Conditions: Relapsing Remitting Multiple Sclerosis
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 1062
Healthy volunteers: no

Brief summary:
Primary Objective:

To evaluate long-term safety of alemtuzumab.

Secondary Objectives:

* To evaluate long term efficacy of alemtuzumab.
* To evaluate the safety profile of participants who received other Disease Modifying Treatment (DMT) following alemtuzumab treatment.
* To evaluate participant-reported Quality of Life (QoL) outcomes and health resource utilization of participant who received alemtuzumab.
* To evaluate as needed re-treatment with alemtuzumab and other DMTs.

Detailed description:
The total duration per participants was up to 5.6 years.

As per Study Investigator discretion, participants can be treated with additional courses of alemtuzumab or any commercialized DMTs.

All participants who completed CAMMS03409 were allowed into the study, which might include specific vulnerable populations. If the investigator decided to treat a participant with a course of alemtuzumab, appropriate cautionary measures were applied as indicated in the approved labelling, or, in ex-European Union countries where Lemtrada was not approved, according to the investigator's brochure.

Arms:
arm 1: All Participants who completed the study CAMMS03409 (extension study of CAMMS223 \[NCT00050778\], CAMMS323 \[NCT00530348\], or CAMMS324 \[NCT00548405\]) and received alemtuzumab within 48 months prior to enrollment were included in this LPS13649 study. Participants received alemtuzumab, intravenous infusion of 12 milligram per day (mg/day) for 3 consecutive days, at the study investigators' discretion; and at least 12 months after the prior treatment course in the current study (LPS13649).

Interventions: intervention 1: alemtuzumab GZ402673
Intervention descriptions: intervention 1: Pharmaceutical form:concentrate for solution for infusion Route of administration: intravenous

Protocol document:
Prot_000.pdf: 
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°9.0 (28-JUN-2013) 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL 03 
COMPOUND: GZ402673 (alemtuzumab) 
A long-term follow-up study for Multiple Sclerosis patients who have completed 
the alemtuzumab Extension Study (CAMMS03409) 
STUDY NUMBER: LPS13649  
STUDY NAME: TOPAZ 
VERSION DATE/STATUS: 28-Jan-2020 / APPROVED 
Version Number: 
1 
EudraCT number: 
2013-003884-71 
UT Number: 
U1111-1148-2987 
IND Number: 
10717 
Date: 
28-Jan-2020
Total number of pages: 
88 
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Page 2 
NAMES AND ADDRESSES OF 
 
COORDINATING 
INVESTIGATOR 
Name: 
Address: 
Tel: 
Fax: 
E-mail: 
NA 
 
MONITORING TEAM’S 
REPRESENTATIVE 
Name: 
Address: 
Tel: 
Fax: 
E-mail: 
 
SPONSOR 
Company: 
Address: 
Genzyme Corporation 
50 Binney St. Cambridge, MA 02142 USA 
 
Genzyme Europe B.V.  
Paasheuvelweg 25, 1105 BP Amsterdam,  
The Netherlands 
 
OTHER EMERGENCY 
TELEPHONE NUMBERS 
 
 
 
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Page 3 
PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY 
 
Document 
Country/countries 
impacted by 
amendment 
Date, version 
Amended Clinical Trial Protocol 03 
All 
28-Jan-2020, version 1 (electronic 3.0) 
Amended Clinical Trial Protocol 02 
All 
24-Jul-2019, version 1 (electronic 2.0) 
Amended Clinical Trial Protocol 01 
All 
27-Feb-2018, version 1 (electronic 1.0) 
Amended Clinical Trial Protocol 02 (US) 
US only 
27-Feb-2018, version 1 (electronic 3.0) 
Protocol Amendment 02 
All 
27-Feb-2018, version 1 (electronic 1.0) 
Amended Clinical Trial Protocol 01 (US) 
US only 
23-Mar-2016, version 1 (electronic 2.0) 
Protocol Amendment 01 (US) 
US only 
23-Mar-2016, version 1 (electronic 2.0) 
Clinical Trial Protocol 
All 
11-Apr-2014, version 1 (electronic 1.0) 
 
AMENDED PROTOCOL 03 (28-Jan-2020) 
This amended protocol 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 amendment addresses safety update based on recent post marketing safety monitoring 
findings. Sponsor has conducted a comprehensive review of safety data from post-marketing use 
with alemtuzumab, updated contraindications for retreatment with alemtuzumab, and updated 
Adverse Event of Special Interest (AESI) list and identified areas where risk mitigation measures 
will be implemented that include increasing frequency of liver function tests from every 3 months 
to every month. 
 
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Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.2.2 Re-treatment 
with alemtuzumab flow 
chart  
And 
Section 9.5.2.2 Patients 
exposed to alemtuzumab 
during this study  
And 
Section 10.1.6 
Alemtuzumab treatment 
And 
Appendix A 
Recommendations for 
using alemtuzumab in 
countries where it is not yet 
available  
Changed the frequency of LFT evaluation from 
every three months to every month. 
And 
Added ECG to be performed before alemtuzumab 
infusion. 
Monitoring potential autoimmune hepatitis 
and updated the safety monitoring 
information 
Section 10.1.6.2 Post-
alemtuzumab treatment 
monitoring 
Changed the frequency of LFT evaluation from 
every three months to every month. 
Monitoring potential autoimmune hepatitis 
Section 1.2.2 Re-treatment 
with alemtuzumab flow 
chart (footnote b) 
And 
Section 9.5.2.2 Patients 
exposed to alemtuzumab 
during this study 
And 
Section 10.1.6.1 Prior to 
alemtuzumab treatment 
visit 
Section 10.1.6.2 Post-
alemtuzumab treatment 
monitoring 
Updated wording of bilirubin assessment to total 
and direct bilirubin  
Clarification of wording 
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Section # and Name 
Description of Change 
Brief Rationale 
Clinical trial summary 
endpoint(s) 
Primary endpoints: Safety 
And 
Section 4 Introduction and 
rationale 
And 
Section 9.1 Primary 
endpoints: safety 
And 
Section 10.4.1.3 Adverse 
event of special interest 
And 
Section 10.4.4 Guidelines 
for reporting adverse 
events of special interest, 
Table 2 - Summary of 
adverse event reporting 
instructions 
The current list of AESIs is updated with below list: 
• 
Acquired hemophilia A 
• 
Progressive multifocal leukoencephalopathy 
(PML) 
• 
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) 
• 
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 
Updated as per recent safety findings and 
benefit risk assessment 
Section 4 Introduction and 
rationale 
Reference to “section 10.1.6 Alemtuzumab 
treatment” added for infusion monitoring procedure. 
Reference for clarity and details 
Section 6.3 Interim 
Analysis 
And 
Section 11.5 Interim 
Analysis 
Updated wording to below text: 
No interim analysis is planned; an annual partial 
database lock will be made available for publication 
purpose. 
Clarification of wording 
Section 8.1.2 Pre-
treatment 
Added below text: 
Physician should also consider the 
contraindications of alemtuzumab when retreating 
patient in this study (Section 10.1.6). 
Updated the safety monitoring information 
Section 9.1 Primary 
Endpoints: Safety 
Added Hemophagocytic lymphohistiocytosis (HLH). 
in project-specific Adverse Events of Special 
Interest (AESIs), which was missed in this section 
in Amendment 2 
Omitted in previous amendment 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 10.1.6 
Alemtuzumab treatment 
Pre-Infusion 
And 
Appendix A 
Recommendations for 
using alemtuzumab in 
countries where it is not yet 
available 
Updated/added the contra-indications list as below: 
- 
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 
Updated the safety monitoring information 
Section 10.1.6 
Alemtuzumab treatment 
Updated the pre-infusion, during infusion, and post-
infusion text: 
The following infusion management procedures 
must be utilized for each infusion and each 
treatment course to reduce serious reactions 
temporally associated with LEMTRADA 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), evaluate infusion-
related risks, and review HCP checklist. It is at 
investigator’s discretion to re-treat or not re-treat 
patient with alemtuzumab after clinical evaluation. 
 
Updated the during infusion with following text: 
The following are recommendations in case of 
clinical abnormalities/severe adverse event:  
- 
Interrupt infusion 
- 
Medically evaluate the patient guided by the 
adverse event profile of LEMTRADA prior to 
considering restarting therapy 
- 
Provide appropriate treatment as needed 
- 
Consider permanently discontinuing the 
LEMTRADA infusion if the patient shows 
clinical symptoms suggesting development of 
Updated the safety monitoring information 
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Section # and Name 
Description of Change 
Brief Rationale 
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: 
- Observation for infusion reactions is 
recommended for a minimum of 2 hours after 
LEMTRADA infusion.  
- 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 seek appropriate medical care. 
Section 10.1.6.1 Prior to 
alemtuzumab treatment 
visit 
Added below parameters 
- ECG 
-vital signs (including heart rate and blood pressure 
measurement 
Updated the safety monitoring information 
Section 14.2 Record 
Retention in Study Sites 
The duration of archiving of study document has 
been updated to 25 years 
Administrative change 
Appendix A 
Recommendations for 
using alemtuzumab in 
countries where it is not yet 
available 
Added HPV and platelet count in baseline tests to be 
conducted before re-treatment with alemtuzumab 
Added LFT in baseline tests (to be performed before 
re-treatment with alemtuzumab) and in monitoring 
activities (to be performed during treatment and for 
48 months after last treatment ) 
Updated safety monitoring information 
Whole document 
Minor editorial and format changes were done 
throughout the document. In Title page, header, 
and table of contents, amended protocol 02 was 
changed to amended protocol 03. LFT abbreviation 
was added in list of abbreviations. Page numbers 
were updated. 
Formatting/Administrative change 
 
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CLINICAL TRIAL SUMMARY  
 
COMPOUND: GZ402673 (Alemtuzumab)  
STUDY No: LPS13649  
TITLE 
A long-term follow-up study for Multiple Sclerosis patients who have completed 
the alemtuzumab Extension Study (CAMMS03409) 
INVESTIGATOR/TRIAL 
LOCATION 
Multinational, multicenter: Argentina, Australia, Belgium, Brazil, USA, Canada, 
Croatia, Czech Republic, Denmark, Germany, Israel, Italy, Mexico, Netherlands, 
Poland, Russia, Serbia, Spain, Sweden, Ukraine, United Kingdom. 
PHASE OF DEVELOPMENT 
Phase 3B/4 
STUDY OBJECTIVE(S) 
Primary objective 
 
To evaluate long-term safety of alemtuzumab. 
Secondary objective(s)  
 
To evaluate long term efficacy of alemtuzumab. 
 
To evaluate the safety profile of patients who received other Disease 
Modifying Treatments (DMT) following alemtuzumab treatment.  
 
To evaluate patient-reported quality of life (QoL) outcomes and health 
resource utilization of patients who received alemtuzumab. 
 
To evaluate as needed re-treatment with alemtuzumab and other 
DMTs. 
STUDY DESIGN 
This study is a Phase 3B/4, international, multicenter, open-label, non-
comparative study to evaluate the long-term safety, efficacy and QoL of 
alemtuzumab in patients who have completed at least 48 months of the extension 
Study CAMMS03409. In addition, impact of treatment on pharmaco-economic 
data will also be evaluated. 
Scheduled visits for safety and efficacy assessments will be performed every 
six months. Quality of life and pharmaco-economic data will be collected every 
twelve months. 
Patients must contact the treating neurologist at the study site (Study 
Investigator) as soon as they experience any sign or symptom of multiple 
sclerosis (MS) relapse. The Study Investigator will decide on the need to 
schedule extra visits (unscheduled visits) to evaluate the patient’s status. 
At the Study Investigator’s discretion patients can be treated with additional 
courses of alemtuzumab (not sooner than 12 months from the previous course) or 
with any commercial DMT. 
If the patient is re-treated with additional courses of alemtuzumab, the patient will 
be followed using the specific recommendations indicated in the IB or in the local 
approved label (when available). Patients will be followed for 48-months after the 
last infusion of alemtuzumab received in the current trial setting. During the 
48-month period, laboratory safety sampling should be collected every month, in 
a local laboratory and they must be reviewed in a timely manner by the Study 
Investigator.  
If the 48-month period of safety follow-up continues after the study ends, the 
patient will be followed by their physician in a regular healthcare setting, in line 
with the local approved Risk Minimization Plan for alemtuzumab, until the 
48-month period is completed. 
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A pharmacogenomics (PGx) substudy will be conducted for exploratory analysis 
of genetic variations predictive of autoimmune conditions, including thyroid and 
immune thrombocytopenia (ITP), related to MS disease and/or the effects of 
alemtuzumab. For research purposes only and on a voluntary basis, a blood 
sample will be proposed to approximately 300 ongoing patients in the TOPAZ 
study who have not provided a PGx sample in the previous studies 
(CAMMS03409, CAMMS223, CAMMS323 and CAMMS324). A blood sample will 
be collected from consenting patients.  
Objectives of the substudy are as follows:  
 
To develop biomarkers predictive of autoimmune conditions including 
thyroid disorders and immune thrombocytopenia. This will include 
collection of samples from patients who have not yet developed any 
auto immune conditions; these samples would be used as controls.  
 
To explore efficacy and safety markers through data analysis. 
 
To explore genetic variation related to MS disease manifestation 
through data analysis. 
Sample collection, handling, storage, and analysis will conform to all applicable 
national guidance and regulations. Details of the PGx sub-study are presented in 
Appendix C. 
STUDY POPULATION 
Main selection criteria 
Inclusion criteria 
I 01. 
Patient has completed at least 48 months of the Extension 
Study CAMMS03409.  
I 02. 
Signed written informed consent form (ICF). 
Exclusion criteria 
E 01. 
Patient participating in another investigational interventional study. 
Total expected number of 
patients 
Approximately (up to) 1248 eligible patients from the Extension 
Study (CAMMS03409) 
In approximately (up to) 180 study centers 
STUDY TREATMENT(s) 
 
Investigational medicinal 
product(s) 
Formulation 
Alemtuzumab 
Concentrate for solution for infusion (sterile concentrate) 
Route(s) of administration 
IV infusion in a supervised medical setting 
Dose regimen 
12 mg/day for 3 consecutive days (36 mg total dose) at least 12 months after the 
prior treatment course. 
Each single-use vial contains 12 mg alemtuzumab (10 mg/mL; total extractable 
volume 1.2 mL). 
Noninvestigational medicinal 
product(s) (if applicable) 
Formulation 
NA 
Route(s) of administration 
 
Dose regimen 
 
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ENDPOINT(S) 
Primary endpoints: Safety 
 
Incidence, duration, grade/intensity, relationship to study drug, and 
outcome of the following: 
- 
Serious Adverse Events (SAEs). 
- 
Adverse Events (AEs). 
- 
Infusion-associated reactions (IAR). 
 
Incidence, nature, seriousness, grade/intensity, relationship to study 
drug, and outcome of the following Adverse Events of Special Interest 
(AESI): 
- 
Autoimmune mediated conditions including, but not limited to: 
- 
Immune thrombocytopenic purpura (ITP). 
- 
Nephropathies including anti-glomerular basement membrane 
(GBM) disease. 
- 
Cytopenias. 
- 
Thyroid disorders. 
- 
Autoimmune hepatitis. 
- 
Acquired hemophilia A 
- 
Hemophagocytic lymphohistiocytosis (HLH). 
- 
Progressive multifocal leukoencephalopathy (PML) 
- 
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) 
- 
Serious infections including serious opportunistic infections (eg, 
Listeria infections, CMV, EBV), HPV associated with cervical 
dysplasia 
- 
Malignancy. 
- 
Pneumonitis 
 
Changes in laboratory parameters. 
Secondary endpoints: Efficacy 
 
Annualized relapse rate (ARR). 
 
Proportion of patients relapse free.  
 
Change over time in Expanded Disability Status Scale (EDSS) scores. 
 
Change over time in brain imaging findings to include: 
- 
Number of Gadolinium (Gd)-enhancing, and new Gd-enhancing 
lesions.  
- 
Number of new/enlarging T2 lesions. 
- 
Number of new T1 (and new hypointense T1) lesions. 
- 
T1 and T2 lesion volume. 
- 
Brain Parenchymal Fraction (BPF). 
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 
Change over time in self-reported QoL as assessed by the Medical 
Outcome Study (MOS) 36-Item Short-Form Health Survey (SF-36) 
Version 2. 
 
Change over time in the Functional Assessment of Multiple Sclerosis 
(FAMS), and  
 
Change over time in the EuroQoL in 5 Dimensions (EQ-5D). 
Other endpoint: Pharmaco-economic 
 
The modified Health Resources Utilization Questionnaire (HRUQ) and 
Health Related Productivity Questionnaire (HRPQ) will be administered 
to obtain pharmaco-economic data. 
ASSESSMENT SCHEDULE 
Safety assessments will be made at each visit and include all AEs, SAEs, and 
AESI. Vital signs will be assessed and recorded at each visit. Physical 
examination will be assessed and recorded once a year. 
Efficacy Assessments will be performed as described in the flowchart, including 
Expanded Disability Status Scale (EDSS); Brain imaging; MOS 36-Item 
Short-Form Health Survey (SF-36); FAMS and EQ-5D questionnaires.  
Potential MS relapse will be considered at each scheduled visit by the Study 
Investigator. Patients will be informed to contact the treating neurologist at the 
study site (Study Investigator) as soon as they observe any sign/symptom 
compatible with a possible relapse between scheduled visits and the Study 
Investigator will determine the need for an unscheduled visit. 
In case of relapse, the Study Investigator will decide on the therapeutic approach. 
The reason(s) for any change in the MS therapy must be collected as well as the 
relapse treatment. 
If the patient is re-treated with a new course of alemtuzumab, the patient will be 
followed during the 48-month period of safety follow-up after the last infusion of 
alemtuzumab. For patients treated with alemtuzumab, laboratory safety sampling 
should be collected every month for 48 months, in a local laboratory and the 
results will be reviewed in a timely manner by the Study Investigator.  
If the 48-month period of safety follow-up continues after the study ends, the 
patient will be followed by their physician in a regular healthcare setting until the 
48-month period is completed. 
PGx samples obtained from consenting patients will be used for exploratory 
biomarker analysis.  
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STATISTICAL CONSIDERATIONS The following represents an overview of planned analyses. Further elaboration of 
statistical issues will be specified in the Statistical Analysis Plan (SAP). 
Safety Analysis: 
All patients will be evaluated for safety based on incidence, duration, 
grade/intensity, seriousness, and relationship of AEs to alemtuzumab. AESIs, 
deaths, and other SAEs will also be evaluated.  
Efficacy Analysis: 
The long-term effects of alemtuzumab will be examined by summarizing the 
efficacy endpoints, including ARR, proportion of patients relapse free, changes in 
EDSS score over time, changes in MRI, QoL, changes in the FAMS, EQ-5d and 
pharmaco-economy, from original study baseline through the last visit in the 
study. 
DURATION OF STUDY  
The study duration will be 5 years (plus a window of 6 months) counted from the 
enrolment date of the first patient.  
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1 
FLOW CHARTS  
1.1 
GRAPHICAL STUDY DESIGN  
 
 
CAMMS03409
Clinical trial
LPS13649 Clinical trial
D1
4 YEARS
(at least 48 months)
CAMMS323
Clinical trial
CAMMS324
Clinical trial
CAMMS223
Clinical trial
12 M
Control visit
24 M
Control visit
36 M
Control visit
48 M
Control visit
60 M
EOS*
6 M
Scheduled 
visit
30 M
Scheduled 
visit
18 M
Scheduled 
visit
54 M
Scheduled 
visit
42 M
Scheduled 
visit
Only for patients treated with alemtuzumab: monthly laboratory safety variables collection for 48 months after last infusion
•
For patients who received alemtuzumab in CAMMS03409 study less than 48  months before entering in LPS13649  study, and
•
For patients receiving retreatment with alemtuzumab during the LPS13649 study 
*      After completion of 5 years of the first patient inclusion , the next scheduled visit for any patient will be performed as EOS visit. 
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1.2 
STUDY FLOW CHARTS  
1.2.2 Re-treatment with alemtuzumab flow chart  
For all the patients re-treated with alemtuzumab and for 48 months after last infusion. 
 
 
Prior to 
treatment 
During 48 months 
1 M 
2 M 
3 M 
4 M 
5 M 
6 M 
7 M 
8 M 
9 M 
10 M 
11 M 
12 M 
Pregnancy test (in women of childbearing 
potential) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
HPV (only in women) 
X a 
 
 
 
 
 
 
 
 
 
 
 
X 
CBC with differential (including platelet count) 
X b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Creatinine and LFT (liver function tests) 
X b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis with microscopy 
X b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TSH 
X b 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Study Investigator review of labs  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Monthly safety laboratory assessment will be performed in local laboratories at the patients’ convenience. 
a If not performed in the previous 12 months. In addition, an HPV screening should be performed approximately 1 year after the last alemtuzumab infusion date, and then every 12 months until the 48 months safety 
follow-up is completed. For women patients re-treated with alemtuzumab during the study, an HPV screening should be performed prior to re-treatment (if not performed in the previous 12 months) and then 
every 12 months until the 48 months safety follow-up is completed. 
b If not performed in the previous 2 weeks. LFT includes: ALT, AST, ALP, albumin, total protein, total bilirubin, and direct bilirubin. 
 
