Prospective Observational Long-term Safety Registry of Multiple Sclerosis Patients Who Have Participated in Cladribine Clinical Studies (PREMIERE)
Conditions: Multiple Sclerosis
Sponsor: EMD Serono

Company substance code: 280922
EMR700568-012
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Observational Study Protocol
Study Protocol Number
EMR700568-012
Title
Prospective observational long-term safety registry 
of Multiple Sclerosis patients who have participated 
in cladribine clinical trials (PREMIERE).
EudraCT Number
2009-017978-21
Sponsor
In USA
EMD Serono, Inc.
An affiliate of Merck KGaA, Darmstadt, Germany
One Technology Place,
Rockland, MA02370
Phone: +1 781 982 9000
Fax: +1 781 681 2902
In Rest of The World
Merck Serono SA – Geneva 
An affiliate of Merck KGaA, Darmstadt, Germany
29 quai des Bergues
1201 Geneva / Switzerland
Medical Responsible 
 
EMD Serono Research & Development Institute, 
Inc. 
A subsidiary of Merck KGaA, Darmstadt, Germany
45A Middlesex Turnpike
Billerica MA 01821, USA
Phone: 
E-mail: 
Sponsor’s 
Legal 
Representative 
(EU)
Merck KGaA, Frankfurter Strasse 250, 64293 
Darmstadt, Germany
Study Protocol Version
20 July 2016 /Version 4.0 including amendment 
No. 2
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Replaces Study Protocol Version
Version 3.0; 23 July 2012
Current Protocol Amendment
Amendment No. 2 (Global), 20 July 2016
This document is the property of Merck KGaA, Darmstadt, Germany, or one of its subsidiaries. 
It is intended for restricted use only and may not – in full or part – be passed on, reproduced, 
published or used without express permission of Merck  KGaA, Darmstadt, Germany, or its 
affiliate. Copyright © 2016 by Merck KGaA, Darmstadt, Germany, or its subsidiary. All rights 
reserved
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SIGNATURE PAGE
Protocol Lead responsible for designing the study:
I approve the design of the study.
Signature
Date of Signature
 
EMD Serono Research & Development Institute, 
Inc. 
A subsidiary of Merck KGaA, Darmstadt, Germany
45A Middlesex Turnpike
Billerica MA 01821, USA
Phone: 
E-mail: 
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PRINCIPAL REGISTRY PHYSICIAN SIGNATURE
Study Title:
Prospective observational long-term safety registry of 
Multiple Sclerosis patients who have participated in 
cladribine clinical trials (PREMIERE).
Protocol Version/Date:
Version 4.0 including amendment 2 / 20 July 2016
Center Number:
Principal Registry Physician’s site number in the registry
Principal Registry Physician:
Principal Registry Physician’s full name, title and 
academic degree (e.g., Associate Professor, M.D., M.Sc., 
Prof. Dr. med., etc.)
I, the undersigned, am responsible for the conduct of the registry at this site and affirm that
! I understand and will conduct the registry according to the protocol, any approved protocol 
amendments, Good Pharmacoepidemiology Practices (GPP) [1], Good Clinical Practice [2] and 
all applicable Regulatory Authority requirements and national laws.
! I will not deviate from the protocol without prior written permission from the Sponsor and prior 
review and written approval from the Institutional Review Board or Independent Ethics 
Committee, except where necessary to prevent immediate danger to a subject.
Signature
Date of Signature
Insert Name, academic qualifications
Insert Position (job title)
Insert Address of Institution
Insert Phone, fax, e-mail
Each Principal Registry Physician (PRP) will sign a copy of this page. The original signed 
signature sheets will be filed in the Registry Master File.
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Further Sponsor Responsible Persons
EMD Serono Research & Development Institute, Inc. 
A subsidiary of Merck KGaA, Darmstadt, Germany 
45A Middlesex Turnpike 
Billerica, MA 01821, USA
Phone: 
 
Email: 
EMD Serono Research & Development Institute, Inc.
A subsidiary of Merck KGaA, Darmstadt, Germany 
One Technology Place 
Rockland, MA02370, USA
Phone: 
E-mail address: 
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Table of contents
Table of contents
..............................................................................................................6
Table of Figures
..............................................................................................................8
List of Abbreviations ...........................................................................................................9
1
Synopsis..............................................................................................11
2
Sponsor, registry physicians and Study Administrative Structure .....14
3
Background Information.....................................................................15
4
Study Objectives.................................................................................17
5
Study design........................................................................................18
5.1
Study Population.................................................................................18
5.2
Study Enrollment................................................................................18
5.2.1
Physician Enrollment..........................................................................18
5.2.2
Subject Enrollment .............................................................................19
5.3
Inclusion Criteria ................................................................................19
5.4
Exclusion Criteria...............................................................................19
5.5
Study Region/Location.......................................................................20
5.6
Study Cohort.......................................................................................20
5.7
Follow-up and Study Duration ...........................................................20
5.7.1
Study Termination ..............................................................................21
5.7.2
Lost to Follow-up ...............................................................................21
6
Study Endpoints..................................................................................21
6.1
Primary Endpoints ..............................................................................21
6.2
Secondary Endpoint............................................................................22
6.3
Definitions related to study Endpoints ...............................................22
7
Assessment of Medication Exposure..................................................24
7.1
Prior Exposure to Cladribine ..............................................................24
8
Data sources and Study Procedures....................................................24
8.1
Data Sources .......................................................................................25
8.2
Schedule of Interviews and Subject Questionnaires...........................26
8.3
Baseline Subject Demographic and Other Characteristics.................26
8.3.1
Registry Baseline Data Elements........................................................27
8.3.1.1
Information from registry enrollment interview.................................27
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8.3.1.2
Information from medical health records review ...............................27
8.3.1.3
Data elements from the clinical trial database....................................27
8.3.1.4
Interviews at pregnancy baseline and offspring baseline ...................28
8.4
Follow-Up Interviews.........................................................................29
8.5
Reporting of Adverse events ..............................................................30
8.5.1
Definitions ..........................................................................................31
8.5.1.1
Adverse Events ...................................................................................31
8.5.1.2
Adverse Drug Reaction.......................................................................31
8.5.1.3
Serious Adverse Events......................................................................31
8.5.1.4
Serious Adverse Drug Reaction..........................................................32
8.5.1.5
Definition of the Adverse Event Reporting Period.............................33
8.5.2
Recording of Adverse Events in the CRF (Methods of Recording 
and Assessing Adverse Events)..........................................................33
8.5.3
Procedure for Reporting Serious Adverse Events ..............................34
8.5.3.1
Pregnancy and In Utero Drug Exposure.............................................34
8.5.4
Safety Reporting to Regulatory Authorities, Investigators and 
Independent Ethics Committees/Institutional Review Boards ...........35
9
Data Analysis and Statistics................................................................36
9.1
Registry size........................................................................................36
9.2
Data analysis.......................................................................................36
9.2.1
General Considerations.......................................................................36
9.2.2
Treatment/Analysis Period .................................................................37
9.3
Study Reporting and Analysis ............................................................37
9.3.1
Missing Data.......................................................................................38
10
Ethical, Scientific and Regulatory Aspects ........................................38
10.1
Good Practice and Scientific Advice (Responsibilities of the PRP) ..38
10.1.1
Guiding Principles ..............................................................................38
10.1.2
Opinion of External Experts and Scientific Boards............................38
10.2
Subject information and informed consent.........................................38
10.3
Subject Identification and Privacy......................................................39
10.4
Independent Ethics Committee or Institutional Review Board..........39
10.5
Regulatory Authorities........................................................................40
11
Registry Management.........................................................................40
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11.1
Manual of operations..........................................................................40
11.2
Case report form handling ..................................................................40
11.3
Source documents...............................................................................41
11.4
Site Filing and Archiving....................................................................41
11.5
Monitoring, Quality Assurance, and Inspection by authorities ..........41
11.6
Changes to the Protocol......................................................................41
11.7
Registry Report and Publication Policy..............................................42
11.7.1
Final Report ........................................................................................42
11.7.2
Publication..........................................................................................42
12
References...........................................................................................42
13
Appendices .........................................................................................44
Appendix I 
Schedule of Interviews .......................................................................44
Appendix II 
Schedule of interviews for pregnancies and offspring .......................45
Appendix III 
Major structural birth defects or genetic syndromes ..........................46
Table of Figures
Figure 1
Registry Overview Diagram...............................................................21
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List of Abbreviations
AE
Adverse event
ADR
Adverse Drug Reaction
CRO
Clinical research organization
CRF
Case Report Form
CTCAE
Common Terminology Criteria for Adverse Events
DSMB
Data Safety Monitoring Board
e-CRF
Electronic Case Report Form
EDC
Electronic Data Capture
EMA
European Medicines Agency
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GDS
Global Drug Safety
GPP
Good Pharmacoepidemiology Practices
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IRB
Institutional Review Board
LLN
Lower limit of normal
LMP
Last menstrual period
MOP
Manual of operations
MS
Multiple Sclerosis
P1
Original cladribine clinical trial physician
P2
Usual health care provider
PRP
Principal registry physician
RRMS
Relapsing-remitting MS
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SADR
Serious Adverse Drug Reaction
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SUSAR
Suspected Unexpected Serious Adverse Reaction
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1
Synopsis
Study title
Prospective observational long-term safety registry of 
Multiple Sclerosis patients who have participated in 
cladribine clinical trials (PREMIERE).
Study number
EMR700568-012
Sponsor
Merck Serono SA - Geneva 
Design
Non-Experimental registry
Study under IND
yes
no
FDA “covered trial”
yes
no
Study center(s)/country(ies)
The registry will include sites that participated in the 
Sponsor oral cladribine clinical trials in Multiple Sclerosis 
(MS), conducted in several countries worldwide including 
North and South America, Europe, Africa, and Asian-
Pacific regions.
It is estimated that, approximately 234 sites will participate 
in the registry (up to 42 in the US).
Planned 
registry 
period 
(first enrollment-last subject 
out)
Enrollment of subjects in the registry will start after subjects 
have completed or discontinued participation in selected 
Sponsor oral cladribine clinical trials in MS. 
