Conditions: Hemorrhagic Stroke Intracerebral Hemorrhage (ICH)
Keywords: stroke intracerebral hemorrhage ICH BAF312 siponimod sphingosine-1-phosphate receptor adult
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 32
Healthy volunteers: no

Brief summary:
This is a randomized, placebo-controlled, subject and investigator-blinded study to evaluate efficacy, safety and tolerability of BAF312 in participants with intracerebral hemorrhage (ICH)

Detailed description:
This was the first trial of BAF312 in ICH patients to evaluate if BAF312 had the potential to limit brain inflammation after ICH, and thereby improve neurological outcome for stroke patients when administered in addition to standard of care.

ICH patients meeting study criteria were randomized at 1:1 ratio into either active or placebo group. Patients received an intravenous infusion (i.v.) treatment within 24 hours of an ICH event and were up titrated for 7 days. Following the i.v. treatment, participants received 10 mg BAF312 or placebo in tablet form (taken daily orally) for an additional 7 days. Participants were followed for an additional 76 days after treatment for neurological and safety conditions during three clinic visits.

Recruitment for the trial was put on hold due to the COVID-19 pandemic. Thirty-two patients had been enrolled in the trial and completed the protocol as planned. After seven months of the trial being on hold, an Interim analysis was conducted and reviewed by the Data Monitoring Committee. Novartis terminated the trial due to lack of potential efficacy.

Arms:
arm 1: Days 1 - 7, IV up titration; days 8 - 14, 10 mg (5 x 2 mg tablets) taken daily orally arm 2: Days 1 - 7, IV up titration; days 8 - 14, 10 mg (5 x 2 mg tablets) taken daily orally - matching placebo

Interventions: intervention 1: BAF312 solution intervention 2: Matching Placebo for BAF312 solution intervention 3: BAF312 tablet intervention 4: Matching Placebo for BAF312 tablet
Intervention descriptions: intervention 1: Solution for intravenous (IV) infusion - 4.5mg/4.5mL intervention 2: Solution for intravenous (IV) infusion - 0mg/4.5mL matching placebo intervention 3: 2 mg film-coated tablet intervention 4: 0 mg film-coated tablet matching placebo

Protocol document:
Prot_000.pdf: 
Novartis Institutes for BioMedical Research
BAF312
Clinical Trial Protocol CBAF312X2207 / NCT03338998
A phase II, patient- and investigator-blinded, randomized, 
placebo-controlled study to evaluate efficacy, safety and 
tolerability of BAF312 (siponimod) in patients with stroke 
due to intracerebral hemorrhage (ICH)
Document type:
Amended Protocol Version
EUDRACT number:
2015-005738-23
Version number:
v02 (Clean)
Clinical Trial Phase:
II
Release date:
25-Mar-2019
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis


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Amended Clinical Trial Protocol Version 02 (Clean)
Protocol No. CBAF312X2207
Site Operations Manual (SOM)
A Site Operations Manual (SOM) accompanies this protocol, providing the operational details 
for study conduct. Note: The SOM will not form part of the Clinical Study Report.
Notification of serious adverse events
Dear Investigator,
You must report a serious adverse event (SAE) (initial or follow-up) to Novartis as summarized 
below. Refer to Section 9.2 of the protocol for SAE criteria and additional requirements.  See 
also page 2 of the Site Operations Manual for further details on the method of reporting a SAE.

Complete SAE report

Submit SAE report to Novartis Chief Medical Office and Patient Safety (CMO&PS)
within 24 hours after awareness of the SAE

Notify the Novartis Medical Lead

The fax number(s) and email address(es) are located in the Site Operations Manual.


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Table of contents
Site Operations Manual (SOM)...........................................................................................2
Notification of serious adverse events.................................................................................2
Table of contents .................................................................................................................3
List of tables ........................................................................................................................7
List of figures ......................................................................................................................7
List of abbreviations............................................................................................................8
Pharmacokinetic definitions and symbols.........................................................................11
Glossary of terms...............................................................................................................12
Protocol Summary.............................................................................................................19
1
Introduction .......................................................................................................................22
1.1
Background............................................................................................................22
1.1.1
Unmet Medical Need ............................................................................22
1.1.2
Pathophysiology of ICH........................................................................22
1.1.3
Pharmacology of Sphingosine-1-Phosphate (S1P) Receptors ..............22
1.2
Nonclinical data.....................................................................................................23
1.2.1
Teratogenicity and reproductive toxicity data.......................................24
1.3
Clinical data...........................................................................................................25
1.3.1
Human safety and tolerability data .......................................................25
1.3.2
Human pharmacokinetic data................................................................26
1.3.3
Human pharmacodynamic data.............................................................27
1.4
Study purpose ........................................................................................................27
2
Objectives and endpoints...................................................................................................27
2.1
Primary objective(s)...............................................................................................27
2.2
Secondary objective(s)...........................................................................................27
2.3
Exploratory objective(s) ........................................................................................28
3
Investigational plan ...........................................................................................................29
3.1
Study design...........................................................................................................29
3.2
Rationale of study design.......................................................................................31
3.3
Rationale for dose/regimen, route of administration and duration of treatment....32
3.4
Rationale for choice of comparator .......................................................................32
3.5
Rationale for choice of background therapy..........................................................32
3.6
Purpose and timing of interim analyses/design adaptations..................................33
3.7
Risks and benefits..................................................................................................33
3.7.1
Blood sample volumes..........................................................................35
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4
Population..........................................................................................................................35
4.1
Inclusion criteria ....................................................................................................35
4.2
Exclusion criteria...................................................................................................36
5
Restrictions for Study Subjects .........................................................................................38
5.1
Contraception requirements...................................................................................38
5.2
Prohibited treatment...............................................................................................39
5.3
Dietary restrictions.................................................................................................39
5.4
Other restrictions ...................................................................................................39
6
Treatment...........................................................................................................................39
6.1
Study treatment......................................................................................................39
6.1.1
Investigational treatment and control drug(s) .......................................40
6.1.2
Additional study treatment....................................................................40
6.2
Treatment arms......................................................................................................40
6.3
Treatment assignment and randomization.............................................................40
6.4
Treatment blinding.................................................................................................41
6.5
Treating the subject................................................................................................42
6.6
Permitted dose adjustments and interruptions of study treatment.........................43
6.7
Emergency breaking of assigned treatment code ..................................................45
6.8
Treatment exposure and compliance .....................................................................46
6.9
Recommended treatment of adverse events ..........................................................46
6.10
Rescue medication.................................................................................................46
6.11
Concomitant treatment...........................................................................................47
7
Study completion and discontinuation ..............................................................................47
7.1
Study completion and post-study treatment ..........................................................47
7.2
Discontinuation of study treatment........................................................................47
7.3
Withdrawal of informed consent ...........................................................................49
7.4
Lost to follow-up ...................................................................................................49
7.5
Study stopping rules ..............................................................................................49
7.6
Early study termination by the sponsor .................................................................50
8
Procedures and assessments ..............................................................................................51
8.1
Assessment schedule .............................................................................................51
8.2
Informed consent procedures.................................................................................53
8.3
Subject screening...................................................................................................53
8.4
Subject demographics/other baseline characteristics.............................................54
8.5
Efficacy / Pharmacodynamics ...............................................................................54
8.5.1
Clinical Outcome Assessments (COAs) ...............................................54
8.6
Safety.....................................................................................................................56


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8.6.1
Physical examination ............................................................................56
8.6.2
Vital signs..............................................................................................56
8.6.3
Clinical laboratory evaluations .............................................................56
8.6.4
Electrocardiogram (ECG) .....................................................................57
8.6.5
Pregnancy test and assessments of fertility...........................................58
8.7
Pharmacokinetics...................................................................................................58
8.8
Other assessments..................................................................................................59
8.9
Use of residual biological samples ........................................................................59
9
Safety monitoring..............................................................................................................59
9.1
Adverse events.......................................................................................................59
9.2
Serious adverse event reporting.............................................................................61
9.2.1
Definition of SAE .................................................................................61
9.2.2
SAE reporting........................................................................................62
9.3
Liver safety monitoring .........................................................................................63
9.4
Renal safety monitoring.........................................................................................64
9.5
Reporting of study treatment errors including misuse/abuse ................................64
9.6
Pregnancy reporting...............................................................................................65
9.7
Prospective suicidality assessment ........................................................................66
9.8
Early phase safety monitoring ...............................................................................66
10 Data review and database management.............................................................................66
10.1
Site monitoring ......................................................................................................66
10.2
Data collection.......................................................................................................67
10.3
Database management and quality control............................................................67
10.4
Data Monitoring Committee..................................................................................68
10.5
Adjudication Committee........................................................................................68
11 Data analysis......................................................................................................................68
11.1
Analysis sets ..........................................................................................................68
11.2
Subject demographics and other baseline characteristics......................................68
11.3
Treatments .............................................................................................................69
11.4
Analysis of the primary variable(s) .......................................................................69
11.4.1
Primary Variable(s)...............................................................................69
11.4.2
Statistical model, hypothesis, and method of analysis..........................69
11.4.3
Handling of missing values/censoring/discontinuations.......................69
11.4.4
Sensitivity analyses ...............................................................................69
11.5
Analysis of secondary variable(s)..........................................................................70
11.5.1
Efficacy / Pharmacodynamics...............................................................70
11.5.2
Safety.....................................................................................................70


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11.5.3
Pharmacokinetics ..................................................................................70
11.5.4
Pharmacokinetic / pharmacodynamic interactions................................71
11.5.5
Other assessments .................................................................................71
11.6
Analysis of exploratory variables ..........................................................................71
11.7
Sample size calculation..........................................................................................72
11.8
Power for analysis of key secondary variables......................................................72
11.9
Interim analyses.....................................................................................................73
12 Ethical considerations........................................................................................................73
12.1
Regulatory and ethical compliance........................................................................73
12.2
Responsibilities of the investigator and IRB/IEC..................................................73
12.3
Publication of study protocol and results...............................................................74
12.4
Quality Control and Quality Assurance.................................................................74
13 Protocol adherence ............................................................................................................74
13.1
Protocol Amendments ...........................................................................................74
14 References .........................................................................................................................76
15 Appendix 1: Liver Event Definitions and Follow-up Requirements.................................80
16 Appendix 2: Specific Renal Alert Criteria and Actions....................................................82
17 Appendix 3: Clinically notable laboratory values and vital signs.....................................84
18 Appendix 4: Modified Rankin Scale .................................................................................85
20 Appendix 6: Glasgow Coma Scale (GCS) ........................................................................94
21 Appendix 7: List of prohibited medications......................................................................95
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List of tables
Table 5-1
Prohibited Medications .........................................................................39
Table 6-1
Overview of study medication ..............................................................40
Table 6-2
Blinding levels ......................................................................................42
Table 8-1
Assessment schedule.............................................................................51
Table 9-1
Guidance for capturing study treatment errors......................................65
Table 15-1
Liver Event Definitions.........................................................................80
Table 15-2
Actions required for Liver Events.........................................................80
Table 15-3
Exclusion of underlying liver disease ...................................................81
Table 16-1
Specific Renal Alert Criteria and Actions.............................................82
Table 16-2
Follow-up of renal events......................................................................83
Table 17-1
Notable Vital Signs And Body Weight.................................................84
Table 21-1
Typical inhibitors of CYP2C9 or CYP3A4 ..........................................95
Table 21-2
Typical inducers of CYP2C9 and/or CYP3A4 .....................................96
List of figures
Figure 6-1
AHA Guidelines for Emergency Cardiovascular Care .........................45
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List of abbreviations
ACR
AE
AHA
Albumin-creatinine ratio
adverse event
American Heart Association
ALT
alanine aminotransferase
aPHE
ASA
absolute perihematoma edema
American Stroke Association
AST
bICH
aspartate aminotransferase
blood intracerebral hemorrhage model
cICH
collaginase intracerebral hemorrhage model
C-SSRS
Columbia Suicide Severity Rating Scale
CFR
U.S. Code of Federal Regulations
CMO&PS
CNS
COAs
Chief Medical Office & Patient Safety
Central nervous system
Clinical outcome assessments
CPK
Creatinine phosphokinase
CPRC
Clinical Pharmacology Review Committee
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CRP
C-reactive protein
CT
computed tomography, refers to X-ray CT in this study
CTCAE
Common Toxicity Criteria for Adverse Events
CV
DAR
DDE
coefficient of variation
dose administration record
direct data entry
DIBD
DIC
Development International Birth Date
Disseminated intravascular coagulation
DMC
Data Monitoring Committee
ECG
eCRFs
Electrocardiogram
Electronic case report forms
EDC
Electronic Data Capture
EMA
European Medicines Agency


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ESO
European Stroke Organisation
eSource
EVD
FAS
Electronic Source
External ventricular drain
Full analysis set
FDA
Food and Drug Administration
GCP
GCS
GEE
Good Clinical Practice
Glasgow Coma Scale
Generalized estimating equation
GGT
Gamma-glutamyl transferase
h
hour
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HDL
High-density lipoprotein
HR
heart rate
i.v.
IB
Intravenous
Investigators brochure
ICH
intracerebral hemorrhage
ICU
intensive care unit
IEC
IN
Independent Ethics Committee
Investigators notification 
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
IUD
IUS
Interactive Response Technology
Intrauterine device
Intrauterine system
IVH
Intraventricular hemorrhage
LDL
Low-density lipoprotein
MedDRA
Medical dictionary for regulatory activities
mg
milligram(s)
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mL
MRI
MTD
NIHSS
milliliter(s)
magnetic resonance imaging
maximum tolerated dose
National Institutes of Health Stroke Scale
NPO
nil per os, or nothing by mouth
oGS
Original Graeb Score
p.o.
Oral
PD
PHE
pharmacodynamic(s)
perihematoma edema
PK
PML
PPS
pharmacokinetic(s)
progressive multifocal leukoencephalopathy
per protocol set
PT
prothrombin time
QD
QM
Once daily
Quality management
rPHE
relative perihematoma edema
RRMS
Relapsing remitting multiple sclerosis
SAE
serious adverse event
sCR
serum creatinine
SD
standard deviation
SOM
Site Operations Manual
SUSAR
TBI
Suspected Unexpected Serious Adverse Reactions
Traumatic brain injury
TBL
total bilirubin
ULN
upper limit of normal
VZV
varicella zoster virus
WBC
white blood cell(s)
WHO
World Health Organization
WoC
Withdrawal of Consent


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Pharmacokinetic definitions and symbols
AUC0-t
The area under the plasma (or serum or blood) concentration-time curve from 
time zero to time 't' where t is a defined time point after administration [mass 
x time / volume]
Cmax
The observed maximum plasma (or serum or blood) concentration following 
drug administration [mass / volume]
T1/2
The terminal elimination half-life [time]


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Cohort
A specific group of subjects fulfilling certain criteria
Control drug
Any drug(s) (an active drug or an inactive drug, such as a placebo) 
which is used as a comparator to the investigational drug being tested 
in the trial
Dosage
Dose of the study treatment given to the subject in a time unit (e.g. 100 
mg once a day, 75 mg twice a day)
Electronic 
Data 
Capture (EDC)
Electronic data capture (EDC) is the electronic acquisition of clinical 
study data using data collection systems, such as Web-based 
applications, interactive voice response systems and clinical laboratory 
interfaces. 
EDC includes the use of Electronic Case Report Forms (eCRFs) which 
are used to capture data transcribed from paper source forms used at the 
point of care.
Enrollment
Point/time of subject entry into the study at which informed consent 
must be obtained (i.e. prior to starting any of the procedures described 
in the protocol)
Epoch
Interval of time in the planned conduct of a study. An epoch is 
associated with a purpose (e.g. screening, randomization, treatment, 
follow-up) which applies across all arms of a study.
eSource
eSource Direct Data Entry (DDE) refers to the capture of clinical study 
data electronically, at the point of care. eSource combines source 
documents and case report forms (eCRFs) into one application, 
allowing for the real time collection of clinical trial information to 
sponsors and other oversight authorities, as appropriate.
Healthy volunteer
A person with no known significant health problems who volunteers to 
be a study participant 
Investigational 
drug
The study drug whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and Directive 
2001/20/EC and is synonymous with “investigational new drug,” 
"Investigational Medicinal Product," or “test substance”
Medication 
pack 
number
A unique identifier on the label of each drug package in studies that 
dispense study treatment using an IRT system
Patient
Personal Data
An individual with the condition of interest
Subject information collected by the Investigator that is transferred to 
Novartis for the purpose of the clinical trial. This data includes subject 
identifier information, study information and biological samples. 


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Randomization 
number
A unique identifier assigned to each randomized subject, corresponding 
to a specific treatment arm assignment
Run in Failure
A subject who is screened but not randomized/treated after the run-in 
period (where run-in period requires adjustment to subject’s 
medications or other intervention)
Screen Failure
A subject who is screened but is not treated or randomized
Source 
Data/Document
Source data refers to the initial record, document, or primary location 
from where data comes. The data source can be a database, a dataset, a
spreadsheet or even hard-coded data, such as paper or eSource
Study treatment
Any drug or combination of drugs administered to the study participants 
as part of the required study procedures; includes investigational 
drug(s), control(s) or background therapy
Study 
treatment 
discontinuation
When the subject permanently stops taking study treatment prior to the 
defined study treatment completion date
Subject
A trial participant (can be a healthy volunteer or a patient)
Subject number
A unique number assigned to each subject upon signing the informed 
consent. This number is the definitive, unique identifier for the subject 
and should be used to identify the subject throughout the study for all 
data collected, sample labels, etc.
Treatment number
A unique identifier assigned in non-randomized studies to each dosed 
subject, corresponding to a specific treatment arm 
Variable
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being tested 
in the study
Withdrawal 
of 
study 
consent 
(WoC)
Withdrawal of consent from the study occurs only when a subject does 
not want to participate in the study any longer, and does not allow any 
further collection of personal data


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Protocol No. CBAF312X2207
Protocol Summary
Protocol number
CBAF312X2207
Full Title
A phase II, patient- and investigator-blinded, randomized, placebo-controlled 
study to evaluate efficacy, safety and tolerability of BAF312 (siponimod) in 
patients with stroke due to intracerebral hemorrhage (ICH).
Brief title
Study of efficacy, safety and tolerability of BAF312 in patients with 
intracerebral hemorrhage (ICH)
Sponsor and 
Clinical Trial 
Phase
Novartis; Phase II
Intervention type
Drug
Study type
Interventional
Purpose and 
rationale
The purpose of the study is to investigate the initial efficacy and safety of 
BAF312 administered on top of standard-of-care compared to placebo in 
patients with stroke due to ICH; and to determine if the overall clinical profile 
of BAF312 warrants further clinical development in ICH. 
Primary 
Objective(s)
To obtain the first efficacy estimate of 2 weeks of BAF312 daily (7 days i.v. 
with up-titration followed by 7 days p.o.) on reducing perihematoma edema 
(PHE) compared to placebo on day 14 after ICH.
Secondary 
Objectives
To assess the safety profile of BAF312 in ICH patients.
To evaluate the pharmacokinetics of BAF312 in ICH patients.
Study design
This is a randomized, patient- and investigator-blinded, placebo-controlled, 
parallel group study of BAF312 on top of standard-of-care for ICH.
Population
The study population consists of adult male or female patients with stroke due 
to ICH between age of 18 and 85 years (inclusive). Approximately 33 patients 
per treatment group (BAF312 or placebo) will be randomized for a total of 
60 patients completing the protocol.
Key Inclusion 
criteria
1.
Male or female patients aged 18 to 85 years (inclusive).
2.
Written informed consent obtained before any study assessment is
performed. If the patient is not able to give the informed consent
personally, consent by a relative or legal representative is acceptable.
3.
Spontaneous, supratentorial intracerebral hemorrhage in cerebral cortex
or deep brain structures (putamen, thalamus, caudate, and associated
deep white matter tracts) with a volume ≥ 10 mL but ≤ 60 mL (calculated
by the ABC/2 method, after Kothari et al 1996) determined by routine
clinical MRI or CT.
4.
Patients with the onset of ICH witnessed and/or last seen healthy no
longer than 24 hrs previously.
5.
Patients with Glasgow Coma Scale (GCS) motor score no less than 5
(brings hand above clavicle on stimulus to head or neck).


