as per local regulations. These visits are to be followed by telephone calls from the study site to assess AEs and concomitant medications. 
h For alemtuzumab-treated patients, abnormal serum creatinine and/or urinalysis findings should be followed according to the guidelines provided in the protocol (guidelines will be based on current adult program 
guidelines) 
i 
Testing will be conducted for human papillomavirus (HPV) infection as and when recommended by local public health authorities. If the testing is positive, the patient may be eligible after the condition has resolved 
as per the Investigator opinion (eg, follow-up HPV test is negative or cervical abnormality has been effectively treated). An annual follow-up is recommended.
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1.2.4 Schedule of events Part 4: Table for PK sampling (Year 1)  
Table 4 - PK Sampling schedule (Year 1)  
PK sampling time 
Day 1  
predose 
Day 5  
End of 
Infusion 
Day 14a,b 
M1a 
M2a 
Schedule 
X 
X 
X 
X 
X 
Sample ID 
S1 
S2 
S3 
S4 
S5 
a A window of ±2 days for sample collection is permitted to ensure that sample collection does not fall on a weekend and allow for patient 
flexibility. 
b The sample will be drawn at local lab, if feasible per country regulation (no site visit). 
Note: “End” refers to the end of the infusion period; these samples should be collected within 15 minutes prior to the end of the infusion from the 
side of the body opposite the alemtuzumab infusion site. 
1.2.5 Schedule of events Part 5: Table for PK sampling (Year 2)  
Table 5 - PK sampling schedule (Year 2)  
PK sampling time 
M12 
M12 
M12 
M13a 
M14a 
Day 1  
predose 
Day 3 EOI 
Day 12a,b 
 
 
Schedule  
X 
X 
X 
X 
X 
Sample ID 
S1 
S2 
S3 
S4 
S5 
a A window of ±2 days for sample collection is permitted to ensure that sample collection does not fall on a weekend. 
b The sample will be drawn at local lab, if feasible per country regulation (no site visit). 
Note: “EOI” refers to the end of the infusion period; these samples should be collected within 15 minutes prior to the end of the infusion from the 
side of the body opposite the alemtuzumab infusion site. 
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2 
TABLE OF CONTENTS 
 
AMENDED CLINICAL TRIAL PROTOCOL NO. 0505 ................................................................................... 1 
PROTOCOL AMENDMENT CHANGES TABLE ........................................................................................... 2 
1 
FLOW CHARTS ............................................................................................................................. 13 
1.1 
GRAPHICAL STUDY DESIGN ...................................................................................................... 13 
1.2 
STUDY FLOW CHART .................................................................................................................. 14 
1.2.1 
Schedule of events Part 1 (Year 1) ................................................................................................ 14 
1.2.2 
Schedule of events Part 2 (Year 2) ................................................................................................ 17 
1.2.3 
Schedule of events Part 3 (Safety monitoring phase Year 3 - Year 5) .......................................... 19 
1.2.4 
Schedule of events Part 4: Table for PK sampling (Year 1) .......................................................... 21 
1.2.5 
Schedule of events Part 5: Table for PK sampling (Year 2) .......................................................... 21 
2 
TABLE OF CONTENTS ................................................................................................................ 22 
2.1 
LIST OF TABLES ........................................................................................................................... 28 
3 
LIST OF ABBREVIATIONS .......................................................................................................... 29 
4 
INTRODUCTION AND RATIONALE ............................................................................................. 31 
5 
STUDY OBJECTIVES ................................................................................................................... 37 
5.1 
PRIMARY ....................................................................................................................................... 37 
5.2 
SECONDARY ................................................................................................................................ 37 
6 
STUDY DESIGN ............................................................................................................................ 38 
6.1 
DESCRIPTION OF THE STUDY ................................................................................................... 38 
6.2 
DURATION OF STUDY PARTICIPATION .................................................................................... 39 
6.2.1 
Duration of study participation for each patient ............................................................................. 39 
6.2.2 
Determination of end of clinical trial (all patients) .......................................................................... 39 
6.3 
INTERIM ANALYSIS ...................................................................................................................... 39 
6.4 
STUDY COMMITTEE .................................................................................................................... 40 
6.4.1 
Scientific advisory committee: ........................................................................................................ 40 
6.4.2 
Data monitoring committee ............................................................................................................ 40 
7 
SELECTION OF PATIENTS .......................................................................................................... 41 
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7.1 
INCLUSION CRITERIA .................................................................................................................. 41 
7.2 
EXCLUSION CRITERIA ................................................................................................................ 41 
7.2.1 
Exclusion criteria related to study methodology ............................................................................ 41 
7.2.2 
Exclusion criteria related to alemtuzumab and/or mandatory background therapies .................... 42 
7.2.3 
Exclusion criteria related to the current knowledge of alemtuzumab and study methodology ...... 43 
8 
STUDY TREATMENTS ................................................................................................................. 46 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S) .......................................................................... 46 
8.1.1 
Administration ................................................................................................................................ 46 
8.1.1.1 
Method of preparation at the clinical site ....................................................................................... 47 
8.1.1.2 
Special precautions for disposal and other handling ..................................................................... 47 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCTS ..................................................................... 47 
8.3 
BLINDING PROCEDURES ............................................................................................................ 48 
8.3.1 
Methods of blinding ........................................................................................................................ 48 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP .............................................. 49 
8.5 
PACKAGING AND LABELING ...................................................................................................... 49 
8.6 
STORAGE CONDITIONS AND SHELF LIFE ................................................................................ 49 
8.7 
RESPONSIBILITIES ...................................................................................................................... 49 
8.7.1 
Treatment accountability and compliance...................................................................................... 50 
8.7.2 
Return and/or destruction of treatments ........................................................................................ 50 
8.8 
CONCOMITANT MEDICATION ..................................................................................................... 50 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT .............................................. 53 
9.1 
PRIMARY ENDPOINT ................................................................................................................... 53 
9.1.1 
Primary efficacy endpoint ............................................................................................................... 53 
9.1.1.1 
Brain MRI ....................................................................................................................................... 53 
9.2 
SECONDARY ENDPOINTS .......................................................................................................... 54 
9.2.1 
Secondary efficacy endpoints ........................................................................................................ 54 
9.2.1.1 
Expanded disability status scale .................................................................................................... 54 
9.2.1.2 
Annualized relapse rate at Year 2 .................................................................................................. 55 
9.2.1.3 
Cognition test scores...................................................................................................................... 55 
9.2.2 
Other secondary endpoints ............................................................................................................ 56 
9.2.2.1 
Pharmacokinetics ........................................................................................................................... 56 
9.2.2.2 
Pharmacodynamic variables .......................................................................................................... 57 
9.2.2.3 
Quality of life endpoints .................................................................................................................. 57 
9.3 
SAFETY ENDPOINTS ................................................................................................................... 58 
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9.3.1 
Adverse events .............................................................................................................................. 59 
9.3.2 
Laboratory safety variables ............................................................................................................ 59 
9.3.3 
ITP, cytopenia, and antiGBM surveillance and monitoring ............................................................ 60 
9.3.4 
Hemophagocytic lymphohistiocytosis ............................................................................................ 61 
9.3.5 
Physical examination and vital signs ............................................................................................. 61 
9.3.6 
Other safety endpoints ................................................................................................................... 62 
9.4 
EXPLORATORY ENDPOINT ........................................................................................................ 62 
9.5 
FUTURE USE OF SAMPLES ........................................................................................................ 62 
9.5.1 
Immune markers (optional) ............................................................................................................ 62 
9.6 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 62 
10 
STUDY PROCEDURES ................................................................................................................ 64 
10.1 
VISIT SCHEDULE .......................................................................................................................... 64 
10.1.1 
Visit 1 Screening visit ..................................................................................................................... 64 
10.1.2 
Visit 2/( M-4) study eligibility confirmation visit .............................................................................. 65 
10.1.3 
Visit 3/Days -14 to -7 ...................................................................................................................... 66 
10.1.4 
Visit 4/M0/D1 (first course of alemtuzumab) .................................................................................. 66 
10.1.5 
Visit 5 to Visit 7/M1 to M3 .............................................................................................................. 68 
10.1.6 
Visit 8/M4 ....................................................................................................................................... 69 
10.1.7 
Visit 9 to Visit 11 /M5 to M7 ........................................................................................................... 69 
10.1.8 
Visit 12/M8 ..................................................................................................................................... 69 
10.1.9 
Visit 13 to Visit 15/M9 to M11 ........................................................................................................ 70 
10.1.10 Visit 16/M12 (second course of alemtuzumab) .............................................................................. 70 
10.1.11 Visit 17 to Visit 18/M13 to M14 ...................................................................................................... 72 
10.1.12 Visit 19/M15 ................................................................................................................................... 72 
10.1.13 Visit 20 to Visit 21/M16 to 17 ......................................................................................................... 73 
10.1.14 Visit 22/M18 ................................................................................................................................... 73 
10.1.15 Visit 23 to Visit 24/M19 to M20 ...................................................................................................... 73 
10.1.16 Visit 25/M21 ................................................................................................................................... 73 
10.1.17 Visit 26-Visit 27/M22-23 ................................................................................................................. 74 
10.1.18 Visit 28/M24 EOTP......................................................................................................................... 74 
10.1.19 Safety monitoring phase Year 3 to Year 5 ..................................................................................... 74 
10.1.20 Relapse Visit .................................................................................................................................. 75 
10.2 
DEFINITION OF SOURCE DATA .................................................................................................. 75 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION ....................................... 75 
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10.3.1 
Temporary treatment discontinuation with investigational medicinal product(s) ........................... 75 
10.3.2 
Permanent treatment discontinuation with investigational medicinal product(s) ........................... 76 
10.3.3 
List of criteria for permanent treatment discontinuation ................................................................. 76 
10.3.4 
Handling of patients after permanent treatment discontinuation ................................................... 76 
10.3.5 
Procedure and consequence for patient withdrawal from study .................................................... 77 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING .......................... 77 
10.4.1 
Definitions of adverse events ......................................................................................................... 77 
10.4.1.1 Adverse event ................................................................................................................................ 77 
10.4.1.2 Serious adverse event ................................................................................................................... 77 
10.4.1.3 Adverse event of special interest ................................................................................................... 78 
10.4.2 
Serious adverse events waived from expedited regulatory reporting to regulatory 
authorities ....................................................................................................................................... 80 
10.4.3 
General guidelines for reporting adverse events ........................................................................... 80 
10.4.4 
Instructions for reporting serious adverse events .......................................................................... 81 
10.4.5 
Guidelines for reporting adverse events of special interest ........................................................... 81 
10.4.6 
Guidelines for management of specific laboratory abnormalities .................................................. 81 
10.4.7 
Guidelines for reporting product complaints (IMP/NIMP/device) ................................................... 82 
10.5 
OBLIGATIONS OF THE SPONSOR ............................................................................................. 83 
10.6 
SAFETY INSTRUCTIONS ............................................................................................................. 83 
10.7 
ADVERSE EVENTS MONITORING .............................................................................................. 83 
11 
STATISTICAL CONSIDERATIONS .............................................................................................. 84 
11.1 
DETERMINATION OF SAMPLE SIZE ........................................................................................... 84 
11.2 
DISPOSITION OF PATIENTS ....................................................................................................... 84 
11.3 
ANALYSIS POPULATIONS ........................................................................................................... 84 
11.3.1 
Modified Intent-to-treat population ................................................................................................. 84 
11.3.2 
Safety population: .......................................................................................................................... 85 
11.4 
STATISTICAL METHODS ............................................................................................................. 85 
11.4.1 
Extent of study treatment exposure ............................................................................................... 85 
11.4.2 
Analyses of efficacy endpoints ....................................................................................................... 86 
11.4.2.1 Analysis of primary efficacy endpoint............................................................................................. 86 
11.4.2.2 Analyses of secondary efficacy endpoints ..................................................................................... 86 
11.4.2.3 Multiplicity considerations .............................................................................................................. 86 
11.4.3 
Analyses of safety data .................................................................................................................. 87 
11.4.3.1 Adverse events .............................................................................................................................. 87 
11.4.3.2 Laboratory safety variables ............................................................................................................ 87 
11.4.3.3 Physical examination and vital signs ............................................................................................. 88 
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11.4.3.4 Other safety endpoints ................................................................................................................... 88 
11.4.4 
Analyses of pharmacokinetic and pharmacodynamic variables .................................................... 88 
11.4.5 
Analyses of exploratory endpoints ................................................................................................. 89 
11.5 
INTERIM ANALYSIS ...................................................................................................................... 89 
12 
ETHICAL AND REGULATORY CONSIDERATIONS ................................................................... 90 
12.1 
ETHICAL AND REGULATORY STANDARDS .............................................................................. 90 
12.2 
INFORMED CONSENT ................................................................................................................. 90 
12.3 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE ................................................................................................................... 91 
13 
STUDY MONITORING................................................................................................................... 92 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S) ....................................................................... 92 
13.2 
RESPONSIBILITIES OF THE SPONSOR ..................................................................................... 92 
13.3 
SOURCE DOCUMENT REQUIREMENTS .................................................................................... 93 
13.4 
USE AND COMPLETION OF ELECTRONIC CASE REPORT FORMS AND ADDITIONAL 
REQUEST ...................................................................................................................................... 93 
13.5 
USE OF COMPUTERIZED SYSTEMS .......................................................................................... 93 
14 
ADDITIONAL REQUIREMENTS ................................................................................................... 94 
14.1 
CURRICULUM VITAE.................................................................................................................... 94 
14.2 
RECORD RETENTION IN STUDY SITES .................................................................................... 94 
14.3 
CONFIDENTIALITY ....................................................................................................................... 94 
14.4 
PROPERTY RIGHTS ..................................................................................................................... 95 
14.5 
DATA PROTECTION ..................................................................................................................... 95 
14.6 
INSURANCE COMPENSATION .................................................................................................... 95 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES ................................. 96 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE ............................................................................................................................................ 96 
14.8.1 
By the Sponsor ............................................................................................................................... 96 
14.8.2 
By the Investigator ......................................................................................................................... 97 
14.9 
CLINICAL TRIAL RESULTS .......................................................................................................... 97 
14.10 
PUBLICATIONS AND COMMUNICATIONS ................................................................................. 97 
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15 
CLINICAL TRIAL PROTOCOL AMENDMENTS .......................................................................... 98 
16 
BIBLIOGRAPHIC REFERENCES ................................................................................................. 99 
17 
APPENDICES .............................................................................................................................. 102 
APPENDIX A 
GUIDANCE ON CONTRACEPTIVE METHODS AND COLLECTION OF 
PREGNANCY INFORMATION .................................................................................................... 103 
APPENDIX B 
GENERAL GUIDANCE FOR THE FOLLOW-UP OF LABORATORY 
ABNORMALITIES BY SANOFI .................................................................................................... 105 
APPENDIX C 
MC DONALD’S CRITERIA FOR DIAGNOSIS OF MS ...................................................... 113 
APPENDIX D 
KURTZKE’S FUNCTIONAL SYSTEMS AND EXPANDED DISABILITY STATUS 
SCALE IN MULTIPLE SCLEROSIS ............................................................................................ 114 
APPENDIX E 
TANNER STAGE CLASSIFICATION ................................................................................ 124 
APPENDIX F 
23-ITEM PEDSQL GENERIC CORE SCALES ................................................................. 125 
APPENDIX G 
NEUROQOL ...................................................................................................................... 133 
APPENDIX H COUNTRY-SPECIFIC REQUIREMENTS ............................................................................ 138 
APPENDIX I PROTOCOL AMENDMENT HISTORY .................................................................................. 141 
 
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2.1 
LIST OF TABLES  
Table 1 - Schedule of events in Year 1 ......................................................................................................... 14 
Table 2 - Schedule of events in Year 2 ......................................................................................................... 17 
Table 3 - Safety monitoring phase Year 3-5 ................................................................................................. 19 
Table 4 - PK Sampling schedule (Year 1) ..................................................................................................... 21 
Table 5 - PK sampling schedule (Year 2)...................................................................................................... 21 
Table 6 - MRI correlative analyses with relapse in adult Phase 3 studies (CAMMS323 and CAMMS324) . 32 
Table 7 - Common terminology criteria for adverse events v3.0, published 09 August 2006. ...................... 45 
Table 8 - List of pharmacokinetic parameters and definitions ....................................................................... 57 
Table 9 - Summary of adverse event reporting instructions .......................................................................... 82 
  
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3 
LIST OF ABBREVIATIONS  
 
ADA: 
antidrug antibody 
AE: 
adverse event 
ALT: 
alanine aminotransferase 
ARR: 
annualized relapse rate 
AUC: 
area under the cumulative serum concentration versus time curve 
AUClast: 
area under the cumulative serum concentration versus time curve extrapolated to 
infinity 
BVMT-R: 
Brief Visuospatial Memory Test-Revised 
CBC: 
complete blood count 
Cmax: 
maximum serum concentration observed 
CMV: 
cytomegalovirus 
CTCAE: 
Common Terminology Criteria for Adverse Events 
DMC: 
Data Monitoring Committee 
DMT: 
disease modifying therapy 
e-CRF: 
electronic-case report form 
EDSS: 
Expanded Disability Status Scale 
EMA: 
European Medicines Agency 
EOS: 
end of safety monitoring phase 
EOTP: 
end of treatment phase 
EU: 
European Union 
GA: 
glatiramer acetate 
GBM: 
glomerular basement membrane 
GCP: 
Good Clinical Practice 
Gd: 
gadolinium 
GEE: 
generalized estimating equations 
H1: 
histamine receptor H1 
H2: 
histamine receptor H2 
HLGT: 
high level group term 
HLH: 
hemophagocytic lymphohistiocytosis 
HLT: 
high level term 
HPV: 
human papillomavirus 
HSV: 
herpes simplex virus 
IAR: 
infusion-associated reaction 
ICF: 
informed consent form 
IEC: 
independent ethics committee 
IFNB: 
interferon beta 
IFNB-1a: 
interferon beta 1-alpha 
IMP: 
Investigational Medicinal Product 
IRB: 
institutional review board 
ITP: 
immune thrombocytopenia 
IV: 
intravenous(ly) 
IVRS: 
interactive voice response system 
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IWRS: 
interactive web response system 
LLN: 
lower limit of normal 
mITT: 
modified intent to treat  
MRI: 
magnetic resonance imaging 
MS: 
multiple sclerosis 
NCI: 
National Cancer Institute 
NIMP: 
noninvestigational medicinal product 
NSAID: 
nonsteroidal anti-inflammatory drug 
PD: 
pharmacodynamic(s) 
PDCO: 
Paediatric Committee 
PI: 
Principal Investigator 
PIP: 
Paediatric Investigation Plan 
PK: 
pharmacokinetic(s) 
PV: 
pharmacovigilance 
QoL: 
quality of life 
RRMS: 
relapsing remitting multiple sclerosis 
SAC: 
Scientific Advisory Committee 
SC: 
subcutaneous(ly) 
SD: 
standard deviation 
SDMT: 
Symbol Digit Modality Test 
T1/2z: 
terminal half-life associated with the terminal slope 
TB: 
tuberculosis 
TEAEs: 
treatment emergent adverse events 
Tmax: 
time to reach Cmax 
uRTI: 
upper respiratory tract infection 
UTI: 
urinary tract infection 
WBC: 
white blood cell 
 
    
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4 
INTRODUCTION AND RATIONALE  
Multiple sclerosis (MS) is a demyelinating disease of the central nervous system that affects 
approximately 2.3 million people worldwide (1). Its clinical course is typically characterized by 
initial episodes of transient neurological compromise with full recovery, followed by a phase of 
cumulative deficits that may increase with each new episode. Most patients eventually develop 
secondary progression leading to a constellation of chronic sequelae including profound muscle 
weakness, impaired gait and mobility, bladder and bowel dysfunction, and cognitive and visual 
impairments. 
MS is typically considered to be a disease of young adults. However, paediatric MS is 
increasingly recognized and accounts for approximately 5 percent of cases (2, 3, 4). Differential 
diagnosis includes leukodystrophies, vasculopathies, sarcoidosis, lymphoma, mitochondrial 
defects, and other metabolic disorders. 
The estimated prevalence of paediatric patients among all patients with MS ranges between 2.7% 
to 10.5% (3), and it is estimated that approximately 20% to 25% of children with MS experience 
breakthrough disease activity that may trigger a switch to another therapy (2, 4). 
The onset of MS in childhood typically occurs during the key formative years. It can restrict 
school attendance and has the potential to negatively affect the developing neural connections 
implicated in learning and higher-order information processing. Fatigue may also have a great 
impact on activities and development. 
Paediatric MS patients develop disability, as well as shift to the secondary progressive phase of 
MS, after a longer disease interval but at a younger age, compared with adult MS patients 
(5, 6, 7).  
With increased recognition of paediatric MS worldwide, children are now being treated earlier 
in their disease course with the goal of limiting long-term disability (8). There is no approved 
disease modifying therapy (DMT) indicated for paediatric MS and the effects of DMTs in 
children have not been formally evaluated in controlled clinical trials. The current treatment and 
prognosis of paediatric MS are based on that of adult patients, because data are limited in 
paediatric MS and it is assumed that the disease response in children is likely to be similar 
(9, 10, 11, 12). 
Off label use of medicinal products in children without proper evidence poses an ethical problem. 
That is why the need for clinical trials with children has now been widely recognised and is 
stimulated by European Union legislation (EU regulation). Trials of alemtuzumab are therefore 
necessary in the paediatric population to develop a better knowledge of the drug’s effects in 
children (safety and efficacy). 
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Alemtuzumab Clinical Data in Adults 
Alemtuzumab is a humanized monoclonal antibody that targets CD52, a cell surface antigen 
present at high levels on B and T lymphocytes and at lower levels on natural killer cells, 
monocytes and macrophages. There is little or no CD52 detected on neutrophils, plasma cells, or 
bone marrow stem cells. Alemtuzumab acts through antibody-dependent cell-mediated 
cytotoxicity and complement-dependent cytotoxicity following cell surface binding to T and 
B lymphocytes. It effects rapid and sustained lymphocyte depletion and has shown potent efficacy 
in treatment-naïve as well as treatment-refractory patients with relapsing remitting multiple 
sclerosis (RRMS). Treatment with alemtuzumab 12 mg/day is efficacious in patients with RRMS 
and was associated with clinically meaningful and statistically significant improvements in 
clinical endpoints, imaging endpoints and composite disease measures, compared with 
subcutaneous (SC), high-dose, high-frequency interferon-beta-1alpha (IFNB-1a). 
MS relapses are caused by focal inflammatory lesions, which are detected by magnetic resonance 
imaging (MRI) as new or enlarging T2-hyperintense and Gd (Gadolinium)-enhancing lesions, in 
brain or spinal cord. Prior studies have established a strong correlation between relapse outcomes 
and the occurrence of such lesions (13). A correlation between effects on MRI measures and 
relapses is also seen in alemtuzumab studies. Table 6 shows the odds ratio for the occurrence of at 
least one relapse (versus no relapses) for patients who developed at least one new or enlarging 
T2 lesion (versus no new/enlarging lesions) over the course of the 2-year study period in studies 
CAMMS323 or CAMMS324. In both studies, a strong and statistically significant relationship is 
seen between risk of T2 lesions and relapse, with patients being at least 50% more likely to 
experience relapse if they have MRI lesion activity. These findings demonstrate that the 
conclusion from prior studies (13) of a strong correlation between this objective MRI outcome 
and relapse rate applies also to alemtuzumab clinical studies of adult MS patients, and support the 
use of new/enlarging T2 lesions as a primary efficacy endpoint in the proposed paediatric MS 
study. 
Table 6 - MRI correlative analyses with relapse in adult Phase 3 studies (CAMMS323 and 
CAMMS324)  
 