However, for analysis purposes, data from the clinical trials 
will also be included. For each subject there are two periods 
of follow-up: the clinical trial will provide follow-up for the 
first period and the registry will provide follow-up for the 
second period. 
The duration of follow-up in the registry will extend up to 
the end of the registry, which is planned for 2018, or 8 years 
after the subject’s first enrolment into a cladribine clinical 
trial, whichever occurs first.
Study objectives
The main purpose of the registry is to collect long-term 
safety data on oral cladribine in subjects with MS and to 
estimate the frequency of serious adverse drug reactions 
(SADR) over a period of time, extending beyond cladribine 
exposure, in a population of subjects who have been 
exposed to oral cladribine. Subjects participating in selected 
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Sponsor cladribine clinical trials in MS or in corresponding 
cladribine extension studies will be eligible for enrollment.
The focus will be on SADR (which include malignancies 
and serious infections), AEs in the ‘Blood and Lymphatic 
System Disorders’ and ‘Neoplasms Benign, Malignant, and 
Unspecified’ System Organ Classes (SOCs), pregnancies 
among exposed women and pregnancy outcomes, including 
congenital anomalies or other important health conditions 
in the offspring. Resolution of persistent lymphopenia will 
also be assessed among subjects with persistent 
lymphopenia.
Study design and plan
This is a subject registry study with a non-experimental 
cohort design that will provide long-term follow-up of 
subjects who participated in Sponsor oral cladribine clinical 
trials in MS.
Subjects will be enrolled through the clinical trial 
investigator or through the usual health care provider of the 
subject (clinical trial physician or otherwise) according to 
the health care system or to current medical practices in 
each of the participating countries.
Overall, the registry is prospective. However, lag interval 
information regarding exposure and events that occur 
between trial end and registry enrollment will be collected 
retrospectively.
Prospective collection of AEs in the ‘Blood and Lymphatic 
System Disorders’ and ‘Neoplasms Benign, Malignant, and 
Unspecified’ System Organ Classes (SOCs) and MS-related 
SAEs will be started upon local approval of protocol 
amendment 1 (version 2.0) dated 23 July 2012.
Planned number of registry
subjects 
The registry target population includes all subjects who 
participated in Sponsor oral cladribine phase I to III clinical 
trials in MS associated with a protocol approved prior to the 
time of submission of the marketing application and 
completed (last patient, last visit) after November 2008. 
This corresponds to five clinical trials (protocols number 
25643, 26593, 27820, 27967 and 28821) and 2175 subjects.
Schedule of visits and interviews Upon receipt of the signed written informed consent,
subjects can be enrolled in the registry. The principal 
registry physician (PRP), or trained personnel from the site 
will perform the registry enrollment interview.
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During the first 2 years after enrollment into the registry, 
each enrolled subject will be interviewed every 3 months at 
the time of routine visits or will be contacted by telephone. 
Thereafter, the contacts will occur yearly until the end of 
follow-up.
The duration of follow-up for offspring of female subjects 
born during registry participation or during the lag interval 
period will be for one year after delivery or until the end of 
registry, whichever occurs first.
Inclusion and exclusion criteria Inclusion Criteria
All subjects enrolled in studies 25643, 26593, 27820, 27967 
and 28821 will be eligible for enrollment in the registry 
once their participation in the clinical trial has ended. The 
following inclusion criteria must be fulfilled:
! Prior enrollment into selected clinical trials, regardless of 
randomization to either IMP or placebo, once 
participation in the clinical trial or in the clinical trial 
extension has ended
! Written informed consent is given
Exclusion Criteria
The following reasons will exclude subjects from registry 
participation:
! Subjects who cannot be reached by phone, 
! Subjects who are unable to answer the registry 
questionnaires and who do not have a next of kin or 
caregiver available to answer the registry questionnaires,
! Subjects who – either during the lag interval or 
subsequently – enter an interventional study.
Primary endpoints
! Cumulative incidence of SADR, including malignancies 
and serious infections
! Time to resolution of lymphopenia, among registry 
participants with persistent lymphopenia
! Cumulative incidence of AE in the ‘Blood and 
Lymphatic System Disorders’ and ‘Neoplasms Benign, 
Malignant, and Unspecified’ System Organ Classes 
(SOCs).
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Secondary endpoint
! Pregnancy 
outcomes, 
including 
congenital 
malformations, spontaneous abortion, elective abortion, 
stillbirth, ectopic pregnancy, molar pregnancy, and other 
important health conditions in the offspring.
Statistical methods (includes 
number of subjects)
The registry target population consists of 2175 subjects. 
There are no plans for any statistical inference. This study 
will 
adhere 
to 
the 
Guidelines
for 
Good 
Pharmacoepidemiology Practices (GPP) [1] and to their 
recommendations regarding the use of statistical inferences 
and significance testing. Accordingly, data evaluations and 
interpretations will be based on point estimates and 95% 
confidence intervals for evaluation of the statistical 
precision around the point estimate.
Good Practice and Guidelines 
(ethical and scientific practice)
This study will be conducted under the Guidelines for Good 
Pharmacoepidemiology Practices [1], the ICH Guideline 
for Good Clinical Practice [2] the international 1991 
International 
Guidelines 
for 
Ethical 
Review 
of 
Epidemiological Studies [3], AHRQ’s guide: Registries for 
Evaluating Patient Outcomes: A User’s Guide [4], and the 
International Ethical Guidelines for Biomedical Research 
Involving Human Subjects [5]. Adherence to these 
guidelines will ensure the quality and integrity of 
pharmacoepidemiologic research, and will serve to provide
adequate documentation of research methods and results.
2
Sponsor, registry physicians and Study Administrative 
Structure 
Details of the administrative structure and associated procedures will be defined in a separate 
Manual of Operations (MOP). 
Merck Serono SA - Geneva, and EMD Serono Inc, will sponsor the study and the study 
implementation will be performed by the sponsor-designated clinical research organization (CRO), 
 (hereunder referred to as “The CRO”).
The study is planned to be performed in countries in North and South America, Europe, Africa, 
and Asian-Pacific regions. It is estimated that, approximately 234 sites will participate in the 
registry (up to 42 in the US). 
A coordinating registry physician will be identified among the principal registry physicians (PRPs) 
participating in the registry. The coordinating registry physician will act as the representative for 
all PRPs for decisions and discussions regarding this study, and will provide expert medical input 
and advice related to the study design and execution. 
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Merck Serono Global Drug Safety will be responsible for safety reporting and evaluation.
3
Background Information
Cladribine (2-chloro-2'-deoxyadenosine [2-CdA]) is a synthetic anti-neoplastic drug that belongs 
to the subgroup of agents called purine analogues. Parenteral cladribine is approved in many 
countries for the treatment of patients with hairy cell leukemia and in some countries for the 
treatment of chronic lymphocytic leukemia.
An oral formulation of cladribine was tested by the Sponsor in patients with early, relapsing-
remitting and relapsing-progressive, multiple sclerosis (MS). MS is a chronic, inflammatory, 
demyelinating disease of the central nervous system and is one of the most common causes of 
neurological disability in young adults. At its onset, MS can be clinically categorized as either 
relapsing-remitting MS (RRMS), observed in 85% of MS subjects, or primary progressive MS. 
Relapses or “attacks” typically present with neurological symptoms and signs developing over 
hours to days, persisting for several days or weeks, and then gradually dissipating [6]. The outcome 
in subjects with relapsing-remitting MS is variable; untreated, approximately 50% of all MS 
subjects require the use of a walking aid within 10 years after clinical onset, although the 
consequences on prognosis of newer treatment regimens are not yet clear. Increased attack 
frequency and poor recovery from attacks in the first years of clinical disease predict a more rapid 
deterioration [7].
Toxicological evaluations of cladribine given parenterally and orally in appropriate animal models 
have not yielded significant findings other than those predicted by the pharmacologic mechanisms 
of this compound. Single-dose and multiple-dose toxicity studies suggested a wide margin of 
safety for the acute toxicity of cladribine relative to the proposed clinical use of the drug and 
demonstrated reversibility of these effects over time. No neurological effects were observed in 
these studies. Reproductive toxicity studies with parenteral administration of cladribine showed 
no effects on female fertility or peri-postnatal development of offspring ("Female fertility study of 
cladribine administered subcutaneously to female mice" [Study 96307] and "Effects of intravenous 
administration of cladribine on pre-and postnatal development, including maternal function in 
mice" [Study 300315]). The observed embryolethal and teratogenic effects are consistent with the 
pharmacologic mechanisms of cladribine. Male fertility also remained unaffected, yet reduced 
testicular weights and increased numbers of nonmotile sperm suggest testicular effects ("Fertility 
study of cladribine administered subcutaneously to male mice" [Study 96003]). Based on the 
results of a mouse carcinogenicity study using intermittent dosing, cladribine is not considered to 
pose a significant carcinogenic risk in humans ("Two year subcutaneous carcinogenicity study of 
cladribine in mice using an intermittent dosing schedule" [Study 95011]). However, because of its 
demonstrated genotoxicity, the carcinogenic potential of cladribine cannot be excluded.
Data from clinical trials show that cladribine causes sustained lymphopenia, which could increase 
the risk of infections. Currently, the long-term effects of cladribine on hematopoiesis are unknown. 
Other delayed health effects including the occurrence of malignancies can also be postulated, and 
safety should be monitored for a period extending beyond pharmacological exposure. 
Additionally, based on preclinical studies, reproductive and developmental toxicity of cladribine 
in humans cannot be ruled out.
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The efficacy and safety of cladribine tablets for the treatment of RRMS were investigated in a 
Merck Serono / EMD Serono-sponsored, Phase III, randomized, double-blind, 3-arm, placebo-
controlled, multicenter study of 1326 subjects with RRMS (Study 25643, CLARITY). This trial 
provides the primary evidence of the efficacy and safety of oral cladribine in RRMS.
Data from clinical trials show that cladribine results in sustained and dose-related lymphopenia. 