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Key Exclusion 
criteria
1.
Infratentorial (midbrain, pons, medulla, or cerebellum) ICH.
2.
Secondary ICH due to aneurysm, brain tumor, arteriovenous
malformation, thrombocytopenia, coagulopathy, acute sepsis, traumatic
brain injury (TBI), or disseminated intravascular coagulation (DIC).
3.
Prior disability due to other disease compromising mRS evaluation,
thereby interfering with the primary outcome, operationally defined as an
estimated mRS score (by history) of ≥ 3 before ICH for patients ≤ 80
years of age.  For ICH patients 81-85 years of age, estimated mRS by
history prior to ICH must be ≤1 (no significant disability despite
symptoms).
4.
[Criterion withdrawn by protocol amendment # 2]
5.
Candidates for surgical hematoma evacuation or other urgent surgical
intervention (i.e., surgical relief of increased intracranial pressure) on
initial presentation.
6.
Patients with intraventricular hemorrhage (IVH) having a Graeb score of
>3 on initial presentation. Patients must not have blood in the 4th
ventricle (0 points), and may only have blood in the 3rd ventricle in the
absence of ventricular expansion (≤1 point). Trace or mild hemorrhage in
either or both lateral ventricles (≤1 point each) is permitted.  Patients
with hydrocephalus determined radiographically on initial presentation
are excluded regardless of Graeb score.
7.
Patients with active systemic bacterial, viral or fungal infections.
8.
Current use of concomitant medications with potent CYP2C9/3A4
inhibitory or induction potential; intravenous immunoglobulin,
immunosuppressive and/or chemotherapeutic medications;
9.
Cardiovascular exclusion criteria:

Cardiac conduction or rhythm disorders including sinus arrest or
sino-atrial block, heart rate <50 bpm, sick-sinus syndrome, Mobitz
Type II second degree AV block or higher grade AV block, or
preexisting atrial fibrillation (either by history or observed at
screening).

PR interval >220 msec. Long QT syndrome or QTcF
prolongation >450 msec in males or >470 msec in females on
screening electrocardiogram (ECG).

Patients receiving treatment with QT-prolonging drugs having a
long half-life (e.g., amiodarone).
Study treatment
Treatment should start as soon as possible, 
after the time of onset of ICH symptoms, defined as the time the patient was 
last witnessed healthy.
The total treatment will last 14 days: 7 days of BAF312 i.v. infusion, titrated 
 followed by 7 days of 
 BAF312 
p.o. daily if the patient passes a swallowing safety evaluation. ICH patients
who do not pass a swallowing safety evaluation per participating institutional
standards will not be transitioned to the p.o. phase of treatment, and BAF312
must be discontinued after Day 7. These patients should continue to be
followed for the remainder of the Assessment schedule; they should not be
terminated from the study.
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Pharmacokinetic 
assessments
Pharmacokinetic (PK) samples will be collected on Days 1, 8 and 14.
Efficacy/PD 
assessments
CT imaging of the brain will be performed 24-48 hours after the initial 
diagnostic scan and on Days
14.
Modified Rankin Scale (mRS) and neurological examinations will be assessed 
on Days
 90.
Key safety 
assessments

Adverse event monitoring

ECGs

Vital signs

Physical and neurological examinations

Monitoring of laboratory markers in blood and urine
Other 
assessments

N/A
Data analysis
The primary analysis will be performed on the Per Protocol analysis set (PPS) 
defined as all patients having received at least the first infusion on Day1 and 
with no major protocol deviations impacting the analysis of efficacy.
The primary endpoint is reduction of absolute perihematoma edema (aPHE) 
volume based on CT imaging at Day 14 after ICH. The objective is to compare 
the mean aPHE between the BAF312 and placebo treatment groups.  
Key words
Stroke, intracerebral hemorrhage (ICH), BAF312, siponimod, sphingosine-1-
phosphate (S1P) receptor, efficacy, safety, tolerability
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1
Introduction
1.1
Background
1.1.1
Unmet Medical Need
Stroke remains one of the leading causes of adult death and disability worldwide. Intracerebral 
hemorrhage (ICH) occurs when diseased blood vessels rupture, causing hemorrhage into brain 
tissue. The most common risk factors associated with ICH are hypertension, smoking, and 
diabetes mellitus. ICH constitutes 10-15% of all strokes, and is a common cause of morbidity 
and mortality (Qureshi et al 2001). Although ICH, or hemorrhagic stroke, accounts for a 
minority of all cases of stroke, it results in 50% of stroke deaths, contributing disproportionately 
to stroke morbidity and mortality (Qureshi et al 2001, Asuzu et al 2016). No pharmacological 
interventions have demonstrated significant efficacy to improve functional outcomes after ICH; 
and less than one third of ICH patients attain functional independence by 6 months after ICH. 
As such, treatment options for ICH are limited, and there is an enormous unmet medical need 
for agents that may improve neurological recovery and reduce disability.
1.1.2
Pathophysiology of ICH
ICH triggers a complex cascade of events in the affected tissue, including inflammatory 
processes and edema formation (Urday et al 2015). Neuroinflammation after ICH involves the 
early activation of resident microglia, release of proinflammatory mediators, and the influx of 
peripheral lymphocytes; and is thought to have a major role in the pathophysiology of secondary 
brain damage. Lymphocytes were found in human cerebrospinal fluid early, starting at 6 hours 
post ICH, and were also detected in perihematoma edema (PHE) in ICH patients. It was found 
that CD4+ T cells are the predominating lymphocyte population in mice on day 1. Along with 
other T cell populations, proinflammatory and immunosuppressive regulatory T cells infiltrate 
the hemorrhagic brain (Mracsko and Veltkamp 2014). Despite this information on the 
infiltration pattern of lymphocytes in experimental ICH, less is known about the interactions 
among these immune cells. Because of the delayed nature of secondary brain damage after ICH, 
adaptive immune cells may play an important role in the subacute and the regenerative phases 
after ICH.
1.1.3
Pharmacology of Sphingosine-1-Phosphate (S1P) Receptors
BAF312 (siponimod) acts as a selective modulator of two of the five sphingosine-1-phosphate 
(S1P) receptors: S1P1 and S1P5. T cells selectively require S1P1 activation for emigration from 
the thymus, and both T- and B cells require this receptor for egress from peripheral lymphoid 
organs (Matloubian et al 2004, Brinkmann et al 2004). 
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Two open label trials with another S1P-receptor modulator, fingolimod (Fu et al 2014a, 
Fu et al 2014b), suggest an impact on edema formation and improved neurological outcome in 
ICH and ischemic stroke. However, limitations of the Fu et al. studies include lack of 
randomization, lack of placebo controls, and small sample sizes.
BAF312 is a second generation S1P receptor modulator that reduces peripheral lymphocyte 
counts approximately 4 – 6 hours (h) after the first dose. The half-life of BAF312 is 
approximately 30 h, which allows reversal of pharmacodynamic effects and recovery of the 
baseline lymphocyte counts within a week after treatment withdrawal. BAF312's mode of action 
is believed to include S1P1-mediated prevention of effector lymphocyte recirculation from 
lymphatic tissue to sites of inflammation, such as the central nervous system (CNS). In addition, 
there may be direct beneficial effects in the CNS mediated by S1P1 and/or S1P5. Evidence from 
preclinical models suggests that BAF312 may target S1P1 on astrocytes and/or S1P5 on 
oligodendrocytes (Choi et al 2011).
We seek to evaluate whether reducing peripheral leukocyte count acutely after ICH would 
reduce PHE and decrease secondary injury after ICH, thereby improving outcomes in a 
prospective, randomized study with another S1P-receptor modulator, BAF312.
For more details, please see the Investigator's Brochure.
1.2
Nonclinical data
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1.3
Clinical data
1.3.1
Human safety and tolerability data
S1P receptor modulators are known to cause dose dependent transient decrease in heart rate 
within 2-3 h of drug intake (Legangneux et al 2013, Hoch et al 2014). 
As of 05-Mar-2018, approximately 3279 unique subjects have been enrolled into the siponimod 
clinical program (inclusive of Phase 1, Phase 2 and Phase 3), of which approximately 2742 
unique subjects (912 healthy volunteers, 1787 patients with MS, 43 patients with PM or DM) 
have received siponimod and 925 subjects (297 healthy subjects and 628 patients) have received 
placebo. This includes subjects who sequentially received placebo and siponimod. In addition, 
1 ICH patient has been enrolled in ongoing placebo-controlled study CBAF312X2207 (this 
study) and 363 subjects (all healthy volunteers) were exposed to other drugs.
The cumulative exposure of clinical trial subjects to siponimod since the Development 
International Birth Date (DIBD) of 05-Mar-2009 is estimated to be approximately 4840 patient-
years. Healthy subjects have received siponimod as single doses or as multiple doses (single 
doses: 0.1 mg to 75 mg, multiple doses: 0.25 mg to 20 mg). Patients with MS have received 
siponimod (0.25 mg to 10 mg) daily from 1 day to 73 months during the clinical development 
program (please see Investigators Brochure).
The safety profile of BAF312 includes the following identified risks: transient effects on heart 
rate and rhythm (bradyarrhythmia and 2nd degree AV block) at treatment initiation that are 
completely avoided by initial up-titration; liver enzyme elevation; lymphopenia due to 
lymphocyte redistribution (main targeted PD effect of BAF312); seizures; hypertension; 
macular edema; and varicella zoster (VZV) infection reactivation.
A placebo-controlled Phase II study of BAF312 in 297 patients with relapsing remitting MS 
(RRMS) showed significant dose-response relationship at Month 3. BAF312 treatment reduced 
the combined unique active lesion count by up to 80% vs. placebo, with the 2 mg dose providing 
near-maximal efficacy.  Five transient symptomatic bradyarrhythmic events without sequelae 
were observed with the two highest doses (3/40 on 2 mg, and 2/50 on 10 mg) without titration. 
Serious adverse events (SAEs) included one death 27 days post-study drug discontinuation, 
likely due to previously unrecognized coronary artery disease. Other safety findings included 
liver enzyme elevations that were thought to be dose-related (4.3% of patients at higher dose 
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levels, 2 and 10 mg, had transaminases >3x upper limit of normal) and one case of macula 
edema in a patient with history of uveitis (Selmaj et al 2013), which has been recognized with 
longer-term BAF312 exposure.
The most common AEs were headache, bradycardia, dizziness and nasopharyngitis.  
A dose-dependent effect of BAF312 treatment on the occurrence of headache, bradycardia and 
dizziness reported as AEs was demonstrated.  Common types of infections observed included 
nasopharyngitis, sinusitis, influenza and urinary tract infections, although no apparent treatment 
relationship was evident.
For more details, please see the Investigator’s Brochure.
1.3.2
Human pharmacokinetic data
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1.3.3
Human pharmacodynamic data
BAF312 is a second generation S1P receptor modulator that leads to the reduction of peripheral 
lymphocyte counts at approximately 4 – 6 hours after dose on Day 1.  The half-life of BAF312 
is approximately 30 h, which allows reversal of pharmacodynamic effects and recovery of the 
baseline lymphocyte counts within a week after treatment withdrawal. The mode of action of 
BAF312 is believed to include S1P1-mediated prevention of effector lymphocyte recirculation 
from lymphatic tissue to sites of inflammation, including the central nervous system (CNS). In 
addition, evidence from preclinical models suggests that there may be direct beneficial effects 
in the CNS mediated by S1P1 and/or S1P5 (Choi et al 2011).
1.4
Study purpose
The purpose of the study is to investigate the initial efficacy and safety of BAF312 administered 
on top of standard-of-care compared to placebo in patients with stroke due to ICH; and to 
determine if the overall clinical profile of BAF312 warrants further clinical development in ICH. 
2
Objectives and endpoints
2.1
Primary objective(s)
Primary objective(s)
Endpoints related to primary objective(s)

To obtain the first efficacy estimate of
BAF312 daily (7 days i.v. with
titration followed by 7 days p.o.)
compared to placebo on reducing
absolute perihematoma edema (aPHE)
volume on Day 14 after ICH.

aPHE volume measured by CT scan on
Day 14 after ICH.
2.2
Secondary objective(s)
Secondary objective(s)
Endpoints related to secondary objective(s)

To assess the safety profile of BAF312
in ICH patients.

Continuous assessment of AEs/SAEs
during the course of the study (90 days).

To evaluate the pharmacokinetics of
BAF312 in ICH patients.

PK measurements of plasma BAF312
concentrations at 0.5, 2 and 6 h after start
of infusion during i.v. titration on Day 1;
and before p.o. dosing on Days 8 and 14.
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2.3
Exploratory objective(s)
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3
Investigational plan
3.1
Study design
This is a randomized, patient- and investigator-blinded, placebo-controlled, parallel group study 
of BAF312 on top of standard-of-care for ICH, consisting of 3 epochs: Screening/Baseline, 
Treatment, and Follow-Up (see Figure 3-1).
Screening/Baseline Epoch
The screening/baseline epoch lasts no longer than 24 hours from the time of onset of ICH, 
defined as the time the patient was last witnessed to be at their normal neurological baseline, 
and consists of:

The initial diagnostic neuroimaging study (CT or MRI) to determine the cause of stroke

Obtaining informed consent

Determining the Glasgow Coma Scale (GCS, Appendix 6) score (see Section 20) on
presentation

Obtaining medical history, including current medications

Hospital admission laboratory studies

Electrocardiogram (ECG)

Pregnancy test for premenopausal female patients

Vital signs and physical examination, including neurological examination, and
Please see Assessment schedule for details.
Treatment Epoch
Patients fulfilling all eligibility criteria must be randomly allocated to one of two treatment 
groups in a ratio of 1:1.  The treatment should start as soon as possible, 
 after the time of the ICH, defined as the time the patient was last witnessed to be 
healthy, defined as functioning at their normal, pre-event neurological baseline.  
The total treatment lasts 14 days (see Figure 3-1): 

7 days of i.v. BAF312 with titration to the final daily dose
Patients must be monitored with CV telemetry or continuous bedside monitoring for the first 
48 hours of i.v. BAF312 treatment. During the 7 days of i.v. infusion treatment, all patients 
must undergo a swallowing safety evaluation per the treating hospital’s institutional guidelines 
and practices.

If the patients pass a swallowing safety evaluation, the 7-day i.v. phase is followed by
7 days of 
 BAF312 p.o. QD.

Patients who do not successfully pass a swallowing safety evaluation must not be
transitioned to the p.o. phase of treatment, and BAF312 must be discontinued after
Day 7; but they should not be terminated from the study. These patients should
continue to be followed for the remainder of the Assessment schedule.
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i.v. Dose Titration
The dose titration schedule is based on estimations of the cardiovascular effects of BAF312 
balanced with the therapeutic need to achieve fast, effective BAF312 concentrations in 
ICH patients, where the timely achievement of expected therapeutic concentrations may be of 
great importance.
The BAF312 i.v. titration schedule, specified in Section 6.2 (Treatment arms), is designed to 
minimize the effects of rapid exposure to high concentrations of S1P receptor modulators on 
heart rate by gradually increasing the BAF312 concentration in the infusion over the first two 
days of treatment.
As described in the accompanying Pharmacy Manual, syringe pump changes must occur every 
6 hours, with a window of -15/+30 minutes.
During the i.v. up-titration period patients must be closely monitored. Special attention should 
be given to monitoring of the HR and cardiac rhythm by continuous CV telemetry in the Stroke 
Unit/Neurointensive Care Unit (Stroke/NICU) setting. In case of symptomatic bradycardia or 
cardiac rhythm abnormalities (e.g. atrioventricular blocks or sinus pauses), the Investigator 
must follow the guidance given in Section 6.6. Under those predefined conditions a dose may 
be postponed or skipped, but not more than 2 times in a row.
p.o. Dose
Eligible patients who pass a swallowing safety evaluation will continue with the 7-day p.o. 
phase of treatment with BAF312 
 QD. The daily dose is delivered as 
 2 mg tablets 
(BAF312 or placebo), to be taken in the morning, with or without food.
During the Treatment Epoch, all patients must undergo study-specific assessments according 
to the Assessment schedule.
Follow-Up Epoch
Patients must return for scheduled outpatient (or inpatient, if still in rehabilitation facility) 
follow-up visits after being discharged from the Stroke/NICU or inpatient hospital floor, 
according to the Assessment schedule. The Follow-Up Epoch will last through the Day 90 visit 
after ICH.
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3.2
Rationale of study design
The study uses a randomized, patient and investigator-blinded, parallel-group design on top of 
standard-of-care, which has been used in other clinical trials investigating new treatments in 
patients with acute stroke due to ICH. Treatments are randomized, and blinded to patients and 
investigators to avoid potential reporting bias. Parallel groups are used because strokes are 
usually one-time events.
Perihematoma edema (PHE) has attracted significant attention as a mechanism of secondary 
injury after ICH, thereby contributing to both short-term morbidity and long-term disability 
(Selim and Norton 2018).  
The modified Rankin Scale (mRS) is a widely-used clinical instrument, and is considered the 
current standard assessment for stroke outcomes by most Health Authorities. The follow-up 
observation period of 90 days for assessing improvement in functional disability is a 
well-established time point for stroke studies, including trials in ICH (CPMP Points to 
Consider 2001). The 90-day mRS score has been used as an endpoint in many contemporary 
clinical stroke trials, including INTERACT2 (Anderson et al 2013), ATACH 
(Qureshi et al 2010), SAMURAI-ICH (Koga et al 2014), and ENOS (The ENOS Trial 
Investigators 2015).
Studies published by Fu et al (2014a, 2014b) with fingolimod showed reduction of PHE and 
potential clinical benefit in stroke treatment with an S1P receptor modulator. The pilot data 
published by Fu et al (2014a) with fingolimod need to be reproduced under more rigorous trial 
conditions in a larger population and in another geography. Despite this earlier study with 
fingolimod, the sponsor has selected BAF312 (siponimod) for further development, as the 
considerably shorter half-life of BAF312 may be advantageous in an acute setting, such as ICH.
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3.3
Rationale for dose/regimen, route of administration and duration 
of treatment
Dose titration is introduced with the aim to reduce the bradycardic effects of S1P1 modulators 
during treatment initiation. The proposed i.v. dose-titration scheme is based on estimations of 
the HR effects of BAF312 and therapeutic need to achieve fast, effective concentrations in ICH 
patients. There is currently no knowledge to predict the duration of treatment necessary to 
reduce secondary brain damage due either to perihematomal edema (PHE) or to other potential 
mechanisms. The choice of i.v. administration in the Stroke Unit/NICU setting is based on the 
standard practice of maintaining acute stroke patients NPO on admission until the presence or 
absence of dysphagia can be determined.
3.4
Rationale for choice of comparator
Placebo is the only possible comparator given the absence of any approved treatment for acute 
stroke due to ICH.  
3.5
Rationale for choice of background therapy
All patients in the study should receive supportive standard-of-care treatment for ICH, as laid 
down in the guidance publications of the American Heart Association and the American Stroke 
Association (Hemphill et al 2015), and the European Stroke Organisation (Steiner et al 2014). 
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3.6
Purpose and timing of interim analyses/design adaptations
3.7
Risks and benefits
The risk to patients in this trial must be minimized by compliance with the eligibility criteria 
and study procedures, close clinical monitoring, and clear instructions to the Investigator on 
how to manage symptomatic bradycardia if it occurs.
Bradyarrhythmic effect – Treatment initiation with BAF312 results in transient decrease in 
HR in a dose-dependent manner, with nadir ~3-4 h after the first dose. In a clinical study in MS 
patients (CBAF312A2201) without dose titration, five cases of second degree AV blocks were 
reported: 3/29 in the 2 mg group and 2/50 in the 10 mg group. Implementation of dose titration 
effectively mitigated the occurrence of bradyarrhythmic events. In this study, the dose is titrated 
to the target daily dose of 
 BAF312. The need to achieve fast therapeutic concentration 
was carefully weighed against the need to prevent bradyarrhythmic effects. Unlike ischemic 
stroke, in which reflex tachycardia and increased blood pressure is typically allowed to persist 
(to some extent) to maximize perfusion of the ischemic penumbra, in hemorrhagic stroke most 
supportive therapies are aimed at lowering blood pressure to minimize likelihood of acute 
expansion of the initial hematoma. Given this, transient bradycardia carries significantly less 
risk in the ICH patient population than in patients with ischemic stroke.
During the first 48 hours of treatment, all patients will be on continuous CV telemetry in Stroke 
Units/Neurointensive Care Units, and special attention will be given to the monitoring of the 
HR. In case of symptomatic bradycardia, the Investigator should follow the guidance given in 
Section 6.6. Under those predefined conditions, BAF312 treatment must be interrupted. When 
the heart rate has recovered, the treatment may be started again, as judged by the Investigator.
Risk of infection - The core PD effect of BAF312 is dose-dependent reduction of peripheral 
lymphocyte counts to 20-30 % of baseline due to their sequestration in the lymphoid tissues.  
As a consequence, there is an increased risk of infections. Patients with low baseline 
lymphocyte count are excluded from the study. There were no reports of increased bacterial 
infections between drug and placebo in the MS population with S1P1 modulators (fingolimod 
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and BAF312). Although the risk of infection is considered small given the short treatment 
duration of 14 days, in this critically-ill population this risk might be higher.
Cases of progressive multifocal leukoencephalopathy (PML), have been reported with another 
S1PR modulator, fingolimod, but is extremely unlikely in this population due to the short 
treatment duration. Nevertheless, signs of CNS infections will be routinely monitored, promptly 
investigated, and treated as per standard medical practice. Although not the preferred imaging 
modality for PML per se, all study patients will have CT imaging of the brain performed at 7 
and 14 days after ICH, as well as ongoing neurological examinations (see Assessment schedule). 
Effective diagnostic and therapeutic strategies should be employed in patients with infections.
Aspiration pneumonia – Respiratory tract infections were reported only in 3 patients with MS 
on BAF312 (N=235) and none on placebo (N=61). While the risk of aspiration pneumonia 
cannot be excluded in this population, it is not believed to be increased by BAF312 treatment. 
All ICH patients must be monitored in the Stroke Unit/NICU setting for at least the first 
48 hours after ICH, and standard-of-care treatment interventions should be implemented in 
cases of aspiration pneumonia.
Urinary tract infections – In the clinical trials conducted in MS patients, the incidence of 
overall infections was not different between placebo and BAF312 (5% in BAF312 and 3.5% in 
placebo). Patients with ICH requiring urinary catheterization might be at a higher risk of urinary 
infections, which should be treated per the standard-of-care in the Stroke Unit/NICU.
Blood pressure – In the healthy volunteer and MS population, the blood pressure lowering 
effect of BAF312 was very weak upon initiation. Small elevations in blood pressure were seen 
with siponimod treatment. The mechanism of these effects is unclear, but is potentially the 
result of unopposed natural sphingosine-1-phosphate ligand stimulation of S1PR type 2/3 
(S1P2/3) endothelial receptors, owing to the strong functional antagonism of S1P1 by 
siponimod (Brinkmann et al 2010). Even taking into account that the population for this study 
is likely to be older, minimal effects are nonetheless expected with this BAF312 dose and short 
treatment duration.
Elevated liver function tests – In the Phase 2 dose-finding study in MS patients, elevated liver 
function tests > 3 x ULN were noted in 4.3% of patients in BAF312 (10 mg and 2 mg) groups. 
However, the short treatment duration of this study will likely reduce the frequency of 
treatment-related liver enzyme elevations.
Macular edema – The occurrence of macular edema with BAF312 in the present study is 
unlikely given the short treatment duration.  However, the Investigator should be aware that 
patients with diabetes mellitus and previous uveitis might be at risk of developing macular 
edema. If the patient reports vision disturbances, they should be referred to an ophthalmologist 
for OCT measurement.
Radiation dose considerations from CT scans – Patients enrolled in this trial will have 
 non-contrast head CT scans- two as part of routine standard-of-care for ICH determination 
and follow-up (one at presentation/inclusion and another 24-48 hours later- corresponding to 
V1 and V2 in the Assessment schedule) and
 follow-up study scans  
 at Days
 