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1.2.1 Study flow chart  
 
Selection 
visit (D1) 
Study assessments each 
year 
Scheduled visits 
Unscheduled 
visits 
EOS 
6 M 
12 M 
Informed consent signature 
X 
 
 
 
 
Inclusion Exclusion criteria 
verification 
X 
 
 
 
 
AE reporting 
X 
X 
X 
X 
X 
Vital signs 
X a 
X 
X 
X 
X 
Physical examination including 
weight  b 
X a 
 
X 
 
X 
MS relapse verification 
X 
X 
X 
X 
X 
EDSS 
X a 
X 
X 
X 
X 
Brain Imaging 
X c 
 
X 
 
X c 
SF-36 - FAMS - EQ-5D 
X a 
 
X 
 
X 
Modified HRUQ/HRPQ 
X d 
 
X 
 
X 
Record concomitant medication 
X 
X 
X 
X 
X 
Collection of blood samples for PGx 
assessment e 
 
X f 
X f 
X f 
X f 
a If not performed in the previous 3 months. 
b Note that weight assessment is included in the vital signs assessment module in the eCRF instead of the physical examinations module. 
Nevertheless, it is to be performed at baseline and on yearly basis and not every 6 months. 
c If not performed in the previous 6 months. 
d If the HRUQ questionnaire was administered in the previous 3 months, then only questions 1 through 9 of the Modified HRUQ/HRPQ need to 
be completed at baseline. 
e For consenting patients only. 
f 
Omit if collected at a previous visit. 
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2 
TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 03 .............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 3 
1 
FLOW CHARTS ............................................................................................................................. 13 
1.1 
GRAPHICAL STUDY DESIGN ...................................................................................................... 13 
1.2 
STUDY FLOW CHARTS ................................................................................................................ 14 
1.2.2 
Re-treatment with alemtuzumab flow chart ................................................................................... 14 
1.2.1 
Study flow chart .............................................................................................................................. 15 
2 
TABLE OF CONTENTS ................................................................................................................ 16 
3 
LIST OF ABBREVIATIONS .......................................................................................................... 21 
4 
INTRODUCTION AND RATIONALE ............................................................................................. 22 
5 
STUDY OBJECTIVES ................................................................................................................... 25 
5.1 
PRIMARY ....................................................................................................................................... 25 
5.2 
SECONDARY ................................................................................................................................ 25 
6 
STUDY DESIGN ............................................................................................................................ 26 
6.1 
DESCRIPTION OF THE PROTOCOL ........................................................................................... 26 
6.2 
DURATION OF STUDY PARTICIPATION .................................................................................... 27 
6.2.1 
Duration of study participation ....................................................................................................... 27 
6.2.2 
Determination of end of clinical trial (all patients) .......................................................................... 27 
6.3 
INTERIM ANALYSIS ...................................................................................................................... 27 
6.4 
STUDY COMMITTEES .................................................................................................................. 27 
7 
SELECTION OF PATIENTS .......................................................................................................... 28 
7.1 
INCLUSION CRITERIA .................................................................................................................. 28 
7.2 
EXCLUSION CRITERIA ................................................................................................................ 28 
8 
STUDY TREATMENTS ................................................................................................................. 29 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S) .......................................................................... 29 
8.1.1 
Administration ................................................................................................................................ 29 
8.1.1.1 
Method of preparation at the clinical site ....................................................................................... 29 
8.1.1.2 
Special precautions for disposal and other handling ..................................................................... 29 
8.1.2 
Pre-treatment ................................................................................................................................. 30 
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8.1.3 
Post-treatment ................................................................................................................................ 30 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) .................................................................. 30 
8.3 
BLINDING PROCEDURES ............................................................................................................ 30 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP .............................................. 30 
8.5 
PACKAGING AND LABELING ...................................................................................................... 31 
8.6 
STORAGE CONDITIONS AND SHELF LIFE ................................................................................ 31 
8.7 
RESPONSIBILITIES ...................................................................................................................... 31 
8.7.1 
Treatment accountability and compliance...................................................................................... 32 
8.7.2 
Return and/or destruction of treatments ........................................................................................ 32 
8.8 
CONCOMITANT MEDICATION ..................................................................................................... 32 
8.8.1 
Forbidden concomitant medications .............................................................................................. 32 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT .............................................. 33 
9.1 
PRIMARY ENDPOINTS: SAFETY ................................................................................................. 33 
9.2 
SECONDARY ENDPOINTS: EFFICACY ...................................................................................... 34 
9.3 
OTHER ENDPOINTS..................................................................................................................... 34 
9.4 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 34 
9.5 
SAFETY MEASUREMENTS .......................................................................................................... 34 
9.5.1 
Adverse events .............................................................................................................................. 34 
9.5.2 
Laboratory safety variables ............................................................................................................ 35 
9.5.2.1 
Patients exposed to alemtuzumab within 48 months prior to inclusion in this study ..................... 35 
9.5.2.2 
Patients exposed to alemtuzumab during this study ..................................................................... 35 
9.5.3 
Vital signs ....................................................................................................................................... 36 
9.5.4 
Physical examination ..................................................................................................................... 37 
9.6 
EFFICACY MEASUREMENTS ...................................................................................................... 37 
9.6.1 
Relapse .......................................................................................................................................... 37 
9.6.2 
Expanded disability status scale (EDSS) ....................................................................................... 37 
9.6.3 
Brain imaging ................................................................................................................................. 38 
9.6.3.1 
Pre- and post-Gadolinium-MRI ...................................................................................................... 38 
9.6.3.2 
MRI-T1 ........................................................................................................................................... 38 
9.6.3.3 
MRI-T2 ........................................................................................................................................... 38 
9.6.4 
MOS 36-item short-form health survey (SF-36) Version 2 ............................................................ 39 
9.6.5 
FAMS, Version 4 ............................................................................................................................ 39 
9.6.6 
EuroQoL in 5 dimensions (EQ-5D) ................................................................................................ 40 
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9.7 
OTHER MEASUREMENTS ........................................................................................................... 40 
9.7.1 
Modified healthcare resource utilization questionnaire (HRUQ)/health related productivity 
questionnaire (HRPQ) .................................................................................................................... 40 
9.7.2 
Exploratory pharmacogenomic assessment .................................................................................. 41 
10 
STUDY PROCEDURES ................................................................................................................ 42 
10.1 
VISIT SCHEDULE .......................................................................................................................... 42 
10.1.1 
Visit 1: selection (D1) ..................................................................................................................... 42 
10.1.2 
Scheduled visits at 6 months (M6±14D, M18±14D, M30±14D, M42±14D, M54±14D) ................. 43 
10.1.3 
Scheduled visits at 12 months (M12±14D, M24±14D, M36±14D, M48±14D) ............................... 43 
10.1.4 
End of study (EOS) visit ................................................................................................................. 44 
10.1.5 
Unscheduled visits ......................................................................................................................... 44 
10.1.6 
Alemtuzumab treatment ................................................................................................................. 45 
10.1.6.1 Prior to alemtuzumab treatment visit ............................................................................................. 46 
10.1.6.2 Post-alemtuzumab treatment monitoring ....................................................................................... 47 
10.2 
DEFINITION OF SOURCE DATA .................................................................................................. 48 
10.3 
HANDLING OF PATIENT TREATMENT DISCONTINUATION AND OF PATIENT STUDY 
DISCONTINUATION ...................................................................................................................... 48 
10.3.1 
Permanent treatment discontinuation with investigational medicinal product(s) ........................... 48 
10.3.2 
List of criteria for permanent treatment discontinuation ................................................................. 48 
10.3.3 
Handling of patients after permanent treatment discontinuation ................................................... 48 
10.3.4 
Procedure and consequence for patient withdrawal from study .................................................... 48 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING .......................... 49 
10.4.1 
Definitions of adverse events ......................................................................................................... 49 
10.4.1.1 Adverse event ................................................................................................................................ 49 
10.4.1.2 Serious adverse event ................................................................................................................... 49 
10.4.1.3 Adverse event of special interest ................................................................................................... 50 
10.4.1.4 Events not to be considered as AEs/SAEs .................................................................................... 52 
10.4.2 
General guidelines for reporting adverse events ........................................................................... 52 
10.4.3 
Instructions for reporting serious adverse events .......................................................................... 53 
10.4.4 
Guidelines for reporting adverse events of special interest ........................................................... 53 
10.5 
OBLIGATIONS OF THE SPONSOR ............................................................................................. 55 
10.6 
SAFETY INSTRUCTIONS FOR USING ALEMTUZUMAB............................................................ 56 
11 
STATISTICAL CONSIDERATIONS .............................................................................................. 57 
11.1 
DETERMINATION OF SAMPLE SIZE ........................................................................................... 57 
11.2 
DISPOSITION OF PATIENTS ....................................................................................................... 57 
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11.3 
ANALYSIS POPULATIONS ........................................................................................................... 57 
11.3.1 
Safety population ........................................................................................................................... 57 
11.3.2 
Efficacy populations ....................................................................................................................... 57 
11.4 
STATISTICAL METHODS ............................................................................................................. 57 
11.4.1 
Analyses of efficacy endpoints ....................................................................................................... 58 
11.4.2 
Analyses of safety data .................................................................................................................. 58 
11.4.3 
Analyses of patient reported outcomes (health-related quality of life/health economics 
variables ......................................................................................................................................... 58 
11.4.4 
Analysis of blood samples for exploratory pharmacogenomics substudy ..................................... 59 
11.5 
INTERIM ANALYSIS ...................................................................................................................... 59 
12 
ETHICAL AND REGULATORY CONSIDERATIONS ................................................................... 60 
12.1 
ETHICAL AND REGULATORY STANDARDS .............................................................................. 60 
12.2 
INFORMED CONSENT ................................................................................................................. 60 
12.3 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) .............. 61 
13 
STUDY MONITORING................................................................................................................... 62 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S) ....................................................................... 62 
13.2 
RESPONSIBILITIES OF THE SPONSOR ..................................................................................... 62 
13.3 
SOURCE DOCUMENT REQUIREMENTS .................................................................................... 63 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST ...................................................................................................................................... 63 
13.5 
USE OF COMPUTERIZED SYSTEMS .......................................................................................... 63 
14 
ADDITIONAL REQUIREMENTS ................................................................................................... 64 
14.1 
CURRICULUM VITAE.................................................................................................................... 64 
14.2 
RECORD RETENTION IN STUDY SITES .................................................................................... 64 
14.3 
CONFIDENTIALITY ....................................................................................................................... 64 
14.4 
PROPERTY RIGHTS ..................................................................................................................... 65 
14.5 
DATA PROTECTION ..................................................................................................................... 65 
14.6 
INSURANCE COMPENSATION .................................................................................................... 65 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES ................................. 66 
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14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE ............................................................................................................................................ 66 
14.8.1 
By the Sponsor ............................................................................................................................... 66 
14.8.2 
By the Investigator ......................................................................................................................... 67 
14.9 
CLINICAL TRIAL RESULTS .......................................................................................................... 67 
14.10 
PUBLICATIONS AND COMMUNICATIONS ................................................................................. 67 
15 
CLINICAL TRIAL PROTOCOL AMENDMENTS .......................................................................... 68 
16 
BIBLIOGRAPHIC REFERENCES ................................................................................................. 69 
17 
APPENDICES ................................................................................................................................ 70 
APPENDIX A 
RECOMMENDATIONS FOR USING ALEMTUZUMAB IN COUNTRIES WHERE IT 
IS NOT YET AVAILABLE ............................................................................................................... 71 
APPENDIX B 
GENERAL GUIDANCE FOR THE FOLLOW-UP OF LABORATORY 
ABNORMALITIES AS REQUIRED BY SANOFI ............................................................................ 73 
APPENDIX C 
EXPLORATORY PHARMACOGENOMICS ASSESSMENT SUBSTUDY ......................... 78 
APPENDIX D 
COUNTRY-SPECIFIC REQUIREMENTS ........................................................................... 81 
APPENDIX E 
PROTOCOL AMENDMENT HISTORY ............................................................................... 82 
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3 
LIST OF ABBREVIATIONS  
 
AE: 
adverse events 
AESI: 
adverse events of special interest 
ARR: 
annualized relapse rate 
BPF: 
brain parenchymal fraction 
CI: 
confidence intervals 
CNS: 
central nervous system 
DMT: 
disease modifying treatment 
EDSS: 
expanded disability status scale 
EOS: 
end of study 
FAMS: 
functional assessment of multiple sclerosis 
Gd: 
gadolinium 
HLA: 
human leukocyte antigen 
HLH: 
hemophagocytic lymphohistiocytosis 
HPV: 
human papilloma virus 
HRPQ: 
health related productivity questionnaire 
HRUQ: 
health resources utilization questionnaire 
IAR: 
infusion-associated reaction 
IB: 
investigator's brochure 
ICF: 
informed consent form 
IMP: 
investigational medical product 
ITP: 
immune thrombocytopenic purpura 
LFT: 
liver function tests 
MOS: 
medical outcome study 
MS: 
multiple sclerosis 
NFD: 
nephrogenic fibrosing dermopathy 
NSF: 
ephrogenic systemic fibrosis 
PGx: 
pharmacogenomics 
QoL: 
quality of life 
SAE: 
serious adverse events 
SAP: 
statistical analysis plan 
SC: 
subcutaneous 
SNP: 
single nucleotide polymorphism 
UK: 
United Kingdom 
 
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4 
INTRODUCTION AND RATIONALE  
Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) that 
affects approximately 2.5 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 
relapsing 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 believed to arise from the interplay of polygenic inherited susceptibility and as yet 
unidentified environmental agents. Age of onset typically ranges from 10 to 59 years, with most 
cases occurring between 20 and 40 years of age. As with most other autoimmune disorders, MS is 
more than twice as common among women. Pathologically, MS is characterized by focal and 
non-focal tissue injury of the brain and spinal cord due to the complex interplay of inflammation, 
demyelination, axonal injury, astrocytosis, and tissue atrophy. Lymphocytes are believed to play 
a central role in MS pathogenesis.  
Alemtuzumab (Lemtrada®) is a humanized monoclonal antibody that binds to CD52, a cell 
surface antigen present at high levels on T and B lymphocytes, and at lower levels on natural 
killer cells, monocytes, and macrophages (2). 
There is little or no CD52 detected on neutrophils, plasma cells, or bone marrow stem cells. 
Alemtuzumab acts through antibody-dependent cellular cytolysis and complement mediated lysis 
following cell surface binding to T and B lymphocytes. 
The mechanism by which alemtuzumab exerts its therapeutic effects in MS is unknown, but may 
involve immunomodulation through the depletion and repopulation of lymphocytes. 
Research suggests that potential immunomodulatory effects in MS may include alterations in the 
number, proportions, and properties of some lymphocyte subsets post-treatment (3). 
Pilot studies in MS patients were conducted at Addenbrooke’s Hospital in the United Kingdom 
(UK). Genzyme Corporation (Genzyme, a Sanofi company) has sponsored Phase 2 and Phase 3 
randomized, comparator-controlled studies in patients with relapsing remitting MS that have 
established superior efficacy for alemtuzumab compared with subcutaneous interferon beta-1a 
(SC IFNB-1a, Rebif®) on clinical and imaging endpoints (4, 5, 6, 7, 8).  
Identified risks of alemtuzumab in patients with MS include:  
 Infusion-associated reactions (IAR)  
 Serious infections  
 Autoimmunity (notably, Immune thrombocytopenic purpura (ITP), thyroid dysfunction 
and nephropathies) 
The most important adverse reactions are autoimmunity (eg, ITP, thyroid disorders, 
nephropathies, cytopenias), IARs, and serious infections. The most common adverse events 
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reported after alemtuzumab treatment (in ≥20% of patients) are rash, headache, pyrexia, and 
respiratory tract infections. Of note, Listeriosis/Listeria meningitis has been reported in 
LEMTRADA treated patients, generally within one month of LEMTRADA infusion. To reduce 
the risk of infection, patients receiving LEMTRADA should avoid ingestion of uncooked or 
undercooked meats, soft cheeses and unpasteurized dairy products two weeks prior to, during, and 
for at least one month after LEMTRADA infusion. 
The Sponsor has conducted a comprehensive review of safety data from post-marketing use of 
alemtuzumab and added the following to the current list of AESIs: 
• 
Autoimmune hepatitis 
• 
Acquired hemophilia A 
• 
Hemophagocytic lymphohistocytosis (HLH) 
• 
Progressive multifocal leukoencephalopathy (PML) 
• 
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 
Cases of serious and life‐threatening stroke (including hemorrhagic and ischemic), myocardial 
infarction and cervicocephalic (ie, vertebral, carotid) arterial dissection have been reported within 
three days of alemtuzumab administration, with most cases occurring within one day. Cases of 
pulmonary alveolar hemorrhage have been reported with onset within 48 hours of alemtuzumab 
infusion. Long term auto immune risks, such as cases of Hemophagocytic lymphohistiocytosis 
(HLH) and autoimmune hepatitis causing clinically significant liver injury, including acute liver 
failure requiring transplant, has been reported. To minimize the risk of these serious adverse 
events, recommendations are provided for infusion related management and long term safety 
monitoring for patients receiving re-treatment of alemtuzumab during the course of the trial:  
 Pre infusion: assess overall health status and risk factors; baseline BP/HR, bleeding risk, 
platelets count. Baseline liver function test. 
 During infusion: continuous or hourly monitoring BP/HR; intermittently ambulation, 
compressive stocking. 
 Post infusion: inform/remind patient any abnormal clinical sign/symptoms related to 
infusion. 
 Periodic liver function test. 
Please refer to Section 10.1.6 for details. 
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Study CAMMS03409 is an open-label extension study designed to provide additional safety 
monitoring for up to 60 months, and as-needed alemtuzumab retreatment to qualifying patients 
who received alemtuzumab in prior Genzyme-sponsored studies CAMMS223, CAMMS323 and 
CAMMS324. In addition, patients who received SC IFNB-1a in the earlier studies had the 
opportunity to receive 2 annual courses of alemtuzumab, and possibly subsequent as-needed 
alemtuzumab retreatment. 
In CAMMS03409, “as needed” retreatment with alemtuzumab could be offered to patients upon 
documented evidence of resumed MS disease activity, subject to safety-related disqualifications. 
The additional course(s) of alemtuzumab were administered at 12 mg/day on 3 consecutive days 
(36 mg total dose) at least 12 months after the prior treatment course. The benefits and risks of 
>2 treatment courses have not been fully established, but results suggest that the safety profile 
does not appear to change with additional courses.  
The present study LPS13649 will provide long term safety and efficacy data on the patients who 
completed the extension study CAMMS03409, as well as on additional as-needed alemtuzumab 
retreatment. In addition, the study will provide information about the safety profile of patients 
who received other commercial DMTs following alemtuzumab treatment. 
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5 
STUDY OBJECTIVES  
5.1 
PRIMARY  
The primary objective is to evaluate long-term safety of alemtuzumab. 
5.2 
SECONDARY  
The secondary objectives are: 
 To evaluate long term efficacy of alemtuzumab. 
 To evaluate the safety profile of patients who received other DMT following alemtuzumab 
treatment.  
 To evaluate patient-reported quality of life (QoL) outcomes and health resource utilization 
of patients who received alemtuzumab. 
 To evaluate as needed re-treatment with alemtuzumab and other DMTs. 
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6 
STUDY DESIGN  
6.1 
DESCRIPTION OF THE PROTOCOL  
This study is a Phase 3B/4, international, multicenter, open-label, non-comparative study to 
evaluate the long-term safety, efficacy and QoL of alemtuzumab in patients who have completed 
at least 48 months of the extension study CAMMS03409. In addition, impact of treatment on 
pharmaco-economic data will be evaluated. 
Patients treated with alemtuzumab within 48 months prior to enrollment in the LPS13649 study 
must be followed-up at monthly intervals until 48 months after the last infusion of alemtuzumab 
(Section 10.1.6.2).  
Scheduled visits for safety and efficacy assessments will be performed every six months. AEs and 
concomitant medications will be monitored continuously. Quality of life, pharmaco-economic 
data and brain imaging will be collected every twelve months. 
Patients must contact the treating neurologist at the study site (Study Investigator) as soon as they 
experience any sign or symptom of MS relapse. The Study Investigator will decide on the need to 
schedule extra visits (unscheduled visits) to evaluate the patient’s status. All procedures and 
assessments will be collected in the e-CRF. 
At the Study Investigator discretion patients can be treated: 
 Patients may receive additional courses of alemtuzumab but not sooner than 12 months 
from any previous alemtuzumab treatment course, or  
 Patients may receive other commercial DMTs. 
In the event that a Study Investigator decides to treat a patient (with alemtuzumab or another 
DMT) the factors contributing to the decision to treat (eg, patient is experiencing clinical and/or 
imaging activity) should be documented in the e-CRF.  
For treatment courses of alemtuzumab the Study Investigator should refer to the safety 
information in the Investigator’s Brochure (IB) or in the approved label in the country/region 
when available. All treatment courses will consist of 12 mg/day alemtuzumab intravenously 
infused once daily on 3 days (Section 8.1). 
If the patient is re-treated with additional courses of alemtuzumab, the patient will be followed 
using the specific recommendations indicated in the IB or in the local approved label (when 
available). Patients will be followed for 48-months after the last infusion of alemtuzumab received 
in the current trial setting. During the 48-month period, laboratory safety sampling should be 
collected every month, in a local laboratory and they must be reviewed in a timely manner by the 
Study Investigator. 
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If the 48-month period of required safety follow-up continues after the study ends, the patient will 
be followed by their physician in a regular healthcare setting, in line with the local approved Risk 
Minimization Plan for alemtuzumab, until the 48-month period is completed. 
A pharmacogenomics (PGx) substudy will be conducted for exploratory analysis of genetic 
variations predictive of autoimmune conditions, including thyroid disorders and immune 
thrombocytopenia (ITP), related to MS disease and/or the effects of alemtuzumab. Objectives of 
the substudy are as follows:  
 To develop biomarkers predictive of autoimmune conditions including thyroid disorders 
and immune thrombocytopenia. This will include collection of samples from patients who 
have not yet developed any auto immune conditions; these samples would be used as 
controls.  
 To explore efficacy and safety markers through data analysis. 
 To explore genetic variation related to MS disease manifestation through data analysis. 
For research purposes only and on a voluntary basis, a blood sample will be collected from 
approximately 300 ongoing patients who signed the optional pharmacogenomic informed consent 
form and who have not previously provided a PGx sample. Details of the PGx substudy are 
presented in Appendix C, “Exploratory Pharmacogenomics Assessment Substudy”.  
6.2 
DURATION OF STUDY PARTICIPATION  
6.2.1 Duration of study participation  
Study duration will be 5 years (plus a window of 6 months) from the day of the enrollment of the 
first patient.  
6.2.2 Determination of end of clinical trial (all patients)  
The end of the clinical trial occurs 5 years (plus a window of 6 months) after the inclusion of the 
first patient. 
6.3 
INTERIM ANALYSIS  
No interim analysis is planned; an annual partial database lock will be made available for 
publication purpose. 
6.4 
STUDY COMMITTEES  
No study committees are planned. 
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7 
SELECTION OF PATIENTS  
7.1 
INCLUSION CRITERIA  
I 01. Patient has completed at least 48 months of the Extension Study CAMMS03409. 
I 02. Signed written informed consent form (ICF).  
7.2 
EXCLUSION CRITERIA  
E 01.  Patient participating in another investigational interventional study. 
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8 
STUDY TREATMENTS  
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S)  
Name of the Investigational Medical Product (IMP):  
 Alemtuzumab. 
Pharmaceutical form:  
 Concentrate for solution for infusion (sterile concentrate). 
Dose of drug per administration:  
 12 mg/day on 3 consecutive days (36 mg total dose).  
 Missed doses should not be given on the same day as a scheduled dose. 
Route of administration: 
 Intravenous infusion. 
8.1.1 Administration  
There is no fixed treatment requirement or schedule. Administration of alemtuzumab will only be 
done following a decision from the Study Investigator that an additional “as needed” course is 
indicated.  
Alemtuzumab will be then administered by IV infusions in a supervised medical setting at a dose 
of 12 mg/day on 3 consecutive days (36 mg total dose) at least 12 months after the prior treatment 
course.  
8.1.1.1 Method of preparation at the clinical site  
Alemtuzumab must be diluted before infusion. The diluted solution should be administered by 
intravenous infusion over a period of approximately 4 hours. 
8.1.1.2 Special precautions for disposal and other handling  
The vial contents should 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 intravenous administration, withdraw 1.2 mL 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 should be inverted gently to mix the solution. 
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Alemtuzumab contains no antimicrobial preservatives and, therefore, care should 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 unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
8.1.2 Pre-treatment  
All the specific recommendations indicated in the IB or in the local approved label (when 
available) should be checked before starting the re-treatment with alemtuzumab. Physician should 
also considered the contraindications of alemtuzumab when retreating patient in this study 
(Section 10.1.6.1).  
Patients should be pre-treated with corticosteroids (eg, 1000 mg methylprednisolone IV) 
immediately prior to alemtuzumab administration on each of the 3 days of treatment.  
Additionally, pretreatment with antihistamines and/or antipyretics prior to alemtuzumab 
administration may also be considered. 
Oral prophylaxis for herpes infection should be administered to all patients starting on the 
first day of treatment and continuing for a minimum of 1 month following treatment with 
alemtuzumab. The choice of the therapy and the dose will be at the discretion of the Study 
Investigator. 
8.1.3 Post-treatment  
Observation for infusion associated reactions is recommended during and for a minimum of 
2 hours after alemtuzumab infusion. 
Patients treated with alemtuzumab must commit to 48-months of follow-up after the last infusion. 
It is possible that this period continues after study completion, in a regular healthcare setting. 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S)  
Not applicable. 
8.3 
BLINDING PROCEDURES  
No blinding procedures are planned. 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP  
No method of assigning patients to treatment group is planned. 
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8.5 
PACKAGING AND LABELING  
The content of the labeling is in accordance with the local regulatory specifications and 
requirements. 
Alemtuzumab will be packaged in 3-vial cartons. Each vial contains 12 mg of alemtuzumab per 
1.2 mL of solution. The vials are single use only and contain no preservatives. The label text for 
the alemtuzumab vial will, at a minimum, include the protocol number, the contents of the vial 
(ie, alemtuzumab 10 mg/mL, 1.2 mL vial), lot number, appropriate cautionary statements, route of 
administration, storage conditions, and name and address of Genzyme (a Sanofi company). Labels 
comply with Good Manufacturing Practices and national legislation. 
8.6 
STORAGE CONDITIONS AND SHELF LIFE  
Alemtuzumab, in vials, should be stored at 2° to 8°C (36 to 46°F). Do not freeze. Do not use 
alemtuzumab beyond the use by date provided on the label or other documentation. Protect from light.  
Alemtuzumab diluted product may be stored at room temperature (15° to 25°C) or refrigerated 
conditions (2° to 8°C), and should be used within 8 hours after dilution. From a microbiological 
point of view, it is recommended that the product should be used immediately. Protect from light. 
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 Study 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. 
All IMP will be dispensed in accordance with the Study 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) should be promptly notified to the 
Sponsor. 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 Study Investigator will be responsible for promptly addressing any 
request made by the Sponsor, in order to recall IMP and eliminate potential hazards. 
Under no circumstances will the Study 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. 
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8.7.1 Treatment accountability and compliance  
As alemtuzumab will be administered by daily IV infusions in a supervised medical setting, on an 
outpatient basis, 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  
The Study Investigator will not destroy the unused IMP unless the Sponsor provides written 
authorization. A detailed treatment log of the destroyed IMP will be established with the Study 
Investigator (or the pharmacist) and countersigned by the Study Investigator and the monitoring 
team.  
8.8 
CONCOMITANT MEDICATION  
A concomitant medication is any treatment received by the patient concomitantly to any IMP(s). 
In the current study, all medications received by the patient from the end of the Extension Study 
CAMMS03409 to Visit 1 of LPS13649 study, and during the study until the last visit will be 
collected. 
Patients who need to be re-treated with alemtuzumab and who are receiving treatment with other 
DMTs, should discontinue the other DMTs according to their local approved label. The potential 
for additive effects on the patient’s immune system must be taken into account. Concomitant use 
of alemtuzumab with some therapies could increase the risk of immunosuppression. 
8.8.1 Forbidden concomitant medications  
Patients should not receive live vaccines 6 weeks prior to alemtuzumab administration or during 
the study. 
All the specific recommendations indicated in the IB or in the local approved label (when 
available) should be checked before starting the re-treatment with alemtuzumab. 
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9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT  
9.1 
PRIMARY ENDPOINTS: SAFETY  
Safety assessments will include the following: 
 Incidence, duration, grade/intensity, relationship to study drug, and outcome of the 
following: 
- 
Serious Adverse Events (SAEs). 
- 
Adverse Events (AEs). 
- 
Infusion-associated reactions (IAR). 
 Incidence, nature, seriousness, grade/intensity, relationship to study drug, and outcome of 
the following project-specific Adverse Events of Special Interest (AESIs): 
- 
Autoimmune mediated conditions including, but not limited to: 
- 
Immune thrombocytopenic purpura (ITP). 
- 
Nephropathies including anti-glomerular basement membrane (GBM) disease.  
- 
Cytopenias. 
- 
Thyroid disorders. 
- 
Acquired hemophilia A 
- 
Autoimmune hepatitis. 
- 
Hemophagocytic lymphohistiocytosis (HLH). 
- 
Progressive multifocal leukoencephalopathy (PML) 
- 
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) 
- 
Serious infections including serious opportunistic infections (eg, Listeria 
infections, CMV, EBV), HPV associated with cervical dysplasia 
- 
Malignancy. 
- 
Pneumonitis 
 Changes in laboratory parameters. 
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9.2 
SECONDARY ENDPOINTS: EFFICACY  
The long-term effects of alemtuzumab will be examined by summarizing from baseline (date of 
the inclusion in the initial studies: CAMMS223, CAMMS323 or CAMMS324) through the last 
study visit the following efficacy endpoints: 
 Annualized relapse rate (ARR). 
 Proportion of patients relapse free. 
 Change over time in Expanded Disability Status Scale (EDSS) scores. 
 Change over time in brain imaging findings to include: 
- 
Number of Gadolinium (Gd)-enhancing, and new Gd-enhancing lesions.  
- 
Number of new/enlarging T2 lesions. 
- 
Number of new T1 (and new hypointense T1) lesions. 
- 
T1 and T2 lesion volume. 
- 
Brain Parenchymal Fraction (BPF). 
 Change over time in self-reported quality of life (QoL) as assessed by the Medical 
Outcome Study (MOS) 36-Item Short-Form Health Survey (SF-36) Version 2. 
 Change over time in the Functional Assessment of Multiple Sclerosis (FAMS), and  
 Change over time in the EuroQoL in 5 Dimensions (EQ-5D). 
9.3 
OTHER ENDPOINTS  
The modified HRUQ/HRPQ will be administered to obtain pharmaco-economic data. 
9.4 
APPROPRIATENESS OF MEASUREMENTS  
The assessments used in this study are standard for evaluation of therapy in patients with MS. 
9.5 
SAFETY MEASUREMENTS  
9.5.1 Adverse events  
Collection of AEs (refer to Section 10.4 for details) spontaneously reported by the patient or 
observed by the Study Investigator extends from the signing of the informed consent form until 
the end of the study visit. All reported AEs will be recorded in the patient’s records and in the 
e-CRF at all visits. 
Patients will be asked to volunteer information concerning AEs with a non-leading question such 
as: “How have you been since your last visit?”  
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An IAR is defined as any adverse event occurring during and within 24 hours of alemtuzumab 
infusion. 
9.5.2 Laboratory safety variables  
9.5.2.1 Patients exposed to alemtuzumab within 48 months prior to inclusion in this 
study  
 The following parameters must be obtained at monthly intervals until 48 months after the 
last infusion of alemtuzumab administered in the study CAMMS03409:  
- 
CBC with differential (including platelet count).  
- 
Serum creatinine.  
- 
Urinalysis (minimally including determination of urine protein and red blood cells) 
with microscopy.1 
 TSH must be obtained every 3 months until 48 months after the last infusion of 
alemtuzumab administered in the study CAMMS03409. 
 For women, a Human Papilloma Virus (HPV) screening must be performed as follows: 
- 
For women within 48 months follow-up at time of study transition from 
CAMMS03409 to TOPAZ, the date of the last alemtuzumab infusion administered in 
the study CAMMS03409 must be checked, and then an HPV screening performed 
approximately 1 year after the last infusion of alemtuzumab, and then every 12 months 
until 48 months safety FU is completed. 
9.5.2.2 Patients exposed to alemtuzumab during this study  
 For women of childbearing potential, a pregnancy test must be obtained prior to treatment 
with alemtuzumab. 
 For women, an HPV screening must be performed as follows: 
- 
For women patients re-treated with alemtuzumab during the TOPAZ study, an HPV 
screening should be performed prior to re-treatment (if not done in the previous 
12 months) and then every 12 months until 48 months safety FU is completed. 
 The following parameters must be obtained prior to treatment with alemtuzumab if not 
performed in the previous 2 weeks: 
- 
ECG 
                                                 