Study CAMMS323 
Study CAMMS324 
Endpoint 
OR 
p-value 
OR 
p-value 
Gadolinium enhancing lesions at Month 24 
1.58 
0.1217 
2.31 
0.0012 
New/enlarging T2 lesions over 24 months 
1.54 
0.0312 
1.52 
0.0200 
New T1 lesions over 24 months 
1.59 
0.0347 
1.69 
0.0078 
MRI activity over 24 months 
1.53 
0.0384 
1.48 
0.0296 
Abbreviation: MRI: magnetic resonance imaging; OR: odds ratio 
Clinical trials with alemtuzumab in adult MS patients have provided a consistent pattern of safety 
observations that include infusion associated reactions (IARs), autoimmune disorders (thyroid 
disorders, immune thrombocytopenia [ITP], nephropathies such as antiglomerular basement 
membrane [antiGBM disease and other cytopenias), and infections. Measures to detect and 
manage these effects were implemented early and refined throughout the clinical program. 
These measures enabled the management of patients within the studies and have laid a foundation 
for the care of patients outside of the clinical trial setting. 
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Most patients treated with alemtuzumab in controlled clinical trials in MS experienced mild to 
moderate IARs during or soon after alemtuzumab 12 mg administration. Common IARs include 
headache, rash, pyrexia, nausea, urticaria, pruritus, insomnia, chills, flushing, fatigue, dyspnea, 
dysgeusia, chest discomfort, generalized rash, tachycardia, dyspepsia, dizziness, and pain. 
Serious reactions occurred in 3% of patients including cases of pyrexia, urticaria, atrial 
fibrillation, nausea, chest discomfort, and hypotension. In addition, anaphylaxis has been reported 
rarely. Prophylactic use of corticosteroids was useful in alleviating IARs and is part of the 
recommended prescribing information for alemtuzumab use in MS patients. In addition, 
modification of the duration of infusion is permitted to help patients tolerate infusions if needed 
and symptomatic medications such as antihistamines and/or antipyretics were administered often 
in the studies. 
Alemtuzumab treatment increases the risk of autoimmune-mediated conditions. Autoimmune 
thyroid disorders occurred in 36 % of patients in clinical trials in MS through 4 years following 
first exposure. Observed autoimmune thyroid disorders included hyperthyroidism and 
hypothyroidism, which occurred at similar rates. Serious thyroid related events occurred in 
<1% patients. No consistent pattern was observed with regards to time of onset after treatment 
initiation, although the highest incidence of thyroid adverse events (AEs) was observed in Year 3 
after the first treatment course. Therefore, as part of the risk minimization strategy for 
autoimmune disorders, thyroid function tests must be obtained prior to the initiation of 
alemtuzumab treatment and every 3 months thereafter until 48 months following the last infusion. 
This will allow the timely detection and treatment of thyroid disorders for patients treated with 
alemtuzumab. 
Immune thrombocytopenia and nephropathies, including antiGBM disease, although potentially 
more serious than thyroid disorders, were observed infrequently. Serious events of ITP have been 
observed in approximately 1% of patients treated with alemtuzumab in clinical trials in MS. 
Fatality in the index case of ITP, which was reported in the Phase 2 study, highlights the 
seriousness of the risks associated with the disorder. However, risk minimization measures 
including patient education and monthly complete blood counts (CBCs) introduced to monitor for 
ITP and other potential autoimmune cytopenias in the clinical studies allowed the prompt 
diagnosis and treatment of patients who subsequently developed these conditions. AntiGBM 
disease was reported rarely in the clinical program. Nephropathies including antiGBM disease 
have been observed in controlled clinical trials in MS. Patient education and monthly testing of 
serum creatinine were effective in identifying cases early to allow prompt treatment. Similarly, 
urinalysis testing was also effective in identifying nephropathies during the clinical studies. 
Accordingly, monthly testing including CBC with differential, platelet count and monitoring for 
any cytopenia as well as serum creatinine testing and urinalysis with microcopy, must be obtained 
prior to treatment with alemtuzumab and every month thereafter until 48 months following the 
last infusion. This will facilitate the early detection and treatment of these disorders, should they 
occur.  
Infections occurred in 71% of patients treated with Lemtrada® 12 mg as compared to 53% of 
patients treated with Rebif® (IFNB-1a) in controlled clinical trials in MS up to 2 years in duration 
and were predominantly mild to moderate in severity. Serious infections occurred in 2.7% of 
patients treated with alemtuzumab as compared to 1.0% of patients treated with IFNB-1a in 
controlled clinical trials in MS. The most frequent infections reported in alemtuzumab-treated 
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patients were nasopharyngitis, urinary tract infections (UTI), upper respiratory tract infections 
(uRTI), sinusitis, influenza, bronchitis, oral herpes and herpes zoster. Prophylactic acyclovir 
treatment was used effectively in the clinical studies to reduce risk of Herpes Simplex virus 
infection (HSV) and therefore patients should receive concomitant acyclovir starting on the first 
day of any alemtuzumab course and continuing for at least 1 month after the last day of the 
course. Preservation of innate immunity and relative sparing of memory lymphocytes, together 
with the preservation of serum immunoglobulins (14), may contribute to the relatively low rate of 
serious infections following alemtuzumab treatment in MS patients.  
During the course of the clinical studies, malignancies were observed in both alemtuzumab- and 
IFNB-1a-treated patients. However, the annualized rates of malignancy were similar across all 
treatment groups, and moreover, the malignancy risk was similar to the background incidence in 
the general population. The risk of malignancy will be further investigated in a long-term 
observational study. 
As previously mentioned, the identified risks of alemtuzumab in patients with RRMS include: 
• IARs (including cerebrovascular, cardiovascular, and pulmonary alveolar hemorrhage 
events). 
• Serious infections. 
• Autoimmunity (notably, ITP, thyroid disorders, or rarely nephropathies and autoimmune 
hepatitis, and hepatic injury). 
Alemtuzumab Post-Marketing Updates in Adult 
In post-marketing pharmacovigilance (PV) monitoring, infrequent cases of temporally associated 
pulmonary alveolar haemorrhage, myocardial ischemia, stroke (including ischemic and 
hemorrhagic stroke) and cervicocephalic (eg, vertebral, carotid) arterial dissection have been 
reported. Reactions may occur following any of the infusions during the treatment course. In the 
majority of cases time to onset was within 1-3 days of alemtuzumab infusion. Patients should be 
informed about the signs and symptoms, and advised to seek immediate medical attention if any 
of these symptoms occur.  
Post marketing PV monitoring has also identified events reported as autoimmune encephalitis, 
autoimmune hepatitis, acquired hemophilia A, thrombotic thrombocytopenic pupura (TTP) and 
hepatic injury. Infrequent events reported as hemophagocytic lymphohistiocytosis (HLH) and 
PML have been noted. The emergence of these events during the clinical development program 
and post-marketing PV reporting prompted the initiation and ongoing modification of risk 
minimization measures. In conclusion, there are recently identified serious but rare risks 
associated with alemtuzumab administration. Risk minimization measures for clinical studies are 
in place, and they have been modified based upon post-marketing PV reporting. 
Alemtuzumab has been approved in the European Union, United States, Canada, Australia, Brazil 
and several other countries as Lemtrada for the treatment of active RRMS in adults with RRMS; 
the specific indicated population varies by country.  
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Study design rationale 
The proposed design will investigate efficacy, safety, and tolerability of alemtuzumab compared 
to other DMTs, (ie, IFNB and glatiramer acetate [GA]) in an open-label, rater-blinded, single-arm, 
before and after switch study, in paediatric patients with RRMS aged from 10 years to less than 
18 years with disease activity on prior DMT, with a rater-blinded MRI endpoint. 
This study is based on the paediatric investigational plan (PIP) agreed with the European 
Medicines Agency (EMA) and its Paediatric Committees (PDCO). 
Patient population 
• The patient population intended for this paediatric study will be narrower than the 
population described in the adult indication to expose only these paediatric patients with 
high medical need, having MS disease activity while on treatment with prior DMT. 
The MS disease activity criteria include having at least 2 recorded MS attacks; at least 1 
MS relapse in the last year during treatment with an IFNB or GA after having been on that 
therapy for at least 6 months, and is currently still taking the same therapy; and having 
either ≥1 new or enlarging T2 hyperintense lesion or gadolinium enhancing lesion while 
on that same prior therapy (IFNB or GA), or 2 or more relapses in the prior year, or tried 
at least 2 MS DMTs. 
The age group eligible to enroll (from 10 years to less than 18 years) has higher MS prevalence 
than younger age groups. 
Interferon-beta (IFNB) and GA have not been formally tested in paediatric MS patients with a 
relapsing-remitting course during placebo-controlled trials. However, class III and IV evidence of 
effectiveness resulting from observational open-label studies have prompted their current use and 
recommendation. Nonetheless, in about 30% of paediatric MS patients, the disease continues to be 
active despite immunomodulatory treatment, supporting the need to explore other therapeutic 
options (15). There are few data to support the use of other DMTs in paediatric populations. 
Considering the high frequency of inadequate response to first-line DMT and the lack of clinical 
trial data regarding the efficacy of switching to other DMTs, this paediatric population has a high 
unmet need. 
Alemtuzumab dose selection 
Alemtuzumab will be administered as a daily intravenous (IV) infusion, similar to adult treatment 
regimen (course 1 at Month 0, 12 mg on 5 consecutive days, and course 2 at Month 12, 12 mg on 
3 consecutive days), giving a cumulative dosage of 60 mg at first course, and 36 mg at second 
course. The adult dose will be adjusted (reduced) proportionately for paediatric patients <50 kg 
based on the patient’s weight. Calculation of a paediatric patient’s dose will be based on patient’s 
last visit weight taken during the physical examination: 
• For patients ≥50 kg: 12 mg/day. 
• For patients <50 kg: 0.24 mg/kg/day (this equates to 12 mg/day for a 50 kg patient). 
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The 0.24 mg/kg/day dose is based on experience using alemtuzumab in the treatment of children 
undergoing bone marrow or solid organ transplantation, and is similar to or lower than doses 
previously used (16). This corresponds to a cumulative dose over 5 days of 1.2 mg/kg at Month 0, 
with a smaller dose of 0.72 mg/kg at Month 12. 
Prophylactic administration of methylprednisolone, antiH1 and antiH2 medications will be a part 
of the alemtuzumab treatment regimen, to minimize infusion associated reactions. 
MRI 
The proposed study will have an MRI-based primary endpoint. Recent publications have 
demonstrated a correlation between the MRI lesions and clinical relapse for IFNB or GA based on 
meta-analysis of data collected in randomized controlled trials (17), and for alemtuzumab (13). 
MRI assessments will be available to investigators to assess safety. 
The period of 4 months for comparison of new or enlarged T2 lesions on prior DMT versus on 
alemtuzumab was selected on advice of paediatric MS experts as representing the optimum 
interval to achieve the scientific aims of the study consistent with current patient care practice for 
children experiencing disease activity while using IFNB or GA. 
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5 
STUDY OBJECTIVES  
5.1 
PRIMARY  
• To evaluate the efficacy, safety and tolerability of alemtuzumab (IV) in paediatric patients 
from 10 to <18 years of age with RRMS who have disease activity on prior DMT. 
5.2 
SECONDARY  
• To assess the pharmacokinetics (PK), pharmacodynamics (PD), antidrug antibody (ADA) 
formation, and potential effects of alemtuzumab on other MS disease characteristics such 
as cognition and quality of life. 
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6 
STUDY DESIGN  
6.1 
DESCRIPTION OF THE STUDY  
This is an open-label, rater-blinded, single-arm, before and after switch study of efficacy, safety 
and tolerability of alemtuzumab in paediatric patients from 10 to <18 years of age with RRMS 
with disease activity on prior DMT. 
The study will consist of: 
• Screening period (0-28 days prior to M-4) - Patients and parents will receive information 
on the study and on alemtuzumab. Inclusion/exclusion criteria will be reviewed. After 
informed consent signature, screening assessments for eligibility will be performed. 
Screening assessments may require more than one visit within the screening period which 
may last a maximum of 28 days. 
• Prior DMT phase (approximately 4 months): M-4 to M0 
- 
Eligibility confirmation visit: At the end of the screening period (at M-4) 
patients/parents will come to the site to confirm patient is eligible for the study. 
Investigator will check that all assessment allow patient inclusion. During this visit 
patients will be reminded to continue their prior DMT (limited to interferon or GA 
only). 
- 
From M-4 visit to D-14 to D-7: Phone calls (approximately every month) will be 
done, to remind patients to continue on their DMT and check patient status. 
- 
Day -14 to D-7 visit: Investigator will confirm patient is eligible for alemtuzumab 
administration and will tell the patient to discontinue current DMT 7 days prior to 
administration of first dose of alemtuzumab at Month 0. 
• Alemtuzumab treatment phase (approximately 2 years) – This phase starts with 
administration of first dose of alemtuzumab at M0, after discontinuation of current DMT, 
and ends at M24. The second dose of alemtuzumab will be administered at M12. The MRI 
based primary efficacy endpoint will be assessed over a 4 month period during this phase 
compared to an equal period during the prior DMT phase. 
Note: end of treatment phase (EOTP) refers to the end of the alemtuzumab treatment phase 
(see graphic study design [Section 1.1]). 
• Safety monitoring phase (approximately 3 years) – Additional safety follow-up and 
monitoring for all patients treated with alemtuzumab will be conducted during this phase 
to yield a total of 5 years of follow-up since first alemtuzumab treatment, including 4 years 
post last treatment with alemtuzumab. 
Note: end of study (EOS) refers to the end of the safety monitoring phase (see graphic 
study design [Section 1.1]). 
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In addition, and for the primary endpoint assessment, two periods have been defined: 
• Period 1: will occur from M-4 up to M0. A baseline MRI will be performed close to M-4 
during the screening period and another at Visit 3. Both MRI will be taken while patients 
are on their prior DMT. It is important to ensure that these 2 MRI assessments are 
performed 4 months (±7 days) apart. 
• Period 2: will occur from M4 to M8: The MRI performed at the M4 visit will be the 
baseline MRI for Period 2. A second MRI will be performed after alemtuzumab first 
course of treatment at M8. It is important to ensure that these 2 MRI assessments are 
performed 4 months (±7 days) apart. 
These two periods will be compared for the primary endpoint analysis. 
6.2 
DURATION OF STUDY PARTICIPATION  
6.2.1 Duration of study participation for each patient  
The maximum study duration per patient will be approximately 5 years and 5 months: 
• Screening period: 0-28 days prior to M-4 from signed informed consent to eligibility 
confirmation. 
• Prior DMT phase: approximately 4 months from signed informed consent and screening 
qualification to prior DMT discontinuation. Alemtuzumab treatment phase: 
approximately 2 years, from first dose alemtuzumab administration to one year after last 
dose of alemtuzumab administration. 
• Safety monitoring phase: approximately 3 years to complete the 48 months safety 
follow-up post last treatment with alemtuzumab. 
6.2.2 Determination of end of clinical trial (all patients)  
The EOS is defined as being the “last patient last visit” planned with the protocol. The last patient 
visit will be considered when the last patient has completed safety monitoring phase (M60). 
The Sponsor reserves the right to discontinue the study at any time. 
6.3 
INTERIM ANALYSIS  
A partial database lock will be done after the last patient has completed efficacy assessments 
including MRI at the end of Period 2. This database lock will allow comparing lesion counts 
between Period 1 (M-4 to M0) and Period 2 (M4-M8). No formal interim analysis will be 
performed. 
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6.4 
STUDY COMMITTEE  
6.4.1 Scientific advisory committee:  
The scientific advisory committee (SAC) is composed of field experts and Sponsor-based 
scientists with clinical and methodological expertise. This Committee, led by a Chairperson, is 
selected by the Sponsor for advice regarding scientific issues and operational conduct of the 
study. The SAC will also review any amendments, and provide input regarding interpretation of 
study results.  
Among its responsibilities, the SAC will receive study status reports from the Sponsor, and will 
review the recommendations from the data monitoring committee (DMC) throughout the study. 
Moreover, the SAC will be responsible for the primary publication(s) emanating from the study. 
The Principal Investigator (PI) of the study will be selected by the Sponsor and will be the first 
author for the primary publication(s). PIs at the 3 sites enrolling the most patients will also be 
included as authors for the primary publication, in addition to the other SAC members. 
Detailed activities and responsibilities of the SAC are provided in the SAC charter. 
6.4.2 Data monitoring committee  
A DMC, operating independently from the Sponsor and Clinical Investigators, will be responsible 
for overseeing the safety of patients and the risk/benefit ratio throughout the study. 
This committee is composed of externally-based individuals with expertise in the disease under 
study, biostatistics and/or clinical research. The primary responsibilities of the DMC are to ensure 
the patients welfare as well as to evaluate and review the safety and other applicable data 
throughout the course of the study and make appropriate recommendations to the Sponsor 
regarding the conduct of the clinical trial. The specific responsibilities of the DMC will be 
described in the DMC charter. 
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7 
SELECTION OF PATIENTS  
7.1 
INCLUSION CRITERIA  
I 01. Patients with RRMS aged from 10 years to less than 18 years at study entry are eligible. 
Patients must meet the criteria of diagnosis of MS as defined by the International 
Paediatric Multiple Sclerosis Study Group criteria for paediatric MS (12) and the criteria of 
MS based on McDonald criteria 2010 (18) (Appendix C). 
Specific to the Russian Federation:  
In the Russian Federation: Patients with RRMS aged ≥12 years to <18 years are eligible at 
study entry (Appendix H). 
I 02. Signed written informed consent/assent obtained from patient and patient’s legal 
representative (parent or guardian) according to local regulations. 
I 03. Expanded Disability Status Scale (EDSS) score of 0.0 to 5.0 (inclusive) at screening 
(Appendix D). 
I 04. At least 2 recorded MS attacks, and at least 1 MS attack (relapse) in the last year during 
treatment with an IFNB or GA after having been on that therapy for at least 6 months, and 
is currently still taking the same therapy. 
I 05. At least 1 of the following: 
- 
≥1 new or enlarging T2 hyperintense lesion or gadolinium enhancing lesion while on 
that same prior therapy (IFNB or GA), OR 
- 
2 or more relapses in the prior year, OR 
- 
tried at least 2 MS DMTs. 
7.2 
EXCLUSION CRITERIA  
Patients who have met all the above inclusion criteria listed in Section 7.1 will be screened for the 
following exclusion criteria which are sorted and numbered in the following 3 subsections:  
NOTE: Prior to initiation of any alemtuzumab treatment course, contraindications should be 
reviewed as pre-treatment verification of eligibility.  
7.2.1 Exclusion criteria related to study methodology  
E 01. Any progressive or nonrelapsing forms of MS. 
E 02. Conditions/situations such as: 
- 
Impossibility to meet specific protocol requirements, 
- 
Current participation in another interventional clinical study. If a patient has been 
enrolled in a clinical trial and treated with a comparator agent that is an approved agent 
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for screening inclusion (INF or GA), they may be considered for this trial if they meet 
all inclusion and exclusion criteria otherwise, 
- 
Patient is the Investigator or any SubInvestigator, research assistant, pharmacist, study 
coordinator, other staff or relative thereof directly involved in the conduct of the 
protocol, 
- 
Uncooperative patient or any condition that could make the patient potentially 
noncompliant to the study procedures in the opinion of the Investigator. 
E 03. Mental condition rendering the patient or parent/guardian unable to understand the nature, 
scope, and possible consequences of the study. 
E 04. Clinically relevant cardiovascular, hepatic, neurological, endocrine, or other major 
systemic disease making implementation of the protocol or interpretation of the study 
results difficult or that would put the patient at risk by participating in the study in the 
opinion of the Investigator. 
E 05. History of drug or alcohol abuse. 
E 06. History of known HIV positivity. 
7.2.2 Exclusion criteria related to alemtuzumab and/or mandatory background therapies  
E 07. Pregnant or breast-feeding female patients or those who plan to become pregnant during 
the study. 
E 08. Unwilling to agree to use a highly effective contraceptive method as defined (Appendix A) 
when receiving a course of alemtuzumab treatment and for 4 months following that course 
of treatment (fertile patients only).  
E 09. Female patients who have commenced menstruating (ie, are of childbearing potential) and 
are unwilling or unable to be tested for pregnancy. 
E 10. Previous treatment with alemtuzumab. 
E 11. Treatment with natalizumab, daclizumab, fingolimod, methotrexate, azathioprine, 
cyclosporine, or mycophenolate mofetil in the last 6 months prior to screening, or as 
determined by the treating physician to have residual immune suppression from these or 
other MS treatments. 
E 12. Treatment with teriflunomide in the last 12 months except if the patient underwent the 
accelerated elimination procedure as per local teriflunomide label. 
E 13. Previous treatment with mitoxantrone, cyclophosphamide, cladribine, rituximab, 
ocrelizumab, leflunomide, or any cytotoxic therapy. 
E 14. Previous treatment with any investigational medication (drug that has not been approved at 
any dose or for any indication). Use of an investigational medication that was subsequently 
licensed and nonstandard use of a licensed medication (eg, using a dose other than the dose 
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that is stated in the licensed product labeling or using a licensed therapy for an alternative 
indication) is not exclusionary. Prior treatment with herbal medications or nutritional 
supplements is also permitted. 
E 15. Intolerance of pulsed corticosteroids, especially a history of steroid psychosis. 
7.2.3 Exclusion criteria related to the current knowledge of alemtuzumab and study 
methodology  
If a patient was deemed a screen failure, he or she may be re-screened for this study up to 2 times. 
If a patient who previously failed screening for any reason is re-screened, the patient must sign a 
new informed consent form and be assigned a new patient number by IWRS/IVRS (the next 
sequential patient number at the site). All screening assessments need to be repeated to confirm 
eligibility for the study. Rescreening assessments may be discussed with the Sponsor on a 
case-by-case basis.  
Medical History 
E 16. History of malignancy. 
E 17. Prior documented history of thrombocytopenia, or platelet count at screening < lower limit 
of normal (LLN). 
E 18. Any disability acquired from trauma or another illness that, in the opinion of the 
Investigator, could interfere with evaluation of disability due to MS. 
E 19. Patients with known Type 1 hypersensitivity or anaphylactic reactions to the active 
substances or any of the excipients, or intolerance of acyclovir or its therapeutic 
equivalent. 
Medical Conditions 
E 20. Major systemic disease or other illness that would, in the opinion of the Investigator, 
compromise patient safety or interfere with the interpretation of study results, eg, current 
peptic ulcer disease, or other conditions that may predispose to hemorrhage, immune 
cytopenias, rheumatoid arthritis, systemic lupus erythematosus, other connective tissue 
disorders, vasculitis, inflammatory bowel disease, severe psoriasis. 
E 21. Medical, psychiatric, cognitive, or other conditions that, in the Investigator’s opinion, 
compromise the patient’s ability to understand the patient information, to give informed 
consent, to comply with the trial protocol, or to complete the study. 
E 22. Major psychiatric disorder that is not adequately controlled by treatment in the opinion of 
the Investigator. 
E 23. Epileptic seizures that are not adequately controlled by treatment. 
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E 24. MRI-related conditions: conditions that could interfere with MRI acquisition and/or 
interpretation of MRI results (eg, claustrophobia, orthopedic implants/treatments, 
orthodontic treatments etc). 
E 25. Known bleeding disorder (eg, dysfibrinogenemia, factor IX deficiency, hemophilia, Von 
Willebrand’s disease, disseminated intravascular coagulation, fibrinogen deficiency, 
clotting factor deficiency). 
Infections 
E 26. Prior history of invasive fungal infections. 
E 27. Active infection, eg, deep-tissue infection, that the Investigator considers sufficiently 
serious to preclude study participation. 
E 28. In the Investigator’s opinion, patient is at high risk for infection (eg, indwelling catheter, 
dysphagia with aspiration, decubitus ulcer, history of prior aspiration pneumonia or 
recurrent urinary tract infection). 
E 29. Infection with hepatitis B, C viruses (positive serology, but not due to hepatitis 
immunization). 
E 30. History of tuberculosis (TB)/latent TB (unless it is documented by a specialist that the 
patient has been adequately treated and can now start treatment with a biologic agent). 
E 31. Testing will be conducted for human papillomavirus (HPV) infection as and when 
recommended by local public health authorities. If the testing is positive, the patient may 
be eligible after the condition has resolved as per the Investigator opinion (eg, follow-up 
HPV test is negative or cervical abnormality has been effectively treated). 
E 32. Any other illness or infection (latent or active) that, in the Investigator’s opinion, could be 
exacerbated by study medication. 
Laboratory Parameters 
E 33. Confirmed platelet count <LLN of the evaluating laboratory at Screening or documented at 
<100 000/μL within the past year on a sample without platelet clumping. 
E 34. CD4+, CD8+, or CD19+ (ie, absolute CD3+CD4+, CD3+CD8+, or CD19+/mm3) 
count <LLN at Screening; if abnormal cell count(s) return to within normal limits, 
eligibility may be reassessed. 
E 35. Absolute neutrophil count <LLN at Screening; if abnormal cell count returns to within 
normal limits, eligibility may be reassessed. 
Note: If the treating physician suspects out-of-range cell count results are based upon issues of 
sample transportation or environmental conditions, the treating physician may request a repeat 
sample to be evaluated locally to confirm the patient is not excluded from the trial. If out-of-range 
cell counts are not confirmed through evaluations performed locally, the treating physician should 
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document (in source data and in a CRF comment) that the central laboratory results are considered 
falsely exclusive, and proceed to enroll the patient. 
E 36. Any hepatic or renal function value Grade 2 or higher at Screening, with the exception of 
hyperbilirubinemia due to Gilbert’s syndrome, unless, in the Investigator’s opinion, the 
abnormality is due to a condition that has resolved (eg, recent interferon treatment 
subsequently discontinued) and levels return to within normal limits. See Table 7 below, 
drawn from the National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events v3.0 (CTCAE), published 09 August 2006. 
Table 7 - Common terminology criteria for adverse events v3.0, published 09 August 2006.  
Hepatic 
 
Bilirubin 
>1.5 x ULN 
SGOT/AST 
>2.5 x ULN 
SGPT/ALT 
>2.5 x ULN 
Alkaline phosphatase 
>2.5 x ULN 
Renal 
 