In the CLARITY trial, the first 2 courses of oral cladribine resulted in decreases in mean absolute 
lymphocyte counts at Week 16 of 40% in the 3.5 mg/kg and 62% in the 5.25 mg/kg group. A partial 
recovery was observed by Week 48. Both cladribine dose groups were retreated with 2 courses of 
cladribine at Weeks 48 and 52. The nadir at Week 55 was comparable to that at Week 16 level in 
both treatment groups. The long-term effects of cladribine on hematopoiesis are unknown.
With regard to the risk of infections related to lymphopenia, in completed clinical trials, the risk 
ratio for herpetic infection was 1.98 (95%CI: 1.14-3.45). The risk ratio for infectious adverse 
events (AEs) and serious adverse events (SAEs) were 1.13 (95%CI: 1.01-1.26) and 1.56 (95%CI: 
0.82-2.94), respectively. 
Other delayed health effects including the possibility of an increased risk of malignancies are of 
interest and safety should therefore be monitored for a period extending beyond pharmacological 
exposure. The relative risk for any malignancy in placebo-controlled phases of completed clinical 
trials, was RR=2.31 (95%CI: 0.27 – 19.80). Although this point estimate suggests a two-fold 
increase in the risk of cancer among cladribine-exposed patients; the estimate is unstable as 
indicated by the wide 95% CI that contains 1. Malignancies were of various types and no 
lymphohematopoietic malignancies were observed.
In the CLARITY trial, pregnant and breastfeeding women were specifically excluded and all 
female study participants were required to use adequate contraception throughout the duration of 
their participation in the trial. Male participants were also required to use contraception so that 
their partners did not become pregnant. Despite these protocol requirements, 24 pregnancies were 
reported in 23 of the 898 female subjects who participated in the CLARITY trial. Of these 
24 pregnancies, 6 occurred among subjects who received treatment with placebo, 7 occurred 
among subjects randomized to the 3.5-mg/kg dose, and 11 occurred among subjects who 
randomized to the 5.25-mg/kg dose of cladribine. Information on the timing of pregnancies in 
relation to cladribine exposure in CLARITY indicated that of the 24 pregnancies, 6 pregnancies 
occurred while the subject was receiving treatment (i.e., within a 28-day treatment course), 
17 pregnancies occurred while the subject was not receiving treatment, and 1 pregnancy occurred 
6 months after the subject had completed the study.
Of the 24 pregnancies, 5 resulted in full-term normal live births (2 pregnancies in the 5.25 mg/kg 
cladribine dose group and 3 pregnancies in the placebo group). Both of the subjects in the 
cladribine 5.25 mg/kg group who delivered full-term normal babies had received 6 courses of 
cladribine tablets; conception had occurred approximately 2 weeks and 6 months, respectively, 
after the subjects had received their sixth course of therapy. Thirteen of the 24 pregnancies were 
terminated by elective abortions, 1 by therapeutic abortion due to choriocarcinoma, 4 pregnancies 
ended in miscarriage (3 in the cladribine treatment groups), and 1 pregnancy was ectopic. 
Although the Sponsor requested information on the terminations of these pregnancies, no 
postmortem examinations had been conducted.
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Limited information regarding the long-term safety of cladribine greater than 4 years is currently 
available. During clinical development, the cladribine Data Safety Monitoring Board (DSMB)
recommended monitoring the long-term occurrence of malignancies and deaths, and pregnancy 
outcomes, in subjects exposed to cladribine. 
In June 2011, Merck Serono announced its decision to no longer pursue the global approval 
process of cladribine tablets for the treatment of relapsing-remitting multiple sclerosis and to 
withdraw the product from the market in the countries where it was authorized and available 
(Australia and Russia).
The original objectives of the PREMIERE registry study were to produce long-term safety data in 
order to better characterize the potential safety risks of cladribine, to build an evidence-based risk 
minimization strategy, and to monitor long-term safety events in a clinical trial population. The 
ultimate goal was to minimize risk in a larger population of MS patients exposed to cladribine 
tablets in the post-marketing setting. As cladribine tablets will no longer be available to MS 
patients in the post-marketing setting, and no large population of patients will be exposed, the 
original objectives of this study are no longer applicable. However, the Sponsor recognizes its 
duty of care to appropriately follow patients who have been exposed to cladribine tablets in the 
clinical trial setting.
4
Study Objectives
The main purpose of this registry is to collect long-term safety data on oral cladribine in subjects 
with multiple sclerosis (MS) and to estimate the frequency of serious adverse drug reactions 
(SADR – see definition in section 8.5.1.4) over a period of time extending beyond oral cladribine 
exposure, in a population of subjects who have been exposed to oral cladribine. Subjects 
participating in selected Sponsor cladribine clinical trials in MS or in corresponding cladribine 
extension studies will be eligible for enrollment.
The focus will be on SADR (which include malignancies and serious infections), AE in the ‘Blood 
and Lymphatic System Disorders’ and ‘Neoplasms Benign, Malignant, and Unspecified’ System 
Organ Classes (SOCs), pregnancies among exposed women and pregnancy outcomes (including 
one year of follow-up of offspring). Resolution of persistent lymphopenia will also be assessed 
among subjects with persistent lymphopenia (see definition in section 6.3).
Primary Objectives
! To quantify and characterize the risk (cumulative incidence) of SADR, including malignancies 
and serious infections
! To assess time to resolution of lymphopenia among registry participants with persistent 
lymphopenia
! To quantify and characterize the risk (cumulative incidence) of AE in the ‘Blood and Lymphatic 
System Disorders’ and ‘Neoplasms Benign, Malignant, and Unspecified’ System Organ Classes 
(SOCs)
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Secondary Objective
! To assess pregnancy outcomes, including congenital malformations or other important health 
conditions in the offspring born to women exposed to oral cladribine
5
Study design
This is a subject registry study with a non-experimental cohort design. The study will provide long-
term follow-up of subjects who participated in Sponsor oral cladribine clinical trials in MS. 
Subjects will be enrolled through the clinical trial investigator or through the usual health care 
provider of the subject (cladribine clinical trial physician or otherwise) according to the health care 
system or to current medical practices in each of the participating countries.
Overall, the registry is prospective. However, lag interval information regarding exposure and 
events that occur between trial end and registry enrollment will be collected retrospectively.
Prospective collection of AEs in the ‘Blood and Lymphatic System Disorders’ and ‘Neoplasms 
Benign, Malignant, and Unspecified’ System Organ Classes (SOCs) and MS-related SAEs will be 
started upon local approval of protocol amendment 1 (version 2.0), dated 23 July 2012.
5.1
Study Population
The registry target population includes all subjects who participated in Sponsor oral cladribine 
Phase I to III clinical trials in MS associated with a protocol approved prior to the time of 
submission of the marketing application and completed (last patient, last visit) after November 
2008. This corresponds to five clinical trials (protocols number 25643, 26593, 27820, 27967 and 
28821) and 2175 subjects.
5.2
Study Enrollment
The CRO contracted by the Sponsor, will be responsible for the operational aspects of the registry, 
e.g., obtaining institutional review board (IRB) or independent ethics committee (IEC) approvals 
and managing enrollment of physicians, and subjects and data collection.
5.2.1
Physician Enrollment
There are two options regarding who may become the “principal registry physician” (PRP), that 
is, the physician who routinely cares for the health of the subject outside of the clinical trial setting 
(e.g., neurologist, primary care physician):
! The physician of the original cladribine clinical trial (P1)
! Another physician, the usual health care provider (P2)
For each subject, only one PRP will be the main clinical contact during follow-up and also 
responsible for validating all information on the defined study events. Subjects will be asked to 
update their physician contact information (including the usual care physician) at each follow-up 
interview.
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If the original cladribine clinical trial physician (P1) is not available for the follow-up of subjects 
for any reason, the CRO should obtain contact details from P1 for the usual health care provider 
(P2) to facilitate the use of P2 as the PRP for the subject in the registry.
5.2.2
Subject Enrollment
As soon as subjects end their participation in the oral cladribine clinical trial in MS (i.e., complete 
the clinical trial or its extension, or drop out from the clinical trial) they are eligible to be enrolled 
in the registry. To maximize enrollment of subjects into the registry, it is expected that the P1 will 
facilitate enrollment by informing the subjects about the registry.
The timing of subject enrollment into the registry relative to the time of clinical trial completion 
may vary. Therefore, the categories of timing of registry enrollment and availability of a PRP 
include the following:
! For subjects whose clinical trial participation ended after the date of registry initiation, the P1 
will provide the subject with a registry overview, obtain informed consent, and enroll the 
subject in the registry.
! For subjects who completed their clinical trial participation or who withdrew from the clinical 
trial prior to the initiation of the registry, the CRO will contact the P1. The P1 will facilitate 
contact with the subject, inform the subject about the registry, and obtain informed consent 
from the subject. In cases where the P1 will not be available for the follow-up of subjects, the 
CRO will request P1support in the identification of the P2 via the subject. P1 will ask the subject 
permission to provide P2’s contact data to the CRO. P2 will then be informed about the registry 
and asked to support the steps needed to enroll the subject in the registry.
5.3
Inclusion Criteria
All subjects in the target population described in section 5.1 will be eligible for enrollment in the 
registry once their participation in the clinical trial has ended. The following inclusion criteria must 
be fulfilled:
! Prior enrollment into selected clinical trials, regardless of randomization to either IMP or 
placebo, once participation in the clinical trial or in the clinical trial extension has ended
! Written informed consent is given
5.4
Exclusion Criteria
The following reasons will exclude subjects from registry participation:
! Subjects who cannot be reached by phone;
! Subjects who are unable to answer the registry questionnaires and who do not have a next of 
kin or caregiver available to answer the registry questionnaires;
! Subjects who – either during the lag interval or subsequently – enter an interventional study.
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5.5
Study Region/Location
The registry will include the sites that participated in the Sponsor’s oral cladribine clinical trials in 
MS, which include countries in North and South America, Europe, Africa, and Asian-Pacific 
regions. 
Language, cultural and regulatory aspects of the potentially large number of participating countries 
will be taken into account during the planning phase of the registry.
5.6
Study Cohort
The cohort of cladribine-treated subjects will consist of all subjects who have consented to 
participate and who were treated with cladribine during the clinical trial period of the identified 
clinical trials or cladribine extension studies in MS. 
