Conditions: Transplant Associated Microangiopathy TAM
Keywords: transplant associated microangiopathy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 7
Healthy volunteers: no

Brief summary:
This was a randomized, SoC-controlled, open-label, multi-center study in patients with TAM after hematopoietic precursor cell transplantation (HPCT) .

Study consisted of up to 28 days of screening period, 16 weeks treatment period that can be extended to 45 weeks.Approximately 40 patients was to be randomized to receive SoC or LFG316 plus SoC. Patients was included in the study if they have diagnosis of TAM and poor prognostic markers. This trial was terminated: LFG316, a monoclonal antibody inhibitor of complement factor 5 (C5), had been studied in seven patients with transplantation-associated microangiopathy (TAM). Due to low confidence of clinical benefit, this study was closed

Detailed description:
This was a randomized, SoC-controlled, open-label, multi-center study in patients with TAM after hematopoietic precursor cell transplantation (HPCT). Study consisted of up to 28 days of screening period, 16 weeks treatment period that can be extended to 45 weeks, 36 weeks follow up, and end of study visit (EOS) at week 52. Duration of follow up depended on duration of treatment. Patients who are treated for more than 41 weeks will proceed directly to EOS visit.

Approximately 40 patients was to be randomized to receive SoC or LFG316 plus SoC. Patients was included in the study if they have diagnosis of TAM and poor prognostic markers.

Patients showing worsening of disease after two weeks of treatment or showing no response at week 4 or any time after will be considered failures and can be switched to receive the alternative treatment (SoC or LFG316). Patients can only switch treatment arms once.

Arms:
arm 1: LFG316 plus SoC (excluding plasmapheresis and prohibited treatment) arm 2: Standard of Care then LFG316 plus SoC

Interventions: intervention 1: LFG316 active drug intervention 2: Standard of care treatment
Intervention descriptions: intervention 1: LFG316 intervention 2: SoC (site specific)

Protocol document:
Prot_000.pdf: 
Novartis Institutes for BioMedical Research
LFG316
Clinical Trial Protocol CLFG316X2202
A randomized, open label, controlled, multiple dose study 
to evaluate the clinical efficacy, safety, tolerability, 
pharmacokinetics and pharmacodynamics of LFG316 in 
patients with transplant associated microangiopathy after 
hematopoieticprecursor cell transplantation
Authors:
Document type:
Amended ProtocolVersion
EUDRACT number:
2014-004972-49
Version number:
v05Clean(incorporating Amendment 05)
Development phase:
II
Release date:
16-Aug-2016
Personal Data
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Site Operations Manual (SOM)
A Site Operations Manual (SOM) accompanies this protocol, providing the operational details 
for study conduct.
Notification of serious adverse events
Refer to Section 9.2of the protocol for definitions and reporting requirements for Serious 
Adverse Events (within 24 hours after awarenessof the SAEto the local Novartis Drug Safety 
and Epidemiology Departmentand notify the Clinical Trial Leader). 
Contact information islisted 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........................................................................................................................6
List of figures......................................................................................................................6
List of abbreviations............................................................................................................7
Pharmacokinetic definitions and symbols.........................................................................10
Protocol synopsis...............................................................................................................19
1 Introduction.......................................................................................................................25
1.1
Background............................................................................................................25
1.1.1
Relevant data summary.........................................................................26
1.2
Study purpose........................................................................................................28
2 Study objectives.................................................................................................................28
2.1
Primary objective(s)...............................................................................................28
2.2
Secondary objective(s)...........................................................................................28
2.3
Exploratory objective(s)........................................................................................29
3 Investigational plan...........................................................................................................30
3.1
Study design...........................................................................................................30
3.2
Rationale for study design.....................................................................................31
3.3
Rationale for dose/regimen, duration of treatment................................................32
3.4 
Rationale for choice of comparator.......................................................................34
3.5
Purpose and timing of interim analyses/design adaptations..................................34
3.6
Risks and benefits..................................................................................................35
4 Population..........................................................................................................................37
4.1
Inclusion criteria....................................................................................................37
4.2
Exclusion criteria...................................................................................................39
5 Restrictions for Study Subjects.........................................................................................40
5.1
Contraception requirements...................................................................................40
5.2
Prohibited treatment...............................................................................................40
5.3
Dietary restrictions and smoking...........................................................................
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6 Treatment...........................................................................................................................41
6.1
Study treatment......................................................................................................41
6.1.1
Investigational treatment.......................................................................41
6.2
Treatment arms......................................................................................................41
6.3
Permitted dose adjustments and interruptions of study treatment.........................41
6.4
Treatment assignment............................................................................................41
6.5
Treatment blinding.................................................................................................42
6.6
Emergency breaking of assigned treatment code..................................................42
6.7
Treatment exposure and compliance.....................................................................42
6.8
Recommended treatment of adverse events..........................................................42
6.9
Rescue medication.................................................................................................42
6.10 Concomitant treatment...........................................................................................42
7 Discontinuation and study completion..............................................................................44
7.1
Discontinuation of study treatment........................................................................44
7.2
Study completion and post-study treatment..........................................................44
7.2.1
Lost to follow-up...................................................................................45
7.3
Withdrawal of consent...........................................................................................45
7.4
Study stopping rules..............................................................................................45
7.5
Earlystudy termination..........................................................................................45
8 Procedures and assessments..............................................................................................46
8.1
Informed consent procedures.................................................................................50
8.2 
Subject demographics/other baseline characteristics.............................................51
8.3
Efficacy..................................................................................................................51
8.3.1
Schistocyte count..................................................................................51
8.3.2
Proteinuria.............................................................................................51
8.3.3
Incidence of transfusion........................................................................51
8.4
Safety.....................................................................................................................51
8.4.1
Performance status................................................................................51
8.4.2
Physical examination............................................................................52
8.4.3
Vital signs..............................................................................................52
8.4.4
Height and weight.................................................................................52
8.4.5
Laboratory evaluations..........................................................................52
8.4.6
Electrocardiogram (ECG).....................................................................53
8.4.7
Pregnancy and assessments of fertility.................................................53
8.4.8
Vaccination(s).......................................................................................53
8.4.9
GvHD....................................................................................................53


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8.5
Pharmacokinetics...................................................................................................53
8.6
Pharmacodynamics markers..................................................................................54
8.7.2
ADAMST13..........................................................................................55
8.7.4
Soluble Biomarkers...............................................................................56
9 Safety monitoring..............................................................................................................56
9.1
Adverse events.......................................................................................................56
9.2
Serious adverse event reporting.............................................................................58
9.2.1
Definition of SAE.................................................................................58
9.2.2
SAE reporting........................................................................................59
9.3
Liver safety monitoring.........................................................................................59
9.4
Renal safety monitoring.........................................................................................61
9.5
Pregnancy reporting...............................................................................................61
9.6
Early phase safety monitoring...............................................................................62
10 Data review and database management.............................................................................62
10.1 Site monitoring......................................................................................................62
10.2 Data collection.......................................................................................................63
10.3 Data Monitoring Committee..................................................................................64
10.4 Adjudication Committee........................................................................................64
11 Data analysis......................................................................................................................64
11.1 Analysis sets..........................................................................................................64
11.2 Subject demographics and other baseline characteristics......................................65
11.3 Treatments (study drug, rescue medication, other concomitant therapies, 
compliance)............................................................................................................65
11.4 Analysis of the primary variable(s).......................................................................65
11.4.1
Variable(s).............................................................................................65
11.4.2
Statistical model, hypothesis, and method of analysis..........................65
11.4.3
Handling of missing values/censoring/discontinuations.......................66
11.4.4
Supportive analyses...............................................................................66
11.5 Analysis of secondary and exploratory variables..................................................66
11.5.1
Efficacy / Pharmacodynamics...............................................................
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11.5.2
Safety.....................................................................................................67
11.5.3
Pharmacokinetics..................................................................................67
11.5.4
Pharmacokinetic / pharmacodynamic interactions................................68
11.5.5
Other assessments.................................................................................68
11.6 Sample size calculation..........................................................................................68
11.7 Power for analysis of key secondary variables......................................................69
11.8 Interim analyses.....................................................................................................69
12 Ethical consideration.........................................................................................................70
12.1 Regulatory and ethical compliance........................................................................70
12.2 Responsibilities of the investigator and IRB/IEC..................................................71
12.3 Publication of study protocol and results...............................................................71
13 Protocol adherence............................................................................................................71
13.1 Protocol Amendments...........................................................................................72
14 References.........................................................................................................................73
15 Appendix 1: Lansky/Karnofsky scores.............................................................................75
15.1 Karnofsky Performance Status Scale (for patients greater than 16 years old)......75
15.2 Lansky Score (for patients less than or equal to 16 years old)..............................76
16 Appendix 2: vital signs in children....................................................................................77
List of tables
Table 5-1
Prohibited treatment..............................................................................40
Table 8-1
Assessment schedule for adult patients (greater or equal 18 years 
old)........................................................................................................46
Table 8-2
Assessment schedule for children (less than 18 years old)...................48
Table 9-1
Liver event and laboratory trigger definitions......................................60
Table 9-2
Follow up requirements for liver events and laboratory triggers..........61
Table 16-1
Vital signs in children...........................................................................77
List of figures
Figure 3-1
Study design..........................................................................................31
Figure 3-2
Predicted Serum Total LFG316 Concentrations...................................33
Figure 11-1
Operating characteristics: Probability of achieving success.................69


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List of abbreviations
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aHUS
atypical hemolytic uremic syndrome
ACR
albumin-creatinine ratio
AE
adverse event
AMD
age-related macular degeneration
ALT
alanine aminotransferase
ALP
alkaline phosphatase
ANCOVA
analysis of covariance
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
BMI
Body Mass Index
CD-ROM
compact disc –read only memory
CFR
Code of Federal Regulation
CTC-AE
Common Terminology Criteria for Adverse Events
CTL
clinical trial leader
DIC
uncompensated disseminated intravascular coagulation
CK
creatinine kinase
CNI
calcineurin inhibitors
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CSR
clinical study report
CTC
Common Toxicity Criteria
CV
coefficient of variation
DBP
diastolic blood pressure
DMC
Data Monitoring Committee
ECG
Electrocardiogram
EDC
Electronic Data Capture
ELISA
Enzyme-linked immunosorbent assay
EMA
European Medicines Agency


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EOS
End of study
Fc
fragment crystallizable region
FSH
Follicle-stimulating hormone
GCP
Good Clinical Practice
GCS-F
Granulocyte-colony stimulating factor
γ-GT
Gamma-glutamyl transferase
GvHD
graft versus host disease
h
hour
HIV
human immunodeficiency virus
HPF
high power field
HSCT
hematopoietic stem cell transplantation
HPCT
hematopoieticprecursor cell transplantation
IA
Interim analysis
IB
Investigators brochure
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IG
Immunogenicity
IgG
Immunoglobulin G
IN
Investigator’s notification
IRB
Institutional Review Board
IUD
intrauterine device
IUS
intrauterine system
i.v.
intravenous
IVIg
Intravenous immunoglobulin
LFT
Liver function test
LDH
lactate dehydrogenase
LLOQ
lower limit of quantification
mAb
Monoclonal antibody
MAC
membrane attack complex (C5b-9)
MedDRA
Medical dictionary for regulatory activities 
mg
milligram(s)


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mL
milliliter(s)
MoA
mode of action
NOAEL
non-observed adverse event level
PCR
protein/creatinine ratio
PD
pharmacodynamic(s)
PG
pharmacogenetic(s)
PNH
Paroxysmal nocturnal hemoglobinuria
PK
pharmacokinetic(s)
RBC
red blood cell(s)
REB
Research Ethics Board
SAD
single ascending dose
SAE
serious adverse event
SBP
systolic blood pressure
SD
standard deviation
SoC
Standard of Care
SOM
site operations manual
SRGvHD 
steroid refractory graft versus host disease 
SUSAR
Suspected Unexpected Serious Adverse Reactions
TAM
transplant associated microangiopathy
TBL
total bilirubin
TBV
total blood volume
TTP
thrombotic thrombocytopenic purpura
ULN
upper limit of normal
ULQ
upper limit of quantification
WBC
white blood cell(s)
WHO
World Health Organization


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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]
AUC/D
Area under the plasma (or serum or blood) concentration-time curve/Dose 
AUClast
The area under the plasma (or serum or blood) concentration-time curve 
from time zero to the time of the last quantifiable concentration [mass x time 
/ volume]
Cmax
The observed maximum plasma (or serum or blood) concentration following 
drug administration [mass / volume]
Cmax/D
The observed maximum plasma (or serum or blood) concentration following 
drug administration/dose
T1/2
The terminal elimination half-life [time]
Tmax 
The time to reach the maximum concentration after drug administration 
[time]


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Protocol synopsis
Protocolnumber
CLFG316X2202
Title
A randomized, open label, controlled, multiple dose study to evaluate the 
clinical efficacy, safety, tolerability, pharmacokinetics and pharmacodynamics 
of LFG316 in patients with transplant associated microangiopathy after 
hematopoieticprecursor cell transplantation
Brief title
Efficacy and safety of LFG316 in transplant associated microangiopathy 
(TAM)patients
Sponsor and Clinical 
Phase
Novartis 
Phase II
Intervention type
Biologic
Study type
Interventional 
Purpose and
rationale
The design of this study addresses the primary objective of establishing 
efficacy in this indicationfor both children and adults. The randomized, 
controlled design allows comparison of LFG316 plus standard of care 
(excluding prohibited treatment) against Standard of Care (SoC)only.
Thestudy will allow inclusion of patients≥2 years oldafter safety of LFG316 
is demonstrated during interim analysis 1 (IA1)with 5 patients ≥12 years old 
treated with LFG316 for 4weeks. There are no pediatric data generated so 
far for LFG316;however eculizumab was administered to pediatric TAM 
patients. The nonclinical data obtained with LFG316 and the clinical data 
obtained with eculizumab supports administration of LFG316 to children 
≥2years old. The option for patients not responding in either arm to switch to 
the alternative arm when certain conditions are met allows all patients the 
opportunity to receive LFG316 treatment in this very rare indication with high 
unmet medical need and also ensures that patients who fail to improve on 
LFG316 are not prevented from receiving the SoC treatment. This element of 
the design does not affect the assessment of efficacy since patients who do 
switch treatments will be considered to be treatment failures in the 
comparison of the randomized treatment groups. An open-label design is 
used instead of a blinded placebo since it is not feasible to blind the 
treatments used in the SoC arm.
Primary Objective(s)
To assess the hematological response rate in patients with TAM receiving 
LFG316 plus standard of care (excluding prohibited treatment) against 
Standard of Care (SoC) only.
Secondary 
Objectives

To assess the safety and tolerability of LFG316 in patients with TAM 

To describe the pharmacokinetics of total LFG316

To evaluate non-relapse mortality in TAM patients treated with 
LFG316 as compared to patients on SoC

To assess complete response rate at 17 weeks in TAM patients 
treated with LFG316 compared to patients receiving standard of care




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-
Thrombocytopenia with platelet count < 50x10e9/L or more than 
50% decrease in platelet count from the highest value achieved 
after transplant 
-
Anemia below lower limit of normal or anemia requiring 
transfusion support as per center standard
-
Schistocytes on peripheral blood smear (>2 per HPF) OR 
histologic evidence of microangiopathy
-
Absence of coagulopathy (no uncompensated disseminated 
intravascular coagulation, DIC) at screening
The presence of TAM high risk features at baseline (or screening if 
baseline visit is skipped):  Patients ≤ 16years must have a Lansky
score of ≤ 70 and patients > 16 must have Karnofsky score ≤70%.
and/or proteinuria (> 30 mg/dL) measured in two urine spot 
analyses.
Hypertension, defined for adults by SBP ≥ 160 mmHg and/orDBP 
≥100 mmHg at baseline (or screening if baseline visit is skipped), 
and for pediatric patients by blood pressure greater than the 95th 
percentile for age, sex, and height (see Table 16-1). Additionally, 
patients who were started on antihypertensive medication after 
HSCT or who have received additional antihypertensive medication 
after HSCT will be eligible, even if they don’t have elevated blood 
pressure.