 14 (V10). Scans from 
 Day 14 will be used for quantitative assessment 
of efficacy of BAF312 via determination of hemorrhage and edema volumes, as described 
elsewhere in this document. The effective radiation dose per scan is expected to be 
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approximately 2 mSv, amounting to a total of 8 mSv including the two standard-of-care scans 
(V1 and V2) (McCollough et al 2015 and Smith-Bindman et al 2009). This is considered to be 
a minor to intermediate risk level corresponding to the benefit to the patient (category IIb based 
on ICRP 62 1992) and is balanced against the possible substantial societal benefit gained from 
the trial (European Commission Radiation Protection 1998 and ICRP 62 1992). The radiation 
dose from CT scans will be in accordance with local clinical practice and regulations.
The investigators must regularly review the degree of burden and the risk threshold for the 
patients enrolled in this study.
There may be unknown risks with BAF312 which may be serious and unforeseen in the ICH 
patient population.
The treatment with BAF312 may benefit ICH patients.  In a pilot study with another S1P1
modulator (fingolimod), treated patients showed a reduction of neurologic impairment 
compared to placebo, regained a Glasgow Coma Scale score of 15 by Day 7; and had a NIHSS 
score reduction of 7.5 vs 0.5 in the placebo group (Fu et al 2014a).
Taking into account the nature of the known risks, the short duration of treatment, and the lack 
of alternative specific therapies for ICH, it is considered that the overall risk-benefit is favorable 
to study the therapeutic effect of BAF321 in ICH patients. 
3.7.1
Blood sample volumes
A maximum of 300 mL of blood is planned to be collected over a period of 3 months from each 
patient as part of the study. Additional samples may be required for safety monitoring.
Timings of blood sample collection are outlined in the Assessment schedule (Section 8.1).
A summary blood log is provided in the Site Operations Manual (SOM). Instructions for all 
sample collection, processing, storage and shipment information is also available in the SOM 
and Central Laboratory Manual.
See Section 8.9 regarding the potential use of residual samples. 
4
Population
The study population consists of adult patients with stroke due to ICH fulfilling the eligibility 
criteria listed below at screening.
Approximately 33 patients per treatment group (~65 patients in total) will be randomized to 
obtain at least 60 completed study subjects (Day 14).
4.1
Inclusion criteria
ICH patients eligible for inclusion in this study must fulfill all of the following criteria:
1. Male or female patients aged 18 to 85 years (inclusive).
2. Written informed consent obtained before any study assessment is performed.
If the patient is not able to give the informed consent personally, consent by a relative or
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3. Spontaneous, supratentorial intracerebral hemorrhage in cerebral cortex or deep brain
structures (putamen, thalamus, caudate, and associated deep white matter tracts) with a
volume ≥ 10 mL but ≤60 mL (calculated by the ABC/2 method, after Kothari et al 1996)
determined by routine clinical MRI or CT.
4. Patients with the onset of ICH witnessed and/or last seen healthy no longer than 24 hrs
previously.
5. Patients with Glasgow Coma Scale (GCS) best motor score no less than 5 (brings hands
above clavicle on stimulus to head or neck).
4.2
Exclusion criteria
ICH patients fulfilling any of the following criteria are not eligible for inclusion in this study:
1. Use of other investigational drugs within 5 half-lives of enrollment, or until the expected
pharmacodynamic effect has returned to baseline (for biologics), whichever is longer.
2. History of hypersensitivity to any of the study drugs or to drugs of similar chemical
classes (e.g., fingolimod).
3. Current use of concomitant medications with potent CYP2C9/3A4 inhibitory or induction
potential.
4. Intentionally blank – removed with protocol amendment #2.
5. Infratentorial (midbrain, pons, medulla, or cerebellum) ICH.
6. Candidates for surgical hematoma evacuation or other urgent surgical intervention (i.e.,
surgical relief of increased intracranial pressure) on initial presentation. If during the
treatment period surgical hematoma evacuation or surgical intervention to lower
intracranial pressure becomes indicated, the investigational treatment should be stopped.
7. Patients with intraventricular hemorrhage (IVH) having a Graeb score (oGS) of >3 on
initial presentation. Patients must not have blood in the 4th ventricle (0 points max), and
may only have blood in the 3rd ventricle in the absence of ventricular expansion (≤1 point
max). Trace or mild hemorrhage in either or both lateral ventricles (≤1 point each) is
permitted. Patients with hydrocephalus determined radiographically on initial presentation
are excluded regardless of oGS (see Section 8.8).
8. Secondary ICH due to:
- aneurysm
- brain tumor
- arteriovenous malformation
- thrombocytopenia, defined as platelet count of <150,000/µl
- known history of coagulopathy
- acute sepsis
- traumatic brain injury (TBI)
- disseminated intravascular coagulation (DIC)
9. Prior disability due to other disease compromising mRS evaluation, thereby interfering
with the primary outcome, operationally defined as an estimated mRS score (by history)
of  ≥ 3 before ICH for patients ≤ 80 years of age. For ICH patients 81-85 years of age,
estimated mRS by history prior to ICH must be ≤1 (no significant disability despite
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10. Preexisting unstable epilepsy.
11. Patients with active systemic bacterial, viral or fungal infections.
12. Concomitant drug-related exclusion criteria:
- Intravenous immunoglobulin, immunosuppressive and/or chemotherapeutic medications.
- Moderate immunosuppressives (e.g. azathioprine, methotrexate) and/or fingolimod
within 2 months prior to randomization.
- Stronger immunosuppressives (e.g.  cyclophosphamide, immunosuppressive mAb)
within (minimally) 6 months prior to randomization, or longer with long-lasting
immunosuppressive medications as determined by the investigator.
13. Cardiovascular exclusion criteria:
- Cardiac conduction or rhythm disorders including sinus arrest or sino-atrial block, heart
rate <50 bpm, sick-sinus syndrome, Mobitz Type II second degree AV block or higher
grade AV block, or preexisting atrial fibrillation (either by history or observed at
screening).
- PR interval >220 msec. Long QT syndrome or QTcF prolongation >450 msec in males
or >470 msec in females on screening electrocardiogram (ECG).
- Patients receiving treatment with QT-prolonging drugs having a long half-life (e.g.,
amiodarone).
14. Any of the following abnormal laboratory values prior to randomization:
- White blood cell (WBC) count < 2,000/μl (< 2.0 x 109/L)
- Lymphocyte count < 800/μl (< 0.8 x 109/L)
15. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female
after conception and until the termination of gestation, confirmed by a positive hCG
laboratory test.
16. Patients with any other medically unstable condition or serious laboratory abnormality as
determined by the investigator.
The Investigator must ensure that all patients being considered for the study meet the inclusion 
criteria, above.
Patient selection is to be established by checking through all eligibility criteria at screening.  
A relevant record (e.g. checklist) of the eligibility criteria must be stored with the source 
documentation at the study site.
Deviation from any entry criterion excludes a patient from enrollment into the study.


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5
Restrictions for Study Subjects
For the duration of the study, patients should be informed and reminded of the restrictions 
outlined in this section.
5.1
Contraception requirements
Women of child bearing potential must be informed that taking BAF312 may involve unknown 
risks to the fetus if pregnancy were to occur during the study; and agree that in order to 
participate in the study they must use highly effective methods of contraception during study. 
Highly Effective contraception methods include:

Total abstinence from heterosexual intercourse (when this is in line with the preferred and 
usual lifestyle of the patient). Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are NOT acceptable methods of 
contraception.

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of 
oophorectomy alone, only when the reproductive status of the woman has been confirmed 
by follow up hormone level assessment.

Male sterilization (at least 6 months prior to screening). For female patients on the study, 
the vasectomized male partner should be the sole partner for that patient.

Other forms of contraception that have comparable efficacy (failure rate <1%), for 
example placement of a non-hormonal intrauterine device (IUD) or intrauterine system 
(IUS).
Study CBAF312X2207 will enroll only ICH patients with basal ganglia (putamen, caudate, 
thalamus) primary hemorrhages. This population consists mainly of older patients with long 
histories of smoking, hypertension, and/or diabetes. The study specifically excludes patients 
with secondary ICH (i.e., due to malignancy, vascular malformation, aneurysm, trauma, etc.), 
which is more often the underlying cause in younger patients. As such, with these 
Inclusion/Exclusion Criteria, it is very unlikely that our study will enroll women of 
child-bearing potential. Furthermore, given the significant short-term disability of our ICH 
patients, it is highly unlikely that they will be sexually active during the treatment phase of our 
study, consisting of the first 14 days after their stroke; or immediately thereafter, when they will 
very likely be in an inpatient rehabilitation hospital.
In the unlikely event that a female ICH patient with child-bearing potential enrolled in our study 
choses to become sexually active immediately after the treatment phase, but while still in the 
follow-up phase of the study, all female ICH patients of child-bearing potential should not use 
hormone-containing methods of systemic contraception, oral or injectable, for the duration of 
the study. Alternative methods of contraception should be discussed between these patients and 
their personal physicians, and be decided upon by the patient with the counsel of her doctor.
Contraception requirements start at the Screening/Baseline Visit, and are to be maintained until 
at least 30 days after the last administration of study drug.


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If there is any question that the patient will not reliably comply, the patient should not be entered 
or continue in the study. Male patients must be informed that if a female partner becomes 
pregnant while he is enrolled in the study, contact with the female partner will be attempted to 
request her consent to collect pregnancy outcome information.  
5.2
Prohibited treatment
Use of medications displayed in Table 5-1 are NOT allowed during treatment with BAF312 
due to increased risk of immunosuppression, confounding of efficacy and/or potential 
interaction with study treatment (NB: CYP2C9 and CYP3A4 are the major metabolizing 
enzymes for BAF312).
Table 5-1
Prohibited Medications
Medication
Action to be taken
Immunosuppressive/chemotherapeutic 
medications or procedures, including 
cyclosporine, azathioprine, methotrexate, and 
immunomodulatory mABs
Stop taking. If not possible, consider 
discontinuation of study treatment
Medication that suppress AV conduction (e.g. 
carbamazepine, non-dihydropyridine calcium-
channel blockers, or cardiac glycosides) with 
the exception of beta-blockers
Stop taking. If not possible, consider 
discontinuation of study treatment
Strong inhibitors of CYP2C9 or CYP3A4 
(Table 21-1)
Stop taking. If not possible, consider 
discontinuation of study treatment
Assess ECG and monitor lymphocyte counts
Potent inducers of CYP2C9 (Table 21-2)
Stop taking. If not possible, consider 
discontinuation of study treatment
5.3
Dietary restrictions

No grapefruit or grapefruit juice is to be consumed during the study until 7 days following
the last dose (i.e., Day 21 after ICH).
5.4
Other restrictions

No strenuous physical exercise (e.g. weight training, aerobics), not including formal
rehabilitation therapy, until after Study Completion evaluation.
6
Treatment
6.1
Study treatment
Details on the requirements for storage and management of study treatment, and instructions to 
be followed for patient numbering, prescribing/dispensing and taking study treatment are 
outlined in the Site Operations Manual.


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6.1.1
Investigational treatment and control drug(s)
Table 6-1
Overview of study medication
Study drug name
Formulation
Unit dose
Packaging
Provided 
by
BAF312/placebo
Film-coated Tablet
2 mg / 0 mg
Double blind 
kits
Novartis
BAF312/placebo
Concentrate for 
Solution for Infusion
4.5 mg /4.5 mL 
for BAF312;
0 mg/4.5mL for 
placebo
Double blind 
kits
Novartis
6.1.2
Additional study treatment
All patients will receive standard of treatment and care for patients with ICH according to the 
AHA/ASA (Hemphill et al 2015) and ESO Guidelines (Steiner et al 2014). No additional 
treatment beyond investigational treatment is required for this trial.
General Stroke Unit/Intensive Care Unit management throughout the study needs to be recorded 
on the Concomitant Medication eCRF. Post ICH rehabilitation, dates and therapy sessions 
should also be recorded on the same CRF.
6.2
Treatment arms
Patients will be assigned to one of the following 2 treatment arms in a ratio of 1:1.
Study treatments are defined as:
BAF312
-OR-
Placebo

Days 1 through 7: matching i.v. placebo

Days 8 through 14; matching p.o. placebo QD
6.3
Treatment assignment and randomization
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list will be produced using a validated system that automates the random 
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assignment of patients to randomization numbers. These randomization numbers are linked to 
the different treatment arms, which in turn are linked to medication numbers. A separate 
medication list will be produced by or under the responsibility of Novartis Drug Supply 
Management using a validated system that automates the random assignment of medication 
numbers to packs containing the investigational drug(s).
The randomization scheme for patients will be reviewed and approved by a member of the 
sponsor Randomization Office.
Follow the details outlined in the Site Operations Manual regarding the process and timing of 
treatment assignment and randomization of patients.
6.4
Treatment blinding
This is a patient and investigator-blinded study. Patients and investigators will remain blinded 
to study treatment throughout the study, except where indicated below.
The identity of the treatments will be concealed by the use of study drugs that are all identical 
in packaging, labeling, schedule of administration, appearance, and odor.
Site staff
All site staff (including study investigators, coordinators, and nurses) will be blinded to study 
treatment throughout the study.
In this study, blinded, third-party Independent Raters will rate perihematoma edema (PHE) on 
CT images and mRS Scores from video-recorded interviews.
Unblinding a single patient at a site for safety reasons (i.e., necessary for patient management) 
will occur via an emergency system in place at the site (see Section 6.7).
Sponsor staff or delegate
The following unblinded sponsor roles are required for this study:

Unblinded clinical staff managing drug re-supply to site.

Unblinded PK sample analyst(s)
The independent statistician(s) and independent programmer(s) will be able to access the 
randomization list and treatment assignment information
All unblinded personnel will otherwise keep randomization lists and data or information that 
could unblind other study team members confidential and secure except as described above.
Following final database lock all roles may be considered unblinded.
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Table 6-2
Blinding levels
Role
Time or Event
Randomization 
list generated
Treatment 
allocation & 
dosing
Safety event 
(single subject 
unblinded)
Interim 
Analysis & 
dose 
escalation
Subjects/Patients
B
B
B
B
Site staff
B
B
B
B
Drug Supply and 
Randomization Office
UI
UI
UI
UI
Unblinded sponsor staff 
(see text for details)
B
UI
UI
UI
Independent
statistician/statistical 
programmer/data analysts
B
UI
UI
UI
Independent DMC used 
for assessing interim 
safety results*
B
UI
UI
UI
All other sponsor staff not 
identified above
B
B
B
B
B - Remains blinded
UI - Allowed to be unblinded on individual patient level
* Semi-blinded by treatment group (Group A, Group B, etc.) unless and until a between-group safety
imbalance is seen by DMC (see Section 11.9 Interim analyses).
6.5
Treating the subject
Once a patient meets all eligibility criteria and is randomized to a treatment arm, the treatment 
should start as soon as possible, 
 after the time of the ICH, defined as the 
time the patient was last witnessed to be healthy.  
The total treatment lasts 14 days:  7 days of BAF312 with i.v. up-titration 
 (see Figure 3-1) followed by 7 days of 
BAF312 p.o. once daily.
As described in the accompanying Pharmacy Manual, syringe pump changes must occur every 
6 hours, with a window of -15/+30 minutes.
During the i.v. up-titration period patients must be closely monitored. Special attention should 
be given to monitoring the HR and cardiac rhythm, with continuous CV telemetry in the Stroke 
Unit/Neurointensive Care Unit (Stroke/NICU) setting for at least the first 48 hours of the i.v. 
treatment phase. In case of symptomatic bradycardia or cardiac rhythm abnormalities (e.g. 
atrioventricular blocks or sinus pauses), the Investigator should follow the guidance given in 
CCI
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Section 6.6. Under those predefined conditions a dose may be postponed or skipped, but not 
more than 2 times in a row.  
During the 7 days of i.v. infusion treatment, all patients must undergo a swallowing safety 
evaluation. Those ICH patients who do not successfully pass a swallowing safety evaluation 
per the treating hospital’s institutional guidelines and practices will not be transitioned to the 
p.o. phase of treatment, and BAF312 must be discontinued after Day 7. Failure to pass a
swallowing safety evaluation should be recorded in the source documentation, and patients who
are unable to safely swallow oral medications should continue to be followed for the remainder
of the Assessment schedule; they should not be terminated from the study. The p.o. phase of
treatment consists of five tablets to be taken whole, with or without food, in the morning.
Because the first i.v. treatment must begin 
 following the time the patient was 
last witnessed to be normal, and may occur at any time during the day or night, the transition 
from i.v. to p.o. BAF312 must also transition from 
 hospital days to calendar days. 
Operationally, if the last syringe infusion ends between 12:00 AM (midnight) and 8:00 AM, the 
subject should be administered their first oral dose on that calendar morning (i.e., between 
8:00 AM-12:00 PM). If the last syringe infusion ends after 8:00 AM, but before 12:00 AM 
(midnight) the following night, the subject should be administered their first oral dose on the 
following calendar morning on awakening.
Once patients have completed the 7-day i.v. phase of treatment, passed a swallowing safety 
evaluation per the treating institution, and successfully transitioned to p.o. BAF312 
administration, they may be discharged to home or transferred to a rehabilitation facility at the 
Investigator and/or treating physician’s discretion.  If the patient is discharged or transferred, 
handling and tracking of investigational drug should occur as detailed below in Section 6.8. 
During the Treatment Epoch, patients must undergo study-specific assessments according to 
the Assessment schedule.
Detailed instruction for i.v. solution preparation and infusion will be provided in a separate 
manual. 
Sponsor-qualified personnel will be readily available to advise on trial-related medical 
questions or problems.
6.6
Permitted dose adjustments and interruptions of study treatment
Continuous cardiac monitoring will be implemented in the Stroke Unit/Neurointensive Care 
Unit setting (telemetry or bedside monitoring) in all patients during days indicated in the 
Assessment schedule. Monitoring will start from 1 hour before first dose and will continue up 
to at least 48 hours after the first drug administration. Continuous cardiac monitoring may be 
done for a longer duration on a case-by-case basis at the discretion of the Investigator and/or 
treating intensivist.
Cardiac safety monitoring data will be used for cardiac rhythm evaluation (mainly 
bradyarrhythmias, such as atrioventricular blocks and sinus pauses) and for HR assessment 
(bradycardia). Bradycardia and/or bradyarrhythmias with BAF312 administration typically 
occur within the first 48 hours of dosing, and are almost completely eliminated with BAF312 
up-titration as proposed.
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Management of Bradycardia or Bradyarrhythmia
The Investigator should be guided by the presence or absence of symptoms during bradycardic 
or bradyarrhythmic episodes (hemodynamic impact) and by the degree of atrioventricular block 
and/or duration of sinus pauses. Asymptomatic and minimally symptomatic patients do not 
necessarily require interruption of BAF312 dosing or taking any other action 
(Neumar et al 2010). In cases in which bradycardia is markedly symptomatic, or inappropriate 
for the clinical condition in the judgement of the treating intensivist, the BAF312 i.v. infusion 
will be interrupted.
Bradycardia with S1P modulators is usually benign, transient, and does not require treatment 
(Schmouder et al 2012). The patient should be assessed to determine if treatment continuation 
is acceptable to the treating physician and the Investigator (e.g., 1st or 2nd degree AV blocks) 
and if treatment will be continued once the patient recovers from symptomatic bradycardia. In 
the case of 3rd degree AV block and/or a hemodynamically-affected patient, the treatment 
should not be reinitiated (Section 7.2). The following AHA guidelines (Figure 6-1; 
Neumar et al 2010) should guide the Investigator: in the algorithm below, if the information 
from box 3 (persistent symptomatic bradycardia) leads to box 4 (monitor and observe) then:
1. The BAF312 infusion should be stopped for one hour,
2. The next dose escalation should be skipped
and 
3. The treatment infusion should be restarted only when the patient is hemodynamically
stable.
If the information from box 3 leads to box 5 (therapeutic intervention), the investigational drug 
should be discontinued and not restarted (Section 7.2).
Any reduction in heart rate, which, in the opinion of the Investigator or treating intensivist, is 
clinically significant and requires intervention (e.g., acutely altered mental status, ongoing 
severe ischemic chest pain, congestive heart failure, hypotension, or other signs of shock) may 
be treated according to standard medical practice, and suggested treatment would include:

Anticholinergics (e.g. atropine subcutaneous or i.v.)

Beta-agonists/sympathomimetics (e.g. dopamine or epinephrine)
Dosing of these will be individualized with respect to the desired clinical effect by the treating 
intensivist.
This cardiovascular AE mitigation plan was deemed appropriate by the FDA on Type B 
Pre-IND review (September 2016) and approved by the Novartis CPRC (October 2016). 
Any changes in administration of study medication must be recorded on the Dosage 
Administration Record CRF.
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Figure 6-1
AHA Guidelines for Emergency Cardiovascular Care
6.7
Emergency breaking of assigned treatment code
Emergency code breaks must only be undertaken when it is required to in order to treat the 
patient safely. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study patient who presents with an emergency 
condition. Emergency treatment code breaks are performed using the IRT. When the 
Investigator contacts the system to break a treatment code for a patient, he/she must provide the 
requested subject identifying information and confirm the necessity to break the treatment code 
for the patient. The Investigator will then receive details of the investigational drug treatment 
for the specified patient and a fax or email confirming this information. The system will 
automatically inform the study monitor for the site and the Study Team that the code has been 
broken.


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It is the Investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT at any time in case of emergency.  In most cases, the Investigator will 
need to provide: 

Protocol Number

Study Drug Name (if available)

Patient Number
In addition, the Investigator must provide oral and written information to inform the patient 
how to contact his/her backup in cases of emergency when he/she is unavailable to ensure that 
un-blinding can be performed at any time.
An assessment will be done by the appropriate site personnel and sponsor after an emergency 
unblinding to assess whether or not study treatment should be discontinued for a given patient.
6.8
Treatment exposure and compliance
BAF312 levels will be determined in patients’ plasma samples, and population pharmacokinetic 
analysis will be done, as detailed in Section 8.7.
For the p.o. phase of the study (Days 8-14), if the patient is discharged from the hospital to 
home, the Investigator must promote compliance by instructing the patient to take the study 
treatment exactly as prescribed and by stating that compliance is necessary for the patient’s 
safety and the validity of the study. The patient must also be instructed to contact the 
Investigator if he/she is unable for any reason to take the study treatment as prescribed.
If the patient is transferred to an inpatient rehabilitation facility, the oral investigational drug 
should be transferred to the rehabilitation hospital pharmacy to be dispensed by the hospital 
pharmacist and administered by the nursing staff as five tablets to be given to the patient every 
morning, with or without food, through and including Day 14 after ICH. It is the responsibility
of the Investigator to ensure appropriate tracking and document drug supply management for 
study drug provided to rehabilitation centers.
Compliance will be assessed by the Investigator and/or study personnel at each visit using pill 
counts and information provided by the patient. This information should be captured in the 
source document at each visit. All study treatment dispensed and returned must be recorded in 
the Drug Accountability Log.
6.9
Recommended treatment of adverse events
Treatment of symptomatic bradycardia and/or bradyarrhythmias should be performed as 
outlined in Section 6.6.
Other AEs should be treated at the discretion of the Investigator.
Medication used to treat AEs must be recorded on the Concomitant Medications/Significant 
Non-Drug Therapies CRF.
6.10
Rescue medication
There is no rescue medication for patients with ICH.


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6.11
Concomitant treatment
Per U.S. and European stroke care guidelines, corticosteroids should not be used for treatment 
of ICH because they are ineffective and increase complications (Hemphill et al 2015, 
Steiner et al 2014).
The Investigator must instruct the patient to notify the study site about any new medications 
he/she takes after the patient was enrolled into the study.
All prescription medications, over-the-counter drugs and significant non-drug therapies 
(including physical therapy and blood transfusions) administered or taken within the timeframe 
defined in the entry criteria prior to the start of the study and during the study, must be recorded 
on the Concomitant Medications/Significant Non-Drug Therapies CRF.
Medication entries should be specific to trade name, the single dose and unit, the frequency and 
route of administration, the start and discontinuation date and the reason for therapy.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the Investigator should contact Novartis before randomizing a patient 
or, if the patient is already enrolled, to determine if the patient should continue participation in 
the study.
7
Study completion and discontinuation
7.1
Study completion and post-study treatment
Each patient will be required to complete the study in its entirety and thereafter no further study 
treatment will be made available to them.
Study completion is defined as when the last patient completes their Study Completion visit, 
and any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator, or in the event of an early study termination decision, the date 
of that decision.
All SAEs reported during the Follow-Up Period must be reported as described in Section 9.2
and the Site Operations Manual.  Documentation of attempts to contact the patient should be 
recorded in the source documentation.
7.2
Discontinuation of study treatment
Discontinuation of study treatment for a patient occurs when study treatment is stopped earlier 
than the protocol planned duration. Discontinuation of study treatment can be decided by either 
the patient or the Investigator.
Study treatment must be discontinued under the following circumstances or emergence of the 
following adverse events:

Patient/guardian decision - patients may choose to discontinue study treatment for any
reason at any time.

The Investigator believes that continuation would negatively impact the safety of the
patient or the risk/benefit ratio of trial participation.


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
Severe hypersensitivity reaction occurs, including any of the following: anaphylaxis, 
fever, chills, urticaria, dyspnea, headache, myalgia, hypotension. Immediate interruption 
of the infusion to administer study treatment is required in such cases.

Any protocol deviation that results in a significant risk to the patient’s safety.

Pregnancy (see Section 8.6 (Safety) and Section 9.6 (Pregnancy reporting))

Use of prohibited treatment as per recommendations in Table 5-1.

If a liver or renal event occurs, follow guidelines outlined in Appendix 1 and Appendix 2
regarding discontinuation of study treatment.

Any laboratory abnormalities that in the judgment of the Investigator, taking into 
consideration the patient’s overall status, prevents the patient from continuing 
participation in the study.

Expansion of initial ICH requiring surgical evacuation.

Development of increased intracranial pressure requiring surgical intervention, including 
subsequent intraventricular expansion of the initial ICH leading to increased ventricular 
pressure requiring surgical management (e.g., EVD placement).

Hemodynamically-significant bradycardia and/or 3rd degree AV block as described in
Section 6.6.
The appropriate personnel from the site and Novartis will assess whether investigational drug 
treatment should be discontinued for any patient whose treatment code has been broken 
inadvertently for any reason.
If discontinuation of study treatment occurs, the Investigator must determine the primary reason 
for the patient’s premature discontinuation of study treatment and record this information on 
the CRF.
Patients who discontinue study treatment, either by choice or due to adverse events as listed 
above, should not be considered withdrawn from the study unless they also withdraw their 
consent (see Section 7.3, Withdraw of Informed Consent). Patients who have discontinued 
BAF312 before Day 14 (V10) but have not withdrawn their consent to participate in the study
should return for the assessments indicated by an asterisk (*) in the Assessment Table. If they 
fail to return for these assessments for unknown reasons, every effort (e.g. telephone, e-mail, 
letter) should be made to contact the patient/pre-designated contact as specified in Section 7.4
(Lost to follow-up). This contact should preferably be done according to the study visit schedule.
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should be collected at clinic visits or via telephone/email contact:

New / Concomitant Treatments

Adverse Events/Serious Adverse Events
The Investigator must also contact the IRT to register the patient’s discontinuation from study 
treatment.


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7.3
Withdrawal of informed consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a subject:
1. Does not want to participate in the study anymore, and
2. Does not allow further collection of personal data
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the
assessment table.
Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a subject’s samples until their time of withdrawal) according to applicable 
law.
All biological samples not yet analyzed at the time of withdrawal may still be used for further 
testing/analysis in accordance with the terms of this protocol and of the informed consent form.
7.4
Lost to follow-up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the Investigator should show "due diligence" by 
documenting in the source documents steps taken to contact the patient, e.g. dates of telephone 
calls, registered letters, etc. A patient cannot be formally considered lost to follow-up until 
his/her scheduled end of study visit would have occurred.
7.5
Study stopping rules
Overall study stopping rules:
Enrollment in the study will be placed on hold if any of the following occurs:

At least 2 or more patients present with hypersensitivity reactions and/or injection 
reactions of moderate-to-severe intensity that are considered related to study-drug.

At least 2 or more patients experience a similar AE which is assessed as life-threatening or 
potentially life-threatening (CTCAE Grade 4-5) and is considered related to the study-
drug; or

The Sponsor considers that the number and/or severity of AEs, abnormal safety 
monitoring tests or abnormal laboratory findings justify putting the study on hold.
The study may resume following the safety review, if the Investigator and Sponsor agree it is 
safe to proceed.


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7.6
Early study termination by the sponsor
The study can be terminated by Novartis at any time. Should this be necessary, patients must 
be seen as soon as possible and treated as a prematurely discontinued patient. The Investigator 
may be informed of additional procedures to be followed in order to ensure that adequate 
consideration is given to the protection of the patient’s interests. The Investigator will be 
responsible for informing IRBs/IECs of the early termination of the trial.
Reasons for early termination:

Unexpected, significant, or unacceptable safety risk to subjects enrolled in the study.

Decision based on recommendations for applicable board(s) after review of safety and 
efficacy data.

Discontinuation of study drug development.


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8
Procedures and assessments
8.1
Assessment schedule
Patients should be seen for all visits/assessments as outlined in the assessment schedule or as close to the designated day/time as possible.
Missed or rescheduled visits should not lead to automatic discontinuation. Patients who prematurely discontinue the study for any reason 
should be scheduled for a visit as soon as possible. At this final visit, all dispensed investigational product should be reconciled, and the 
adverse event and concomitant medications recorded on the CRF.
Table 8-1
Assessment schedule
Study Phase
Screening/Baseline
Treatment
Follow-up
Visit Numbers1
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
Days
-1
1
2
3
4
5
6
7
8
14 ± 1
30 ± 5
90 ± 10
Informed consent
X
Glasgow Coma Scale
X
Medical history/current medical conditions
X
X*
X*
X*
Routine Clinical Laboratory Tests
X
X
X
X
X
X*
X*
X*
ECG evaluation
X
X
X
X
X 
Pregnancy
X
X*
Inclusion / Exclusion criteria
X
Vital Signs
X
X
X
X
X
X
X
X
X
X*
X*
X*
Physical examination
X
X*
X*
X*
Neurological Examination
X
X*
X*
X*
Study drug dose-i.v. infusion
<--------------------------------------------------------->
Study drug dose -p.o. QD
<------------->
PK blood samples
X2
X3
X3
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Study Phase
Screening/Baseline
Treatment
Follow-up
Visit Numbers1
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
Days
-1
1
2
3
4
5
6
7
8
14 ± 1
30 ± 5
90 ± 10
CT scan
X
X4
X*
Modified Rankin Scale (mRS)
Estimate by history
X*
Study completion information
X*
Concomitant therapies
<-------------------------------------------------------------------------------------------------------------------------------------------->
Adverse events
<-------------------------------------------------------------------------------------------------------------------------------------------->
Serious adverse events
<-------------------------------------------------------------------------------------------------------------------------------------------->
1 Visit structure given for internal programming purpose only
2 PK samples at 0.5hr, 2hr, and 6hr after start of first infusion; 2mL at each time point
3 Before administration of oral dose. These samples should still be collected if the subject does not transition to the oral phase of the study.
4 CT scan #2 to be performed between 24 and 48 hours after initial diagnostic scan.
* Assessments to be completed for patients who have discontinued BAF312 treatment before Day 14 unless they have also withdrawn consent.
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8.2
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent.
If applicable, in cases where the patient’s representative gives consent (if allowed according to 
local requirements), the patient must be informed about the study to the extent possible given 
his/her understanding. If the patient is capable of doing so, he/she must indicate assent by 
personally signing and dating the written informed consent document or a separate assent form.
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the subject source documents.
Novartis will provide to investigators a proposed informed consent form that complies with the 
International Conference on Harmonisation E6 GCP guideline and regulatory requirements and 
is considered appropriate for this study.
 The procedures set out in the main consent form concerning the storage, 
maintenance of privacy, and release of the data or specimens for the main study will also be 
adhered to for any future research. Any changes to the proposed consent form suggested by the 
investigator must be agreed to by Novartis before submission to the IRB/IEC.
Women of child bearing potential should be informed that taking the study treatment may 
involve unknown risks to the fetus if pregnancy were to occur during the study. 
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed. Any new 
information regarding the safety profile of the investigational drug that is identified between IB 
updates will be communicated as appropriate, for example, via an Investigator Notification or 
an Aggregate Safety Finding. New information might require an update to the informed consent 
and then must be discussed with the patient.
Ensure patients are informed of the contraception requirements outlined in Section 4.2
(Exclusion criteria) and in Section 5.1 (Contraception requirements).
A copy of the approved version of all consent forms must be provided to the Novartis monitor 
after IRB/IEC approval.
Refer to the Site Operations Manual for a complete list of Informed Consent Forms included in 
this study.
8.3
Subject screening
It is permissible to re-screen a patient if s/he fails the initial screening and if re-screening 
occurs within 24 hours of the patient last seen normal; however, each case must be discussed 
and agreed with the Sponsor on a case-by-case basis.
Information on what data should be collected for screening failures is outlined in the Site 
Operations Manual.
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8.4
Subject demographics/other baseline characteristics
Demographic and baseline characteristic data will be collected on all patients. Relevant medical 
history/current medical conditions data will also be collected until signature of informed 
consent.  Details are outlined in the Site Operations Manual.
Investigators have the discretion to record abnormal test findings on the medical history CRF, 
if in their judgment, the test abnormality occurred prior to the informed consent signature.
8.5
Efficacy / Pharmacodynamics
8.5.1
Clinical Outcome Assessments (COAs)
CT Imaging
Reduction of perihematoma edema (PHE) measured by CT imaging at 14 days after ICH 
is the primary endpoint for measuring BAF312 efficacy in this study. Studies of the 
trajectory 
of 
perihematoma
edema 
(PHE) 
assessed 
with 
either 
MR 
(Venkatasubramanian et al 2011) or CT imaging (Staykov et al 2011) largely agree on the 
average time course of its development, which increases to a plateau between days 7-14 after 
ICH.  In a study of fingolimod in ICH (Fu et al 2014a), the authors showed that while there 
were no differences in hematoma volume between active drug- and placebo-treated patients, 
absolute PHE volume (aPHE) was lower in fingolimod-treated patients at Day 7 but not at 
Day 14; and relative PHE (rPHE; aPHE/hematoma volume) was significantly lower in 
fingolimod-treated patients at both Day 7 and Day 14 after ICH. Analyzing data from the 
VISTA-ICH archive, Murthy et al (2015) showed an association between early PHE expansion 
within 72 hours after ICH and poorer 90 day functional outcomes in basal ganglia hemorrhages 
≤ 30 cc in volume. Recently (Volbers et al 2018) it has also been shown that peak PHE is an 
independent predictor of 90 day functional outcome after supratentorial ICH.
Although the presence of intraventricular hemorrhage (IVH) has been shown to worsen 
outcomes to some extent in ICH patients (Steiner et al 2006; Mayer et al 2009), the larger the 
initial hematoma is, the greater is the likelihood that the ICH patient will present with some 
degree of IVH on initial presentation, while on the other hand much smaller ICH volumes (e.g., 
< 10 ml) do not generate significant PHE. To balance the presence of IVH with ICH volumes 
capable of generating PHE, we have elected to set the following subject exclusion criteria based 
on the original Graeb score (oGS; Graeb et al 1982), which grades IVH severity on a scale of 
0-12. The third and fourth ventricles are each scored as 0 (no blood present), 1 (blood present,
ventricle size normal), or 2 (ventricle filled with blood and expanded); and the two lateral
ventricles are each scored as 0 (no blood), 1 (trace of blood or mild bleeding), 2 (< 50% of
ventricle filled with blood), 3 (>50% of ventricle filled with blood), or 4 (ventricle filled with
blood and expanded), for a total maximum score of 2 + 2 + 4 + 4 = 12. Blood within the 4th
ventricle, and to some extent in the 3rd ventricle is a risk factor for hydrocephalus requiring
surgical intervention, which would eliminate ICH patients from our study. As such, patients
presenting with any 4th ventricular blood (max = 0), any evidence of 3rd ventricular expansion
(max = 1), and more than trace or mild blood in either or both lateral ventricles (max = 1 each),
thereby having an oGS > 3 will be excluded from participating in this study.