There will be no control/comparison group. Subjects who were on placebo during a clinical trial 
but who switched to cladribine in the extension study will contribute person-time to the cohort of 
cladribine-treated subjects from the moment they initiate cladribine. Person-time prior to 
cladribine initiation in subjects originally randomized to placebo, will not be used in the calculation 
of study endpoints incidences.
5.7
Follow-up and Study Duration
Study duration
Enrollment of subjects in the registry will start after subjects completed or discontinued 
participation in an oral cladribine clinical trial in MS. The end of the registry is planned for 2018, 
which corresponds to 8 years after the last subject was included in the targeted clinical trials (see 
section 5.1). 
Follow-up of MS subjects
The duration of follow-up for all subjects will extend up to the end of the registry, which is planned 
for 2018, or 8 years after enrollment into the first cladribine clinical trial (first visit), whichever 
occurs first.
Subjects with ongoing SAEs, including lymphopenia (i.e. who have not reached a lymphocyte count 
CTCAE Grade 0 or 1) at the end of PREMIERE, will be followed-up by the Global Drug Safety 
department until resolution (see definition of the reporting period in section 8.5.1.5).
Follow-up of offspring
The duration of follow-up for offspring of female subjects born during registry participation or 
during the lag interval period will be one year after delivery or until the registry end date, 
whichever occurs first.
Subjects with ongoing pregnancies or offspring born during registry participation or during the 
lag interval period who are not at least 1 year old at the end of the registry will be followed-up by 
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the Global Drug Safety department until pregnancy outcome is known and offspring is 1 year old, 
respectively (see definition of the reporting period in section 8.5.1.5).
5.7.1
Study Termination
Termination of a subject from the registry will occur if the subject decides not to continue his/her 
participation in the registry or if the subject becomes unable to continue participating. Subjects 
will be informed that they have the right to withdraw from the registry at any time, without 
prejudice, and that they are not obliged to state their reasons. If a subject declares his or her wish 
to discontinue from the registry, the PRP will attempt to establish whether the underlying reason 
is related to an adverse event (AE) or other study endpoint. The PRP will complete a Subject 
Discontinuation form and enter the discontinuation information into the electronic case report form 
of the discontinued subject.
5.7.2
Lost to Follow-up
Before considering a subject “lost to follow-up,” the PRP or trained site personnel will make every 
attempt to contact the subject and maintain him/her in the registry and to ensure that an outcome 
of interest has not been the underlying reason for the non-response of the subject. If no response 
is obtained, the CRO will enquire directly with other known health care providers and/or with next 
of kin/caregivers named by the subject via PRP to check whether the reason for failure to respond 
is health-related, to determine the vital status of the subject, and, in the case of deceased subjects, 
to ascertain the cause of death. 
Figure 1
Registry Overview Diagram
6
Study Endpoints
6.1
Primary Endpoints
! Cumulative incidence of SADR, including malignancies and serious infections
! Time to resolution of lymphopenia, among registry participants with persistent lymphopenia
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! Cumulative incidence of all AEs in the “Blood and Lymphatic System Disorders” System 
Organ Class (SOC) and in the “Neoplasms Benign, Malignant, and Unspecified” SOC
6.2
Secondary Endpoint
! Pregnancy outcomes, including congenital malformations, spontaneous abortion, elective 
abortion, stillbirth, ectopic pregnancy, molar pregnancy, and other important health conditions 
in the offspring
6.3
Definitions related to study Endpoints
Resolution of Persistent Lymphopenia
Subjects who complete or drop out of a cladribine clinical trial with a Grade 3 or Grade 4 
lymphopenia as defined by the Common Terminology Criteria for Adverse Events (CTCAE) [8] 
will be defined as having ‘persistent lymphopenia’ and will be monitored until lymphopenia 
resolves. Resolution is the achievement of a CTCAE Grade 1 or Grade 0 lymphocyte count.
According to the CTCAE version 4.03 [8], lymphopenia grades are defined as follows:
! Grade 1: < lower limit of normal (LLN) to 800/mm3 or < LLN to 0.8 × 109/L
! Grade 2: < 800–500/mm3 or < 0.8–0.5 × 109/L
! Grade 3: < 500–200/mm3 or < 0.5–0.2 × 109/L
! Grade 4: < 200/mm3 or < 0.2 × 109/L
Pregnancy and Pregnancy Outcomes
Pregnancies occurring among female subjects exposed to cladribine will be identified by a subject-
reported positive pregnancy test and at least a 2-week delay in menses, or a subject-reported 
pregnancy diagnosed by a physician.
Pregnancy outcomes will be characterized by using the following definitions (in italics) according 
to the European Medicines Agency guideline [9].
Live births
Complete expulsion or extraction from its mother of a product of conception irrespective of the 
duration of the pregnancy, which after such separation, breathes or shows any evidence of life.
Normal
Abnormal:
Pre-term, term, post-term birth
Pre-term birth: less than 37 completed weeks (less than 259 days) of 
gestation.
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Term birth: from 37 to less than 42 completed weeks (259 to 293 days).
Post-term birth: 42 completed weeks or more (294 days or more)
Small for gestational age infants/ intrauterine growth retardation
Intrauterine growth retardation (small for gestational age): the observed 
weight of a live born infant or size of a fetus is lower than expected on the 
basis of gestational age.
Gestational age or length: the duration of gestation is measured from the 
first day of the last normal menstrual period. Gestational age is expressed 
in completed days or completed weeks (e.g., events occurring 280 to 286 
days after the onset of the last menstrual period are considered to have 
occurred at 40 weeks of gestation).
Drug withdrawal syndrome in the neonate
Malformations
Morbidity
Fetal death
Death prior to complete expulsion or extraction from its mother of a product of conception, 
irrespective of the duration of pregnancy; the death is indicated by the fact that after such 
separation the fetus does not show any evidence of life. Early fetal death (before 22 completed 
weeks of gestation) comprises ectopic pregnancy and miscarriage.  
Ectopic
Extrauterine pregnancy, early fetal death most often in the Fallopian tube.
Miscarriage
Spontaneous abortion, molar pregnancy.
Stillbirth 
Late fetal death (after 22 completed weeks of gestation).
Termination of pregnancy
Induced abortion, elective abortion. Artificial interruption of pregnancy.
In cases of induced or spontaneous abortions and intra-uterine death, it should be mentioned 
whether the embryo/fetus had apparent congenital malformations.
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Major structural birth defects or genetic syndromes
Descriptions of major congenital anomalies and congenital syndromes of offspring will be 
collected. 
A simplified version of the British Pediatric Association code list will be used for the definition of 
this endpoint. See Section 13 Appendix III.
Developmental disabilities and important health conditions
Data on routine developmental milestones achievement and important health conditions as 
reported by a physician will be collected in offspring for the duration of follow-up (see Section 
5.7).
7
Assessment of Medication Exposure 
After enrollment of subjects in the registry, in accordance with the non-experimental nature of this 
study, no treatment will be assigned to participants by registry protocol. Physicians will prescribe 
medications according to their own clinical criteria and practices. Information regarding use of 
marketed immunosuppressant medications will be collected during the registry.
Subjects will no longer be eligible to participate in PREMIERE if they enroll in an interventional
clinical trial, as it may not be possible to know medication exposure.
7.1
Prior Exposure to Cladribine
Data on the subject’s prior exposure to cladribine from the clinical trial period will be copied from 
the clinical trial database and will include the following variables:
! Date of cladribine start;
! Cumulative cladribine exposure (mg per kg of body weight) 
! Dose and schedule;
! Date(s) of temporary and/or permanent treatment discontinuation(s).
8
Data sources and Study Procedures
Subjects will be provided information on the registry and will be requested to sign informed 
consent before any data is collected. 
For subjects who refuse to enroll in the registry, attempts will be made to collect selected data, 
including reason for refusal, and to request informed consent for the use of their baseline data 
collected during their participation in the clinical trial.
When a subject has signed the informed consent, a unique subject identification number will be 
assigned. This number will consist of ten characters for the registry protocol number, three digits 
for a site number and four digits for a sequentially assigned subject number (i.e., 0001, 0002, 0003, 
etc.).
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Example: the fifth subject enrolled at site 001 in protocol 0700568012
0700568012
001
0005
Protocol No.
Site No.
Subject No.
Should the subject withdraw from the study, his or her unique subject identification number will 
not be reallocated.
8.1
Data Sources
Data will be obtained from several sources, namely:
The subject questionnaires administered by the PRP or trained site personnel
! Medical record information collected by the PRP at his or her own institution providing 
information on subject health events and exposure to other immunosuppressants 
! The clinical trial database, providing data previously collected during the oral cladribine clinical 
trials in MS and their extension
The specifics of these data sources are described in the following paragraphs.
Subject Interviews
After registry enrollment, data will be collected by the PRP or trained site personnel (see Section
13 Appendix I, schedule of Interviews) either during the routine clinical visit or by telephone 
contact. Structured questionnaires administered to the subject or in cases when the subject is 
unable, to the next of kin, or caregiver.  
There will be a limited number of subjects who withdrew or completed the clinical trial before the 
registry was established and who have no follow-up data recorded in their medical record (or the 
medical record is not accessible). Information from this time interval between clinical trial end and 
registry enrollment, referred to as the “lagged data period,” will be collected directly from the 
subject. As much as possible medical confirmation will be sought through the PRP.
Medical Records
For subjects who withdrew or completed the clinical trial before the registry was established (but 
who are still followed at the site), health records will be retrospectively reviewed to ascertain 
SADRs, pregnancies, and lymphocyte counts, as well as exposure to immunosuppressants 
occurring during the lagged data period.
Clinical Trial Database
Data collected from the clinical trial period will include demographic characteristics, exposure to 
cladribine and lymphocyte counts at the end of the trial. This data will be linked with the clinical 
trial data after enrollment of the subject in the registry.
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8.2
Schedule of Interviews and Subject Questionnaires
Timing and Frequency of Interviews
On Day 1 of registry enrollment, the interviewer (PRP or trained site personnel) will verify that 
the informed consent has been signed and will proceed to administer the registry enrollment 
questionnaire.