Able to receive antibiotic prophylaxis against N. meningitides for the 
duration of the study.
Meningococcal vaccine(s) prior to LFG316 treatment if prior 
vaccination cannot be confirmed. The choice of vaccine(s) should 
take into account the serotypes prevalent in the geographic areas in 
which study patients will be enrolled. In case vaccination is not 
possible or will result in an unfavorable risk benefit ratio as judged 
by the investigator, vaccination can be postponed until deemed likely 
to be effective. 
Patients <18 years old should receive vaccination for the prevention 
of S. pneumoniae and H. influenzae type b prior to LFG316 
administration.In case vaccination is not possible or will result in an 
unfavorable risk benefit ratio as judged by the investigator, 
vaccination can be postponed until deemed likely to be effective.
Weight of at least 10kg.


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Exclusion criteria
Key exclusion criteria

Use of other investigational drugs at the time of enrollment, or within 
5 half-lives of enrollment, or until the expected PD effect has returned 
to baseline, whichever is longer; or even longer if required by local 
regulations.Concomitant investigational treatment, including 
treatment in the context of a clinical trial with marketed drugs (off-
label) may be acceptable but requires approval by the sponsor on the 
case by case basis.

Known hypersensitivity to any constituent of the study medication

Patients with steroid refractory graft versus host disease (SRGvHD). 
SRGvHD is defined as progression (=increase in overall grade) after 
5 days on ≥2mg/kg methylprednisolone or equivalent OR no 
improvement (no decrease in overall grade) after 10 days on ≥ 
2mg/kg methylprednisolone or equivalent. If patients are receiving 
steroids for GvHD prophylaxis as per center standard, progression 
after 5 days and no responseafter 10 days after doubling the steroid 
dose will be regarded as steroid refractory.

Patients with ALT >10x ULNat screening.

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 (at screening 
or baseline).

Women of child-bearing potential, defined as all women 
physiologically capable of becoming pregnant, unless they are using 
highly effective methods of contraception during dosing and for 
45days after stopping study medicationas specified in Section4.2.

Sexually active males unwilling to use a condom during intercourse 
while taking drug and for 45 daysafter stopping investigational 
medication. A condom is required to be used also by vasectomized 
men in order to prevent delivery of the drug via seminal fluid. Male 
patients should not father a child in this period

Positive HIV (ELISA and Western blot) test result (checked at 
screening).Historical local data will be acceptable if it the test was 
done within one monthbeforestart of HSCT conditioningand not 
more than 3 months before study visit 3. 

A positive Hepatitis B surface antigen or Hepatitis C test result at 
screening.Historical local data will be acceptable if it the test was 
done within one month before start of HSCT conditioning and not 
more than 3 months beforestudyvisit 3.Patients with any severe, 
progressive or uncontrolled acute or chronic medical condition (such 
as uncontrolled infectious disease or sepsis) or clinical laboratory 
abnormalities that in the investigator’s opinion would make the 
patient inappropriate for entry into this study (at screening or 
baseline).

Patients with proven TTP asper historical data (as defined by 
ADAMST13 activity test) and if already available results of 
ADAMST13 test done at screening 

Patients previously treated with eculizumab for TAM

Patients with known or suspected hereditary complement pathway 
deficiency. This exclusion criterion is not applicable to patients with 
complement pathway abnormalities/upregulation known to be 
associated with increased risk of transplant associated
microangiopathy


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Investigational and 
reference therapy
LFG316 
 
LFG316 
Site specific SoC
Efficacy/PD
assessments
Schistocyte count
Incidence of transfusion
Assessment of proteinuria
Safety assessments
blood chemistry, hematology, proteinuria, bodyheight and weight, 
urinalysis, ECG evaluation, Adverse events, body temperature, blood 
pressure, physical examination, pulse rate, pregnancy test, 
Lansky/Karnofsky score
Other assessments
PK
ADAMST13
Data analysis
A patient is considered to be a hematological responder at 17 weeks if both 
of the following criteria are met:
1. Schistocytes <2/microscopic high power field (HPF).
2.Transfusion independent (no need for TAM-related transfusions (platelets 
and erythrocytes)
Patients who discontinue the randomized treatment before 16 weeks due to 
lack of efficacy (whether according to the protocol-defined rules allowing a 
switch to the alternative treatment arm, or not) will be considered non-
responders in this analysis. Data from these patients collected after switching 
treatment will be considered as supportive data but will not be included in the 
primary analysis.
The primary analysis will compare all randomized patients according to the 
treatment they were assigned. A supportive analysis will compare patients 
according to the degree of complement blockade achieved.
The analysis of hematological response at 17 weeks will present posterior 
probabilities of meeting the outcome criteria as defined above. The prior 
distribution for the response rate in each group will be assumed to be a 
neutral non-informative Beta (1/3, 1/3) distribution.
 
 
 
 
C 
t C fid til If 
ti
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The effect of presence/absence of proteinuria at baseline (a key prognostic 
factor of response) on the response rates in eachgroup will be investigated. 
The effects of other covariates such as donor type and conditioning regimen 
will also be investigated.
Secondary variables supporting the secondary objectives will include:
Complete response, defined as hematologicalresponse and no proteinuria as 
determined by proteinuria<30mg/dL and eGFRdoubled or not less than 
0.85x lower limit of normal

Non-relapse mortality

Overall survival

Complete response will be analyzed in the same way as the primary 
variable of hematological response. Non-relapse mortality and overall 
survival will be summarized using time to even methods.
Further details on the analysis and presentation of these variables will be 
provided in the RAP.
All other data will be summarized and listed by treatment as appropriate.
Key words
Transplant associated microangiopathy(TAM); hematopoieticprecursor cell 
transplantation(HPCT), 
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1
Introduction
1.1
Background
Transplant Associated Microangiopathy(TAM;or transplant-associated TA-TAM) is a 
complication of allogeneic hematopoietic stem cell transplantation (HSCT). TAM is a 
secondary microangiopathy associated with total body irradiation, high dose chemotherapy, 
viral reactivation and use of calcineurin inhibitors and rapamycin. TAM does not fall into 
either major category of thromboticmicroangiopathies (TMA), i.e. atypical hemolytic uremic 
syndrome (aHUS) or thrombotic thrombocytopenic purpura (TTP) (Chapin et al 2014). 
Theexact mechanism of TAM is poorly understood, but is thought to involve initial 
complement activation and C5-dependent effector mechanisms, which also lead to 
immunoglobulin consumption. The trigger appears to be endothelial cell damage, leading to a 
prothrombotic state in the microvasculature.  TAM can gives rise to renal, gastrointestinal and 
neurological dysfunction depending on the area of the vascular bed involved. TAM is 
associated with high morbidity and mortality, with some estimates of associated mortality as 
high as 80% (Chapin et al 2014). Complement involvement is suggested by recent clinical 
data with the C5 targeted antibody eculizumab. Preliminary data indicates that 4 of 6 subjects 
undergoing HSCT procedures had a beneficial responseafter eculizumab administration
(Jodele et al 2014a). In total as of this writing (March 2015) 25 patients have been reported to 
have undergone eculizumab treatment withmixed results. Positive response in the published 
cases seems to be associated with low body weight, high dose per weight and absence of 
severe acute graft versus host disease. 
LFG316 is a fully human monoclonal IgG antibody that targets complement factor 5 (C5). 
There is experience with the use of LFG316 in intravenous and intravitreal formulations in the 
clinic (an intravitreal formulation of LFG316 is currently being evaluated for the treatment of
age-related macular degeneration (AMD)). However as an intravenous formulation of
LFG316 will be usedin TAM, the clinical results with intravenous use are considered most 
relevant and are presented below.
LFG316 will be dosed on a per weight basis for the TAM indication. Therefore, LFG316dose 
will be individualized which is expected to result in superior efficacy, especially in dose 
sensitive indications.
This studyis planned in severe TAM which Novartis proposes to define based on the presence 
of both diagnostic and high risk criteria (please refer toSection 4.1).
Because a highunmet medical need in TAM is in children(Jodele et al 2014b), the study will 
allow inclusion of pediatric patients after safety of LFG316 has been demonstrated in5adult 
patients who have been treated with LFG316 for at least 4weeks. 


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1.1.1
Relevant data summary
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1.2
Study purpose
The main purpose of the study is to gather preliminary evidence of LFG316 efficacy in 
treatment of transplant associated microangiopathy (TAM) after hematopoetic precursor cell 
transplantation.
2
Study objectives
2.1
Primary objective(s)
Objective
Endpoint
To assess the hematological response rate in 
patients with TAM receiving LFG316 
compared to  standard of care (SoC)
Hematological response at 17 weeks where a 
patient is considered to be a responder if both 
of the following criteria are met:
1. Schistocytes<2/microscopic high power field 
(HPF).
2.Transfusion independent (no need for 
TAM-related transfusions (platelets and 
erythrocytes))
2.2
Secondary objective(s)
Objective
Endpoint
To assess the safety and tolerability of 
LFG316 in patients with TAM  
All safety parameters including: blood 
chemistry, hematology, proteinuria, body
height/weight, urinalysis, ECG evaluation, 
Adverse events, body temperature, blood 
pressure, physical examination, pulse rate, 
Lansky/Karnofsky score
To describe the pharmacokinetics of total 
LFG316 
Serum total LFG316 concentrations
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Objective
Endpoint
To evaluate non-relapse mortality in TAM 
patients treated with LFG316 as compared to 
patients on SoC
Non-relapse mortality is any death not 
considered to be related to a relapse of 
underlying disease
To assess complete response rate at 17 weeks 
in TAM patients treated with LFG316 
compared to patients receiving standard of 
care 
Complete response is defined 
ashematologicalresponse andno proteinuria 
as determined by 
proteinuria<30mg/dLand
eGFRdoubledfrom baselineor not less 
than 0.85 x lower limit of normal
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3
Investigational plan
3.1
Study design
This is a randomized, SoC-controlled, open-label, multi-center study in patientswith TAM 
after hematopoieticprecursor cell transplantation(HPCT)from a related or unrelated donor 
for malignant and nonmalignant disease after myeloablative or non-myeloablative 
conditioning. 
The study will consistof up to 28 days of screening period, 16 weeks treatment period that 
can be extended to maximum of total45 weeks(in case ofongoing symptoms of TAM ),
36weeks follow up, and end of study visit (EOS) at week52 (Figure 3-1).Duration of follow 
up will depend on duration of treatment. Patients who are treated for more than 41 weeks will 
proceed directly to EOS visit.
Approximately 40 patients will be randomizedto receive standard of care treatment (SoC) 
(including but not limited to immunosuppressive drugs, such as rituximab, and 
plasmapheresis) or LFG316 plus SoC(excluding plasmapheresis and prohibited treatment as 
per Table 5-1). Patients will be included in the study if they have diagnosis of TAM and poor 
prognostic markers as specified in Section 4. 
 
 
Patients randomizedto LFG316 will receive 
 onstudydays1, 8,and 15,
followed byweekly doses of 
 for remainingtreatment duration of total 16weeks.  
 
 
Patients showing worseningdisease(definition below)after two weeks of treatment (day15)
or lateruntil visit at week 3,will be considered failures and can be switched to receive the 
alternative treatment (SoC or LFG316).
increasing schistocyte count (+50% or more as compared to baseline),
and/or increase inerythrocyte or platelettransfusion need (increase of 50% or more  in 
number of transfusions during 2 weeks prior to study visit as compared to  number of 
transfusions needed two weeks before treatment initiation),
and/or  increasing proteinuria (+50% or more as compared to baseline)
Patients showing no response(definition below) between visit at week 4 (day 29)andvisit at 
week 16will be considered to be treatment failures and can be switched to the other treatment 
arm. Switching the treatment can occur immediately after data is available.
no decrease in schistocyte count ( as compared to baseline) 
and/or continuederythrocyte or platelettransfusion need (less than 25% improvement  
in number of transfusions during 2 weeks prior to study visit as compared to number 
of transfusions needed twoweeks before treatment initiation)
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and/or  non-responding  proteinuria (less than 25% reduction in proteinuria compared 
to baseline)
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Patients can only switchstudy treatment arms once.
Unscheduled visits will be allowedto check for above parametersin case the data is not 
available at day 15 or day 29 or at later scheduled visitsand there is suspicion of insufficient 
improvement. Patients who switch from SoC to LFG316 will need to repeat the visit and 
dosing schedule starting from visit 3 when first dose of study medication is administered. 
Patients who change from LFG316 to SoC will continue with their visits as per 
Assessmentschedule. 
Patients who have ongoing symptoms of TAM may be continued on LFG316 for maximum of 
total 45 weeks if deemedsafe by the investigator. Decision on continuation of the dose after
week 16 will be discussed and agreed with the sponsor on a case by case basis. 
All patients will receive prophylactic doses of antibiotics active against N. meningitidisduring 
the entireLFG316treatment periodand at least8 weeks after the last treatmentwith LFG316. 
The choice of antibiotic medication will be as per hospital standard. 
The primary endpoint assessment will be done at week 17 (i.e. 1 week after last dose on week 16). 
Figure 3-1
Study design
3.2
Rationale forstudy design
The design of this study addresses the primary objective of establishing efficacy in this 
indication. The randomized, controlled,stratified design allows comparison of LFG316 
against SoC.
 