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Following the initial diagnostic CT, repeat CT images will be obtained between 24-48 hours 
after the diagnostic scan, and on Days
 14 
 Only non-contrast study CT scans will be obtained on Days
 14.  The 
non-contrast scan acquired on each patient at first follow-up (i.e., 24-48 hours after the 
diagnostic scan) will serve as the baseline for our analysis. All CT scans will be uploaded 
through a secure server, 
Additional CT or MRI scans may be performed, in particular in the event of changes in the 
patient’s clinical course, according the site’s local standard of care for ICH patients.
Modified Rankin Scale (mRS)
The modified Rankin Scale (mRS), attached as Appendix 4-Section 18 is a widely-used, 
clinician-assessed instrument, and is considered the current standard assessment for stroke 
outcomes by most Health Authorities. It consists of 6 grades of disability, higher scores 
indicating more severe disability (0 = asymptomatic, 6 = dead). The strength of the mRS is that 
it captures the full spectrum of limitations in activity and participation after stroke with 
reasonable inter-rater reliability (Banks and Marotta 2007). The mRS can be administered by 
investigators, study nurses, and research assistants. Training in administration of the mRS 
interview will be provided to site personnel as necessary, and proficiency certification will be 
monitored and centrally recorded. In this study, mRS interviews will be video recorded, then 
securely transferred to and rated by a Central Independent Adjudication Panel. Individual (rater) 
mRS scores (and the panel average) as well as the panel consensus score for each interview will 
be recorded.
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8.6
Safety
The methods, assessment, specification, and recording for each assessment will be detailed in 
the Site Operations Manual.
8.6.1
Physical examination
A complete physical examination will be performed at the visits indicated in the 
Assessments schedule (Table 8-1) and will include an assessment of skin, head and neck, lymph 
nodes, heart, lungs, abdomen, back, neurological function and comments on general appearance. 
All significant findings that are present prior to signing informed consent must be reported on 
the relevant medical history/current medical conditions eCRF. Significant findings made after 
signing the informed consent that meet the definition of an AE and must be recorded on the 
adverse events eCRF. Due to the seriousness of the illness at baseline it might not be possible 
to assess all aspects of physical examination.
8.6.2
Vital signs
Vital signs will include pulse rate, systolic and diastolic blood pressure in supine position, 
respiratory rate, and temperature which will be assessed at the visits indicated in Table 8-1.
8.6.3
Clinical laboratory evaluations
Due to the emergency setting of the patient, screening/baseline laboratory evaluation can be 
performed locally. A central laboratory will be used for all other time points for the analysis of 
all specimens collected. Timings of blood sample collection are outlined in the Table 8-1. 
Details on the collections, shipment of samples and reporting of results by the central laboratory 
are provided to investigators in the laboratory manual. Abnormal laboratory parameters, 
inconsistent with clinical presentation of stroke or which cause suspicion of an underlying 
medical condition, should be repeated for confirmation. Additional local lab samples will be 
taken according the site’s local practice to adhere to local standard of care for ICH patients.
8.6.3.1
Hematology
Blood samples will be collected at the scheduled visits indicated in Table 8-1. The parameters 
assessed will include: red blood cell count, total and differential WBC count (basophils, 
eosinophils, lymphocytes, monocytes, neutrophils), platelet count, hemoglobin, hematocrit, 
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mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin 
concentration and red blood cell morphology.
Due to the seriousness of the condition, local lab blood sampling needed for the routine medical 
care will have to be taken as well. The Treating Physician will take special care that after 
the initiation of study treatment absolute total WBC count and lymphocyte counts are 
only communicated to persons on the treatment team who need to know this result for 
clinical decision making. It is imperative that this information is not communicated more 
broadly: the Treating Physician must under no circumstances communicate this information to 
ward personnel, and particularly not to local Independent Raters, those study team members 
who will be conducting follow-up mRS assessments on ICH patients.
For study blinding purposes after the baseline visit only the absolute counts for eosinophils, 
basophils, neutrophils and monocytes will be communicated to sites by the central laboratory. 
The absolute total WBC, and lymphocyte counts will be measured at each visit by the central 
laboratory, will be blinded from the sponsor and the Investigator; and will only be 
communicated to the site Principal Investigator in case of an abnormality which might require 
an AE evaluation  and/or could result in a change in patient treatment.
8.6.3.2
Clinical chemistry
Blood samples will be collected at the scheduled visits indicated in Table 8-1 and the parameters 
assessed will include: electrolytes (Na, K, Cl, bicarbonate, Ca, Mg, P), non-fasting glucose, 
albumin, alkaline phosphatase, creatinine, ALT, AST, GGT, amylase, total bilirubin, 
conjugated bilirubin, and CRP. After the initial screening chemistry, total cholesterol, 
triglycerides, HDL, and LDL may or may not be repeated at the discretion of the Investigator.
8.6.4
Electrocardiogram (ECG)
Continuous cardiac monitoring must be implemented via bedside monitoring or telemetry in all 
patients during days when the patient is in the Stroke Unit/Neurointensive Care Unit. Cardiac 
monitoring must be performed from 1 hour before dosing to 48 hours after the first drug 
administration. Continuous cardiac monitoring may be done for a longer duration on a case-by-
case basis at the discretion of the Investigator and the treating physician.
Standard twelve-lead ECGs will be performed for all patients at the time points as indicated in
Table 8-1. All ECG data must be stored and made available to the sponsor upon request. 
For telemetry, in the event of clinical significant abnormalities, rhythm strips should be captured 
and printed, or annotated by the Investigator/treating physician, and kept with the source 
documents. In the case of no CV abnormalities, source notes confirming review of telemetry 
data are sufficient. Cardiac safety monitoring data will used for cardiac rhythm evaluation 
(mainly bradyarrhythmias, such as atrioventricular blocks and sinus pauses) and for HR 
assessments.
Clinically significant abnormalities should be recorded on the Medical History/Adverse event 
eCRF page.
Symptomatic events, particularly when requiring medical intervention may lead to patient 
discontinuation. Treatment interruption or omitting a dose of BAF312 should be guided by the 
considerations outlined in Section 6.6.


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8.6.5
Pregnancy test and assessments of fertility
Urine pregnancy testing will be done for all female study subjects of childbearing potential at 
baseline and Day 30 (V11). Positive urine pregnancy tests will be confirmed with serum 
pregnancy testing.
Women are considered post-menopausal and not of child bearing potential if they have had 
12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate, history of vasomotor symptoms, etc.) or have had surgical bilateral oophorectomy 
(with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks prior to 
ICH. In the case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow up FSH level assessment is she considered not of child-bearing 
potential.
8.7
Pharmacokinetics
Pharmacokinetic (PK) samples will be collected at the time points defined in the 
Assessment schedule (Section 8.1). Follow instructions outlined in the Site Operations Manual 
regarding sample collection, numbering, processing and shipment. 
As only sparse PK samples will be collected in the study, no PK parameters will be estimated. 
PK samples will be pooled with PK data of other available studies in order to assess the effect 
of various covariates on the plasma concentrations of BAF312 in patients with stroke due to 
ICH through a population pharmacokinetic analysis (see Section 11.5.3).
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8.8
Other assessments
8.9
Use of residual biological samples
Residual blood samples may be used for another protocol-specified endpoint.
9
Safety monitoring
9.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a patient after
providing written informed consent for participation in the study until the end of study visit. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
In addition, all reports of intentional misuse and abuse of the study treatment are also considered 
an adverse event irrespective if a clinical event has occurred. See Section 9.5 for an overview 
of the reporting requirements.
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The occurrence of adverse events must be sought by non-directive questioning of the patient at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the patient during or between visits or through physical examination finding, laboratory test 
finding, or other assessments.
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms,

they are considered clinically significant, or

they require therapy.
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patients with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
subject and identifying adverse events. Alert ranges for liver and kidney related events are 
included in Appendix 1 and Appendix 2, respectively.
Adverse events should be recorded on the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, and accompanied by the following information:
1. CTCAE severity grade (1-5)
If CTCAE grading does not exist for an adverse event, use: 1=mild, 2=moderate, 3=severe 
4=life threatening* (see Section 9.2 for definition of a serious adverse event (SAE))
*Note: There may be cases where a CTCAE with a grade of 4 (life-threatening) may not 
necessarily be an SAE (e.g. certain laboratory abnormalities in the absence of meeting other 
seriousness criteria).
CTCAE grade 5 (death) is not used, but is collected as a seriousness criteria and also 
collected in other CRFs (e.g. Study Completion, Death/Survival).
2. Its relationship to the study treatment (no/yes).
3. Its duration (start and end dates); or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported.
4. Whether it constitutes a SAE (see Section 9.2 for definition of SAE) and which 
seriousness criteria have been met. 
5. Action taken regarding investigational treatment. All adverse events must be treated 
appropriately. Treatment may include one or more of the following: 

no action taken (e.g. further observation only)

investigational treatment interrupted/withdrawn

concomitant medication or non-drug therapy given

hospitalization/prolonged hospitalization (see Section 9.2 for definition of SAE)
6. Its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown).
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB) or will be communicated between IB updates in the 


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form of Investigator Notifications. Once an adverse event is detected, it must be followed until 
its resolution or until it is judged to be permanent, and assessment should be made at each visit 
(or more frequently, if necessary) of any changes in severity, the suspected relationship to the 
investigational drug, the interventions required to treat it, and the outcome.
The investigator must also instruct each patient to report any new adverse event (beyond the 
protocol observation period) that the patient, or the patient’s personal physician, believes might 
reasonably be related to study treatment. This information must be recorded in the investigator’s 
source documents; however, if the AE meets the criteria of an SAE, it must be reported to 
Novartis.
*Refer to the Site Operations Manual for data capture methodology regarding AE collection for
patients that fail screening.
9.2
Serious adverse event reporting
9.2.1
Definition of SAE
An SAE is defined as any adverse event (appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the following 
criteria:

is fatal or life-threatening

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless
hospitalization is for:
1. routine treatment or monitoring of the studied indication, not associated with any
deterioration in condition
2. elective or pre-planned treatment for a pre-existing condition (that is unrelated to
the indication under study) and has not worsened since the start of study drug
3. treatment on an emergency outpatient basis for an event not fulfilling any of the
definitions of a SAE given above and not resulting in hospital admission
4. social reasons and respite care in the absence of any deterioration in the patient’s
general condition

is medically significant, e.g. defined as an event that jeopardizes the patient or may require
medical or surgical intervention.
Life-threatening in the context of a SAE refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to International Conference on Harmonisation-
E2D Guideline 2003).
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the patient or might 
require intervention to prevent one of the other outcomes listed above. Examples of such events 
are intensive treatment in an emergency room or at home for allergic bronchospasm, blood 


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dyscrasias or convulsions that do not result in hospitalization or development of dependency or 
abuse (please refer to International Conference on Harmonisation-E2D Guideline 2003).
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All AEs (serious and non-serious) are captured on the CRF; SAEs also require individual 
reporting to Novartis Chief Medical Office and Patient Safety (CMO&PS) as per Section 9.2.2.
9.2.2
SAE reporting
IMPORTANT: To comply with regulations, all suspected, unexpected, serious adverse 
reactions (SUSARs) occurring in a clinical trial must be reported in an expedited timeframe (7 
or 15 days) to Competent Authorities.
However, regulations do allow that certain adverse experiences that would ordinarily fall 
under the SAE definition can be handled differently. These exemptions from reporting of 
SAEs are particularly relevant to studies in high morbidity and high mortality 
populations where study subjects are generally sicker, such as patients with ICH, and 
often carry significant concomitant disease burdens.

Event(s) common in the patient population under study: The unblinding of single SAEs
that are relatively common in the patient population under study, for SUSAR reporting,
often does not increase the understanding of safety, and can damage the integrity of the
blinded nature and analysis of a study. The following SAEs commonly seen in the ICH
patient population will still be captured by the investigators as SAEs in the CRF and
reported to Novartis, but they will not be unblinded during the course of the study, even if
considered "related" to study treatment by the reporting investigator, nor reported on an
expedited basis to regulatory authorities:
1. Ventricular extension of hemorrhage with increased ventricular pressure
requiring surgical intervention (e.g., external ventricular drainage), and
2. Expansion of initial intracerebral hemorrhage requiring surgical evacuation.
Additionally, these safety data will be reviewed in an expedited timeframe of 15 days by the 
external DMC.
Screen Failures 
Note the following requirement for Screen Failures: SAEs occurring after the patient has 
provided informed consent until the time the patient is deemed a Screen Failure must be 
reported to Novartis.
Randomized Subjects
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until the study completion visit, must be reported to Novartis 
within 24 hours of learning of its occurrence as described below.
Any SAEs experienced after this period should only be reported to Novartis if the investigator 
suspects a causal relationship to study treatment.


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All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.
Follow- up information provided must describe whether the event has resolved or continues, if 
and how it was treated, whether the blind was broken or not (if applicable) and whether the 
patient continued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event must be reported as a follow-up to that event regardless of 
when it occurs.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment a Chief Medical Office and 
Patient Safety (CMO& PS) Department associate may urgently require further information from 
the investigator for Health Authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same study treatment 
that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) 
will be collected and reported to the competent authorities and relevant ethics committees in 
accordance with EU Guidance 2011/C 172/01 or as per national regulatory requirements in 
participating countries.
Follow the detailed instructions outlined in the Site Operations Manual regarding the 
submission process for reporting SAEs to Novartis. Note: SAEs must be reported to Novartis 
within 24 hours of the investigator learning of its occurrence/receiving follow-up information.
9.3
Liver safety monitoring
To ensure patient safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed.
Please refer to Table 15-1-Appendix 1 for complete definitions of liver events.
Follow-up of liver events
Every liver event defined in Table 15-1-Appendix 1 should be followed up by the investigator 
or designated personnel at the trial site, as summarized below. Additional details on actions 
required in case of liver events are outlined in Table 15-2-Appendix 1.

Repeating liver chemistry tests (ALT, AST, TBL, PT/INR, ALP and G-GT) to confirm 
elevation within 48-72 hours.
These liver chemistry repeats should always be performed using the central laboratory, with the 
results provided via the standard electronic transfer.  If results will not be available from the 
central laboratory within 24 hours, then the repeats can also be performed at a local laboratory 
to monitor the safety of the patient. If a liver event is subsequently reported, any local liver 
chemistry tests previously conducted that are associated with this event should have results 
reported on the unscheduled local laboratory CRF.


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
If the initial elevation is confirmed, close observation of the subject will be initiated, 
including consideration of treatment interruption if deemed appropriate.

Discontinuation of the investigational drug (refer to Section 7.2 (Discontinuation of study 
treatment), if appropriate

Hospitalization of the patient if appropriate

Causality assessment of the liver event

Thorough follow-up of the liver event should include

Repeating liver chemistry tests two or three times weekly. Testing should include ALT, 
AST, ALP, PT/INR, and GGT. If total bilirubin is elevated > 2 x ULN, fractionation into 
direct and indirect bilirubin is required. To rule out muscular origin of transaminase 
elevations, CPK should be measured along with liver chemistry tests. Frequency of 
retesting can decrease to once a week or less if abnormalities stabilize or the study drug 
has been discontinued and the patient is asymptomatic. Retesting should be continued up 
to resolution.

Obtaining a more detailed history of symptoms and prior or concurrent diseases.

Obtaining a history of concomitant drug use (including nonprescription medications and 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and 
special diets.

Exclusion of underlying liver disease, as specified in Table 15-3.

Imaging such as abdominal US, CT or MRI, as appropriate

Obtaining a history of exposure to environmental chemical agents.

Considering gastroenterology or hepatology consultations.
All follow-up information, and the procedures performed must be recorded as appropriate in 
the CRF. Refer to the Site Operations Manual for additional details. 
9.4
Renal safety monitoring
Every renal laboratory trigger or renal event must be followed up by the investigator or 
designated personnel at the trial site. Recommended follow-up assessments are listed in 
Appendix 2.
All follow-up information, and the procedures performed must be recorded as appropriate in 
the CRF. Refer to the Site Operations Manual for additional details.
9.5
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient/subject 
or consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects.


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All study treatment errors and uses outside of what is foreseen in the protocol will be collected 
in the dose administration record (DAR) CRF. Study treatment errors are only to be reported to 
Chief Medical Office and Patient Safety (CMO& PS) department if the treatment error is 
associated with an SAE.
All instances of misuse or abuse must be documented in the adverse event (AE) CRF 
irrespective of the misuse/abuse being associated with an AE/SAE. In addition, all instances of 
misuse or abuse must be reported to Novartis Chief Medical Office and Patient Safety (CMO& 
PS). As such, instances of misuse or abuse are also to be reported using the SAE form/CRF. 
Table 9-1 summarizes the reporting requirements.
Table 9-1
Guidance for capturing study treatment errors
Treatment error type
Document in Dose
Administration (DAR) CRF 
Document in AE 
CRF
Complete SAE 
form/CRF 
Unintentional study 
treatment error
Yes
Only if associated 
with an AE
Only if associated 
with an SAE
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a 
SAE
For more information on AE and SAE definition and reporting requirements, please see 
Section 9.1 and Section 9.2, respectively.
9.6
Pregnancy reporting
This study enrolls women who are considered unlikely to be of child-bearing potential; thus 
pregnancy is not an expected outcome for any female study participant. However, in the case 
that a pregnancy in a female study participant should occur, please follow the below reporting 
guidelines.
To ensure patient safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications.
Pregnancy must be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Chief Medical Office and Patient Safety (CMO&PS) 
Department. Pregnancy follow-up should be recorded on the same form and should include an 
assessment of the possible relationship to the study treatment.
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form.
The study drug must be discontinued, though the patient may stay in the study, if she wishes to 
do so. All assessments that are considered as a risk during pregnancy must not be performed. 
The patient may continue all other protocol assessments.
Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother.


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Pregnancy outcome information should continue to be collected from newborn infants and 
continue for up to one year from birth of the infant.
9.7
Prospective suicidality assessment
The ICH patients who will be enrolled in this study will have major, significant neurological 
impairment during and after dosing with BAF312 or placebo, which will confound the 
assessment of suicidality. This would make any such prospective suicidality assessment, such 
as the C-SSRS, of questionable value. Novartis, therefore, will not include a suicidality 
assessment as part of this 
 study of BAF312 in ICH.
9.8
Early phase safety monitoring
The Investigator will monitor adverse events in an ongoing manner and inform the Sponsor of 
any clinically relevant observations. Any required safety reviews will be made jointly between 
medically qualified personnel representing the Sponsor and Investigator. Such evaluations may 
occur verbally, but the outcome and key discussion points will be summarized in writing (email) 
and made available to both Sponsor and all Investigator(s). Criteria pertaining to stopping the 
study/treatment or adapting the study design are presented above.
When two or more clinical site(s) are participating in the clinical study, the Sponsor will advise 
the Investigator(s) at all sites in writing (e-mail) (and by telephone if possible) of any new, 
clinically relevant safety information reported from another site during the conduct of the study 
in a timely manner.
10
Data review and database management
10.1
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and CRFs with the investigators and their staff. 
During the study, Novartis employs several methods of ensuring protocol and GCP compliance 
and the quality/integrity of the sites’ data. The field monitor will visit the site to check the 
completeness of patient records, the accuracy of entries on the eCRFs, the adherence to the 
protocol and to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits.  Continuous remote 
monitoring of each site’s data may be performed by a centralized organization.   Additionally, a 
central analytics organization may analyze data & identify risks & trends for site operational 
parameters, and provide reports to Novartis Clinical Teams to assist with trial oversight.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
patient's file. [Data not requiring a separate written record will be defined before study 
start and will be recorded directly on the CRFs.] The investigator must also keep the original 
informed consent form signed by the patient (a signed copy is also given to the patient).
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The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the CRF entries. Novartis monitoring standards require full verification for the 
presence of informed consent, adherence to the inclusion/exclusion criteria, documentation of 
SAEs, and of data that will be used for all primary variables. Additional checks of the 
consistency of the source data with the CRFs are performed according to the study-specific 
monitoring plan. No information in source documents about the identity of the patients will be 
disclosed.
10.2
Data collection
Designated investigator staff will enter the data required by the protocol into the EDC system. 
Designated investigator site staff will not be given access to the system until they have been 
trained. 
Automatic validation procedures within the system check for data discrepancies during and 
after data entry and, by generating appropriate error messages, allow the data to be confirmed 
or corrected online by the designated investigator site staff. The Investigator must certify that 
the data entered into the electronic Case Report Forms are complete and accurate.
After database lock, the investigator will receive copies of the patient data for archiving at the 
investigational site. 
10.3
Database management and quality control
Novartis staff (or CRO working on behalf of Novartis) review the data entered into the CRFs 
by investigational staff for completeness and accuracy and instruct the site personnel to make 
any required corrections or additions. Queries are sent to the investigational site using an 
electronic data query. Designated investigator site staff is required to respond to the query and 
confirm or correct the data. If the electronic query system is not used, a paper Data Query Form 
will be faxed to the site. Site personnel will complete and sign the faxed copy and fax it back 
to Novartis staff that will make the correction to the database. The signed copy of the Data 
Query Form is kept at the investigator site.
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Concomitant procedures, non-drug therapies, medical history/current medical conditions and 
adverse events will be coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology.
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
Blood samples for Pharmacokinetics will be processed centrally and the results will be sent 
electronically to Novartis (or a designated CRO).
Randomization codes and data about all study drug(s) dispensed to the patient will be tracked 
using an Interactive Response Technology (IRT). The database will be sent electronically to 
Novartis (or a designated CRO).
Each occurrence of a code break via IRT will be reported to the clinical team and monitor.  The 
code break functionality will remain available until study shut down or upon request of Novartis.