Creatinine 
>1.5 x ULN 
Abbreviations: AST: aspartate aminotransferase; ALT: alanine aminotransferase; SGOT: serum glutamic oxaloacetic transaminase; SGPT: 
serum glutamic-pyruvic transaminase; ULN: upper limit of normal. 
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8 
STUDY TREATMENTS  
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S)  
Name of the Investigational Medicinal Product (IMP): 
Alemtuzumab. 
Pharmaceutical form: 
Concentrate for solution for infusion (sterile concentrate). Each vial contains 12 mg/1.2 mL of 
solution. 
Dose of drug per administration:  
First course: at Month 0 for 5 consecutive days 
Calculation of the dose used will be determined based on patient weight taken at the first infusion 
visit, of the first course, during the physical examination: 
• For patients ≥50 kg: 12 mg/day. 
• For patients <50 kg: 0.24 mg/kg/day. 
Second course: at Month 12 for 3 consecutive days 
Calculation of the dose used will be determined based on patient weight taken at the first infusion 
visit, of the second course, during the physical examination: 
• For patients ≥50 kg: 12 mg/day. 
• For patients <50 kg: 0.24 mg/kg/day. 
Route of administration: 
IV infusion. 
8.1.1 Administration  
Alemtuzumab will be administered only after a decision from the Study Investigator. 
First course: Alemtuzumab will be administered by IV infusions for 5 consecutive days at 
Month 0 in a supervised medical setting at a dose of: 
• For patients ≥50 kg: 12 mg/day. 
• For patients <50 kg: 0.24 mg/kg/day. 
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Second Course will occur 12 months after the first course. 
Second Course: Alemtuzumab will be administered by IV infusion for 3 consecutive days at 
Month 12 in a supervised medical setting at a dose of: 
• For patients ≥50 kg: 12 mg/day. 
• For patients <50 kg: 0.24 mg/kg/day (this equates to 12 mg/day for a 50 kg patient). 
8.1.1.1 Method of preparation at the clinical site  
Alemtuzumab must be diluted before infusion. The diluted solution must be administered by 
IV infusion. The infusion duration will be approximately 4 hours starting within 8 hours after 
dilution. Extend the duration of the infusion if clinically indicated. 
Additional requirements for alemtuzumab infusion and monitoring during and post infusion are 
specified in Section 10.1.4 Visit 4/M0/D1 (first course of alemtuzumab) and Section 10.1.10 
Visit 16/M12 (second course of alemtuzumab). 
8.1.1.2 Special precautions for disposal and other handling  
The vial contents must be inspected for particulate matter and discoloration prior to 
administration. Do not use if particulate matter is present or the concentrate is discolored. Do not 
shake the vials prior to use. 
For IV administration, withdraw the prescribed amount of alemtuzumab from the vial into a 
syringe using aseptic technique. Inject into 100 mL of sodium chloride 9 mg/mL (0.9%) solution 
for infusion or glucose (5%) solution for infusion. This medicinal product must not be diluted 
with other solvents. The bag must be inverted gently to mix the solution. 
Alemtuzumab contains no antimicrobial preservatives and, therefore, care must be taken to ensure 
the sterility of the prepared solution. It is recommended that the diluted product be administered 
immediately. Each vial is intended for single use only. 
Any partially used, unused, or damaged drug vials should be disposed of in accordance with local 
requirements. 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCTS  
A) Premedications: 
• Day -1 (day before first IV infusion at each course) in the morning: 
- 
Oral prednisone/prednisolone 1 mg/kg or 50 mg one dose, whichever is lower, or 
equivalent, 
- 
H2 antagonist according to the local label (eg, ranitidine). 
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• Day -1 (day before first IV infusion at each course) in the evening: 
- 
H1 antagonist according to the local label (eg, cetirizine), 
- 
H2 antagonist according to the local label (eg, ranitidine). 
• On days of IV infusions (1 hour prior to infusion): 
- 
H2 antagonist: eg, ranitidine or equivalent, 
- 
NSAID/antipyretic: paracetamol or equivalent, 
- 
H1 antagonist IV diphenhydramine (25 mg or appropriate weight based dosing based 
on local health authority recommendations [Appendix H]), immediately followed by: 
- 
IV methylprednisolone: administer 1000 mg on infusion Days 1, 2, 3 (all courses) and 
≥500 mg on infusion Days 4 and 5 (if 5 days of infusion). 
Notes: 
• 
a) If diphenhydramine IV is not available, an equivalent H1 antagonist can be used at an equivalent dosing, via IV route, 
b) If no H1 antagonist is available in IV formulation, an oral formulation of an 
equivalent compound can be used at an equivalent dosing, 2 hours prior to infusion. 
• Day 4 and Day 5 of the first course: 
- 
H1 antagonist, H2 antagonist, and antipyretics as needed, 
- 
Fluid intake will be encouraged. 
B) Concomitant medications: 
• Acyclovir 200 mg oral twice daily (or therapeutic equivalent) will also be provided/given 
at the beginning on the first day of each treatment course and continuing for a minimum of 
1 month following treatment with alemtuzumab. 
8.3 
BLINDING PROCEDURES  
8.3.1 Methods of blinding  
This study has an open-label design. All enrolled patients will be on prior DMT when entering 
into the study and will be treated with alemtuzumab during alemtuzumab treatment phase. No 
randomization will be done. 
The study will be rater-blinded for MRI. All brain scans will be reviewed and interpreted by one 
or more MRI experts at an independent, central facility with no access (ie, blinded) to treatment 
thereby avoiding bias. Refer to Section 9.1.1.1 and Section 9.2.1.1. 
The MRI assessments will be available to the investigators to assess safety. 
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8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP  
All enrolled patients will be on prior DMT when entering into the study and up to approximately 
4 months. After this period all patients will stop their prior DMT and will be treated with 
alemtuzumab during alemtuzumab treatment phase. 
No randomization will be performed.  
An interactive voice response system (IVRS)/interactive web response system (IWRS) will be 
used for this study to manage and control alemtuzumab dispensation. The treatment kit number 
list is generated centrally by Sanofi. Alemtuzumab will be packaged in accordance with this list. 
8.5 
PACKAGING AND LABELING  
Packaging will be in accordance with the administration schedule. The content of the labeling will 
be in accordance with the local regulatory specifications and requirements. 
8.6 
STORAGE CONDITIONS AND SHELF LIFE  
Investigators or other authorized persons (eg, pharmacists) are responsible for storing 
alemtuzumab in a secure and safe place in accordance with local regulations, labeling 
specifications, policies and procedures. 
Control of storage conditions for alemtuzumab will be provided by the Sponsor, especially control 
of temperature (eg, refrigerated storage) and information on in-use stability and instructions for 
handling alemtuzumab. 
Alemtuzumab, in vials, must be stored between +2°C to + 8°C (+36°F to +46°F). Do not freeze 
and do not shake. Do not use alemtuzumab beyond the use by date provided on the label or other 
documentation. Protect from light. 
Prior to administration, protect diluted alemtuzumab solution from light and store for as long as 
8 hours either at room temperature 15°C to 25°C (59°F to 77°F) or keep refrigerated at conditions 
2°C to 8°C (36°F to 46°F). From a microbiological point of view, it is recommended that the 
product should be used immediately. Partially used, unused or damaged drug vials should be 
disposed according to institutional policies. 
Alemtuzumab will be used in accordance with the approved protocol and must not be used for any 
other purpose. 
8.7 
RESPONSIBILITIES  
The Investigator, the hospital pharmacist, or other personnel allowed to store and dispense the 
IMP will be responsible for ensuring that the IMP used in the clinical trial is securely maintained 
as specified by the Sponsor and in accordance with applicable regulatory requirements. 
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All IMP will be dispensed in accordance with the Investigator's prescription and it is the 
Investigator's responsibility to ensure that an accurate record of IMP issued and returned is 
maintained. 
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) must be promptly notified to the Sponsor 
(see Section 10.4.7). Some deficiencies may be recorded through a complaint procedure. 
A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
Sponsor. In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor, in order to recall the IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party, allow the IMP to be 
used other than as directed by this clinical trial protocol, or dispose of IMP in any other manner. 
8.7.1 Treatment accountability and compliance  
As alemtuzumab will be administered by daily IV infusions in a day hospital supervised medical 
setting, by qualified center personnel, responsibility for compliance with mandatory safety 
assessments resides with the Study Investigator. 
8.7.2 Return and/or destruction of treatments  
For IMP provided by the Sponsor: 
Reconciliation of all used, partially-used or unused treatments must be performed at the site by the 
Investigator and the monitoring team using treatment log forms. 
Written authorization for destruction will be given by the sponsor once the reconciliation has been 
completed. This destruction can be performed at the site depending on local regulations and site 
specific capabilities; alternatively, study drug may be returned to the sponsor or designee for 
destruction. The Investigator will not destroy the used and unused IMP unless the Sponsor 
provides written authorization. 
8.8 
CONCOMITANT MEDICATION  
A concomitant medication is any treatment received by the patient concomitantly to any IMP(s). 
Concomitant treatments have been detailed for all phases of the study and are not limited to the 
treatment received with the IMP (treatment phase). Concomitant use of alternative medications 
(eg, herbal treatments, botanicals, etc) for treatment of MS is discouraged due to concerns of 
possible interactions with study treatment. Patients should be questioned about their use of such 
nonprescription therapies, all of which will be listed as concomitant medications. 
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Prior DMT period 
Therapy with disease-modifying MS treatments that the patient is currently being administered 
(ie, limited to interferons and GA only) will be permitted during the screening and prior DMT 
Treatment Phase. If the investigator determines that the patient needs to be treated with another 
DMT, the patient will be discontinued from the study. 
Prior DMT will be discontinued 7 days before alemtuzumab first administration. Refer to 
Section 6.1 for further details. 
No concomitant therapy with any other disease-modifying MS treatments either licensed or 
investigational will be permitted during the screening and prior DMT period. 
Concomitant use of systemic corticosteroids for the treatment of MS relapse is allowed during the 
DMT period. 
Alemtuzumab treatment phase 
Patients who receive any alemtuzumab treatment will continue study participation even if they do 
not complete the planned treatment regimen. Patients who discontinue study treatment can 
continue study participation. If a patient is not willing to continue study participation, all efforts 
should be made to have the EOTP visit performed by the patient. 
No concomitant therapy with any disease-modifying MS treatments either licensed or 
investigational, including interferons and GA, will be permitted during the alemtuzumab 
treatment phase. If the investigator determines that the patient needs to be treated with another 
DMT, the patient will be discontinued from the study. 
In addition, no other investigational MS therapy, including investigational symptomatic therapy, 
will be permitted. Use of live vaccines is specifically prohibited for alemtuzumab-treated patients 
for the 30 days prior to the first alemtuzumab administration at Month 0 and for the 2 years 
duration of the alemtuzumab treatment phase of the study. 
Concomitant use of systemic corticosteroids for the treatment of MS relapse is allowed during this 
period. 
Safety monitoring phase 
The safety of MS disease-modifying drugs in patients who receive alemtuzumab has not been 
established. Alemtuzumab treatment may have long-lasting, unknown effects on a patient’s 
immune system. Concomitant therapy with any disease-modifying MS treatments following 
treatment with alemtuzumab has not been studied in a controlled study conducted by Sanofi 
Genzyme. Investigators should consider the potential for adverse effects associated with 
subsequent or concomitant treatment with cytotoxic or immunosuppressant drugs in patients who 
have received alemtuzumab. 
Participating patients are prohibited from use of any investigational MS therapy. 
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It is investigator criteria to determine if the patient needs to be treated with another DMT, and in 
which case the patient will be discontinued from the study. 
Concomitant use of systemic corticosteroids for the treatment of MS relapse is allowed during the 
course of the Study. Relapses may be treated with systemic corticosteroids if clinically necessary 
and as per Investigator judgment in doses appropriate for paediatric population. 
The use of systemic corticosteroids or adrenocorticotrophic hormone within 2 weeks prior to MRI 
assessment is not permitted due to potential interference with MRI assessment. 
It is recommended that patients complete local immunization requirements at least 6 weeks prior 
to treatment with alemtuzumab. The ability to generate an immune response to any vaccine 
following alemtuzumab treatment has not been studied. 
The safety of immunization with live viral vaccines following a course of alemtuzumab treatment 
has not been formally studied in controlled clinical trials in MS. Live vaccines must not be 
administered to MS patients who have recently received a course of alemtuzumab. Also, some 
experts urge caution in using live pathogen vaccinations in people with MS (National MS Society 
web site). 
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9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT  
The assessments will be performed according to the schedule presented in the Study Flowchart. 
See Section 1.2 and Section 10 for further details. 
9.1 
PRIMARY ENDPOINT  
9.1.1 Primary efficacy endpoint  
The primary endpoint is the number of new or enlarging T2 lesions on brain MRI, during 
continuation of prior DMT (Period 1) compared to an equal period after the first course of 
alemtuzumab treatment (Period 2). The primary efficacy endpoint will be assessed by brain MRI. 
9.1.1.1 Brain MRI  
For primary endpoint assessment, two periods have been defined 
• Period 1: will occur from M-4 up to M0. An MRI will be performed during the screening 
period and another at Visit 3. Both MRI will be taken while patients are on their prior 
DMT. The two MRIs will be compared by a central assessor to count the number of new 
or enlarging T2 lesions. It is important to ensure that these 2 MRI assessments are 
performed 4 months (±7 days) apart. 
• Period 2: will occur from M4 to M8: The MRI performed at the M4 visit will be the 
baseline MRI for Period 2. A second MRI will be performed after alemtuzumab first 
course of treatment at M8. The two MRIs will be compared by a central assessor to count 
the number of new or enlarging T2 lesions. It is important to ensure that these 2 MRI 
assessments are performed 4 months (±7 days) apart. 
It is expected that Periods 1 and 2 will be of the same length ±7 days.  
“Baseline” MRI will be collected during the screening visit (baseline for Period 1) and the 
M4 visit (baseline for Period 2). The “baseline” lesion volume for the corresponding period will 
be adjusted in the generalized estimating equation (GEE) model. 
Screening MRI is expected to be reviewed locally by PI only for study eligibility confirmation. 
The MRI assessments will also be available to the investigators to assess safety. 
In addition to primary endpoint MRIs (Screening, D-7, M4, M8) other MRIs will be performed at 
M12, M24/at EOTP, and then annually in the Safety Monitoring Phase. 
All brain MRIs will be reviewed and interpreted by one or more MRI experts at an independent, 
central facility with no access (ie, blinded) to patients’ treatment thereby avoiding bias. 
An MRI manual explaining the instructions for standard image acquisition requirements, data 
transfer, archiving and shipping, and outlining the phantom data approval process will be 
provided to all centers. 
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MRI should not be conducted within 2 weeks of steroid administration due to potential 
interference with MRI assessment. 
9.2 
SECONDARY ENDPOINTS  
Secondary endpoints include the efficacy, quality of life and pharmacokinetic/Pharmacodynamic 
endpoints are listed below, and will be assessed as shown in Section 9.2.1 and Section 9.2.2: 
Efficacy: 
• The number of patients with new or enlarging T2 lesions during continuation of prior 
DMT (Period 1) compared to an equal period after the first course of alemtuzumab 
treatment (Period 2). 
• EDSS (descriptive analysis, ie percentages of stable/improved/worsened since the end of 
Period 1).  
• Annualized relapse rate (ARR) at Year 2. 
• Cognition test scores: Brief Visuospatial Memory Test – Revised (BVMT-R) and Symbol 
Digit Modality Test (SDMT); administered at least every 6 months over 2 years. 
Quality of life: 
• Established generic paediatric QoL measures administered every 6 months over 2 years. 
Pharmacokinetics/Pharmacodynamics: 
• PK serum concentration and PK parameters (Cmax, Tmax, AUC, AUClast, T1/2z) calculated 
where possible. 
• PD assessment including lymphocyte subsets.  
9.2.1 Secondary efficacy endpoints  
9.2.1.1 Expanded disability status scale  
Patient disability will be evaluated using the EDSS (Appendix D), which has long been 
considered the standard for assessing disability in patients with MS (19). 
The EDSS is an ordinal clinical rating scale which ranges from 0 (normal neurologic examination) 
to 10 (death due to MS) in half-point increments. Briefly, the assessing neurologist rates 
7 functional systems (pyramidal, cerebellar, brainstem, sensory, bowel and bladder, visual ratings) 
in conjunction with observations and information concerning the patient’s mobility, gait, and use 
of assistive devices to assign an EDSS score. 
EDSS steps 1.0 to 4.5 refer to people with MS who are fully ambulatory, while EDSS steps 5.0 to 
9.5 are defined by the impairment to ambulation. 
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The EDSS will be performed by the neurologist at the following visits: Screening, D-7, M4, M8, 
M12, M15, M18, M21, M24/at EOTP; every 6 months in Safety Monitoring Phase, and at every 
relapse visit. 
9.2.1.2 Annualized relapse rate at Year 2  
Subjects/parents/guardians will be instructed to contact their Investigator immediately should any 
symptoms suggestive of an MS relapse appear. The subject must be examined as soon as possible, 
within 7 days from the onset date of the relapse. 
Relapses are defined as new or recurrent neurological symptoms not associated with fever or 
infection, lasting at least 24 hours, and accompanied by new objective neurological findings upon 
examination by the neurologist and documented by the functional system scores. The subject must 
have objective signs on the neurologist’s examination confirming the event. 
New or recurrent symptoms that occur less than 30 days following the onset of a relapse should be 
considered part of the same relapse. The Investigator can, at his/her discretion, treat the patient 
with corticosteroids. 
Relapses will not be considered as AEs (see AE Section 10.4.3). 
9.2.1.3 Cognition test scores  
9.2.1.3.1 Brief visuospatial memory test - revised  
The Brief Visuospatial Memory Test - Revised (BVMT-R) is a commonly used, commercialized, 
assessment tool to measure visuospatial learning and memory abilities across research and clinical 
settings.  
A visual display of six simple figures arranged in a 2 × 3 matrix on separate pages is shown to 
participants patients for three consecutive 10-second trials. After each trial, participants are to 
draw as many designs as accurately as they can and in the correct location. They are again asked 
to reproduce the designs in the exact layout after a 25-minute delay filled with other distractor 
tasks. A forced-choice recognition trial is administered immediately following the delayed 
memory trial. An optional copy trial is included at the end of the test where the participants are 
asked to copy the figure display as accurately as they can. Scoring of the immediate and delayed 
recall as well as copy trials are based on the accuracy of the drawings and the location of the 
figures. For each figure, one point is awarded to each satisfactory domain resulting in a maximum 
of 12 points per trial. 
Brief Visuospatial Memory Test-Revised will be assessed at Screening, D-7, M4, M8, M12, M18, 
M24/at EOTP; annually in Safety Monitoring Phase. Central scoring will be performed by an 
independent rater who is blinded to treatments (ie, current DMT or alemtuzumab). 
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9.2.1.3.2 Symbol digit modality test  
Cognitive impairment will be assessed using the Symbol Digit Modality Test (SDMT) Brief and 
easy to administer, the SDMT has demonstrated remarkable sensitivity in detecting not only the 
presence of brain damage, but also changes in cognitive functioning over time and in response to 
treatment. The SDMT involves a simple substitution task that normal children and adults can 
easily perform. Using a reference key, the examinee has 90 seconds to pair specific numbers with 
given geometric figures. Responses can be written or oral, and for either response mode, 
administration time is just 5 minutes. For this study, only ORAL form of response is desired 
(ie, patient does NOT write down the responses, instead, patient is instructed to verbally call out 
the numbers that correspond to the symbols and the administer writes down his/her responses. 
9.2.2 Other secondary endpoints  
9.2.2.1 Pharmacokinetics  
For patients receiving alemtuzumab, serum concentrations and PK parameters will be studied 
9.2.2.1.1 Sampling time  
The sampling times for blood collection can be found in the Study Flow Chart Section 1.2.4 and 
Section 1.2.5.  
9.2.2.1.2 Pharmacokinetics handling procedure  
Special procedures for collection, storage, and shipment of plasma samples collected for 
EFC13429 concentrations will be provided in a separate laboratory manual. 
9.2.2.1.3 Bioanalytical method  
Details of the bioanalytical methods are described in Appendix B and detailed in a separate 
laboratory manual. 
9.2.2.1.4 Pharmacokinetics parameters  
The following PK parameters will be calculated, using noncompartmental methods from the 
cumulative serum alemtuzumab concentrations. The parameters will include, but may not be 
limited to the following Table 8: 
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Table 8 - List of pharmacokinetic parameters and definitions  
Parameters 
Drug/Analyte 
Matrix 
Definition/Calculation 
Cmax 
Alemtuzumab 
Serum 
Maximum serum concentration observed 
Tmax 
Alemtuzumab 
Serum 
Time to reach Cmax 
AUClast  
Alemtuzumab 
Serum 
Area under the cumulative serum concentration versus time curve 
calculated using the trapezoidal method from time zero to the real time tlast 
AUC 
Alemtuzumab 
Serum 
Area under the cumulative serum concentration versus time curve 
extrapolated to infinity according to the following equation:  
 
Values with percentage of extrapolation >30% will not be reported 
t1/2z 
Alemtuzumab 
Serum 
Terminal half-life associated with the terminal slope (λz) determined 
according to the following equation: 
 
where λz is the slope of the regression line of the terminal phase of the 
cumulative serum concentration versus time curve, in semi-logarithmic 
scale. Half-life is calculated by taking the regression of at least 3 points. 
9.2.2.2 Pharmacodynamic variables  
Pharmacodynamic assessments of lymphocyte subsets will be performed in order to characterize 
the PD profile of 2 treatment courses of alemtuzumab in paediatric patients. 
9.2.2.2.1 Assessment methods  
Lymphocyte phenotyping 
To monitor the extent of lymphocyte depletion and repopulation, lymphocyte phenotyping, 
including a standard, 6-color TBNK (T cells, B cells, and natural killer cells) panel (CD3+, CD4+, 
CD8+, CD19+, CD16+, CD56+, total lymphocytes, and helper/suppressor ratio [CD4+/CD8+]), 
will be performed. Lymphocyte phenotyping will be assessed at screening, D-14 to D-7, M1, M4, 
M8, M12, M13, M15, M18, M21, M24/at EOTP; annually in Safety Monitoring Phase. 
9.2.2.3 Quality of life endpoints  
Quality of Life (QoL) will be assessed by established generic paediatric QoL measures. 
PedsQL questionnaire 
The PedsQL™ Measurement Model is a modular approach to measuring health-related 
quality of life (HRQOL) in healthy children and adolescents and those with acute and chronic 
z
C
AUC
AUC
last
last