 
There are no pediatric data generated so far for LFG316;however eculizumab was 
administered to pediatric TAM patients. The published case reports of C5a blockade in 
TAMcomprise 25 patients of whom 16 were pediatric (age range 1.2-11years) 
(deFontebruneetal2015, Jodeleetal2014a, Jodeleetal2014c, Okano et al 2014). 
Nounexpected safety events related to C5 blockade were reported. No case ofinvasive 
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meningitis, a known risk of C5a blockade, was reported in TAM so far. Prophylactic 
antibiotics active against N. menigitidis will be usedtomitigate the risk of the infection.
Based on published information in the Eudract database, studies witheculizumab are ongoing 
in pediatric subjects (2-17 years of age) with PNH and in pediatric subjects aged 1month and 
upwards with atypical hemolytic uremic syndrome (AHUS).
The nonclinical data obtained with LFG316 and the clinical data obtained with eculizumab
supports administration ofLFG316 to children≥12 years old, followed by children≥2 years 
old.Given theavailable data andhigh risk of the disease with standard of care treatment, 
excluding children from this treatment does not seem to bejustifiable. 
The option for patients not responding in either arm to switch to the alternative arm when 
certain conditions are metallows all patients the opportunity to receive LFG316 treatment in 
this very rare indication with high unmet medical need and also ensuresthat patients who fail 
to improve on LFG316 are not prevented from receiving the SoC treatment. This element of 
the design does not affect the primary assessment of efficacy since patients who do switch 
treatments will be considered to be treatment failures in the comparison of the randomized 
treatment groups. An open-label design is used since it is not feasible to blind the treatments 
used in the SoC arm. 
3.3
Rationale fordose/regimen, duration of treatment
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The doseand dose frequencyof LFG316 havebeen chosen to allow maximal durable 
complement inhibitionthroughout the dose interval. 
 
 
 
 
 
 
 
 
 
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3.4
Rationale for choice of comparator
In severe TAM there is no unified established standard of care treatment. As such, severe 
TAM is distinct from non-severe TAM where discontinuation of calcineurin inhibitors (CNIs) 
is the standard of care (as here CNI treatment is thought to be the cause of the disease 
(Kimetal2015)). Due to the relative rarityand severity of the disease,physicians often apply 
multiple (off-label) treatments in parallel. Among the most commonly used treatments are 
steroids, cyclophosphamide, rituximab anddefibrotide. Off-label use of eculizumab is 
reported increasingly (Kim et al 2015). Although plasmapheresis is widely viewed as being 
futile in this indication it is still used by some centers as a last line measure in patients who 
have failed to respond to other treatments. LFG316 will be compared with site specific SoC, 
since TAM is a potentially fatal disease and placebo treatment is not considered ethically 
acceptable.
Patients in LFG316 treatmentgroup will not be allowed plasmapheresis because of drug 
wash-out. All other SoC treatments that do not interfere with the mode of action (MoA)of 
LFG316(e.g. corticosteroids, rituximab) are allowed in all patients included in the study. 
Direct signaling, complement dependent cellular cytotoxicity (CDC) and antibody dependent 
cellular cytotoxicity all appear to play a role in rituximab efficacy (Weiner 2010). 
SinceLFG316 will suppress free C5 concentrations and hence is likely to reduce CDC, it is 
possible that the administration of LFG316 may negate some of the mechanisms of efficacy of 
rituximab.However, the magnitude of this effect is unknownandrituximab remains an
allowed concomitant medication.Drugs that have the same mode of action as LFG316 
(eculizumab)are prohibited(please refer to Table 5-1for full list of prohibited treatments).
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3.5
Purpose and timing of interim analyses/design adaptations


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3.6
Risks and benefits
TAM is a life-threatening complication after allogeneic hematopoietic stem cell 
transplantation (HSCT).In surviving patients TAM may be associated with morbidities such 
as hypertension, chronic kidney disease, pulmonary hypertension gastrointestinal and central 
nervous system disease.Currently there is no approved and effective therapy for TAM. 
Classical treatment regimens consist of supportive measures that include withdrawal of 
triggering agents such as calcineurin inhibitors, treatment of co-existing conditions such as 
infections that may promote TAM and management of hypertension. Eculizumab was used 
successfully in a limited number ofpatients (Jodele et al 2014a). 
 
 
The prevalenceof TAM post-HSCThas recently been reported to be 39% in a prospective 
cohort study in children (Jodele et al 2014b). The 1-year non relapse mortality was43.6% in 
subjects with TAM and 7.8% inHSCT subjects without TAM(p<0.0001).A retrospective 
analysis of 539 adult and pediatric patients reported a cumulative incidence of TAM at five 
years of 14% with a mortality of 50%. Adults and children were both similarly affected 
(Uderzo et al 2006). Similar findings were reported in a more recent paper by Cho analyzing 
outcomes of 672 patients (Cho et al 2010
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). 
The published case reports of C5a blockadewith eculizumabin TAM comprise many children 
and adolescents;in addition there areongoingstudiesin pediatric subjects 2-17 years of age 
in PNH and in pediatric subjects aged 1 month and upwards in the atypical hemolytic uremic 
syndrome (AHUS) indication.
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In a recent report, moderate liver toxicity possibly related to C5 blockade with eculizumab in 
children with aHUS has been reported (Hayes et al 2014). However, the authors of this report 
suggest that this observation is more likely disease-related rather than drug-related because 
liver toxicity has not been observed with an anti-C5 therapyin any other indication. In the 
proposed study liver function tests will be monitored, therefore, abnormalities in LFTs will be 
detected and can be acted upon as appropriate. No data is published on liver transaminase 
elevation specifically in TAM patients. However, there is unequivocal input by physicians 
treating TAM patients that such elevations are commonly seen and that these elevations can 
exceed upper level of normal thresholds manifold. There is strong consensus that this should 
not be viewed as a reason to withhold treatment with C5 blockade. 
Themain risks of anti-C5 therapies are related to infections. 
 
 The most 
important adverse effect associated with systemic eculizumab, however, is infection by 
Neisseria (N). meningitidis(e.g. meningitis). These infectionswere so far not reported in 
TAM patients butare consistent with reports of occasional,but recurrent,meningococcal 
infections seen in patients with total hereditary C5 deficiency (Haeneyetal1980; 
Cesbronetal1985; Sanal et al 1992; Delgado-Cerviño et al 2005; López-Leraetal2009; 
Zerzrietal2010); pneumococcal infections were also reported in hereditary complement 
deficiency. 
The risk to patients in this trial will be minimized by, antibiotics prophylaxis active against 
N.meningitidismandatory during the entireLFG316treatment period,adherence to the 
eligibility criteria, and close clinical monitoring.In additionall patientsshouldbe vaccinated 
against N. and patients <18year of ageshould receive vaccination for the prevention of S. 
pneumoniaeand H. influenzaetype b prior to LFG316 administration.In case vaccinationsare
not possible or will result in an unfavorable risk benefit ratio as judged by the investigator, 
vaccination can be postponed until deemed useful.For example patients with severe 
thrombocytopenia might need platelet transfusion support to tolerate s.c. or i.m. injections 
needed for vaccinations. The inherent risk of platelet infusion might lead to suchan
unfavorable risk/benefit ratio if a very low efficacy of vaccination is expected.  
Although no such events have been reported so far, as with other therapeutic antibodies, 
LFG316 is expected to carry the risk of anaphylaxis or hypersensitivity reactions. 
Fluids,vasopressors, antihistamines, bronchodilatators, and oxygen should be available at the 
clinical site to assure quick administration if needed.Overall, the potentialbenefits of anti-C5 
therapy outweigh the risks in this population of TAM patients. 
For adult patients (≥18 years) assuming 16 weeks treatmentblood volumecollected over 
52weeks of the study durationwill be approx.up to800 mL, assuming maximal duration of 
45weeks blood volumeduring the studywill beapprox.up to1050 mL.The maximum blood 
volume collected from adult patients over consecutive 8 weeks will be up toapproximately
450mL.For the pediatric patient population the maximum blood volume collectedwill depend on 
patient weight.
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For children > 20kg blood volume drawn for analyses isapprox. 170mL for the 
standard 16 week treatment. In case of treatment extensionto maximum allowable 
treatment duration of 45 weeksthis would increase toup toapproximately 250mL. 


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For children <20kg the maximal blood volumedrawnis up to approximately 125mL
and 190mL respectively.Daily blood collection in children is ≤1% of the total blood 
volume(TBV)and maximum blood collected over 4 week is approximately 5% of 
TBV(this is only the case for the first 4 weeks of the study).Asper EMA guidance 
the maximum blood volume collected should be <3% of TBV. However, given the 
high unmet medical need and the extremely poor prognosis with standard of care the 
deviation seems to be justifiable. 
For the remaining study duration maximal blood volume collected in pediatric patient 
population over 4 consecutive weeks is less than 3% of the total blood volume.  
Additional samples for monitoring of any safety findings would be in addition to this. This is 
not considered to be a risk for this population.
Topical anesthesia might be administered at the site of blood collection in particular in 
pediatric population.
Women of child bearing potential andsexually activemale study participants need to be 
informed that taking the study drug 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 adhere to 
the contraception requirement for the duration of the study. If there is any question that the 
subject will not reliably comply, thesubjectshould not be enrolled.
There may be unknown risks of LFG316 which may be serious and unforeseen.
4
Population
Approximately 40 male and female patients undergoing allo-HSCT for malignant and 
nonmalignant disease with high-risk TAM will be included in the study. The investigator must 
ensure that all patients being considered for the study meet the following eligibility criteria. 
No additional criteria should be applied by the investigator, in order that the study population 
will be representative of all eligible subjects. Patient selection is to be established by checking 
through all eligibility criteria at screening or baseline as specified below. A relevant record 
(e.g. checklist) ofthe 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. Patients who drop out from the study for reasons other than lack of efficacy or adverse 
events considered by Investigator to be related to study treatment may be replaced.
4.1
Inclusion criteria
1. Written informed consent/assent before any study-specific screening procedures. 
Forpediatric patients, consent will be obtained from parent(s) or legal guardian(s) and the 
signature of at least 1 parent or guardian will be required. Investigators will also obtain 
assent of patients according to local, regional or national guidelines.
2. Patients after allogeneic stem cell transplantation from a related or unrelated, HLA-
matched or mismatched donor with the diagnosis of transplant related microangiopathy. 
Patients having received any of the following stem cell sources are eligible: G-CSF 
mobilized peripheral blood stem cells, bone marrow, umbilical cord blood.  


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3. Male and female TAM patients ≥ 2years oldat the time of first dose administration. 
Patients<12years old can only be included in the study after first IA has shown that it is 
safe and well tolerated in patients ≥ 12 years old (Section 3.5).
4. The presence of TAM as per below diagnostic criteria at baseline (or screening if baseline 
visit is skipped). All the criteria have to be met for the patients included in the study:
Elevatedlactate dehydrogenase (any elevation above normal range)
Thrombocytopenia with platelet count < 50x10e9/L or more than 50% decrease in 
platelet count from the highest value achieved after transplant 
Anemia below lower limit of normal or anemia requiring transfusion support as per 
center standard
Schistocytes on peripheral blood smear (>2 per HPF) OR histologic evidence of 
microangiopathy
Absenceof coagulopathy(no uncompensated disseminated intravascular coagulation, 
DIC)at screening
5. The presence of TAMhigh risk featuresat baseline (or screening if baseline visit is 
skipped): Patients ≤ 16 years must have a Lanskyscore of ≤70 and patients> 16 must 
haveKarnofsky score ≤ 70% and/or proteinuria (>30 mg/dL) measured in two urine spot 
analyses.
6. Hypertension, defined for adults by SBP ≥ 160 mmHg and/orDBP ≥ 100 mmHg at 
baseline (orscreening if baseline visit is skipped), and for pediatric patients by blood 
pressure greater than the 95th percentile for age, sex, and height (seeTable 16-1). 
Additionally, patients who were started on antihypertensive medication after HSCT or 
who have received additional antihypertensive medication after HSCT will be eligible, 
even if they don’t have elevated blood pressure.
7. Able to receive antibiotic prophylaxis against N. meningitides for the duration of the study.
8. Meningococcal vaccine(s) prior to LFG316 treatment if prior vaccination cannot be 
confirmed. The choice of vaccine(s) should take into account the serotypes prevalent in the 
geographic areas in which study patients will be enrolled. In case vaccination is not possible 
or will result in an unfavorable risk benefit ratio as judged by the investigator, vaccination can 
be postponed until deemed likely to be effective. 
9. Patients <18 years old should receive vaccination for the prevention of S. pneumoniae and 
H. influenzae type b prior to LFG316 administration. In case vaccination is not possible or 
will result in an unfavorable risk benefit ratio as judged by the investigator, vaccination can be 
postponed until deemed likely to be effective.
10. Weight of at least 10kg.


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4.2
Exclusion criteria
1. Use of other investigational drugs at the time of enrollment, or within 5 half-lives of 
enrollment, or until the expected PD effect has returned to baseline, whichever is longer; 
or even longer if required by local regulations.Concomitant investigational treatment, 
including treatment in the context of a clinical trial with marketed drugs (off-label) may be 
acceptable but requires approval by the sponsor on the case by case basis.
2. Known hypersensitivity to any constituent of the study medication. 
3. Patients with steroid refractory graft versus host disease(SRGvHD). SRGvHD is defined 
as progression (=increase in overall grade) after 5 days on ≥2mg/kg methylprednisoloneor 
equivalent OR no improvement (no decrease in overall grade) after 10 days on ≥2mg/kg 
methylprednisoloneor equivalent.If patients are receiving steroids for GvHD prophylaxis 
as per center standard, progression after 5 days and no responseafter 10 days after 
doubling the steroid dose will be regarded as steroid refractory.
4. Patients with ALT >10x ULNat screening.
5. 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(at screening or baseline).
6. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing and for 45days after stopping study medication. Highly effective 
contraception methods include:
Total abstinence (when this is in line with the preferred and usual lifestyle of the
subject. Periodic abstinence (i.e., calendar, ovulation, symptothermal, postovulation 
methods) and withdrawal are not acceptable methods of contraception.
Female sterilization (have had surgical bilateral oophorectomy (with or without
hysterectomy), total 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 m prior to screening). The vasectomized male partner 
should be the sole partner for that subject.
Use of oral, injected or implanted hormonal methods of contraception or placement of 
an intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal 
contraception that have comparable efficacy (failure rate <1%), for example hormone 
vaginal ring or transdermal hormone contraception.
In case of use of oral contraception women should have been stabile on the same pill 
for aminimum of 3 months before taking study treatment.
7. Sexually active males unwilling to use a condom during intercourse while taking drug and
for 45daysafter stopping investigational medication. A condom is required to be used
also by vasectomized men in order to prevent delivery of the drug via seminal fluid. Male
patients should not father a child in this period.
8. Positive HIV (ELISA and Western blot) test result(checked at screening).Historical local 
data will be acceptable if it the test was done within one month before start of HSCT 
conditioning and not more than 3 months before study visit 3. 