1 Note: For sites using homecare nurses service, or where microscopy is not routinely done if urine dipstick 
analysis is negative, the following procedure will be implemented: Homecare nurses/investigator site staff 
will perform a urine dipstick which will secure the detection of any potential haematuria and/or 
proteinuria. If urine dipstick is positive, the investigator would need to ask the patient to come to the site 
to have microscopy performed at the local lab. At any time, as per investigator criteria, according to the 
patient’s status, the patient can be asked to have a microscopy at the local lab to confirm any potential 
diagnosis. 
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- 
CBC with differential (including platelet count).  
- 
Serum creatinine.  
- 
TSH. 
- 
Liver function test (ALT, AST, ALP, albumin, total protein, direct bilirubin, and total 
bilirubin) 
- 
Urinalysis (minimally including determination of urine protein and red blood cells) 
with microscopy. (Please also refer to footnote in Section 9.5.2). 
 The following parameters must be obtained at monthly intervals until 48 months after the 
last infusion of alemtuzumab:  
- 
CBC with differential (including platelet count).  
- 
Serum creatinine. 
- 
Liver function test (ALT, AST, ALP, albumin, total protein, total bilirubin and direct 
bilirubin)  
- 
Urinalysis (minimally including determination of urine protein and red blood cells) 
with microscopy. (Please also refer to footnote in Section 9.5.2). 
 TSH must be obtained every 3 months until 48 months after the last infusion of 
alemtuzumab if retreated. LFT may be performed at any time if clinically indicated at 
Investigators’ discretion. 
9.5.3 Vital signs  
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]). 
 For all the patients: vital signs will be recorded at selection visit (D1) (if not recorded in 
the previous 3 months) and then every 6 months. 
 For patients treated with alemtuzumab: on days when alemtuzumab is infused, vital signs 
will be recorded before steroid administration, at a time after steroid administration (prior 
to alemtuzumab infusion), and 1 hour after the start of alemtuzumab infusion and hourly 
during and after infusion until observation post-infusion has ended (two hours after the 
end of the infusion or until stabilization). 
If clinically significant vital sign changes from previous visit are noted the changes will be 
documented as AEs in the e-CRF. Clinical significance is defined as any variation that has 
medical relevance and may result in an alteration in medical care. The Study Investigator will 
continue to monitor the patient until the parameter returns to baseline or until the Study 
Investigator determines that follow-up is no longer medically necessary.  
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9.5.4 Physical examination  
A physical examination, including weight, will be performed at D1 (if not performed in the 
previous 3 months) and then every 12 months. Any clinically significant abnormalities should be 
reported in the patient e-CRF as an AE. Weight should be taken with the patient wearing 
undergarments or very light clothing and no shoes and with an empty bladder. It is recommended 
to use the same scale throughout the study. 
9.6 
EFFICACY MEASUREMENTS  
9.6.1 Relapse  
Relapse is defined as new neurological symptoms or worsening of previous neurological 
symptoms with an objective change on neurological examination. Symptoms must be attributable 
to MS, last at least 48 hours, be present at normal body temperature (ie, no infection, excessive 
exercise, or excessively high ambient temperature), and be preceded by at least 30 days of clinical 
stability. 
EDSS must be completed to confirm the relapse. 
If the MS relapse is confirmed, the therapeutic approach will be decided by the Study 
Investigator, and all the treatments will be described in the e-CRF. Patients will be followed up at 
the discretion of the Study Investigator and all the procedures and assessments will be collected in 
the e-CRF. 
MS relapse will be verified at each visit. On the other hand, patients will be informed to contact 
the Study Investigator as soon as they observe any sign/symptom compatible with a possible 
relapse, in order to schedule an extra visit (see Section 10.1.4). 
Relapses will not be considered as AEs (see Section 10.4.1.2). 
9.6.2 Expanded disability status scale (EDSS)  
Patient disability will be evaluated using the EDSS, which has long been considered the standard 
for assessing disability in patients with MS. The EDSS must be performed by a qualified 
practitioner who has completed the Neurostatus certification training.  
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, 
cerebral, and other) in the context of a standard neurological examination and then uses these 
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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EDSS will be collected at D1 (if not collected in the previous 3 months) and then at each 
scheduled visit (every 6 months) and unscheduled visits for MS relapse. 
9.6.3 Brain imaging  
Brain imaging will be performed at D1 (if not performed in the previous 6 months) and then every 
12 months. It will be also performed at the end of study visit, if not performed in the previous 
6 months. MRIs will be read and interpreted locally by qualified site personnel and/or designee 
(eg, neuroradiologist). MRIs should be reviewed locally by qualified site personnel for signs of 
Non-MS pathology. For study purposes, per-protocol scans will be also submitted to a central 
imaging vendor for scan quality control and analysis. 
9.6.3.1 Pre- and post-Gadolinium-MRI  
The most frequently used surrogate marker of inflammatory disease activity in Phase 1 and 
Phase 2 studies in MS is the rate of new gadolinium-enhancing MRI lesion formation. 
Gadolinium-enhancing lesions in MS patients generally indicate active foci of inflammatory 
demyelination in the CNS. In 2 studies, alemtuzumab has been shown to have a profound effect 
on this measure.  
Gadolinium-containing contrast agents have been linked with Nephrogenic Systemic 
Fibrosis/Nephrogenic Fibrosing Dermopathy (NSF/NFD) in patients with impaired kidney 
function. There have been no reported cases in alemtuzumab-treated MS patients to date. 
Nonetheless, the Study Investigator should confirm that the patient is eligible to receive 
gadolinium according to their imaging center’s guidelines, for example based on age, medical 
status, and most recent creatinine level, prior to performing gadolinium-enhanced imaging. 
9.6.3.2 MRI-T1  
These brain scans can be used to assess the number and volume of T1 hypointense lesions 
(“Black Holes”), which also indicate axonal loss and tissue matrix damage. Three dimensional 
(3D) T1 weighted Gradient Echo imaging will also be performed as it affords greater spatial 
resolution and thus enhances detection of smaller lesions. 
9.6.3.3 MRI-T2  
The total MRI T2 lesion volume has been used as a surrogate marker of disease activity in the 
beta-interferon studies. T2-weighted MRI assessments will also include proton density and fluid 
attenuated inversion recovery (FLAIR) sequences. The inflammatory demyelination and edema 
characteristic of active MS lesions as well as the sclerotic gliosis of end-stage MS plaques 
contribute to the MRI T2 lesion volume, which thus reflects the “burden of disease” in these 
patients.  
Cerebral volume is also estimated from MRI-T2/PD acquisitions to quantify global 
neuro-degeneration, which is largely due to axonal loss in MS. In this study the rate of cerebral 
atrophy will be determined from the MRI T2/PD brain scans as changes in the BPF. 
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The number of new or enlarging hyperintense lesions as detected by T2 weighted MRI has been 
used as a surrogate marker of efficacy in recent MS studies.  
9.6.4 MOS 36-item short-form health survey (SF-36) Version 2  
The SF-36 is a self-administered questionnaire designed to assess generic Health Related Quality 
of Life (HRQoL) in healthy and ill adult populations. The SF-36 consists of 36 items organized 
into the 8 scales shown below (see Table 1). The SF-36 also yields 2 summary measures of 
physical health (the Physical Component Summary [PCS]) and mental health (the Mental 
Component Summary [MCS]) derived from scale aggregates. Higher global scores are associated 
with better quality of life.  
Table 1 - Components of the SF-36  
Scale  
Number of items 
Definition of scale 
Physical Functioning (PF)  
10 
Limitations in physical activity because of health problems  
Social Functioning (SF)  
2 
Limitations in social activities because of physical or emotional problems
Role Limitations Physical (RP)  
4 
Limitations in usual role activities because of physical health 
problem  
Bodily Pain (BP) 
2 
Presence of pain and limitations due to pain  
General Medical Health (GH)  
5 
Self-evaluation of personal health  
Mental Health (MH)  
5 
Psychological distress and well-being.  
Role Limitations Emotional (RE) 3 
Limitations in usual role activities because of emotional problems.  
Vitality (VT)  
4 
Energy and fatigue  
General Health Perceptions  
Single item 
(Not applicable) 
The reliability of the 8 scales and 2 summary measures has been estimated using both internal 
consistency and test-retest methods. With rare exceptions, published reliability statistics have 
exceeded the minimum standard of 0.70 recommended for measures used in group comparisons in 
more than 25 studies; most have exceeded 0.80. Reliability estimates for physical and mental 
summary scores usually exceed 0.90. 
SF-36 will be collected at D1 (if not collected in the previous 3 months) and then every 
12 months, and the end of study visit. 
9.6.5 FAMS, Version 4  
The FAMS is a widely accepted, MS-specific, quality of life questionnaire. It has been developed 
and validated in 23 languages, and shows adequate test-retest reliability and internal consistency. 
The FAMS is a self-report multidimensional index comprising a total of 58 items on 7 subscales: 
mobility (7 items); symptoms (7 items); emotional well being (7 items); general contentment 
(7 items); thinking and fatigue (9 items); family/social well being (7 items); and additional 
concerns (14 items, these are not scored). The response period for this measure is the past 7 days. 
Each item (except those for “additional concerns”) is rated on a 5-point scale of 0 to 4. The sum of 
the 44 scored items is the total score, which ranges from 0 to 176, with higher numbers reflecting 
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a higher quality of life. The total score is the primary criterion by which the effect of treatment on 
quality of life will be assessed; however, subscale totals will also be evaluated. 
FAMS will be collected at D1 (if not collected in the previous 3 months) and then every 
12 months and the end of study visit. 
9.6.6 EuroQoL in 5 dimensions (EQ-5D)  
The EQ-5D is a generic, standardized instrument that provides a simple, descriptive profile and 
a single index value for health status that can be used in the clinical and economic evaluation of 
health care as well as in population health surveys. The EQ-5D comprises 5 dimensions of health: 
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension 
consists of 3 levels (some, moderate, extreme problems), generating a total of 243 theoretically 
possible health states.  
The index has been validated in 36 languages. The response period is the day of assessment only. 
Assessments will also be made using the EuroQol Visual Analogue Scale (EQ-VAS), which 
captures the self-rating of current health status using a visual "thermometer" with the end points of 
100 (best imaginable health state) at the top and zero (worst imaginable health state) at the 
bottom. 
EQ-5D will be collected at D1 (if not collected in the previous 3 months) and then every 
12 months, and at the end of study visit. 
9.7 
OTHER MEASUREMENTS  
9.7.1 Modified healthcare resource utilization questionnaire (HRUQ)/health related 
productivity questionnaire (HRPQ)  
Patients’ use of healthcare resources, non-medical resources, and informal care as well as their 
work capacity will be assessed at scheduled study visits using a modified questionnaire 
(HRUQ/HRPQ) designed to evaluate the economic impact of MS. 
The questionnaire addresses the following content areas:  
 Employment situation and changes in employment situation due to MS. 
 Admissions and stays in hospital, rehabilitation centers, or nursing homes. 
 Typical MS-related investments (eg, stair and bed lift, ramps, rails) and devices 
(eg, walking aids, wheelchairs). 
 Assistance by community or social services (eg, home nurse, transportation), or help from 
family or friends. 
 Patient reported data regarding employment status. 
Information on resource use is obtained retrospectively, and each type of resource is collected for 
a time period that would minimize recall bias.  
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Each question requires a binary answer (yes/no) followed by details on the type and quantity of 
the resource. All resources that are expected to be used are prespecified in order to minimize 
errors due to spelling, and hence no open fields or free text (eg, “other”) are permitted. 
Modified HRUQ/HRPQ will be collected at D1 (if the HRUQ questionnaire was administered in 
the previous 3 months, then only questions 1 through 10 of the Modified HRUQ/HRPQ need to be 
completed at baseline, D1). The modified HRUQ/HRPQ will continue to be collected every 
12 months and at the end of study visit. 
9.7.2 Exploratory pharmacogenomic assessment  
For research purposes only and on a voluntary basis, a blood sample will be collected from 
consenting patients for exploratory analysis of genetic variations related to MS disease and/or 
alemtuzumab effects. The results of these analyses will not be provided to the Investigator or the 
patient. DNA sample collection, handling, storage, and analysis will conform to all applicable 
guidance and regulations. Details can be found in Appendix C. 
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10 
STUDY PROCEDURES  
Procedures will be performed following the standard clinical practice of each study center. 
10.1 
VISIT SCHEDULE  
10.1.1 Visit 1: selection (D1)  
This visit must be conducted within 3 months (6 months for US, see Appendix D) after 
completion of the Extension Study CAMMS03409. When possible, Visit 1 will be performed at 
the same time as the last visit of the Extension Study CAMMS03409. 
Prior to any assessments, information for the patient regarding the aims and methods of the study, 
its constraints and risks will be reviewed with the patient and a written summary in the form of an 
informed consent will be given to the patient. The patient must sign the informed consent before 
continuing the visit. The patient will keep the same patient number as used in the Extension 
Study CAMMS03409. 
The following items will be checked/performed and recorded: 
 Informed consent signature. 
 Eligibility by review of Inclusion/Exclusion criteria (Section 7). 
 Date of the last infusion of alemtuzumab.  
- 
If the treatment was administered within the previous 48 months, the patient must be 
followed-up as described in Section 10.1.6.2. 
 Safety assessments (Section 9.5). 
- 
Collection of AEs still ongoing at the end of the Extension Study CAMMS03409. 
- 
Collection of the AE that occurred between the final visit of the CAMMS03409 study 
and Visit 1.  
- 
Collection of laboratory results, if any, performed between the final visit of the 
CAMMS03409 study and Visit 1. 
- 
Vital signs and physical examination (only if not performed and collected in the 
previous 3 months). 
 Efficacy assessments (Section 9.6). 
- 
MS relapse verification. 
- 
EDSS (only if not performed and collected in the previous 3 months). 
- 
Brain imaging to include: G-MRI, MRI-T1 and MRI-T2 T1 pre- and post-Gadolinium 
(Gd), T2/PD, FLAIR and T1 sagittal sequences (only if not performed and collected in 
the previous 6 months). 
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Health questionnaires: SF-36, FAMS and EQ-5D (only if not performed in the 
previous 3 months). 
 Pharmaco-economic assessment: modified HRUQ/HRPQ (Section 9.7) (only if not 
collected in the previous 3 months). 
 Previous medication (from the end of the Extension Study CAMMS03409 to Visit 1 of 
LPS13649 study). 
 Concomitant medication. 
An appointment should be scheduled for next visit in 6 months (±14 days). 
10.1.2 Scheduled visits at 6 months (M6±14D, M18±14D, M30±14D, M42±14D, M54±14D)  
The following items will be checked/performed and recorded: 
 Safety assessments (Section 9.5). 
- 
AE collection. 
- 
Vital signs. 
 Efficacy assessments (Section 9.6). 
- 
MS relapse verification. 
- 
EDSS. 
 Concomitant medication. 
 Blood sample collection for pharmacogenomic analysis (for consenting patients only).  
An appointment should be scheduled for the next visit in 6 months (±14 days). 
10.1.3 Scheduled visits at 12 months (M12±14D, M24±14D, M36±14D, M48±14D)  
The following items will be checked/performed and recorded: 
 Safety assessments (Section 9.5). 
- 
AE collection. 
- 
Vital signs and physical examination. 
 Efficacy assessments (Section 9.6). 
- 
MS relapse verification. 
- 
EDSS. 
- 
Brain imaging to include: G-MRI, MRI-T1 and MRI-T2 T1 pre- and post-Gadolinium 
(Gd), T2/PD, FLAIR and T1 sagittal sequences. 
- 
Health questionnaires: SF-36, FAMS and EQ-5D. 
 Pharmaco-economic assessment: modified HRUQ/HRPQ (Section 9.7). 
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 Concomitant medication. 
 Blood sample collection for pharmacogenomic analysis (for consenting patients only). 
Omit if already collected during a prior study visit.  
An appointment should be scheduled for the next visit in 6 months (±14 days). 
10.1.4 End of study (EOS) visit  
This visit will be performed in one of the following situations: 
 At the end of the study. This visit corresponds to the Visit M60±14D. 
 At the end of the study period of 5 years, for all the ongoing patients, the next scheduled 
site visit will be changed into an EOS visit. 
 If the patient is prematurely withdrawn from the study. 
The following items will be checked/performed and recorded: 
 Safety assessments (Section 9.5). 
- 
AE collection. 
- 
Vital signs and physical examination. 
 Efficacy assessments (Section 9.6). 
- 
MS relapse verification. 
- 
EDSS. 
- 
Brain imaging to include: G-MRI, MRI-T1 and MRI-T2 T1 pre- and post-Gadolinium 
(Gd), T2/PD, FLAIR and T1 sagittal sequences (only if not performed in the previous 
6 months). 
- 
Health questionnaires: SF-36, FAMS and EQ-5D. 
 Pharmaco-economic assessment: modified HRUQ/HRPQ (Section 9.7). 
 Concomitant medication. 
 Blood sample collection for pharmacogenomic analysis (for consenting patients only). 
Omit if already collected during a prior study visit. 
10.1.5 Unscheduled visits  
At any time during the study the Study Investigator can schedule an extra visit if necessary. 
The Study Investigator will decide on the procedures to be performed. Data of all performed 
procedures will be collected in the e-CRF. At least the following items will be checked/performed 
and recorded: 
 Safety assessments (Section 9.5). 
- 
AE collection. 
- 
Vital signs. 
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 Efficacy assessments (Section 9.6). 
- 
MS relapse verification. 
- 
EDSS. 
 Concomitant medication. 
The Study Investigator determines whether patients are eligible for treatment: 
 Patients may receive additional courses of alemtuzumab (see Section 8.1.1) but not sooner 
than 12 months from any previous alemtuzumab treatment course, or  
 Patients may receive other commercial DMTs. 
In case of treatment the Study Investigator must document: 
 Clinical factors for deciding treatment, and/or 
 Imaging factors for deciding the treatment.  
10.1.6 Alemtuzumab treatment  
At any time during the study, the Study Investigator can decide to treat the patient with 
alemtuzumab (provided that the patient has not had alemtuzumab in prior 12 months). 
All the specific recommendations indicated in the IB or in the local approved label (when 
available) should be checked before starting the re-treatment with alemtuzumab.  
The following infusion management procedures must be utilized for each infusion and each 
treatment course to reduce serious reactions temporally associated with LEMTRADA 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), evaluate infusion-
related risks, and review HCP checklist. Physician should also consider following 
contraindications of alemtuzumab when retreating patient 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 
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Known coagulopathy or on concomitant anti-coagulant therapy 
It is at investigator’s discretion to re-treat or not re-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 
abnormalities/severe adverse event: 
- 
Interrupt infusion 
- 
Medically evaluate the patient guided by the adverse event profile of LEMTRADA 
prior to considering restarting therapy 
- 
Provide appropriate treatment as needed 
- 
Consider permanently discontinuing the LEMTRADA 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 
LEMTRADA infusion.  
- 
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 seek appropriate medical care. 
For monitoring potential risk of autoimmune hepatitis, liver function test must be performed for 
patients who newly initiate retreatment of alemtuzumab, LFT to be performed prior infusion of 
retreatment as baseline, and monthly for 48 months after the last infusion of retreatment of 
alemtuzumab. In addition, LFT may be performed at any time if clinically indicated at 
Investigators’ discretion 
10.1.6.1 Prior to alemtuzumab treatment visit  
The following items will be checked and recorded: 
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 Clinical factors for deciding treatment. 
 Imaging factors for deciding the treatment.  
 For women, an HPV screening must be performed if not done in the previous 12 months. 
The following parameters must be obtained prior to initiation of treatment with alemtuzumab: 
 ECG 
 vital signs (including heart rate and blood pressure measurement 
 Pregnancy test (for women of childbearing potential).  
 CBC with differential, including platelet count (if not performed in the previous 
two weeks). 
 Serum creatinine (if not performed in the previous two weeks).  
 TSH and liver function test (ALT, AST, ALP, albumin, total protein, direct and total 
bilirubin) (if not performed in the previous 2 weeks). 
 Urinalysis (minimally including determination of urine protein and red blood cells) with 
microscopy (if not performed in the previous 2 weeks). (Please also refer to footnote in 
Section 9.5.2). 
10.1.6.2 Post-alemtuzumab treatment monitoring  
The following parameters must be obtained at monthly intervals (± 3 days) until 48 months after 
the last infusion of alemtuzumab:  
 CBC with differential (including platelet count).  
 Serum creatinine.  
 Liver function test (ALT, AST, ALP, albumin, total protein, direct and total bilirubin) 
 Urinalysis (minimally including determination of urine protein and red blood cells) with 
microscopy (if not performed in the previous 2 weeks). (Please also refer to footnote in 
Section 9.5.2). 
TSH must be obtained every 3 months (±3 days) until 48 months after the last infusion of 
alemtuzumab. 
For women, an HPV screening must be performed every 12 months (±14 days) until 48 months 
safety FU is completed. 
The blood and urine sampling will be performed in local laboratories at the patients’ convenience. 
Results must be sent to the Study Investigator. The Study Investigator must review laboratory data 
as soon as the results are available and they will be recorded in the e-CRF. 
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If the 48-month period of safety follow-up continues after the study ends, the patient will be 
followed by their physician in a regular healthcare setting, in line with the local approved Risk 
Minimization Plan for alemtuzumab, until the 48-month period is completed.  
10.2 
DEFINITION OF SOURCE DATA  
Source documents 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, MRI, chest X-ray or signed documented X-ray and reports, ECG tracings and reports, 
laboratories reports, medication dispensing records, computer printouts, electronic 
data/information sources and any other documentation regarding the patient.  
10.3 
HANDLING OF PATIENT TREATMENT DISCONTINUATION AND OF PATIENT STUDY 
DISCONTINUATION  
Any IMP discontinuation should be fully documented in the e-CRF. In any case, the patient 
should remain in the study as long as possible. 
10.3.1 Permanent treatment discontinuation with investigational medicinal product(s)  
Permanent treatment discontinuation is any treatment discontinuation associated with the 
definitive decision from the Study Investigator or the patient not to re-expose the patient to the 
IMP at any time. 
10.3.2 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 Study Investigator’s decision. All efforts should be 
made to document the reasons for treatment discontinuation and this should be documented in the 
e-CRF. 
10.3.3 Handling of patients after permanent treatment discontinuation  
Patients will be followed-up according to the Study Investigator judgment up to the study 
completion, or up to recovery or stabilization of any AE to be followed-up as specified in this 
protocol, whichever comes last.  
Patients re-treated with alemtuzumab must be followed as described in Section 10.1.6. 
10.3.4 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. 
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If possible, the patients are assessed using the procedure normally planned for the EOS visit 
(Section 10.1.4). 
If a patient has consented to participate in the PGx substudy and withdraws from the TOPAZ 
study, the patient’s PGx sample will be stored for analysis unless the patient specifically indicates 
that it cannot be used following the time of study withdrawal. If the patient withdraws consent of 
sample use, the samples must be destroyed. 
For patients who fail to return to the site, the Study Investigator should make the best effort to 
recontact the patient (eg, contacting patient’s family or private physician, reviewing 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). 
At time of withdrawal, any patient who has received an infusion with alemtuzumab less than 
48 months ago should be reminded of the importance to continue to check for symptoms of 
autoimmune conditions and to have monthly laboratory tests performed until the 48-month period 
is completed. 
The SAP will specify how these patients lost to follow-up 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 adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation 
patient administered a pharmaceutical product and which does not necessarily must have a causal 
relationship with this treatment. 
10.4.1.2 Serious adverse event  
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
 Results in death, or 
 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 
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 Is a medically important event 
Medical and scientific judgment should 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 must be considered as 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. 
 Chronic neurodegenerative diseases (newly diagnosed) or aggravated during the study 
(only if judged unusual/significant by the Study 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).  
10.4.1.3 Adverse event of special interest  
An adverse event of special interest (AESI) is an AE (serious or non-serious) of scientific and 
medical concern specific to the Sponsor’s product or program, for which ongoing monitoring and 
immediate notification by the Study 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 or removed during a study by protocol amendment. 
AESI will be reported to the Sponsor in the same timeframe as SAEs, ie, within 24 hours, as 
detailed in Section 10.4.4.  
The following AE will be considered as AESI: 
 Hypersensitivity or anaphylaxis 
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 Pregnancy of a woman entered in the study; 
- 
Pregnancy occurring in a woman 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 woman participant is mandatory until the outcome has 
been determined. 
 Symptomatic overdose (serious or non-serious) with IMP. 
- 
An overdose (accidental or intentional) with the IMP is an event suspected by the 
Study Investigator or spontaneously notified by the patient and defined as 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. 
Of note, asymptomatic overdose must be reported as a standard AE. 
 Increase in alanine transaminase (ALT) (see the “Increase in ALT” flow diagram in 
Appendix B of the protocol). 
 Other product specific AESIs: 
- 
Autoimmune mediated conditions including, but not limited to: 
- 
Immune thrombocytopenic purpura (ITP). 
- 
Nephropathies including anti-glomerular basement membrane (GBM) disease. 
- 
Cytopenias.  
- 
Thyroid disorders. 
- 
Acquired hemophilia A 
- 
Autoimmune hepatitis. 
- 
Hemophagocytic lymphohistiocytosis (HLH). 
- 
Progressive multifocal leukoencephalopathy (PML) 
- 
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) 
- 
Serious infections including serious opportunistic infections (eg, Listeria infections, 
CMV, EBV), HPV associated with cervical dysplasia 
- 
Malignancy. 
- 
Pneumonitis 
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10.4.1.4 Events not to be considered as AEs/SAEs  
Medical conditions present at the initial trial visit (Visit1) that do not worsen in severity or 
frequency during the trial are defined as baseline medical conditions, and are not to be considered 
AEs. However, baseline medical conditions other than the disease under trial that worsen in 
severity or frequency during the trial should be recorded and reported as AEs. 
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 eCRF. Therefore, symptoms, relapses or worsening of MS will not be considered as AEs nor 
captured on the AE module of the eCRF 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). 
10.4.2 General guidelines for reporting adverse events  
 All AEs, regardless of seriousness or relationship to IMP, spanning from the signature of 
the informed consent 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 CRF. At Visit 1 
the ongoing AEs started during the Extension Study CAMMS03409, or occurred between 
the final visit of the CAMMS03409 study and Visit 1, are also to be recorded. 
 Whenever possible, diagnosis or single syndrome should be reported instead of symptoms. 
The Study 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 Study 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.  
 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 or ECG abnormalities 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. 
 AEs/AESIs that are ongoing at the end of the patient’s participation in CAMMS03409 
should be followed during the LPS13649 study. 
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10.4.3 Instructions for reporting serious adverse events  
In the case of occurrence of an SAE, the Study Investigator must immediately: 
 ENTER (within 24 hours) the information related to the SAE in the appropriate screens of 
the e-CRF; the system will automatically send a notification to the monitoring team after 
approval of the Study Investigator within the e-CRF or after a standard delay. 
 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. 
 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. 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 Study 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. 
10.4.4 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 10.4.3, even if not fulfilling a seriousness criterion, 
using the corresponding screens in the e-CRF. 
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Table 2 - Summary of adverse event reporting instructions  
Event 
category 
Reporting 
timeframe 
Specific events in this 
category 
Case report form completion 
 
