Conditions: Peripheral Artery Disease (PAD); Intermittent Claudication
Keywords: PAD peripheral artery/arterial disease peripheral vascular disease leg pain claudication leg pain with exercise exercise test walk test
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 46
Healthy volunteers: no

Brief summary:
This study is designed to determine whether LLG783 displays the clinical safety and efficacy profile, after multiple i.v. doses, to support further development in patients with PAD and intermittent claudication.

Detailed description:

Arms:
arm 1: Patients will receive LLG783 i.v. infusion every 4 weeks for 12 weeks. arm 2: Patients will receive placebo to LLG783 i.v. infusion every 4 weeks for 12 weeks.

Interventions: intervention 1: LLG783 intervention 2: Placebo
Intervention descriptions: intervention 1: LLG783 concentrate solution for infusion/injection suitable for i.v. administration as well as s.c. administration. intervention 2: Placebo to LLG783 concentrate solution for infusion/injection suitable for i.v. administration as well as s.c. administration.

Protocol document:
Prot_000.pdf: 
Novartis Institutes for BioMedical Research
LLG783
Clinical Trial Protocol CLLG783X2201
A Patient and Investigator-blinded, randomized, placebo-
controlled study of LLG783 in patients with peripheral 
artery disease (PAD) and intermittent claudication
Document type:
Amended Protocol Version
EUDRACT number:
2017-000706-37
Version number:
v02 Incorporating version 01 (Clean)
Clinical Trial Phase:
IIa
Release date:
01-Nov-2017
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. Note: The SOM will not form part of the Clinical Study Report.
Notification of serious adverse events
Dear Investigator,
You must report a serious adverse event (SAE) (initial or follow-up) to Novartis as 
summarized below. Refer to Section 9.2 of the protocol for SAE criteria and additional 
requirements. See also page 2 of the SOM for further details on the method of reporting a 
SAE.

Complete SAE report

Submit SAE report to Novartis Chief Medical Office and Patient Safety (CMO& PS)
within 24 hours after awareness of the SAE

Notify the Novartis Medical Lead for this study

The fax number(s) and email address(es) are located in the SOM.


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Table of contents 
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Protocol No. CLLG783X2201 
Site Operations Manual (SOM) ........................................................................................... 2 
Notification of serious adverse events ................................................................................. 2 
Table of contents ................................................................................................................. 3 
List of tables ........................................................................................................................ 7 
List of figures ...................................................................................................................... 7 
List of abbreviations ............................................................................................................ 8 
Phannacokinetic definitions and symbols ......................................................................... 11 
Glossaiy of tenns ............................................................................................................... 12 
Amendment 2 (November 2017) ....................................................................................... 14 
Amendrnent 1 (July 2017) ................................................................................................. 16 
Protocol surnmary .............................................................................................................. 17 
1 
Introduction ....................................................................................................................... 20 
1.1 
Background ............................................................................................................ 20 
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1.4 
Study pmpose ........................................................................................................ 24 
2 
Objectives and endpoints ................................................................................................... 25 
2.1 
Prirnaiy objective(s) ............................................................................................... 25 
2.2 
Secondary objective(s) ........................................................................................... 25 
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3 
Investigational plan ........................................................................................................... 28 
3 .1 
Study design ........................................................................................................... 28 
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3.6 
Pmpose and timing of interim analyses/design adaptations .................................. 32 
3. 7
Risks and benefits .................................................................................................. 3 2 