During the first 2 years after enrollment into the registry the PRP or trained site personnel will 
interview the subject every 3 months. Thereafter, the contacts will be every year until the end of 
follow-up (see Section 13 Appendix I, schedule of Interviews).
A window of ± 2 weeks around the date of the scheduled visit during the first two years and of ± 
4 weeks thereafter, is acceptable. The structured questionnaire will be administered during routine 
clinical visits or by phone.  The PRP or trained site personnel will enter the questionnaire responses 
collected in the electronic case report form.  The completed questionnaires are source documents 
and will be filed with the registry participant’s medical records on site, per Section 11.4 of the 
protocol. 
At each scheduled contact, information on SAEs, AEs related to ‘Blood and Lymphatic System 
Disorders’ and ‘Neoplasms Benign, Malignant, and Unspecified’ SOCs, lymphocyte counts, and 
immunosuppressant medications will be collected through a structured questionnaire administered 
by phone or during a routine visit by the PRP or trained site personnel. A detailed schedule of 
interviews is provided in the Section 13 Appendix I, schedule of Interviews. 
Pregnancies: When a pregnancy is identified in a female subject, a specific pregnancy baseline 
questionnaire will be administered (see Section 8.3). During the pregnancy, the schedule of phone 
interviews will be adapted so that at least one such interviews takes place between months 4 
through 7 after the last menstrual period (LMP), and another at month 10. After the end of the 
pregnancy, the schedule of interviews will shift to the regular periodicity. 
Offspring of female subjects: Data will be collected from the PRP after birth, ideally in parallel 
to the interview of the mother at month 10 post-LMP, at age 6 months, and at age 1 year. No 
interviews on the offspring will be performed in the frame of the registry after the date of the 
registry end. Offspring who are not at least 1 year old at the end of the registry will be followed-
up by the Global Drug Safety department (see definition of the reporting period in section 8.5.1.5).
A schedule of interviews for pregnancies and offspring is provided in Section 13 Appendix II, 
Schedule of Interviews for Pregnancies and Offspring.
To manage missed interviews or shifts in scheduled interviews of subjects, the registry will 
maintain the schedule as originally planned.
8.3
Baseline Subject Demographic and Other Characteristics
The registry enrollment of a subject will be based on subject interview and, for some subjects, will 
require information from subject health records. Another component of the enrollment process will 
consist of inclusion of data collected during the clinical trial period, which will be copied from the 
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clinical trial database to the registry database after completion of the subject enrollment into the 
registry.
8.3.1
Registry Baseline Data Elements
Registry baseline data elements include the following data:
8.3.1.1
Information from registry enrollment interview
At the registry enrollment interview, the following data will be collected from all subjects unless 
prohibited by country regulations: 
! Identification/contact information of subject, next of kin/caregiver, and current treating 
physician(s).
In subjects who have a lagged interval period and whose medical record is not accessible, a specific 
questionnaire will address the following:
! Treatment exposure to immunosuppressant medications, including type of treatment and date 
started;
! Occurrence of SAEs including time and outcome;
! Occurrence of AEs in the ‘Blood and Lymphatic System Disorders’ and ‘Neoplasms Benign, 
Malignant, and Unspecified’ SOCs including time and outcome
! In subjects tagged as “lymphopenic subjects” ascertainment of performance of a blood test 
during the lagged data period, and categorization of lymphocyte counts as normal, abnormal or 
unknown, if available.
8.3.1.2
Information from medical health records review
For subjects with lagged data period, Sponsor will review data from medical records and the PRP 
will enter the following data into the registry participant electronic case report form:
! Treatment exposure to immunosuppressant medications, including type of treatment, and date 
started;
! Occurrence of SAEs including time and outcome;
! Occurrence of a pregnancy in participant woman, including date of LMP, and outcome;
! In subjects tagged as “lymphopenic subjects” ascertainment of performance of a blood test 
during the lagged data period, and categorization of lymphocyte counts as normal, Grade 1 
through Grade 4 or unknown, if available.
8.3.1.3
Data elements from the clinical trial database
The focus will be on data collected during the subject’s participation in the clinical trial or its 
extension period as specified following:
! Demographic data, including date of birth, gender, and race;
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! Treatment exposure data for cladribine, including time (date started and date stopped), dose, 
and duration;
! Evidence of CTCAE Grade 3 or Grade 4 lymphopenia at the completion or dropout of the 
clinical trial, and lymphocyte count. These subjects will be tagged as “lymphopenic subjects” 
until resolution of their lymphopenia (see definition of resolution in Section 6.3).
8.3.1.4
Interviews at pregnancy baseline and offspring baseline
Pregnancies: For women who become pregnant during registry participation, a specific pregnancy 
baseline questionnaire will be added to collect pregnancy-related information.
The information that will be collected during pregnancy follows the specifications provided in the 
EMA guideline on the exposure to medicinal products during pregnancy [9].
Maternal Information
! Contact information for the gynecologist-obstetrician or physician who follows the pregnancy
! Occupation, highest education level attained
! Maternal weight
! Obstetrical history: number of previous pregnancies and outcome (live birth, miscarriage, 
elective termination with specification of gestational length and context, late fetal death, ectopic 
pregnancy, molar pregnancy), previous maternal pregnancy complications, previous 
fetal/neonatal abnormalities and type, history of subfertility.
! Maternal and medical history: risk factors for adverse pregnancy outcomes including 
environmental or occupational exposures, e.g., hypertension, diabetes, seizure disorder, asthma, 
allergic disease, heart disease, depression or other psychiatric disorders, sexually transmitted 
diseases, hepatitis, AIDS (specify viral load, CD4 count), other.
! Current pregnancy: date of last menstrual period (LMP); pregnancy gestational age at the time 
of baseline interview (specify if based on ultrasound or LMP); estimated date of delivery; 
number of fetuses; treatment for infertility (specify); exposure to products subject to medical 
prescription, over-the-counter products, pregnancy supplements such as folic
acid, 
multivitamins (name, dosage, and route; date of first use; date of end of treatment; duration) 
and indication; recreational drug use, e.g., tobacco, alcohol, illicit drugs (specify amount and if 
stopped during pregnancy); results of serology tests, e.g., rubella, toxoplasmosis; complications 
during pregnancy and date (including adverse drug reactions); disease course during pregnancy 
and any complications; antenatal checkups (specify dates and results), e.g., fetal ultrasound, 
serum markers (AFP, others), chorionic villi biopsy (CVS), amniocentesis.
! Family history: history of congenital abnormality, psychomotor retardation in the family 
(specify paternal/maternal and relationship), consanguinity between parents (specify degree).
Pregnancy offspring: For children born of female subject, a specific baseline interview will be 
conducted to capture information about congenital malformation and general health and 
development status. Contact data for the pediatrician or physician following the child will be 
obtained.
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Baseline Neonatal Information
! Outcome of pregnancy
! Date of birth of the child
! Gestational age at birth
! Gender
! Results of neonatal physical examination including weight at birth, length, head circumference 
at birth
! Malformations/anomalies diagnosed at birth
! Conditions at birth (including Apgar scores at 1 and 5 minutes, need for resuscitation, admission 
to ICU)
! Dysmaturity
! Neonatal illness, hospitalization, drug therapies
8.4
Follow-Up Interviews
For MS subjects, the information to be ascertained in the follow-up interviews fall into five main 
categories:
! Updates in contact information
! Occurrence of SAEs (including time of event and outcome) 
! Occurrence of AEs in the ‘Blood and Lymphatic System Disorders’ and ‘Neoplasms Benign, 
Malignant, and Unspecified’ SOCs (including time of event and outcome)
! Capture of any lymphocyte count assessments performed since last visit
! Prescription of immunosuppressant medications including type and start date
It is expected that subjects in PREMIERE will attend their routine MS care visits. The PRP is 
expected to request blood count and differential if lymphopenia has not resolved (i.e., lymphocyte 
count is equal or greater than 0.8 × 109/L). All lymphocyte count results will be captured by the 
PRP regardless of monitoring frequency. Participating PRP will be instructed to have blood count 
and differential performed at least yearly until resolution of lymphopenia (i.e., a Grade 1 or Grade
0 lymphopenia), or end of the study period.
Pregnancy
The follow-up interview during pregnancy will collect information regarding the progress of the 
pregnancy, exposure to potential risk factors, and the expected date of delivery. Information will 
also be collected on potential adverse pregnancy outcomes during that period: spontaneous 
abortion, elected abortion, stillbirth, ectopic pregnancy, and molar pregnancy. The follow-up 
interview at month 10 or at the end of pregnancy will provide information about the outcome —
spontaneous abortion, elected abortion, stillbirth, live birth, or premature; overdue, presence of 
congenital anomalies, ectopic pregnancy, molar pregnancy, and the date of birth of the baby. Note 
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that the option of an elective abortion may be an issue in some countries, and may yield invalid 
answers.
Delivery Information
! Mode of delivery
! Labor/delivery complications (fetal distress/amniotic fluid abnormal)
! Abnormal placenta
Fetal Information
To be collected in case of elective termination, spontaneous abortion, and late fetal death.
! Reason for termination
! Gestational age at termination
! Results of physical examination (gender, external anomalies) and pathology
Offspring
Follow-up information on the child includes any physician-diagnosed abnormal developmental 
milestones; structural malformations not detected in the neonate, and other important health
conditions. A contact with the paediatrician will be attempted to validate information.
8.5
Reporting of Adverse events
After registry enrollment, as for all study information, the primary source of data is the subject. 
AE/SAE data will be obtained at scheduled or unscheduled interviews based on information 
spontaneously provided by the subject and/or thorough questioning of the subject. To elicit 
pregnancy and AEs/SAEs, questioning at each interview should begin with simple non-leading 
questions.
To identify AEs/SAEs, or a pregnancy, a section of the standard phone interview will ask the 
subject about all clinically relevant health events (see Section 8.2). Information on offspring of 
female subjects should be requested for one year after delivery.
If a subject is hospitalized in relation to an SAE or a pregnancy is reported, the trained site should, 
in a timely manner, make every effort to follow-up with the treating physician or relevant 
concerned health care provider to obtain all information necessary for the accurate reporting of the 
event.