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9. A positive Hepatitis B surface antigen or Hepatitis C test resultat screening.Historical 
local data will be acceptable if it the test was done within one month before start of HSCT 
conditioning and not more than 3 months before study visit 3. 
10.Patients with any severe, progressive or uncontrolled acute or chronic medical condition 
(such as uncontrolled infectious disease or sepsis) or clinical laboratory abnormalities that 
in the investigator’s opinion would make the patient inappropriate for entry into this study
(at screening or baseline).
11.Patients withprovenTTPas per historical data(as defined by ADAMST13 activity test)
and if already available results of ADAMST13 test done at screening.
12.Patients previously treated with eculizumabfor TAM.
13.Patients with known or suspected hereditary complement pathway deficiency. This 
exclusion criterion is not applicable to patients with complement pathway 
abnormalities/upregulation known to be associated with increased risk of transplant 
associatedmicroangiopathy
5
Restrictions for Study Subjects
During recruitment, screening/informed consent review, and baseline visit, the subjects must
be informed and reminded of the restrictionsas defined in Section 5.1and Section 5.2.
5.1
Contraception requirements
Please refer to exclusion criteria (Section 4.2) for details of contraception requirementsfor the study. 
5.2
Prohibited treatment
Use of treatmentsspecified in Table 5-1is NOT allowed after start of the treatment.
Table 5-1
Prohibited treatment
Medication
Wash-out
Action to be taken
Eculizumabin either treatment arm
NA
Discontinue study treatment
High dose IVIgin the LFG316 treatment 
arm**
NA
To be discussed with Sponsor on case by 
case basis
Plasmapheresis in the LFG316 treatment 
arm
NA
To be discussed with Sponsor on caseby 
case basis
Live vaccinations*in LFG316 treatment 
arm
NA
To be discussed with Sponsor on case by 
case basis
*not allowed to be administered during the LFG316 treatment period and 2 months after last dose of LFG316.
**In case of IgG levels below age specific normal ranges (as specified by local laboratories) the use of 
Intravenous immunoglobulins (IVIg) up to 0.5g/kg/BW with the intention to substitute IgG to reach a 
low-normal age adjustedbloodlevels is acceptable. Administration of IVIgshould be timed to be 
spaced at least 36 hours before or after administration of LFG316(Section 6.10).
5.3
Dietaryrestrictions and smoking
No restrictions.


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6
Treatment
6.1
Study treatment
Details on the storage and management of study medication, and instructions for prescribing 
and taking study treatmentare outlined in Section 3 of the SOM.Instruction on preparation of 
study medication will be included in the Pharmacy manual.
LFG316 will be administered weekly as intravenous injection(i.v.)for total of 16weeks
(canbe prolonged to maximum total 45 weeks as described in Section 3.1):
days 1,8,and 15: 
day 22 up to end of treatment (week 16): 
There will be no placebo in the study. Reference therapy will be a standard of care of each 
clinical center.
Topical anesthesia might be administered at the site of thei.v. catheter.
6.1.1
Investigational treatment
The investigational drug, LFG316,will be prepared by Novartis and supplied to the 
Investigator.For details regarding LFG316 preparation and administration, please refer to 
Pharmacy manual.
6.2
Treatment arms
Patients will be assigned to one of the following two treatment arms in a ratio of 1:1
A: LFG316 administered weekly as describedin Section 6.1plus SoC (excluding prohibited 
treatment as perTable 5-1)
B: SoC(excluding prohibited treatment as per Table 5-1)
6.3
Permitted dose adjustments and interruptions of study treatment
 
If per judgment of Investigator, patientsneed continuation of 
the therapybased on the presence of TAM symptoms, LFG316 can be administered weekly 
up to week 45.
6.4
Treatment assignment
Randomization numberswill be assigned in ascending, sequential order to eligible subjects 
(see Site Operations Manual for details)within the threeage groups.This study is stratified 
for randomization by age group based on the age at the day of randomization. The three strata 
are adult patients ≥
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18 years old, youth patients 12-17 years old inclusive, and children 
patients less than 12 years old. Any replacementpatients will be within the same age group. 
The investigator will enter the randomization number on the CRF. The randomization 
numbers will be generated to ensure that treatment assignment is unbiased and concealed 
from subjects and investigator staffuntil after study enrollment. Arandomization list will be 


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produced by or under the responsibility of Novartis Drug Supply Management using a 
validated system that automates the random assignment of treatment arms to randomization 
numbers in the specified ratiowithin the three strata defined by age. Therandomization 
scheme for subjects will be reviewed and approved by a member of the Novartis IIS 
Randomization Group.For details regarding randomization process refer to SOM-Section3.4.
6.5
Treatment blinding
This is an open label study; howeverthe allocation of patients to treatment will be performed 
in a blinded manner such that treatment allocation is known to the investigator,patientand 
Novartis study teamonly after enrollment(randomization)into the study.
Additionally schistocyte count should be performed byaperson blinded to study treatment. 
6.6
Emergency breaking of assigned treatmentcode
Not applicable
6.7
Treatment exposure and compliance
LFG316 will be administered via intravenous infusion by the Investigator or designated study 
staff over a maximum of 2 hours. For details please refer to the Pharmacy manualprovided 
separately. Compliancewill be assuredby close medical supervision of the study personnel 
and study Monitors. Serum concentrations of total LFG316 (measure of treatment exposure) 
will be determined in all subjects treated withLFG316, as detailed inSection 8.5.
6.8
Recommended treatment of adverse events
Treatment of AEs should follow standard practice. Medication used to treat AEs must be 
recorded on the Concomitant medications/Significant non-drug therapies CRF.
As with other therapeutic antibodies, LFG316 is expected to carry therisk of anaphylaxis or 
hypersensitivity reactions. Fluids, vasopressors, antihistamines, bronchodilatators, and oxygen 
should be available at the clinical site to assure quick administration if needed.
6.9
Rescue medication
Pleaserefer to Section 3.1for description of the treatment switch in case no improvement is 
observed after treatment with LFG316 or SoC. Use of rescue medication must be recorded on 
the Concomitant medications/Significant non-drug therapies CRF after start of study drug.
6.10
Concomitant treatment
All prescription medications, over-the-counter drugs and significant non-drug therapies 
(including 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 section of the 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.  
Incase of IgG levels below age specific normal ranges (as specifiedby local laboratories) the 


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use of Intravenous immunoglobulins (IVIg)up to 0.5g/kg/BW with the intention to substitute
IgG to reach a low-normal age adjusted blood levels is acceptable. Administration of IVIg
should be timed to be spaced at least 36 hours before or after administration of LFG316.
Administration of high dose IVIg(2g/kg BW or higher) in single doses is not acceptablein 
LFG316 treatment armduring the study duration.
Meningococcal vaccine(s) shouldbe administered prior to LFG316 treatment according to 
recommendations for patients with complement deficiencies if prior vaccination cannot be 
confirmed. The choice of vaccine(s) should take into account the serotypes prevalent in the 
geographic areas in which study patients will be enrolled. Based on recommendations, 
revaccination at the start of LFG316 therapy should be considered for previously vaccinated 
subjects as well as during LFG316 therapy for subjects who will receive prolonged treatment.
Whenever possible, meningococcal vaccine(s) should be administered at least two weeks prior 
to starting LFG316.In addition, patients<18 years old should receive vaccination for the 
prevention of S.pneumoniaeand H. influenzaetype b prior to LFG316 treatment.In case 
vaccinationsarenot possible or will result in an unfavorable risk benefit ratio as judged by the
Investigator, vaccination can be postponed until it is likely to be effective.
If patients are not already on antibiotic prophylaxis or treatment active against local strains of 
N. meningitis and S. pneumoniaeduring any time duringthe treatment with LFG316 or 
8weeks after lastdose, penicillin V 500 mg twice a day or erythromycin 500 mg 
(orequivalently effective doses in pediatric patients) twice a day must be given to patients in 
LFG316 treatmentarm. If local strains of either of these bacteria are resistant to either of
these or the patient is allergic or cannot otherwise tolerate the standard prophylactic treatment, 
the choice of antibiotic will be made upon local guidelines or the recommendation of the local 
ID consultant.


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7
Discontinuationand study completion
7.1
Discontinuation of study treatment
Subjectsmay voluntarily discontinuestudy treatment for any reason at any time.
The investigator mustdiscontinue study treatment for a given subject if, on balance, he/she 
believes that continuationwould be detrimental to the subject’s well-being.
Study treatment mustbe discontinued under the following circumstances: 
Subject withdraws consent.
Patients showing worsening disease between week 2 and 3,or absence of response at 
week 4 oranytime thereafter (as defined in the study Section 3.1) will be considered a 
failure and can be switched to receive the alternative treatment (SoC or LFG316). 
Patients on LFG316 that as per judgmentof Investigator require plasmapheresisor 
prohibited medication as per Section 5.2.
Patients with confirmed TTP (as per ADAMST13test result).
Treatment discontinuation and switch to SoC might also occur after consultation with 
Sponsor in case of treatment related SAE, or any other AE that in judgmentof Investigator 
warrants LFG316 treatment discontinuation. 
Patients who wish to discontinue eitherstudy treatment,whether initially allocated or 
subsequently switched,but who didnot withdraw their consent,will be asked to continue with 
study visits as per assessment schedule if possible.Every effort will be made to assess the 
parameters required for assessment of hematological and complete response at the time of 
discontinuation (i.e.,schistocytes, transfusion independence, proteinuria<30mg/dL and 
eGFR).In case patientwithdraws consent, theprocedure described in Section 7.3needs to be 
followed.
7.2
Study completion and post-study treatment
Each subject 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 
subject completes their End of Study 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 total study termination decision, the date of that decision.
At a minimum, subjects will be contacted for safety evaluations during the 30 days following 
the Study Completion visit, including a final post-study safety contact at the 30-day point. 
Documentation of attempts to contact the subjectshould be recorded in the source 
documentation.
The investigator must provide follow-up medical care for all subjects who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care.


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7.2.1
Lostto follow-up
For subjects 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 subject, e.g. dates of 
telephone calls, registered letters, etc. A subject should not be formally considered lost to 
follow-up until his/her scheduled end of study visit would have occurred.
7.3
Withdrawal of consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any 
time.
Withdrawal of consent occursonly when a subject does not want to participate in the study 
anymoreanddoes not want any further visits or assessmentsanddoes not want any further 
study related contactanddoes not allow analysis of already obtained biologic material. If not 
allabove criteria are met, please refer to procedure outline in Section 7.1.
If a subjectwithdraws consent, the investigator must make every effort to determine the 
primary reason for this decision and record this information. Study treatment must be 
discontinued and no further assessments conducted. Allbiological material that has not been 
analyzed at the time of withdrawal must not be used. Further attempts to contact the subject 
are not allowed unless safety findings require communicating or follow-up.
7.4
Study stopping rules
The study may be put on hold pending full safety data review done bytheData Monitoring 
Committee (DMC)if one or more of the following criteria are met: 
Two or more investigational drug (LFG316) related SAEs are reported 
Other clinically significant events that in the opinion of the investigator or sponsor 
preclude continuation ofdosing (especially events that are suspected to be drug 
related).
A DMCwill also review available safety data after the first 5 patients complete 4weeks of 
LFG316 treatmentand approximately every 3 months thereafter during the study. 
When possible,DMC meetings will be aligned with planned IAs. Inthecase of any safety 
concerns identified during the study (as described above) or faster than anticipated 
recruitment, DMCmeetings might happen more regularly.
7.5
Early study termination
The studycan be terminated at any time for any reason by Novartis. Should this be necessary, 
subjectsshould be seen as soon as possible and treated as a prematurely withdrawn subject. 
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 subject’s interests.
TheInvestigator will be responsible for informing IRBs/IECs of the early termination of the 
trial.