AE 
form 
Safety 
comple-mentary 
forma 
Other 
specific 
forms 
Adverse Event 
(non-SAE, 
non-AESI) 
Routine 
Any AE that is not SAE or AESI 
Yes 
No 
No 
Serious 
Adverse Event 
(non-AESI or 
AESI) 
Expedited  
(within 24 
hours) 
Any AE meeting seriousness criterion 
per Section 10.4.1.2 
Yes 
Yes 
No 
Adverse Event 
of Special 
Interest 
Expedited  
(within 24 
hours) 
Hypersensitivity or anaphylaxis 
Yes 
Yes 
No 
 
 
Pregnancy 
Yes 
Yes 
Yes 
 
 
Symptomatic overdose 
Yes 
Yes 
No 
 
 
ALT ≥3 ULN or ≥2 baseline 
Yes 
Yes 
Yes 
 
 
Autoimmune mediated conditions 
including, but not limited to: 
 
Immune thrombocytopenic 
purpura (ITP) 
 
Nephropathies including 
anti-glomerular basement 
membrane (GBM) disease 
 
Cytopenias 
 
Thyroid disorders 
 
Autoimmune hepatitis 
 
Acquired hemophilia A 
Yes 
Yes 
No 
 
 
Serious infections including serious 
opportunistic infections (eg, Listeria 
infections, CMV, EBV), HPV associated 
with cervical dysplasia 
Yes 
Yes 
No 
 
 
Hemophagocytic lymphhostiocytosis 
(HLH) 
Yes 
Yes 
No 
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Event 
category 
Reporting 
timeframe 
Specific events in this 
category 
Case report form completion 
 
AE 
form 
Safety 
comple-mentary 
forma 
Other 
specific 
forms 
 
 
Progressive Multifocal 
Leukoencephalopathy (PML) 
Pneumonitis 
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) 
Malignancy 
Yes 
 
Yes 
Yes 
 
Yes 
Yes 
Yes 
 
 
 
Yes 
Yes 
 
Yes 
Yes 
 
Yes 
Yes 
Yes 
 
 
 
Yes 
No 
 
No 
No 
 
No 
No 
No 
 
 
 
No 
AE = adverse event; AESI = adverse event of special interest; GBM = Glomerular Basement Membrane; SAE = serious adverse event. 
a If an SAE or an AESI ongoing from the CAMMS study is reported in TOPAZ study, the Safety Complementary Form need not be 
completed. 
10.5 
OBLIGATIONS OF THE SPONSOR  
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, IECs/IRBs as appropriate and to the Study Investigators.  
 All SAEs that are expected and at least reasonably related to the IMP to the regulatory 
authorities, according to local regulations. 
 The following AESI, to those regulatory authorities who require such reporting:  
- 
Malignancy. 
In this study, some AEs are considered related to the underlying condition and thus will not be 
considered unexpected. 
Any other AE not listed as an expected event in the IB will be considered unexpected. 
The Sponsor will report all safety observations made during the conduct of the trial in the clinical 
study report. 
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10.6 
SAFETY INSTRUCTIONS FOR USING ALEMTUZUMAB  
For more information about alemtuzumab, please refer to IB or to the approved label in the 
country/region when available. 
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  
11.1 
DETERMINATION OF SAMPLE SIZE  
There are no sample size calculations for this long term safety study. Sample size will be based on 
elective participation of patients who were enrolled (and completed at least 48 months) into the 
prior CAMMS03409 extension study.  
11.2 
DISPOSITION OF PATIENTS  
All CAMMS03409 patients that fulfill the inclusion/exclusion criteria are eligible for enrollment. 
A detailed description of patient disposition will be provided. It will include: 
 A summary of data on patient discontinuation 
 A summary of data on overall Screening and qualification status of all patients 
 An account of all identified protocol deviations 
In addition, the treatment regimen for all patients will be summarized. This includes summarizing 
the percentage of patients receiving alemtuzumab on an as-needed basis, and the time to 
treatment. 
11.3 
ANALYSIS POPULATIONS  
11.3.1 Safety population  
All patients who have signed the ICF will be included in the safety population. 
11.3.2 Efficacy populations  
The population on which efficacy analyses will be performed consists of all enrolled patients who 
have received study drug in CAMMS223, CAMMS323, CAMMS324 or CAMMS03409. 
11.4 
STATISTICAL METHODS  
All data collected in this study will be reported using summary tables, figures, and patient data 
listings. Summary statistics will be computed and displayed by treatment group (assigned in the 
original study) and scheduled assessment time. Summary statistics for continuous variables will 
minimally include n, mean, standard deviation, minimum, median, and maximum. For categorical 
variables, frequencies and percentages will be presented. Graphical displays will be provided as 
appropriate. No formal inferential hypothesis tests will be performed, however 2-sided 
95% confidence intervals (CI) will be provided where appropriate. 
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11.4.1 Analyses of efficacy endpoints  
The long-term effects of alemtuzumab in patients who received alemtuzumab prior to the 
extension Study CAMMS03409 (eg, in Studies CAMMS223, CAMMS323, or CAMMS324) will 
be examined by summarizing the efficacy endpoints from prior study baseline through the end of 
study participation for each patient. Efficacy will be evaluated using proportion of patients relapse 
free, relapse rate, ARR, change over time in EDSS, MRI, and QoL measures, starting at baseline 
of the earlier studies.  
The same efficacy evaluations will be made for patients who received SC IFNB-1a prior to the 
extension Study CAMMS03409 and who subsequently received alemtuzumab in the extension 
study. For these patients, efficacy will be assessed from the time of their first study treatment in 
CAMMS323 and CAMMS324 or from the time of randomization in CAMMS223. 
The number of patients with a relapse event, the total number of relapses, and the annualized 
relapse rate over the years of follow-up will be produced. The annualized relapse rate will be 
estimated using a negative binomial model with robust variance estimation. The model will be 
stratified by clinical study.  
A detailed description of the methods utilized to analyze each of the efficacy endpoints will be 
provided in the SAP.  
11.4.2 Analyses of safety data  
All patients in the study will be evaluated for safety. A summary of safety will be evaluated based 
on incidence, duration, grade/intensity, seriousness, and relationship of AEs to study drugs, and 
on changes in physical examination, vital signs, and clinical laboratory results, particularly 
hematological parameters and biochemical, immunological, and clinical indications of ITP, 
infection, and thyroid dysfunction observed in this study. Deaths and other SAEs will also be 
evaluated. Particular attention will be paid to the development of autoimmune disorders including 
the incidence of ITP, autoimmune thyroid disorders and anti-GBM disease. Further elaboration of 
statistical issues will be provided in the SAP. 
11.4.3 Analyses of patient reported outcomes (health-related quality of life/health 
economics variables  
Change over time in self-reported quality of life (QoL) as assessed by the Medical Outcome Study 
(MOS) 36-Item Short-Form Health Survey (SF-36) Version 2, the Functional Assessment of 
Multiple Sclerosis (FAMS), and the EuroQoL in 5 Dimensions (EQ-5D), will be analyzed relative 
to the baseline obtained at the start of the original studies. 
Change over time in modified HRUQ/HRPQ will also be analyzed. 
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11.4.4 Analysis of blood samples for exploratory pharmacogenomics substudy  
PGx samples obtained from consenting patients will be used for exploratory biomarker analysis, 
including (1) targeted gene sequencing to validate the candidate ITP biomarker panel and (2) de 
novo association analysis to identify predictive markers using whole exome sequencing 
(WES)/genome-wide association study (GWAS) data. Details can be found in Appendix C. 
11.5 
INTERIM ANALYSIS  
No interim analysis is planned; an annual partial database lock will be made available for 
publication purpose. 
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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 Study Investigator, delegated Study 
Investigator staff and Subinvestigator, in accordance with the principles laid down by the 
18th World Medical Assembly (Helsinki, 1964) and all applicable amendments laid down by the 
World Medical Assemblies, 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 Study Investigator (according to applicable regulatory requirements), or a person designated 
by the Study Investigator, and under the Study Investigator's responsibility, should fully inform 
the patient of all pertinent aspects of the clinical trial including the written information giving 
approval/favorable opinion by the Ethics Committee (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 informed consent form 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 informed consent form will be provided to the patient.  
Ongoing patients agreeing to participate in the exploratory PGx substudy must sign an additional, 
separate informed consent. 
The informed consent form used by the Study 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. 
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12.3 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC)  
As required by local regulation, the Study Investigator or the Sponsor must submit this clinical 
trial protocol to 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, informed consent form, IB, Study Investigator’s curriculum vitae 
[CV], etc) and the date of the review should be clearly stated on the written (IRB/IEC) 
approval/favorable opinion. 
IMP will not be released at the study site and the Study Investigator will not start the study before 
the written and dated approval/favorable opinion is received by the Study Investigator and the 
Sponsor. 
During the clinical trial, any amendment or modification to the clinical trial protocol should be 
submitted to the IRB/IEC before implementation according to applicable regulations, unless the 
change is necessary to eliminate an immediate hazard to the patients, in which case the IRB/IEC 
should be informed as soon as possible. It should 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 IB will be sent to the IRB/IEC, except in countries where alemtuzumab is 
already approved for treatment in MS. 
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 Study 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 Study Investigator agrees to provide reliable data and all information requested by the 
clinical trial protocol (with the help of the CRF, Discrepancy Resolution Form [DRF] 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 Study 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 Study 
Investigator. The Study 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 CRFs. Thus, the main duty of 
the monitoring team is to help the Study 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, 
Study 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 CRF entries against the source 
documents, except for the pre-identified source data directly recorded in the CRF. The informed 
consent form 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 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 CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST  
It is the responsibility of the Study Investigator to maintain adequate and accurate 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 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 (DRF) to 
which the Study 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 Study 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 Study Investigator must maintain confidential all study documentation, and take measures to 
prevent accidental or premature destruction of these documents. 
The Study 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 Study Investigator must notify the Sponsor prior to destroying any study essential documents 
following the clinical trial completion or discontinuation. 
If the Study Investigator's personal situation is such that archiving can no longer be ensured by 
him/her, the Study 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 CRFs, the IB and the results obtained during 
the course of the clinical trial, is confidential, prior to the publication of results. The Study 
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 Study Investigator. The Study 
Investigator shall inform the Subinvestigators of the confidential nature of the clinical trial. 
The Study 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 Study 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 Study 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 Study 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 Study 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 Study Investigator in compliance 
with all applicable laws and regulations. 
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 Study 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 Study Investigator should permit auditing by or on the 
behalf of the Sponsor and inspection by regulatory authorities. 
The Study 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 Study 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 Study 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 Study 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 Study 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; 
 Non-compliance of the Study 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 Study Investigator of its decision by written notice. 
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14.8.2 By the Investigator  
The Study 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 Study Investigator. 
14.10 PUBLICATIONS AND COMMUNICATIONS  
The Study 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 Study 
Investigator shall have the right to publish or present independently the results of this study in 
agreement with other Investigators and stakeholders. The Study 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 Study 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 Study 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  
The Study Investigator should not implement any deviation from, or changes of the clinical trial 
protocol without agreement by the Sponsor and prior review and documented approval/favorable 
opinion from the IRB/IEC of an amendment, 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 Study 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 according to applicable local regulations, unless there are 
overriding safety reasons. 
In some instances, an amendment may require a change to the informed consent form. The Study 
Investigator must receive an IRB/IEC approval/favorable opinion concerning the revised informed 
consent form prior to implementation of the change and patient signature should be re-collected if 
necessary. 
 
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16 
BIBLIOGRAPHIC REFERENCES  
1. National Multiple Sclerosis Society. Multiple sclerosis: Just the facts [Online]. 2011 [cited 
2011 Oct 27]. Available from: URL:http://www.nationalmssociety.org/about-multiple-
sclerosis/index.aspx. 
2. Moreau T, Coles A, Wing M, Thorpe J, Miller D, Moseley I, et al. CAMPATH-IH in 
multiplesclerosis. Mult Scler. 1996;1(6):357-65. 
3. CCDS - Internal Confidential Document Final 09-Apr-2012. 
4. Coles AJ, Compston DA, Selmaj KW, Lake SL, Moran S, Margolin DH, et al. Alemtuzumab 
vsInterferon Beta-1a in early multiple sclerosis. N Engl J Med. 2008;359(17):1786-801. 
5. Coles AJ, Deans J, Compston A. Campath-1H treatment of multiple sclerosis: lessons from 
thebedside for the bench. Clin Neurol Neurosurg. 2004;106(3):270-4. 
6. Coles AJ, Wing M, Smith S, Coraddu F, Greer S, Taylor C, et al. Pulsed monoclonal 
antibodytreatment and autoimmune thyroid disease in multiple sclerosis. Lancet. 
1999;354(9191):1691-5. 
7. Cohen JA, Coles AJ, Arnold DL, Confavreux C, Fox EJ, Hartung HP, et al. Alemtuzumab 
versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple 
sclerosis: a randomised controlled phase 3 trial. Lancet. 2012;380(9856):1819-28. 
8. Coles AJ, Twyman CL, Arnold DL, Cohen JA, Confavreux C, Fox EJ, et al. Alemtuzumab for 
patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised 
controlled phase 3 trial. Lancet. 2012;380(9856):1829-39.  
 