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3.7.1
Blood sample volumes ..........................................................................33
4
Population..........................................................................................................................33
4.1
Inclusion criteria ....................................................................................................34
4.2
Exclusion criteria...................................................................................................35
5
Restrictions for Study Subjects .........................................................................................37
5.1
Contraception requirements...................................................................................37
5.2
Prohibited treatment...............................................................................................38
5.3
Dietary restrictions and smoking...........................................................................38
5.4
Other restrictions ...................................................................................................38
6
Treatment...........................................................................................................................38
6.1
Study treatment......................................................................................................38
6.1.2
Additional study treatment....................................................................39
6.2
Treatment arms......................................................................................................39
6.3
Treatment assignment and randomization.............................................................39
6.4
Treatment blinding.................................................................................................40
6.5
Treating the patient................................................................................................41
6.6
Permitted dose adjustments and interruptions of study treatment.........................42
6.7
Emergency breaking of assigned treatment code ..................................................42
6.8
Treatment exposure and compliance .....................................................................43
6.9
Recommended treatment of AEs...........................................................................43
6.10
Rescue medication.................................................................................................44
6.11
Concomitant treatment...........................................................................................44
7
Study completion and discontinuation ..............................................................................44
7.1
Study completion and post-study treatment ..........................................................44
7.2
Discontinuation of study treatment........................................................................45
7.3
Withdrawal of informed consent ...........................................................................46
7.4
Lost to follow-up ...................................................................................................47
7.5
Study Stopping rules..............................................................................................47
7.6
Early study termination by the sponsor .................................................................47
8
Procedures and assessments ..............................................................................................48
8.1
Assessment Schedule.............................................................................................48
8.2
Informed consent procedures.................................................................................54
8.3
Patient screening....................................................................................................55
8.4
Patient demographics/other baseline characteristics .............................................55
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8.5
Efficacy / Pharmacodynamics ...............................................................................55
8.5.1
6-minute walk test.................................................................................55
8.6
Safety.....................................................................................................................55
8.6.1
Physical examination ............................................................................55
8.6.2
Vital signs..............................................................................................55
8.6.3
Height and weight .................................................................................56
8.6.4
Laboratory evaluations..........................................................................56
8.6.5
Electrocardiogram.................................................................................57
8.7
Pharmacokinetics...................................................................................................57
8.7.1
Pharmacokinetics ..................................................................................57
8.9
Use of residual biological samples ........................................................................61
9
Safety monitoring..............................................................................................................61
9.1
Adverse events.......................................................................................................61
9.2
Serious adverse event reporting.............................................................................63
9.2.1
Definition of SAE .................................................................................63
9.2.2
SAE reporting........................................................................................64
9.3
Liver safety monitoring .........................................................................................65
9.4
Renal safety monitoring.........................................................................................66
9.5
Reporting of study treatment errors including misuse/abuse ................................66
9.6
Pregnancy reporting...............................................................................................67
9.7
Prospective suicidality assessment ........................................................................67
9.8
Early phase safety monitoring ...............................................................................67
10 Data review and database management.............................................................................68
10.1
Site monitoring ......................................................................................................68
10.2
Data collection.......................................................................................................68
10.3
Database management and quality control............................................................69
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10.4
Data Monitoring Committee..................................................................................69
10.5
Adjudication Committee........................................................................................70
11 Data analysis......................................................................................................................70
11.1
Analysis sets ..........................................................................................................70
11.2
Patient demographics and other baseline characteristics.......................................70
11.3
Treatments .............................................................................................................70
11.4
Analysis of the primary variable(s) .......................................................................70
11.4.1
Primary Variable(s)...............................................................................70
11.4.2
Statistical model, hypothesis, and method of analysis..........................70
11.4.3
Handling of missing values/censoring/discontinuations.......................71
11.4.4
Summary statistics of safety..................................................................71
11.4.5
Sensitivity analyses ...............................................................................72
11.5
Analysis of secondary variable(s)..........................................................................72
11.5.1
Pharmacokinetics ..................................................................................72
11.5.2
Pharmacokinetic / pharmacodynamic relationships..............................72
11.5.3
Pain-free walk distance .........................................................................72
11.7
Sample size calculation..........................................................................................74
11.8
Interim analyses.....................................................................................................74
12 Ethical considerations........................................................................................................75
12.1
Regulatory and ethical compliance........................................................................75
12.2
Responsibilities of the investigator and IRB/IEC..................................................75
12.3
Publication of study protocol and results...............................................................76
12.4
Quality Control and Quality Assurance.................................................................76
13 Protocol adherence ............................................................................................................76
13.1
Protocol Amendments ...........................................................................................77
14 References .........................................................................................................................78
15 Appendix 1: Liver Event Definitions and Follow-up Requirements.................................80
16 Appendix 2:  Specific Renal Alert Criteria and Actions...................................................82
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List of tables
Table 5-1
Prohibited medication ...........................................................................38
Table 6-1
Overview of study medication ..............................................................39
Table 6-2
Blinding and un-blinding plan ..............................................................40
Table 8-1
Assessment Schedule ............................................................................49
Table 9-1
Guidance for capturing study treatment errors......................................66
Table 15-1
Liver Event Definitions.........................................................................80
Table 15-2
Actions required for Liver Events.........................................................80
Table 15-3
Exclusion of underlying liver disease ...................................................81
Table 16-1
Follow-up of renal events......................................................................83
List of figures
Figure 3-1
Study Design .........................................................................................28