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8
Procedures and assessments
Table 8-1
Assessment schedule for adult patients (greater or equal 18 years old)
Study PhaseScreening Baseline (2)
EOS
V
isit Numbers (1)
V1 
V2 
V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 V13 V14 V15 V16 V17 V18 V19 V20 V21 V22 V23 V24 V25 V26-V54  (9) V501 V502 V503 V777
Study Day(s)* -28 to -4
-3 to -1
1 
2 5 
8 
9 12 15 16 19 22 23
29 36
43 50
57 64
71
78
85 92 99
106
113-309
113 182 293 364
Week
w5
w6 w7 w8 w9 w10 w11 w12 w13 w14 w15 w16
W17-45
w17 w26 w42 w52
Informed consent
X
Medical history/current medical conditions (16)
X
Hepatit
is and HIV Screen
S
Inclusion /
 Exclusion 
S
S
Act
ivated partial thromboplastin t
ime
X
Demography
X
Pregnancy test (3)
X 
X
X
X
X
X (12)
X 
X
X 
X
FSH (4)
X
Lansky/Karnofsky
 score
X
X
X
X
X (12)
X
Dose administration
X
X
X
X 
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
Adverse events***
GvHD
Physical examination
S 
S
S(7) 
S(7)
S(7)
S(7)
S(7) S(7) S(7) S(7)
S
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S
Height/weight (5)
X 
X 
X
X
X
X 
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
Body temperature**
X 
X
X(7) 
X(7)
X(7)
X(7)
X(7) X(7) X(7) X(7)
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
Pulse rate**
X 
X
X(7) 
X(7)
X(7)
X(7)
X(7) X(7) X(7) X(7)
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
Blood pressure**
X 
X
X(7) 
X(7)
X(7)
X(7)
X(7) X(7) X(7) X(7)
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
ECG evaluation**
X 
X 
X
X
X
X 
X
X
X
X (12)
X 
X 
X 
X
Hematology/blood chemistry/urinalysis (13)**
X 
X 
X
X
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X(14)
X 
X 
X 
X
Schistocyte count**
X
X 
X X X 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
Spot urine analysis
X 
X
X
X
X 
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X 
X(7) X X X(7) X X X(7) X 
X
X(7) X
X(7) X(8) X(8) X(8) X(8) X(8) X(8) X(8) X(8) X(8) X(8) X(8) 
X(8)
X 
X 
X 
X
X 
X
X(7) X X X(7) X X X(7) X 
X
X(7) X
X(7) X(8) X(8) X(8) X(8) X(8) X(8) X(8) X(8) X(8) X(8) X(8)
X(14)
X 
X 
X 
X
Incidence of transfusion (6)
X(8)
X(8)
X(8)
X(8)
X(14)
X 
X
X 
X
PK blood collect
ion 
(15)
X(7) X x X(7) X
x X(7) X 
x
X(7) X
X(7)
X(8)
X(8)
X(8)
X(8)
X(8)
X(14)
X 
X 
X 
X
X 
X
X(7) X X X(7) X X X(7) X 
X
X(7) X
X(7) X(8) X(8) X(8) X(8) X(8) X(8) X(8) X(8) X(8) X(8) X(8)
X(14)
X 
X 
X 
X
 
X 
X
X(7) X X X(7) X
X X(7) X 
X
X(7) X
X(7) X(8) X(8) X(8) X(8) X(8) X(8) X(8) X(8) X(8) X(8) X(8)
X(14)
X 
X 
X 
X
ADAMST13 in plasma
X
X
X
Concomitant
 therapies
Comments
Study complet
ion 
inf
o
X
as required
as required
recorded for entire study duration
as required
as required
Treatment (11)
Fo
l
low up
w1
w2
w3 
w4
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*Allowed visit window
s: +/-1 day for visits at days 2-29 (except for visits 5, 8, and 11when +1/-2 days visit window is allow
ed);
 +/-2 day for visit at days 36-106 (or until LFG316 is administered), +/-15 days after day 106 until E
OS. After visit 3 merging of the visits is not allowed 
** If not specified otherwise all safety assessm
ents should be performed pre-dose
*** SAE to be reported until 30 days after the last study visit
S- collected only as source data
(1) Visit structure given for internal program
m
ing purpose only
(2) If Screening visit is conducted within 3 days prior to planned dosing Baseline visit is not required
(3)  For all women, serum pregnancy testing is required at screening and EOS regardless of reported reproductive/menopausal status. Urine pregnancy tests at remaining visits  
 need to be performed only in women of child-bearing potential.
(4) For postmenopausal women, FSH
 is m
easured at Screening to assist in confirming m
enopausal status.
(5) body height will be checked only at screening
(6) Erythrocyte and platelet transfusions will be recorded separately
(7) Done pre and post-dose  in LFG316 treatment group and only once (if applicable pre-dose) in SoC treatment group 
(8) Done pre-dose in LFG316 treatment arm and (if applicable) in SoC treatment arm
(9)Weekly LFG316 injections at weeks17- 45 are allowed as per Section 3.1
(11) For patients who switch from
 SoC to LFG316 dosing schedule starts from visit 3. Patients who change from LFG316 to SoC w
ill continue w
ith their visits as per assessment schedule.   
(12) done every 4 weeks 
(14) Done pre-dose, every four weeks
(15) collected only  in LFG316 treatment group 
(16) Including GvHD 
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Table 8-2
Assessment schedule for children(less than18 years old)
Study PhaseScreening Baseline (2)
EOS
V
isit Numbers (1)
V1
V2
V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 V13 V14 V15 V16 V17 V18 V19 V20 V21 V22-V50 (9) V501 V502 V503 V777
Study Day(s)* -28 to -4
-3 to -1
1 
5
8
12 15 19 22
29
36
43
50
57 64 71 78 85 92 99
106
113-309
113 182 293
364
Week
w4
w5 w6
w7
w8
w9 w10 w11 w12 w13 w14 w15 w16
W17-45
w17 w26 w42 w52
Informed consent
X
Medical history/current medical condit
ions (18)
X
Hepatit
is and HIV
 Screen
S
Inclusion 
/ Exclusion 
S
S
Activ
ated partial thromboplastin time
X
Demography
X
Pregnancy test (3)
X
X
X
X
X
X (12)
X 
X
X 
X
Lansky/Karnofsky
 score
X
X
X
X
X (12)
X
Dose administration
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
Adverse events***
GvHD
Physical examination**
S 
S 
S(7) 
S(7)
S(7)
S(7) S(7) S(7) S(7) S(7)
S 
S
S 
S 
S 
S 
S 
S
S(7)
S 
S 
S 
S
height/weight (5)**
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
Body temperature**
X 
X 
X(7) 
X(7)
X(7)
X(7) X(7) X(7) X(7) X(7)
X 
X
X 
X 
X 
X 
X 
X
X(7)
X 
X 
X 
X
Pulse rate**
X 
X 
X(7) 
X(7)
X(7)
X(7) X(7) X(7) X(7) X(7)
X 
X
X 
X 
X 
X 
X 
X
X(7)
X 
X 
X 
X
Blood pressure**
X 
X 
X(7) 
X(7)
X(7)
X(7) X(7) X(7) X(7) X(7)
X 
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
ECG evaluat
ion**
X 
X 
X 
X 
X 
X 
X
X
X
X (12)
X 
X
X 
X
Hematology/blood chemistry/urinalysis (13)**
X
X 
X 
X 
X 
X 
X
X
X
X (12)
X 
X
X 
X
Schistocyte count**
X 
X 
X 
X 
X 
X 
X
X
X
X (12)
X 
X
X 
X
Spot urine analysis
X 
X
X 
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X(8) 
X(8)
X(8)
X(8) X(8) X(8) X(8) X(8) X(8) X(8) X(8) X(8) X(8) X(8) X(8) X(8)
X(8)
X 
X 
X 
X
X
X(8) 
X(8)
X(8)
X(8) X(8)
X(8)
X(8)
X(14)
X 
X 
X 
X
Incidence of transfusion (6)
X(8)
X(8)
X(8)
X(8)
X(14)
X 
X
X 
X
PK blood collection (15, 17)
X(7) X X(7) X X(7) X X(7) X(7)
X(8)
X(8)
X(8)
X(8)
X(8)
X(14)
X 
X
X 
X
X
X(7) X X(7) X X(7) X X(7) X(7)
X(8)
X(8)
X(8)
X(8)
X(8)
X(14)
X 
X 
X 
X
X
X(7) X X(7) X X(7) X X(7) X(7)
X(8)
X(8)
X(8)
X(8)
X(8)
X(14)
X 
X 
X 
X
ADAMST13 in 
plasma
X
X
X
Concomitant therapies
Comments
Study complet
ion info
X
as required
recorded for entire study duration
as required
as required
Treatment (11)
Fol
low up
w1 
w2
w3
as required
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*Allowed v
isit windows: +/-1 day for v
isits at days 2-29 (except for v
isits 4,6, and 8 when +1/-2 days visit w
indow is allo
wed); 
 +/-2 day for v
isit at days 36-106 (or until LFG31
6 is administered), +/-15 days after day 106 until EOS. Af
ter v
isit 3 merging of the v
isits is not allo
wed 
** If not specif
ied otherw
ise all safety assessments should be performed pre-dose
*** SAE to be reported until 30
 days after the last study v
isit
S- collected only as source data
(1) Visit structure g
iven for in
ternal programming purpose only
(2) If Screening v
isit is conducted w
ithin 3 days pr
ior to planned dosing Baseline
 v
isit is not required
(3)  on
ly for menstruating fema
les, serum pregnancy testing is required at screening and EOS, ur
ine pregnancy tests at remaining visits
(5) body he
ight will b
e checked only at screening, v
21 and EOS
(6) Erythrocyte and platelet transfusions will be re
corded separately
(7) Done pre and post-dose  in LFG316 treatment group and only once (
if applicable pre-dose) in
 SoC treatment group 
(8) Done pre-dose in LFG316 treatment arm and (
if applicable) in SoC
 treatment arm
(9)Weekly LFG316 injections at weeks17- 45 are allowed as per Section 3.1 
(11) For patients who switch from SoC to LFG316 dosing schedule starts from v
isit 3. Patients who change from LFG316 to SoC w
ill continue w
ith their v
isits as per assessment schedule.   
(12) done every 4 weeks starting from visit 23
(14) Done pre-dose, every four weeks
(15) collected only  in LFG316 treatment group 
(16) sample collected only in patients >20kg
(18) Including GvHD 
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8.1
Informed consent procedures
Eligiblesubjects may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent(assent in case of 
children).
All subjects must be counseled about the risk of meningococcal infections as well as other 
infections, such as those caused by S.pneumoniae, H.influenzaetype b, and Aspergillus
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as a part of the informed consent process.
If incapable of doing so, in cases where the subject’s representative gives consent, the subject 
should be informed about the study to the extent possible given his/her understanding. If the 
subject is capable of doing so, he/she should 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 (i.e. all 
of the procedures described in the protocol). The process of obtaining informed consent 
should be documented in the subject source documents.
The date of signing off theinformed consent form (and the date of withdrawal, iflater 
withdrawn) should be documented in the CRF.
Novartis will provide to investigators a proposed informed consent form that complies with 
the ICH GCP guideline and regulatory requirements and is considered appropriate for this 
study. Any changes to the proposed consent form suggested by the investigator must be 
agreed to by Novartis before submission to the IRB/IEC.
Pregnancy outcomes must be collected for the female partners of anymales who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother. 
 
 
 
A copy of the approved version of all consent forms must be provided to the Novartis monitor 
after IRB/IEC approval.
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8.2
Subject demographics/other baseline characteristics
Subject demographic and baseline characteristic data willbe collected on all subjects.
Relevant medical history/current medical conditions data includes data until signature of 
informed consent. Where possible, diagnoses and not symptoms will be recorded.
Investigators have the discretion to record abnormal test findings on the medical history CRF 
whenever in their judgment, the test abnormality occurred prior to the informed consent 
signature.
8.3
Efficacy
Efficacyassessments are specifiedbelow, with the methods for assessment and recording 
specified in the SOM.Assessments will be performed/samples collected at the timepoint(s) 
defined in the Assessment schedule.
8.3.1
Schistocyte count
Blood sampleswill be collected to evaluate schistocyte count at timepoints specified in the 
Assessment schedule. Schistocyte assessment will be part of the blood hematology panel.
Person performing schistocyte count will be blinded to treatment received by the patient.
Details regarding sample processing will be provided in the laboratory manual.Schistocyte 
count will be performed at central laboratory.
8.3.2
Proteinuria
Urine sampleswill be collected at timepoints specified in the Assessment scheduleto 
evaluate proteinuria using spot urine analysis.Concentration of protein in the urine will be 
compared to the creatinine level(protein/creatinine ratio; PCR). Details regarding sample 
processing will be provided in the laboratory manual.Assessment of PCR will be performed 
at central laboratory.
8.3.3
Incidence of transfusion
Site will record incidence of both erythrocyte and platelet transfusion during entire study.
Inaddition history of transfusion from time of transplant will be recorded in CRF.
8.4
Safety
Safetyassessments are specifiedbelow;methods for assessment and recording are specified in 
the Laboratory manual provided separately, with the Assessment Scheduledetailing when 
each assessment is to be performed.
8.4.1
Performance status
Performance status will be scored using the Karnofsky (for patients older than 16 years) or 
Lansky (for patients less than or equal to 16 years old) performance scales, depending on the 
patient’s age (Section 15). For patients that have their 17th birthday during the study, 
performance status will continue to be assessedby the Lansky scale, in order to preserve 
continuity.


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8.4.2
Physical examination
A complete physical examination will include the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, vascular and neurological.Detailed procedure for physical examination is 
provided in the Site Operations Manual.
8.4.3 
Vital signs
Body temperature
Blood pressure (BP) 
Pulse 
8.4.4
Height and weight
Height
Body weight
Body mass index (BMI) will be calculated (Body weight (kg) / [Height (m)]2)
8.4.5
Laboratory evaluations
Clinically relevant deviations of laboratory test results occurring during or at completion of 
the study must be reportedin CRFandcan bediscussed with Novartis personnel. The results 
should be evaluated for criteria defining an adverse event and reported as such if the criteria 
are met. Repeated evaluations are mandatory until normalization of the result(s) or until the 
change is no longer clinically relevant. In case of doubt, Novartis personnel should again be 
contacted.Central laboratory will be used in the study but in exceptional cases local 
laboratory tests can be used in case patientsneed immediate treatment. In this case site should 
still collect sample for central laboratory analysis and provide GCP-required local laboratory 
documentation in advance. Also date of the local laboratory assessments should be within 
allowed window for screeningor baselinevisitas defined by inclusion/exclusion criteria. 
Detailed procedure for collection and preparation of the samples will be provided in 
Laboratory Manual.
Hematology
Hemoglobin, hematocrit, red blood cell count,reticulocytes,white blood cell count with 
differential and platelet count will be measured.In addition schistocytes will be measuredas 
described in Section 8.3.1.
Clinical chemistry
Sodium, potassium, creatinine, urea, uric acid, chloride, albumin, calcium, alkaline 
phosphatase, total bilirubin, LDH, γGT, AST, ALT, aPTT, PT/INR, CK, glucose, total 
cholesterol, triglycerides,haptoglobin.If the total bilirubin concentration is increased above 
1.5 times the upper limit of normal, direct and indirect reacting bilirubin should be 
differentiated.In additionbloodconcentrations of IgG will be determined.