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17 
APPENDICES  
 
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Appendix A 
Recommendations for using alemtuzumab in countries where it is 
not yet available  
 
Timing 
Activity 
Detail 
Before  
re-treatment with 
alemtuzumab 
Contraindications 
• 
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 
Recommended screening 
Evaluate for active and inactive (“latent”) TB (per local guidelines). 
Consider screening patients at high risk of HBV and/or HCV infection. 
Exercise caution in prescribing alemtuzumab to patients identified as 
carriers of HBV and/or HCV. 
Baseline tests 
ECG 
HPV 
Complete Blood Count with differential (including platelet count). 
Serum creatinine, LFT. 
Thyroid function tests, such as TSH. 
Urinalysis with microscopya. 
Understanding of 
Benefits & Risks 
The patient has been informed about and understands the risks of serious 
autoimmune disorders, infections and malignancies, and the measures to 
minimize risk (eg, watching for symptoms, carrying the Patient Alert Card 
and the need to commit to periodic monitoring for 48 months after the last 
treatment). 
6 weeks prior to 
treatment 
(if needed) 
Vaccinations 
It is recommended that patients have completed local immunization 
requirements. 
Consider VZV vaccination of antibody negative patients before initiating 
a course of alemtuzumab treatment. 
Immediately prior 
to treatment 
Pre-treatment 
Immediately prior to alemtuzumab pre-treat with corticosteroids on each of 
the first 3 days of any treatment course. 
Pre-treatment for IARs 
Pretreatment with antihistamines and/or antipyretics prior to alemtuzumab 
administration may also be considered. 
Oral prophylaxis for herpes 
Administer 200 mg aciclovir (or equivalent) twice a day from first day of 
treatment and continuing for a minimum of 1 month following treatment. 
General health 
Consider delaying initiation of alemtuzumab administration in patients with 
active infection until the infection is fully controlled 
Pregnancy & contraception 
Ensure women of child bearing potential use effective contraceptive 
measures when receiving a course of treatment with alemtuzumab and for 
4 months following the course of treatment. 
If patient is pregnant, administer only if the potential benefit justifies the 
potential risk to the fetus. 
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Timing 
Activity 
Detail 
During treatment 
and for 48 months 
after last 
treatment 
Monitoring Activities 
Complete Blood Count w/Differential and Serum creatinine, LFT: Monthly 
until 48 months from last treatment. 
Urinalysis with microscopya. Monthly until 48 months from last treatment. 
Thyroid function tests: Every 3 months until 48 months from last treatment. 
a Note: For sites using homecare nurses service, or where microscopy is not routinely done if urine dipstick analysis is negative, the following 
procedure will be implemented: Homecare nurses/investigator site staff will perform a urine dipstick which will secure the detection of any 
potential haematuria and/or proteinuria. If urine dipstick is positive, the investigator would need to ask the patient to come to the site to have 
microscopy performed at the local lab. At any time, as per investigator criteria, according to the patient’s status, the patient can be asked to 
have a microscopy at the local lab to confirm any potential diagnosis. 
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Appendix B 
General guidance for the follow-up of laboratory abnormalities as 
required by Sanofi  
 
 
Neutrophils < 1500/mm3 or according to ethnic 
group
NEUTROPENIA
Repeat immediately a full blood count if value 
close to 1500/mm3
Neutrophils < 1500/mm3 confirmed 
with signs of infection  
Neutrophils < 1500/mm3 confirmed 
with no signs of infection  
1.
DISCONTINUE
Investigational Medicinal 
Product, hospitalization 
should be considered
2.
PERFORM biological 
investigations for infection
1.
DISCONTINUE
Investigational 
Medicinal Product
2.
INVESTIGATE for 
infection
In both situations
3.
INFORM the local monitor
4.
INVESTIGATE previous treatments particularly long-term, even a long time ago, 
exposure to toxic agents, e.g., benzene, X-rays, etc.
5.
PERFORM and collect the following investigations (results): 
•
RBC and platelet counts
•
Serology: EBV, (HIV), mumps, measles, rubella
6.
DECISION for bone marrow aspiration: to be taken in specialized unit
7.
For studies with PK sampling: COLLECT/STORE one sample following 
handling procedures described in PK section and freeze 1 serum sample (5 mL) on 
Day 1 (cessation of investigational medicinal product) and Day 5 (for further 
investigations)
8.
MONITOR the leukocyte count 3 times per week for at least one  week, then twice a 
month until it returns to normal
Note: 
•The procedures described in the above flowchart are to be discussed with the patient only in case 
the event occurs. If applicable (according to local regulations), an additional consent (e.g., for 
HIV testing) will only be obtained in the case the event actually occurs.
•For individuals of African descent, the relevant value of concern is <1000/mm3
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Platelets < 100 000/mm3 (rule out EDTA – induced 
pseudo-thrombocytopenia)
THROMBOCYTOPENIA
Repeat immediately the count (rule out EDTA 
anticoagulant in the sample)
Platelets  < 100 000/mm3 confirmed 
with bleeding  
Platelets  < 100 000/mm3 confirmed 
with no bleeding
1.
DISCONTINUE
Investigational Medicinal 
Product
2.
HOSPITALIZATION
should be considered
1.
DISCONTINUE
Investigational Medicinal 
Product
2.
INVESTIGATE for 
bleeding
In both situations
3.
INFORM the local Monitor
4.
QUESTION about last intake of quinine (drinks), alcoholism, heparin administration
5.
PERFORM or collect the following investigations: 
•
Complete blood count, schizocytes, creatinine
•
Bleeding time and coagulation test (fibrinogen, INR or PT, aPTT), Fibrin 
Degradation Product
•
Viral serology: EBV, HIV, mumps, measles, rubella
6.
For studies with PK sampling: COLLECT/STORE 1 sample following handling 
procedures described in PK sections and freeze 1 serum sample (5 mL) on Day 1 
(end of treatment) and Day 5 to test for drug-induced antiplatelets antibodies
7.
DECISION for bone marrow aspiration: to be taken in specialized unit
•
On Day 1 in the case of associated anemia and/or leukopenia
•
On Day 8 if platelets remain < 50 000/mm3
8.
MONITOR the platelet count every day for at least one week and then regularly 
until it returns to normal
Note: 
The procedures above flowchart are to be discussed with the patient only in case described in the 
the event occurs. If applicable (according to local regulations), an additional consent (e.g., for 
HIV testing) will only be obtained in the case the event actually occurs.
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INCREASE IN ALT
ALT 3 ULN (if baseline ALT <ULN) 
Or, ALT 2 times the baseline value 
(if baseline ALT ULN)
ALT 5 ULN
(if baseline ALT < ULN)
Or, ALT 3 times the baseline 
value
(If baseline ALT ULN)
ALT > 5 ULN
(if baseline ALT < ULN)
Or, ALT > 3 times the 
baseline value
(if baseline ALT ULN)
Total bilirubin 2 ULN
Total bilirubin > 2 ULN
DISCONTINUE 
ADMINISTRATION OF 
INVESTIGATIONAL 
MEDICINAL PRODUCT
In ANY CASE, FOLLOW the instructions #1 to 7 listed in the box below. 
1. INVESTIGATE THE CLINICAL CONTEXT in the previous 72 hours, specifically for malaise with or without 
loss of consciousness, dizziness, and/or hypotension and/or episode of arrhythmia; rule out muscular injury
2. 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, anti-HCV and HCV RNA , anti-CMV IgM and anti-HEV IgM antibodies, and 
depending on the clinical context, check for recent infections, eg, EBV, Herpes viruses and toxoplasma 
- Hepatobiliary ultrasonography (can be completed by other imaging investigations if needed)
3. CONSIDER auto-antibodies: anti-nuclear, anti-DNA, anti-smooth muscle, anti-LKM
4. CONSIDER consultation with hepatologist
5. CONSIDER patient hospitalization if INR>2 (or PT<50%) and/or central nervous system disturbances suggesting 
hepatic encephalopathy
6. MONITOR LFTs
- If investigational medicinal product is continued: every 48 hours until return to normal (<2ULN) or 
baseline. If ALT elevation persists beyond 2 weeks then perform LFTs every 2 weeks and 15 to 30 days after 
the last dose according to the study protocol.
- If investigational medicinal product is discontinued: as closely as possible to every 48 hours until 
stabilization then every 2 weeks until return to normal (<2ULN) or baseline or for at least 3 months, whichever 
comes last.
7. For studies with PK sampling: COLLECT/STORE 1 sample following handling procedures described in PK 
sections and freeze 1 serum sample (5 mL) 
COMPLETE the 
specific CRF form for 
“ALT increase” 
And INFORM the 
Monitoring Team 
within 24 hours
Monitor LFTs 
every 48 hours
If Not Possible
Investigational Medicinal Product 
administration can be continued, as 
long as – under close monitoring –
conditions for stopping are not met
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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.
For studies with PK sampling: 
COLLECT/STORE 1 sample 
following handling procedures 
described in PK sections and freeze 1 
serum sample (5 mL)
6.
MONITOR renal function until 
return to baseline level (every day at 
the beginning, then every week)
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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)
- For studies with PK sampling: COLLECT/STORE 1 sample following handling procedures 
described in PK section and freeze 1 serum sample (5 mL) 
- 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 
Exploratory pharmacogenomics assessment substudy  
Background information 
The autoimmunity adverse events associated with LEMTRADA are identified potential risks and 
pose a potential barrier to a greater use of the product, including autoimmune thyroid disorders 
(36%), immune thrombocytopenia (ITP; 2%), and nephropathies (0.3%). If biomarkers for 
autoimmunity were known, more patients could potentially benefit from LEMTRADA treatment. 
A team effort has been under way to discover a panel of biomarkers that could predict which 
patients are at risk of developing autoimmunity events. Blood samples collected from 
LEMTRADA-treated MS patients within clinical studies were preserved for biomarker discovery. 
Genomics and proteomics profiling were conducted on a cohort of LEMTRADA-treated MS 
patients, including patients who developed treatment-emergent autoimmune disorders and patients 
who, to date, have not developed such disorders. The search for the associated markers was 
focused on single nucleotide polymorphism (SNP), human leukocyte antigen (HLA)-allele, 
HLA-amino acid polymorphism, serum cell-free microRNA, serum protein, and serum 
autoantibody. 
Correlative analysis of this biomarker data with the development of autoimmune conditions 
indicated no robust signals for protein biomarkers. Interestingly, we identified candidate SNPs 
that are potentially associated with the development of ITP with this preliminary discovery data 
set. Although potential predictors have been identified, more samples are needed to validate this 
data. Samples from the TOPAZ study together with samples from patients from previous clinical 
trials (CAMMS03409, CAMMS223, CAMMS323 and CAMMS324) and from post-marketing 
patients will provide a large enough cohort to validate the to validate the preliminary findings 
(and potentially efficacy/non-responders). Samples from patients who have not yet developed any 
autoimmune conditions would be used as controls.  
The goal of this exploratory substudy is to obtain additional data to identify a biomarker for 
autoimmune events so that LEMTRADA can be safely administered to patients who need the 
treatment. 
Objectives 
The following high level objectives are proposed:  
 Develop biomarkers predictive of autoimmune conditions including thyroid and ITP. This 
will include collection of samples from patients who have not yet developed any 
autoimmune conditions. These samples would be used as controls.  
 Explore efficacy and safety markers through data analysis 
 Explore genetic variation related to MS disease manifestation through data analysis 
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Rationale  
TOPAZ patients have >7 years post LEMTRADA treatment experience. The intent is to collect 
blood samples from approximately 300 consenting patients for the purpose of exploratory 
analyses of genetic variations related to MS disease and/or alemtuzumab effects.  
Investigational plan 
For research purposes only and for those patients who signed the optional pharmacogenomic 
informed consent form, a blood sample will be collected at the study visit for exploratory analysis 
of genetic variations related to MS disease and/or alemtuzumab effects as specified in the study 
flow chart, and this sample will be stored.  
Samples will be processed for DNA isolation and for genetics analysis. Genomic data generated 
from these samples (including samples collected from TOPAZ patients with no autoimmunity) 
will be used to validate a predictive marker panel from discovery cohort analysis. DNA sample 
collection, handling, storage, and analysis will conform to all applicable national guidance and 
regulations as follows.  
This blood sample will be transferred to a site that will, on behalf of Sanofi, store it until the time 
of analysis.  
The blood sample, and the DNA that is extracted from it, will be assigned a second number, 
a Genetic ID (deidentification code) that is different from the Subject ID. This “double coding” is 
performed to separate a subject’s medical information and DNA data. 
The clinical study data (coded by Subject ID) will be stored in the clinical data management 
system (CDMS), which is a distinct database in a separate environment from the database 
containing the pharmacogenetic data (coded by Genetic ID). The key linking Subject ID and 
Genetic ID will be maintained by a third party, under appropriate access control. The matching of 
clinical data and pharmacogenetic data, for the purpose of data analysis, will be possible only by 
using this key, which will be under strict access control. All data will be reported only in coded 
form in order to maintain confidentiality. 
The samples will be stored at a secure site specialized for such investigations under the 
responsibility of the Sponsor for up to 15 years after completion of the final study report of the 
LPS13649 study. All data is anonymized. If the patient withdraws consent to participate in the 
PGx substudy, the patient’s PGx sample will be destroyed. 
Patient selection criteria 
Sample size will be based on elective participation of approximately 300 patients who are enrolled 
into the TOPAZ study. 
Pharmacogenomic sampling 
PGx samples will be collected from consenting TOPAZ patients that have not previously provided 
a PGx sample in parent studies.  
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Three aliquots at 2.5 mL each of whole blood (from each patient) will be drawn. 
Detailed information about samples storage will be provided by the sponsor in the laboratory 
manual.  
PGx blood samples will be maintained until the end of this study, when the conclusion is 
finalized, or 15 years, or as approved locally 
Planned sample analysis 
These samples will be used for exploratory analysis of genetic variations predictive of 
autoimmune conditions related to MS and or the effects of alemtuzumab and or MS disease 
manifestation using genetic analysis platform technologies  
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Appendix D 
Country-specific requirements  
1. Requirements for US 
Section 10.1.1 
This visit must be conducted within 6 months after completion of the Extension 
Study CAMMS03409. When possible, Visit 1 will be performed at the same time as the last visit 
of the Extension Study CAMMS03409. 
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Appendix E 
Protocol amendment history  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
before the Clinical Trial Summary. 
1. Amended Clinical Trial Protocol 01 (US) based on Amendment 01 (US) [23-Mar-2016] 
This amendment 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 
To extend the time-window between CAMMS03409 and TOPAZ study from 3 to 6 months to 
allow as many patients as possible to enroll in the TOPAZ study for a long term follow-up. 
 
Section # and Name 
Description of Change 
Brief Rationale 
10.1.1. Visit 1: Selection (D1) 
This visit has to be conducted within 6 months 
after completion of extension study 
CAMMS03409 
See above 
2. Amended Clinical Trial Protocol 02 (US), Amended Clinical Trial Protocol 01 based on 
Amendment 02 [27-Feb-2018] 
This amendment 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 
 To add an optional pharmacogenomics substudy 
TOPAZ patients have >7 years post Lemtrada treatment experience. The intent is to collect a 
blood sample from consenting patients (who have not already provided a PGx sample in parent 
studies) for the purpose of exploratory analysis of genetic variations predictive of autoimmune 
conditions related to MS disease and/or alemtuzumab effects.  
The samples from TOPAZ patients will be used for validating preliminary findings to identify a 
biomarker for autoimmune events.  
 To harmonize the list of Adverse Events of Special Interest (AESI) within sections 
To harmonize different sections of the protocol and for consistency with other Lemtrada projects. 
 To clarify procedure for routine urinalysis and microscopy 
To be in line with urinalysis procedures in a real life setting. 
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 To clarify timing of HPV screening in women 
HPV screening was not mandatory in previous studies and it was necessary to clarify the timing of 
HPV screening in TOPAZ study. 
 To clarify interim analysis objective 
An annual partial database lock will be done instead of an Interim analysis. 
 To update information regarding risk of Listeria infection according new Lemtrada 
SmPC 
To be in line with new Lemtrada SmPC. 
 
Section # and Name 
Description of Change 
Brief Rationale 
Clinical Trial Summary; Section 
1.2.1 Study flow chart; 6.1 
Description of the protocol, 
9.7.2 Exploratory Pharmacogenomic 
assessment; 10.1 Visit schedule; 
11.4.4 Analysis of blood samples for 
exploratory pharmacogenomics 
substudy; 12.2 Informed consent; 
Appendix C Exploratory 
Pharmacogenomics Assessment 
Substudy 
Add the following text: 
A pharmacogenomics (PGx) substudy will be conducted 
for exploratory analysis of genetic variations predictive of 
autoimmune conditions, including thyroid and immune 
thrombocytopenia (ITP), related to MS disease and/or the 
effects of alemtuzumab. For research purposes only and 
on a voluntary basis, a blood sample will be proposed to 
approximately 300 ongoing patients in the TOPAZ study 
who have not provided a PGx sample in the previous 
studies (CAMMS03409, CAMMS223, CAMMS323 and 
CAMMS324). A blood sample will be collected from 
consenting patients.  
Objectives of the substudy are as follows:  
 
To develop biomarkers predictive of 
autoimmune conditions including thyroid 
disorders and immune thrombocytopenia. This 
will include collection of samples from patients 
who have not yet developed any auto immune 
conditions; these samples would be used as 
controls.  
 
To explore efficacy and safety markers through 
data analysis. 
 
To explore genetic variation related to MS 
disease manifestation through data analysis. 
Sample collection, handling, storage, and analysis will 
conform to all applicable national guidance and 
regulations. Details of the PGx sub-study are presented in 
Appendix C. 
To add an optional 
pharmacogenomics 
substudy 
 
Clinical Trial Summary; 9.1 Primary 
endpoints: Safety; 10.4.1.3 Adverse 
Events of Special Interest; 
10.4.4 Guidelines for reporting 
adverse events of special interest 
Replaced with the following text: 
Other project specific AESI(s) 
Autoimmune mediated conditions including, but not 
limited to: 
- 
Immune thrombocytopenic purpura (ITP) 
- 
Nephropathies including anti-glomerular 
basement membrane (GBM) disease 
See above 
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Section # and Name 
Description of Change 
Brief Rationale 
- 
Cytopenias  
- 
Thyroid disorders 
Serious infections, including serious opportunistic 
infections 
Malignancy 
Cervical dysplasia 
9.5.2 Laboratory safety variables; 
10.1.6 Alemtuzumab treatment; 
Appendix A Recommendations for 
using Alemtuzumab in countries 
where it is not yet available. 
Replaced with the following text: 
Urinalysis (minimally including determination of urine 
protein and red blood cells) with microscopy.1 
A footnote has been added: 
1 Note: For sites using homecare nurses service, or where 
microscopy is not routinely done if urine dipstick analysis 
is negative, the following procedure will be implemented: 
Homecare nurses/investigator site staff will perform a 
urine dipstick which will secure the detection of any 
potential haematuria and/or proteinuria. If urine dipstick is 
positive, the investigator would need to ask the patient to 
come to the site to have microscopy performed at the 
local lab. At any time, as per investigator criteria, 
according to the patient’s status, the patient can be asked 
to have a microscopy at the local lab to confirm any 
potential diagnosis. 
See above 
1.2.2 Re-treatment with 
Alemtuzumab flow chart; 
9.5.2 Laboratory Safety Variables; 
10.1.6 Alemtuzumab Treatment. 
Add the following text: 
For women, a Human Papilloma Virus (HPV) screening 
must be performed as follows: 
For women within 48 months follow-up at time of study 
transition from CAMMS03409 to TOPAZ, the date of the 
last alemtuzumab infusion administered in the study 
CAMMS03409 must be checked, and then an HPV 
screening performed approximately 1 year after the last 
infusion of alemtuzumab, and then every 12 months until 
48 months safety FU is completed. 
For women, an HPV screening must be performed as 
follows: 
For women patients re-treated with alemtuzumab during 
the TOPAZ study, an HPV screening should be 
performed prior to re-treatment (if not done in the 
previous 12 months) and then every 12 months until 48 
months safety FU is completed. 
See above 
6.3 Interim analysis; 11.5 Interim 
analysis 
An annual partial database lock will be made available 
See above 
4 Introduction and rationale 
Add the following text: 
Of note, Listeriosis/Listeria meningitis has been reported 
in LEMTRADA treated patients, generally within one 
month of LEMTRADA infusion. To reduce the risk of 
infection, patients receiving LEMTRADA should avoid 
ingestion of uncooked or undercooked meats, soft 
cheeses, and unpasteurized dairy products two weeks 
prior to, during, and for at least 1 month after LEMTRADA 
infusion. 
See above 
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3. Amended Clinical Trial Protocol 02 (24-Jul-2019) 
This amended protocol 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 
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 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 # and Name 
Description of Change 
Brief Rationale 
1.2.2 Re-treatment with 
alemtuzumab chart flow  
Add liver function test along with TSH footnote b: 
… LFT includes: ALT, AST, ALP, albumin, total 
protein and bilirubin. 
Monitoring potential autoimmune hepatitis 
4 INTRODUCTION AND 
RATIONALE 
Add the following text: 
… 
During post-marketing use, additional risks of 
alemtuzumab have been identified recently that 
include: 
 
Stroke (hemorrhagic and ischemic).  
 
Cervicocephalic (ie, vertebral, carotid) 
arterial dissection.  
 
Pulmonary alveolar hemorrhage. 
 
Acute acalculous cholecystitis. 
 
Autoimmune hepatitis. 
 
Hemophagocytic lymphohistiocytosis 
(HLH). 
Cases of serious and life‐threatening stroke 
(including hemorrhagic and ischemic), myocardial 
infarction and cervicocephalic (ie, vertebral, 
carotid) arterial dissection have been reported 
Update recent safety findings and benefit 
risk assessment 
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Section # and Name 
Description of Change 
Brief Rationale 
within three days of alemtuzumab administration, 
with most cases occurring within one day. Cases of 
pulmonary alveolar hemorrhage have been 
reported with onset within 48 hours of 
alemtuzumab infusion. Long term auto immune 
risks, such as cases of Hemophagocytic 
lymphohistiocytosis (HLH) and autoimmune 
hepatitis causing clinically significant liver injury, 
including acute liver failure requiring transplant, has 
been reported. To minimize the risk of these 
serious adverse events, recommendations are 
provided for infusion related management and long 
term safety monitoring for patients receiving 
re-treatment of alemtuzumab during the course of 
the trial  
 
Pre infusion: assess overall health status 
and risk factors; baseline BP/HR, 
bleeding risk, platelets count. Baseline 
liver function test. 
 
During infusion: continuous or hourly 
monitoring BP/HR; intermittently 
ambulation, compressive stocking. 
 
Post infusion: inform/remind patient any 
abnormal clinical sign/symptoms related 
to infusion.  
 
Periodic liver function test. 
9.5.2.2 Patients exposed to 
alemtuzumab during this 
study 
Liver function test must be performed prior 
retreatment with alemtuzumab and repeated every 
3 months for  
48 months. … LFT may be performed at any time if 
clinically indicated at Investigators’ discretion. 
Monitoring potential autoimmune hepatitis 
10.1.6 Alemtuzumab 
treatment 
Add the following text: 
The following infusion management procedures 
must be utilized for each infusion and each 
treatment course: 
 
Pre-infusion: Physicians should identify 
potential cardiovascular and 
cerebrovascular risk factors (eg, screen 
for pre-existing hemorrhagic, 
cardiovascular (including venous 
thromboembolism) and cerebrovascular 
risk factors, lung disease, concomitant 
medications (eg, antiplatelet agents, 
anticoagulants) and review of infusion-
related risks, and HCP checklist.  
 