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The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked and the treatment codes will be unblinded and made available for data analysis. 
Any changes to the database after that time can only be made after written agreement by 
Novartis management.
10.4
Data Monitoring Committee
An independent Data Monitoring Committee (DMC) has been appointed and will be provided 
regularly with semi-blinded safety data. The DMC will provide recommendations to the sponsor 
to continue the trial according to the protocol and any relevant amendments, or to make changes 
or adjustments to the study protocol that may be required to ensure patient safety and preserve 
trial integrity. The DMC may also advise to put the study on hold pending further data analysis, 
or to discontinue the trial.
10.5
Adjudication Committee
11
Data analysis
The analysis will be conducted on all patient data at the time the trial ends. Any data analysis 
carried out independently by the Investigator must be submitted to Novartis before publication 
or presentation.
11.1
Analysis sets
The Full Analysis Set will include all patients who are randomized and received at least one 
dose of study drug after randomization.
The Safety Analysis Set will include all patients that received at least one dose of study drug.
The Per Protocol Set (PPS) will include all patients in the full analysis set (FAS) having received 
at least the first infusion on Day 1 and no protocol deviations with relevant impact on efficacy 
data.
The PK Analysis Set will include all patients with at least one available valid (i.e., not flagged 
for exclusion) PK concentration measurement, who received any study drug and experienced 
no protocol deviations with relevant impact on PK data.
For all analysis sets, patients will be analyzed according to the study treatment(s) received.
11.2
Subject demographics and other baseline characteristics
All data for background and demographic variables will be listed by treatment arm and patient. 
Summary statistics will be provided by treatment arm.
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Patient demographics will include age, sex, race, ethnicity, height, weight and BMI.
Other baseline disease characteristics include relevant medical history, current relevant 
medication, blood pressure, GCS score, 
 historically estimated pre-stroke mRS
score, hematoma volume, location of hematoma, time from first symptoms of ICH or last seen 
neurologically normal, and any other relevant information. 
11.3
Treatments
Data for study drug administration and concomitant therapies will be listed by treatment group 
and patient.
11.4
Analysis of the primary variable(s)
The primary aim of this study is to obtain the first efficacy estimate of 
 BAF312 daily 
(7 days i.v. with titration followed by 7 days p.o.) compared to placebo on reducing absolute 
perihematoma edema (aPHE) volume on Day 14 after ICH.
11.4.1
Primary Variable(s)
The primary efficacy variable is the aPHE volume measured on Day 14 which will be measured
from the CT images by a central reading lab.
11.4.2
Statistical model, hypothesis, and method of analysis
It is expected that the distribution of aPHE is right-skewed (as it is a positive-valued 
measurement), so a log-transformation will be applied. The log-transformed absolute PHE 
volume on Day 14 will be analyzed using analysis of covariance (ANCOVA) model, with 
treatment as a classification factor and the baseline log-transformed aPHE as covariate. The 
mean difference (BAF312 vs. placebo) and its 90% CI will be calculated, and these estimates 
will be back-transformed to give a geometric mean ratio and 90% CI between BAF312 and 
placebo. 
The primary analysis will be done on the PPS.
11.4.3
Handling of missing values/censoring/discontinuations
The analysis will be done on the available data recorded on the Day 14 CT scan.
11.4.4
Sensitivity analyses
CCI
CCI
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11.5
Analysis of secondary variable(s)
The secondary objectives are to assess the safety profile, and to evaluate the pharmacokinetics 
of BAF312 in ICH patients.
11.5.1
Efficacy / Pharmacodynamics
Not Applicable
11.5.2
Safety
Vital signs
All vital signs data will be listed by treatment group, patient, and visit/time and if ranges are 
available abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics 
will be provided by treatment and visit/time.
ECG evaluations
All ECG data will be listed by treatment group, patient and visit/time, abnormalities will be 
flagged. Summary statistics will be provided by treatment and visit/time.
Clinical laboratory evaluations
All laboratory data will be listed by treatment group, patient, and visit/time and if normal ranges 
are available abnormalities will be flagged. Summary statistics will be provided by treatment 
and visit/time.
Adverse events
All information obtained on adverse events will be displayed by treatment group and subject.
The number and percentage of patients with adverse events will be tabulated by body system 
and preferred term with a breakdown by treatment. A patient with multiple adverse events 
within a body system is only counted once towards the total of this body system.
11.5.3
Pharmacokinetics
BAF312 plasma concentration data will be listed by treatment, patient, and visit/sampling time 
point. 
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11.5.4
Pharmacokinetic / pharmacodynamic interactions
Not applicable.
11.5.5
Other assessments
Not applicable.
11.6
Analysis of exploratory variables 
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11.7
Sample size calculation
Based on the literature (Staykov et al 2011; Volbers et al 2011), the reported variability 
(Coefficient of Variation, CV) of absolute PHE volume in ICH patients within first 12 to 
16 days of ICH is in the range 70% to 92%, and that of relative PHE is in the range 64% to 
114%. Assuming a CV of 90%, the design with 60 evaluable patients expected to have data on 
aPHE at day 14 (30 on BAF312 and 30 Placebo) has 80% power to detect statistically significant 
treatment difference at 1-sided α=0.05, when the true mean percent reduction in PHE at a given 
time point (BAF312 over Placebo) is 40%.
11.8
Power for analysis of key secondary variables
Not applicable.
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11.9
Interim analyses
12
Ethical considerations
12.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented and reported in accordance with the 
International Conference on Harmonisation Harmonized Tripartite Guidelines for Good 
Clinical Practice, with applicable local regulations (including European Directive 2001/20/EC, 
US CFR 21, and Japanese Ministry of Health, Labor, and Welfare), and with the ethical 
principles laid down in the Declaration of Helsinki.
12.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, patient recruitment procedures (e.g. 
advertisements) and any other written information to be provided to patients. Prior to study start, 
the investigator is required to sign a protocol signature page confirming his/her agreement to 
conduct the study in accordance with these documents and all of the instructions and procedures 
found in this protocol and to give access to all relevant data and records to Novartis monitors, 
auditors, Novartis Quality Assurance representatives, designated agents of Novartis, IRBs/IECs, 
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and regulatory authorities as required. If an inspection of the clinical site is requested by a 
regulatory authority, the investigator must inform Novartis immediately that this request has 
been made.
For this multi-center trial, a Coordinating Investigator will be selected by Novartis by the time 
of Last Patient Last Visit to be a reviewer and signatory for the clinical study report. 
12.3
Publication of study protocol and results
The key design elements of this protocol will be posted in a publicly accessible database such 
as clinicaltrials.gov. In addition, upon study completion and finalization of the study report the 
results of this trial will be either submitted for publication and/or posted in a publicly accessible 
database of clinical trial results.
12.4
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management (QM) system that includes all activities 
involved in quality assurance and quality control, including the assignment of roles and 
responsibilities, the reporting of results, and the documentation of actions and escalation of 
issues identified during the review of quality metrics, incidents, audits and inspections.
Audits of investigator sites, vendors, and Novartis systems are performed or overseen by 
Novartis Pharma Auditing and Compliance Quality Assurance (or CRO working on behalf of 
Novartis), a group independent from those involved in conducting, monitoring or performing 
quality control of the clinical trial. The clinical audit process uses a knowledge/risk based 
approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes.
13
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of patients should be 
administered as deemed necessary on a case by case basis. Under no circumstances is an 
investigator allowed to collect additional data or conduct any additional procedures for any 
research related purpose involving any investigational drugs under the protocol.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be implemented. 
All significant protocol deviations will be recorded and reported in the CSR.
13.1
Protocol Amendments
Any change to the protocol can only be made in a written protocol amendment that must be 
approved by Novartis, Health Authorities where required, and the IRB/IEC prior to 
implementation.


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Amendments that are intended to eliminate an apparent immediate hazard to patients may be 
implemented immediately, provided the Health Authorities are subsequently notified by 
protocol amendment and the reviewing IRB/IEC is notified.
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 9 (Safety Monitoring) must be followed and the Study Lead 
informed.


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14
References
Anderson CS, Heeley E, Huang Y, et al (2013) Rapid blood-pressure lowering in patients 
with acute intracerebral hemorrhage. N. Engl. J. Med. p. 2355-65.
Asuzu D, Nystrӧm K, Amin H, et al (2016) Validation of TURN, a simple predictor of 
symptomatic intracerebral hemorrhage after IV thrombolysis. Clin Neurol Neurosurg. P. 71-5.
Banks JL, Marotta CA (2007) Outcomes validity and reliability of the modified Rankin scale: 
implications for stroke clinical trials: a literature review and synthesis. Stroke p. 1091-6.
Brinkmann V, Billich A, Bauruker T et al (2010) Fingolimod (FTY720): discovery and 
development of an oral drug to treat multiple sclerosis. Nat Rev Drug Discov p. 883-97.
Brinkmann V, Cyster JG, Hla T (2004) FTY720: sphingosine 1-phosphate receptor-1 in the 
control of lymphocyte egress and endothelial barrier function. Am. J. Transplant. p. 1019-25.
Chae SS, Paik JH, Allende ML et al (2004) Regulation of limb development by the 
sphingosine 1-phosphate receptor S1p1/EDG-1 occurs via the hypoxia/VEGF axis. Dev. Biol. 
p. 441-7.
Choi JW, Gardell SE, Herr DR, et al (2011) FTY720 (fingolimod) efficacy in an animal 
model of multiple sclerosis requires astrocyte sphingosine 1-phosphate receptor 1 (S1P1) 
modulation. Proc. Natl. Acad. Sci. U.S.A. p. 751-6.
CPMP (2001) Points to consider on clinical investigation of medicinal products for the 
treatment of acute stroke. 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC5
00003342.pdf
European Commission Radiation Protection, (1998) Guidance on Medical Exposures in 
Medical and Biomedical Research.
Fu Y, Hao J, Zhang N, et al (2014a) Fingolimod for the treatment of intracerebral 
hemorrhage: a 2-arm proof-of-concept study. JAMA Neurol p. 1092-101.
Fu Y, Zhang N, Ren L, et al (2014b) Impact of an immune modulator fingolimod on acute 
ischemic stroke. Proc. Natl. Acad. Sci. U.S.A. p. 18315-20.
Graeb DA, Robertson WD, Lapointe JS et al (1982) Computed Tomographic Diagnosis of 
Intraventricular Hemorrhage:  Etiology and Prognosis.  Radiology p. 91-96.
Hemphill JC, Greenberg SM, Anderson CS, et al (2015) Guidelines for the Management of 
Spontaneous Intracerebral Hemorrhage: A Guideline for Healthcare Professionals From the 
American Heart Association/American Stroke Association. Stroke p. 2032-60.
Hoch M, D'Ambrosio D, Wilbraham D, et al (2014) Clinical pharmacology of ponesimod, a 
selective S1P1 receptor modulator, after uptitration to supratherapeutic doses in healthy 
subjects. Eur J Pharm Sci p. 147-53.
ICRP 62 (1992) Radiological Protection in Biomedical Research. ICRP Publication 62. 
Annals of ICRP. Oxford: Permagon Press.


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Koga M, Arihiro S, Hasegawa Y, et al (2014) Intravenous nicardipine dosing for blood 
pressure lowering in acute intracerebral hemorrhage: the Stroke Acute Management with 
Urgent Risk-factor Assessment and Improvement-Intracerebral Hemorrhage study. J Stroke 
Cerebrovasc Dis p. 2780-7.
Kono M, Mi Y, Liu Y, et al (2004) The sphingosine-1-phosphate receptors S1P1, S1P2, and 
S1P3 function coordinately during embryonic angiogenesis. J Biol Chem. p. 29367-73. 
Kothari RU, Brott T, Broderick JP, et al (1996) The ABCs of measuring intracerebral 
hemorrhage volumes. Stroke p. 1304-5.
Legangneux E, Gardin A, Johns D (2013) Dose titration of BAF312 attenuates the initial heart 
rate reducing effect in healthy subjects. Br J Clin Pharmacol p. 831-41.
Lu L, Barfejani AH, Qin T, et al (2014) Fingolimod exerts neuroprotective effects in a mouse 
model of intracerebral hemorrhage. Brain Res. p. 89-96.
Matloubian M, Lo CG, Cinamon G, et al (2004) Lymphocyte egress from thymus and 
peripheral lymphoid organs is dependent on S1P receptor 1. Nature p. 355-60.
Mayer SA, Davis SM, Skolnick BE, et al (2009) Can a Subset of Intracerebral Hemorrhage 
Patients Benefit From Hemostatic Therapy With Recombinant Activated Factor VII? Stroke 
p. 833-840.
McCollough CH, Bushberg JT, Fletcher JG, et al (2015) Answers to Common Questions 
About the Use and Safety of CT Scans. Mayo Clin. Proc. p. 1380-92.
Mracsko E, Veltkamp R (2014) Neuroinflammation after intracerebral hemorrhage. Front Cell 
Neurosci p. 388.
Murthy SB, Moradiya Y, Dawson J, et al (2015) Perihematomal Edema and Functional 
Outcomes in Intracerebral Hemorrhage: Influence of Hematoma Volume and Location. Stroke 
p. 3088-92.
Neumar RW, Otto CW, Link MS, et al (2010) Part 8: adult advanced cardiovascular life 
support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and 
Emergency Cardiovascular Care. Circulation p. S729-67.
Qureshi AI, Palesch YY, Martin R, et al (2010) Effect of systolic blood pressure reduction on 
hematoma expansion, perihematomal edema, and 3-month outcome among patients with 
intracerebral hemorrhage: results from the antihypertensive treatment of acute cerebral 
hemorrhage study. Arch. Neurol. p. 570-6.
Qureshi AI, Tuhrim S, Broderick JP, et al (2001) Spontaneous intracerebral hemorrhage. N. 
Engl. J. Med. p. 1450-60.
Rodriguez-Luna D, Stewart T, Dowlatshahi D, et al (2016) Perihematomal Edema Is Greater 
in the Presence of a Spot Sign but Does Not Predict Intracerebral Hematoma Expansion. 
Stroke p. 350-5.
Commercially Confidential Information


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Page 78
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Rolland WB, Manaenko A, Lekic T, et al. (2011) FTY720 is Neuroprotective and Improves 
Functional Outcomes after Intracerebral Hemorrhage in Mice. Acta Neurochir Suppl; 111: 
213–217.
Rolland WB, Lekic T, Krafft PR, et al. (2013) Fingolimod Reduces Cerebral Lymphocyte 
Infiltration in Experimental Models of Rodent Intracerebral Hemorrhage. Exp Neurol; 241: 
45–55.
Sanchez T, Estrada-Hernandez T, Paik JH, et al (2003) Phosphorylation and action of the 
immunomodulator FTY720 inhibits vascular endothelial cell growth factor-induced vascular 
permeability. J. Biol. Chem. p. 47281-90.
Schmouder R, Hariry S, David OJ (2012) Placebo-controlled study of the effects of 
fingolimod on cardiac rate and rhythm and pulmonary function in healthy volunteers. Eur. J. 
Clin. Pharmacol. p. 355-62.
Selim M and Norton C (2018) Perihematomal edema: Implications for intracerebral 
hemorrhage research and therapeutic advances. J. Neuro. Res.  p. 1-7
Selmaj K, Li DK, Hartung HP, et al (2013) Siponimod for patients with relapsing-remitting 
multiple sclerosis (BOLD): an adaptive, dose-ranging, randomised, phase 2 study. Lancet 
Neurol.  p. 70102-9.
Smith-Bindman R, Lipson J, Marcus R, et al (2009) Radiation dose associated with common 
computed tomography examinations and the associated lifetime attributable risk of cancer. 
Arch. Intern. Med. p. 2078-86.
Staykov D, Wagner I, Volbers B, et al (2011) Natural course of perihemorrhagic edema after 
intracerebral hemorrhage. Stroke p. 2625-9.
Steiner T, Al-Shahi Salman R, Beer R, et al (2014) European Stroke Organisation (ESO) 
guidelines for the management of spontaneous intracerebral hemorrhage. Int J Stroke p. 840-
55.
Steiner T, Diringer MN, Schneider D et al (2006) Dynamics of intraventricular hemorrhage in 
patients with spontaneous intracerebral hemorrhage: risk factors, clinical impact, and effect of 
hemostatic therapy with recombinant activated factor VII. Neurosurgery p.767-773.
Sun W, Peacock A, Becker J, et al (2012) Correlation of leukocytosis with early neurological 
deterioration following supratentorial intracerebral hemorrhage. J Clin Neurosci p. 1096-100.
The ENOS Trial Investigators (2015) Efficacy of nitric oxide, with or without continuing 
antihypertensive treatment, for management of high blood pressure in acute stroke (ENOS): a 
partial-factorial randomised controlled trial. Lancet p. 617-28.
Urday S, Kimberly WT, Beslow LA, et al (2015) Targeting secondary injury in intracerebral 
haemorrhage--perihaematomal oedema. Nat Rev Neurol p. 111-22.
Venkatasubramanian C, Mlynash M, Finley-Caulfield A, et al (2011) Natural history of 
perihematomal edema after intracerebral hemorrhage measured by serial magnetic resonance 
imaging. Stroke p. 73-80.


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Volbers B, Staykov D, Wagner I, et al (2011) Semi-automatic volumetric assessment of 
perihemorrhagic edema with computed tomography. Eur J Neurol. p. 1323-8.
Wang Q, Markopoulos P, Yu B, et al (2017) Interactive wearable systems for upper body 
rehabilitation: a systematic review. J Neuroeng Rehabil p. 20.
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15
Appendix 1: Liver Event Definitions and Follow-up 
Requirements
Table 15-1
Liver Event Definitions
Definition
Thresholds
Potential Hy’s law cases

ALT or AST > 3 × ULN and TBL > 2 × ULN without initial 
increase in ALP to > 2 × ULN
ALT or AST elevation with 
coagulopathy

ALT or AST > 3 × ULN and INR > 1.5 (in the absence of 
anticoagulation)
ALT or AST elevation 
accompanied by symptoms

ALT or AST > 3 × ULN accompanied by (general) malaise, 
fatigue, abdominal pain, nausea, or vomiting, or rash, or 
eosinophilia
Isolated ALT or AST 
elevation

ALT or AST > 8 × ULN

5 x ULN < ALT/AST ≤ 8 x ULN

3 x ULN < ALT/AST ≤ 5 x ULN
Isolated ALP elevation

ALP > 2 × ULN (in the absence of known bone pathology)
Others

Any clinical event of jaundice (or equivalent term)

Any adverse event potentially indicative of liver toxicity
Table 15-2
Actions required for Liver Events
Criteria
Actions required
Potential Hy’s Law case

Discontinue the study treatment immediately 

Hospitalize, if clinically appropriate

Establish causality

Complete CRFs per liver event guidance*
ALT or AST elevation with coagulopathy
ALT or AST elevation accompanied by 
symptoms
Isolated ALT or AST elevation > 8 × ULN
Jaundice
Isolated ALT or AST elevation > 5 to ≤ 8 × 
ULN

If confirmed, consider interruption or 
discontinuation of study drug 

If elevation persists for more than 2 weeks, 
discontinue the study drug 

Establish causality

Complete CRFs per liver event guidance*
Isolated ALT or AST elevation > 3 to ≤ 5 × 
ULN (patient is asymptomatic)

Monitor liver chemistry tests two or three times 
weekly
Isolated ALP elevation

Repeat liver chemistry tests within 48-72 hours

If elevation is confirmed, measure fractionated 
ALP; if >50% is of liver origin, establish hepatic 
causality

Complete CRFs per liver event guidance*
Any AE potentially indicative of liver toxicity

Consider study treatment interruption or 
discontinuation 

Hospitalize if clinically appropriate

Complete CRFs per liver event guidance*
*Liver event guidance for CRF completion is available in the Site Operations Manual


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Table 15-3
Exclusion of underlying liver disease
Disease
Assessment
Hepatitis A, B, C, E

IgM anti-HAV; HBsAg, IgM anti-HBc, HBV DNA; anti-HCV, HCV 
RNA, IgM & IgG anti-HEV, HEV RNA
CMV, HSV, EBV infection

IgM & IgG anti-CMV, IgM & IgG anti-HSV; IgM & IgG anti-EBV
Autoimmune hepatitis

ANA & ASMA titers, total IgM, IgG, IgE, IgA
Alcoholic hepatitis

Ethanol history, GGT, MCV, CD-transferrin
Nonalcoholic steatohepatitis

Ultrasound or MRI
Hypoxic/ischemic 
hepatopathy

Medical history: acute or chronic CHF, hypotension, hypoxia, 
hepatic venous occlusion. Ultrasound or MRI.
Biliary tract disease

Ultrasound or MRI, ERCP as appropriate.
Wilson disease

Ceruloplasmin
Hemochromatosis

Ferritin, transferrin
Alpha-1-antitrypsin deficiency

Alpha-1-antitrypsin


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16
Appendix 2: Specific Renal Alert Criteria and Actions
Table 16-1
Specific Renal Alert Criteria and Actions
Criteria
Action required
Serum creatinine (sCr) increase
25 – 49% compared to baseline

Consider causes and possible interventions

Follow up within 2-5 days
Serum creatinine increase > 50%

Consider causes and possible interventions

Repeat assessment within 24-48h if possible

Consider drug interruption or discontinuation 
unless other causes are diagnosed and 
corrected 

Consider hospitalization and specialized 
treatment
Protein-creatinine or albumin-creatinine ratio 
increase ≥ 2-fold
or
new onset dipstick proteinuria ≥ 1+
or
Albumin-creatinine ratio (ACR) ≥ 30 mg/g or 
≥ 3 mg/mmol;
or
Protein-creatinine ratio (PCR )≥ 150 mg/g or 
>15 mg/mmol

Consider causes and possible interventions

Assess serum albumin & serum protein

Repeat assessment to confirm

Consider drug interruption or discontinuation 
unless other causes are diagnosed and 
corrected 
New onset glucosuria on urine dipstick 
(unless related to concomitant treatment, 
diabetes)
Assess & document:

Blood glucose (fasting)

Serum creatinine

Urine albumin-creatinine ratio
New hematuria on dipstick
Assess & document:

Urine sediment microscopy

Assess sCr and urine albumin-creatinine ratio

Exclude infection, trauma, bleeding from the 
distal urinary tract/bladder, menstruation

Consider bleeding disorder
Additional specialized assessments are available to assess renal function or renal pathology. 
(Note: In exceptional cases when a nephrologist considers a renal biopsy, it is strongly 
recommended to make specimen slides available for evaluation by Novartis to potentially 
identify project-wide patterns of nephrotoxicity.)