+
=
z
1/2Z
0.693
 
t

=
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health conditions. The PedsQL Measurement Model integrates seamlessly both generic core 
scales and disease-specific modules into one measurement system. 
The 23-item PedsQL Generic Core Scales (Appendix F) were designed to measure the core 
dimensions of health as delineated by the World Health Organization, as well as role (school) 
functioning. 
Paediatric NeuroQoL questionnaire 
Paediatric NeuroQoL (Quality of Life in Neurological Disorders) is a measurement system that 
evaluates and monitors the physical, mental, and social effects experienced by children living with 
neurological conditions. Physical effects (fatigue and pain) and mental effects (cognitive function, 
anxiety, and depression) experienced by patients will be assessed (Appendix G). 
PedsQL and paediatric NeuroQoL questionnaire will be assessed at Screening, D-14 to D-7, M4, 
M8, M12, M18, M24/at EOTP; and annually in Safety Monitoring Phase. 
9.3 
SAFETY ENDPOINTS  
Safety endpoints will be assessed by:  
• AE reporting at each visit. 
• Physical examination and vital signs: Screening, D-14 to D-7, M0/D1, M4, M8, M12, 
M15, M18, M21, M24/at EOTP; every 6 months in the safety monitoring phase, and at 
every relapse visit. 
• Additionally, vital signs will be collected hourly during alemtuzumab infusion and post 
infusion observation period. 
• Clinical chemistry laboratories: Screening, D-14 to D-7, M4, M8, M12, M15, M18, M21, 
M24/at EOTP; quarterly in the safety monitoring phase. In addition, only serum creatinine 
will be assessed at M0/D1, monthly in alemtuzumab treatment phase (Year 1 and 2); 
monthly in the safety monitoring phase (inclusive of chemistry panel). 
• Hematology: Screening, D-14 to D -7, M0/D1, and monthly in alemtuzumab treatment 
phase (Year 1 and 2); EOTP, and monthly in the safety monitoring phase. 
• Urinalysis: Screening, D-14 to D -7, monthly in alemtuzumab treatment phase (Year 1 and 
2); EOTP, and monthly in the safety monitoring phase. 
• Thyroid Function tests: Screening, D-14 to D -7, quarterly in alemtuzumab treatment 
phase (Year 1 and 2); EOTP, and quarterly in the safety monitoring phase. 
• Tanner staging: Screening, M12, M24/at EOTP; annually in the safety monitoring phase. 
• Pregnancy testing (females only): Screening (blood test), D-14 to D -7 and M12 (urine 
test). 
• Assessment of ADA: M0/D1 (baseline), post dose M1, M3, M12 (prenext dose), M13, 
M15, M24/at EOTP; and annually in the safety monitoring phase. 
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9.3.1 Adverse events  
Adverse events reported by the patient or observed by the Investigator will be monitored, and 
include: 
• Occurrence, seriousness, grade/intensity, relationship to study drug, resolution, and 
outcome of serious adverse event (SAE), adverse event of special interest (AESI) , and 
AEs. 
• Assessment of IARs: An IAR is defined as any AE occurring during alemtuzumab 
infusion or within the 24 hour post-infusion period. However, some IARs may occur 
beyond 24 hours (such as pulmonary alveolar hemorrhage, stroke, cervicocephalic arterial 
dissection, myocardial ischemia, thrombocytopenia and myocardial infarction). Toxicity 
grade (severity) of IAR is based on CTCAE. The timing of IAR in relation to 
alemtuzumab administration and distribution of IARs based on toxicity grade (severity) 
observed in the study for both study periods will be assessed.  
Refer to Section 10.4.1 for details. 
9.3.2 Laboratory safety variables  
The clinical laboratory data consist of blood analysis (including hematology, clinical chemistry, 
and urinalysis). Clinical laboratory values will be analyzed after conversion into standard 
international units. International units will be used in all listings and tables. 
All laboratory data listed in this section will be measured at a central laboratory. The laboratory 
data will be collected at designated visits as shown in study flow chart Section 1.2. 
It is preferred that CBCs with platelet count (for monitoring for any cytopenia as well as), serum 
creatinine, and urinalysis with microscopy be analyzed at the central laboratory, but under special 
circumstances (eg, if patient is unable to visit the study center weekly or monthly, or results are 
needed urgently), the assay may be performed at a local laboratory provided that test results are 
entered into the e-CRF in a timely manner. In addition, at some visits during the safety monitoring 
phase, there is an option for the nurse to obtain samples for clinical chemistry laboratories, 
hematology, thyroid function tests, urinalysis and serum creatinine at the patient’s home if needed 
(refer to study flow chart Section 1.2). 
The following laboratory safety variables will be analyzed: 
• Hematology and differential panel: red blood cell count, hematocrit, hemoglobin, mean 
corpuscular hemoglobin, white blood cell count with differential count (neutrophils, 
eosinophils, basophils, monocytes, and lymphocytes) and platelets. 
• Complete Chemistry panel: glucose, serum creatinine, blood urea nitrogen (BUN), 
sodium, potassium, chloride, bicarbonate, magnesium, calcium, uric acid, aspartate 
aminotransferase, alanine aminotransferase (ALT), gamma-glutamyl transferase, lactate 
dehydrogenase, total bilirubin, direct/indirect bilirubin, alkaline phosphatase, inorganic 
phosphorus, total protein, albumin, globulin, albumin/globulin ratio, triglycerides, total 
cholesterol and creatinine phosphokinase. 
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• Urinanalysis: pH, ketones, protein, glucose, blood, urobilinogen, bilirubin, microscopic 
sediment, specific gravity. 
• Thyroid function testing: thyroid stimulating hormone and if abnormal T3 and T4. 
• Hepatitis B and C serology testing. 
• HPV serology testing: Testing will be conducted for human papillomavirus (HPV) 
infection as and when recommended by local public health authorities. If the testing is 
positive, the patient may be eligible after the condition has resolved as per the Investigator 
opinion (eg, follow-up HPV test is negative or cervical abnormality has been effectively 
treated). An annual follow-up is recommended. 
• Tuberculosis test screening. It should be performed as per local health care authority 
recommendations. 
Pregnancy testing: β-Human chorionic gonadotropin. 
In accordance with international recommendations (20), sampling blood volume will be 
minimized to approximately 1% of total blood volume at each visit and approximately 3% of total 
blood volume over a 4 week period.  
Blood sample volume will range from 9 to 57 ml, depending on tests required at study visits 
(ie, an average blood sample amount of 23 ml per visit). The total amount of blood withdrawn 
will be approximately 350 ml in Year 1 and 200 ml in Year 2. During the safety monitoring phase, 
approximately 120 ml will be drawn each year. However, additional blood samples may be 
collected at the Investigator’s discretion for patient safety monitoring. 
9.3.3 ITP, cytopenia, and antiGBM surveillance and monitoring  
In an effort to identify ITP early and minimize the risk of bleeding due to low platelet counts, this 
protocol requires safety measures including monthly blood testing to monitor CBCs with platelet 
count for monitoring for any cytopenia. Patients with certain abnormalities may be required to 
have more frequent blood tests. See Appendix B (Immune thrombocytopenia). 
If a cytopenia is suspected, appropriate medical intervention should be promptly initiated, 
including referral to specialist. 
Alemtuzumab has also been associated with antiGBM disease, which can cause a pulmonaryrenal 
syndrome known as Goodpasture’s disease (21, 22). AntiGBM disease is a rare autoimmune 
disorder in which circulating antibodies are directed against an antigen normally present in the 
basement membranes of renal glomeruli and pulmonary alveoli. The target antigen is the alpha-3 
chain of type IV collagen. The resultant clinical syndrome encompasses a spectrum ranging from 
mild or no renal involvement to rapidly progressive glomerulonephritis. Patients may develop 
pulmonary hemorrhage. 
In an effort to identify potential cases of antiGBM disease early, all patients in the study will 
undergo monthly evaluation of serum creatinine levels alone or as part of a full chemistry panel 
and laboratory urinalysis (minimally including examination of protein and hemoglobin) with 
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microscopy.  Follow up of abnormal results will be guided by the algorithm below in Appendix B 
(Anti-Glomerular Basement Membrane Disease). 
9.3.4 Hemophagocytic lymphohistiocytosis  
During postmarketing use, HLH has been reported in patients treated with alemtuzumab. 
Hemophagocytic lymphohistiocytosis is a life-threatening syndrome of pathologic immune 
activation characterized by clinical signs and symptoms of extreme systemic inflammation, 
including fever, swollen lymph nodes, bruising or skin rash. It is associated with high mortality 
rates if not recognized early and treated. Symptoms have been reported to occur within a few 
months to four years following the initiation of treatment. Patients who develop disease 
manifestations of pathologic immune activation should be evaluated immediately, and a diagnosis 
of HLH as well as referral of the patient to a specialist should be considered. 
9.3.5 Physical examination and vital signs  
Whenever possible, the same physician should perform the physical examination at all study 
visits. The findings of each examination will be recorded. 
A standard physical examination for clinical and neurological assessments which includes 
examination of major body systems, height and body weight will be performed. 
Physical examination and vital signs will be performed at screening, D-14 to D-7, M0/D1, M4, 
M8, M12, M15, M18, M21, M24/at EOTP; every 6 months safety monitoring phase, and at every 
relapse visit. 
The following vital signs: respiratory rate, heart rate, systolic and diastolic blood pressure and 
body temperature, will be measured during each physical examination and at the following 
timepoints during alemtuzumab treatment: 
• Before methylprednisolone infusion. 
• At a time after methylprednisolone infusion and prior to alemtuzumab infusion. 
• 1 hour after the start of alemtuzumab infusion and hourly during and after infusion, until 
2 hours after infusion has ended or longer until stabilization. 
Body temperature will be collected using the same method at each assessment for a given patient.  
Blood pressure will be measured under standardized conditions using the same method at each 
assessment for a given patient. It will be determined at each study visit using a well calibrated 
apparatus. Both systolic and diastolic blood pressure must be recorded.  
The date of the first menarche should be captured if applicable. 
The Tanner stage (Appendix E) should be assessed until complete sexual maturity at the specified 
time points, see Study flowchart Section 1.2 for further details. 
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The Tanner scale (also known as the Tanner stages I-V) is a scale of physical development in 
children, adolescents and adults (23, 24). The scale defines physical measurements of 
development based on external primary and secondary sex characteristics, such as the size of the 
breasts, genitalia, and development of pubic hair. Tanner scale is performed either at the study site 
by the paediatric neurologist or paediatrician or at a designated site arranged by the Investigator. 
9.3.6 Other safety endpoints  
The other safety endpoints will be assessed by: 
• Antidrug antibody formation (ADA). 
Assessment of ADA formation will be performed at M0/D1 (baseline), post dose, M1, M3, M12 
(prenext dose), M13, M15, M24/at EOTP, and annually in the safety monitoring phase. 
IV infusion of alemtuzumab has been associated with the development of antialemtuzumab 
antibodies and inhibitory antibodies. Serum samples will be tested by established assay methods 
for the presence of antialemtuzumab antibodies and titers will be quantified for positive samples. 
9.4 
EXPLORATORY ENDPOINT  
T1 weighted lesions and brain volume will be assessed on MRI as an exploratory endpoint MRI 
throughout the study period. 
9.5 
FUTURE USE OF SAMPLES  
9.5.1 Immune markers (optional)  
Based on the increased risk of autoimmune events observed with alemtuzumab, serum will be 
collected to support investigation of potential biomarkers predictive of the response to 
alemtuzumab. The markers to be tested may include cytokines and possibly other serum 
components; the specific markers to be assessed will be guided by results of ongoing biomarker 
investigations with alemtuzumab. 
If the patient accepts to sign the specific informed consent form (ICF), “Future Use of Samples”, 
serum samples and peripheral blood mononuclear cell will be collected at the visit specified in the 
study flow chart (designated “immune markers”) and these samples will be stored to support 
future investigation of potential biomarkers predictive of autoimmunity, such as serum cytokines. 
9.6 
APPROPRIATENESS OF MEASUREMENTS  
The primary endpoint is the number of new or enlarging T2 lesions during continuation of prior 
DMT (Period 1) and during an approximately equal period of time after Course 1 of alemtuzumab 
treatment (Period 2) This endpoint was agreed upon by the Paediatric Committee (PDCO to 
protect the study population from any significant treatment-free period and provide an analysis of 
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an imaging biomarker for comparative purposes. The number of new or enlarging hyperintense 
lesions as detected by T2-weighted MRI has been used as a surrogate marker of efficacy in MS 
studies (25, 26). Cranial MRI will be performed at the times specified in Section 1.2. 
In the analysis of secondary endpoints, 4 primary areas will be prioritized. Safety and tolerability 
for up to 4 years after last dose of alemtuzumab will be assessed using descriptive statistics and 
evaluated in comparison to the adult data for the treatment of MS using alemtuzumab. Adverse 
events of special interest will be examined including the subsequent development of infusion-
related reactions, events of autoimmunity particularly thyroid, ITP and nephropathies; serious 
infections. Certain exclusion criteria related to prior disease states associated with such reactions 
will be emphasized during screening. Routine lab monitoring during the course of the study and 
followup over 4 years following last infusion is planned.  
EDSS score changes occurring following Period 1 will be analyzed. The EDSS will be performed 
by the neurologist at the following visits: Screening, Day-14 to Day -7, Months 4, 8, 12, 15, 18, 
21, and 24/at EOTP, every 6 months in the safety monitoring phase, and at every relapse visit. 
The EDSS has long been considered the standard for assessing disability in patients with MS 
(27, 28).  
The annualized relapse rate (ARR) will be assessed at Year 2. The annualized relapse rate is 
widely used and generally accepted as an indicator of the efficacy of drugs to reduce cerebral 
inflammation in MS studies (27, 28).  
Cognition test scores (BVMT-R and SDMT) will be tested over 2 years. Cognitive decline is 
recognized as a prevalent and debilitating symptom of multiple sclerosis (MS), especially deficits 
in episodic memory and processing speed. The change from baseline in cognitive outcomes are to 
be analysed descriptively. The SDMT is a test of speed that screens for organic cerebral 
dysfunction and has been validated and used in numerous MS clinical trials (29, 30). 
The BVMT-R is a test of memory that has been validated in MS and has been used in clinical 
trials (31). Quality of life measures will be assessed using the validated pediatric Neuro-QOL 
which will be measured at least every 6 months over 2 years. This measure assesses how disease 
and health factors affects children’s lives (32). 
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10 
STUDY PROCEDURES  
All the study procedures will be performed following the standard clinical practice of each study 
center. Refer to the Section 1.2 for more details. 
10.1 VISIT SCHEDULE  
The visit schedule consists of the following visits: 
10.1.1 Visit 1 Screening visit  
This visit has to be conducted maximum 28 days prior to M-4 visit.  
Prior to any assessments, information for the parents/patient regarding the aims and methods of 
the study, its constraints and risks, and educational material consistent with the risk management 
plan for alemtuzumab will be reviewed with the parents/patient and a written summary in the 
form of an informed consent will be given to the parents/patient. 
The patient/patient’s legal guardian must sign the informed consent/assent prior to any action 
related to the study. 
The screening visit will include the following investigations (refer to Section 1.2.1): 
• Recording of medical/surgical history. 
• Physical examination and vital signs: A standard physical examination for clinical and 
neurological assessments which includes examination of major body systems, height and 
body weight. Tanner stage will be assessed as well. 
• The following vital signs will be recorded: systolic and diastolic blood pressure 
(millimeters of mercury [mm Hg]), heart rate (beats/minute), respiratory rate 
(breaths/minute), and temperature (degrees Celsius [°C] or degrees Fahrenheit [°F]). 
• Demographics (gender, age, and race). 
• Recording of prior MS medications and concomitant medications. 
• Laboratory screening:  
- 
Hematology (CBC with differential, including platelet count for monitoring for any 
cytopenia),  
- 
Chemistry panel: Glucose, creatinine, blood urea nitrogen (BUN), sodium, potassium, 
chloride, bicarbonate, magnesium, calcium uric acid, aspartate aminotransferase, ALT, 
gamma-glutamyl transpeptidase (GGT), lactate dehydrogenase, total bilirubin, 
direct/indirect bilirubin, alkaline phosphatase, inorganic phosphorus, total protein, 
albumin, globulin, albumin/globulin ratio, triglycerides, cholesterol and creatinine 
phosphokinase will be assessed, 
- 
Thyroid function testing (thyroid stimulating hormone), 
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- 
Serology tests: hepatitis B/C and HPV. Other serology test may be required according 
the patient vaccination status, 
- 
Urinalysis (pH, ketones, cells, protein, glucose, blood, urobilinogen, bilirubin, 
microscopic sediment, specific gravity), 
- 
TB testing (as per local practice), 
- 
For women: Beta human chorionic gonadotropin pregnancy test for women of 
childbearing potential, who have commenced menstruating. 
• Blood sample collection for lymphocyte phenotyping. 
• Perform MRI scan without contrast. It is important to ensure that this MRI assessment is 
performed 4 months (±7 days) apart to the MRI assessment on D-7 visit. The MRI 
assessments will be available to investigators to assess safety. 
• Perform EDSS assessment. 
• Perform SDMT and BVMT-R test. 
• Recording of PedsQL/Ped NeuroQoL. 
• Remind patient to continue on their DMT. 
• Commence AE/SAE reporting. 
Note: The above investigations may be performed on separate visits as long as all are completed 
within the 28 days prior to inclusion (V2, M-4). If any of the examinations/measurements does 
not fulfill the inclusion/exclusion criteria at the screening visit, they may be repeated before 
Visit 2. 
10.1.2 Visit 2/( M-4) study eligibility confirmation visit  
The following items will be checked/performed and recorded for all patients: 
• Review any potential AEs/SAEs and concomitant mediation used since Visit 1. 
• Review/confirm eligibility criteria based on review of inclusion/exclusion criteria. 
Only patients who meet all the inclusion criteria and none of the exclusion criteria will be 
included in the study. Each patient will receive an incremental identification number 
corresponding to his/her order of enrollment in the study. 
- 
If the patients do not meet eligibility criteria, they will be considered screen failures. 
These patients may be re-assessed and included in the study if they meet all eligibility 
criteria, 
- 
After this visit, during DMT phase until Day -7 visit, Investigator or designee will 
perform monthly phone calls to remind patients and parents about continuation of 
DMT and check patient status. 
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10.1.3 Visit 3/Days -14 to -7  
Visit 3 assessments can be performed over multiple days as long the time windows below are 
respected.  
The following items will be checked/performed and recorded for all patients: 
• Perform MRI scan without contrast. It is important to ensure that this MRI assessment is 
performed 4 months (±7 days) from the MRI assessment done at screening. 
• Physical examination including vital signs. 
• AEs/SAEs (if any) will be monitored. 
• Concomitant medication (if any) will be checked and reported. 
• Blood and urine sample for laboratory assessments (hematology and chemistry) including 
thyroid function test; pregnancy test (for females of childbearing potential), and urinalysis 
will be collected at Day -14 in order that results can be available at the latest on Day -7. 
• Check for prior DMT compliance. 
• Perform EDSS assessment. 
• Perform SDMT and BVMT-R test. 
• Recording of PedsQL/Ped NeuroQoL. 
• Day -7 (phone call or visit): The Investigator will assess and confirm eligibility for 
alemtuzumab administration. If the patient is eligible for alemtuzumab administration, 
the prior DMT will be discontinued. 
Premedication will be given to the patient and patient will be instructed to take premedication the 
day prior to the alemtuzumab administration in the morning and in the evening according to the 
schedule. Refer to Section 8.2 for further details. 
10.1.4 Visit 4/M0/D1 (first course of alemtuzumab)  
Alemtuzumab treatment must be initiated and supervised by a neurologist experienced in the 
treatment of patients with MS. Specialists and equipment required for the timely diagnosis and 
management of the most frequent adverse reactions, especially autoimmune conditions and 
infections, must be available.  
During the alemtuzumab infusion days, patients are not required to stay hospitalized overnight; 
however it remains at Investigator’s discretion to decide if patient needs to be hospitalized during 
infusion periods. 
Observation for infusion reactions is recommended during and for at least 2 hours (based on local 
requirements) after alemtuzumab infusion. 
The day prior to first alemtuzumab administration patient should take the premedication as 
specified in Section 1.2.1 and Section 8.2. 
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On days of alemtuzumab infusion, and 1 hour prior to the infusion, H1 antagonist IV should be 
administered immediately followed by 1000mg IV methylprednisolone (whichever is lower), on 
the first 3 days of alemtuzumab administration and ≥500 mg on infusion Days 4 and 5. H2 
antagonist medications and NSAID/antipyretic should be administered on the 5 days of 
alemtuzumab administration as needed. Study patients should also receive antiviral prophylaxis 
for herpetic viral infection beginning on Day 1 and continuing for a minimum of 1 month. If 
diphenhydramine IV is not available, an equivalent  H1 antagonist can be used at an equivalent 
dosing, via IV route. If no H1 antagonist is available in IV formulation, an oral formulation of an 
equivalent compound can be used at an equivalent dosing, 2 hours prior to infusion. 
Alemtuzumab will be administered as daily IV infusion on 5 consecutive days in a supervised 
medical setting. Calculation of the dose used will be based on patient weight .Vital signs during 
infusion days will be monitored. 
The following assessments should be done as listed in the study flow chart (refer to Section 1.2.1): 
• Physical examination and vital signs. 
• Check for compliance. 
• Preinfusion blood samples collection for clinical laboratory assessments and for ADA. 
• Blood sample collection for serum creatinine and ALT. 
• Blood samples collection for immune markers (optional) and PK. 
• AE/SAE will be monitored (if any). 
• Concomitant medication will be checked and reported (if any). 
• The Investigator or designee will contact the IVRS to obtain a treatment kit number. 
The following infusion management procedures must be utilized for each infusion and each 
treatment course: 
- 
Pre-infusion : Physicians should obtain a baseline ECG and vital signs (including heart rate 
and blood pressure measurement), screen for pre-existing hemorrhagic, cardiovascular 
(including venous thromboembolism) and cerebrovascular risk factors, screen for lung 
disease, review concomitant medications (eg, antiplatelet agents, anticoagulants), perform 
laboratory tests (complete blood count with differential, serum transaminases, serum 
creatinine, test of thyroid function and urinalysis with microscopy), and evaluate infusion-
related risks. Physician should also apply the following contraindications when treating 
patients in this study: 
▪ Hypersensitivity to the active substance, or to any of the excipients 
▪ Human Immunodeficiency Virus (HIV) infection 
▪ Severe active infection 
▪ Uncontrolled hypertension 
▪ History of arterial dissection of the cervicocephalic arteries 
▪ History of stroke 
▪ History of angina pectoris or myocardial infarction 
▪ Known coagulopathy or on concomitant anti-coagulant therapy 
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It is at investigator’s discretion to treat or not treat patient with alemtuzumab after clinical 
evaluation. 
- 
During infusion: Continuous/frequent monitoring of heart rate, blood pressure assessment (at 
least hourly) and overall clinical status of the patients including consideration of the volume 
of fluids administered. The following are recommendations in case of clinical 
abnormities/severe adverse event: 
▪ Interrupt infusion 
▪ Medically evaluate the patient guided by the adverse event profile of alemtuzumab 
prior to considering restarting therapy 
▪ Provide appropriate treatment as needed 
▪ Consider permanently discontinuing the alemtuzumab infusion if the patient shows 
clinical symptoms suggesting development of a serious adverse event associated 
with the infusion (myocardial ischemia, hemorrhagic stroke, cervico-cephalic arterial 
dissection or pulmonary alveolar hemorrhage). 
▪ Implement appropriate measures for patients at risk of venous thromboembolism: 
repeated ambulation during infusion and/or compression stockings. 
- 
Post-infusion: Observation and education of patients 
▪ Observation for infusion reactions is recommended for a minimum of 2 hours after 
alemtuzumab infusion; 2 hours after infusion, patients should be cautious and 
reporting if any of the infusion reactions develop within 48 hours. 
▪ 
Patients with clinical symptoms suggesting development of a serious adverse event 
temporarily associated with the infusion (myocardial ischemia, hemorrhagic stroke, 
cervico-cephalic arterial dissection or pulmonary alveolar hemorrhage) should be 
closely monitored until complete resolution of the symptoms. The observation time 
should be extended as appropriate. 
▪ Patients with persistent blood pressure elevation should be referred to an appropriate 
medical facility for continued monitoring and treatment. 
▪ The patients should be educated on the potential for delayed onset of infusion 
associated reactions and symptoms and signs of cardiovascular or cerebrovascular 
events, and instructed to report symptoms and/or seek appropriate medical care. 
 
10.1.5 Visit 5 to Visit 7/M1 to M3  
The following assessments should be done as listed in the study flow chart: 
• Blood sample collection for clinical laboratory assessments and urinalysis. 
• Blood samples collection for ADA at Visit 5 and Visit 7 and for lymphocyte phenotyping 
at Visit 5. 
• Blood sample collection for thyroid function test at Visit 7. 
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• Blood samples collection for PK on Visit 5 and Visit 6. 
• AE/SAE will be monitored (if any). 
• Concomitant medication will be checked and reported (if any). 
10.1.6 Visit 8/M4  
The following assessments should be done as listed in the study flow chart: 
• AE/SAE will be monitored (if any). 
• Concomitant medication will be checked and reported (if any). 
• Physical examination and vital signs. 
• Blood samples collection for clinical laboratory assessments, clinical chemistry, and 
urinalysis. 
• Blood sample collection for lymphocyte phenotyping. 
• Perform MRI scan without contrast. 
• Perform EDSS assessment. 
• Perform SDMT and BVMT-R test. 
• Recording of PedsQL/ Ped NeuroQoL. 
• Blood samples collection for immune markers (optional). 
10.1.7 Visit 9 to Visit 11 /M5 to M7  
The following assessments should be done as listed in the study flow chart: 
• AE/SAE will be monitored (if any). 
• Concomitant medication will be checked and reported (if any). 
• Blood samples collection for clinical laboratory assessments, serum creatinine, ALT, and 
urinalysis, including thyroid function test only at Visit 10. 
10.1.8 Visit 12/M8  
The following assessments should be done as listed in the study flow chart: 
• AE/SAE will be monitored (if any). 
• Concomitant medication will be checked and reported (if any). 
• Physical examination and vital signs. 
• Blood samples collection for clinical laboratory assessments (hematology and chemistry) 
including urinalysis. 
• Blood samples collection for lymphocyte phenotyping. 
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• Perform MRI scan without contrast. 
• Perform EDSS assessment. 
• Perform SDMT and BVMT-R test. 
• Recording of PedsQL/Ped NeuroQoL. 
10.1.9 Visit 13 to Visit 15/M9 to M11  
The following assessments should be done as listed in the study flow chart: 
• AE/SAE will be monitored (if any). 
• Concomitant medication will be checked and reported (if any). 
• Blood samples collection for clinical laboratory assessments, serum creatinine, ALT, and 
urinalysis. 
• Perform thyroid function test only at Visit 13. 
• The day prior to alemtuzumab administration patient should take the premedication as 
specified in Section 1.2.1 and Section 8.2. 
10.1.10 
Visit 16/M12 (second course of alemtuzumab)  
Visit 16 (M12) can occur within -7 days or +30 days of the scheduled visit. 
The following assessments should be done as listed in the study flow chart:  
• Physical examination and vital signs. 
• Perform Tanner staging. 
• Blood and urine samples collection for clinical laboratory assessments including 
pregnancy test (for females of childbearing potential), thyroid function test, urinalysis and 
for ADA. 
• Blood samples collection for lymphocyte phenotyping. 
• Blood samples collection for PK and immune markers (optional). 
• Assess and confirm eligibility for alemtuzumab administration. 
• Alemtuzumab will be administered as daily IV infusion on 3 consecutive days in a 
supervised medical setting. Calculation of the dose used will be based on patient weight. 
Observation for infusion reactions is recommended during and for at least 2 hours (based 
on local requirements) after alemtuzumab infusion. 
• The Investigator or designee will contact the IVRS to obtain a treatment kit number. 
• On days of Alemtuzumab infusion, and 1 hour prior to the infusion, H1 antagonist IV 
should be administered immediately followed by 30mg/kg or 1000mg IV 
methylprednisolone (whichever is lower). H2 antagonist medications and 
NSAID/antipyretic should be administered on the 3 consecutive days of alemtuzumab 
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administration as needed. Study patients should also receive antiviral prophylaxis for 
herpetic viral infection beginning on Day 1 and continuing for a minimum of 1 month. If 
diphenhydramine IV is not available, an equivalent H1 antagonist can be used at an 
equivalent dosing, via IV route. If no H1 antagonist is available in IV formulation, an oral 
formulation of an equivalent compound can be used at an equivalent dosing, 2 hours prior 
to infusion. 
• Vital signs during infusion days will be monitored. 
• AE/SAE will be monitored (if any). 
• Concomitant medication will be checked and reported (if any). 
The following infusion management procedures must be utilized for each infusion and each 
treatment course: 
- 
Pre-infusion : 
Physicians should obtain a baseline ECG and vital signs (including heart rate and blood 
pressure measurement), screen for pre-existing hemorrhagic, cardiovascular (including 
venous thromboembolism) and cerebrovascular risk factors, screen for lung disease, review 
concomitant medications (eg, antiplatelet agents, anticoagulants), perform laboratory tests 
(complete blood count with differential, serum transaminases, serum creatinine, test of 
thyroid function and urinalysis with microscopy), and evaluate infusion-related risks. 
Physician should also apply the following contraindications when treating patients in this 
study: 
▪ Hypersensitivity to the active substance, or to any of the excipients 
▪ Human Immunodeficiency Virus (HIV) infection 
▪ Severe active infection 
▪ Uncontrolled hypertension 
▪ History of arterial dissection of the cervicocephalic arteries 
▪ History of stroke 
▪ History of angina pectoris or myocardial infarction 
▪ Known coagulopathy or on concomitant anti-coagulant therapy 
 