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Urinalysis
Urine test by dipstick e.g. Combur9: leucocytes, nitrite, pH, protein, glucose, ketones, 
urobilinogen, bilirubin, blood/ hemoglobin. In addition to urine dipstick, spot urine will be 
done as described in Section 8.3.2.
If the dipstick result is positive for protein, nitrite, leucocytes and/or blood, the sample will be 
sent for microscopicanalysis of WBC, RBC and casts.
Test to detect medications
Blood sample will be taken to check serum levels of medications frequently administered to 
patients after HSCT. Level of the tacrolimus, sirolimus and cyclosporinewill be checked at 
the same timepoints when bloodhematology/chemistry is being doneby central laboratory.
8.4.6
Electrocardiogram (ECG)
PR interval, QRS duration, heart rate, RR, QT, QTc. 
The Fridericia QT correction formula (QTcF) should be used for drug development decisions. 
8.4.7
Pregnancyand assessments of fertility
All femalesthat had their first menstruation will need to have serum pregnancy test at
Screening and EOS. For postmenopausal women, FSH is measured at screening to assist in 
confirming menopausal status. Urine pregnancy tests need to be performed at remaining visits 
only in women of child-bearing potential.
8.4.8
Vaccination(s)
Please refer to Section 6.10.
8.4.9
GvHD
The medical history and the presence of the graft versus host disease(GvHD) will be 
monitored during the study and recorded in CRF.
8.5
Pharmacokinetics
PK samples will be collected at the timepoints defined in theAssessmentschedule. 
Furtherdetails on sample collection, numbering, processing and shipment can be found in the 
inSOMand/orLaboratory Manual.
Determination of the concentration of total LFG316 in serum will be performed using an 
ELISA or LC/MS assay. A detailed description of themethod used to quantify the 
concentration of total LFG316 will be included in the bioanalytical raw data of the study and 
in the bioanalytical data report. The lower limit of quantification (LLOQ) will be specified in 
the total LFG316 bioanalytical report. Pharmacokinetic (PK) samples will be obtained and 
evaluated in all subjectstreated with LFG316.Total LFG316 concentrations will be expressed 
as μg/mL. Allconcentrations below the limit of quantification or missing data will be labeled 
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will be treated as zero in summary statistics for concentration data only. They will not be 
considered for calculation of PK Parameters. PK samples remaining after completion of the 
determination of total LFG316may be used for exploratory assessmentsor other bioanalytical 
purposes (e.g. cross check between different sites, stability assessment). Given the exploratory 
nature of the work, the analytical method used for those assessments will not be validated.  
The following pharmacokinetic parameters will be determined (if feasible) using 
non-compartmental method(s) with Phoenix WinNonlin (Version 6.2 or higher): 
AUC(0-tlast), AUC(0-t) , Cmax , tmax , Cmax/D, AUC/D. Thelinear trapezoidal rule will be 
used for AUC calculation.
8.6
Pharmacodynamics markers
PD samples will be collected at the timepoints defined in the Assessment schedule
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Furtherdetails on sample collection, numbering, processing and shipment can be found in the 
Laboratory Manualand/orSOM.


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8.7
Other assessments
8.7.2
ADAMST13
ADAMST13 activity will be evaluated to rule out Thrombotic ThrombocytopenicPurpura 
(TTP). Details on sample collection and processing will be provided in SOM and/or
Laboratory Manual.Patients lacking ADAMST13 activity will be discontinued and replaced
(only in case ADAMST13 data not available prior to V3).
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8.7.3
Exploratory Biomarkerassessments
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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 subject or 
clinical investigation subject after providing written informed consentfor participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
The occurrence of adverse events should be sought by non-directive questioning of the subject 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the subject during or between visits or through physical examination, laboratory test, 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, 
they require therapy. 
Clinically significant abnormal laboratory values or test results shouldbe 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 patientswith 
underlying disease. Investigators have the responsibility for managing the safety of individual 
subjectand identifying adverse events. Alert ranges for liver related eventsare included in
Section 9.3
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Adverse events must be recorded on the Adverse Events CRF for subjects thatpass screening 
and enterinto the study. The adverse events should be reported according to the signs, 
symptoms or diagnosis associated with them, and accompanied by the following information:
1. Adverse events will be assessed according to Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03. If CTC-AE grading does not exist for an adverse event, use:
1=mild, 
2=moderate,
3=severe
4=life threatening.
CTC-AE grade 5 (death) is not used, but is collected in other CRFs (e.g. Study Completion, 
Death/Survival).
2. its relationship to thestudy treatment (no/yes), or
investigational treatment (no/yes), or other study treatment(non-investigational) (no/yes), 
orboth or indistinguishable,
3. its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved should be reported.
4. whether it constitutes a serious adverse event (SAE) See Section 9.2for definition of SAE
5. action taken regarding [study/investigational] treatment(select as appropriate). 
All adverseevents should be treated appropriately. Treatment may include one or more of 
the following: 
no action taken (i.e. further observation only)
study treatmentdosage adjusted/temporarily interrupted 
study treatmentpermanently discontinued due to this adverse event 
concomitant medication given 
non-drug therapy given 
subjecthospitalized/subject’shospitalization prolonged 
Once an adverse event is detected, it should 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 study drug, the 
interventions required to treat it, and the outcome.
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB) or Core Data Sheet (for marketed drugs) or will be 
communicated betweenIB updates in the form of Investigator Notifications. This information 
will be included in the subjectinformed consent and should be discussed with the subject
during the study as needed.


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The investigator should also instruct each subjectto report any new adverse event (beyond the 
protocol observation period) that the subject, or the subject’spersonal physician, believes 
might reasonably be related to study treatment. This information should be recorded in the 
investigator’s source documents;however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis.
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 existinghospitalization, unless 
hospitalization is for:
routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
elective or pre-planned treatment for a pre-existing condition and has not worsened 
since the start of study drug
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 
social reasons and respite care in the absence of any deterioration in the patient’s 
general condition
is medically significant, i.e. defined as an event that jeopardizes the subjector may require 
medical or surgical intervention.
Life-threatening in the context of a SAE refers to a reaction in which the subjectwas at risk of 
death atthe time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if more severe.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
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 dyscrasias or convulsions that do not result in hospitalization or
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All AEs (serious and non-serious) are captured on the CRF;SAEs also require individual 
reporting to DS&E as per Section 9.2.2.
9.2.2
SAE reporting
To ensure subjectsafety, every SAE, regardless of causality, occurring after the subjecthas 
provided informed consent and until 30 days after the last study visit.must be reported to 
Novartis within 24 hours of learning of its occurrenceas described below. Any SAEs 
experienced after thisshould only be reported to Novartis if the investigator suspects a causal 
relationship to study treatment. 
Recurrent episodes, complications, or progression of the initial SAE must be reported as 
follow-up to the original episode, regardless of when the event occurs. This report must be 
submitted within 24 hours of the investigator receiving the follow-up information. An SAE 
that is considered completely unrelated to a previously reported one should be reported 
separately as a new event.
Information about all SAEs (either initial or follow up information)is collected and recorded 
on the paper Serious Adverse Event Report Form. The investigator must assess the 
relationship to each specific component of study treatment (if study treatment consists of 
several drugs)complete the SAE Report Form in English, and send the completed, signed 
form by fax within 24 hours after awarenessof the SAEto the local Novartis Drug Safety and 
Epidemiology Department, notifying the Clinical Trial Leader.Contact information islisted 
in the Site Operations Manual. 
The original copy of the SAE Report Form and the fax confirmation sheet must be kept with 
the sourcedocumentation at the study site.Follow-up information shouldbe provided using a 
new paper SAE Report Form stating that this is a follow-up to a previously reported SAE.
Follow-up information provided should describe whether the event has resolved or continues, 
if and how it was treated, whether the treatment codewas broken or not and whether the 
subjectcontinued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event should 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 investigational treatment a Drug Safety 
and Epidemiology 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 
investigational 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.
9.3
Liver safety monitoring
To ensure subject safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
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The following twocategoriesof abnormalities / adverse events have to be considered during 
the course of the study:
Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter
Liver events, which will require close observation and follow-up 
Pleaserefer to Table 9-1and Table9-2for complete definitions of liver laboratory triggers 
and liver events.
Every liver laboratorytrigger orliver event should be followed up by the investigator or 
designated personal at the trial site, as summarized below and detailed inTable9-2.
For the liver laboratory trigger:
Repeating the liver function test (LFT)within the next week to confirm elevation
These LFT repeats should be performed using the central laboratory if possible. If this is not 
possible, then the repeats can be performed at a local laboratory to monitor the safety of the 
patient. Repeats laboratory should then be performed at central laboratory as soon as possible. 
For the liver events:
Repeating the LFT to confirm elevation as appropriate
Hospitalization of the subject if appropriate
A causality assessment of the liver eventvia exclusion of alternative causes (e.g. 
disease, co-medications)
If liver safety eventsare possibly related to the study drug and are unlikely to be part 
of the TAM presentation, discontinuation of the investigational drugmay be 
consideredafter consultation with Sponsor. 
An investigation of the liver event which needs to be followed until resolution
These investigations can include serology tests, imaging and pathology assessments, 
hepatologist’s consultancy, based on investigator’s discretion. All follow-up information, and 
the procedures performed should be recorded as appropriate in the CRF.
Table 9-1
Liver event and laboratory trigger definitions
Definition/ threshold
Liver laboratory triggers
>5x ULN < ALT / AST 
Liver events
ALT or AST > 10× ULN
ALP > 5× ULN (in the absence of known bone pathology)
TBL > 5× ULN (in the absence of known Gilbert syndrome, unless 
elevation attributed to PNH hemolysis, e.g. unconjugated fraction)
ALT or AST > 5× ULN and INR > 1.5 
Any adverse event potentiallyatypical for TAM and indicative of a liver 
toxicity * 


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Table 9-2
Follow up requirements for liver events and laboratory triggers
Criteria
Actions required
Follow-up monitoring
ALT or AST
> 5 × ULN
Establish causalityand define if likely 
caused by TAM or likely other reason for 
abnormality
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc(frequency 
at investigator discretion)
> 10 × ULN
Establish causality and define if likely 
caused by TAM or likely other reason for 
abnormality. If change persistsover 2 
visits inform sponsor and consider 
presenting to DMCfor discussion.
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc(frequency 
at investigator discretion)
ALP (isolated)
> 5× ULN (in the 
absence of known 
bone pathology)
Repeat LFT if elevation persists. 
Establish causalityand define if likely 
caused by TAM or likely other reason for 
abnormality. If change persist over 2 
visits inform sponsor and consider 
presenting to DMCfor confirmation
Investigator discretion
Monitor LFT within 1to 4 weeks or 
at next visit
9.4
Renal safety monitoring
Because renal events are defined as inclusion and response criteria, renal safety events may 
trigger AE reports but if deemed consistent with TAM presentation will not lead to study drug 
discontinuation. If renal safety events are deemed related to study drug they will be presented 
to the DMCto decide if further action is needed
9.5
Pregnancy reporting
To ensure patient safety, each pregnancy in a subjecton study drug must be reported to 
Novartis within 24hours 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. The study drug must be discontinued, though the subjectmay 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 subjectmay continue all other protocol assessments. 
Pregnancymust be recorded on a Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. 
Pregnancyfollow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the Novartis study drug of any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on anSAE Report Form.


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9.6
Early phase safetymonitoring
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. 
Suchevaluations may occur verbally, but the outcome and key discussion points will be 
summarized in writing (e-mail) 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. 
Duringthe studyNovartis employs several methods of ensuring protocol and GCP 
compliance and the quality/integrity of the sites’ data. Themonitor will visit the site to check 
the completeness of subjectrecords, the accuracy of entries on the CRFs, the adherence to the 
protocol and to Good Clinical Practice, the progress of enrollment, and to ensure that study 
drug is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the monitor during these visits.
Continuous remote monitoring of each site’s data may be performed by Novartis.
Additionally, a central analytics organization may analyse 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 subject 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 
subject
's file. The investigator must also keep the original informed consent form signed by 
the subject (a signed copy is given to the subject).
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 eligibilitycriteria, documentation of 
SAEs, and the recording of data that will be used for all primary and safety 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 subjects will be disclosed.


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10.2
Data collection
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Designated investigator staff will enter the datarequired by the protocol into the Electronic 
Case Report Forms using fully validated software that conforms to 21 CFR Part 11 
requirements. Designated investigator site staff will not be given access to the EDC system 
until they have been trained. Automatic validation programs check for data discrepancies and, 
by generating appropriate error messages, allow the data to be confirmed or corrected before 
transfer of the data to the CRO working on behalf of Novartis. TheInvestigator must certify 
that the dataentered into the Electronic Case Report Forms are complete and accurate. 
Afterdatabase lock, the investigator will receive a CD-ROM or paper copies of the subject 
data for archiving at the investigational site.
Data not requiring a separate written record will be defined in the Site Operations Manual and 
assessment schedule and canbe recorded directly on the CRFs. All other data captured for this 
study will have an external originating source (either written or electronic)withthe CRF not 
being considered as source.
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
CRO working on behalf of Novartisreview the data entered into the eCRFs 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 CRO
working on behalf of Novartiswho will make the correction to the database.
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
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).
ECG readings will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
At the conclusion of a non-IRT study, the occurrence of any emergency code breaks will be 
determined after return of all code break reports and unused drug supplies to Novartis. 