During infusion: in addition to 
continuous/frequent monitoring of heart 
rate, blood pressure assessment (at least 
hourly) and overall clinical status of the 
 
See above 
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Section # and Name 
Description of Change 
Brief Rationale 
patients including consideration of the 
volume of fluids administered. The 
following are recommendations in case of 
clinical abnormities: 
- 
Adjust or interrupt infusion, as 
necessary; if clinically significant 
changes in vital functions are 
observed, additional monitoring, 
including ECG, should be 
considered. 
- 
When re-starting, consider a slower 
rate of infusion. 
- 
Appropriate management of blood 
pressure during infusion, including 
pharmacotherapy as necessary. 
- 
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. 
- 
Minimum until 2 hours after infusion 
has ended or longer until 
stabilization. 
- 
Patients with persistent blood 
pressure elevation should be 
referred to an appropriate medical 
facility for continued monitoring and 
treatment. 
- 
Education on delayed infusion 
associated reactions and symptoms 
and signs of cardiovascular or 
cerebrovascular events. 
- 
Instructions to patients to seek 
urgent medical care if there are 
signs and symptoms of 
cardiovascular, pulmonary or 
cerebrovascular events. 
For monitoring potential risk of autoimmune 
hepatitis, liver function test must be performed for 
patients who newly initiate retreatment of 
alemtuzumab, LFT to be performed prior infusion of 
retreatment as baseline, every 3 months for 
48 months after the last infusion of retreatment of 
alemtuzumab. In addition, LFT may be performed 
at any time if clinically indicated at Investigators’ 
discretion. 
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Section # and Name 
Description of Change 
Brief Rationale 
10.1.6.1 Prior to 
alemtuzumab treatment 
visit 
10.1.6.2 Post-
alemtuzumab treatment 
monitoring  
10.4.1.3 Adverse event of 
special interest and 
Table 2 
Add liver function test (ALT, AST, ALP, albumin, 
total protein and bilirubin) 
Add liver function test (ALT, AST, ALP, albumin, 
total protein and bilirubin) and editorial correction 
Add hemophagocytic lymphohistiocytosis (HLH) 
See above 
See above 
See above 
 
 
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According to template: QSD-002643 VERSION 7.0 (20-FEB-2019) 
Page 1
STATISTICAL ANALYSIS PLAN 
A long-term follow-up study for Multiple Sclerosis patients who have completed 
the alemtuzumab Extension Study (CAMMS03409) 
Alemtuzumab – LPS13649 
GZ402673-LPS13649 
STATISTICIAN: 
DATE OF ISSUE: 09-Mar-2020 
Total number of pages: 
42 
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Statistical Analysis Plan  
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Page 2 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN .................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................................................... 5 
1 
OVERVIEW AND INVESTIGATIONAL PLAN ................................................................................. 6 
1.1 
STUDY DESIGN AND RANDOMIZATION ...................................................................................... 6 
1.2 
OBJECTIVES ................................................................................................................................... 6 
1.2.1 
Primary objectives ............................................................................................................................ 6 
1.2.2 
Secondary objectives ....................................................................................................................... 6 
1.3 
DETERMINATION OF SAMPLE SIZE ............................................................................................. 7 
1.4 
STUDY PLAN ................................................................................................................................... 7 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL .................................. 9 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN........................ 9 
2 
STATISTICAL AND ANALYTICAL PROCEDURES ..................................................................... 10 
2.1 
ANALYSIS ENDPOINTS ................................................................................................................ 10 
2.1.1 
Demographic and baseline characteristics .................................................................................... 10 
2.1.2 
Concomitant medications ............................................................................................................... 11 
2.1.3 
Efficacy endpoints .......................................................................................................................... 11 
2.1.3.1 
Relapse Related Efficacy Endpoints .............................................................................................. 12 
2.1.3.2 
Expanded Disability Status Scale (EDSS) ..................................................................................... 12 
2.1.3.3 
Brain imaging ................................................................................................................................. 12 
2.1.4 
Safety endpoints ............................................................................................................................. 13 
2.1.4.1 
Adverse events variables ............................................................................................................... 13 
2.1.4.2 
Deaths ............................................................................................................................................ 15 
2.1.4.3 
Laboratory safety variables ............................................................................................................ 15 
2.1.4.4 
Vital signs variables ........................................................................................................................ 16 
2.1.4.5 
Electrocardiogram variables ........................................................................................................... 16 
2.1.5 
Quality-of-life endpoints .................................................................................................................. 16 
2.1.5.1 
Medical Outcomes Study Short Form-36, Version 2 ...................................................................... 16 
2.1.5.2 
Functional Assessment of Multiple Sclerosis (FAMS), Version 4 .................................................. 17 
2.1.5.3 
EuroQoL-5D (EQ-5D) ..................................................................................................................... 17 
2.1.6 
Other endpoints .............................................................................................................................. 17 
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2.1.6.1 
Modified healthcare resource utilization questionnaire (HRUQ) / Health related productivity 
questionnaire (HRPQ) .................................................................................................................... 17 
2.2 
DISPOSITION OF PATIENTS ....................................................................................................... 18 
2.2.1 
Randomization and drug dispensing irregularities ......................................................................... 19 
2.3 
ANALYSIS POPULATIONS ........................................................................................................... 19 
2.3.1 
Safety populations .......................................................................................................................... 19 
2.3.1.1 
Retreated population ...................................................................................................................... 19 
2.3.1.2 
48 months follow-up population ..................................................................................................... 19 
2.3.2 
Efficacy populations ....................................................................................................................... 19 
2.3.3 
Subgroup population ...................................................................................................................... 19 
2.4 
STATISTICAL METHODS ............................................................................................................. 20 
2.4.1 
Demographics and baseline characteristics .................................................................................. 20 
2.4.2 
Prior or concomitant medications ................................................................................................... 20 
2.4.3 
Extent of investigational medicinal product exposure .................................................................... 20 
2.4.3.1 
Extent of investigational medicinal product exposure .................................................................... 20 
2.4.4 
Analyses of efficacy endpoints ....................................................................................................... 21 
2.4.4.1 
Analysis of efficacy endpoint(s) ...................................................................................................... 21 
2.4.4.2 
Multiplicity issues ............................................................................................................................ 23 
2.4.5 
Analyses of safety data .................................................................................................................. 23 
2.4.5.1 
Analyses of adverse events ........................................................................................................... 24 
2.4.5.2 
Deaths ............................................................................................................................................ 27 
2.4.5.3 
Analyses of laboratory variables .................................................................................................... 27 
2.4.5.4 
Analyses of vital sign variables ...................................................................................................... 28 
2.4.5.5 
Analyses of electrocardiogram variables ....................................................................................... 29 
2.4.6 
Analyses of quality of life/health economics variables ................................................................... 29 
2.5 
DATA HANDLING CONVENTIONS............................................................................................... 29 
2.5.1 
General convention ........................................................................................................................ 29 
2.5.2 
Missing data ................................................................................................................................... 29 
2.5.3 
Windows for time points ................................................................................................................. 31 
2.5.3.1 
Algorithm for Determining Analysis Visit Windows for Safety Observations .................................. 31 
2.5.3.2 
Algorithm for Determining Analysis Visit Windows for Efficacy Observations ............................... 32 
2.5.4 
Unscheduled visits ......................................................................................................................... 32 
2.5.5 
Pooling of centers for statistical analyses ...................................................................................... 33 
2.5.6 
Statistical technical issues ............................................................................................................. 33 
3 
INTERIM ANALYSIS ..................................................................................................................... 34 
4 
DATABASE LOCK ........................................................................................................................ 35 
5 
SOFTWARE DOCUMENTATION .................................................................................................. 36 
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Page 4 
6 
REFERENCES ............................................................................................................................... 37 
7 
LIST OF APPENDICES ................................................................................................................. 38 
APPENDIX A 
POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES CRITERIA ....................... 39 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
AE: 
adverse events 
AESIs: 
Adverse event of special interest 
ALP: 
alkaline phosphatase 
ALT: 
alanine aminotransferase 
ANCOVA: 
ranked analysis of covariance 
ARR: 
Annualized relapse rate 
AST: 
aspartate aminotransferase 
ATC: 
anatomic category 
BPF: 
Brain parenchymal function 
CMQ: 
Custom MedDRA queries 
DAT: 
Delayed alemtuzumab treatment 
DMT: 
Disease modifying therapy 
ECG: 
Electrocardiogram 
EDSS: 
Expanded disability status scale 
EQ-5D: 
EuroQoL in 5 dimensions 
FAMS: 
Functional assessment of multiple sclerosis 
GEE: 
generalized estimating equation 
HLGT: 
High-level group term 
HLT: 
High-level term 
HRPQ: 
Health related productivity questionnaire 
HRUQ: 
Healthcare resource utilization questionnaire 
IAR: 
Indusion-associated reaction 
IAT: 
Immediate alemtuzumab treatment 
IFNB-1a: 
interferon beta-1a 
IMP: 
investigational medicinal product 
KM: 
Kaplan-Meier 
LFT: 
liver function tests 
LLT: 
Lower-level term 
MedDRA: 
Medical dictionary for regulatory activities 
MMRM: 
mixed model for repeated measures 
MRI: 
Magnetic resonance imaging 
PCSA: 
potentially clinical significant abnormality 
PH: 
proportional hazard 
PT: 
Perferred term 
QoL: 
quality of life 
SAE: 
serious adverse events 
SC: 
subcutaneous 
SF-36: 
MOS 36 item short form health survey 
SMQ: 
standard MedDRA queries 
SOC: 
System organ class 
WHO-DD: 
World Health Organization drug dictionary, WHO drug dictionary 
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1 
OVERVIEW AND INVESTIGATIONAL PLAN   
1.1 
STUDY DESIGN AND RANDOMIZATION 
This study is a Phase 3B/4, international, multicenter, open-label, noncomparative study to 
evaluate the long-term safety, efficacy and QoL of alemtuzumab in patients who have completed 
at least 48 months of the extension study CAMMS03409. In addition, impact of treatment on 
pharmacoeconomic data will also be evaluated. 
Patients treated with alemtuzumab within 48 months prior to enrollment in the LPS13649 study 
must be followed-up at monthly intervals until 48 months after the last infusion of alemtuzumab. 
If the patient is re-treated with additional courses of alemtuzumab, the patient will be followed 
using the specific recommendations indicated in the IB or in the local approved label (when 
available). Patients will be followed for 48-months after the last infusion of alemtuzumab received 
in the current trial setting. During the 48-month period, laboratory safety sampling should be 
collected every month, in a local laboratory and they must be reviewed in a timely manner by the 
Study Investigator. 
Study duration will be 5 years (plus a window of 6 months) from the day of the enrollment of the 
first patient. 
A pharmacogenomics (PGx) substudy will be conducted for exploratory analysis of genetic 
variations predictive of autoimmune conditions, including thyroid disorders and immune 
thrombocytopenia (ITP), related to MS disease and/or the effects of alemtuzumab. The data will 
be analyzed separately. 
1.2 
OBJECTIVES 
1.2.1 Primary objectives 
The primary objective is to evaluate long-term safety of alemtuzumab. 
1.2.2 Secondary objectives 
The secondary objectives are: 
 
To evaluate long term efficacy of alemtuzumab. 
 
To evaluate the safety profile of patients who received other disease modifying therapy 
(DMT) following alemtuzumab treatment. 
 
To evaluate patient-reported quality of life (QoL) outcomes and health resource utilization 
of patients who received alemtuzumab. 
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 
To evaluate as needed re-treatment with alemtuzumab and other DMTs. 
1.3 
DETERMINATION OF SAMPLE SIZE 
There are no sample size calculations for this long-term safety study. Sample size will be based on 
elective participation of patients who were enrolled (and completed at least 48 months) into the 
CAMMS03409 extension study. 
1.4 
STUDY PLAN 
The whole clinical trial of alemtuzumab consists of three study periods:  
CAMMS223/323/324 prior studies (2 years): to compare the efficacy and safety of alemtuzumab 
to subcutaneous (SC) interferon beta-1a (IFNB-1a, Rebif) in treatment-naïve patients with 
relapsing-remitting multiple sclerosis (RRMS) who had recent MS disease activity as 
demonstrated by clinical relapses. 
CAMMS03409 extension study (at least 4 years): to examine the long-term efficacy and safety of 
alemtuzumab in MS patients who received alemtuzumab during prior studies 
CAMMS223/323/324 and the efficacy and safety of 2 fixed annual alemtuzumab courses in 
patients who previously received SC IFNB-1a during prior studies. 
LPS13649 (TOPAZ) extension study (5 years): to evaluate the long-term safety, efficacy and 
Quality of life (QoL) of alemtuzumab in patients who have completed at least 48 months of the 
extension study CAMMS03409. 
 
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Scheduled visits for safety and efficacy assessments will be performed every six months. AEs and 
concomitant medications will be monitored continuously. Quality of life, pharmaco-economic data 
and brain imaging will be collected every twelve months (Table 1). 
Table 1 – Study flow chart 
 
 
Selection 
visit (D1) 
Study assessments each 
year 
Scheduled visits 
Unscheduled 
visits 
EOS 
6 M 
12 M 
Informed consent signature 
X 
 
 
 
 
Inclusion Exclusion criteria 
verification 
X 
 
 
 
 
AE reporting 
X 
X 
X 
X 
X 
Vital signs 
X a 
X 
X 
X 
X 
Physical examination including 
weight  b 
X a 
 
X 
 
X 
MS relapse verification 
X 
X 
X 
X 
X 
EDSS 
X a 
X 
X 
X 
X 
Brain Imaging 
X c 
 
X 
 
X c 
SF-36 - FAMS - EQ-5D 
X a 
 
X 
 
X 
Modified HRUQ/HRPQ 
X d 
 
X 
 
X 
Record concomitant medication 
X 
X 
X 
X 
X 
Collection of blood samples for PGx 
assessment e 
 
X f 
X f 
X f 
X f 
a If not performed in the previous 3 months. 
b Note that weight assessment is included in the vital signs assessment module in the eCRF instead of the physical examinations module. 
Nevertheless, it is to be performed at baseline and on yearly basis and not every 6 months. 
c If not performed in the previous 6 months. 
d If the HRUQ questionnaire was administered in the previous 3 months, then only questions 1 through 9 of the Modified HRUQ/HRPQ need to 
be completed at baseline. 
e For consenting patients only. 
f 
Omit if collected at a previous visit. 
For all the patient retreated with alemtuzumab and for 48 months after last infusion (Table 2).   
 
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Table 2 - Re-treatment with Alemtuzumab Flow Chart 
 
Prior to 
treatment 
During 48 months 
1 M 2 M 3 M 4 M 5 M 6 M 7 M 8 M 9 M 
10 
M 
11 
M 
12 
M 
Pregnancy test (in women of 
childbearing potential) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
HPV (only in women) 
X a 
 
 
 
 
 
 
 
 
 
 
 
X 
CBC with differential (including 
platelet count) 
X b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Creatinine and LFT (liver 
function tests) 
X b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis with microscopy 
X b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TSH 
X b 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Study Investigator review of 
labs  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Monthly safety laboratory assessment will be performed in local laboratories at the patients’ convenience. 
a If not performed in the previous 12 months. In addition, an HPV screening should be performed approximately 1 year after the last 
alemtuzumab infusion date, and then every 12 months until the 48 months safety follow-up is completed. For women patients re-treated with 
alemtuzumab during the study, an HPV screening should be performed prior to re-treatment (if not performed in the previous 12 months) and 
then every 12 months until the 48 months safety follow-up is completed. 
b If not performed in the previous 2 weeks. LFT includes: ALT, AST, ALP, albumin, total protein, total bilirubin, and direct bilirubin. 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL  
Not applicable. 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN 
Not applicable 
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2 
STATISTICAL AND ANALYTICAL PROCEDURES 
2.1 
ANALYSIS ENDPOINTS 
2.1.1 Demographic and baseline characteristics 
The TOPAZ baseline value is defined as the available value assessed on or prior to the V01 
Selection visit, unless otherwise specified. The last available value in previous studies can be 
considered as the baseline if they were evaluated within the pre-specified time window. For brain 
imaging result, if the last non-missing assessment performed within 6 months prior to the V01 
selection visit, it can be considered as baseline. For vital sign, physical examination, EDSS and 
questionnaires, the time window is 3 months.  
For efficacy endpoints (EDSS, MRI), the baseline from prior studies will be considered as long-
term baseline, which is defined as last available assessment prior to first dose of alemtuzumab or 
SC IFNB-1a administration.  
All baseline safety and efficacy parameters (apart from those listed below) are presented along 
with the on-treatment summary statistics in the safety and efficacy sections (Section 2.4.5 and 
Section 2.4.4). 
Demographic characteristics 
Demographic variables are: 
 
Age (quantitative and qualitative variable: <65, [65 – 75] and >75 years) 
 
Sex (Male, Female) 
 
Race (White, Black, Asian, American Indian or Alaska Native, Native Hawaiian or Other, 
Pacific Islander, Other) 
 
Ethnicity (Hispanic/Latino, Not Hispanic/Latino) 
 
Weight 
 
Height 
 
Body Mass Index (BMI) 
 
Geographic Region (USA/Canada/Australia, Latin America, EU, Non-EU Europe and 
Israel) 
 
Time since first dose of alemtuzumab infusion (in years) 
Baseline Physical Examination 
Baseline physical examination, i.e., number (%) of patients who are normal/abnormal at baseline 
will be summarized.      
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Disease characteristics at baseline   
Specific disease history includes  
 
Baseline EDSS (TOPAZ baseline and long-term baseline) 
 
Time (years) since initial/last clinical episode  
 
Brain imaging characteristics (e.g. Gadolinium-Enhancing lesion count, T1-Hyperintense 
Lesion Volumes and T2-Hyperintense Lesion Volumes) (TOPAZ baseline and long-term 
baseline) 
Any technical details related to computation, dates, and imputation for missing dates are described 
in Section 2.5.  
2.1.2 Concomitant medications 
A concomitant medication is any treatment received by the patient concomitantly to any 
investigational medicinal product (IMP)(s) in the current study, all medications received by the 
patient from the end of the Extension Study CAMMS03409 to Visit 1 of LPS13649 study, and 
during the TOPAZ study until the last visit will be collected. 
Any technical details related to computation, dates, imputation for missing dates are described in 
Section 2.5. 
2.1.3 Efficacy endpoints 
Efficacy endpoints are considered as secondary objective.  
The long-term effects of alemtuzumab will be examined by summarizing from baseline through 
the last study visit of our study by the following efficacy endpoints: 
 
Annualized relapse rate (ARR) 
 
Proportion of patients relapse free 
 
Change over time in Expanded Disability Status Scale (EDSS) scores 
 
Change over time in brain imaging characteristics to include: 
- 
Number of Gadolinium (Gd)-enhancing, and new Gd-enhancing lesions 
- 
Number of new/enlarging T2 lesions 
- 
Number of new T1 (and new hypointense T1) lesions 
- 
T1 and T2 lesion volume 
- 
Brain Parenchymal Fraction (BPF) 
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2.1.3.1 Relapse Related Efficacy Endpoints 
Relapse is defined as new neurological symptoms or worsening of previous neurological 
symptoms with an objective change on neurological examination. Symptoms must be attributable 
to MS, last at least 48 hours, be present at normal body temperature (i.e., no infection, excessive 
exercise, or excessively high ambient temperature), and be preceded by at least 30 days of clinical 
stability. 
MS relapse will be verified at each visit. On the other hand, patients will be informed to contact 
the Study Investigator as soon as they observe any sign/symptom compatible with a possible 
relapse, in order to schedule an extra visit. 
2.1.3.1.1 Annualized Relapse Rate 
The number of patients with a relapse event, the total number of relapses, and the annualized 
relapse rate over the years of follow-up will be produced. 
2.1.3.1.2 Proportion of Patients who are Relapse Free  
Patients will be considered relapse free at each measurement time and at the end of the study if 
they did not experience a protocol defined relapse in the relevant time period.  
2.1.3.2 Expanded Disability Status Scale (EDSS) 
Patient disability will be evaluated using the EDSS, which has long been considered the standard 
for assessing disability in patients with MS.  
EDSS will be collected at D1 (if not collected in the previous 3 months) and then at each 
scheduled visit (every 6 months) and unscheduled visits for MS relapse. For the change from 
baseline in EDSS analysis, unscheduled EDSS assessments will not be used (except for early 
study discontinuation assessments). 
2.1.3.3  Brain imaging 
Brain imaging will be performed at D1 (if not performed in the previous 6 months) and then every 
12 months. It will be also performed at the end of study visit, if not performed in the previous 6 
months. MRIs will be read and interpreted locally by qualified site personnel and/or designee (e.g., 
neuroradiologist). MRIs should be reviewed locally by qualified site personnel for signs of Non-
MS pathology. For study purposes, per-protocol scans will be also submitted to a central imaging 
vendor for scan quality control and analysis. 
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2.1.3.3.1 Number of lesions 
The cumulative count is the primary interest, which is defined as the sum of the lesion counts at 
each successive year from the D1 screening to the end of study. The lesion counts will also be 
analyzed yearly.   
2.1.3.3.2 Volume of lesions and BPF 
Percentage change of T1 and T2 volume as well as brain parenchymal function (BPF) are the 
primary interest, which is defined as absolute difference between post-baseline result and baseline 
result divided by the baseline times 100%.  
2.1.4 Safety endpoints 
The safety endpoints are the primary endpoint for this study.  
The safety analysis will be based on the reported adverse events and other safety information, such 
as clinical laboratory data and vital signs. 
Observation period  
The on-study observation period is defined as the time from start of screening visit until the end of 
the study (defined as last protocol planned visit or the resolution/stabilization of all serious 
adverse events and adverse events with prespecified monitoring).   
2.1.4.1 Adverse events variables 
All adverse events will be coded to a lower-level term (LLT), preferred term (PT), high-level term 
(HLT), high-level group term (HLGT), and associated primary system organ class (SOC) using the 
version of Medical Dictionary for Regulatory Activities (MedDRA) currently in effect at Sanofi at 
the time of database lock OR specify version if already known from project specifics. 
Incidence, duration, grade/intensity, relationship to study drug, and outcome of the AE will be 
analyzed for serious adverse events (SAEs), adverse events (AEs), infusion-associated reactions 
(IAR).  
Incidence, nature, seriousness, grade/intensity, relationship to study drug, and outcome will be 
summarized for the project-specific adverse events of special interest (AESIs). 
Record the occurrence of adverse events (including serious adverse events and adverse events of 
special interest) from the time of signed informed consent until the end of the study. 
Adverse events of special interest include the following terms: 
 Hypersensitivity or anaphylaxis 
 Pregnancy of a woman entered in the study; 
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- 
Pregnancy occurring in a woman patient entered in the clinical trial. It will be qualified 
as an SAE only if it fulfills one of the seriousness criteria. 
- 
Follow-up of the pregnancy in a woman participant is mandatory until the outcome has 
been determined. 
 Symptomatic overdose (serious or non-serious) with IMP. 
- 
An overdose (accidental or intentional) with the IMP is an event suspected by the 
Study Investigator or spontaneously notified by the patient and defined as 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. 
Of note, asymptomatic overdose must be reported as a standard AE. 
 Increase in alanine transaminase (ALT). 
 Other product specific AESIs: 
- 
Autoimmune mediated conditions including, but not limited to: 
- 
Immune thrombocytopenic purpura (ITP). 
- 
Nephropathies including anti-glomerular basement membrane (GBM) disease. 
- 
Cytopenias.  
- 
Thyroid disorders. 
- 
Acquired hemophilia A 
- 
Autoimmune hepatitis. 
- 
Hemophagocytic lymphohistiocytosis (HLH). 
- 
Progressive multifocal leukoencephalopathy (PML) 
- 
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) 
- 
Serious infections including serious opportunistic infections (eg, Listeria infections, 
CMV, EBV), HPV associated with cervical dysplasia 
- 
Malignancy. 
- 
Pneumonitis 
The standardized MedDRA queries (SMQ) or Custom MedDRA queries (CMQ) will be applied 
as appropriate to select AESIs.  
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Infusion-associated reactions (IAR) is defined as any adverse event occurring during and within 
24 hours of alemtuzumab infusion. It will be analyzed separately for retreated patients.  
2.1.4.2 Deaths 
The deaths observation period are per the observation periods defined above.  
 