In the cases where the subject reports a SAE that is not being treated by the PRP, the registry 
informed consent will have requested the subject’s authorization to contact the treating physician 
and/or other relevant concerned health care provider for full SAE interview.
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8.5.1
Definitions
8.5.1.1
Adverse Events
An AE is defined as any untoward medical occurrence in the form of signs, symptoms, abnormal 
laboratory findings, or disease that emerges or worsens relative to study baseline.
When reporting an abnormal laboratory finding, a clinical diagnosis should be recorded rather than 
the abnormal value itself, if this is available. For example, record “anemia” rather than “decreased 
red blood cell count” or “hemoglobin = 10.5 g/dL”.
AEs may include the following types of occurrences:
! Medical experiences, such as injury, surgery, accidents, or illnesses, and significant 
abnormalities in clinical laboratory values, psychological testing, or physical examination 
findings. 
In cases of surgical or diagnostic procedures, the condition/illness leading to such a procedure is 
considered as the AE rather than the procedure itself.
8.5.1.2
Adverse Drug Reaction
An adverse drug reaction (ADR) is a response to a medicinal product which is noxious and 
unintended, and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy 
of disease or for the restoration, correction, or modification or physiological functions. Response 
in this context means that a causal relationship between a medicinal product and an adverse event 
is at least a reasonable possibility.
8.5.1.3
Serious Adverse Events 
Any SAE requires expedited reporting to the Sponsor’s (GDS) Global Drug Safety Department.
A serious adverse event (SAE) is defined as any adverse event occurring at any dose that results 
in any of the following outcomes, which are seriousness criteria:
! Results in death. In case of a fatality, the cause of death is considered as the SAE, and the death 
is its outcome
! Is life-threatening. The term “life-threatening” in this definition refers to an event in which the 
subject is at risk of death at the time of the event; it does not refer to an event that hypothetically 
might have caused death if it were more severe.
! Requires in-patient hospitalization or prolongation of existing hospitalization.
! Results in persistent or significant disability/incapacity.
! Is a congenital anomaly/birth defect.
! Is otherwise considered as medically important.
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Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered a serious adverse drug experience when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in patient hospitalization, or the 
development of drug dependency or drug abuse.
The treating physician or other relevant concerned health care provider will be asked to assess the 
relationship of the SAEs to cladribine using the following definitions:
! Probable: A causal relationship is clinically/biologically highly plausible, and there is a 
correlation between the onset of the SAE and administration of cladribine, and between 
withdrawal of cladribine and resolution of the SAE.
! Possible: A causal relationship is clinically/biologically plausible and there is a correlation 
between the onset of the SAE and administration of cladribine.
! Unlikely: A causal relationship is improbable, and another documented cause of the SAE is 
most plausible.
! Unrelated: A causal relationship can be definitively excluded, and another documented cause 
of the SAE is most plausible.
In this protocol, any adverse pregnancy outcome (e.g., spontaneous abortion, fetal death in utero, 
ectopic pregnancy, chronic fetal distress, stillbirth, neonatal death, or prematurity-related 
complication more than is typical for prematurity) should be considered serious. Serious adverse 
events occurring to offspring of a female subject should also be reported and evaluated as SAEs.
SAEs of particular interest
Any malignant neoplasia, including non-melanoma skin cancer as well as all serious infections 
should be considered as a medically significant adverse event and reported to the Sponsor using 
an SAE Report Form with all related information.  
Events Not to Be Considered as AEs / SAEs
Medical conditions present at the enrollment registry visit that do not worsen in severity or 
frequency during follow-up in the registry or that do not occur or worsen in severity or frequency 
during the lag interval period are defined as Baseline Medical Conditions, and are NOT to be 
considered adverse events. 
8.5.1.4
Serious Adverse Drug Reaction
A serious adverse drug reaction (SADR) is an adverse drug reaction that fulfils at least one 
seriousness criterion as defined in section 8.5.1.3.
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8.5.1.5
Definition of the Adverse Event Reporting Period
SAEs are documented from the day informed consent is signed until the subject’s last interview 
(end of study). Beyond that date, ongoing SAEs, including persistent Grade 3 or Grade 4 
lymphopenia, and pregnancies will be followed up until event resolution/stabilization or pregnancy 
outcome is known by the Global Drug Safety Department. Offspring of female subject born during 
registry participation who are less than 1 year old at the end of the registry will be followed up 
until 1 year of age by the Global Drug Safety Department. 
If PRP/reporter becomes aware of a SAE, which occurred during the lag interval period, but was 
not reported within a prior cladribine trial, s/he should report this event to the Global Drug Safety 
department.
If a subject is documented as lost-to follow-up, ongoing SAEs will not be followed up.
8.5.2
Recording of Adverse Events in the CRF (Methods of 
Recording and Assessing Adverse Events)
Complete, accurate, and consistent data on all SAEs experienced for the duration of the reporting 
period and on all AEs in the ‘Blood and Lymphatic System Disorders’ and ‘Neoplasms Benign, 
Malignant, and Unspecified’ SOCs will be reported on an ongoing basis in the appropriate section 
of the Case Report Form (CRF). In addition, all SAEs will be documented and reported using an 
SAE Form.
It is important that each report include a description of the event, its duration (onset and resolution 
dates/times), its relationship with cladribine, any other potential causal factors, any treatment given 
or other action taken, and its outcome. 
The AE/SAE recording should comply with the following guidelines. Whenever possible, 
recognized medical terms should be used to describe AEs rather than colloquialisms (for example, 
“influenza” rather than “flu”), and abbreviations should be avoided.
! AEs/SAEs should be described using a specific clinical diagnosis, if this is available, rather 
than a list of component signs or symptoms (for example, “congestive heart failure” rather than 
“dyspnea, rales, and cyanosis”).
! Signs and symptoms that are not linked (as "co-manifestations”) to an identified disease or 
syndrome, or for which an overall diagnosis is not available, should be reported as individual 
events.
! Provisional diagnoses (e.g., “suspected myocardial infarction”) are acceptable but should be 
followed up to a definite diagnosis if one becomes available.
Complete and appropriate data on all SAEs and on all AEs in the ‘Blood and Lymphatic System 
Disorders’ and ‘Neoplasms Benign, Malignant, and Unspecified’ SOCs experienced for the 
duration of the study will be reported on an ongoing basis in the corresponding pages of the CRF. 
It is important that each report includes a description of the event, its duration (onset and resolution 
dates or whether it is ongoing), its relationship to cladribine, any other potential causal factors, any 
concomitant treatment given or other action taken, and its outcome as of the end of the study.
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8.5.3
Procedure for Reporting Serious Adverse Events
In the event of any new SAE occurring during the reporting period, the PRP must immediately 
(i.e., within a maximum 24 HOURS after becoming aware of the event) inform Sponsor, by fax or 
by e-mail. 
Reporting procedures and timelines are the same for any new information – i.e. follow-up 
information – on a previously reported SAE.
All written reports should be transmitted using the GDS Alert Report Form, which must be 
completed by the PRP/Reporter following specific completion instructions.
Relevant pages from the CRF may be provided in parallel (e.g., medical history, concomitant 
drugs). In all cases, the information provided in the GDS Alert Report Form must be consistent 
with the data on the event that are recorded in the corresponding sections of the CRF.
The PRP/Reporter must respond to any request for follow-up information (e.g., additional 
information, outcome and final evaluation, specific records where needed) or to any question the 
Sponsor may have on the SAE within the same timelines as described for initial reports. This is 
necessary to permit a prompt assessment of the event by the Sponsor and (as applicable) to allow 
the Company to meet strict regulatory timelines associated with expedited safety reporting 
obligations.
Requests for follow-up will usually be made by the Global Drug Safety of Merck Serono. The 
Global Drug Safety department may contact the PRP directly to obtain clarification or to discuss 
a particularly critical event.
The interviewer must notify the Sponsor within 24 hours of his/her awareness of a new SAE or of 
new follow-up information on a previously reported SAE.
To do so, the interviewer and/or the treating physician must complete a Sponsor GDS Alert Report 
following specific instructions (GDS Alert Report Form Completion Instructions), using 
preferably the electronic template, and send it directly to the Global Drug Safety department by 
electronic mail or facsimile, using the dedicated e-mail address and facsimile numbers specified 
below:
!
!
 
8.5.3.1
Pregnancy and In Utero Drug Exposure
All pregnancies with an estimated conception date during the period defined in Section 8.5.1.5
must be recorded by convention in the AE page/section of the CRF. The PRP/reporter must notify 
the Sponsor in an expedited manner of any pregnancy using the Pregnancy Report Form, which 
must be transmitted according to the same process as described for SAE reporting in Section 8.5.3.
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Investigators must actively follow up, document and report on the outcome of all of these 
pregnancies, even if the subjects are withdrawn from the registry. Offspring of female subjects
will be followed-up for one year after delivery or until the registry end, whichever occurs first.
The Investigator must notify the Sponsor of the outcomes using the Pregnancy Report Form, and 
in case of abnormal outcome, the GDS Alert Report Form when the subject sustains an event and 
the GDS Parent-Child/Fetus Adverse Event Report Form when the child/fetus sustains an event).
Any abnormal outcome must be reported in an expedited manner as described in Section 8.5.3,
while normal outcomes must be reported within 45 days from delivery.
8.5.4
Safety Reporting to Regulatory Authorities, Investigators and 
Independent Ethics Committees/Institutional Review Boards
The Sponsor will send appropriate safety notifications to regulatory authorities in accordance with 
applicable laws and regulations.
The PRP must comply with any applicable site-specific requirements related to the reporting of 
SAEs (and in particular deaths) involving his/her subjects to the Ethics Committee/Institutional 
Review Board (EC/IRB) that approved the study.
In accordance with International Conference on Harmonization (ICH) Good Clinical Practice 
(GCP) guidelines, the Sponsor will inform the PRP of “findings that could adversely affect the 
safety of subjects, impact the conduct of the registry or alter the EC’s/IRB’s approval/favorable 
opinion to continue the registry.” In particular and in line with respective regulations, the Sponsor 
will inform the PRP of adverse events that are both serious and unexpected and are considered to 
be related to cladribine (“suspected unexpected serious adverse reactions” or SUSARs). The PRP 
should place copies of these Safety reports in the Registry Site File at the site. National regulations 
with regard to Safety report notifications to Investigators will be taken into account.