It is at investigator’s discretion to treat or not treat patient with alemtuzumab after clinical 
evaluation. 
- 
During infusion: Continuous/frequent monitoring of heart rate, blood pressure assessment (at 
least hourly) and overall clinical status of the patients including consideration of the volume 
of fluids administered. The following are recommendations in case of clinical 
abnormities/severe adverse event: 
▪ Interrupt infusion 
▪ Medically evaluate the patient guided by the adverse event profile of alemtuzumab 
prior to considering restarting therapy 
▪ Provide appropriate treatment as needed 
▪ Consider permanently discontinuing the alemtuzumab infusion if the patient shows 
clinical symptoms suggesting development of a serious adverse event associated 
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with the infusion (myocardial ischemia, hemorrhagic stroke, cervico-cephalic arterial 
dissection or pulmonary alveolar hemorrhage). 
▪ Implement appropriate measures for patients at risk of venous thromboembolism: 
repeated ambulation during infusion and/or compression stockings. 
- 
Post-infusion: Observation and education of patients 
▪ Observation for infusion reactions is recommended for a minimum of 2 hours after 
alemtuzumab infusion; 2 hours after infusion, patients should be cautious and 
reporting if any of the infusion reactions develop within 48 hours. 
▪ 
Patients with clinical symptoms suggesting development of a serious adverse event 
temporarily associated with the infusion (myocardial ischemia, hemorrhagic stroke, 
cervico-cephalic arterial dissection or pulmonary alveolar hemorrhage) should be 
closely monitored until complete resolution of the symptoms. The observation time 
should be extended as appropriate. 
▪ Patients with persistent blood pressure elevation should be referred to an appropriate 
medical facility for continued monitoring and treatment. 
▪ The patients should be educated on the potential for delayed onset of infusion 
associated reactions and symptoms and signs of cardiovascular or cerebrovascular 
events, and instructed to report symptoms and/or seek appropriate medical care. 
• Perform MRI scan without contrast. 
• Perform EDSS assessment. 
• Perform SDMT and BVMT-R test. 
• Recording of PedsQL/Ped NeuroQoL. 
10.1.11 Visit 17 to Visit 18/M13 to M14  
The following assessments should be done as listed in the study flow chart: 
• AE/SAE will be monitored (if any). 
• Concomitant medication (if any) will be checked at Visit 17 and Visit 18. 
• Blood samples collection for hematology, ALT, serum creatinine, and urinalysis. 
• Blood samples collection for lymphocyte phenotyping and for ADA at Visit 17 only. 
• Blood samples collection for PK. 
10.1.12 Visit 19/M15  
The following assessments should be done as listed in the study flow chart: 
• AE/SAE will be monitored (if any). 
• Concomitant medication will be checked and reported (if any). 
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• Physical examination, including vital signs. 
• Perform EDSS assessment. 
• Blood samples collection for hematology, clinical chemistry laboratory assessments 
including thyroid function test and urinalysis. 
• Blood samples collection for lymphocyte phenotyping and ADA. 
10.1.13 Visit 20 to Visit 21/M16 to 17  
The following assessments should be done as listed in the study flow chart: 
• AE/SAE will be monitored (if any). 
• Concomitant medication will be checked and reported (if any). 
• Blood samples collection for hematology, ALT, serum creatinine, and urinalysis. 
10.1.14 Visit 22/M18  
The following assessments should be done as listed in the study flow chart: 
• AE/SAE will be monitored (if any). 
• Concomitant medication will be checked and reported (if any). 
• Physical examination including vital signs. 
• Blood samples collection for clinical laboratory assessments, clinical chemistry, thyroid 
function test, and urinalysis. 
• Blood samples collection for lymphocyte phenotyping. 
• Blood samples collection for immune markers (optional). 
• Perform EDSS assessment. 
• Perform SDMT and BVMT-R test. 
• Recording of PedsQL/Ped NeuroQoL. 
10.1.15 Visit 23 to Visit 24/M19 to M20  
The following assessments should be done as listed in the study flow chart: 
• AE/SAE will be monitored (if any). 
• Concomitant medication will be checked and reported (if any). 
• Blood samples collection for hematology, ALT, serum creatinine, and urinalysis. 
10.1.16 Visit 25/M21  
The following assessments should be done as listed in the study flow chart: 
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• AE/SAE will be monitored (if any). 
• Concomitant medication will be checked and reported (if any). 
• Physical examination including vital signs. 
• Blood samples collection for clinical laboratory assessments including thyroid function 
test and urinalysis. 
• Perform EDSS assessment. 
• Blood samples collection for lymphocyte phenotyping. 
10.1.17 Visit 26-Visit 27/M22-23  
The following assessments should be done as listed in the study flow chart: 
• AE/SAE will be monitored (if any). 
• Concomitant medication will be checked and reported (if any). 
• Blood samples collection for hematology, ALT, serum creatinine and urinalysis. 
10.1.18 Visit 28/M24 EOTP  
The following assessments should be done as listed in the study flow chart: 
• AE/SAE will be monitored (if any). 
• Concomitant medication will be checked and reported (if any). 
• Physical examination including vital signs. 
• Blood samples collection for clinical laboratory assessments including thyroid function 
test, ADA, and urinalysis. 
• Blood samples collection for lymphocyte phenotyping. 
• Blood samples collection for immune markers (optional). 
• Perform Tanner staging. 
• Perform MRI scan without contrast. 
• Perform EDSS assessment. 
• Perform SDMT and BVMT-R test. 
• Recording of PedsQL/Ped NeuroQoL. 
10.1.19 Safety monitoring phase Year 3 to Year 5  
The following assessments should be done as listed in the study flow chart: 
• AE/SAE will be monitored (if any). 
• Perform EDSS assessment at every 6 months. 
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• Concomitant medication will be checked and reported (if any). 
• Physical examination including vital signs at every 6 months. 
• Blood sample collection for hematology, urinalysis, ALT, and serum creatinine every 
month. 
• Perform clinical chemistry assessments including thyroid function test every 3 months. 
• Perform MRI scan without contrast, PedsQL/Ped NeuroQoL, and cognitive tests yearly. 
• Perform Tanner staging yearly. 
• Blood samples collection for lymphocyte phenotyping and ADA yearly. 
10.1.20 Relapse Visit  
The following assessments should be done as listed in the study flow chart: 
• Physical examination, including vital signs. 
• AE/SAE will be recorded (if any). 
• Perform EDSS assessment. 
• Concomitant medication will be checked and reported (if any). 
10.2 
DEFINITION OF SOURCE DATA  
Source data are defined as original documents, data, and records. This includes, but is not limited 
to the following: hospital records, clinic and office charts, study-specific source document 
worksheets including Neurostatus-EDSS worksheets, phone logs, memoranda, evaluation 
checklists, laboratory requisitions, and reports, MRI reports and images, local laboratory reports 
(if applicable), medication dispensing records, patient questionnaires, computer printouts, 
electronic data/information sources including IVRS/IWRS notifications, and any other 
documentation regarding the patient. 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION  
During infusion courses, the IMP should be continued whenever possible. In case the IMP is 
stopped, it should be determined whether the stop can be made temporarily; permanent IMP 
discontinuation should be a last resort. Any IMP discontinuation must be fully documented in the 
electronic-Case Report Form (e-CRF). In any case, the patient should remain in the study as long 
as possible. 
10.3.1 Temporary treatment discontinuation with investigational medicinal product(s)  
Temporary treatment discontinuation may be considered by the Investigator because of suspected 
AEs. Reinitiation of treatment with the IMP will be done under close and appropriate clinical/and 
or laboratory monitoring once the Investigator will have considered according to his/her best 
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medical judgment that the responsibility of the IMP(s) in the occurrence of the concerned event 
was unlikely and if the selection criteria for the study are still met (refer to Section 7.1 and 
Section 7.2). 
For all temporary treatment discontinuations, duration must be recorded by the Investigator in the 
appropriate pages of the e-CRF.  
10.3.2 Permanent treatment discontinuation with investigational medicinal product(s)  
Permanent treatment discontinuation is any treatment discontinuation associated with the 
definitive decision from the Investigator or the patient not to re-expose the patient to the IMP at 
any time.  
10.3.3 List of criteria for permanent treatment discontinuation  
The patients may withdraw from treatment with the IMP if they decide to do so, at any time and 
irrespective of the reason, or this may be the Investigator’s decision. All efforts should be made to 
document the reason(s) for treatment discontinuation and this should be documented in the e-CRF 
in the EOTP Visit. 
Patients must discontinue the IMP for the following reasons: 
• Pregnancy or intention for pregnancy. 
• At patient/parents request (ie, withdrawal of the consent for treatment). 
• If, in the Investigator's opinion, continuation with the administration of the IMP would be 
detrimental to the patient's well-being. 
• Intercurrent condition that requires discontinuation of the IMP (eg, laboratory 
abnormalities, please refer to decision tree in Appendix B). 
• Life threatening events (such as such as myocardial ischemia, pulmonary alveolar 
hemorrhage, HLH,…) 
• At the specific request of the Sponsor. 
Any abnormal laboratory value will be immediately repeated for confirmation (within 24 hours if 
possible), before making a decision of permanent discontinuation of the IMP for the concerned 
patient. 
10.3.4 Handling of patients after permanent treatment discontinuation  
Patients will be followed-up according to the study procedures specified in this protocol up to the 
scheduled date of study completion, or up to recovery or stabilization of any AE to be 
followed-up as specified in this protocol, whichever comes last. 
All cases of permanent treatment discontinuation must be recorded by the Investigator in the 
appropriate pages of the e-CRF when considered as confirmed. 
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10.3.5 Procedure and consequence for patient withdrawal from study   
The patients may withdraw from the study before study completion if they decide to do so, at any 
time and irrespective of the reason. Withdrawal of consent for treatment should be distinguished 
from withdrawal of consent for follow-up visits and from withdrawal of consent for nonpatient 
contact follow-up, eg, medical records check. Patients requesting withdrawal should be informed 
that withdrawal of consent for follow-up may jeopardize the public health value of the study. 
If possible, the patients are assessed using the procedure normally planned for the end-of-study 
visit. 
Patients who withdraw should be explicitly asked about the contribution of possible AEs to their 
decision to withdraw consent, and any AE information elicited must be documented. Preferably 
the patient should withdraw consent in writing and, if the patient or the patient’s representative 
refuses or is physically unavailable, the site should document and sign the reason for the patient’s 
failure to withdraw consent in writing.  
All study withdrawals must be recorded by the Investigator in the appropriate screens of the 
e-CRF and in the patient’s medical records when considered as confirmed. In the medical record, 
at least the date of the withdrawal and the reason should be documented. 
For patients who fail to return to the site, unless the patient withdraws consent for follow-up, the 
Investigator must make the best effort to recontact the patient (eg, contact patient’s family or 
private physician, review available registries or health care databases), and to determine his/her 
health status, including at least his/her vital status. Attempts to contact such patients must be 
documented in the patient’s records (eg, times and dates of attempted telephone contact, receipt 
for sending a registered letter). 
The statistical analysis plan (SAP) will specify how these patients lost to follow-up for their 
primary endpoints will be considered. 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING  
10.4.1 Definitions of adverse events  
10.4.1.1 Adverse event  
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment. 
10.4.1.2 Serious adverse event  
An SAE is any untoward medical occurrence that at any dose: 
• Results in death, or, 
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• Is life-threatening, or, 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which 
the patient 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. 
• Requires inpatient hospitalization or prolongation of existing hospitalization, or, 
• Results in persistent or significant disability/incapacity, or, 
• Is a congenital anomaly/birth defect. 
• Is a medically important event. 
Medical and scientific judgment must be exercised in deciding whether expedited 
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 
patient or may require medical or surgical intervention (ie, specific measures or corrective 
treatment) to prevent one of the other outcomes listed in the definition above. 
Note: The following list of medically important events is intended to serve as a guideline for 
determining which condition has to be considered a medically important event. The list is not 
intended to be exhaustive: 
• Intensive treatment in an emergency room or at home for: 
- 
Allergic bronchospasm, 
- 
Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia, etc), 
- 
Convulsions (seizures, epilepsy, epileptic fit, absence, etc). 
• Development of drug dependence or drug abuse. 
• ALT >3 x ULN + total bilirubin >2 x ULN or asymptomatic ALT increase >10 x ULN. 
• Suicide attempt or any event suggestive of suicidality. 
• Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling). 
• Bullous cutaneous eruptions. 
• Cancers diagnosed during the study or aggravated during the study (only if judged 
unusual/significant by the Investigators in oncology studies). 
• Chronic neurodegenerative diseases (newly diagnosed) or aggravated during the study 
(only if judged unusual/significant by the Investigators in studies assessing specifically the 
effect of a study drug on these diseases). 
• Suspected transmission of an infectious agent: if any suspected transmission of an 
infectious agent via a medicinal product (eg, product contamination). 
Hospitalization for the scheduled alemtuzumab infusions, not related with any AE, due to 
Investigator decision or local requirement, will not be considered as an SAE. 
10.4.1.3 Adverse event of special interest  
Any AESI will be reported to the Sponsor in the same timeframe as SAEs, ie, within 24 hours, as 
detailed in Section 10.4.4. 
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An AESI is an AE (serious or nonserious) of scientific and medical concern specific to the 
Sponsor’s product or program, for which ongoing monitoring and immediate notification by the 
Investigator to the Sponsor is required. Such events may require further investigation in order to 
characterize and understand them. Adverse events of special interest may be added, modified or 
removed during a study by protocol amendment.  
The following AE will be considered as an AESI: 
• Hypersensitivity or anaphylaxis. 
• Pregnancy occurring in a female patient entered in the clinical trial. It will be qualified as 
an SAE only if it fulfills one of the seriousness criteria (see Section 10.4.1.2). Follow-up 
of the pregnancy in a female participant is mandatory until the outcome has been 
determined. 
• Symptomatic overdose (serious or nonserious) with IMP/non-investigational medicinal 
product (NIMP). 
- 
An overdose (accidental or intentional) with the IMP is an event suspected by the 
Investigator or a nurse and defined as an increase of at least 30% of the dose to be 
administered in the specified duration or if the dose is administered in less than half 
the recommended duration of administration, 
- 
An overdose with the NIMP is an event suspected by the Investigator or spontaneously 
notified by the patient (not based on systematic pills count) and defined as at least 
twice the intended dose within the intended therapeutic interval, adjusted according to 
the tested drug, 
- 
Of note, asymptomatic overdose has to be reported as a standard AE. 
• Increase in ALT (see the “Increase in ALT” flow diagram in Appendix B of the protocol). 
• Other product specific AESI(s): 
- 
Autoimmune mediated conditions including but not limited to autoimmune 
encephalitis, cytopenias, ITP, autoimmune hepatitis, nephropathies including anti-
glomerular basement membrane (GBM) disease, thyroid disorders and acquired 
Hemophilia A (see Appendix B) 
- 
Temporally associated* pulmonary alveolar hemorrhage 
- 
Temporally associated* myocardial ischemia, myocardial infarction 
- 
Temporally associated* stroke 
- 
Temporally associated* cervicocephalic arterial dissection 
(* Temporally associated: 1 to 3 days after the last infusion)  
- 
HLH, 
- 
Progressive multifocal leukoencephalopathy (PML) 
- 
Pneumonitis, 
- 
Serious infections including serious opportunistic infections (eg, Listeria 
infections, CMV, EBV), HPV associated with cervical dysplasia 
- 
Malignancy 
- 
Thrombotic thrombocytopenic purpura 
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10.4.2 Serious adverse events waived from expedited regulatory reporting to regulatory 
authorities  
Not applicable. 
10.4.3 General guidelines for reporting adverse events  
• All AEs, regardless of seriousness or relationship to IMP/NIMP, spanning from the 
signature of the ICF form until the end of the study as defined by the protocol for that 
patient, are to be recorded on the corresponding page(s) or screen(s) of the e-CRF. 
• Whenever possible, diagnosis or single syndrome should be reported instead of symptoms. 
The Investigator should specify the date of onset, intensity, action taken with respect to 
IMP, corrective treatment/therapy given, additional investigations performed, outcome, 
and his/her opinion as to whether there is a reasonable possibility that the AE was caused 
by the IMP or by the study procedure(s). 
• The Investigator should take appropriate measures to follow all AEs until clinical recovery 
is complete and laboratory results have returned to normal, or until progression has been 
stabilized, or until death, in order to ensure the safety of the patients. This may imply that 
observations will continue beyond the last planned visit per protocol, and that additional 
investigations may be requested by the monitoring team up to as noticed by the Sponsor in 
the protocol and informed consent. At the prespecified study end date, patients who 
experience an ongoing SAE or an AESI should be followed until resolution, stabilization, 
or death and related data will be collected.  
• When treatment is prematurely discontinued, the patient’s observations will continue until 
the end of the study as defined by the protocol for that patient. 
• Laboratory, vital signs are to be recorded as AEs only if:  
- 
Symptomatic and/or,  
- 
Requiring either corrective treatment or consultation, and/or, 
- 
Leading to IMP discontinuation or modification of dosing, and/or,  
- 
Fulfilling a seriousness criterion, and/or,  
- 
Defined as an AESI. 
In this protocol, symptoms and signs of exacerbation or worsening of the disease under trial will 
usually be captured in the context of efficacy assessment, and recorded on the relapse module of 
the e-CRF. Therefore, symptoms, relapses or worsening of MS will not be considered as AEs nor 
captured on the AE module of the e-CRF unless this event is considered possibly or probably 
related to the IMP (ie, worsening is not consistent with the anticipated natural progression of the 
disease) and/or the MS relapse meets the criteria for a serious AE (eg, requires hospitalization). 
However, for all associated symptoms or events or if an event that was initially considered a 
possible MS relapse but upon evaluation is found to be any other type of event (some example but 
not limited to: fever, injury, musculoskeletal event, systemic illness, mood disorder, etc) the event 
must be captured as an AE/SAE. 
Instructions for AE reporting are summarized in Table 9. 
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10.4.4 Instructions for reporting serious adverse events  
In the case of occurrence of an SAE or AESI, the Investigator or any designees must immediately: 
• ENTER (within 24 hours) the information related to the SAE or AESI in the appropriate 
screens of the e-CRF; the system will automatically send a notification to the monitoring 
team after approval of the Investigator within the e-CRF or after a standard delay. 
• There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In such case, care should be taken to ensure that the patient's identity is 
protected and the patient's identifiers in the study are properly mentioned on any copy of a 
source document provided to the Company. For laboratory results, include the laboratory 
normal ranges 
• All further data updates should be recorded in the e-CRF as appropriate, and further 
documentation as well as additional information (for laboratory data, concomitant 
medications, patient status, etc) should be sent (by fax or e-mail) to the monitoring team 
within 24 hours of knowledge of the SAE or AESI. In addition, every effort should be 
made to further document any SAE that is fatal or life-threatening within a week (7 days) 
of the initial notification. 
• A back-up plan (using a paper CRF process) is available and should be used when the 
e-CRF system does not work. 
Any SAE brought to the attention of the Investigator at any time after the end of the study for the 
patient and considered by him/her to be caused by the IMP with a reasonable possibility, should 
be reported to the monitoring team. 
10.4.5 Guidelines for reporting adverse events of special interest  
For AESIs, the Sponsor must be informed immediately (ie, within 24 hours), as per SAE 
notification guidelines described in Section 10.4.4 even if not fulfilling a seriousness criterion, 
using the screens in the e-CRF. 
Instructions for AE reporting are summarized in Table 9.  
10.4.6 Guidelines for management of specific laboratory abnormalities  
Decision trees for the management of certain laboratory abnormalities by sanofi are provided in 
Appendix B.  
The following laboratory abnormalities should be monitored, documented, and managed 
according to the related flow chart in protocol appendices.  
• Neutropenia. 
• Thrombocytopenia. 
• ALT increase. 
• Acute renal insufficiency. 
• Suspicion of rhabdomyolysis. 
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Table 9 - Summary of adverse event reporting instructions  
Event 
category 
Reporting 
timeframe 
Specific events in this category 
Case Report Form completion 
AE form 
Safety  
Complementary 
Form 
Other 
specific 
forms 
AE (nonSAE, 
nonAESI) 
Routine 
Any AE that is not an SAE or AESI 
Yes 
No 
No 
SAE (nonAESI 
or AESI) 
Expedited (within 
24 hours) 
Any AE meeting seriousness criterion per 
Section 10.4.1.3 
Yes 
Yes 
No 
AESI  
Expedited (within 
24 hours) 
Acute hypersensitivity/ anaphylaxis 
Yes 
Yes 
No 
 