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Protocol No. CBAF312X2207
Whenever a renal event is identified, a detailed subject history and examination are indicated 
to identify, document and potentially eliminate risk factors that may have initiated or 
contributed to the event:

Blood pressure assessment (after 5 min rest, with an appropriate cuff size)

Signs and symptoms such as fever, headache, shortness of breath, back or abdominal pain, 
dysuria, hematuria, dependent or periorbital edema

Changes in blood pressure, body weight, fluid intake, voiding pattern, or urine output

Concomitant events or procedures such as trauma, surgical procedures, cardiac or hepatic 
failure, contrast media or other known nephrotoxin administration, or other potential 
causes of renal dysfunction, e.g., dehydration, hemorrhage, tumor lysis
Table 16-2
Follow-up of renal events
Action
Follow up
Assess*, document and record in the Case 
Report Form (CRF) or via electronic data 
load. Review and record possible contributing 
factors to the renal event (co-medications, 
other co-morbid conditions) and additional 
diagnostic procedures (MRI etc) in the CRF.

Urine dipstick and sediment microscopy

Blood pressure and body weight

Serum creatinine, electrolytes (sodium, 
potassium, phosphate, calcium), bicarbonate 
and uric acid

Urine output
Monitor subject regularly (frequency at 
investigator’s discretion) until:

Event resolution: (sCr within 10% of baseline or 
protein-creatinine ratio within 50% of baseline)
or

Event stabilization: sCr level with ±10% 
variability over last 6 months or protein-
creatinine ratio stabilization at a new level with 
±50% variability over last 6 months.
* Urine osmolality: in the absence of diuretics or chronic kidney disease this can be a very 
sensitive metric for integrated kidney function that requires excellent tubular function. A high 
urinary osmolality in the setting of an increase in sCr will point toward a “pre-renal” cause 
rather than tubular toxicity.


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17
Appendix 3: Clinically notable laboratory values and vital 
signs 
Table 17-1
Notable Vital Signs And Body Weight
Vital Sign Variable
Notable Criteria
Pulse (beats/min)
>120 bpm Or < 50 bpm 
Systolic BP (mmHg)
≥ 160 mm Hg Or ≤ 90 mm Hg 
Diastolic BP (mmHg)
≥ 100 mmHg Or ≤ 50 mmHg 
Temperature (°C)
>38.3 °C/ 101°F 
Body weight (kg)
± 7% from baseline weight


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Appendix 4: Modified Rankin Scale


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20
Appendix 6: Glasgow Coma Scale (GCS)
From: www.glasgowcomascale.org


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Appendix 7: List of prohibited medications
The aim of this document is to provide a specific list of drugs that should not be co-administered 
with BAF312 because of their CYP2C9/3A4 inhibitory or induction potential.
Due to the constant information arising on drugs, these lists are by no mean exhaustive and 
medical judgment should always prevail. These lists are adapted to the patient population and 
the exclusion criteria of the study CBAF312X2207 only.
Only potent CYP2C9 and CYP3A4 inhibitors may have a significant effect on BAF312 
exposure and should not be co-administered with BAF312 (Table 21-1).
Potent CYP2C9 and/or CYP3A4 inducers (Table 21-2) should not be coadministered with 
BAF312 to avoid a potential decrease of efficacy of BAF312 in case of under-exposure due to 
CYP2C9/CYP3A4 induction (note that topical use is permitted).
Table 21-1
Typical inhibitors of CYP2C9 or CYP3A4 
Antibiotics:
Antivirals:
Clarithromycin
Boceprevir
Sulfaphenazole
Telaprevir
Telithromycin
Troleandomycin
Protease Inhibitors:
Others:
Indinavir
Amiodarone
Lopinavir
Ataciguat
Nelfinavir
Azapropazone
Ritonavir
Benzbromarone
Saquinavir
Bucolome
Tipranavir
Cobicistat
Antifungals:
Conivaptan
Fluconazole
Elvitegravir
Itraconazole
Mibefradil
Ketoconazole
Nefazodone
Miconazole
Oxandrolone
Posaconazole
Tielinic Acid
Voriconazole


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Table 21-2
Typical inducers of CYP2C9 and/or CYP3A4 
Aprepitant
Ginkgo
Rifabutin
Avasamide
Lersivirine
Rifampin
Bosentan
Lopinavir
Ritonavir
Carbamazepine
Mitotane
Secobarbital
Dalcetrapid
Modafinil
Semagacestat
Efavirenz
Nafcillin
St. John’s wort
Enzalutamide
Nelfinavir
Talviraline
Escalicarbazepine
Nevirapine
Thioridazine
Etravirin
Phenobarbital
Tipranavir
Genistein
Phenytoin
Vigabatrin

SAP_001.pdf: 
Biostatistics & Statistical Programming / 
Novartis Institutes for BioMedical Research
BAF312
CBAF312X2207 / NCT03338998
A phase II, patient and investigator-blinded, randomized, 
placebo-controlled study to evaluate efficacy, safety and 
tolerability of BAF312 in patients with stroke due to 
intracerebral hemorrhage (ICH)
Statistical Analysis Plan (SAP)
Author(s):
Document type:
SAP Documentation – NIBR
Document status:
Final
Release date:
29-Mar-2021
Number of pages:
35
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
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Table of contents
Table of contents .................................................................................................................3
List of tables ........................................................................................................................4
List of abbreviations............................................................................................................5
1
Introduction .........................................................................................................................7
1.1
Scope of document ..................................................................................................7
1.2
Study reference documentation ...............................................................................7
1.3
Study objectives.......................................................................................................7
1.3.1
Primary objective ....................................................................................7
1.3.2
Secondary objective ................................................................................7
1.3.3
Exploratory objective(s)..........................................................................8
1.4
Study design and treatment......................................................................................9
2
First interpretable results (FIR) ...........................................................................................9
3
Interim/DMC analyses.......................................................................................................10
4
Statistical methods.............................................................................................................12
4.1
Analysis sets ..........................................................................................................12
4.2
Data analysis general information: ........................................................................13
4.3
Subgroup of interest...............................................................................................14
4.4
General definitions.................................................................................................14
5
Statistical methods for primary objective..........................................................................15
5.1
Primary objective...................................................................................................15
5.1.1
Variables ...............................................................................................15
5.1.2
Descriptive analyses..............................................................................15
5.1.3
Statistical model, assumptions and hypotheses.....................................15
5.2
Secondary objectives .............................................................................................16
5.2.1
Variables ...............................................................................................16
5.2.2
Descriptive analyses..............................................................................17
5.2.3
Statistical model, assumptions and hypotheses.....................................17
6
Statistical methods for Pharmacokinetic (PK) parameters................................................18
6.1
Secondary Objective:.............................................................................................18
6.2
Variables................................................................................................................18
6.3
Descriptive analyses ..............................................................................................18
6.4
Statistical model, assumptions and hypotheses .....................................................18
7
Exploratory objectives.......................................................................................................18
7.1.1
Variables ...............................................................................................18
7.1.2
Descriptive analyses..............................................................................19
8
Statistical methods for safety and tolerability data............................................................21


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8.1
Variables................................................................................................................21
8.2
Descriptive analyses ..............................................................................................21
8.3
Graphical presentation...........................................................................................28
10 Sample size consideration .................................................................................................29
11 Reference list.....................................................................................................................29
12 Appendix ...........................................................................................................................30
12.1
SAS code ...............................................................................................................30
12.2
Definition of benefit for individual endpoints.......................................................34
List of tables
Table 4-1
Protocol deviation and analysis sets......................................................12
Table 8-1
Notable vital signs and body weight .....................................................24
Table 8-2
Liver event definition............................................................................26
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List of abbreviations
AE
Adverse event
AESI
Adverse event of special interest
aPHE
absolute Perihematoma Edema
ATC
Anatomical Therapeutic Classification
AUC
Area Under the Curve
bid
bis in diem/twice a day
BMI
Body Mass Index
CSR
Clinical Study Report
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events
C-SSRS
Columbia-Suicide Severity Rating Scale
DBL
Database Lock
DMC
Data Monitoring Committee 
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
FAS
Full Analysis Set
FIR
First Interpretable Results
GCS
Glasgow Coma Scale
HLT
High level terms
i.v.
Intravenous 
IA
Interim Analysis
ICH
Intracerebral hemorrhage
MedDRA
mRS
NF-L
NIBR
PAS
Pharmacokinetics Analysis Set
PDT
Programming Deliverables Tracker
PHE
Perihematoma Edema
PK
Pharmacokinetics
PPS
Per-Protocol Set
PT
Preferred Terms
p.o.
Oral
PRO
Patient-reported Outcomes
QD
Qua’que di’e / once a day
RAP
Report and Analysis Process
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SAS
Statistical Analysis System
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Medical Dictionary for Drug Regulatory Affairs 
modified Rankin Scale
Neurofilament light
Novartis Institute for BioMedical Research
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SOPs
Standard Operating Procedures
SMQ
Standardized MedDRA Queries
SOC
System Organ Class
TFLs
Tables, Figures, Listings
WHO
World Health Organization
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1
Introduction
1.1
Scope of document
This document details the planned statistical analysis for data collected in the study 
CBAF312X2207.
Clinical Study Report (CSR) deliverables (tables, figures, listings - TFLs) and further 
programming specifications are described in separate documents. 
This statistical analysis plan (SAP) describes the primary analysis for which a CSR is planned. 
Interim analyses (IA) may be conducted to support decision making concerning the current 
clinical study. Nevertheless, a Data Monitoring Committee (DMC) will review unblinded safety 
and efficacy data on a regular basis and three DMC is planned for this study.
1.2
Study reference documentation
The SAP is finalized under the amended study protocol version v02 dated on 25-Mar-2019. 
The Novartis Institutes for BioMedical Research (NIBR) standard SAP and TLFs shells 
templates version Final 3.0, 24-Mar-2017 (Effective 3-Apr-2017) and Final 3.0, 04-Jul-2017 
(Effective 01-Aug-2017), are respectively used. 
The electronic Case Report Form (eCRF) version 5.0 dated on 11-Nov-2019 version is used for 
TLFs shells development. The DMC charter used for this study is: nibr-BAF312 DMC 
charter.pdf dated 28-Aug-2020.
1.3
Study objectives
The purpose of the study is to investigate the initial efficacy and safety of BAF312 administered 
on top of standard-of-care compared to placebo in patients with stroke due to ICH; and to 
determine if the overall clinical profile of BAF312 warrants further clinical development in ICH.
1.3.1
Primary objective
Primary objective
Endpoints related to 
primary objective
Analysis
To obtain the first efficacy estimate of 
BAF312 daily (7 days i.v. with titration followed by 
7 days p.o.) compared to placebo on reducing 
absolute perihematoma edema (aPHE) volume on 
Day 14 after ICH. 
aPHE volume 
measured by CT scan 
on Day 14 after ICH
1.3.2
Secondary objective
The secondary objectives are:
Secondary objective(s)
Endpoints related to secondary 
objective(s)
Analysis
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To assess the safety profile of BAF312 
in ICH patients.
Continuous assessment of Adverse 
events (AEs)/Serious AEs during 
the course of the study (90 days).
Refer SAP 
section 5.2
To evaluate the pharmacokinetics (PK) 
of BAF312 in ICH patients.
PK 
measurements 
of 
plasma 
BAF312 concentrations at 0.5, 2 and 
6 h after start of infusion during i.v. 
titration on Day 1; and before p.o. 
dosing on Days 8 and 14.
Refer SAP 
section 5.2
and 
Section 6
1.3.3
Exploratory objective(s)
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1.4
Study design and treatment
This is a randomized, patient- and investigator-blinded, placebo-controlled, parallel group study 
of BAF312 (siponimod) on top of standard-of-care for intracerebral hemorrhage (ICH), 
consisting of 3 epochs: Screening/Baseline, Treatment, and Follow-Up as indicated in Figure 
1-1.
Approximately 33 patients per treatment group (~65 patients in total) will be randomized, with an 
expected drop-out rate of approximately 10% to obtain at least 60 completed study subjects (Day 
14). Patients will be assigned to one of the following 2 treatment arms, BAF312 or Placebo, in 
a ratio of 1:1.
Reduction of perihematoma edema (PHE) measured by CT imaging at 14 days after ICH is the 
primary endpoint for measuring BAF312 efficacy in this study. 
Regular DMC will occur in order to provide recommendations to the sponsor to continue the 
trial according to the protocol and any relevant amendments, or to make changes or adjustments 
to the study.
2
First interpretable results (FIR)
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3
Interim/DMC analyses
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4
Statistical methods
4.1
Analysis sets
All randomized subjects: 
They correspond to all patients included in the study who fulfilled the inclusion/exclusion 
criteria. 
Full Analysis Set (FAS): 
The FAS will include all patients who are randomized and received any amount of study drug.
Safety Set (SAF):
The Safety Analysis Set will include all patients that received any amount of study drug.
Per Protocol Set (PPS):
The PPS will include all patients in the FAS having received at least 2 full days of  I.V. treatment 
and no protocol deviations listed in Table 4.1 with relevant impact on efficacy data.
PK Analysis Set (PAS):
The PAS will include all patients with at least one available valid (i.e., not flagged for exclusion) 
PK concentration measurement, who received any study drug and experienced no protocol 
deviations listed in table 4.1 with relevant impact on PK data.
For all analysis sets, patients will be analyzed per the study treatment(s) received.
All listings will use Randomized patients.
Frequency counts and percentages (using FAS as denominator) of patients in each of the above 
defined analysis sets will be summarized. In addition, listings of patients excluded from each 
of the analysis sets will be provided.
The analysis sets and protocol deviation are related to this study as follows:
Table 4-1
Protocol deviation and analysis sets
Text description of deviation
Subjects are excluded from Per protocol analysis set in case of these PDs: 

Any protocol deviation from the category “Eligibility and Entry Criteria” which are all at
least major (except if not considered by clinical team before the database lock).
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Text description of deviation

Any protocol deviation from the category “IP Compliance” corresponding to the major or 
critical deviation below:

Wrong medication pack dispensed resulting in injection of placebo during the whole 
i.v. phase followed by intake of BAF312 in the oral part.

Any intake of prohibited medication corresponding to a protocol deviation category 
“Concomitant Medications Criteria” and taken during a certain period and likely to impact 
efficacy analysis.
Subjects are excluded from PK analysis in case of same PDs as PPS except 

Any intake of prohibited medication corresponding to a protocol deviation category 
“Concomitant Medications Criteria” and taken during a certain period and likely to impact 
PK analysis.
If updates to this table are needed, an amendment to the SAP needs to be implemented prior to
data base lock (DBL). The list of deviation will be review regularly to make sure the analysis 
set definition is as needed.
Prior to the locking of the database for final blind data reviews a blinded data review report will 
be written in order to establish analysis set assignment and to identify the potential reason(s) 
for exclusion of subjects from one or more of the analysis sets. As one of the criteria will request 
unblinded information a second version of the blind data review report will be created post 
database lock in order to indicate the final analysis set assignment as per IQVIA best practice.
4.2
Data analysis general information:
Data will be analyzed by IQVIA Biostatistics and Statistical Programming personnel according 
to the data analysis section 11 of the study protocol as detailed in this analysis plan. IQVIA 
standard operating procedures (SOPs) will be followed and some of the Novartis SOPs will be 
used, if deemed appropriate. Few analyses may be performed by NIBR Biostatistics group 
which is specified in advance in appropriate section.
SAS® version 9.4 (or later version if available at time of database lock) will be used for all 
analyses.
Data from all patients who signed informed consent will be used in the analysis; no center effect 
will be assessed as it is expected to have small sample size of enrollment at each individual 
centers.  Each analysis will use all data in the database up to the analysis cut-off date, determined 
prior to database lock.
General presentation of descriptive summaries and listings
The following summary statistics will be presented unless otherwise stated specifically. 
Qualitative/categorical data (e.g., gender, race) will be summarized by frequency counts and 
percentages. Percentages will be calculated using the number of patients in the relevant 
treatment arm or subgroup as the denominator.
Continuous data (e.g., age, body weight) will be summarized using appropriate descriptive 
statistics (i.e. mean, standard deviation (SD), lower quartile (q1), median, upper quartile (q3), 


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minimum, and maximum) by treatment arm. Based on the nature of the data, few analyses 
requires additional statistics such as geometric mean, geometric coefficient of variation (CV) 
and it will be specifically requested respective section.
In general, listings will be presented 

with country/center/subject identifier and age/sex/race as a mandatory column unless
otherwise specified

by treatment and patient
4.3
Subgroup of interest -
Result to swallowing test (success or fail) will be used as a covariate and as a subgroup for 
descriptive summary of mRS score.
4.4
General definitions
Study Treatment:
Patients will be assigned to one of the two treatment (BAF312/Placebo) arms in a ratio of 1:1. 
Study treatment will be noted as BAF312/Placebo throughout this document and CSR 
deliverables.
Patients and investigators (including all site staff) will remain blinded to study treatment 
throughout the study.
Study Day:
The study day for safety/efficacy assessments (e.g. adverse event onset, laboratory abnormality 
occurrence, vital sign measurement, Electrocardiogram (ECG), PK sampling mRS scores, etc.,) 
will be calculated using the first administration of i.v. dose date as the reference date. For 
assessments occurring:
on or after the first administration of i.v. dose date, the study day will be calculated as (date 
of assessment/occurrence) – (date of first administration of i.v. dose) + 1. Then study day 1 will 
be the day of first administration of i.v. dose.
before the first administration of i.v. dose date, the study day will be calculated as (date of 
assessment/occurrence) – (date of first administration of i.v. dose).
For example, if a serious adverse event starts 1 day before the first administration of i.v. dose
date, the study day displayed on the listing will be negative, i.e. -1.
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Baseline: 
For all evaluations, the last available assessment before or on the date/time of first dose is taken 
as ‘baseline’ value or ‘baseline’ assessment.
Unscheduled Assessment:
In general, descriptive summary statistics will not include unscheduled/repeat assessment. 
For all analyses regarding abnormal assessments or analyses based on worst post–baseline value 
(e.g. laboratory, ECGs, vital signs), all post-baseline values will be included (scheduled, 
unscheduled, repeat). All unscheduled and repeat measurements will be included in listings.
Analysis visit window:
No time-window will be applied in this study.
In summary by visit the scheduled EOS visit will be included. If appropriate EOS visit could 
be mapped to the next scheduled visit.
On treatment:
It corresponds to any event or any assessment occurring between the 1st study drug injection 
date and the last injection/intake date.
5
Statistical methods for primary objective
5.1
Primary objective
To obtain the first efficacy estimate of 
 BAF312 daily (7 days i.v. with titration followed 
by 7 days p.o.) compared to placebo on reducing absolute perihematoma edema (aPHE) volume 
on Day 14 after ICH.
5.1.1
Variables
The primary efficacy variable is the aPHE volume measured on Day 14, which. will be 
measured from the CT images by a central reading lab.
The primary analysis will be done on the PPS. A sensitivity analysis will be done on the FAS.
5.1.2
Descriptive analyses
Summary statistics of aPHE will be presented by treatment at Day 14 in the same output as the 
inferential result. 
5.1.3
Statistical model, assumptions and hypotheses
It is expected that the distribution of aPHE is right-skewed (as it is a positive-valued 
measurement), so a log-transformation will be applied. The log-transformed absolute PHE 
volume on Day 14 will be analyzed using analysis of covariance (ANCOVA) model, with 
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treatment as a classification factor and the baseline log-transformed aPHE as covariate. The 
mean difference (BAF312 vs. placebo) and its two-sided 90% CI will be calculated, and these 
estimates will be back-transformed to give adjusted geometric mean and the respective CV 
along with  a geometric mean ratio and two-sided 90% CI of BAF312 vs. placebo. One-sided 
p-value will be provided to test superiority of  BAF312 to placebo.
5.1.3.1
Handling of Missing Data
Every effort will be made to obtain complete data during clinical conduct of the study. 
The analysis will be done on the available data recorded on the Day 14 CT scan. 
5.1.3.2
Supportive Analyses
5.1.3.3
Graphical presentation of results
Percentage of ordinal mRS score at Day 90 will be displayed by treatment.
5.2
Secondary objectives
The secondary objectives are to assess the safety profile, and to evaluate the pharmacokinetics 
of BAF312 in ICH patients.
5.2.1
Variables

Safety profile of BAF312 in ICH patients will be evaluated by continuous assessment
of AEs/SAEs during the course of the study (90 days). Safety set will be used for this
analysis.