The reference safety document against which the assessment of expectedness is made is the 
Investigator’s Brochure. 
In this registry, any unexpected SAEs with an investigator’s causal relationship of “unknown/not 
assessable” will not be considered by default as “possibly” related and will not be a SUSAR, unless 
the Sponsor upgrades it.
When specifically required by regulations and guidelines, the Sponsor will provide appropriate 
Safety reports directly to the concerned lead Independent Ethics Committee (IEC)/IRB and will 
maintain records of these notifications. When direct reporting by the Sponsor is not clearly defined 
by national or site-specific regulations, the Investigator will be responsible for promptly notifying 
the concerned IEC/IRB of any Safety reports provided by the Sponsor and of filing copies of all 
related correspondence in the Investigator Site File.
For trials covered by the European Directive 2001/20/EC, the Sponsor’s responsibilities regarding 
the reporting of SAEs/SUSARs will be carried out in accordance with that Directive and with the 
related detailed guidances.
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Reporting of SAEs to regulatory authorities will be in accordance with national regulations and 
international guidelines1 for reporting of SAEs occurring during clinical trials. 
9
Data Analysis and Statistics
There are no plans for any statistical inference. This study will adhere to the Guidelines for Good 
Pharmacoepidemiology Practices (GPP) [1]. Accordingly, data evaluations and interpretations 
will be based on point estimates and 95% confidence intervals for evaluation of the statistical 
precision around the point estimate.
Statistical analysis of all data will occur at the end of the registry, and will be performed by the 
CRO, using SAS® statistical software (
).
The MedDRA dictionary will be used for coding all primary and secondary endpoints and all 
reportable SAEs. 
9.1
Registry size
The purpose of this registry is to comprehensibly capture SADR, AEs in the ‘Blood and Lymphatic 
System Disorders’ and ‘Neoplasms Benign, Malignant, and Unspecified’ SOCs, pregnancy 
outcomes, and resolution of persistent lymphopenia in subjects exposed to cladribine tablets during 
the clinical trials. As a result, the cohort size will not be determined using sample size estimating 
methodology. The registry target population consists of 2175 subjects.
9.2
Data analysis
9.2.1
General Considerations
The analysis set will consist of all subjects enrolled in the registry at the time of the analysis.
For safety analyses, subjects will be analyzed according to their actual exposure to oral cladribine. 
Life table analysis is the traditional method for evaluating the mortality/morbidity of a fixed 
population that is followed for a period of time, and the frequency of the events are evaluated at
predefined time intervals. Commonly, if effects exist, they are most likely not constant over time, 
and the life table methodology elucidates the time dependence of the events in relation to the onset 
of an exposure. The most important aspect of the life table method is the incorporation in the 
survival analysis of the duration of the time taken to reach the outcome event [10, 11, 12].
Therefore, the main analysis will be to estimate cumulative incidence rates using life-table 
methodology.
                                                
1 Reporting requirements for cases derived from observational (noninterventional) post-authorisation safety studies 
sponsored by the pharmaceutical industry are laid down in Volume 9A of the Rules governing Medicinal Products in 
the European Union – Guidelines on Pharmacovigilance for Medicinal Products for Human Use. However, it is 
unclear how Volume 9A guidance applies in a preapproval situation. Volume 10 only applies to clinical trials.
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9.2.2
Treatment/Analysis Period
The most relevant analysis period will be the cumulative analysis period, which starts from the 
date of first dose of clinical trial medication to the end of the registry follow-up. In addition, three 
treatment periods are identified: a) the initial treatment period, from the date of first dose of clinical 
trial medication to end of the clinical trial participation; b) the extension treatment period (when 
subjects elects to enroll in a cladribine extension trial) from the date of first dose of cladribine to 
the end of extension trial participation, c) and the registry study period (where subjects do not 
receive any experimentally assigned treatment) from the date of enrollment into the registry to the 
end of registry participation. 
The primary analysis will correspond to the cumulative analysis period, which starts from the date 
of first dose of clinical trial medication to the end of registry follow-up. 
Baseline Assessments
Demographic characteristics (e.g., age, sex) at baseline of the registry will be described using 
descriptive statistics for continuous variables or proportions for categorical variables at entry into 
the registry. Summaries will be provided by region/country. 
Safety Analysis
Primary Endpoints
The cumulative incidence of SADRs and of AEs in the ‘Blood and Lymphatic System Disorders’
and ‘Neoplasms Benign, Malignant, and Unspecified’ SOCs will be summarized, and time to 
resolution of persistent lymphopenia will be estimated using the life table methodology. The first 
occurrence of each endpoint occurring during the cumulative analysis period will be considered 
in the analysis. Cumulative incidence analyses will be presented by MedDRA System Organ Class, 
High Level Group Term, High Level Term, and Preferred Term.
Secondary Endpoints
The proportion of women and the frequency of the pregnancy outcomes including congenital 
disorders and important health conditions in the offspring (defined in Section 6.3), will be 
descriptively summarized. These outcomes will also be described individually for each subject 
who experiences an outcome. 
9.3
Study Reporting and Analysis
Study Progress and Safety Reports
Periodic Progress Reports will be prepared and submitted to Health Authorities as required. 
Safety data from this registry will be included in periodic reports submitted to Health Authorities 
according to applicable regulations. 
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9.3.1
Missing Data
Several attempts will be made to contact subjects and to limit missing data. However, there will 
be no imputation for missing data. For time-to-event analysis, subjects who do not respond after 
repeated attempts to contact them will be censored. Details will be included in the Statistical 
Analysis Plan (SAP).
10
Ethical, Scientific and Regulatory Aspects
10.1
Good Practice and Scientific Advice (Responsibilities of the 
PRP)
10.1.1
Guiding Principles
To help ensure the quality and integrity of pharmacoepidemiologic research, and to provide 
adequate documentation of research methods and results, this study will be conducted under the 
Guidelines for Good Pharmacoepidemiology Practices [1], the ICH Guidelines for Good Clinical 
Practice [2] where applicable, the international 1991 International Guidelines for Ethical Review 
of Epidemiological Studies [3], AHRQ’s guide: Registries for Evaluating Patient Outcomes: A 
User’s Guide [4], and the International Ethical Guidelines for Biomedical Research Involving 
Human Subjects [5].
Outside the preapproval context, the study will comply with the definition of the non-
interventional (non-experimental) study provided in Article 2(c) of Directive 2001/20/EC and its 
refinement provided in Chapter 1.7 Section 1 of Volume 9A of The Rules Governing Medicinal 
Products in the European Union [13]: “In this context, it is considered important to clarify that 
interviews, questionnaires, and blood samples may be considered as normal clinical practice.”
10.1.2
Opinion of External Experts and Scientific Boards
The cladribine DSMB provided guidance to the Sponsor during the development of the registry 
protocol. External experts from 
 also collaborated in the development of the 
Registry protocol. 
The cladribine DSMB has been kept updated on the status of the registry since its initiation in 2009 
and has been informed of all serious adverse events reported for subjects involved in the registry. 
As the cladribine development program has been terminated, the DSMB is no longer required.  
The DSMB will, however, continue to be informed of the progress of the registry until their final 
meeting late in 2012.
10.2
Subject information and informed consent
Before a subject can participate in the registry, he or she must give written informed consent.  The 
informed consent process will be in accordance with ICH GCP, the Declaration of Helsinki and 
local regulatory requirements.  At registry enrollment, all subjects will be informed of the registry 
objectives and overall requirements. Informed consent for enrollment into the registry, access to 
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data from the clinical trial, and from treating physician or hospital will be obtained by the PRP 
before any registry-related activities to collect data from or about that subject are carried out.
Adequate information on risks of the study which, in this case, are limited to potential break of 
confidentiality of some personal identifier and health information, must therefore be given to the 
subject by the PRP before informed consent is obtained (a person designated by the PRP may give 
the information, if permitted by local regulations). 
Subjects with legal incapacity or limited legal capacity will usually not participate in the registry 
(see Section 5.4)
Depending on the national regulations, the form may include consent for direct contact with the 
subject and retrieval of information or supportive documentation from health care providers and/or 
administrative sources other than the PRP. Also, subjects who refuse to enroll in the registry will 
be asked to sign consent for use of their clinical trial data to compare registry non-participants with 
registry participants in terms of demographics, cancer risk factors, and severity of MS. 
10.3
Subject Identification and Privacy
A registry study number (a unique, 17-character standard ID number) will be assigned to each 
subject to allow linkage with the clinical trial identification number and its database. The previous 
clinical trial study number will also be captured. To keep the subject’s identify confidential, the 
registry will use the study registry number of the subject throughout the study.
Each subject’s data collected in the registry will be stored under the registry individual subject 
number. The CRO will store personal contact information securely and separately from all other 
data collected in the registry, so that subjects can be contacted regularly for interviews. Data 
protection and privacy regulations will be observed in capturing, forwarding, processing, and 
storing subject data.
Subjects will be informed accordingly, and will be asked to give their consent on data-handling 
procedures in accordance with national regulations.
Subject and Data Confidentiality:
Every effort will be made to protect participant confidentiality according to the local and 
international data privacy and medical record confidentiality guidance [14].
10.4
Independent Ethics Committee or Institutional Review Board
Prior to commencement of the registry at a given site, the registry protocol will be submitted 
together with its associated documents (e.g., Informed Consent Form, registry CRF) to the 
responsible Independent Ethics Committee (IEC)/ Institutional Review Board (IRB) for its 
favorable opinion/approval. The written favorable opinion/approval of the IEC/IRB will be filed 
in the Investigator Site File and a copy will be filed in the registry master file at the CRO location.
The registry must not start at any site before the Sponsor has obtained written confirmation of a 
favorable opinion/approval from the concerned IEC/IRB. The IEC/IRB will be asked to provide 
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documentation of the date of the meeting at which the favorable opinion/approval was given, and 
of the members and voting members present at the meeting. Written evidence of favorable 
opinion/approval that clearly identifies the registry, the protocol version and the Subject 
Information and Consent Form version reviewed should be provided. Where possible, copies of 
the meeting minutes should be obtained.