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10.3
Data Monitoring Committee
A Data Monitoring Committee (DMC)will monitor subjects for early symptoms and signs of 
meningococcalinfection. TheDMC will review available safety data after the first 5patients
≥ 12 years old randomized to LFG316completed 4weeks of treatmentand approximately 
every 3 months thereafter during the study.Other safety, dosing and treatmentduration 
questions regarding individual patients may bealsobrought to the DMC if requested by the 
Investigator and/or the Sponsor.Ifpossible,DMC meetings will be aligned with planned IAs.
In case of any safety concerns identified during the study (as described above) or fasterthan 
anticipated recruitment(especially in pediatric patient population), DMC meetings might 
happen more regularly.
Further details will beprovided in Data Monitoring Committee charter.
10.4
Adjudication Committee
Not required.
11
Data analysis
11.1
Analysis sets
For the safety, PK and PDanalysis sets, subjects will be analyzed according to the study 
treatment(s) received.
The full analysis set will include all subjects that received any study drug.
The safety analysis set will include all subjects that received any study drug.
The PK analysis set will include all subjects with available PK data and no protocol 
deviations with relevant impact on PK data.
The PD analysis set will include all subjects with available PD and mode-of-action biomarker 
data and no protocol deviations with relevant impact on PD data.Patients who switch 
treatments according to the protocol defined rules will be indicated as having received two 
treatments in the listings,and data from the period after switching will in general be 
summarized separately. Thus in general there may be four treatment groups in the summary 
tables:
LFG316
SoC
LFG316 then SoC(in case of switch in treatment as described in Section 3.1)
SoC then LFG316(in case of switch in treatment as described in Section 3.1
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11.2
Subject demographics and other baseline characteristics
All data for backgroundand demographic variables will be listed by treatment group and 
subject. Summary statistics will be provided by treatment group.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed bytreatment group and subject.
11.3
Treatments (study drug, rescue medication, other concomitant 
therapies, compliance)
Data for study drug administration, standard of care therapyand concomitant therapies will be 
listed by treatment groupandsubject.
11.4
Analysis of the primary variable(s)
11.4.1
Variable(s)
The primary efficacy variable is hematological response.
A patient is considered to be a hematological responder at 17 weeks if both of the following 
criteria are met:
1. Schistocytes <2/microscopic high power field (HPF).
2. Transfusion independent (no need for TAM-related transfusions (platelets and erythrocytes)
Patients who discontinue the randomized treatment before 16 weeks due to lack of efficacy 
(whether according to the protocol-defined rules allowing a switch to the alternative treatment 
arm, or not) or due to treatment-related safety reasons will be considered non-responders in 
this analysis. Data from these patients collected after switching treatment will be considered 
as supportive data but will not be included in the primary analysis.
11.4.2
Statistical model, hypothesis, and method of analysis
The primary analysis will compare all randomized patients according to the treatment they 
were assigned. 
Results for hematological response will be categorized as providing evidence of good, 
satisfactory or poor efficacy as defined by the rules below. 
Good efficacy: Pr (Δ>30%¦ data) ≥0.5 and Pr (Δ>0¦ data) ≥0.9
Satisfactory efficacy:  Pr (Δ≥10%
¦ data) ≥0.5 and Pr (Δ>0
¦ data) ≥0.9
Poor efficacy: Pr (Δ≥10%¦ data) < 0.5 or Pr (Δ>0¦ data) < 0.9
where Δ is the differencein percentage pointsin response rates (LFG316 -control).
The analysis of hematological response at 17 weeks will present posterior probabilities of 
meeting the outcome criteria as defined above. The prior distribution for the response rate in 
each group will be assumed to be a neutral non-informative Beta (1/3, 1/3) distribution.


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11.4.3
Handling of missing values/censoring/discontinuations
Patients who discontinue treatment due to lack of efficacy (defined as either meeting the 
criteria defined in Section 3.1for switching treatments or having reason for discontinuation 
marked as “lack of efficacy” at the study completion visit) are defined to be non-responders. 
Other patients,for whom hematological response cannot be assessed due to discontinuation 
for treatment-related safety reasons,will be considered to be non-responders. Hematological 
response for patients who discontinue for any other reason will be determined based on their 
available data at the time of discontinuation. 
Given the severe nature of the indication and the need for close monitoring of these patients it 
is expected that there will be very little truly missing data.
11.4.4
Supportive analyses
A supportive analysis will compare patients according to the degree of complement blockade 
achieved. And given schistocyte counts, erythrocytes, platelets, and proteinuria are involved 
in definitions of treatment failure or successeach will be summarized and plotted over time, 
with the possibility of further analyses.
The effect of presence/absence of proteinuria at baseline (a key prognostic factor of response) 
on the response rates in each group will be investigated. 
 
11.5
Analysis of secondary and exploratory variables
11.5.1
Efficacy / Pharmacodynamics
Secondary variables supporting the secondary objectives will include:
Complete response, defined as hematologicalresponse and no proteinuria as 
determined by proteinuria<30mg/dLand eGFRdoubled or not less than 0.85 x lower 
limit of normal
Number of patients switching treatment and timeat which the switch occurred
Non-relapse mortality

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Overall survival
Complete response will be analyzed in the same way as the primary variable of hematological 
response. The number of patients switching treatment will be summarized. Time to treatment 
switch, non-relapse mortality and overall survival will be summarized using time to event
methods. Further details will be provided in the Reporting and Analysis Plan (RAP).
Further details on the analysis and presentation of these variables will be provided in the RAP.
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11.5.2
Safety
Vital signs
All vital signs data will be listed by treatment, subject, and visit/time and if ranges are 
available abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics 
will be provided by treatmentand visit/time.
ECG evaluations
All ECG data will be listed by treatment, subject 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, subject, 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 andsubject.
The number and percentage of subjects with adverse events will be tabulated by body system 
and preferred term with a breakdown by treatment. A subject with multiple adverse events 
within a body system is only counted once towards thetotal of this body system.
Other evaluations
11.5.3
Pharmacokinetics
Total LFG316 serum concentration data will be listed by treatment, subject, and 
visit/sampling time point. Descriptive summary statistics will beprovided by treatment and 
visit/sampling time point, includingthe frequency (n, %) of concentrations belowthe LLOQ 
and reported as zero. 
Summary statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and 
geometric), median, minimum and maximum. Anexception to this is Tmax where median, 
minimum and maximum will be presented. Concentrations below LLOQ will be treated as 
zero in summary statisticsand for PK parameter calculations. A geometric mean will not be 
reported if the dataset includes zero values.Pharmacokinetic parameters will be calculated as 
described inSection 8.5
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11.5.4
Pharmacokinetic / pharmacodynamic interactions
The relationship of PD, mode-of-action, and efficacy biomarkers with the exposure to 
LFG316 will be explored.
11.5.5
Other assessments
11.6
Sample size calculation
At least 40 TAM patients are planned to be included in the studyinitially. Patients will be 
randomized to either SoC (n=20) or LFG316 (n=20) treatment arm. Results for hematological 
response will be categorized as providing evidence of good, satisfactory or poor efficacyas 
defined by the rules in Section 11.4.2
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11.7
Power for analysis of key secondary variables
Not applicable
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11.8
Interim analyses
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12
Ethical consideration
12.1
Regulatory and ethical compliance
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This clinical study was designed and shall be implemented and reported in accordance with 
the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC, US Code of Federal Regulations 
Title21, and Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles 
laid down in the Declaration of Helsinki.


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12.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution should 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, subject recruitment 
procedures (e.g.advertisements) and any other written information to be provided to subjects. 
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, 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 multi-center trials, a Coordinating Investigator will be selected by Novartis around 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
Novartis assures that 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.
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 subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances should an 
investigator collect additional data or conduct any additional procedures for any research 
related purpose involving any investigational drugs.
Investigators must apply due diligence to avoid protocol deviations. If the 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/REB it cannot be implemented. All significant protocol deviations will be recorded 
and reported in the CSR.


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13.1
Protocol Amendments
Any change or addition 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/IECprior to 
implementation. 
Onlyamendments that areintended to eliminate an apparent immediate hazard to subjects 
may be implemented,provided the Health Authorities and the reviewing IRB/IEC are 
subsequentlynotified by protocol amendment.
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study,even if this action represents a deviation from the protocol. In such cases,the CTL 
should be informed and (serious) adverseevent reporting requirements (Section 9) followed 
as appropriate.


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14
References
Available upon request
CesbronJY, Maillet F, Valance J, et al (1985)Homozygotic C5 deficiency disclosed by 
purulent Neisseria meningitidis meningitis. Presse Med; 14(45):2287-9; French
Chapin J, Shore T, Forsberg P, et al (2014) Hematopoietic Transplant-Associated Thrombotic 
Microangiopathy: Case Report and Review of Diagnosis and Treatments. Clin Adv Hematol 
Oncol; 12(9):565-73
Cho BS, Yahng SA, Lee SE, et al (2010) Validationof recentlyproposedconsensuscriteria
for thromboticmicroangiopathyafterallogeneichematopoieticstem-celltransplantation. 
Transplantation; 90(8):918-26
de Fontbrune FS, Galambrun C, Sirvent A, et al (2015) Use of Eculizumab in Patients With 
Allogeneic Stem Cell Transplant-Associated Thrombotic Microangiopathy: A Study From the 
SFGM-TC. Transplantation; in press
Delgado-Cerviño E, Fontán G, López-Trascasa M (2005) C5 complement deficiency in a 
Spanish family. Molecular characterization of the double mutation responsible for the defect. 
Mol Immunol; 42(1):105-11.
Golub MS, Gershwin ME, Hurley LS, et al (1984) Studies of marginal zinc deprivation in 
rhesus monkeys. IV. Growth of infants in the first year. Am J Clin Nutr; 40(6):1192-202
HaeneyMR, Thompson RA, Faulkner J, et al (1980) Recurrent bacterial meningitis in patients 
with genetic defects of terminal complement components.Clin Exp Immunol; 40(1):16-24
Hayes W, Tschumi S, Ling SC,et al (2014). Eculizumab hepatotoxicity in pediatric aHUS 
Pediatr Nephrol; 30(5):775-81.
Jodele S, Dandoy CE, Danziger-Isakov L, et al(2016a). Terminal complement blockade after 
HSCT is safe without meningococcal vaccination. Biol Blood Marrow Transplant. doi: 
10.1016/j.bbmt.2016.03.032. Article in press.
JodeleS,Fukuda T,Mizuno K,et al(2016b). VariableEculizumabClearance Requires 
PharmacodynamicMonitoring to Optimize TherapyforThrombotic Microangiopathy after 
HematopoieticStem Cell Transplantation. Biol Blood Marrow Transplant.;22(2):307-15. doi: 
10.1016/j.bbmt.2015.10.002. Epub 2015 Oct 9.
Jodele S, Fukuda T, Vinks A,et al (2014a) Eculizumab therapy in children with severe 
hematopoietic stem cell transplantation-associated thrombotic microangiopathy. Biol Blood 
Marrow Transplant; 20(4):518-25
JodeleS, Davies SM, Lane A, et al (2014b) Diagnostic and risk criteria for HSCT-associated 
thrombotic microangiopathy: a study in children and young adults. Blood; 124(4):645-53
Jodele S, Laskin BI, Dandoy CE, et al (2014c) A new paradigm: Diagnosis and management 
of HSCT-associated thrombotic microangiopathy as multi-system endothelial injury. Blood 
rev; in press


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Jodele S, Zhang K, Zou F et al (2016c) The genetic fingerprint of susceptibility for transplant-
associated thrombotic microangiopathy.Blood;127(8):989-96
Kim SS, Patel M, Yum K, et al (2015) Hematopoietic stem cell transplant-associated 
thrombotic microangiopathy: review of pharmacologic treatment options. Transfusion; 
55(2):452-8
López-Lera A, Garrido S, de la Cruz RM, et al (2009) Molecular characterization of three new 
mutations causing C5 deficiency in two non-related families. Mol Immunol; 46(11-12):2340-7
OkanoM, Sakata N, Ueda S, et al (2014) Recovery from life-threatening transplantation-
associated thrombotic microangiopathy using eculizumab in a patient with very severe 
aplastic anemia. Bone Marrow Transplant; 49(8):1116-8
Roach B, Kim Y, Jerome E, et al (1981) Influence of age and sex on serum complement 
components in children. Am J Dis Child;135(10):918-20
SanalO, Loos M, Ersoy F, et al (1992) Complement component deficiencies and infection: 
C5, C8 and C3 deficiencies in three families.Eur J Pediatr; 151(9):676-9
Uderzo C, Bonanomi S, Busca A,et al (2006) Riskfactorsand severeoutcomein thrombotic
microangiopathyafterallogeneichematopoieticstem cell transplantation. Transplantation; 
82(5):638-44
Weiner GJ (2010) Rituximab: mechanism of action. Semin Hematol.; 47(2):115-23. doi: 
10.1053/j.seminhematol.2010.01.011.
Wolach B1, Dolfin T, Regev R, et al (1997) The development of the complement system after 
28 weeks
' gestation. Acta Paediatr;86(5):523-7.
ZerzriY, Kallel-Sellami M, Abdelmalek R, et al (2010) Hereditary complement C5 
deficiency: study of 3 Tunisian adult cases and literature review. Tunis Med; 88(4):269-76; 
French


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15
Appendix 1: Lansky/Karnofsky scores
15.1
Karnofsky Performance Status Scale (for patients greater than 16 
years old)
Able to carry on normal 
activity and work; no special 
care needed
100% Normal; no complaints
90%
Able to carry on normal activity; minor signs or 
symptoms of disease
80%
Normal activity with effort; some signs or symptoms 
of disease
Unable to work; able to live 
at home and care for most 
personal needs; varying 
amount of assistance needed
70%
Cares for self; unable to carry on normal activity or 
work
60%
Requires occasional assistance; able to care for most 
personal needs
50%
Requires considerable assistance and frequent 
medical care
Unable to care for self; 
requires equivalent of 
institutional or hospital care; 
disease may be progressing 
rapidly
40% 
Disabled; requires special care and assistance
30%
Severely disabled; hospitalization is indicated though 
death not imminent
20%
Very sick; hospitalization necessary; active 
supportive treatment necessary
10%
Moribund; fatal processes progressing rapidly
0
Dead


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15.2
Lansky Score (for patients less than or equal to 16 years old)
100
Fully active, normal
90
Minor restrictions in physically strenuous activity
80
Active, but tires more quickly
70
Both greater restriction of play and less time spent in play activity
60 
Up and around, but minimal active play; keeps busy with quieter activities
50
Gets dressed but lies around much of the day; no active play but able to participate in 
all quiet play and activities
40
Mainly in bed; participates in quiet activities
30
Bed-bound; needs assistance even for quiet play
20
Often sleeping; play entirely limited to very passive activities
10
No play; does not get out of bed
0
Unresponsive


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Appendix 2:vital signs in children
Table 16-1
Vital signs in children


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SAP_001.pdf: 
Biostatistics & Statistical Programming / 
Novartis Institutes for BioMedical Research
LFG316
CLFG316X2202
A randomized, open label, controlled, multiple dose study 
to evaluate the clinical efficacy, safety, tolerability, 
pharmacokinetics and pharmacodynamics of LFG316 in 
patients with transplant associated microangiopathy after 
hematopoietic precursor cell transplantation
Statistical Analysis Plan (SAP)
Author(s):
 