PK of BAF312 in ICH patients will be evaluated by PK measurements of plasma
BAF312 concentrations at 0.5, 2 and 6 h after start of infusion during i.v. titration on
Day 1; and before p.o. dosing on Days 8 and 14. PK Analysis set will be used.
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5.2.2
Descriptive analyses
Both secondary endpoints are descriptive in nature, there will not be any inferential statistics 
presented. Descriptive statistics will be presented for concentration vs time by treatment arm.
5.2.3
Statistical model, assumptions and hypotheses
The analyses will be descriptive. No hypothesis will be tested.
Safety profile of BAF312:
The incidence of any treatment emergent adverse events (TEAEs), serious TEAEs overall and 
by severity will be summarized by treatment using frequency counts, percentages of patients 
and 95% Confidence Intervals (CIs) for percentages obtained using Clopper – Pearson method.
Treatment emergent adverse events are defined as any event starting or worsening on treatment 
(i.e. between the 1st study drug injection date and the last study drug injection/intake date).
These secondary safety endpoints will be summarized by treatment arm for the safety analysis 
set.
PK of BAF312:
Refer SAP section 6.
5.2.3.1
Model checking procedures
There will be no imputation for missing values.
5.2.3.2
Graphical presentation of results
Graphical presentation may be provided for most frequent TEAEs sorted by relative risk. For 
PK, refer section 6.


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6
Statistical methods for Pharmacokinetic (PK) parameters
One of the secondary objectives is to evaluate the pharmacokinetics of BAF312 in ICH patients.
6.1
Secondary Objective:
PK of BAF312 in ICH patients will be evaluated by PK measurements of plasma BAF312 
concentrations at 0.5, 2 and 6 h after start of infusion during i.v. titration on Day 1; and before 
p.o. dosing on Days 8 and 14. All PK analyses will be performed based on the PAS.
6.2
Variables
As only sparse PK samples will be collected in the study, no PK parameters will be estimated. 
PK samples will be pooled with PK data of other available studies in order to assess the effect 
of various covariates on the plasma concentrations of BAF312 in patients with stroke due to 
ICH through a population pharmacokinetic analysis and it is not scope of this SAP.
Only evaluable PK concentration data will be used in the analyses and summary statistics.
Unscheduled samples will not be used for descriptive statistics. It will be flagged in the 
corresponding concentration listing. 
6.3
Descriptive analyses
Summary statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and 
geometric), median, minimum and maximum. Concentrations below the limit of quantification 
will be treated as zero in summary statistics and excluded from geometric mean and geometric 
Coefficient of Variation (CV%) computation. Linear mean concentration vs. time will be 
graphically presented. In addition, individual patient concentration vs. time will also be 
presented.
BAF312 plasma concentration data will be listed by treatment, patient, and visit/sampling time 
point. All individual data will be listed on all randomized subjects and those excluded from the 
PK analysis will be flagged. Statistical model, assumptions and hypotheses
The analyses will be descriptive. No hypothesis will be tested.
7
Exploratory objectives
7.1.1
Variables 
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7.1.2
Descriptive analyses
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8
Statistical methods for safety and tolerability data
The following safety analyses will be performed based on the Safety Set.
8.1
Variables
Adverse events, vital signs (blood pressure, pulse rate, body temperature), ECG intervals, 
laboratory measurements, as well as subject demographics, baseline characteristics, and 
treatment information.
8.2
Descriptive analyses
Subject demographics and other baseline characteristics
The FAS will be used for all patient demographic and baseline characteristic summaries and 
listings, unless otherwise specified. 
All data for background and demographic variables will be listed by treatment and patient. 
Summary statistics will be provided by treatment. Descriptive statistics, frequency counts and 
percentages will be tabulated by treatment arm, as appropriate. 
Baseline demographic includes following,

Age (in years)

Age category in years (<70; >=70)

Sex (Male, Female)

Race (Caucasian, Black, Asian, Native American, Pacific Islander, Unknown, Other)

Ethnicity (Hispanic or Latino, East Asian, Southeast Asian, South Asian, West Asian,
Russian, Mixed Ethnicity, Not Reported, Unknown, Other)

Weight (kg)

Height (cm)

Body Mass Index (BMI) – calculated as weight (kg) / (height (m))2
Other baseline characteristics includes,

Glasgow Coma Scale (GCS) total score

GCS total score in categories (<13 a.u., >=13 a.u.)

Baseline blood pressure includes systolic (mmHg), diastolic (mmHg), pulse
(Beats/min), and Temperature (°C)
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
Baseline aPHE volume (mL)

Baseline location of hematoma

Time from first symptoms of ICH or last seen neurologically normal status (day). This
time will be computed up to the start of study drug.
Patients who signed study informed consent and pharmacogenetic informed consent with date 
will be presented in listings by treatment and patient.
Medical History
Medical history and ongoing conditions will be listed by treatment arm. Medical history and 
current medical conditions will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) terminology.
Patient disposition
The FAS will be used for the patient disposition summaries. The summary by treatment arm 
will show:

Number (%) of randomized patients who were not treated;

Number (%) of randomized patients who were treated;

Number (%) of patients who completed the study treatment;

Number (%) of patients who discontinued the study treatment;

Reasons for study treatment discontinuation.
Frequency counts and percentages of patients for each of analysis set will be presented 
separately by treatment. Any protocol deviation (selection criteria not met, patient not 
withdrawn as per protocol, key procedures not performed as per protocol, treatment deviation, 
prohibited concomitant medication, other Good Clinical Practice (GCP) deviation) will be 
tabulated by the deviation type and treatment.
All protocol deviations will be presented in a listing by treatment and patient. Summary of 
protocol deviation with categories will be presented by treatment.
Data presented for screen failure patients

Screen failure patients will not be included any analysis.
Study drug exposure and compliance
The total treatment lasts 14 days with two treatment phases (i.v. to p.o.) based on dose 
administration. 
7 days of i.v. BAF312 with titration to the final daily dose 
;
During the 7 days of i.v. infusion treatment, all patients must undergo a swallowing safety 
evaluation per the treating hospital’s institutional guidelines and practices.
If the patients pass the swallowing safety evaluation, 7 days of 
 BAF312 p.o. QD.
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Patients who do not successfully pass a swallowing safety evaluation must not be transitioned 
to the p.o. phase of treatment, and BAF312 must be discontinued after Day 7; but they should 
not be terminated from the study. These patients should continue to be followed as per the 
protocol assessment schedule.
Eligible patients who pass a swallowing safety evaluation will continue with 7-day p.o. phase 
of treatment with BAF312 
 QD.
Information on the dose administration, amount, frequency (includes dose titration), reason for 
the dose change, start date and end date in eCRF pages collected for each of the treatment phase. 
Overall study drug exposure, study drug exposure for individual phase (i.v. and p.o.) will be 
calculated as follows,
Overall drug exposure (days) =[date of last study treatment – date of first study treatment+1]
Study drug exposure in i.v. phase (days) =[date of last dose in i.v. phase– date of first dose in 
i.v. phase +1]
Study drug exposure in p.o. phase (days) =[date of last dose in p.o. phase– date of first dose in
p.o. phase +1]
Overall drug exposure, study drug exposure in i.v. and p.o. phase will be summarized by 
treatment. In addition, frequency counts and percentages of patients who have dose decreases, 
increases in planned dose or dose interruptions, the corresponding reasons and average length 
of dose interruptions will be summarized separately for i.v. phase and p.o. phase. 
Listing of drug administration will be presented with i.v. treatment phase on day 1-7 and another 
listing for p.o. phase on day 8-14. 
During the 7 days of i.v. infusion treatment, all patients will undergo a swallowing safety 
evaluation. A listing will be provided for swallowing test by treatment.
Compliance using pill count in p.o. phase:
Study drug compliance of patients who transitioned from i.v. to p.o. phase will be evaluated 
using “Drug Accountability Oral Medication” eCRF page. 
The relative consumed tablet count (%) is defined as the ratio of total count consumed to total 
count prescribed. Where the total count consumed is calculated as the sum of counts dispensed 
minus the sum of counts returned and where the prescribed count corresponds to the count 
prescribed by the investigator for a p.o. phase that the patient should have taken during this 
phase.
The relative consumed tablet will be summarized by treatment.
Prior, concomitant and post therapies
Prior and concomitant therapies are defined as any medication, and significant non-drug 
therapies administered to a subject preceding or coinciding with the study assessment period.
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List (WHO DRL), which employs the WHO Anatomical Therapeutic Chemical 
(WHO ATC) classification system.
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Concomitant therapies will include medications and significant non-drug therapies taken during 
treatment phase. Prior therapies will include medications or significant non-drug therapies 
starting and ending prior to the start of study treatment.
Concomitant and prior therapies will be summarized by ATC class, preferred term and 
treatment arm using safety set. Medications starting prior to the start of study treatment and 
continuing after the start of study treatment will be counted in both summaries.
All prior and concomitant therapies will be listed.
Vital signs
Vital signs will include pulse rate, systolic and diastolic blood pressure in supine position and 
temperature which will be assessed at the all visits from screening/baseline to 90 days.
Summary statistics of vital sign results and change from baseline will be provided by treatment 
and visit/time.
Change from baseline will only be summarized for patients with both baseline and post baseline 
values and will be calculated as:
change from baseline = post baseline value – baseline value.
Table 8-1
Notable vital signs and body weight
Vital Sign Variable
Notable Criteria
Pulse (beats/min)
>120 bpm or < 50 bpm
Systolic BP (mmHg) 
≥ 160 mmHg or ≤ 90 mmHg
Diastolic BP (mmHg)
≥ 100 mmHg or ≤ 50 mmHg
Temperature (°C)
>38.3 °C/ 101°F
Body weight (kg)
More than 7% decrease from baseline weight
Listing will be provided with vital signs results and notable values will be flagged by treatment 
and patients. Box plot will be presented for each of vital sign parameter over visits by treatment.
ECG evaluations
Standard 12-lead ECGs will be performed for all patients at screening/baseline, day 1-3, day 7. 
ECGs measurement HR, PR, QT, QRS, and QTcF will be listed by treatment, patient and 
visit/time, abnormalities will be flagged. Summary statistics of raw value and change from 
baseline will be provided by treatment and visit/time.
Change from baseline will only be summarized for patients with both baseline and post baseline 
values and will be calculated as:
change from baseline = post baseline values – baseline value.
Additionally, the number and proportion of patients with abnormal values below will be 
summarized:

QT > 500 ms;

QTcF > 500 ms;

QTcF > 480 ms;


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
QTc F> 450 ms;

QTcF changes from baseline > 30 ms;

QTcF changes from baseline > 30 ms and QTcF>450 ms;

QTcF changes from baseline > 30 ms and QTcF>480 ms;

QTcF changes from baseline > 30 ms and QTcF>500 ms;

QTc changes from baseline > 60 ms;

QTcF changes from baseline > 60 ms and QTcF>450 ms;

QTcF changes from baseline > 60 ms and QTcF>480 ms;

QTcF changes from baseline > 60 ms and QTcF>500 ms;

HR decrease >25% to a HR <50 bpm

HR increase >25% to a HR >100 bpm

PR > 220 ms.

PR increase >25% to PR >220 ms

QRS>120 ms

QRS increase > 25% to QRS > 120 ms
Cardiac monitoring will be performed from 1 hour before dosing and up to 48 hours after the 
first drug administration. Any abnormalities in the continuous monitoring (i.e., pre-dose to 48 
hours) will be reported in AE eCRF page, but will not be presented separately in listings.
Clinical laboratory evaluations
Due to the emergency setting of the patient, screening/baseline laboratory evaluation can be 
performed by locally. A central laboratory will be used for all other timepoints for the analysis 
of all specimens collected.
Laboratory data from all sources (central and local laboratories) will be combined. All 
laboratory values will be converted into International System (SI) units. 
Raw values as well as absolute and relative change from baseline values for hematology, 
biochemistry and urinalysis (quantitative and qualitative) laboratory parameters will be 
summarized descriptively per time point and treatment arm.
Urinalysis parameters will be listed.
Change from baseline will only be summarized for patients with both baseline and post baseline 
values and will be calculated as:
change from baseline = post baseline values – baseline value
Shift tables based on normal ranges to compare baseline to the worst post-baseline value will 
be provided by parameter and treatment arm for hematology, biochemistry and urinary 
laboratory data.
A listing of all laboratory values with values flagged to show the corresponding range 
classifications (High, Low) relative to the laboratory reference ranges will be provided by 
laboratory category and treatment arm.
Normal ranges by laboratory parameter will be provided in a separate listing.


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Liver event definition:
The liver event criteria Table 8-2 will be evaluated using clinical chemistry parameters.
Table 8-2
Liver event definition
Definition
ALT or AST > 3 × ULN and TBL > 2 × ULN without initial increase in ALP to > 2 × ULN (Potential 
Hy’s law cases)
ALT or AST > 3 × ULN and INR > 1.5 
ALT or AST > 3 × ULN 
ALP > 2 × ULN 
AST = Aspartate aminotransferase; also known as SGOT, ALT = Alanine aminotransferase; also 
known as SGPT, INR=International Normalized Ratio, ALP = Alkaline phosphatase, TBL = Total 
bilirubin, DBL = conjugated (direct) bilirubin.
For all patients with liver values (AST, ALT, ALP, TBL) matching the thresholds of 5xULN or 
any criteria of the above table (Table 8-2), single patient LFT profile graphs will be generated 
showing all AST, ALT, ALP, TBL lab values reported for this study and the time of study
treatment for these patients a listing of patients with these liver abnormalities will be provided.
Nephrotoxicity (Specific Renal Criterion)
Patients who meet renal toxicity criteria will be diagnosed/followed up and captured eCRF will 
be reported in listing as well as summarized. 
Pregnancy test and assessments of fertility
Pregnancy testing will be done for all female patients of childbearing potential at 
screening/baseline and follow-up visits (Day 30 or Day 90).  Listing will be produced by 
treatment and patients.
Adverse events (AEs)
All information obtained (e.g. relatedness to study drug, action taken etc.) on adverse events 
will be displayed by treatment and patient. AEs will be coded using the latest version of 
MedDRA available at the time of clinical database lock. 
AEs summarized will be all events recorded during the study. Any AE with a missing start date 
will be considered as starting in the study.
The number and percentage of subjects with adverse events will be tabulated by body system 
and preferred term with a breakdown by treatment. A patient with multiple AEs within a body 
system is only counted once towards the total of this body system. 
The following AE summaries will be produced by treatment:

AEs, regardless of study drug relationship by primary system organ class and preferred
term

AEs, regardless of study drug relationship by primary system organ class and preferred
term and severity

AEs, regardless of study drug relationship by primary system organ class and preferred
term and maximum CTCAE grade (all grades and grade 3/4 )


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
AEs, with suspected study drug relationship by primary system organ class and by
preferred term

Serious adverse events (SAEs), regardless of study drug relationship, by primary system
organ class and preferred term

SAEs, with suspected study drug relationship, by primary system organ class and
preferred term

AEs leading to study drug discontinuation, regardless of study drug relationship, by
primary system organ class and preferred term

AEs requiring dose adjustment or study-drug interruption, regardless of study drug
relationship, by primary system organ class and preferred term

AEs requiring additional therapy, regardless of study drug relationship, by primary
system organ class and preferred term

Non-serious AEs (ie, AEs excluding serious AEs), regardless of study drug relationship,
by primary system organ class and preferred term
Fatal AEs suspected to be related to study treatment will be provided by SOC and PT.

Fatal SAEs regardless of study drug relationship will be provided by SOC and PT.
AEs will be summarized by presenting the number and percentage of patients having at least 
one AE, and having at least one AE by system organ class and/or preferred, severity and relation 
to study drug by treatment arm. 
An overall summary of type of AEs (e.g. serious, leading to study drug discontinuation, 
requiring dose adjustment or/and interruption) will be presented by treatment (overall and 
severe). The overall summary will present the number and percentage of patients having at one 
AE and the occurrence of event. If for a same patient, several consecutive AEs (irrespective of 
study treatment causality, seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is ≤ 1 day gap between the (non missing)
end date of the preceding AE and the (non missing) start date of the consecutive AE.

more than one occurrence will be counted if there is > 1 day gap between the end date
of the preceding AE and the start date of the consecutive AE, or if start date or end
date are missing.
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block (e.g., among AE's in a ≤ 1 day gap block, if 
at least one SAE is occurring, then one occurrence is calculated for that SAE).
Any information collected (e.g. relation to study drug, action taken etc.) will be listed as well 
as the duration of the AE. If start date or end date is partially missing, it will be imputed as 
described in this SAP appendix, before to compute the duration of the AE. 
The listings of all deaths, serious adverse events, adverse events leading to study drug 
discontinuation, and adverse events requiring dose adjustment or interruption will also be 
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For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables will be 
provided by system organ class and preferred term on the safety set population. The first one 
will be on non-serious treatment emergent adverse events (non-serious TEAEs) with an 
incidence greater than 1%. The second one will be on serious treatment emergent adverse events
(serious TEAEs) or SAEs suspected to be related to study treatment. These two tables will be 
produced by Novartis.
Deaths
Deaths will be summarized by primary system organ class and preferred term by treatment. 
Listing of all death will be produced for patient who signed informed consent and randomized. 
Other safety evaluations
Not Applicable.
Immunogenicity
All immunogenicity results will be listed by subject and visit/time.
8.3
Graphical presentation 
Boxplots to visualize trends in longitudinal safety data (vitals, ECG, lab parameter) will be 
presented. An evaluation of Drug Induced Serious Hepatotoxicity (eDISH) plot will also be 
presented.
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10
Sample size consideration
The detailed sample size calculation of primary and secondary endpoint provided in protocol 
section 11.7.
11
Reference list
[1] CPMP (2001) Points to consider on clinical investigation of medicinal products for the
treatment 
of 
acute 
stroke.
http://www.ema.europa.eu/docs/en_GB/document_library
/Scientific_guideline/2009/09/WC500003342.pdf
[2] D. Spiegelhalter, K. Abrams, J. Myles Bayesian Approaches to Clinical Trials and Health-
Care Evaluation John Wiley & Sons, Malden MA (2004)
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12
Appendix
12.1
SAS code
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12.2
Definition of benefit for individual endpoints
Measurement
Endpoint
Direction of benefit*
Questionnaire
mRS
Decrease
Computed tomography scan
HV
Decrease
* In the direction of
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Personal Protected Data