Amendments to the protocol will also be submitted to the concerned IEC/IRB, before 
implementation in case of substantial changes in a manner consistent with national regulations (see 
Section 11.6). Relevant safety information will be submitted to the relevant IECs/IRBs during the 
course of the registry in accordance with national regulations and requirements.
10.5
Regulatory Authorities
The protocol and any applicable documentation (e.g., Informed Consent Form) will be submitted 
or notified to the appropriate regulatory authorities in accordance with the regulations of the 
countries involved in the registry.
11
Registry Management
11.1
Manual of operations
Each participating site will receive the Manual of Operations (MOP), which describes all processes 
that the PRP or representative must understand. 
11.2
Case report form handling
Data will be collected utilizing a web-based electronic data capture (EDC) system. 
The PRP or the trained study site personnel will enter the data required by the registry directly into 
the web-based system at the time of subject enrollment and during follow-up of individual 
outcomes. Instructions for proper completion of the electronic case report forms (e-CRFs) and on 
how to use the EDC system will be provided to the site. An access code with login password will 
be provided to the registry physician following training. Any additional persons authorized to enter 
data into the e-CRFs will be provided with a personal access code following training. The PRP is 
responsible for ensuring that all section of the e-CRF are complete and correct and those entries 
can be verified against source data. 
If a PRP becomes involved in follow-up with other clinicians, the associated documentation 
provided by other clinicians will be maintained in the subject’s registry file at the site.
Data will undergo an automated data quality review process, which checks for completeness and 
accuracy. In case of data deficiencies, electronic queries will be generated and sent to the site for 
correction.
The PRP and trained site personnel will obtain subject-reported data through standardized 
structured subject questionnaires administered.
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11.3
Source documents
The PRP should maintain source documents for each subject enrolled in the registry. Investigator 
evaluations recorded directly into the e-CRF and subject questionnaires will be considered as 
source data. Any documentation provided by other clinicians, who may be seeing the subject 
during the registry, will be considered as source notes and maintained at site.
11.4
Site Filing and Archiving
The Investigator will be provided with an Investigator Site File upon initiation of the registry. This 
file will contain all documents necessary for the conduct of the registry and will be updated and 
completed throughout the registry. It must be available for review by the Monitor, must be ready 
for inspection by Health Authorities during and after the registry, and must be safely archived for 
at least 15 years after the end of the registry. The documents to be archived include the Subject 
Identification List and the signed subject Informed Consent Forms. If archiving of the Investigator 
Site File is no longer possible at the site, the Investigator must notify the Sponsor.
All original subject files (medical records and completed registry participant Questionnaires) must 
be stored at the site (hospital, research institute, or practice) for the longest possible time permitted 
by the applicable regulations, and/or as per ICH GCP guidelines, whichever is longer. In any case, 
the Investigator should ensure that no destruction of medical records is performed without the 
written approval of the Sponsor.
11.5
Monitoring, Quality Assurance, and Inspection by authorities
The PRP and study staff will be trained on the study procedure prior to registry start. Monitoring 
will be performed either by site visit or remotely to check the completeness of subject 
questionnaires and the accuracy of entries on the e-CRFs. Details of monitoring plan will be found 
in the Manual of Operations. The protocol, each step of the data capture procedures, the handling 
of data, as well as the eventual registry report; will be subject to independent Clinical Quality 
Assurance Audits. The CRO, the Sponsor and the Heath Authorities may conduct site audits at 
any time during or after registry operations to ensure the validity and integrity of the data.
11.6
Changes to the Protocol
Changes to the protocol will be documented in written Protocol Amendments. Major (substantial, 
significant) amendments will usually require submission to the Health Authorities and to the 
relevant IEC/IRB for approval or favorable opinion. In such cases, the amendment will be 
implemented only after approval or favorable opinion has been obtained.
Minor (non substantial) protocol amendments, including administrative changes, will be filed by 
Sponsor or the CRO and at each PRP clinic. They will be submitted to the relevant IEC/IRB or to 
Health Authorities where requested by pertinent regulations.
Any amendment that could have an impact on the subject’s agreement to participate in the registry, 
e.g., changing the number of interviews, requires the subject’s informed consent prior to 
implementation.
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11.7
Registry Report and Publication Policy
11.7.1
Final Report
After completion of the registry, a final study report will be written by the CRO in consultation 
with Sponsor, the Coordinating Registry Physician selected principal registry physicians and 
selected group of experts.
11.7.2
Publication
Findings of the trial that have public health impact will be communicated to regulatory agencies 
and the public according to regulatory and scientific guidance. Publications will follow the 
International Committee of Medical Journal Editors guidelines. [15]
Each participating PRP will inform the Sponsor in advance about any plans to publish or present 
data from the registry.
Any publications and presentations of the results (abstracts in journals or newspapers, oral 
presentations, etc.) will require pre submission review by the Sponsor.
12
References
1. International 
Society 
for 
Pharmacoepidemiology 
(ISPE). 
Guidelines 
for 
good 
pharmacoepidemiology 
practices 
(GPP), 
revision 
2. 
April 
2007. 
Available 
at 
http://www.pharmacoepi.org/resources/guidelines_08027.cfm. Accessed 20 December 2011.
2. International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use. Note for guidance on good clinical practice 
(CPMP/ICH/135/95). 
2002. 
http://www.emea.europa.eu/pdfs/human/ich/013595en.pdf. 
Accessed 20 December 2011.
3. Council for International Organizations of Medical Sciences (CIOMS). 1991 International 
guidelines for ethical review of epidemiological studies. 1991. Available at: 
http://www.cioms.ch/publications/guidelines/1991_texts_of_guidelines.htm 
Accessed 
20 
December 2011.
4. Gliklich RE, Dreyer NA (editors). Registries for Evaluating Patient Outcomes: A User’s 
Guide. Prepared by Outcome DEcIDE Center (Outcome Sciences, Inc., dba Outcome) under 
Contract No. HHSA290200500351TO1. AHRQ Publication No. 07-EHC001-1. Rockville, 
MD: Agency for Healthcare Research and Quality; April 2007.
5. Council for International Organizations of Medical Sciences (CIOMS). International ethical 
guidelines for biomedical research involving human subjects. 2002. Available at: 
http://www.cioms.ch/publications/layout_guide2002.pdf Accessed 20 December 2011.
6. Confavreaux C, Vukusic S. Natural history of multiple sclerosis: a unifying concept. Brain 
2006; 129: 606-16.
7. Kremenchutzky M, Rice GPA, Baskerville J, Wingerchuk DM, Ebers GC. The natural history 
of multiple sclerosis: a geographically based study 9: observations on the progressive phase of 
the disease. Brain 2006; 129: 584-98.
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8. National Cancer Institute, Cancer Therapy Evaluation Program. Common Terminology 
Criteria 
for 
Adverse 
Events 
v4.03 
(CTCAE). 
14 
June 
2010. 
Available 
at 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html 
(see 
CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf).  Accessed 20 December 2011. 
9. European Medicines Agency (EMEA), Committee for Medicinal Products for Human Use. 
Guideline on the exposure to medicinal products during pregnancy: need for post-authorisation 
data 
[EMEA/CHMP/313666/2005]. 
14 
November 
2005. 
Available 
at 
http://www.emea.europa.eu/pdfs/human/phvwp/31366605en.pdf . Accessed 20 December 
2011. 
10. Cutler SJ, Ederer F. Maximum utilization of the life table method in analyzing survival. J 
Chronic Dis 1958 Dec; 8(6): 699-712.
11. Chiang CL. Introduction to stochastic processes in biostatistics. Wiley, New York, 1968.
12. Kahn HA, Sempos CT (editors). Follow-up studies: life tables. In: Statistical methods in 
epidemiology; 168-205. Oxford University Press, New York, 1989.
13. European Commission. The rules governing medicinal products in the European Union. 
Volume 9A - Pharmacovigilance for Medicinal Products for Human Use. September 2008. 
Available at: http://ec.europa.eu/health/documents/eudralex/vol-9/index_en.htm. Accessed 20 
December 2011.
14. International Society for Pharmacoepidemiology (ISPE). Data privacy, medical record 
confidentiality, and research in the interest of public health. 1997. Available at: 
http://www.pharmacoepi.org/resources/privacy.cfm. Accessed 20 December 2011.
15. International Committee of Medical Journal Editors. Uniform requirements for manuscripts 
submitted to biomedical journals: writing and editing for biomedical publication. Updated 
April 2010. Available at: http://www.icmje.org/. Accessed 20 December 2011.
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13
Appendices
Appendix I 
Schedule of Interviews
Registry Period
Day 1
Year 1
Year 2
Year 3
Mo
36
Year 4
Mo 
48
Year 5
Mo 
60
Year 6
Mo 72
Year 7
Mo 84
Year 8 or 
2018
Mo 96
(Whichever 
comes first)
Registry 
baseline
M
o 
3
Mo 
6
Mo 
9
Mo 
12
Mo 
15
M
o 
18
M
o 
21
Mo 
24
Informed consent
X
Inclusion/exclusio
n criteria
X
Baseline 
questionnaire 
X
Identification of 
lymphopenia
X
Follow-up 
questionnaire
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Registry 
Completion /
Early Termination
Lag Questionnaire 
(Only if 
applicable)
X
IC = informed consent; 
a A window of ± 2 weeks around the date of the scheduled visit during the first two years and of ± 4 weeks thereafter in follow-up scheduled interviews is allowed.
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Appendix II 
Schedule of interviews for pregnancies and offspring
Offspring Age
Pregnancy Period
Pregnancy Reported
4 - 7 Months after LMPa
10 Months after LMPa
6 moa
1 yra
Pregnancy baseline 
questionnaire
X
Pregnancy follow-up 
questionnaire 
X
X
Baseline neonatal 
questionnaire
X
Offspring follow-up 
questionnaire
X
X
LMP = last menstrual period.
a Ideally will coincide with scheduled follow-up interview.
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Appendix III 
Major structural birth defects or genetic syndromes
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