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List of abbreviations
6MWT
six-minute walk test
ABI
Ankle-brachial index
ADA
Anti-drug antibody(ies)
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BMI
body mass index
BP
blood pressure
BUN
blood urea nitrogen
CD-ROM
compact disc – read only memory
CFR
U.S. Code of Federal Regulation
CK
creatinine kinase
CMO&PS
Chief Medical Office & Patient Safety
CNS
central nervous system
CO2
carbon dioxide
CRF
case report form
CRO
Contract Research Organization
CV
coefficient of variation
ECG
Electrocardiogram
EDC
Electronic Data Capture
ELISA
Enzyme-linked immunosorbent assay
FDA
Food and Drug Administration
FIH
First in Human
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
GLP
Good Laboratory Practice
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
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HEK
human embryonic kidney (cells)
HIV
human immunodeficiency virus
IA
interim analysis
IB
Investigator’s brochure
IC
informed consent
ICF
Informed Consent Form
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IG
immunogenicity
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
intrauterine device
IUS
intrauterine system
i.v.
intravenous
LDH
lactate dehydrogenase
LLOQ
lower limit of quantification
LOCF
last observation carried forward
MedDRA
Medical dictionary for regulatory activities
MDRD
modification of diet in renal disease
mg
milligram(s)
mL
milliliter(s)
MRSD
maximum recommended starting dose
MWD
maximum walking distance
NADPH
nicotinamide adenine dinucleotide phosphate
NIRS
near-infrared spectroscopy
NOAEL
no observable adverse effect level
PAD
peripheral artery disease
PD
pharmacodynamics(s)
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PK
pharmacokinetic(s)
PRO
patient reported outcome
PT
prothrombin time
QoL
quality of life
RBC
red blood cell(s)
ROS
reactive oxygen species
s.c.
subcutaneous
SAE
serious adverse event
SOM
Site Operations Manual
TMDD
target mediated drug disposition
ULN
upper limit of normal
WBC
white blood cell(s)
WOCBP
Women of child-bearing potential
WOCF
worst observation carried forward
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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]
AUCinf
The area under the plasma (or serum or blood) concentration-time curve from 
time zero to infinity [mass x time / volume]
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]
AUCtau
The area under the plasma (or serum or blood) concentration-time curve from 
time zero to the end of the dosing interval tau [mass x time / volume]
CL
The systemic (or total body) clearance from plasma (or serum or blood) 
following intravenous administration [volume / time]
CL/F
The apparent systemic (or total body) clearance from plasma (or serum or blood) 
following extravascular administration [volume / time]
Cmax
The observed maximum plasma (or serum or blood) concentration following 
drug administration [mass / volume]
Cmin,ss
The lowest plasma (or serum or blood) concentration observed during a dosing 
interval at steady state [mass / volume]
MRT
Mean residence time determined as AUMCinf/AUCinf following intravenous 
administration [time]
T1/2
The terminal elimination half-life [time]
Tmax
The time to reach the maximum concentration after drug administration [time]
VL
Volume of distribution
Vss
The volume of distribution at steady state following intravenous administration 
[volume]
Vz/F
The apparent volume of distribution during the terminal elimination phase 
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Glossary of terms
Assessment
A procedure used to generate data required by the study
Cohort
A specific group of patients fulfilling certain criteria
Control drug
Any drug(s) (an active drug or an inactive drug, such as a placebo) 
which is used as a comparator to the investigational drug being tested in 
the trial
Dosage
Dose of the study treatment given to the patient in a time unit 
(e.g. 100 mg once a day, 75 mg twice a day)
Electronic Data 
Capture (EDC)
Electronic data capture (EDC) is the electronic acquisition of clinical 
study data using data collection systems, such as Web-based 
applications, interactive voice response systems and clinical laboratory 
interfaces. 
EDC includes the use of Electronic Case Report Forms (eCRFs) which 
are used to capture data transcribed from paper source forms used at the 
point of care.
Enrollment
Point/time of patient entry into the study at which informed consent 
must be obtained (i.e. prior to starting any of the procedures described in 
the protocol)
Epoch
Interval of time in the planned conduct of a study. An epoch is 
associated with a purpose (e.g. screening, randomization, treatment, 
follow-up) which applies across all arms of a study.
Investigational 
drug
The study drug whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and Directive 
2001/20/EC and is synonymous with “investigational new drug,” 
"Investigational Medicinal Product," or “test substance”
Patient
An individual with the condition of interest
Randomization 
number
A unique identifier assigned to each randomized patient, corresponding 
to a specific treatment arm assignment
Screen Failure
A patient who is screened but is not treated or randomized
Source 
Data/Document
Source data refers to the initial record, document, or primary location 
from where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper or eSource
Study treatment
Any drug or combination of drugs administered to the study participants 
as part of the required study procedures; includes investigational drug(s), 
control(s) or background therapy
Study treatment 
discontinuation
When the patient permanently stops taking study treatment prior to the 
defined study treatment completion date
Subject
A trial participant (can be a healthy volunteer or a patient)