 
Pregnancy 
Yes 
Yes 
Yes 
 
 
Symptomatic overdose 
Yes 
Yes 
No 
 
 
ALT>=3ULN or >= 2 baseline 
Yes 
Yes 
Yes 
 
 
Autoimmune mediated conditions including but not 
limited to autoimmune encephalitis, cytopenias, ITP, 
autoimmune hepatitis, nephropathies including anti-
glomerular basement membrane (GBM) disease, 
thyroid disorders and acquired Hemophilia A 
Temporally associated* pulmonary alveolar 
hemorrhage 
Temporally associated* myocardial ischemia, 
myocardial infarction 
Temporally associated* stroke 
Temporally associated* cervicocephalic arterial 
dissection 
(* Temporally associated: 1 to 3 days after the last 
infusion)  
HLH, 
Progressive multifocal leukoencephalopathy (PML) 
Pneumonitis, 
Serious infections including serious opportunistic 
infections (eg, Listeria infections, CMV, EBV), HPV 
associated with cervical dysplasia 
Malignancy  
Thrombotic thrombocytopenic purpura 
Yes 
Yes 
No  
Abbreviations: AE: adverse events; AESI: adverse event of special interest; ALT: alanine aminotransferase; IMP: investigational medicinal 
product; ITP: immune thrombocytopenia; nonSAE: nonserious adverse events. 
10.4.7 Guidelines for reporting product complaints (IMP/NIMP/device)  
Any defect in the IMP/NIMP/device (alemtuzumab/oral prednisone/prednisolone 1 mg/kg or 
50 mg, and H2 antagonist) must be reported as soon as possible by the Investigator to the 
monitoring team that will complete a product complaint form within required timelines. 
Appropriate information (eg, samples, labels or documents like pictures or photocopies) related to 
product identification and to the potential deficiencies may need to be gathered. The Investigator 
will assess whether or not the quality issue has to be reported together with an AE or SAE. 
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10.5 
OBLIGATIONS OF THE SPONSOR  
Adverse events that are considered expected will be specified by the reference safety information 
(label). 
During the course of the study, the Sponsor will report in an expedited manner: 
• All SAEs that are both unexpected and at least reasonably related to the IMP (SUSAR), to 
the regulatory authorities, independent ethics committee (IECs)/institutional review boards 
(IRBs) as appropriate and to the Investigators. 
• All SAEs that are expected and at least reasonably related to the IMPs to the regulatory 
authorities, according to local regulations. 
The Sponsor will report all safety observations made during the conduct of the trial in the clinical 
study report. 
10.6 
SAFETY INSTRUCTIONS  
For more information about alemtuzumab, please refer to label.  
10.7 
ADVERSE EVENTS MONITORING  
All events will be managed and reported in compliance with all applicable regulations, and 
included in the final clinical study report. 
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11 
STATISTICAL CONSIDERATIONS  
A SAP will be written and finalized prior to database lock to give guidance to the statistical 
analysis. It will be in compliance with the International Council for Harmonization (ICH) and 
Food and Drug Administration’s Guidance for Industry: Statistical Principles for Clinical Trials. 
The Sponsor or its designee will perform the statistical analysis of the data from this study. 
The analysis will be performed using the SAS® statistical software system Version 9.1 or higher. 
11.1 
DETERMINATION OF SAMPLE SIZE  
At least 60 patients aged from 10 years to less than 18 years will be screened in this study to 
account for screen failures, to ensure that at least 50 patients are evaluable. According to the 
means and variability reported in other paediatric MS studies (17), it was assumed that there is an 
average of 9 new or enlarging T2 lesions during continuation of prior DMT (Period 1) and an 
overdispersion parameter of 0.7 for both study periods. Further assuming a conservative within-
person correlation of 0.25 for the lesion counts, a 10% dropout rate, and a two-tailed significance 
level of 0.05, this sample size will provide at least 85% power to detect a 50% reduction in the 
number of new or enlarging T2 lesions after the first course of alemtuzumab (Period 2) compared 
to the equal-length Period 1. These sample size calculations were simulated using a correlated, 
repeated measures negative binomial regression model with GEE with robust variance estimation 
to account for the within-patient correlation in lesion counts between treatment Period 1 (prior 
DMT) and Period 2 (alemtuzumab).  
11.2 
DISPOSITION OF PATIENTS  
Appropriate tracking documents for screening, enrollment and follow-up of patients will be 
established in each center, as needed and in accordance with local regulations. 
Screened patients are defined as any patient who signed the informed consent. 
This is an open-label, single-arm, before and after switch study without randomization. 
Patients who were screened but did not receive any dose of alemtuzumab will be reported 
separately, but will not be included in any efficacy or safety population. 
11.3 
ANALYSIS POPULATIONS  
11.3.1 Modified Intent-to-treat population  
Modified Intent-to-treat (mITT): The primary analysis will be conducted on the population of 
patients who have received at least 1 dose of alemtuzumab and also have evaluable data for both 
Period 1 and Period 2. The mITT population will be used for the analyses of the primary and 
secondary efficacy endpoints. 
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11.3.2 Safety population:  
The safety population consists of patients who have received at least 1 dose of alemtuzumab. 
Safety and tolerability analyses will be conducted on all patients in the safety population. At the 
first database lock after the last patient has completed efficacy assessments including MRI at end 
of Period 2, some patients will have follow-up beyond the end of Period 2, all available 
information will be used for safety and tolerability analyses. 
PK: the PK population consists of patients who have received at least 1 dose of alemtuzumab and 
also have evaluable PK data. 
PD: the PD population consists of patients who have received at least 1 dose of alemtuzumab and 
also have evaluable PD data. 
For patient study status, the total number of patients in each of the following categories will be 
presented in the clinical study report using a flowchart diagram or summary table: 
• Screened patients. 
• Screened failure patients and reasons for screen failure (if data is available). 
• Number and percentage of patients who did not complete prior DMT phase, with 
corresponding reasons. 
• Number and percentage of patients who did not complete Period 2 with alemtuzumab, 
with corresponding reasons. 
• Number and percentage of patients who did not complete safety monitoring phase (will be 
included in final study report only), with corresponding reasons. 
11.4 
STATISTICAL METHODS  
Analyses for the primary and secondary efficacy endpoints will be conducted using the mITT 
population. Analyses for the safety endpoints will be conducted using the safety population. 
Analyses for the PD endpoints will be conducted using the PD populations. Analyses for the PK 
endpoints will be conducted using the PK populations. Analyses for the exploratory endpoints will 
be conducted using the safety population. 
In the descriptive analyses, summary statistics for continuous variables will minimally include n, 
mean, standard deviation (SD), minimum, median, and maximum. For categorical variables, 
frequencies and percentages will be presented. Graphical displays will be provided as appropriate. 
Unless otherwise specified, all baseline values will be defined as the last nonmissing value prior 
to the first course of alemtuzumab. 
11.4.1 Extent of study treatment exposure  
Alemtuzumab will be administered by IV infusions in a supervised medical setting at a dose of: 
• For patients ≥50 kg: 12 mg/day. 
• For patients <50 kg: 0.24 mg/kg/day. 
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There are two courses. The first treatment course includes 5 consecutive days of infusion, and the 
second treatment course is administered 12 months after the first treatment course and includes 3 
consecutive days of infusion. The numbers and percentages of patients that received each possible 
level of total dose will be presented in the clinical study report. 
11.4.2 Analyses of efficacy endpoints  
Analyses for the primary and secondary efficacy endpoints will be conducted using the mITT 
population. 
11.4.2.1 Analysis of primary efficacy endpoint  
The number of new or enlarging T2 lesions during continuation of prior DMT (Period 1) and in an 
equal-length period after the first course of alemtuzumab treatment (Period 2) will be analyzed 
and compared using a repeated measures negative binomial regression model with GEE. The 
default log link function will be used to model the expected number of lesions. The robust, 
sandwich covariance matrix will be constructed assuming an unstructured/exchangeable working 
correlation matrix. 
The primary statistical objective is to test superiority of alemtuzumab versus prior DMT at 5% 
level of significance. No missing data is expected as the mITT population is restricted to the 
patients with evaluable data for both Period 1 and Period 2. 
11.4.2.2 Analyses of secondary efficacy endpoints  
The annualized relapse rate at Year 2 will be estimated using a negative binomial model with 
robust variance estimation. 
The EDSS, descriptive statistics, (eg, percentages of stable/improved/worsened since the end of 
Period 1) will be calculated. 
Descriptive statistics (eg, mean, median, min, max, SD, quartiles) and 95% confidence interval for 
the means, when appropriate, will be calculated for the change from baseline in cognitive 
outcomes and QoL measures at each prescheduled, postbaseline assessment visit. 
The proportion of patients with new or enlarging T2 lesions during Period 1 and Period 2 will be 
analyzed and compared using repeated measures logistic regression model with GEE and robust 
variance estimation. The analyses will be similar to the primary endpoint analyses with the 
exception of the use of the logit link function and the Bernoulli distribution. 
11.4.2.3 Multiplicity considerations  
There is no formal hypothesis testing for the secondary efficacy endpoints, therefore the study 
overall type I error will not need to be adjusted for multiplicity. 
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11.4.3 Analyses of safety data  
11.4.3.1 Adverse events  
AE observation period: 
• Pretreatment AEs are defined as those AEs that developed or worsened prior to the 1st 
alemtuzumab dose. 
• On treatment AEs are defined as those AEs that developed or worsened after the 1st 
alemtuzumab dose and until the end of the study (Month 60). 
• Posttreatment AEs are defined as those AEs that developed or worsened after the 
ontreatment period. 
On-study period will include pretreatment and ontreatment period. Treatment emergent adverse 
events (TEAEs) for analysis purpose will include all ontreatment AEs. 
The primary analysis of adverse event reporting will be on TEAEs. Pretreatment AEs will be 
summarized separately. 
The incidence of TEAEs (including IARs), AESI, will also be tabulated (frequencies and 
percentages) by severity, grade/intensity, and relationship to study drug. In tabulating severity of 
AEs on a per patient basis, the greatest severity will be assigned to a patient when there is more 
than one occurrence of the same AE with different reported severities. Relationships of the AE to 
treatment will be categorized as not related, or related. The highest level of association will be 
reported in patients with differing relationships for the same AE. Actions taken regarding 
treatment and patient outcome will also be listed. 
In addition to IARs analysis above, TEAEs that occurs from start of infusion up to 72 hours 
postinfusion will be summarized if applicable.  
The incidence of AEs leading to study discontinuations will also be summarized by treatment 
group, with details provided in the listing. 
Death: The following deaths summaries will be generated: 
• Number (%) of patients who died by study period (TEAE, on-study) and reasons for death 
summarized on the safety population. 
• TEAE leading to death (death as an outcome on the AE e-CRF page as reported by the 
Investigator) by primary system organ class (SOC), high level group term (HLGT), high 
level term (HLT) and preferred term (PT) showing number (%) of patients sorted by 
internationally agreed order of SOC and alphabetic order of HLGT, HLT, and PT. 
11.4.3.2 Laboratory safety variables  
Observed measurements and changes from baseline to scheduled study visits in biochemistry, 
hematology, and urinalysis will be descriptively summarized. All laboratory values will be 
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classified as normal, above normal, or below normal based on normal ranges provided by the 
laboratory. Patients who have at least one incidence of potentially clinically significant 
abnormalities (PCSA) during the TEAE period will be summarized. Individual listings of patients 
with PCSA will be presented. 
The liver function test, alanine aminotransferase (ALT) will be used to assess possible liver 
function injure. Time to onset of the initial ALT elevation (>3ULN) will be analyzed using 
Kaplan-Meier estimate. The normalization (to ≤1 ULN) of ALT will be summarized by categories 
of elevation (3 x, 5 x, 10 x, 20 x ULN) with the following categories of normalization: never 
normalized, normalized before permanent discontinuation of study drug, and normalized after 
permanent discontinuation of study drug. Note that a patient will be counted only under the 
maximum elevation category. 
11.4.3.3 Physical examination and vital signs  
Potentially clinically significant findings observed during the TEAE observation period for vital 
signs (including but not limited to blood pressure, heart rate, respiratory rate, etc.) will be 
summarized by study visit. Listings of abnormal findings/values from these data as well as from 
physical examination inclusive of body weight and height, as well as Tanner stage in paediatric 
patients, will be presented. Change in vital signs during and immediately following IV 
administration from preinfusion will also be summarized. 
11.4.3.4 Other safety endpoints  
Observed measurements and changes from baseline to study time points in antialemtuzumab 
antibody titers will be summarized using descriptive statistics. 
11.4.4 Analyses of pharmacokinetic and pharmacodynamic variables  
The list of pharmacokinetics parameters is listed in Section 9.2.2.1.4. 
PK exposures (Cmax and AUClast) for alemtuzumab will be determined using noncompartmental 
analysis. Values will be reported for individual subjects and summarized using descriptive 
statistics by study week as appropriate. 
Pharmacodynamic endpoints as described in Section 9.2.2.2 will be summarized using descriptive 
statistics at each scheduled study visit. Observed measurements as well as change from baseline 
will be summarized. If a linear trend in the change of a PD endpoint is observed, longitudinal 
model may be employed to model change from baseline over time. In addition, 95% confidence 
interval of changes will be presented. 
Correlation between PD endpoints, biomarkers, efficacy assessments, and exploratory endpoints 
may be explored as appropriate. 
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11.4.5 Analyses of exploratory endpoints  
For the exploratory endpoint of T1 weighted lesion counts, observed measurements will be 
summarized by visit using descriptive statistics including the number of available observations, 
mean, SD, median, minimum, and maximum. It may be categorized into different levels and 
summarized using the number and percentage of patients among the safety population. 
For the exploratory endpoint of brain volume, observed measurements and change over time from 
baseline to each postbaseline visit with MRI will be summarized using descriptive statistics 
including the number of available observations, mean, SD, median, minimum, and maximum. 
11.5 
INTERIM ANALYSIS  
A partial database lock will be done after the last patient has completed efficacy assessments 
including MRI at the end of Period 2. This database lock will allow comparing brain lesion counts 
between Period 1 (M-4 to M0) and Period 2 (M4-M8).  No formal interim analysis will be 
performed. 
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12 
ETHICAL AND REGULATORY CONSIDERATIONS  
12.1 
ETHICAL AND REGULATORY STANDARDS  
This clinical trial will be conducted by the Sponsor, the Investigator, and delegated Investigator 
staff and Subinvestigator, in accordance with consensus ethics principles derived from 
international ethics guidelines, including the Declaration of Helsinki, and the ICH guidelines for 
good clinical practice (GCP), all applicable laws, rules, and regulations. 
This clinical trial will be recorded in a free, publicly accessible, internet-based registry, no later 
than 21 days after the first patient enrollment, in compliance with applicable regulatory 
requirements and with sanofi public disclosure commitments.  
12.2 
INFORMED CONSENT  
The Investigator (according to applicable regulatory requirements), or a person designated by the 
Investigator, and under the Investigator's responsibility, should fully inform the patient and 
parents of all pertinent aspects of the clinical trial including the written information giving 
approval/favorable opinion by the IRB/IEC. All participants should be informed to the fullest 
extent possible about the study, in language and terms they are able to understand. 
Prior to a patient’s participation in the clinical trial, the written ICF should be signed, name filled 
in and personally dated by the patient or by the patient’s legally acceptable representative, and by 
the person who conducted the informed consent discussion. A copy of the signed and dated 
written ICF will be provided to the patient. 
In addition, participants will assent as detailed below or will follow the ethics committee 
(IRB/IEC) approved standard practice for paediatric participants at each participating center 
(age of assent to be determined by the IRB’s/IEC’s or be consistent with the local requirements). 
Participants who can read the assent form and who can write will do so before writing their name 
and dating or signing and dating the form. 
Participants who can write but cannot read will have the assent form read to them before writing 
their name on the form. 
Participants who can understand but who can neither write nor read will have the assent form read 
to them in presence of an impartial witness, who will sign and date the assent form to confirm that 
assent was given. 
Prior to collection of blood for PK and immune markers, the optional PK/immune markers ICF 
(written) must be signed, name filled in, and personally dated by the patient or by the subject’s 
legally acceptable representative, and by the person who conducted the informed consent 
discussion. A copy of the signed and dated written optional ICF will be provided to the patient. 
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The ICF and the assent form, used by the Investigator for obtaining the Patient’s Informed 
Consent must be reviewed and approved by the Sponsor prior to submission to the appropriate 
ethics committee (IRB/IEC) for approval/favorable opinion. 
In relation with the population of patients exposed in the trial ie, paediatric/minor patients, the 
IRB/IEC must ensure proper advice from specialist with paediatrics expertise (competent in the 
area of clinical, ethical and psychosocial problems in the field of paediatrics) according to national 
regulations. This must be documented. 
12.3 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE  
As required by local regulation, the Investigator or the Sponsor must submit this clinical trial 
protocol to the health authorities (competent regulatory authority) and the appropriate IRB/IEC, 
and is required to forward to the respective other party a copy of the written and dated 
approval/favorable opinion signed by the chairman with IRB/IEC composition. 
The clinical trial (study number, clinical trial protocol title and version number), the documents 
reviewed (clinical trial protocol, ICF, Investigator’s Brochure with any addenda or labeling 
documents, summary of product characteristics, package insert, Investigator’s curriculum vitae, 
etc) and the date of the review must be clearly stated on the written (IRB/IEC) approval/favorable 
opinion. 
The IMP will not be released at the study site and the Investigator will not start the study before 
the written and dated approval/favorable opinion is received by the Investigator and the Sponsor. 
During the clinical trial, any amendment or modification to the clinical trial protocol must be 
submitted to the health authorities (competent regulatory authority), as required by local 
regulation, in addition to the IRB/IEC before implementation, unless the change is necessary to 
eliminate an immediate hazard to the patients, in which case the health authorities (competent 
regulatory authority) and the IRB/IEC must be informed as soon as possible. They must also be 
informed of any event likely to affect the safety of patients or the continued conduct of the clinical 
trial, in particular any change in safety. All updates to the Investigator’s Brochure or labeling 
information, will be sent to the IRB/IEC and to health authorities (competent regulatory 
authority), as required by local regulation. 
A progress report is sent to the IRB/IEC at least annually and a summary of the clinical trial’s 
outcome at the end of the clinical trial.  
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13 
STUDY MONITORING  
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S)  
The Investigator is required to ensure compliance with all procedures required by the clinical trial 
protocol and with all study procedures provided by the Sponsor (including security rules). 
The Investigator agrees to provide reliable data and all information requested by the clinical trial 
protocol (with the help of the e-CRF, discrepancy resolution form or other appropriate instrument) 
in an accurate and legible manner according to the instructions provided and to ensure direct 
access to source documents by Sponsor representatives. 
If any circuit includes transfer of data particular attention should be paid to the confidentiality of 
the patient's data to be transferred. 
The Investigator may appoint such other individuals as he/she may deem appropriate as 
Subinvestigators to assist in the conduct of the clinical trial in accordance with the clinical trial 
protocol. All Subinvestigators shall be appointed and listed in a timely manner. 
The Subinvestigators will be supervised by and work under the responsibility of the Investigator. 
The Investigator will provide them with a copy of the clinical trial protocol and all necessary 
information. 
13.2 
RESPONSIBILITIES OF THE SPONSOR  
The Sponsor of this clinical trial is responsible to regulatory authorities for taking all reasonable 
steps to ensure the proper conduct of the clinical trial as regards ethics, clinical trial protocol 
compliance, and integrity and validity of the data recorded on the e-CRFs. Thus, the main duty of 
the monitoring team is to help the Investigator and the Sponsor maintain a high level of ethical, 
scientific, technical and regulatory quality in all aspects of the clinical trial. 
At regular intervals during the clinical trial, the site will be contacted, through monitoring visits, 
letters or telephone calls, by a representative of the monitoring team to review study progress, 
Investigator and patient compliance with clinical trial protocol requirements and any emergent 
problems. These monitoring visits will include but not be limited to review of the following 
aspects: patient informed consent, patient recruitment and follow-up, SAE documentation and 
reporting, AESI documentation and reporting, AE documentation, IMP allocation, patient 
compliance with the IMP regimen, IMP accountability, concomitant therapy use and quality of 
data. 
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13.3 
SOURCE DOCUMENT REQUIREMENTS  
According to the ICH GCP, the monitoring team must check the e-CRF entries against the source 
documents, except for the preidentified source data directly recorded in the e-CRF. The ICF will 
include a statement by which the patient allows the Sponsor’s duly authorized personnel, the 
ethics committee (IRB/IEC), and the regulatory authorities to have direct access to original 
medical records which support the data on the e-CRFs (eg, patient's medical file, appointment 
books, original laboratory records, etc). These personnel, bound by professional secrecy, must 
maintain the confidentiality of all personal identity or personal medical information (according to 
confidentiality and personal data protection rules). 
13.4 
USE AND COMPLETION OF ELECTRONIC CASE REPORT FORMS AND 
ADDITIONAL REQUEST  
It is the responsibility of the Investigator to maintain adequate and accurate e-CRFs (according to 
the technology used) designed by the Sponsor to record (according to Sponsor instructions) all 
observations and other data pertinent to the clinical investigation in a timely manner. All e-CRFs 
should be completed in their entirety in a neat, legible manner to ensure accurate interpretation of 
data. 
Should a correction be made, the corrected information will be entered in the e-CRF overwriting 
the initial information. An audit trail allows identifying the modification.  
Data are available within the system to the Sponsor as soon as they are entered in the e-CRF. 
The computerized handling of the data by the Sponsor may generate additional requests 
(discrepancy resolution form) to which the Investigator is obliged to respond by confirming or 
modifying the data questioned. The requests with their responses will be managed through the 
e-CRF. 
13.5 
USE OF COMPUTERIZED SYSTEMS  
The complete list of computerized systems used for the study is provided in a separate document 
which is maintained in the Sponsor and Investigator study files. 
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14 
ADDITIONAL REQUIREMENTS  
14.1 
CURRICULUM VITAE  
A current copy of the curriculum vitae describing the experience, qualification and training of 
each Investigator and Subinvestigator will be signed, dated and provided to the Sponsor prior to 
the beginning of the clinical trial. 
14.2 
RECORD RETENTION IN STUDY SITES  
The Investigator must maintain confidential all study documentation, and take measures to 
prevent accidental or premature destruction of these documents. 
The Investigator should retain the study documents at least 25 years after the completion or 
discontinuation of the clinical trial. 
However, applicable regulatory requirements should be taken into account in the event that a 
longer period is required. 
The Investigator must notify the Sponsor prior to destroying any study essential documents 
following the clinical trial completion or discontinuation. 
If the Investigator's personal situation is such that archiving can no longer be ensured by him/her, 
the Investigator shall inform the Sponsor and the relevant records shall be transferred to a 
mutually agreed upon designee.  
14.3 
CONFIDENTIALITY  
All information disclosed or provided by the Sponsor (or any company/institution acting on their 
behalf), or produced during the clinical trial, including, but not limited to, the clinical trial 
protocol, personal data in relation to the patients, the e-CRFs, the Investigator's Brochure, and the 
results obtained during the course of the clinical trial, is confidential, prior to the publication of 
results. The Investigator and any person under his/her authority agree to undertake to keep 
confidential and not to disclose the information to any third party without the prior written 
approval of the Sponsor. 
However, the submission of this clinical trial protocol and other necessary documentation to the 
ethics committee (IRB/IEC) is expressly permitted, the IRB/IEC members having the same 
obligation of confidentiality. 
The Subinvestigators shall be bound by the same obligation as the Investigator. The Investigator 
shall inform the Subinvestigators of the confidential nature of the clinical trial. 
The Investigator and the Subinvestigators shall use the information solely for the purposes of the 
clinical trial, to the exclusion of any use for their own or for a third party's account. 
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14.4 
PROPERTY RIGHTS  
All information, documents and IMP provided by the Sponsor or its designee are and remain the 
sole property of the Sponsor. 
The Investigator shall not and shall cause the delegated Investigator staff /Subinvestigator not to 
mention any information or the product in any application for a patent or for any other intellectual 
property rights. 
All the results, data, documents and inventions, which arise directly or indirectly from the clinical 
trial in any form, shall be the immediate and exclusive property of the Sponsor. 
The Sponsor may use or exploit all the results at its own discretion, without any limitation to its 
property right (territory, field, continuance). The Sponsor shall be under no obligation to patent, 
develop, market or otherwise use the results of the clinical trial. 
As the case may be, the Investigator and/or the Subinvestigators shall provide all assistance 
required by the Sponsor, at the Sponsor's expense, for obtaining and defending any patent, 
including signature of legal documents. 
14.5 
DATA PROTECTION  
• The patient's personal data, which are included in the Sponsor database shall be treated in 
compliance with all applicable laws and regulations. 
• When archiving or processing personal data pertaining to the Investigator and/or to the 
patients, the Sponsor shall take all appropriate measures to safeguard and prevent access 
to this data by any unauthorized third party. 
• The Sponsor also collects specific data regarding Investigator as well as personal data 
from any person involved in the study which may be included in the Sponsor’s databases, 
shall be treated by both the Sponsor and the Investigator in compliance with all applicable 
laws and regulations. 
• Subject race or ethnicity will be collected in this study because these data are required by 
several regulatory authorities. 
14.6 
INSURANCE COMPENSATION  
The Sponsor certifies that it has taken out a liability insurance policy covering all clinical trials 
under its sponsorship. This insurance policy is in accordance with local laws and requirements. 
The insurance of the Sponsor does not relieve the Investigator and the collaborators from any 
obligation to maintain their own liability insurance policy. An insurance certificate will be 
provided to the IECs/IRBs or regulatory authorities in countries requiring this document.  
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14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES  
For the purpose of ensuring compliance with the clinical trial protocol, good clinical practice, and 
applicable regulatory requirements, the Investigator should permit auditing by or on the behalf of 
the Sponsor and inspection by regulatory authorities. 
The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study 
records for review, being understood that these personnel is bound by professional secrecy, and as 
such will not disclose any personal identity or personal medical information. 
The Investigator will make every effort to help with the performance of the audits and inspections, 
giving access to all necessary facilities, data, and documents. 
As soon as the Investigator is notified of a planned inspection by the authorities, he will inform 
the Sponsor and authorize the Sponsor to participate in this inspection. 
The confidentiality of the data verified and the protection of the patients should be respected 
during these inspections. 
Any result and information arising from the inspections by the regulatory authorities will be 
immediately communicated by the Investigator to the Sponsor. 
The Investigator shall take appropriate measures required by the Sponsor to take corrective 
actions for all problems found during the audit or inspections. 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE  
14.8.1 By the Sponsor  
The Sponsor has the right to terminate the participation of either an individual site or the study at 
any time, for any reason, including but not limited to the following:  
• The information on the product leads to doubt as to the benefit/risk ratio. 
• Patient enrollment is unsatisfactory. 
• The Investigator has received from the Sponsor all IMP, means, and information necessary 
to perform the clinical trial and has not included any patient after a reasonable period of 
time mutually agreed upon. 
• Noncompliance of the Investigator or Subinvestigator, delegated staff with any provision 
of the clinical trial protocol, and breach of the applicable laws and regulations or breach of 
the ICH GCP. 
• The total number of patients are included earlier than expected. 
In any case the Sponsor will notify the Investigator of its decision by written notice. 
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14.8.2 By the Investigator  
The Investigator may terminate his/her participation upon thirty (30) days' prior written notice if 
the study site or the Investigator for any reason becomes unable to perform or complete the 
clinical trial.  
In the event of premature discontinuation of the study or premature close-out of a site, for any 
reason whatsoever, the appropriate IRB/IEC and regulatory authorities should be informed 
according to applicable regulatory requirements. 
14.9 
CLINICAL TRIAL RESULTS  
The Sponsor will be responsible for preparing a clinical study report and to provide a summary of 
study results to the Investigator. 
14.10 PUBLICATIONS AND COMMUNICATIONS  
The Investigator undertakes not to make any publication or release pertaining to the study and/or 
results of the study prior to the Sponsor’s written consent, being understood that the Sponsor will 
not unreasonably withhold its approval. 
As the study is being conducted at multiple sites, the Sponsor agrees that, consistent with 
scientific standards, a primary presentation or publication of the study results based on global 
study outcomes shall be sought. However, if no multicenter publication is submitted, underway, 
or planned within twelve (12) months of the completion of this study at all sites, the Investigator 
shall have the right to publish or present independently the results of this study in agreement with 
other Investigators and stakeholders. The Investigator shall provide the Sponsor with a copy of 
any such presentation or publication for review and comment at least 30 days in advance of any 
presentation or submission for publication. In addition, if requested by the Sponsor, any 
presentation or submission for publication shall be delayed for a limited time, not to exceed 
90 days, to allow for filing of a patent application or such other justified measures as the Sponsor 
deems appropriate to establish and preserve its proprietary rights.  
The Investigator shall not use the name(s) of the Sponsor and/or its employees in advertising or 
promotional material or publication without the prior written consent of the Sponsor. The Sponsor 
shall not use the name(s) of the Investigator and/or the collaborators in advertising or promotional 
material or publication without having received his/her and/or their prior written consent(s). 
The Sponsor has the right at any time to publish the results of the study. 
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15 
CLINICAL TRIAL PROTOCOL AMENDMENTS  
All appendices attached hereto and referred to herein are made part of this clinical trial protocol. 
The Investigator should not implement any deviation from, or changes to the clinical trial protocol 
without agreement by the Sponsor and prior review and documented approval/favorable opinion 
from the IRB/IEC and/or notification/approval of health authorities (competent regulatory 
authority) of an amendment, as required by local regulation, except where necessary to eliminate 
an immediate hazard(s) to clinical trial patients, or when the change(s) involves only logistical or 
administrative aspects of the trial. Any change agreed upon will be recorded in writing, the 
written amendment will be signed by the Investigator and by the Sponsor and the signed 
amendment will be filed with this clinical trial protocol. 
Any amendment to the clinical trial protocol requires written approval/favorable opinion by the 
IRB/IEC prior to its implementation, unless there are overriding safety reasons. 
In case of substantial amendment to the clinical trial protocol, approval from the health authorities 
(competent regulatory authority) will be sought before implementation. 
In some instances, an amendment may require a change to the ICF. The Investigator must receive 
an IRB/IEC approval/favorable opinion concerning the revised ICF prior to implementation of the 
change and patient signature should be recollected if necessary. 
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16 
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14. Coles AJ, Wing M, Smith S, Coraddu F, Greer S, Taylor C, et al. Pulsed monoclonal antibody 
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28. Lublin F. Multiple sclerosis trial designs for the 21st century: building on recent lessons. J 
Neurol. 2005;252 Suppl 5:v46-53. 
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Outcome Assessments Consortium. Validity of the Symbol Digit Modalities Test as a 
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minimal assessment of cognitive function in multiple sclerosis (MACFIMS). J Int 
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31. Sumowski JF, Benedict R, Enzinger C, Filippi M, Geurts JJ, Hamalainen P et al. Cognition in 
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32. Stevens K. Developing a descriptive system for a new preference-based measure of health-
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APPENDICES  
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Appendix A 
Guidance on contraceptive methods and collection of pregnancy 
information  
Women Of Child Bearing Potential 
A woman is considered of reproductive potential (WOCBP), ie, fertile, following menarche and 
until becoming postmenopausal unless permanently sterile. Permanent sterilization methods 
include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. 
Women of Child Bearing Potential must use one of the highly effective methods from the lists 
below: 
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctlya 
• Combined (estrogen- and progestogen-containing ) hormonal contraception associated 
with inhibition of ovulation: 
- 
Oral, 
- 
Intravaginal, 
- 
Transdermal. 
• Progestogen-only hormone contraception associated with inhibition of ovulation: 
- 
Oral, 
- 
Injectable. 
Highly Effective Methods That Are User Independent 
• Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation. 
• Intrauterine device (IUD). 
• Intrauterine hormone-releasing system (IUS). 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and 
the preferred and usual lifestyle of the subject. 
NOTE: 
a. 
Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with local regulations 
regarding the use of contraceptive methods for subjects participating in clinical studies. 
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COLLECTION OF PREGNANCY INFORMATION 
Female subjects who become pregnant 
• The Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study. 
• Information will be recorded on the appropriate form and submitted to the Sponsor within 
24 hours of learning of a participant's pregnancy. 
• Participant will be followed to determine the outcome of the pregnancy. The Investigator 
will collect follow-up information on participant and neonate, which 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 procedure. 
• In this study pregnancy is considered to be an AESI and will be reported as such, any 
pregnancy complication or elective termination of a pregnancy will be reported as an AE 
or SAE. 
• A spontaneous abortion is always considered to be an SAE and will be reported as such. 
• Any SAE occurring as a result of a poststudy pregnancy which is considered reasonably 
related to the study treatment by the Investigator, will be reported to the Sponsor as 
described in Section 10.4.1.3. While the Investigator is not obligated to actively seek this 
information in former study subjects, he or she may learn of an SAE through spontaneous 
reporting. 
Male subjects with partners of reproductive potential who become pregnant 
• The Investigator will attempt to collect pregnancy information on any female partner of a 
male study subject who becomes pregnant while participating in this study. This applies 
only to subjects who receive study treatment. 
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. 
• Partner will also be followed to determine the outcome of the pregnancy. Information on 
the status of the mother and child will be forwarded to the Sponsor. 
• Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery 
date. Any termination of the pregnancy will be reported regardless of fetal status (presence 
or absence of anomalies) or indication for procedure. 
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Appendix B 
General guidance for the follow-up of laboratory abnormalities by 
sanofi  
Immune thrombocytopenia 
All patients will be monitored with monthly laboratory tests. The table below summarizes the 
minimum recommendations for ITP monitoring. 
Summary of Minimum Recommendations for ITP Monitoring of All Patients 
Test 
Result 
Action Items 
Changes In 
Monitoring 
Platelet Count 
LLN 
Immediate repeat 
Hematology 
If Repeat 
LLNWeekly 
Hematology Until 
Stable* 
  
100,000/
µL 
Immediate repeat 
Hematology;  
Hematology Consult if 
confirmed 
If Repeat LLN 
Weekly Hematology 
Until Stable* 
  
50,000/µ
L 
Immediate repeat 
Hematology;  Emergency 
Hematology Consult if 
confirmed 
If Repeat LLN  
Weekly Hematology 
Until Stable* 
Platelet Drop (but still within normal 
range) 
100,000/µ
L from 
prior 
Investigator Notified 
Investigator Discretion 
  
140,000/µ
L from 
prior 
Repeat Hematology 
If Repeat < LLN 
Weekly Hematology 
Until Stable  
ITP Signs or Symptoms 
Any ITP 
Signs or 
Symptoms 
Immediate site contact to 
determine further 
evaluation 
As outlined above 
*Weekly CBC Protocol:  Weekly platelet counts for at least 8 weeks. 
  Return to Monthly when:    
     - Platelet counts  8 are within the normal range  
      (or) 
      - Platelet counts stabilize (8 consecutive readings 100,000/µL and average of last 4 counts  average of 4 prior counts) 
    After documenting stabilization, continue monthly monitoring as long as platelet counts remain 100,000/µL; If a subsequent 
platelet count is confirmed to be <100,000, the patient should resume weekly monitoring.  
In addition to the above recommendations, the ongoing and long-term management of all patients 
with ITP will be subject to the clinical judgment of the treating hematologist.  
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Definition of ITP:For the purposes of this study, patients will be considered to have a diagnosis 
of ITP if they have all of the following: 
• Normal Hgb. 
• Normal WBC, though the differential will likely reflect lymphopenia as a result of the 
alemtuzumab treatment. 
• No splenomegaly. 
• No evidence of alternative nonautoimmune etiology of thrombocytopenia (eg, 
cytomegalovirus [CMV] infection). 
• Normal peripheral smear except for a decrease in platelets without clumping.  
AND either of the following: 
• A confirmed platelet count equal to or above 50,000/L but below 100,000/L on at least 
2 consecutive occasions over a period of at least 1 month, or,  
• A confirmed platelet count below 50,000/L without clumping documented on at least 
2 consecutive occasions over any period of time. 
It is recognized that confounding medical conditions may result in other abnormalities to the 
CBC, which can render diagnosis more difficult.  Nonetheless, any alemtuzumab-treated 
patient who meets the ITP criteria specified immediately above will receive no further 
alemtuzumab and will be immediately referred for hematologic consultation.   
If upon review of the peripheral smear platelet clumping is present indicative of 
pseudothrombocytopenia, the Hematology Panel should be repeated at a laboratory using an 
anticoagulant other than ethylenediamine tetraacetic acid (EDTA).  In addition, examination of 
the peripheral smear should reveal a normal platelet estimate. 
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Anti-Glomerular Basement Membrane Disease  
Alemtuzumab has also been associated with anti–GBM disease, which can cause a 
pulmonaryrenal syndrome known as Goodpasture’s disease. (Clatworthy, 2008, N Engl J Med; 
Coles, 2006, J Neurol) Anti–GBM disease is a rare autoimmune disorder in which circulating 
antibodies are directed against an antigen normally present in the basement membranes of renal 
glomeruli and pulmonary alveoli. The target antigen is the alpha-3 chain of type IV collagen. The 
resultant clinical syndrome encompasses a spectrum ranging from mild or no renal involvement to 
rapidly progressive glomerulonephritis. Patients may develop pulmonary hemorrhage. Signs and 
symptoms that commonly occur in patients with antiGBM disease include: 
• Gross hematuria (red or tea colored urine). 
• Hemoptysis.  
• Edema (particularly lower extremity edema). 
• Nonspecific symptoms can include malaise, fatigue, upper respiratory infection, rash. 
In an effort to identify potential cases of antiGBM disease early, all patients will undergo monthly 
evaluation of serum creatinine levels alone or as part of a full chemistry panel and laboratory 
urinalysis (minimally including examination of protein and hemoglobin) with microscopy. Follow 
up of abnormal results will be guided by the algorithm below in 2 the figures below. 
Monthly Urinalysis and Serum Creatinine 
 