Document type: 
SAP Documentation –NIBR 
Document status:
Final
Release date:
30-Aug-2017
Number of pages:
15
Personal Data
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
1 Introduction.........................................................................................................................5
1.1
Scope of document..................................................................................................5
1.2
Study reference documentation...............................................................................5
1.3
Study objectives.......................................................................................................5
1.3.1
Primary Objective...................................................................................5
1.3.2
Secondary Objectives..............................................................................5
1.3.3
Exploratory Objectives............................................................................5
1.4
Study design and treatment......................................................................................6
2 First interpretable results (FIR)...........................................................................................7
3 Interim analyses...................................................................................................................7
4 Statistical methods: Analysis sets........................................................................................7
5 Statistical methods for pharmacokinetic (PK) parameters..................................................9
5.1
Variables..................................................................................................................9
5.2
Descriptive analyses................................................................................................9
5.2.1
Graphical presentation of results.............................................................9
6 Statistical methods for Efficacy and Pharmacodynamic (PD) parameters..........................9
6.1
Primary estimand...................................................................................................10
6.1.1
Definition of primary estimand: Hematological response (P1)............10
6.2
Secondary estimands for non-relapse mortality....................................................11
6.2.1
Definition of secondary estimand for non-relapse mortality:...............11
6.3
Secondary estimand for complete response:..........................................................11
6.3.1
Definition of secondary estimand for complete response:....................11
6.4
Secondary estimand for overall survival...............................................................11
6.4.1
Definition of secondary estimand for overall survival (S3):.................11
6.5
Other exploratory secondary variables..................................................................11
6.6
Exploratory objectives...........................................................................................12
6.6.1
Descriptive analyses..............................................................................12
7 Statistical methods for safety and tolerability data............................................................12
7.1.1
Variables...............................................................................................12
7.1.2
Descriptive analyses..............................................................................13
8 Statistical methods for Biomarker data.............................................................................14


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List of tables
Table4-1
Protocol deviation codes and analysis sets..............................................8
Table 6-1
Summary of key protocol estimands.....................................................10


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1
Introduction 
1.1
Scopeof document
The SAP (Statistical Analysis Plan) documents contain detailed information to aid the 
production of Statistics & Programming input into the Clinical Study Report (CSR) for trial 
“CLFG316X2202”.
The SAP describes the implementation of the statistical analysis plannedfollowing study 
termination which is reduced in scope comparedtothe original protocol.Objectives and other 
text remain as in the protocol.
1.2
Study reference documentation
This SAP has been developed using Clinical Trial Protocol version v05(incorporating 
Amendment 05) dated 16AUG2016. 
1.3
Study objectives
1.3.1
Primary Objective
To assess the hematological response rate in patients with TAM receiving LFG316 compared 
to standard of care (SoC).
1.3.2
Secondary Objectives
To assess the safety and tolerability of LFG316 in patients with TAM
To describe the pharmacokinetics of total LFG316
To evaluate non-relapse mortality in TAM patients treated with LFG316 as compared 
to patients on SoC
Toassesscompleteresponserateat17weeks inTAMpatients treatedwith
LFG316comparedtopatientsreceivingstandardofcare
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1.3.3
Exploratory Objectives




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and/or increase in erythrocyte or platelet transfusion need (increase of 50% or more in 
number of transfusions during 2 weeks prior to study visit as compared to number of 
transfusions needed two weeks before treatment initiation),
and/or increasing proteinuria (+50% or more as compared to baseline)
Patients showing no response (definition below) between visit at week 4 (day 29) and visit at 
week 16 were considered to be treatment failures and could be switched to the other treatment 
arm. Switching the treatment could occur immediately after data is available.
no decrease in schistocyte count (as compared to baseline)
and/or continued erythrocyte or platelet transfusion need (less than 25% improvement 
in number of transfusions during 2 weeks prior to study visit as compared to number 
of transfusions needed two weeks before treatment initiation)
and/or non-responding proteinuria (less than 25% reduction in proteinuria compared to 
baseline)
Patients can only switch study treatment arms once.
2
First interpretable results (FIR)
First interpretable results (FIR) will not beprovided for this trial.
3 
Interim analyses 
4
Statistical methods: Analysis sets
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For patients for which the actual first treatment received does not match the randomized 
treatment then the treatment actually first received will be used for grouping by treatments 
received.
All patients whoreceive study drug or SoC and with no protocol deviations with relevant 
impacton safety will be included in the safety analysis set.
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 study drug or SoC and who 
experienced no protocol deviations with relevant impact on PK data.
Patients who switch treatments according to the protocol defined rules will be indicated as 
having received two treatments in the listings, and data from the period after switching will in 
general be summarized separatelyif required. Thus in general there may be up to 6treatment 
groups in the summary tables:
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LFG316
SoC
LFG316 thenSoC (in case of switch in treatment)
SoC thenLFG316 (in case of switch in treatment)
All LFG316 first
All SoC first
with the first four, mutually exclusive, used in listings, ‘by treatment’.
The analysis sets and protocol deviation codes are related as follows:
Table 4-1
Protocol deviation codes and analysis sets
Category 
Deviation 
code
Text description of deviation
Data exclusion
Patients are excluded from all (safety)analysis in case of these PDs: 
Exclude patient
completely from 
all (safety)
analysis sets
I01
ICF not obtained
Patients are excluded from PK analysis in case of these Protocol 
Deviations: 
Exclude patient
from PK analysis 
set 
E11
Patients previously treated with eculizumab for TAM 
Unless 
sufficiently long 
ago to not affect 
PK.
Patients are excluded from PD analysis in case of these Protocol 
Deviations:
Exclude patient
from PD analysis 
set
E01
Use of other investigational drugs at the time of enrollment, 
or within 5 half-lives of enrollment, or until the expected PD 
effect has returned to baseline, whichever is longer; or even 
longer if required by local regulations.Investigational drug 
does not include off label use of drugs. Non-marketed drugs 
used in expanded access programs that are used as local 
standard of care may be acceptable but have to be agreed 
with the sponsor on a case by case basis.


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Category 
Deviation 
code
Text description of deviation
Data exclusion
E11
Patients previously treated with eculizumab for TAM
Unless 
sufficiently long 
ago to not affect 
PD.
If updates to this table are needed,anamendment tothe SAP needs tobe implemented priorto
DBL.
5
Statistical methods for pharmacokinetic (PK) parameters
5.1
Variables 
The following pharmacokinetic parameters will be determined (if feasible) using non-
compartmental method(s) with Phoenix WinNonlin (Version 6.2 or higher): AUC(0-tlast), 
AUC(0-t), Cmax, tmax, Cmax/D, AUC/D. The linear trapezoidal rule will be used for AUC 
calculation.
5.2
Descriptive analyses
Total LFG316 serum concentration data will be listed by treatment(excludingpatients 
receivingSoC alone), patient,and visit/samplingtimepoint.Descriptivesummarystatistics
willbeprovidedby drug treatmentand visit/samplingtimepoint,including thefrequency
(n,%)ofconcentrationsbelowtheLLOQ and reported as zero.
Summary statisticswillincludemean (arithmeticandgeometric),SD,CV(arithmeticand 
geometric), median, minimum andmaximum. An exceptiontothisisTmax where
median, minimum andmaximum will bepresented.ConcentrationsbelowLLOQwill be
treatedas zeroinsummary statisticsandforPKparametercalculations.Ageometricmean
willnotbe reported ifthedatasetincludeszerovalues.Pharmacokinetic parameterswillbe 
listed bytreatment and patient.
5.2.1
Graphical presentation of results
Arithmetic mean (SD) and geometric mean (95% CI) serum concentration data will be plotted 
across timeup to a timepoint where there is sufficient datafor calculation of means
Overlaying individual serum concentration-time profiles will be generated along with 
concentration versus time profiles for individual patients.
6
Statistical methods for Efficacy and Pharmacodynamic (PD) 
parameters
Summary of key estimandsfor efficacy


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Efficacy estimands are defined for this trial to address the efficacy objectives of the trial and 
to provide supportive evidence for those objectives. These estimands are defined in detail in 
the subsequent sections and are summarized in Table 6-1.Although they will be calculated for 
each patient and treatment they will not be analysed, only listed. The outputs forsafety, 
tolerability, PK, 
PD and PK/PD 
relationshipsare described in other sections of this SAP.
Table 6-1
Summary of key protocol estimands
Estimand
Variable estimand is 
based on
Section
P1
Primary
Hematological 
response at 17 weeks 
on initially randomized 
treatment
6.1.1
S1
Secondary -non-
relapse mortality
Non-relapse death or 
switching up to 17 
weeks
6.2.1
S2
Secondary -  
complete response
Complete response at 
17 weeks on initially 
randomized treatment
6.3.1
S3
Secondary for 
overall survival
All cause death over 
one year
6.4.1
6.1
Primaryestimand
The primary estimand addresses the primary objective:
To assess the hematological response rate in patients with transplant associated 
microangiopathy (TAM)receiving LFG316 plus standard of care(SoC)(excluding 
prohibited treatment) against SoC only.
This estimand addressesthe scientific question of whether treatment with LFG316 only 
increaseshematological response rate compared to treatment with SoConly.  It is assumed 
that treatment switching implies that the randomized treatment has failed and that the patient 
is deteriorating.
6.1.1
Definition of primary estimand:Hematological response(P1)
Population: TAM patients with high risk of death as perthe inclusion/exclusioncriteria
Variable: Hematological response at 17 weeks

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Measure of intervention effect:Difference between response rates for LFG316 versus SoC 
in the absence of a switch to alternative treatment(considered failure)
A patient is considered to have hematological response at a given timepoint if both of the 
following criteria are met:
1. Schistocytes <2/microscopic high power field (HPF).
2. Transfusion independent (no need for TAM-related transfusions [platelets and 
erythrocytes])


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Patients meeting the definition of hematological response at week 17 whilst still remaining on 
their randomized treatment are considered to be responders.
Therefore patients who switch treatments before week 17 are considered to be non-responders.
Patients who do not meet the responder criteria and have missing data are also considered to 
be non-responders.
6.2
Secondary estimandsfor non-relapse mortality
This secondary estimand addresses the following secondary objective:
To evaluate non-relapse-relatedmortality(any death not considered to be related to a 
relapse of underlying disease)in TAM patients treated with LFG316 as compared to 
patients on SoC
6.2.1
Definition of secondary estimandfor non-relapse mortality:
Population: TAM patients with high risk of death as per the inclusion/exclusioncriteria
Variable: Time to non-relapse-relatedmortalityup to17 weeks on initially randomized 
treatment.
6.3
Secondary estimandfor complete response:
6.3.1
Definition of secondary estimandfor complete response:
Population: TAM patients with high risk of death as per the inclusion/exclusion criteria
Variable: Completeresponse at 17 weeks
Complete responseisdefined ashematological response and no proteinuria as determined by 
proteinuria<30 mg/dLand eGFRdoubled or not less than 0.85 x lower limit of normal
6.4
Secondary estimandfor overall survival
6.4.1
Definition of secondary estimandfor overall survival(S3):
Population: TAM patients with high risk of death as per the inclusion/exclusion criteria
Variable: Time to all cause death up to 1 yearon initially randomized treatment.
6.5
Other exploratorysecondary variables
The followingvariables will also be listed and plotted over timeto support theassessment of 
efficacyas they are components of hematological response (first three) and of complete 
response (all five). 
Schistocytes
Platelets
Erythrocytes
Proteinuria
eGFR  


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6.6
Exploratory objectives
6.6.1
Descriptive analyses
Use in the text below of “treatment group” refers to the initially assigned treatment but, if 
necessary or useful, allowsfor use of the four treatment sequences that include switching, as 
described in Section 4.
Overlaying plots will be provided over time on study per patient with a colour change to 
indicateanytreatment switch. 
7
Statistical methods for safety and tolerability data
7.1.1
Variables 
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Adverse events, vital signs (blood pressure, pulse rate, body temperature), ECG intervals, 
laboratory measurements, as well as patientdemographics, baseline characteristics, and 
treatment informationare the relevant variables.
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7.1.2
Descriptive analyses
Use in the text below of “treatment group” refers to the initially assigned treatment but, if 
necessary or useful,allows for use of the four treatment sequences that include switching, as 
described in Section 4.
Patientdemographics and other baseline characteristics
All data for background and demographic variables will be listed by treatment group and 
patient. Summary statistics will be provided by treatment group.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment group and patient.
Treatment
Data for study drug administration and concomitant therapies will be listedby treatment 
group andpatient.
Vital signs
All vital signs data will be listed by treatmentgroup, patient, and visit/time and if ranges are 
available,abnormalities (and relevant orthostatic changes) will be flagged. 
ECG evaluations
All ECG data will be listed by treatmentgroup, patientand visit/time;abnormalities will be 
flagged.
Clinical laboratory evaluations
All laboratory data will be listed by treatmentgroup, patient, and visit/time and if normal 
ranges are available,abnormalities will be flagged. A separate listing is provided presenting 
all parameters in a patientwith any abnormal values. Overlaying plots will be provided over 
time on study per patient with a colour change to indicate any treatment switch. 
Adverse events
All informationobtained on adverse events will be displayed by treatmentgroupandpatient.
The number and percentage of patients with adverse events will be tabulated by body system 
and preferred term with a breakdown by treatment. A patientwith multiple adverse events 
within a body system is only counted once towards the total of this body systemand treatment.
Where the duration of an AE spans a switching of treatment, it will only be counted for the 
treatment in which it initially occurred.


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Other safety evaluations
Lansky/Karnofsky scores
Lansky/Karnofsky scores will be listed by treatment group, patientand visit/time along with 
changes from baseline.Summary statistics (frequency counts) will be provided by treatment 
group and visit/time.Overlaying plots will be provided over time on study per patient with a 
colour change to indicate any treatment switch.
ADAMST13
All ADAMST13 results will be listed by patientand visit/time. 
Transfusions
Information on transfusions will be listed by patientand visit/time. 
8
Statistical methods forBiomarker data
Handling of LLOQ and ULOQ
Biomarker data are reported as concentration results, measured using a specific assay with a 
working range defined by the two limits: Lower limit of quantification (LLOQ) and Upper 
limit of quantification (ULOQ). Values which fall below the LLOQ or above the ULOQ are 
reported as < LLOQ * dilution factor (dilution factor: if sample diluted and concentration 
measured still below LLOQ) and > ULOQ * dilution factor, respectively.
To ensure that biomarkers only have numerical values, censored values will be imputed as 
follows
Values below the LLOQ are replaced by LLOQ/2.

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Values above the ULOQ are replaced by ULOQ.
Imputed values are used for summary statistics, inferential analyses and plots (with a special 
symbol). Values below LLOQ and values above ULOQ are shown as such in the listings. In 
the summary table, the frequency (n, %) of values below the LLOQ and abovethe ULOQ, 
respectively, will be included. 
If the proportion of imputed data is more than 20% for any treatment group at any time point, 
a footnote is added to the summary statistics table stating that the proportion of values outside 
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the limits of quantification is more than 20% for some treatment groups at some time points 
and that in such cases summary statistics may be heavily biased.
If the proportion of imputed data for a given biomarker, across all treatment groups and time 
points, is more than 50%,no summary statistics are provided and the data are only listed.