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Subject number
A unique number assigned to each patient upon signing the informed 
consent. This number is the definitive, unique identifier for the patient
and should be used to identify the patient throughout the study for all 
data collected, sample labels, etc.
Variable
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being tested 
in the study
Withdrawal of 
consent
Withdrawal of consent from the study is defined as when a patient does 
not want to participate in the study any longer, and does not want any 
further visits or assessments, and does not want any further study related 
contact, and does not allow analysis of already obtained biologic 
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Protocol summary
Protocol number
CLLG783X2201
Full Title
A Patient and Investigator-blinded, randomized, placebo-controlled study of 
LLG783 in patients with peripheral artery disease (PAD) and intermittent 
claudication
Brief title
Study of pharmacodynamics, pharmacokinetics, safety and tolerability of 
LLG783 in patients with peripheral artery disease (PAD) and intermittent 
claudication
Sponsor and Clinical 
Trial Phase
Novartis 
Phase IIa
Intervention type
Biologic
Study type
Interventional 
Purpose and 
rationale
This study is designed to determine whether LLG783 displays the clinical 
safety and efficacy profile, after multiple i.v. doses, to support further 
development in patients with PAD and intermittent claudication.
Primary Objective(s)

To evaluate the safety and tolerability of LLG783 in patients with PAD
and intermittent claudication after 16 weeks of exposure to LLG783.

To evaluate the effect of LLG783 on functional capacity after 3 months
of treatment in patients with PAD and intermittent claudication.
Secondary 
Objectives

To investigate the PK of LLG783 in patients with PAD and intermittent
claudication.

To evaluate the effect of LLG783 on symptomatic functional capacity
after 3 months of treatment in patients with PAD and intermittent
claudication.
Study design
This is a non-confirmatory, randomized, patient and investigator-blinded, 
placebo-controlled, parallel-group study
Population
Approximately 40 male and female patients, ages 40-85 years of age 
(inclusive) with clinical evidence of PAD and intermittent claudication will be 
enrolled into this study.
Key Inclusion criteria

Clinical evidence of PAD and intermittent claudication. Intermittent
claudication, as defined by pain with exertion in either leg

On stable medical therapy for PAD and PAD symptoms, which may
include statins, aspirin, and anti-platelet medications (as medically
indicated) unless individually contraindicated, for at least 4 weeks prior
to the screening visit.

Vital signs must be within the following ranges:
o
body temperature between 35.0-37.5°C
o
systolic blood pressure, 90-159 mm Hg
o
diastolic blood pressure, 50-99 mm Hg
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o
pulse rate, 50 - 90 bpm

Moderately impaired ambulatory function judged by the investigator to
be due primarily to PAD and assessed by a maximum walk distance
between 50 and 400 meters (inclusive of these values) at the screening
6MWT.
Key Exclusion 
criteria

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.

Patients who meet any of the following PAD related criteria:
o
Patients actively attending and participating in a supervised
exercise rehabilitation program (patients who have already
completed such a program and remain symptomatic may be
included).
o
Patients with any condition other than PAD that limits walking
ability.
o
Known inflammatory disease of the arteries (other than
atherosclerosis; e.g. Thromboangiitis obliterans).
o
Clinical evidence of critical limb ischemia including new or non-
healing ulcers (felt secondary to critical limb ischemia), new or
recent onset of resting pain in the lower extremities particularly at
night (felt secondary to critical limb ischemia) and/or gangrene of
the lower extremities (Fontaine stage III-IV) .

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 150 days after stopping
of investigational drug.

Any of the following concomitant cardiovascular or metabolic conditions
or diseases:
o
Myocardial infarction within 6 months of screening.
o
Stroke within 6 months of screening.
o
History of clinically significant ventricular arrhythmias, according to
the discretion of the investigator, within 6 months of screening.
o
Significant ECG abnormalities, according to the discretion of the
investigator, at screening.
o
History of sustained and clinically significant supraventricular
arrhythmias (e. g. associated with hemodynamic compromise)
within 6 months of screening.
o
Chronic heart failure New York Heart Association Class III or IV.
o
Known presence of aortic aneurysm > 5 cm.
o
Uncontrolled diabetes as defined by a random fasting glucose level
of 13 mmol/L or 240 mg/dL or a HbA1c greater than 9% as
measured at screening. Diabetes should be treated as appropriate
during the study.
Study treatment