 
Monthly Urinalysis with Microscopy*, SCr
(Performed at Central Lab; local lab permissible but not preferred)
Referral to nephrologist for 
non-GBM disease
Site evaluation,
Treat UTI if indicated,
Non-urgent referral to 
nephrologist
See Fig. 9-2
Normal SCr
Abnormal SCr 
(or, if baseline SCr is 
abnormal, increase of 
≥25%)
Negative for 
Blood
Negative for Blood
Positive for Protein and/or 
WBC
Positive for 
Blood
Abnormal SCr 
(or, if baseline SCr is 
abnormal, increase of 
≥25%)
Normal SCr
Site evaluation,
Non-urgent referral to 
nephrologist
Abbreviations: SCr=Serum creatinine; GBM=glomerular basement membrane; UTI=urinary tract infection; WBC=white blood cells
*Morning urine preferred; false positive rate high during menses and one week after. If monthly urinalysis is positive for blood, SCr is 
normal, and the patient is menstruating, the urinalysis should be repeated one week following menses. If a patient has chronic 
microscopic hematuria or proteinuria that is being evaluated or already adequately evaluated, monthly surveillance should focus on 
changes in these levels and on SCr.
Continue 
Monitoring
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Follow-up of Abnormal Urine or Serum Creatinine Results 
 
 
Monthly Urinalysis with Microscopy, SCr
Non-urgent referral to a 
nephrologist
Resume routine 
monitoring
Persistent microscopic 
hematuria with normal 
SCr X 3 weeks
If at any time blood 
clears and SCr is 
normal or unchanged
Site evaluation, non-
urgent referral to 
nephrologist
Repeat normal or stable
SCr 
increasing?
WEEKLY Urinalysis with Microscopy & 
SCr for up to 3 weeks
Repeat Urinalysis with 
Microscopy 
& SCr in 2-3 days
HIGH concern, URGENT referral 
to nephrologist**
≤50% increase
>50% increase
Normal SCr and no increase from baseline* 
or screening
Normal SCr but increase from baseline* or 
screening
Abnormal SCr
Positive for Blood
Abbreviations: SCr=serum creatinine
*Comparison is versus the lowest of pre-treatment values for that patient.
**While awaiting nephrology consult, consider repeating SCr in 2-3 days and refer emergently/consider hospitalization if 
SCr rising.
YES
Resume routine 
monitoring
Blood 
persists
No blood
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*If unable to retest in 72 hours, use original lab results to decide on further reporting/monitoring/discontinuation.  
Note: 
• 
“Baseline” refers to ALT sampled at baseline visit; or if baseline value unavailable, to the latest ALT sampled before the baseline 
visit. The algorithm does not apply to the instances of increase in ALT during screening. 
• 
See Section 10.4 for guidance on safety reporting. 
• 
Normalization is defined as ≤ ULN or baseline value, if baseline value is >ULN. 
INCREASE IN ALT
ALT > 3 ULN
Confirm ALT > 3 ULN
Retest within 72 hours of initial 
sample*
No
Yes
COMPLETE the specific CRF forms for 
„ALT Increase” and inform the 
Monitoring Team within 24 hours
Total Bilirubin > 2 ULN 
No
Yes
ALT > 5 ULN (if baseline ALT ≤ 2 ULN), or 
ALT >8 ULN (if baseline ALT > 2 ULN)
Continue IMP administration
No
Monitor LFTs every 72 hours
IMP administration can be continued as 
long as – under close monitoring –
conditions for permanent 
discontinuation or temporary 
interruption per protocol are not met
Yes
Permanent Discontinuation of IMP
In ANY CASE, FOLLOW the instructions listed in the box below: 
1.
INFORM the Site Monitor who will forward the information to the Study Manager
2.
INVESTIGATE specifically for malaise with or without loss of consciousness, dizziness, and/or hypotension and/or episode of 
arrhythmia in the previous 72 hours; rule out muscular injury
3.
PERFORM the following tests:
- LFTs: AST, ALT, alkaline phosphatase, total and conjugated bilirubin and prothrombin time / INR
- CPK, serum creatinine, complete blood count
- Anti-HAV IgM, anti-HBc IgM (HBV-DNA if clinically indicated), anti-HCV and HCV RNA, anti-
CMV  IgM and anti-HEV IgM antibodies
- Depending on the clinical context, check for recent infection with EBV, herpes viruses, and toxoplasma
- Hepatobiliary ultrasonography (or other imaging investigations if needed)
4.
CONSIDER Auto-antibodies: antinuclear, anti-DNA, anti-smooth muscle, anti-LKM
5.
CONSIDER consulting with hepatologist
6.
CONSIDER patient hospitalisation if INR>2 (or PT<50%) and/or central nervous system disburbances suggesting hepatic 
encephalopathy
7.
MONITOR LFTs after discontinuation of IMP:
- As closely as possible (or every 48 hours) until stabilization, then every 2 weeks until return to normal/baseline or clinical 
resolution.
8.
FREEZE serum sample (5ml x 2)
9.
In case of SUSPICION of GILBERT Syndrome, a DNA diagnostic test should be done
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Acute renal failure is to be recorded as an AE only if at least 1 of the criteria listed in the general 
guidelines for reporting AEs in Section 10.4.5 is met. 
Rapid increase in serum creatinine over 150 µmol/L 
or rapid decrease in creatinine clearance below
50 mL/mn
ACUTE RENAL FAILURE
Can be rapidly reversed:
• By volume repletion
• Or relief of urinary tract 
obstruction (according to etiology)
Cannot be rapidly reversed: 
• Occurrence/aggravation of life 
threatening symptoms of ARF: anemia, 
hyperkalemia, hyperuricemia, metabolic 
acidosis, cardiac insufficiency, 
pulmonary edema, arrhythmia, DIC, etc.
• And/or predominant elimination of 
Investigational Medicinal Product by 
renal route
1.
Investigational Medicinal 
Product may be continued
2.
MONITOR serum creatinine 
until return to baseline level
1.
INFORM the local monitor
2.
DISCONTINUE
Investigational Medicinal Product 
administration
3.
HOSPITALIZATION should be 
considered and seek for nephrologic  
advice
4.
PERFORM the following 
examinations: 
•
BP, HR, hydration status, ECG
•
Blood count
•
Liver function tests + CPK
•
Biochemistry, including urea
•
Urinalysis
5.
COLLECT/STORE one sample 
following handling procedures 
described in PK sections (for studies 
with PK sampling) and freeze one 
serum sample (5 mL) on Day 1 
(cessation of investigational 
medicinal product)
6.
MONITOR renal function until 
return to baseline level (every day at 
the beginning, then every week)
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Suspicion of rhabdomyolysis is to be recorded as an AE only if at least 1 of the criteria in the 
general guidelines for reporting AEs in Section 10.4.5 is met. 
If Increase in CPK (expressed in ULN)
> 3 ULN
Repeat immediately the count.
If confirmed, inform the local monitor and
INVESTIGATE for the origin:
- PERFORM:
•
ECG
•
CPK-MB -MM 
•
Troponin
•
Creatinine
•
Iono (k+, Ca2+)
•
Transaminases + Total and conjugated bilirubin
•
Myoglobin (serum and urines)
- COLLECT/STORE one sample following handling procedures described in PK sections (for 
studies with PK sampling) and freeze one serum sample (5 mL) on Day 1 (cessation of 
investigational medicinal product). 
- INTERVIEW the patient about a recent intensive muscular effort, trauma, convulsions, electrical 
injury, injury or stress to the skeletal muscle, multiple intramuscular injections, recent surgery, 
concomitant medications, consumption of alcohol, morphine, cocaine.
- SEARCH for alternative causes to cardiac or muscular toxicity, ie: stroke, pulmonary infarction, 
dermatomyositis or polymyositis, convulsions, hypothyroidism, delirium tremens, muscular 
dystrophies.
If either the cardiac origin or the 
rhabdomyolysis is confirmed or if CPK 
> 10 ULN:
1. DISCONTINUE Investigational 
Medicinal Product administration
2. MONITOR CPK every 3 days for the 
first week then once weekly until return 
to normal or for at least 3 months
3. HOSPITALIZATION should be 
considered
If the cardiac origin or the rhabdomyolysis is 
ruled out and if CPK 10 ULN:
MONITOR CPK every 3 days for the first week 
then once weekly until return to normal or for 
at least 3 months
Muscular symptoms (myalgia, pain, weakness, 
dark urines)
Systematic CPK assessment as per 
protocol
Perform CPK
SUSPICION OF RHABDOMYOLYSIS
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Appendix C 
Mc Donald’s criteria for diagnosis of MS  
 
 
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Appendix D 
Kurtzke’s Functional Systems and Expanded Disability Status Scale 
in Multiple Sclerosis  
 
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Appendix E 
Tanner stage classification  
The Tanner stages assessment for each patient at each site should be performed, if possible by the 
same Investigator/designee trained to assess pubertal development. 
Boys - development of external genitalia 
Stage 1: Pre-adolescent. Testes, scrotum, and penis are of about the same size and proportion as 
in early childhood. 
Stage 2: The scrotum and testes have enlarged and there is a change in the texture of the scrotal 
skin. There is also some reddening of the scrotal skin. 
Stage 3: Growth of the penis has occurred, at first mainly in length but with some increase in 
breadth. There has been further growth of testes and scrotum. 
Stage 4: Penis further enlarged in length and breadth with development of glans. Testes and 
scrotum further enlarged. There is also further darkening of the scrotal skin. 
Stage 5: Genitalia adult in size and shape. No further enlargement takes place after Stage 5 is 
reached. 
Girls - breast development 
Stage 1: Pre-adolescent; elevation of papilla only. 
Stage 2: Breast bud stage; elevation of breast and papilla as a small mound, enlargement of areola 
diameter. 
Stage 3: Further enlargement of breast and areola, with no separation of their contours. 
Stage 4: Projection of areola and papilla to form a secondary mound above the level of the breast. 
Stage 5: Mature stage; projection of papilla only, due to recession of the areola to the general 
contour of the breast.  
Boys/Girls - pubic hair 
Stage 1: Pre-adolescent; the vellus over the pubes is not further developed than that over the 
anterior abdominal wall, ie, no pubic hair. 
Stage 2: Sparse growth of long, slightly pigmented, downy hair, straight or only slightly curled, 
appearing chiefly at the base of the penis (boys) or along the labia (girls).  
Stage 3: Considerably darker, coarser, and more curled. The hair spreads sparsely over the 
junction of the pubes.  
Stage 4: Hair is now adult in type, but the area covered by it is still considerably smaller than in 
most adults. There is no spread to the medial surface of the thighs. 
Stage 5: Adult in quantity and type, distributed as an inverse triangle of the classically feminine 
pattern (girls). Spread to the medial surface of the thighs, but not up the linea alba or elsewhere 
above the base of the inverse triangle. 
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Appendix F 
23-item PedsQL Generic Core Scales  
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Appendix G 
NeuroQOL  
Physical (fatigue and pain) and mental (cognitive function, anxiety, depression) 
 
 
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Appendix H Country-specific requirements  
AMENDMENT FOR RUSSIA: 
Amendment 01 RU: 23-Jan-2017  
This protocol amendment (Amendment 01 RU) is considered to be nonsubstantial based on the 
criteria set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the 
Council of the European Union [because it neither significantly impacts the safety or 
physical/mental integrity of participants nor the scientific value of the study]. 
Overall Rationale for the Amendment 
I01. was modified at the request of the Ministry of Health of the Russian Federation. 
Protocol amendment summary of changes table 
Section # 
and Name 
Description of Change 
Brief Rationale 
Section 7.1, 
Inclusion 
criteria 
Restrict inclusion to patients with 
RRMS aged 12 to <18 years at 
study entry 
In the future, it is intended to also include children aged ≥10 to <12, as 
for the other countries, when the Russian Ministry of Health and Local 
Ethics Committees will grant an authorization for this age range. 
 
AMENDMENTS FOR GREAT BRITAIN: 
Amendment 02 GB: 05-May-2017  
This protocol amendment (Amendment 02 GB) is considered to be nonsubstantial based on the 
criteria set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the 
Council of the European Union [because it neither significantly impacts the safety or 
physical/mental integrity of participants nor the scientific value of the study]. 
Overall Rationale for the Amendment 
The protocol was modified at the request of the Medicines and Healthcare Products Regulatory 
Agency (MHRA) address concerns about contraceptive methods 
Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 6.3, Interim 
analysis 
Replace “An interim analysis will be performed to assess the primary 
endpoint. A partial database lock will be done after the last patient has 
completed efficacy assessments including MRI at the end of Period 2. 
This data base lock will allow the comparison of lesion counts between 
Period 1 (M-4 to M0) and Period 2 (M4-M8).” With “Not applicable.” 
Inconsistency between 
section 6.3 and 
section 11.5 on a pre-
planned Interim 
Analysis 
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Section 7.2, Exclusion 
criteria 
“Unwilling to agree to use a reliable and effective contraceptive method as 
defined for contraception in the informed consent form (ICF) when 
receiving a course of alemtuzumab treatment and for 4 months following 
that course of treatment (fertile patients only) (Appendix A).” is replaced 
with “Unwilling to agree to use a highly effective contraceptive method as 
defined in Appendix A when receiving a course of alemtuzumab treatment 
and for 4 months following that course of treatment 
 fertile patients only) (Appendix A).” 
To provide 
recommendations 
related to 
contraception 
requirements in line 
with the Clinical Trial 
Facilitation Group 
(CTFG) guidance 
2014 
 
Amendment 05 GB: 21-May-2018 
This protocol amendment (Amendment 05 GB) is considered to be nonsubstantial based on the 
criteria set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the 
Council of the European Union [because it neither significantly impacts the safety or 
physical/mental integrity of participants nor the scientific value of the study]. 
Overall Rationale for the Amendment 
The primary driver for this amendment was to make an H1 antagonist other than intravenous (IV) 
diphenhydramine available in countries where IV diphenhydramine is not available. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Clinical trial summary 
The clinical trial summary was edited to reflect changes to the 
protocol. 
 
Section 8.2, 
Noninvestigational 
medicinal products 
The possibility to use an IV H1 antagonist other than 
diphenhydramine or an oral formulation, if no H1 antagonist IV 
formulation is available, at an appropriate dosing, is offered. 
Lack of availability of IV 
diphenhydramine in some 
countries 
 
AMENDMENT FOR ITALY: 
Amendment 04 IT: 12-Mar-2018  
This protocol amendment (Amendment 04 IT) is considered to be nonsubstantial based on the 
criteria set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the 
Council of the European Union [because it neither significantly impacts the safety or 
physical/mental integrity of participants nor the scientific value of the study]. 
Overall Rationale for the Amendment 
The primary driver for this amendment was to make an H1 antagonist other than intravenous (IV) 
diphenhydramine available in countries where IV diphenhydramine is not available. 
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Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Clinical trial summary 
The clinical trial summary was edited to reflect changes to the 
protocol. 
 
Section 8.2, 
Noninvestigational 
medicinal products 
The possibility to use an IV H1 antagonist other than 
diphenhydramine or an oral formulation, if no H1 antagonist IV 
formulation is available, at an appropriate dosing, is offered. 
Lack of availability of IV 
diphenhydramine in some 
countries 
 
AMENDMENT FOR FRANCE: 
Amendment 06 FR: 21-May-2018 
This protocol amendment (Amendment 05 FR) is considered to be nonsubstantial based on the 
criteria set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the 
Council of the European Union [because it neither significantly impacts the safety or 
physical/mental integrity of participants nor the scientific value of the study]. 
Overall Rationale for the Amendment 
The primary driver for this amendment was to make an H1 antagonist other than intravenous (IV) 
diphenhydramine available in countries where IV diphenhydramine is not available. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Clinical trial summary 
The clinical trial summary was edited to reflect changes to the 
protocol. 
 
Section 8.2, 
Noninvestigational 
medicinal products 
The possibility to use an IV H1 antagonist other than 
diphenhydramine or an oral formulation, if no H1 antagonist IV 
formulation is available, at an appropriate dosing, is offered. 
Lack of availability of IV 
diphenhydramine in some 
countries 
 
 
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Appendix I Protocol amendment history  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly after the title page. 
Amended protocol 04 (09 Mar 2020) 
In Europe, this amended protocol 04 is considered to be substantial based on the criteria set forth 
in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union because it significantly impacts the safety or physical/mental integrity of 
participants. 
OVERALL RATIONALE FOR THE AMENDMENT 
The amendment provides additional updates and safety measures based on safety concerns that 
have been identified from post-marketing use of alemtuzumab in adults. Updates include 
additional safety measures, contraindications and adverse events of special interest (AESIs) 
important for patient safety. Details of updates are outlined below. 
Protocol amendment summary of changes table 
Section No. and name 
Description of change 
 
Brief rationale 
Clinical trial summary 
And 
Section 7.2 Exclusion criteria 
Added a note in the exclusion criteria with following text: 
 
NOTE: Prior to initiation of any alemtuzumab treatment course, 
contraindications should be reviewed as pre-treatment verification of 
eligibility. 
Update of safety 
information following 
Pharmacovigilance 
Risk Assessment 
Comittee (PRAC) 
recommendations 
during the EU Article 
20 Procedure. 
Section 1.2.1 Schedule of 
events Part 1 (Year 1) 
Added additional footnote 'v' in flow chart 1.2.1 part 1 (year 1) with 
below text: 
Contraindications, including the following must be checked before 
infusion: severe active infection, uncontrolled hypertension, history of 
arterial dissection of the cervicocephalic arteries, history of stroke, 
history of angina pectoris or myocardial infarction, known 
coagulopathy or on concomitant anti-coagulant therapy 
Update of the safety 
information following 
the PRAC 
recommendations 
Section 4 Introduction and 
Rationale 
In sub-section “Alemtuzumab Post-Marketing Updates in Adult”, 
added “temporally associated” before “pulmonary alveolar 
haemorrhage, myocardial ischemia…” 
In sub-section “Alemtuzumab Post-Marketing Updates in Adult”, 
added acquired hemophilia A and PML in Post-marketing PV 
monitoring identified events 
Update based on adult 
post-marketing data  
Section 8.6 Storage 
Conditions and Shelf Life 
And 
Section 10.1.4 Visit 4/M0/D1 
(first course of 
alemtuzumab) 
LEMTRADA has been replaced by alemtuzumab. 
Administrative change 
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Section No. and name 
Description of change 
 
Brief rationale 
And 
Section 10.1.10 Visit 16/M12 
(second course of 
alemtuzumab) 
Section 9.3.1 Adverse 
events 
Added thrombocytopenia and myocardial infarction in assessment of 
IARs 
Update of the safety 
information 
Section 10.1.4 Visit 4/M0/D1 
(first course of 
alemtuzumab) 
And 
Section 10.1.10 Visit 16/M12 
(second course of 
alemtuzumab) 
Updated the pre-infusion text: 
The following infusion management procedures must be utilized for 
each infusion and each treatment course to reduce serious reactions 
temporally associated with alemtuzumab infusion: 
• 
Pre-infusion: Physicians should obtain a baseline ECG and 
vital signs (including heart rate and blood pressure measurement), 
screen for pre-existing hemorrhagic, cardiovascular (including 
venous thromboembolism) and cerebrovascular risk factors, screen 
for lung disease, review concomitant medications (eg, antiplatelet 
agents, anticoagulants), perform laboratory tests (complete blood 
count with differential, serum transaminases, serum creatinine, test 
of thyroid function and urinalysis with microscopy), and evaluate 
infusion-related risks. It is at investigator’s discretion to treat or not 
treat patient with alemtuzumab after clinical evaluation. Physician 
should also apply the following contraindications when treating 
patients in this study: 
• 
Hypersensitivity to the active substance, or to any of the 
excipients 
• 
Human Immunodeficiency Virus (HIV ) infection 
• 
Severe active infection   
• 
Uncontrolled hypertension 
• 
History of arterial dissection of the cervicocephalic arteries 
• 
History of stroke 
• 
History of angina pectoris or myocardial infarction 
• 
Known coagulopathy or on concomitant anti-coagulant therapy 
 
Deleted review of HCP checklist. 
 
Updated the during infusion with following text: 
The following are recommendations in case of clinical 
abnormities/severe adverse event:  
- 
Interrupt infusion 
- 
Medically evaluate the patient guided by the adverse event 
profile of alemtuzumab prior to considering restarting therapy 
- 
Provide appropriate treatment as needed 
- 
Consider permanently discontinuing the alemtuzumab infusion 
if the patient shows clinical symptoms suggesting development 
of a serious adverse event associated with the infusion 
(myocardial ischemia, hemorrhagic stroke, cervico-cephalic 
arterial dissection or pulmonary alveolar hemorrhage). 
Updated the post infusion with following text: 
Update of patient 
monitoring and safety 
procedures 
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Section No. and name 
Description of change 
 
Brief rationale 
- Observation for infusion reactions is recommended for a 
minimum of 2 hours after alemtuzumab infusion; 2 hours after 
infusion, patients should be cautious and reporting if any of the 
infusion reactions develop within 48 hours. 
- Patients with clinical symptoms suggesting development of a 
serious adverse event temporarily associated with the infusion 
(myocardial ischemia, hemorrhagic stroke, cervico-cephalic 
arterial dissection or pulmonary alveolar hemorrhage) should 
be closely monitored until complete resolution of the 
symptoms. The observation time should be extended as 
appropriate. 
- The patients should be educated on the potential for delayed 
onset of infusion associated reactions and symptoms and 
signs of cardiovascular or cerebrovascular events, and 
instructed to report symptoms and/or seek appropriate medical 
care. 
Section 10.4.1.3 Adverse 
event of special interest 
 
Added following AESIs: 
• 
Autoimmune mediated conditions including but not limited 
to autoimmune hepatitis, acquired Hemophilia A 
• 
Temporally associated* pulmonary alveolar hemorrhage 
• 
Temporally associated* myocardial ischemia, myocardial 
infarction 
• 
Temporally associated* stroke 
• 
Temporally associated* cervicocephalic arterial dissection 
(* Temporally associated: 1 to 3 days after the last 
infusion) 
• 
Progressive multifocal leukoencephalopathy (PML) 
 
Updated wording of serious and opportunistic infections to below 
text: 
Serious infections including serious opportunistic infections (eg, 
Listeria infections, CMV, EBV), HPV associated with cervical 
dysplasia 
 
Moved cervical dysplasia with HPV. 
Deleted hemolytic anemia, autoimmune neutropenia, autoimmune 
pancytopenia 
Update of the safety 
information following 
the Article 20 
Procedure. 
Section 10.4.4 Instructions 
for reporting serious adverse 
events 
The following old text: 
SEND (preferably by fax or e-mail) a photocopy of all examinations 
carried out and the dates on which these examinations were 
performed, to the representative of the monitoring team whose 
name, fax number, and email address appear on the clinical trial 
protocol. Care should be taken to ensure that the patient's identity is 
protected and the patient's identifiers in the clinical trial are properly 
mentioned on any copy of a source document provided to the 
Sponsor. For laboratory results, include the laboratory normal 
ranges. 
Is replaced by: 
Administrative change 
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Section No. and name 
Description of change 
 
Brief rationale 
There may be instances when copies of medical records for certain 
cases are requested by the Sponsor. In such case, care should be 
taken to ensure that the patient's identity is protected and the 
patient's identifiers in the study are properly mentioned on any copy 
of a source document provided to the Company. For laboratory 
results, include the laboratory normal ranges 
Section 10.4.6 - Table 9 - 
Summary of adverse event 
reporting instructions 
Added following AESIs: 
• 
Autoimmune mediated conditions including but not limited 
to autoimmune hepatitis, nephropathies including anti-
glomerular basement membrane (GBM) disease, acquired 
Hemophilia A 
• 
Temporally associated* pulmonary alveolar hemorrhage 
• 
Temporally associated* myocardial ischemia, myocardial 
infarction 
• 
Temporally associated* stroke 
• 
Temporally associated* cervicocephalic arterial dissection 
(* Temporally associated: 1 to 3 days after the last 
infusion) 
• 
Progressive multifocal leukoencephalopathy (PML) 
• 
Pneumonitis  
 
Updated wording of serious and opportunistic infections to below 
text: 
Serious infections including serious opportunistic infections (eg, 
Listeria infections, CMV, EBV), HPV associated with cervical 
dysplasia 
 
Moved cervical dysplasia with HPV. 
Deleted hemolytic anemia, autoimmune neutropenia, autoimmune 
pancytopenia, and glomerulonephritis 
Update of the safety 
information following 
the Article 20 
Procedure. 
Section 14.2 Record 
Retention in Study Sites 
The duration of archiving of study document has been updated to 25 
years 
Administrative change 
 
Amended protocol 03 (21 June 2019) 
In Europe, this amended protocol (amendment 03) is considered to be substantial based on the 
criteria set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the 
Council of the European Union because it significantly impacts the safety or physical/mental 
integrity of participants. 
OVERALL RATIONALE FOR THE AMENDMENT 
This amended protocol is written to provide information about new safety concerns that have been 
identified from post-marketing use with alemtuzumab. This includes reports of autoimmune 
hepatitis and hemophagocytic lymphohistiocytosis (HLH), as well as temporally associated 
serious cardiovascular reactions. Substantial changes in this amended protocol are related to 
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providing information on the new safety concerns and measures to minimize the risks of patients 
included in clinical trials.  
The Sponsor has conducted a comprehensive review of safety data and identified two areas where 
risk mitigation measures will be implemented in this pediatric study; 1. infusion-related risks, 
specifically hemorrhagic risks, and 2. autoimmune hepatitis where additional laboratory tests may 
be of value. 
Protocol amendment summary of changes table 
Section No. and name 
Description of change 
 
Brief rationale 
Clinical trial summary 
ALT assessments 
Update to match 
changes to other part 
of document 
Section 1.2.1 Schedule of 
events Part 1 (Year 1) and 
Section 10.1.10 
 
Change of the window visit for second infusion to allow a slightly 
bigger window for scheduling 
Monitoring of postinfusion period increased 
To allow more flexibility 
for second visit 
Highlight of the 
monitoring cytopenia 
and postinfusion 
Section 4 Introduction and 
rationale 
 Details of the rationale for the amendment 
 
Schedule of events, Part 1, 
Part 2, Part 3 
Monitoring of cytopenia and additional assays of alanine 
aminotransferase  were added 
Additional monitoring 
and risk mitigation 
measures 
Section 9.3.1 Adverse event 
Some infusion associated reactions (IARs) may occur beyond 24 
hours 
Clarification of IAR 
Section 9.3.2, Laboratory 
safety variables  
Monitoring of cytopenia  was added 
If a cytopenia or autoimmune hepatitis is confirmed, appropriate 
medical intervention should be promptly initiated, including referral to 
specialist. 
In case of such symptoms or signs, alemtuzumab should only be re-
administered following careful consideration. 
Clarification for 
additional monitoring 
Section 9.3.3, ITP and 
antiGBM surveillance and 
monitoring 
Monitoring of cytopenia was added 
Additional monitoring 
Section 9.3.4 HLH 
Description of HLH and monitoring 
Additional monitoring 
Section 9.3.5 Physical 
examination and vital signs 
Added to postinfusion monitoring: until 2 hours after infusion has 
ended or longer until stabilization 
Reinforcement of 
alemtuzumab 
postinfusion monitoring 
Section 10.1.1, Visit 1 
Screening visit 
Monitoring of cytopenia is added 
Additional monitoring 
Section 10.1.4 Visit 4/M0/D1 
(first course of 
alemtuzumab) and Section 
10.1.10 Visit 16/M12 
(second course of 
alemtuzumab) 
Indications are provided for rigorous infusion management 
 
 
• 
 
Detail  of the risk 
mitigation measures for 
alemtuzumab infusion 
 
 
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Section No. and name 
Description of change 
 
Brief rationale 
Section 10.1.4 Visit 4/M0/D1 
(first course of 
alemtuzumab), Section 
10.1.7 Visit 9 to Visit 11 /M5 
to M7, Section 10.1.10 Visit 
16/M12, Section 10.1.9 Visit 
13 to Visit 15/M9 to M11 , 
Section 10.1.11 Visit 17 to 
Visit 18/M13 to M14, Section 
101.13 Visit 20 to Visit 
21/M16 to 17, Section 
10.1.15 Visit 23 to Visit 
24/M19 to M20, Section 
10.1.17 Visit 26-Visit 
27/M22-23, Section 10.1.19 
Safety monitoring phase 
Year 3 to Year 5 
• 
ALT assay added 
 
Additional monitoring 
and risk mitigation 
measures 
  
10.3.3 List of criteria for 
permanent treatment 
discontinuation 
• 
Permanent discontinuation in case of life threatening 
events (such as such as myocardial ischemia, pulmonary 
alveolar hemorrhage, HLH,…) were added.  
Additional criteria for 
permanent 
discontinuation 
Section 10.4.1.3 Adverse 
events of specific interest 
• 
HLH added 
Additional monitoring 
Section 10.4.6 (Table 9) 
• 
Addition of autoimmune hepatitis and HLH 
Additional monitoring 
Section 11.4.3.1 
TEAEs that occur from start of infusion up to 72 hours postinfusion 
will be summarized if applicable. 
Additional analyses 
Section 11.4.3.2 Laboratory 
safety variables 
Description of the analyses of hepatic enzymes 
Additional analyses 
 
 
Amended Protocol 02: 04-Jan-2019 
The primary driver for this amendment is to make an H1 antagonist other than intravenous (IV) 
diphenhydramine available in countries where IV diphenhydramine is not available. This and 
secondary drivers for the amendment are described in the Protocol amendment summary of 
changes table immediately below. Nonsubstantial changes such as to those to improve readability, 
consistency, grammar, and adherence to the Sponsor’s stylistic guidelines are not described 
specifically. 
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Protocol amendment summary of changes table 
Section No. 
and name 
Description of change 
 
Brief rationale 
Clinical trial 
summary 
Update 
Update to match 
changes to other part 
of document 
Schedule of 
events, Part 1 
For recommended visit windows: “D-7” was replaced with “D-14 to D-7” and 
was reflected in the flowchart. 
For Visit 3: “All lab results/assessments should be available prior to D-7 to 
confirm patient eligibility. If patient is eligible to receive alemtuzumab a follow 
up call should be performed and INF/Copaxone should be stopped at D-7.” was 
added. 
For tuberculosis testing: “Only if the QuantiFERON TB Gold test is used” was 
appended to “Tuberculosis skin testing on site and tuberculosis skin testing via 
local laboratories are allowed.” “Home nursing visits or visits to local 
laboratories followed by shipping of samples to the central laboratory are 
allowed for study visits that require only laboratory tests. These are to be 
followed by telephone calls from the study site to assess AEs. If Quantiferon 
test results are indeterminate, confirmation via skin testing is required.” was 
added.  
For hematology, urinalysis and thyroid function: “However for study visits that 
only require laboratory sampling, home nursing or local laboratories may be 
used for sample collection and shipment to the central laboratory, as per local 
regulations. These visits are to be followed by telephone calls from the study 
site to assess AEs.” was added.  
Clarification. 
 