Death on-study:  deaths occurring during the on-study observation period 
 
Death poststudy:  deaths occurring after the end of the study  
2.1.4.3 Laboratory safety variables 
Clinical laboratory data consists of blood analysis, including hematology, clinical chemistry, and 
urinalysis.  Clinical laboratory values after conversion will be analyzed into standard international 
units and international units will be used in all listings and tables. 
For patients exposed to alemtuzumab within 48 months prior to inclusion in this study, samples 
for clinical laboratories will be taken at monthly for CBC with differential (including platelet 
count), serum creatinine, liver function and urinalysis. TSH must be obtained every 3 months and 
HPV test should be performed yearly until 48 months after the last infusion of alemtuzumab 
administered in the study CAMMS03409. 
For patients exposed to alemtuzumab during this study, pregnancy test, HPV test must be obtained 
before the infusion in TOPAZ study if they were not done within 12 months prior to the treatment. 
CBC with differential (including platelet count), serum creatinine, TSH, liver function test (ALT, 
AST, ALP, albumin, total protein, direct bilirubin and total bilirubin) and urinalysis (minimally 
including determination of urine protein and red blood cells) with microscopy are also required to 
be assessed before alemtuzumab infusion if they were not assessed within 2 weeks prior to 
treatment. Samples for CBC with differential (including platelet count), serum creatinine, liver 
function and urinalysis will be analyzed monthly. The TSH will be performed quarterly. The HPV 
test will be performed yearly. In addition, unscheduled liver function tests may be performed at 
any time if clinically indicated at Investigators’ discretion. 
 The laboratory parameters will be classified as follows:   
 
Hematology  
- 
Red blood cells and platelets and coagulation:  hemoglobin, hematocrit, red blood 
cell count, platelet count 
- 
White blood cells:  white blood cell count, neutrophils, lymphocytes, monocytes, 
basophils, eosinophils 
 
Clinical chemistry  
- 
Renal function:  creatinine, creatinine clearance 
- 
Liver function:  alanine aminotransferase, aspartate aminotransferase, alkaline 
phosphatase, total protein, albumin, direct bilirubin and total bilirubin 
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 
TSH 
Urine samples will be collected minimally including determination of urine protein and red blood 
cells with microscopy. 
2.1.4.4 Vital signs variables 
Vital signs include systolic and diastolic blood pressure (millimeters of mercury [mmHg]), heart 
rate (beats/minute [bpm]), respiratory rate (breaths/minute), body temperature (degrees Celsius 
[°C]) and weight (kg). 
 
For all the patients: vital signs will be recorded at selection visit (D1) (if not recorded in 
the previous 3 months) and then every 6 months.  
 
For patients treated with alemtuzumab: on days when alemtuzumab is infused, vital signs 
will be recorded before steroid administration, at a time after steroid administration (prior 
to alemtuzumab infusion), and 1 hour after the start of alemtuzumab infusion and hourly 
during and after infusion until observation post-infusion has ended (two hours after the end 
of the infusion). 
2.1.4.5 Electrocardiogram variables 
ECG is required within 2 weeks prior to alemtuzumab infusion including heart rate, PR, QRS, QT, 
and corrected QTc (according to Bazett/Fridericia). 
2.1.5 Quality-of-life endpoints 
Questionnaires including MOS 36-item short-form health survey (SF-36) Version, Functional 
Assessment of Multiple Sclerosis (FAMS), EuroQoL in 5 dimensions (EQ-5D) will be assessed 
on selection visit (D1) and every 12 months.  
 
Change over time in self-reported quality of life (QoL) as assessed by the Medical 
Outcome Study (MOS) 36-Item Short-Form Health Survey (SF-36) Version 2. 
 
Change over time in the Functional Assessment of Multiple Sclerosis (FAMS), and 
 
Change over time in the EuroQoL in 5 Dimensions (EQ-5D). 
2.1.5.1 Medical Outcomes Study Short Form-36, Version 2 
The SF-36 is an extensively validated and widely used measure of quality of life (QoL) that 
assesses patients’ perceptions of health status and its impact on their lives (1).  It consists of 36 
items organized into 8 scales (physical functioning, social functioning, role limitations physical, 
bodily pain, general medical health, mental health, role limitations emotional, and vitality).  Two 
summary measures of physical and mental health, the Physical Component Summary (PCS) and 
Mental Component Summary (MCS), respectively, are derived from scale aggregates.  Higher 
scores are associated with better QoL.  
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SF-36 scores will be transformed using general US population norms so that all scales have a 
mean of 50 and a standard deviation of 10 as described in the SF-36 Users Manual (2).  Therefore, 
scores can be directly compared across scales, as well as to the general population norm of 50. 
2.1.5.2 Functional Assessment of Multiple Sclerosis (FAMS), Version 4 
The FAMS is a widely accepted, MS-specific, quality of life questionnaire (3)(4).  The FAMS is a 
self-report multidimensional index comprising a total of 58 items on 7 subscales:  mobility  
(7 items); symptoms (7 items); emotional well-being (7 items); general contentment (7 items); 
thinking and fatigue (9 items); family/social well-being (7 items); and additional concerns (14 
items, these are not scored).  Each item (except those for “additional concerns”) is rated on a  
5-point scale of 0 to 4.  The sum of the 44 scored items is the total score, which ranges from 0 to 
176.  A higher FAMS score reflects a higher quality of life.  The total score is the primary 
criterion by which the effect of treatment on quality of life will be assessed; however, subscale 
totals will also be evaluated. 
2.1.5.3 EuroQoL-5D (EQ-5D) 
The EQ-5D is a generic, standardized instrument that provides a simple, descriptive profile and a 
single index value for health status (4)(5).  The EQ-5D comprises 5 dimensions of health: 
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.  Each dimension 
consists of 3 levels (some, moderate, extreme problems), generating a total of 243 theoretically 
possible health states.  Country-specific value sets convert these health states into utility scores 
describing the preference of the population for one health state over another. 
Assessments will also be made using the EQ Visual Analogue Scale (EQ-VAS), which captures 
the self-rating of current health status using a visual "thermometer" with the end points of 100 
(best imaginable health state) at the top and zero (worst imaginable health state) at the bottom. 
2.1.6 Other endpoints 
2.1.6.1 Modified healthcare resource utilization questionnaire (HRUQ) / Health related 
productivity questionnaire (HRPQ) 
Patients’ use of healthcare resources, non-medical resources, and informal care as well as their 
work capacity will be assessed at scheduled study visits using modified healthcare resource 
utilization questionnaire (HRUQ) and health related productivity questionnaire (HRPQ) designed 
to evaluate the economic impact of MS. 
 
The questionnaire addresses the following content areas: 
 
Employment situation and changes in employment situation due to MS 
 
Admissions and stays in hospital, rehabilitation centers, or nursing homes 
 
Typical MS-related investments (eg, stair and bed lift, ramps, rails) and devices (eg, 
walking aids, wheelchairs) 
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 
Assistance by community or social services (eg, home nurse, transportation), or help from 
family or friends. 
 
Patient reported data regarding employment status. 
Information on resource use is obtained retrospectively, and each type of resource is collected for 
a time period that would minimize recall bias. 
Each question requires a binary answer (yes/no) followed by details on the type and quantity of the 
resource. All resources that are expected to be used are prespecified in order to minimize errors 
due to spelling, and hence no open fields or free text (eg, “other”) are permitted. 
Modified HRUQ / HRPQ will be collected at D1 (if the HRUQ questionnaire was administered in 
the previous 3 months, then only questions 1 through 10 of the Modified HRUQ/HRPQ need to be 
completed at baseline, D1). The modified HRUQ / HRPQ will continue to be collected every 12 
months and at the end of study visit. 
2.2 
DISPOSITION OF PATIENTS 
This section describes patient disposition for both patient study status and the patient analysis 
populations. 
Screened patients are defined as any patients who signed the informed consent.  
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: 
 
Enrolled patients 
 
Screen failure patients and reasons for screen failure 
 
Retreated patients 
 
Patients who did not complete the study period as per protocol 
 
Patients who discontinued study period by main reason for permanent treatment 
discontinuation 
For all categories of patients, percentages will be calculated using the number of all enrolled 
patients as the denominator.  Reasons for treatment discontinuation will be supplied in tables 
giving numbers and percentages in overall group, retreated group and by subgroups (IAT vs 
DAT).   
All critical or major deviations will be summarized in tables giving numbers and percentages of 
deviations in overall group and by subgroups (IAT vs DAT). 
Additionally, the analysis populations for safety, efficacy, and subgroup population (see  
Section 2.3) will be summarized in a table by number of patients on the enrolled population. 
 
Safety population 
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- 
Retreated population 
- 
48 months follow-up population 
 
Efficacy population 
 
Subgroup population 
- 
IAT population 
- 
DAT population 
2.2.1 Randomization and drug dispensing irregularities 
Not applicable. 
2.3 
ANALYSIS POPULATIONS 
2.3.1 Safety populations 
All patients who have signed the ICF will be included in the safety population. 
2.3.1.1 Retreated population 
The population is defined as safety patients who have received study drug in TOPAZ study. 
2.3.1.2 48 months follow-up population 
The population is defined as all safety patients who have received study drug in CAMMS223, 
CAMMS323, CAMMS324 or CAMMS03409, that didn’t complete 48 months of follow-up at the 
screening visit in TOPAZ study. 
2.3.2 Efficacy populations 
The population on which efficacy analyses will be performed consists of all enrolled patients who 
have received study drug in CAMMS223, CAMMS323, CAMMS324 or CAMMS03409. 
2.3.3 Subgroup population 
All subgroup populations are subgroup of enrolled patients. 
Immediate alemtuzumab treatment (IAT) subgroup: Patients who received alemtuzumab 12 
mg/day from CAMMS323 or CAMMS324 study. 
Delayed alemtuzumab treatment (DAT) subgroup: Patients who received SC IFNB-1a from 
CAMMS323 or CAMMS324 and then received alemtuzumab 12 mg/day in CAMMS03409 study. 
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2.4 
STATISTICAL METHODS 
2.4.1 Demographics and baseline characteristics 
Continuous data will be summarized using the number of available data, mean, standard 
deviation (SD), median, minimum and maximum. Categorical and ordinal data will be 
summarized using the number and percentage of patients.  
Parameters will be summarized on the enrolled population analyzed in overall group and by 
subgroups (IAT vs DAT).   
Parameters described in Section 2.1.1 will be summarized b in overall group and by subgroups 
(IAT vs DAT) using descriptive statistics.  
2.4.2 Prior or concomitant medications 
The concomitant medications will be presented for the enrolled population. All the medication 
that taken in TOPAZ study will be considered as concomitant medications.  
Medications will be summarized in overall group and by subgroups (IAT vs DAT) according to 
the WHO-DD dictionary, considering the first digit of the anatomic category (ATC) class 
(anatomic category) and the first 3 digits of the ATC class (therapeutic category).  All ATC codes 
corresponding to a medication will be summarized, and patients will be counted once in each ATC 
category (anatomic or therapeutic) linked to the medication. Therefore patients may be counted 
several time for the same medication.  
The tables for concomitant medications will be sorted by decreasing frequency of ATC followed 
by all other therapeutic classes based on the incidence in the overall group. In case of equal 
frequency regarding ATCs (anatomic or therapeutic categories and/or generic names), alphabetical 
order will be used.  
In addition, the alternative MS therapies will be summarized separately. Alternative MS 
medication will be determined based on the anatomic or therapeutic categories and generic name. 
2.4.3 Extent of investigational medicinal product exposure  
The extent of IMP exposure will be assessed and summarized within safety population  
(Section 2.3.1.1). 
2.4.3.1 Extent of investigational medicinal product exposure 
The extent of IMP exposure will be assessed by the duration of IMP exposure in TOPAZ study for 
retreated patients. 
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Duration of IMP exposure is defined as last dose date – first dose date + 1 day, regardless of 
unplanned intermittent discontinuations (see Section 2.5.1 for calculation in case of missing or 
incomplete data).   
Alemtuzumab exposed duration will also be summarized in exposed person-years and total 
number of courses in overall group and by subgroups (IAT vs DAT) for all safety population. 
Person-years are estimated as the date of first study treatment in prior studies minus the date when 
the patient is determined to have ended the TOPAZ study.  
 
2.4.4 Analyses of efficacy endpoints 
The efficacy population will be used for all efficacy analyses.  
For MRI endpoints, EDSS, questionnaires endpoints, only data collected in TOPAZ study will be 
used for analysis in addition of baseline information from previous studies. The long-term 
baseline is defined as the last available assessment prior to first dose of alemtuzumab or SC IFNB-
1a administration in prior studies. It will be applied to long-term efficacy analysis. 
For relapse endpoints, data from prior studies (CAMMS323, CAMMS324 and CAMMS03409) 
should be obtained. 
The main long-term analysis for efficacy endpoints is IAT versus DAT comparison. The efficacy 
of immediate alemtuzumab treatment (Subgroup IAT defined in Section 2.3.3) and delayed 
alemtuzumab treatment (Subgroup DAT defined in Section 2.3.3) groups will be compared for 
relapse related endpoints, EDSS assessment as well as MRI endpoints.  
The analysis in reference of long-term baseline in prior studies by total number of alemtuzumab 
courses (i.e. <=3 vs >3) will be summarized as well.   
 
2.4.4.1 Analysis of efficacy endpoint(s) 
2.4.4.1.1 Annualized relapse rate (ARR) 
The estimated annualized relapse rate using negative binomial model with robust variance 
estimation will be presented by year and in overall. The observed total number of relapses is the 
dependent variable, the log total amount of follow-up time in years for each patient will be the 
offset variable and analysis group indicator (IAT vs DAT) and geographic region will be the 
covariates in the model. Both IAT vs DAT comparison and ARR by alemtuzumab courses will be 
analyzed. The analysis period starts from prior studies (CAMMS323/324) until the end of TOPAZ 
study. The model will also be stratified by previous clinical study. 
The observed annualized relapse rate will be reported as well, which is defined as the total number 
of relapses divided by the total years of follow-up for each patient.  
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The ARR will be presented separately for retreated population in overall group.  
2.4.4.1.2  Proportion of Relapse free patients 
The proportion of patients with relapse-free each year from prior studies (CAMMS323/324) until 
the end of TOPAZ study will be estimated based on Kaplan-Meier methods. The complementary 
log-log transformation will be used to construct 95% confidence intervals. A Kaplan-Meier graph 
summarizing the event probability over time will be presented by subgroups (IAT vs DAT) and by 
alemtuzumab courses. Hazard ratio and corresponding 95% confidence interval will be calculated 
using Cox proportional hazards (PH) regression with robust variance estimation (6).  Covariates 
for the Cox PH model will include analysis groups and geographic region and prior clinical 
studies.  Inference will be based on the Wald test of the log hazard ratio (estimated regression 
coefficient from the model).  The analysis period starts from prior studies (CAMMS323/324) until 
the end of TOPAZ study. 
The Kaplan-Meier (KM) estimates will be summarized for retreated population separately. 
2.4.4.1.3 EDSS 
The observed value, change from baseline as well as percentage change from baseline will be 
presented descriptively. The change from baseline in EDSS  will be analyzed using a mixed model 
for repeated measures (MMRM) (7)(8)(9) with baseline EDSS score, analysis group indicator 
(IAT and DAT), geographic region, study visit and study visit by analysis group interaction as 
covariates. The TOPAZ study baseline at study entry is considered as post-baseline for efficacy 
analysis. The comparison of the change from baseline in EDSS with the MMRM will include the 
change from baseline to each consecutive year which can be constructed using the linear contrasts 
of the estimated regression parameters.  All post-baseline EDSS scores will be included in the 
MMRM; patients without any post-baseline scores will not be included.  For this model, 
imputation will not be used.  
Similar analysis for change of EDSS by alemtuzumab courses and for retreated population will be 
analyzed as well. 
2.4.4.1.4 MRI lesion count 
The observed lesion count and change from baseline will be presented descriptively by analysis 
groups.  
The cumulative count of lesions will be compared between IAT and DAT groups through a 
repeated negative binomial regression adjusted for the long-term baseline count, analysis groups 
and geographic region. The comparison of proportion of patients with lesion at any time post-
baseline between IAT and DAT group will be analyzed using repeated measure generalized 
estimating equation (GEE) with logistic link. Covariates will include long-term baseline lesion 
count, geographic region, and analysis groups. 
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Similar analysis for MRI lesion count by alemtuzumab courses and for retreated population will 
be analyzed as well. 
2.4.4.1.5 MRI volume and BPF 
The observed value, change from baseline as well as percentage change from baseline will be 
presented descriptively. 
The percent change in lesion volume / BPF from year to year and the percent change from long-
term baseline will be calculated by analysis groups. To compare between IAT and DAT patients, 
the percent change from baseline in MRI lesion volume will be analyzed yearly using the ranked 
analysis of covariance (ANCOVA) model with adjustment for baseline lesion volume, analysis 
groups (IAT and DAT) and geographic region. 
Similar analysis for MRI volume by alemtuzumab courses and for retreated population will be 
analyzed as well. 
2.4.4.2 Multiplicity issues 
Not applicable. 
2.4.5 Analyses of safety data 
The summary of safety results will be presented in overall group and by subgroups (IAT vs DAT). 
Only data collected in TOPAZ study will be used for analysis in additional of baseline information 
from previous studies. 
General common rules 
All safety analyses will be performed on the safety population as defined in Section 2.3.1.1, unless 
otherwise specified, using the following common rules: 
 
The baseline value is defined as the available value assessed on or prior to the V01 
Selection visit, unless otherwise specified. If laboratory, vital sign and physical 
examinations were performed in CAMMS03409 study within the pre-specified time-
windows, then the last assessment within the time-window can be considered as baseline 
when the corresponding V01 assessments are missing.  
 
The potentially clinically significant abnormality (PCSA) values are defined as abnormal 
values considered medically important by the Sponsor according to predefined 
criteria/thresholds based on literature review and defined by the Sponsor for clinical 
laboratory tests and vital signs (PCSA version dated May 2014 [Appendix A]) 
 
PCSA criteria will determine which patients had at least 1 PCSA during the treatment-
emergent adverse event period, taking into account all evaluations performed during the 
treatment-emergent adverse event period, including nonscheduled or repeated evaluations.  
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The number of all such patients will be the numerator for the on-treatment PCSA 
percentage 
 
The treatment-emergent PCSA denominator by group for a given parameter will be based 
on the number of patients assessed for that given parameter in the treatment-emergent 
adverse event period in overall group and by subgroups (IAT vs DAT) on the safety 
population. 
 
For quantitative safety parameters based on central laboratory/reading measurements, 
descriptive statistics will be used to summarize results and change from baseline values by 
visit and analysis group.   
 
The analysis of the safety variables will be essentially descriptive and no systematic testing 
is planned.   
2.4.5.1 Analyses of adverse events 
Generalities 
All the reported AE will be considered as treatment emergent adverse event (TEAE).  
Adverse event incidence tables will present by SOC, HLGT, HLT, and PT, sorted in alphabetical 
order in overall group and by subgroups (IAT vs DAT), the number (n) and percentage (%) of 
patients experiencing an adverse event.  Multiple occurrences of the same event in the same 
patient will be counted only once in the tables.  The denominator for computation of percentages 
is the safety population in overall group and by subgroups (IAT vs DAT). 
Sorting within tables ensures the same presentation for the set of all adverse events within the 
observation period.  For that purpose, the table of all treatment-emergent adverse events presented 
by SOC and PT sorted by the internationally agreed SOC order and decreasing frequency of PTs in 
overall group within SOCs will define the presentation order for all other tables unless otherwise 
specified.   
Analysis of all treatment-emergent adverse events 
The following treatment-emergent adverse event summaries will be generated for the safety 
population. 
 
Overview of treatment-emergent adverse events, summarizing number (%) of patients with 
any 
- 
Treatment-emergent adverse event 
- 
Serious treatment-emergent adverse event 
- 
Treatment-emergent adverse event leading to death 
- 
Treatment-emergent adverse event leading to permanent treatment discontinuation 
 
All treatment-emergent adverse event by primary SOC, HLGT, HLT, and PT, showing 
number (%) of patients with at least 1 treatment-emergent adverse event sorted by the SOC 
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internationally agreed order.  The other levels (HLGT, HLT, PT) will be presented in 
alphabetical order 
 
All treatment-emergent adverse events by primary SOC and PT, showing the number (%) 
of patients with at least 1 treatment-emergent adverse event, sorted by the internationally 
agreed SOC order and by decreasing incidence of PTs within each SOC.  This sorting 
order will be applied to all other tables, unless otherwise specified 
 
All treatment-emergent adverse events regardless of relationship and related by primary 
SOC, HLGT, HLT and PT, showing the number (%) of patients with at least 1 treatment-
emergent adverse event, sorted by the internationally agreed SOC order.  The other levels 
(HLGT, HLT, PT) will be presented in alphabetical order 
All treatment-emergent adverse events by maximal severity, presented by primary SOC 
and PT, showing the number (%) of patients with at least 1 treatment-emergent adverse 
event by severity (ie, mild, moderate, or severe), sorted by the sorting order defined above 
Analysis of all treatment emergent serious adverse event(s) 
 
All treatment-emergent serious adverse events by primary SOC, HLGT, HLT, and PT, 
showing the number (%) of patients with at least 1 serious treatment-emergent adverse 
event, sorted by the internationally agreed SOC order.  The other levels (HLGT, HLT, PT) 
will be presented in alphabetical order 
 
All treatment-emergent serious adverse events by primary SOC and PT, showing the 
number (%) of patients with at least 1 treatment-emergent adverse event, sorted by the 
internationally agreed SOC order and by decreasing incidence of PTs within each SOC.  
This sorting order will be applied to all other tables, unless otherwise specified 
 
All treatment-emergent serious adverse events regardless of relationship and related to 
IMP, by primary SOC, HLGT, HLT, and PT, showing the number (%) of patients with at 
least 1 treatment-emergent serious adverse event, sorted by the internationally agreed SOC 
order.  The other levels (HLGT, HLT, PT) will be presented in alphabetical order 
 
The event rate per patient-year (the number of events in question divided by total treatment 
exposure in patient years) will be provided for SAEs by SOC and PT 
 
By-patient listing of treatment-emergent SAEs showing analysis group (IAT vs DAT), 
patient ID, time since first dose of Alemtuzumab infusion in years, age, gender, race, 
primary SOC decode, PT decode, verbatim (diagnosis), onset date and study day, date of 
death (if relevant), recovery date/time, event duration, outcome, intensity/grade, 
relationship to study treatment, action taken with study treatment AE serious criteria. 
Analysis of all treatment-emergent adverse event(s) leading to treatment discontinuation 
 
All treatment-emergent adverse events leading to treatment discontinuation by primary 
SOC, HLGT, HLT, and PT, showing the number (%) of patients sorted by the 
internationally agreed SOC order.  The other levels (HLGT, HLT, PT) will be presented in 
alphabetical order 
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 
All treatment-emergent adverse events leading to treatment discontinuation by primary 
SOC and PT, showing the number (%) of patients with at least 1 treatment-emergent 
adverse event, sorted by the internationally agreed SOC order and by decreasing incidence 
of PTs within each SOC.  This sorting order will be applied to all other tables, unless 
otherwise specified 
 
By-patient listing of treatment-emergent adverse events leading to treatment 
discontinuation showing analysis group (IAT vs DAT), patient ID, time since first dose of 
Alemtuzumab infusion in years, age, gender, race, primary SOC decode, PT decode, 
verbatim (diagnosis), onset date and study day, date of death (if relevant), recovery 
date/time, event duration, outcome, intensity/grade, relationship to study treatment, action 
taken with study treatment AE serious criteria. 
Analysis of adverse events of special interest (AESI) 
 
All treatment-emergent adverse events of special interest by primary SOC, HLGT, HLT, 
and PT, showing the number (%) of patients sorted by the internationally agreed SOC 
order.  The other levels (HLGT, HLT, PT) will be presented in alphabetical order 
 
All treatment-emergent adverse events of special interest by primary SOC and PT, 
showing the number (%) of patients with at least 1 treatment-emergent adverse event, 
sorted by the internationally agreed SOC order and by decreasing incidence of PTs within 
each SOC.  This sorting order will be applied to all other tables, unless otherwise specified 
 
All treatment emergent adverse events of special interest by PT, showing the number (%) 
of patients, sorted by decreasing incidence of PT 
 
The event rate per patient-year (the number of events in question divided by total treatment 
exposure in patient years) for non-temporary AESI(s) will be provided by SOC and PT 
 
The frequency of treatment-emergent adverse events over time will be provided for the 
non-temporary treatment-emergent AESIs, where the time intervals will be defined as: <2 
courses, 2 – 4 courses, 4 – 6 courses, 6 – 8 courses, etc.  In each time interval, the 
denominator for calculation of percentage will be the number of patients who entered the 
time interval and the numerator will be the number of patients with at least 1 treatment 
emergent AESI occurring in this time interval.  Note that only the first event will be 
counted and all recurrent events will not be included 
 
For retreated population, the frequency of treatment-emergent temporary adverse events 
over time will be provided for the temporally associated AESIs (pulmonary alveolar 
hemorrhage, myocardial ischemia, myocardial infarction, stroke, cervicocephalic arterial 
dissection), where the time intervals will be defined as: during alemtuzumab infusion day 
1, during alemtuzumab infusion day 2, during alemtuzumab infusion day 3, 1 day after 
alemtuzumab infusion, 2 days after alemtuzumab infusion and 3 days after alemtuzumab 
infusion.  In each time interval, the denominator for calculation of percentage will be the 
number of patients who entered the time interval and the numerator will be the number of 
patients with at least 1 treatment emergent AESI occurring in this time interval.  Note that 
only the first event will be counted and all recurrent events will not be included 
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 
By-patient listing of treatment-emergent adverse events of special interest showing 
analysis group (IAT vs DAT), patient ID, number of alemtuzumab courses age, gender, 
race, AESI group, primary SOC decode, PT decode, verbatim (diagnosis), onset date and 
study day, date of death (if relevant), recovery date/time, event duration, outcome, 
intensity/grade, relationship to study treatment, action taken with study treatment AE 
serious criteria. 
Analysis of infusion associated reaction (IAR) 
 
All infusion associated reaction by primary SOC, HLGT, HLT, and PT, showing the 
number (%) of patients sorted by the internationally agreed SOC order.  The other levels 
(HLGT, HLT, PT) will be presented in alphabetical order 
 
All infusion associated reaction by primary SOC and PT, showing the number (%) of 
patients with at least 1 treatment-emergent adverse event, sorted by the internationally 
agreed SOC order and by decreasing incidence of PTs within each SOC.  This sorting 
order will be applied to all other tables, unless otherwise specified 
 
By-patient listing of treatment-emergent adverse events of special interest showing 
analysis group (IAT vs DAT), patient ID, age, gender, race, primary SOC decode, PT 
decode, verbatim (diagnosis), onset date and study day, date of death (if relevant), recovery 
date/time, event duration, outcome, intensity/grade, relationship to study treatment, action 
taken with study treatment AE serious criteria. 
2.4.5.2 Deaths 
The following summaries of deaths will be generated for the safety population. 
 