 
Ease of operation for 
sites; minimize office 
visits for patients. 
Schedule of 
events, Part 2 
For recommended visit windows: “D-7 day visit” was replaced by “D-14 to D-7 
visit: 
For hematology, urinalysis and thyroid function: “However for study visits that 
only require laboratory sampling, home nursing or local laboratories may be 
used for sample collection and shipment to the central laboratory, as per local 
regulations. These visits are to be followed by telephone calls from the study 
site to assess AEs and concomitant medications.” was added. 
Clarification. 
Minimize office visits 
for patients. 
Schedule of 
events, Part 3 
For clinical chemistry, hematology, thyroid function, and serum creatinine: “If 
home nursing cannot be implemented, local laboratories may be used for 
sample collection and shipment to the central laboratory, as per local 
regulations. These visits are to be followed by telephone calls from the study 
site to assess AEs and concomitant medications.” has been added. 
For urinalysis: “However for study visits that only require laboratory sampling, 
home nursing or local laboratories may be used for sample collection and 
shipment to the central laboratory, as per local regulations. These visits are to 
be followed by telephone calls from the study site to assess AEs and 
concomitant medications.” was added. 
Minimize office visits 
for patients. 
Section 6.1 
Description of the 
study 
“As late as possible” was appended to “A baseline MRI will be performed close 
to.” 
Two instances of “D-7” were replaced with “D-14 to D-7.” 
“A baseline MRI will be performed as late as possible during the screening 
period and another at Day -7 visit.” was replaced with “A baseline MRI will be 
performed close to M-4 during the screening period and another at Visit 3.” 
Clarification. 
Section 6.4.1 
Scientific advisory 
committee 
“First” was deleted in “PIs at the first 3 sites enrolling the most patients will also 
be included as authors for the primary publication, in addition to the other SAC 
members. 
Clarification. 
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Section No. 
and name 
Description of change 
 
Brief rationale 
Section 7.1, 
Inclusion criteria 
“Should” was replaced by “must” in the requirement for patients to meet the 
criteria of diagnosis of MS as defined by the International Paediatric Multiple 
Sclerosis Study Group criteria for pediatric MS and the criteria of MS based on 
the 2010 McDonald criteria. 
Clarification. 
Section 7.2.1 
Exclusion criteria 
related to study 
methodology 
“If a patient has been enrolled in a clinical trial and treated with a comparator 
agent that is an approved agent for screening inclusion (INF or GA), they may 
be considered for this trial if they meet all inclusion and exclusion criteria 
otherwise.” was added. 
Clarification for 
countries in which 
there are no approved 
treatments for pediatric 
MS. 
Section 7.2.3 
Exclusion criteria 
related to the 
current knowledge 
of alemtuzumab 
and study 
methodology 
“If a patient was deemed a screen failure, he or she may be re-screened for this 
study up to 2 times. If a patient who previously failed screening for any reason 
is re-screened, the patient must sign a new informed consent form and be 
assigned a new patient number by IWRS/IVRS (the next sequential patient 
number at the site). All screening assessments need to be repeated to confirm 
eligibility for the study. Rescreening assessments may be discussed with the 
Sponsor on a case-by-case basis.” was added. 
Clarification. 
“Note: If the treating physician suspects out-of-range cell count results are 
based upon issues of sample transportation or environmental conditions, the 
treating physician may request a repeat sample to be evaluated locally to 
confirm the patient is not excluded from the trial. If out-of-range cell counts are 
not confirmed through evaluations performed locally, the treating physician 
should document (in source data and in a CRF comment) that the central 
laboratory results are considered falsely exclusive, and proceed to enroll the 
patient.” was added. 
For resolution of 
suspected issues 
involving shipping from 
certain study sites. 
Section 8.1.1.1 
Method of 
preparation at the 
clinical site 
“Should” was replaced by “must” in “The diluted solution should be 
administered by IV infusion”. 
Clarification. 
Section 8.1.1.2 
Special 
precautions for 
disposal and other 
handling 
“Should” was replaced by “must” in “The vial contents should be inspected …”, 
“The bag should be inverted gently …”, and “care should be taken to ensure the 
sterility …” 
Clarification. 
Section 8.2, 
Noninvestigational 
medicinal 
products 
The possibility to use an IV H1 antagonist other than diphenhydramine or an 
oral formulation, if no H1 antagonist IV formulation is available, at an 
appropriate dosing, is added. 
IV methylprednisolone dosing was updated. 
Lack of availability of 
IV diphenhydramine in 
some countries. 
Update to current 
standard of care. 
Section 8.6, 
Storage 
conditions and 
shelf life 
“Should” was replaced by “must” in “Lemtrada, in vials, should be stored …” 
Clarification. 
Section 8.7, 
Return and/or 
destruction of 
treatments 
“The Investigator will not destroy the used and unused IMP unless the Sponsor 
provides written authorization” was added.  
Clarification. 
Section 8.8 
Concomitant 
medication 
“Should” was replaced by “must” in “Live vaccines should not be administered 
…” 
Clarification. 
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Section No. 
and name 
Description of change 
 
Brief rationale 
Section 9.1.1.1 
Brain MRI 
“A baseline MRI” was replaced with “An MRI.” 
“Day -7 visit” was replaced with “Visit 3”. 
“It is expected that Periods 1 and 2 will be of the same length ±7 days.” was 
added. 
Clarification. 
Section 9.2.2.2.1 
Assessment 
methods 
“D-7” was replaced with “D-14 to D-7.” 
Clarification. 
Section 9.2.2.3 
Quality of life 
endpoints 
“D-7” was replaced with “D-14 to D-7.” 
Clarification. 
9.3 Safety 
endpoints 
“D-7” was replaced with “D-14 to D-7” in 6 places. 
Clarification. 
Section 9.3.2, 
Laboratory safety 
variables 
“Animotransaminase” was replaced by “aminotransferase” in the chemistry 
panel.  
Details for the amount of blood taken during the study were provided to reflect 
compliance with international guidelines on blood withdrawal in the pediatric 
population. 
Correction. 
Commitment to 
Federal Agency for 
Medicines and Health 
Products (Belgium). 
9.3.4 Physical 
examination and 
vital signs 
“D-7” was replaced with “D-14 to D-7.” 
Clarification. 
Section 9.6 
Appropriateness 
of measurements 
The section “Appropriateness of measurements” was added. 
Unintentional 
omission. 
Section 10.1.1 
Visit 1 Screening 
visit 
“The parents/patient will be provided with educational material consisting of a 
patient guide containing a description of the risks associated with the use of 
alemtuzumab as well as a description of the best course of action if sign and 
symptoms of those risks present themselves (eg, how to reach your doctors).” 
was deleted. 
This text was deleted 
because the patient 
guide wasn’t 
implemented.  
Section 10.1.3 
Visit 3/Day -7 
to -14 
The section title was changed to “Visit 3/Days -14 to -7.” “Visit 3 assessments 
can be performed over multiple days as long as the time windows below are 
respected.” was added. “Investigator will assess and confirm eligibility fo 
alemtuzumab administration. If patient is eligible for alemtuzumab 
administration, prior DMT will be discontinued” was moved and was edited to 
read, “Day -7 (phone call or visit): The Investigator will assess and confirm 
eligibility for alemtuzumab administration. If the patient is eligible for 
alemtuzumab administration, the prior DMT will be discontinued.” 
“Blood sample collection for lymphocyte phenotyping” was deleted.  
Clarification. 
 
 
 
 
Deletion of repeated 
information. 
Section 10.1.4 
Visit 4/M0/D1 (first 
course of 
alemtuzumab) 
“Should” was replaced by “must” in “Specialists and equipment required for the 
timely diagnosis and management of the most frequent adverse reactions, 
especially autoimmune conditions and infections, should be available.” 
“Should” was replace by “must” in “Alemtuzumab treatment should be initiated 
…” 
The possibility to use an IV H1 antagonist other than diphenhydramine or an 
oral formulation, if no IV H1 antagonist  formulation is available, at an 
appropriate dosing, was added. 
Clarification. 
 
 
Lack of availability of 
IV diphenhydramine in 
some countries. 
 
Update to current 
standard of care. 
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Section No. 
and name 
Description of change 
 
Brief rationale 
The premedication regimen for IV methylprednisolone was revised (half dose 
on infusion Days 4 and 5). 
Section 10.1.10 
Visit 16/Month 12 
(alemtuzumab 
Course 2) 
The possibility to use an IV H1 antagonist other than diphenhydramine or an 
oral formulation, if no IV H1 antagonist  formulation is available, at an 
appropriate dosing, was added. 
Lack of availability of 
IV diphenhydramine in 
some countries. 
Section 10.3.3 
List of criteria for 
permanent 
treatment 
discontinuation 
“Should” was replaced by “must” in “Patients should discontinue the IMP for the 
following reasons.” 
Clarification. 
Section 10.3.5, 
Procedure and 
consequence for 
patient withdrawal 
from study 
“Should” was replaced by “must” in “and AE information elicited should be 
documented,” All study withdrawals should be recorded …”, and “Investigator 
should make the best effort to …” 
Clarification. 
Section 10.4.1.2, 
Serious adverse 
event 
“Should” was replaced by “must” in “Medical and scientific judgment should be 
exercised …” 
Clarification. 
Section 11.2, 
Disposition of 
patients 
Screened patients are defined as those who signed the informed consent form. 
Clarification. 
Section 11.4.3.1, 
Adverse events 
On treatment AEs are defined as those AEs that developed or worsened after 
the first alemtuzumab dose and until the end of the study (Month 60). 
Clarification. 
 
Amended Protocol 01: 08-Nov-2017 
This amended protocol (Amended Protocol 01) is considered to be nonsubstantial based on the 
criteria set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the 
Council of the European Union [because it neither significantly impacts the safety or 
physical/mental integrity of participants nor the scientific value of the study]. 
Overall Rationale for the Amendment 
This amendment provides mainly clarifications of various existing contents in the protocol. 
Additionally, clarifications sought by Belgian Health Authority are addressed in this amendment. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief 
Rationale 
Clinical trial summary, Study 
design 
The “current DMT” is clarified as being limited to beta interferon therapy 
or glatiramer acetate. 
Clarification 
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Clinical trial summary, Main 
selection criteria 
“Signed informed consent/assent” is replaced with “Signed written 
informed consent/assent”. “after having been on that therapy for at least 
6 months” is replaced with “after having been on that therapy for at least 
6 months and is currently still taking the same therapy”. 
Clarification 
Clinical trial summary, Dose 
regimen 
“For patients <50 kg: 0.24 mg/kg/day” is replaced with “For patients <50 
kg: 0.24 mg/kg/day (this equates to 12 mg/day for a 50 kg patient).” 
Clarification 
Clinical trial summary, NIMP 
formulation 
“Oral prednisone/prednisolone,1 mg/kg or 50 mg, whichever is lower” is 
replaced with “Oral prednisone/prednisolone,1 mg/kg or 50 mg, 
whichever is lower or equivalent” 
Clarification 
Clinical trial summary, 
Secondary endpoints 
“EDSS (descriptive statistics, e.g., percentages of stable/ 
improved/worsened since the end of Period 1)” is added 
Clarification 
Clinical trial summary, 
Planned database lock date 
“There will be two database locks in this study. The first database lock 
will be after the last patient has completed efficacy assessments 
including MRI at the end of Period 2” is replaced by “A partial database 
lock will be done after the last patient has completed efficacy 
assessments including MRI at the end of Period 2. This database lock 
will allow comparing lesion counts between Period 1 (M-4 to M0) and 
Period 2 (M4-M8). No formal interim analysis will be performed.” 
Clarification 
Clinical trial summary, Study 
committees 
“The members will remain blinded until completion of the study” was 
removed from the description of the Scientific Advisory Committee. 
Clarification 
Section 1.2.1, Schedule of 
events Part 1 (Year 1) 
The following footnotes were added:  
e Subject race will be collected in this study because these data are 
required by several regulatory authorities. 
i testing for Herpes zoster is recommended, in accordance with local 
public health authority recommendations. Herpes zoster (varicella zoster) 
vaccination (VZV) of antibody-negative patients should be considered 
prior to treatment with alemtuzumab. In addition if patient receives any 
vaccination during screening or Alemtuzumab Treatment Phase, relevant 
antibody titers will be assessed before and approximately 6 weeks after 
completing vaccination course (inactivated vaccines only). 
j Testing will be conducted for human papillomavirus (HPV) infection as 
and when recommended by local public health authorities. If the testing is 
positive, the patient may be eligible after the condition has resolved as 
per the Investigator opinion (eg, follow-up HPV test is negative or cervical 
abnormality has been effectively treated). An annual follow-up is 
recommended. 
“The MRI assessments will be available to investigators to assess safety” 
was appended to footnote l. 
Clarification 
Section 1.2.2, Schedule of 
events Part 2 (Year 2) 
The following footnotes were added: 
c The MRI assessments will be available to investigators to assess 
safety.  
j Testing will be conducted for human papillomavirus (HPV) infection as 
and when recommended by local public health authorities. If the testing is 
positive, the patient may be eligible after the condition has resolved as 
per the Investigator opinion (eg, follow-up HPV test is negative or cervical 
abnormality has been effectively treated). An annual follow-up is 
recommended. 
Clarification. 
HPV test added 
per local health 
authority 
request. 
Section 1.2.3, Schedule of 
events (safety monitoring 
phase (Year 3-5)) 
The following footnotes were added: 
c The MRI assessments will be available to investigators to assess 
safety.  
j Testing will be conducted for human papillomavirus (HPV) infection as 
and when recommended by local public health authorities. If the testing is 
positive, the patient may be eligible after the condition has resolved as 
Clarification. 
HPV test added 
per local health 
authority 
request. 
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per the Investigator opinion (eg, follow-up HPV test is negative or cervical 
abnormality has been effectively treated). An annual follow-up is 
recommended. 
Section 1.2.4, Schedule of 
events Part 4: Table for PK 
sampling (Year 1) 
The possibility of sample collection via local labs was added. 
Patient 
convenience 
Section 1.2.5, Schedule of 
events Part 5: Table for PK 
sampling (Year 2) 
The possibility of sample collection via local labs was added. 
Patient 
convenience 
Section 4, Introduction and 
rationale 
“The MS disease activity criteria include having at least 2 recorded MS 
attacks; at least 1 MS relapse in the last year during treatment with an 
IFNB or GA after having been on that therapy for at least 6 months,” is 
appended by “and is currently still taking the same therapy”. 
“For patients <50 kg: 0.24 mg/kg/day” is appended by “(this equates to 
12 mg/day for a 50 kg patient).” 
“MRI assessments will be available to investigators to assess safety” is 
added. 
Clarification 
Section 6.1, Description of the 
study 
“During this visit patients will be reminded to continue their prior DMT” is 
appended by “(limited to interferon or GA 
only).” 
Clarification 
Section 6.3, Interim analysis 
The two database locks are clarified as a partial, informal interim lock 
and the final lock. 
Clarification 
Section 6.4.1 Scientific 
advisory committee 
“The members will remain blinded until completion of the study” is 
removed. 
Clarification 
Section 7.1, Inclusion criteria 
I02. Signed informed consent/assent …” is replaced with “Signed written 
informed consent/assent …” 
I04. “treatment with an IFNB or GA after having been on that therapy for 
at least 6 months” is appended with “months, and is currently still taking 
the same therapy.” 
Clarification 
Section 7.2.2 Exclusion 
criteria related to 
alemtuzumab and/or 
mandatory background 
therapies 
E08 “Unwilling to agree to use a reliable and effective contraceptive 
method as defined for 
contraception in the informed consent form (ICF) when receiving a 
course of alemtuzumab 
treatment and for 4 months following that course of treatment (fertile 
patients only) 
(Appendix A)” is replaced with: 
E08 “Unwilling to agree to use a highly effective contraceptive method as 
defined (Appendix A) when receiving a 
course of alemtuzumab treatment and for 4 months following that course 
of treatment (fertile patients only). 
Local health 
authority request 
Section 7.2.3, Exclusion 
criteria related to the current 
knowledge of alemtuzumab 
and study methodology 
The following was added: “Re-screening could be possible due to logistic 
reasons (eg, blood samples defective, lost, or other reason, non-medical) 
or the conditions resolved for eligibility.” 
E29 “Infection with hepatitis B, C viruses (positive serology)." Was 
appended with “but not due to hepatitis immunization). 
Clarification 
Section 8.1.1, Administration  
“For patients <50 kg: 0.24 mg/kg/day” is appended with “(this equates to 
12 mg/day for a 50 kg patient).” 
Clarification 
Section 8.1.1.1, Method of 
preparation at the clinical site 
The time of infusion relative to dilution is clarified. It is allowed to extend 
the infusion time if clinically indicated. Additional requirements for 
infusion and monitoring are referenced. 
Clarification 
Section 8.2, 
Noninvestigational medicinal 
products 
An equivalent medication to “oral prednisone/prednisolone 1 mg/kg or 50 
mg one dose, whichever is lower” is allowed. 
Clarification 
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Section 8.3.1, Methods of 
blinding 
“The MRI assessments will be available to the investigators to assess 
safety” is added. 
Clarification 
Section 8.7 Responsibilities 
“Should” is replaced by “must” in “Any quality issue noticed with the 
receipt or use of an IMP (deficiency in condition, appearance, pertaining 
documentation, labeling, expiration date, etc) should be promptly notified 
…” 
Clarification 
Section 8.7.2, Return and/or 
destruction of treatments 
“Authorization for destruction will be given by the sponsor” is prepended 
by “Written”. 
Clarification 
Section 8.8, Concomitant 
medication 
“Concomitant use of alternative medications (eg, herbal treatments, 
botanicals, etc) ..” is prepended with “A concomitant medication is any 
treatment received by the patient concomitantly to any IMP(s). 
Concomitant treatments have been detailed for all phases of the study 
and are not limited to the treatment received with the IMP (treatment 
phase).” 
“Therapy with disease-modifying MS treatments that the patient is 
currently being administered (ie interferons and GA) will be permitted 
during the screening and prior DMT Treatment Phase. Prior DMT will be 
discontinued 7 days before alemtuzumab first administration. Refer to 
Section 6.1 for further details” is replaced with “Therapy with disease-
modifying MS treatments that the patient is currently being administered 
(ie, limited to interferons and GA only) will be permitted during the 
screening and prior DMT Treatment Phase. If the investigator determines 
that the patient needs to be treated with another DMT, the patient will be 
discontinued from the study. Prior DMT will be discontinued 7 days 
before alemtuzumab first administration. Refer to Section 6.1 for further 
details.” 
“No concomitant therapy with any disease-modifying MS treatments 
either licensed or investigational, including interferons and GA, will be 
permitted during the alemtuzumab treatment” is replaced appended with 
“phase. If the investigator determines that the patient needs to be treated 
with another DMT, the patient will be discontinued from the study.” 
Clarification 
Section 9.1.1.1, Brain MRI 
“The MRI assessments will also be available to the investigators to 
assess safety” is added. 
Clarification 
Section 9.2, Secondary 
endpoints 
A summary of secondary endpoints is added.  
Clarification 
Section 9.2.1.3.1, Brief 
visuospatial memory test – 
revised 
“Central scoring will be performed by an independent rater who is blinded 
to treatments (ie, current DMT or alemtuzumab)” is added. 
Clarification 
9.2.1.3.2 ,Symbol digit 
modality test 
It is clarified that oral responses are expected of the patient, which will be 
written down by the person administering the test. 
Clarification 
Section 9.3.2, Laboratory 
safety variables 
Text regarding HPV testing is added. 
Request of local 
health authorities 
Section 10.1.1, Visit 1 
Screening visit: 
Race is added to the demographic variables collected. HPV testing is 
added to the list of serology tests performed. “The MRI assessments will 
be available to investigators to assess safety” is added. 
Clarification 
Section 10.1.3, Visit 3/Day-7: 
The section title is changed to Visit 3/Day -14 to -7. Urine sampling is 
added. 
Clarification 
Section 10.1.10, Visit 16/M12 
(second course of 
alemtuzumab): 
Urine sampling is added 
Clarification 
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Section 10.3, Handling of 
patient temporary or 
permanent treatment 
discontinuation and of patient 
study discontinuation 
“Should” is replaced with “must” in “Any IMP discontinuation should be 
fully documented in the electronic-Case Report Form (e-CRF).” 
Clarification 
Section 10.3.1, Temporary 
treatment discontinuation with 
investigational medicinal 
product(s) 
“Should is replaced with “must” in “For all temporary treatment 
discontinuations, duration should be recorded by the 
Investigator in the appropriate pages of the e-CRF.” 
Clarification 
Section 10.3.4, Handling of 
patients after permanent 
treatment discontinuation 
“Should” is replaced with “must” in “All cases of permanent treatment 
discontinuation should be recorded by the Investigator in 
the appropriate pages of the e-CRF when considered as confirmed.” 
Clarification 
Section 10.4.1.3, Adverse 
event of special interest 
“Adverse events of special interest may be added, modified or removed 
during a study by protocol amendment” is added.  
“Caused” is replaced with “suspected” in “An overdose (accidental or 
intentional) with the IMP is an event caused by the Investigator or a 
nurse and defined as an increase of at least 30% of the dose to be 
administered in the specified duration or if the dose is administered in 
less than half the recommended duration of administration.” 
Listeria infection is added to the list of serious opportunistic infections 
considered to be AESIs. 
Clarification 
Section 10.4.3, General 
Guidelines for reporting 
adverse events 
Following of AEs, SAEs, and AESIs by Investigators after the last 
planned visit is clarified. 
Clarification 
Section 10.4.6, Guidelines for 
management of specific 
laboratory abnormalities 
Cervical dysplasia and thyroid malignancy are added to the list of 
malignancies among specific laboratory abnormalities.  
Clarification 
Section 10.4.7, Guidelines for 
reporting product complaints 
(IMP/NIMP/device) 
This section was added to the protocol. 
Clarification 
Section 10.5, Obligations of 
the Sponsor 
The text “Adverse events that are considered expected will be specified 
by the reference safety information (label)” was added. 
Clarification 
Section 10.6, Safety 
instructions 
“IB” is replace by “label” in For more information about alemtuzumab, 
please refer to IB.” 
Clarification 
Section 11.1, Determination of 
sample size 
“Approximately 60 patients aged from 10 years to less than 18 years will 
be enrolled in this study to account for screen failures, and to ensure at 
least 50 patients are evaluable” is replaced with “At least 60 patients 
aged from 10 years to less than 18 years will be enrolled in this study to 
account for screen failures to ensure at least 50 patients are evaluable.” 
Clarification 
Section 11.4.2.2, Analyses of 
secondary efficacy endpoints 
“For EDSS, descriptive statistics, (e.g., percentages of 
stable/improved/worsened since the end of Period 1) will be calculated” 
is added. 
Clarification 
Section 11.5, Interim analysis 
That there will be a partial, informal database lock for the interim analysis 
is clarified. 
Clarification 
Section 14.5, Data protection 
The reason for collection of race and ethnicity data is clarified. 
Clarification 
Appendix F – 23 –Item 
PedsQL Generic Core scales 
This was deleted. 
Clarification 
 
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