Number (%) of patients who died by study period (on-study, poststudy)  
 
Deaths in nonrandomized patients or randomized but not treated patients 
 
Treatment-emergent adverse events leading to death (death as an outcome on the adverse 
event case report form page as reported by the Investigator) by primary SOC , HLGT, 
HLT, and PT showing number (%) of patients sorted by internationally agreed SOC order, 
with HLGT, HLT, and PT presented in alphabetical order within each SOC .  
2.4.5.3 Analyses of laboratory variables  
Laboratory analysis will be conducted for retreated population and 48 months follow-up 
population. The baselines for each population are defined as below.  
 
Retreated population baseline:  The last non-missing assessment prior to first dose of 
alemtuzumab in TOPAZ study. The baseline should be taken within 2 weeks prior to the 
treatment for laboratory assessment except for HPV and pregnancy test. For HPV and 
pregnancy test, it can be taken in 12 months before the treatment. 
 
48 months follow-up population baseline: The last non-missing assessment prior to the last 
dose of alemtuzumab in previous studies. The baseline should be taken within 2 weeks 
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prior to the treatment for laboratory assessment except for HPV and pregnancy test. For 
HPV and pregnancy test, it can be taken in 12 months before the treatment. 
The summary statistics (including number, mean, median, Q1, Q3, standard deviation, minimum 
and maximum) of all laboratory variables (central laboratory values and changes from baseline) 
will be calculated for each visit or study assessment (baseline, each postbaseline time point, last 
on-treatment and/or worst on-treatment value and/or other specific assessment) in overall group 
and by subgroups (IAT vs DAT).  This section will be organized by biological function  
Section 2.1.4.3. 
The incidence of PCSAs (list provided in Appendix A) at any time during the treatment-emergent 
adverse event period will be summarized by biological function and in overall group and by 
subgroups (IAT vs DAT) whatever the baseline level and/or according to the following baseline 
status categories:  
 
Normal/missing 
 
Abnormal according to PCSA criterion or criteria 
For parameters for which no PCSA criteria are defined, similar table(s) using the normal range 
will be provided. 
Drug-induced liver injury 
The liver function tests, namely AST, ALT, alkaline phosphatase, direct bilirubin and total 
bilirubin, are used to assess possible drug-induced liver toxicity.  The proportion of patients with 
PCSA values at any postbaseline visit by baseline status will be displayed in overall group and by 
subgroups (IAT vs DAT) for each parameter.   
Time to onset of the initial ALT and AST elevation (>3 x ULN) and total bilirubin elevation 
(>2 x ULN) (time to first observation of ALT > 3 x ULN or total bilirubin > 2 x ULN, whichever 
comes first) will be analyzed using Kaplan-Meier estimates, using the midpoint of the time 
interval between the first assessment showing the elevation and the previous assessment, 
presented in overall group and by subgroups (IAT vs DAT).   
Listing of possible Hy’s law cases identified (eg, patients with any elevated ALT>3 x ULN, and 
associated with an increase in bilirubin ≥2 x ULN) with ALT, AST, alkaline phosphatase and total 
bilirubin. 
Summarize the incidence of liver-related adverse events in overall group and by subgroups (IAT 
vs DAT).  The selection of preferred terms will be based on the hepatic disorder SMQ.  
2.4.5.4 Analyses of vital sign variables 
Vital sign analysis will be done for all safety population and for retreated population.  
The infusion related vital sign analysis will be done separately for retreated population. The 
baseline for infusion related analysis is the assessment taken before steroid administration. 
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The summary statistics (including number, mean, median, Q1, Q3, standard deviation, minimum 
and maximum) of all vital signs variables (central laboratory values and changes from baseline) 
will be calculated for each visit or study assessment (baseline, each postbaseline time point, last 
on-treatment and/or worst on-treatment value and/or other specific assessment) in overall group 
and by subgroups (IAT vs DAT).  For parameters provide a list of parameters for which plots will 
be displayed; mean changes from baseline with the corresponding standard error will be plotted 
over time (at same time points) in overall group and by subgroups (IAT vs DAT).  
The incidence of PCSAs at any time during the treatment-emergent adverse event period will be 
summarized in overall group and by subgroups (IAT vs DAT) irrespective of the baseline level 
and/or according to the following baseline status categories:  
 
Normal/missing 
 
Abnormal according to PCSA criterion or criteria 
2.4.5.5 Analyses of electrocardiogram variables 
By-patient listing will be provided for retreated patients as needed. 
2.4.6 Analyses of quality of life/health economics variables 
Descriptive statistics for observe value, change from baseline as well as percentage change from 
baseline will be presented in reference of long-term baseline from prior studies by subgroups (IAT 
vs DAT). MMRM model may be applied if necessary as supportive. 
2.5 
DATA HANDLING CONVENTIONS 
2.5.1 General convention 
For long-term analysis, the reference date is the date of first alemtuzumab or SC IFNB-1a 
treatment in prior studies.  
2.5.2 Missing data 
For categorical variables, patients with missing data are not included in calculations of 
percentages unless otherwise specified.  When relevant, the number of patients with missing data 
is presented. 
Handling of computation of treatment duration if investigational medicinal product end of 
treatment date is missing  
For the calculation of the treatment duration, the date of the last dose of IMP is equal to the date of 
last administration reported on the end-of-treatment case report form page.  If this date is missing, 
the exposure duration should be left as missing.  
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The last dose intake should be clearly identified in the case report form and should not be 
approximated by the last returned package date. 
Handling of medication missing/partial dates 
No imputation of medication start/end dates or times will be performed.  If a medication date or 
time is missing or partially missing and it cannot be determined whether it was taken prior or 
concomitantly, it will be considered a concomitant medication. 
Handling of adverse events with missing or partial date/time of onset 
Missing or partial adverse event onset dates and times will be imputed so that if the partial adverse 
event onset date/time information does not indicate that the adverse event started prior to 
treatment or after the treatment-emergent adverse event period, the adverse event will be classified 
as treatment-emergent.  No imputation of adverse event end dates/times will be performed.  These 
data imputations are for categorization purpose only and will not be used in listings.  No 
imputation is planned for date/time of adverse event resolution. 
Handling of adverse events when date and time of first investigational medicinal product 
administration is missing 
When the date and time of the first IMP administration is missing, all adverse events that occurred 
on or after the day of randomization should be considered as treatment-emergent adverse events.  
The exposure duration should be kept as missing. 
The last dose intake should be clearly identified in the case report form and should not be 
approximated by the last returned package date. 
Handling of missing assessment of relationship of adverse events to investigational medicinal 
product  
If the assessment of the relationship to IMP is missing, then the relationship to IMP has to be 
assumed and the adverse event considered as such in the frequency tables of possibly related 
adverse events, but no imputation should be done at the data level. 
Handling of missing severity/grades of adverse events 
If the severity/grade is missing for 1 of the treatment-emergent occurrences of an adverse event, 
the maximal severity on the remaining occurrences will be considered.  If the severity is missing 
for all the occurrences, a “missing” category will be added in the summary table. 
Handling of potentially clinically significant abnormalities  
If a patient has a missing baseline he will be grouped in the category “normal/missing at baseline.” 
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For PCSAs with 2 conditions, one based on a change from baseline value or a normal range and 
the other on a threshold value, with the first condition being missing, the PCSA will be based only 
on the second condition. 
For a PCSA defined on a threshold and/or a normal range, this PCSA will be derived using this 
threshold if the normal range is missing; eg, for eosinophils the PCSA is > 0.5 GIGA/L or >ULN 
if ULN ≥0.5 GIGA/L.  When ULN is missing, the value 0.5 should be used. 
Measurements flagged as invalid by the laboratory will not be summarized or taken into account 
in the computation of PCSA values.   
2.5.3 Windows for time points 
This D1 selection visit must be conducted within 3 months (6 months for US) after completion of 
the Extension Study CAMMS03409. When possible, the visit will be performed at the same time 
as the last visit of the Extension Study CAMMS03409. For the follow-up visits, the protocol 
specified time window is ± 14 days of target dates for the post-baseline scheduled visits. The 
target dates for the scheduled visits are based on the calendar date of the D1 selection. All 
scheduled visits including those that occurred outside the specified windows will be included in 
the efficacy analysis. 
2.5.3.1 Algorithm for Determining Analysis Visit Windows for Safety Observations  
For the safety assessment, the reference date for the derivation of relative days of events or 
findings will be corresponding to TOPAZ baseline definition specified in Section 2.4.5. 
Selected safety variables will be summarized by the following analysis window: 
 
CBC with differential (including platelet count), Serum Creatinine, liver function and 
Urinalysis (assessed monthly for all the patients re-treated with alemtuzumab and for 48 
months after last infusion) 
 
TSH (assessed every 3 months for all the patients re-treated with alemtuzumab and for 48 
months after last infusion) 
 
Vital signs variable (assessed every 6 months from TOPAZ Day 1 to TOPAZ Month 60, at 
End of Study (EOS) visit, and at unscheduled visits.) 
If a patient withdraws after the date of first study treatment, but prior to the first scheduled visit, 
data from the early withdrawal visit will be assigned to the analysis visit corresponding to the first 
scheduled visit.  For all other visits, the lower bound and the upper bound for the analysis visit 
windows are defined as the midpoints of the target date of scheduled visits. If the date of the early 
withdrawal or an unscheduled visit falls in between the lower bound and the upper bound for a 
scheduled visit, then it will be assigned to that visit.  For example, for the vital sign data, the lower 
and upper bound for the Month 18 analysis visit in a 6 month visit schedule will be Month 15 and 
Month 21 respectively, i.e. Month 18 ±3 months. If the early withdrawal visit date for the vital 
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sign assessment falls at Month 20 (i.e., between Month 15 and Month 21), then this early 
withdrawal visit will be assigned to the Month 18 analysis visit.   
If only one record is within an analysis visit window, the data from that record will be used in the 
summary statistics and by visit analyses.  If more than one record is within the same analysis visit 
window, the record from the regularly scheduled visit will be used in the summary statistics and 
by visit analyses. If more than one record is from a regularly scheduled visit, or more than one 
record is from unscheduled visits within the same analysis visit window, the record from the visit 
nearest to the middle of the interval will be used in the summary statistics and by visit analyses. If 
two visits are “tied” before and after the middle of the interval, the later record will be used in the 
summary statistics and by visit analyses.  If the scheduled visit does not have any record but the 
windowed unscheduled visit is in an analysis visit window, data from the unscheduled visit will be 
used for the summary statistics and by visit analyses. 
2.5.3.2 Algorithm for Determining Analysis Visit Windows for Efficacy Observations 
For the efficacy assessment, the reference date for the derivation of relative days of events or 
findings will be D1 selection visit.  
Selected efficacy variables will be summarized by the following analysis window: 
 
EDSS (assessed every 6 months from TOPAZ Day 1 to TOPAZ Month 60, at End of Study 
(EOS) visit, and at unscheduled visits.) 
 
SF-36, FAMS and EQ-5D (assessed yearly from TOPAZ Day 1 to TOPAZ Month 60, and 
at End of Study (EOS) visit.) 
 
MRI assessments (assessed yearly from TOPAZ Day 1 to TOPAZ Month 60, and at End of 
Study (EOS) visit.)  
The algorithm for determining analysis visit windows and the observations to be used in the safety 
analyses will be applied to the above efficacy assessments in a similar manner. For efficacy 
analyses, all visits up to the end of the study, including those outside the protocol specified 
windows will be included.  
2.5.4 Unscheduled visits 
Unscheduled MRI scans EDSS and questionnaires will be assigned to the appropriate analysis 
window. Otherwise, only scheduled visit efficacy measurements will be used for by visit analysis 
to exclude the temporary fluctuations in the clinical status that may occur with a relapse. 
Laboratory and vital sign data from unscheduled visits will be used in PCSA and descriptive 
analysis. The unscheduled visits will also be assigned to the appropriate analysis time for the 
summary of change from baseline by visit. The one closest to the targeted visit date will be used in 
the presence of multiple measurements within the same time window. 
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2.5.5 Pooling of centers for statistical analyses 
Not applicable. 
2.5.6 Statistical technical issues 
Not applicable. 
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3 
INTERIM ANALYSIS 
A yearly interim analysis is planned for this study. Only data collected in TOPAZ study will be 
used for this interim analysis. Generally, demographic and disposition of patients, summary of 
safety results, and summary of efficacy results will be provided. 
For safety, key safety results including TEAE, SAE, AESI, death, AEs leading to treatment 
discontinuation along with related laboratory values and vital sign values in which details are 
provided in Section 2.4.5 will be provided in the interim analysis report. For efficacy, the interim 
analysis is performed for EDSS, relapse and MRI related efficacy endpoints and Quality of life 
outcomes in which details are provided in Section 2.4.4. Summary of demographics and 
disposition of patients will also be provided.  
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4 
DATABASE LOCK 
The database is planned to be locked approximately at 6 months after first patient completed 5 
years of follow-up. 
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5 
SOFTWARE DOCUMENTATION 
All summaries and statistical analyses will be generated using SAS version 9.0 or higher. 
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6 
REFERENCES 
1. Ware JE, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual 
framework and item selection. Med Care. Jun 1992;30(6):473-83. 
2. Ware JE, Kosinski M. SF-36 Physical and Mental Health Summary Scales. Lincoln, 
RI:QualityMetric Incorporated, 2001. 
3. Cella DF, Dineen K, Arnason B, Reder A, Webster KA, Karabatsos G, et al. Validation of the 
Functional Assessment of Multiple Sclerosis Quality of Life Instrument. Neurology. Jul 
1996;47(1):129-39. 
4. Solari A. Role of health-related quality of life measures in the routine care of people with 
multiple sclerosis. Health Qual Life Outcomes. 18 Mar 2005;3:16. 
5. Brooks R. EuroQol: the current state of play. Health Policy. Jul 1996;37(1):53-72. 
6. Lin DY, Wei LJ.  The robust inference for the Cox proportional hazards model.  J of American 
Statistical Association. 1999;84(408):1074-8. 
7. Mallinckrodt CH, Clark WS, David SR. Accounting for dropout bias using mixed-effects 
models.  J Biopharm Stat. Feb-May 2001;11(1-2):9-21. 
8. Mallinckrodt CH, Kaiser CJ, Watkin JG, Molenberghs G, Carroll RJ. The effect of correlation 
structure on treatment contrasts estimated from incomplete clinical trial data with likelihood-
based repeated measures compared with last observation carried forward ANOVA. Clin Trials. 
2004;1(6):477-89. 
9. Coles A, Compston DAS, Selmaj KW, Lake SL, Moran S, Margolin DH, et al. Alemtuzumab 
vs interferon beta-1a in early multiple sclerosis. N Engl J Med. 23 Oct 2008;359(17):1786-
801. 
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7 
LIST OF APPENDICES 
Appendix A: 
Potentially clinically significant abnormalities (PCSA) criteria 
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Appendix A 
Potentially clinically significant abnormalities criteria  
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for Phase 2/3 studies (oncology excepted) 
(Version 3.0 May 2014) 
Parameter 
PCSA 
Comments 
Clinical Chemistry 
ALT 
By distribution analysis : 
>3 ULN 
>5 ULN 
>10 ULN 
>20 ULN 
Enzymes activities must be expressed in ULN, not in IU/L.  
Concept paper on DILI - FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Categories are cumulative. 
First row is mandatory. Rows following one mentioning 
zero can be deleted. 
AST 
By distribution analysis : 
>3 ULN 
>5 ULN 
>10 ULN 
>20 ULN 
Enzymes activities must be expressed in ULN, not in IU/L.  
Concept paper on DILI – FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Categories are cumulative. 
First row is mandatory. Rows following one mentioning 
zero can be deleted. 
Alkaline Phosphatase 
>1.5 ULN 
Enzymes activities must be expressed in ULN, not in IU/L. 
Concept paper on DILI – FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Total Bilirubin 
>1.5 ULN 
>2 ULN 
Must be expressed in ULN, not in µmol/L or mg/L. Categories 
are cumulative. 
Concept paper on DILI - FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Conjugated Bilirubin 
>35% Total Bilirubin and TBILI>1.5 ULN 
Conjugated bilirubin dosed on a case-by-case basis. 
ALT and Total Bilirubin 
ALT>3 ULN and TBILI>2 ULN 
Concept paper on DILI - FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
To be counted within a same treatment phase, whatever the 
interval between measurements. 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for Phase 2/3 studies (oncology excepted) 
(Version 3.0 May 2014) 
Parameter 
PCSA 
Comments 
CPK 
>3 ULN 
>10 ULN 
FDA Feb 2005. 
Am J Cardiol April 2006. 
Categories are cumulative. 
First row is mandatory. Rows following one mentioning 
zero can be deleted. 
CrCl (mL/min) 
(Estimated creatinine clearance based on the 
Cockcroft-Gault equation)  
<15 (end stage renal disease) 
≥15 - <30 (severe decrease in GFR) 
≥30 - < 60 (moderate decrease in GFR) 
≥60 - <90 (mild decrease in GFR) 
≥90 (normal GFR) 
FDA draft Guidance 2010 
Pharmacokinetics in patients with impaired renal function-
study design, data analysis, and impact on dosing and 
labeling 
eGFR (mL/min/1.73m2) 
(Estimate of GFR based on an MDRD equation)  
 
<15 (end stage renal disease) 
≥15 - <30 (severe decrease in GFR) 
≥30 - < 60 (moderate decrease in GFR) 
≥60 - <90 (mild decrease in GFR) 
≥90 (normal GFR) 
FDA draft Guidance 2010 
Pharmacokinetics in patients with impaired renal function-
study design, data analysis, and impact on dosing and 
labeling 
Creatinine 
≥150 μmol/L (Adults) 
≥30% change from baseline 
≥100% change from baseline 
Benichou C., 1994. 
Uric Acid 
Hyperuricemia  
Hypouricemia  
 
>408 μmol/L 
<120 μmol/L  
Harrison- Principles of internal Medicine 17th Ed., 2008. 
Blood Urea Nitrogen 
≥17 mmol/L 
 
Chloride 
<80 mmol/L 
>115 mmol/L 
 
Sodium 
≤129 mmol/L 
≥160 mmol/L 
 
Potassium 
<3 mmol/L 
≥5.5 mmol/L 
FDA Feb 2005. 
Total Cholesterol 
≥7.74 mmol/L  
Threshold for therapeutic intervention. 
Triglycerides 
≥4.6 mmol/L 
Threshold for therapeutic intervention. 
Lipasemia 
≥3 ULN 
 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for Phase 2/3 studies (oncology excepted) 
(Version 3.0 May 2014) 
Parameter 
PCSA 
Comments 
Amylasemia 
≥3 ULN 
 
Glucose 
Hypoglycaemia 
Hyperglycaemia 
 
≤3.9 mmol/L and <LLN 
≥11.1 mmol/L (unfasted); ≥7 mmol/L (fasted) 
 
ADA May 2005. 
ADA Jan 2008. 
HbA1c 
>8% 
 
Albumin 
≤25 g/L 
 
CRP 
>2 ULN or >10 mg/L (if ULN not provided) 
FDA Sept 2005. 
Hematology 
WBC 
<3.0 GIGA/L (Non-Black); <2.0 GIGA/L (Black) 
≥16.0 GIGA/L 
Increase in WBC: not relevant. 
To be interpreted only if no differential count available. 
Lymphocytes 
>4.0 GIGA/L 
 
Neutrophils 
<1.5 GIGA/L (Non-Black);<1.0 GIGA/L (Black) 
International Consensus meeting on drug-induced blood 
cytopenias, 1991. 
FDA criteria. 
Monocytes 
>0.7 GIGA/L 
 
Basophils 
>0.1 GIGA/L 
 
Eosinophils 
>0.5 GIGA/L or >ULN (if ULN≥0.5 GIGA/L) 
Harrison- Principles of internal Medicine 17th Ed., 2008. 
Hemoglobin 
≤115 g/L (Male); ≤95 g/L (Female) 
≥185 g/L (Male); ≥165 g/L (Female) 
 
Decrease from Baseline ≥20 g/L 
Criteria based upon decrease from baseline are more relevant 
than based on absolute value. Other categories for decrease 
from baseline can be used (≥30 g/L, ≥40 g/L, ≥50 g/L). 
Hematocrit 
≤0.37 v/v (Male) ; ≤0.32 v/v (Female) 
≥0.55 v/v (Male) ; ≥0.5 v/v (Female) 
 
RBC 
≥6 Tera/L 
Unless specifically required for particular drug development, 
the analysis is redundant with that of Hb. 
Otherwise, consider FDA criteria. 
Platelets 
<100 GIGA/L 
≥700 GIGA/L 
International Consensus meeting on drug-induced blood 
cytopenias, 1991. 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for Phase 2/3 studies (oncology excepted) 
(Version 3.0 May 2014) 
Parameter 
PCSA 
Comments 
Urinalysis 
pH 
≤4.6 
≥8 
 
Vital signs 
HR 
≤50 bpm and decrease from baseline ≥20 bpm 
≥120 bpm and increase from baseline≥20 bpm 
To be applied for all positions (including missing) except 
STANDING. 
SBP 
≤95 mmHg and decrease from baseline 
≥20 mmHg 
≥160 mmHg and increase from baseline 
≥20 mmHg 
To be applied for all positions (including missing) except 
STANDING. 
DBP 
≤45 mmHg and decrease from baseline 
≥10 mmHg 
≥110 mmHg and increase from baseline 
≥10 mmHg 
To be applied for all positions (including missing) except 
STANDING. 
Orthostatic Hypotension 
Orthostatic SDB 
Orthostatic DBP 
 
 
≤-20 mmHg 
≤-10 mmHg 
 
Weight 
≥5% increase from baseline  
≥5% decrease from baseline 
FDA Feb 2007. 
 
 
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