LLG783

Placebo
Pharmacokinetic 
assessments

AUCinf, AUClast, AUC0-t, AUC0tau, Cmax and Tmax
Efficacy/PD 
assessments

Maximum walking distance assessed by 6-minute walk test (6MWT)

Pain-free walking distance assessed by 6MWT


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Key safety 
assessments 
Data analysis 
Keywords 
•
Monitoring of AEs, including observations made during physical
examinations
•
Vital signs
•
Laboratory evaluations (blood and urine)
•
ECGs
Corporate Confidential Information 
•
All safety and tolerability data (including AEs, vital signs, laboratory
evaluations, and ECGs) will be listed by subject and summarized by 
treatment.
•
The change from baseline in maximum walking distance (MWD) will be
analyzed in a repeated measures mixed effects model with treatment,
day, and the treatment-by-day interaction as fixed effects and baseline
MWD as a covariate.
The least-square mean change from baseline in MWD for each day will
be estimated from the model for each treatment along with the
treatment difference and the associated p-value and two-sided 80%
confidence interval.
Peripheral artery disease, PAD, intermittent claudication, claudication, 
6-minute walk test, Corporate Confidential Information 
peripheral 
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1
Introduction
1.1
Background
Intermittent claudication is a common complication in peripheral artery disease (PAD) 
patients, affecting ~10 million people in the United States and over 150 million people 
worldwide (Fowkes et al 2017). As a result of lower extremity skeletal muscle ischemia,
patients suffer from muscle fatigue and pain on exertion, which limits mobility and reduces
quality
of
life
(QoL).
Current
drug
therapy has
limited
efficacy, and surgical 
revascularization 
is 
not
an
option
for
many
patients
(Go et al 2014; 
Hirsch and Duval 2013).
The most relevant data for the present study are summarized in the sections below. 
For detailed information, please refer to the Investigator's Brochure (IB).
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1.4
Study purpose
This study is designed to determine whether LLG783 displays the clinical safety and efficacy 
profile, after multiple i.v. doses, to support further development in patients with PAD and 
intermittent claudication.
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2
Objectives and endpoints
2.1
Primary objective(s)
Primary objective(s)
Endpoints related to primary objective(s)

To evaluate the safety and tolerability of
LLG783 in patients with PAD and
intermittent claudication after 16 weeks of
exposure to LLG783.

AEs (including observations made
during physical examinations as
appropriate)

Incidence

Severity

Vital signs including:

Pulse rate

Blood pressure (BP)

Respiratory rate

Body temperature

Laboratory evaluations

Hematology

Clinical chemistry

Urinalysis

Electrocardiogram (ECG) intervals

To evaluate the effect of LLG783 on
functional capacity after 3 months of
treatment in patients with PAD and
intermittent claudication.

Maximum walking distance assessed
by 6-minute walk test (6MWT)
2.2
Secondary objective(s)
Secondary objective(s)
Endpoints related to secondary 
objective(s)

To investigate the PK of LLG783 in patients
with PAD and intermittent claudication.

PK parameters will be determined,
including: AUCinf, AUClast, AUC0-t,
AUC0tau, Cmax and Tmax

To evaluate the effect of LLG783 on
symptomatic functional capacity after 3
months of treatment in patients with PAD
and intermittent claudication.

Pain-free walking distance assessed by
6MWT


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CCI
CCI
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Assessments of functional capacity (6MWT) will be made at weeks 8 and 16 (days 57 and
113) following the first dose of study medication, with follow-up functional assessments at
weeks 24 and 32 (days 169 and 225) following the first dose of study medication (i.e. 2 and
4 months following the last dose of medication, see Figure 3-1). These follow-up assessments
will be performed to help define durability of clinical response as LLG783 exposure declines.
The primary endpoint of improved walk distance will be adjudicated based on the 8 and
16 week data points, though the 24 and 32 week data may be used in final statistical modeling.
Safety assessments will include physical examinations, ECGs, vital signs, standard clinical 
laboratory evaluations (hematology, blood chemistry, and urinalysis), as well as AE and SAE
monitoring.
Patients who discontinue the study for reasons other than safety prior to the week 16 visit may 
be replaced in order to ensure ability to assess 40 patients with a functional assessment after 
16 weeks of exposure.
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Because patients will all receive standard-of-care for PAD, there will be no disadvantage to 
those receiving placebo over active drug. 
PAD patients will be monitored for any effects on standard 
hematologic, coagulation, renal, liver and other chemistries routinely measured to detect 
changes in homeostasis. However, there may be unknown risks of LLG783 in PAD patients 
which may be serious.
Though there is no reason to believe that patients with PAD will be at 
increased risk of adverse outcomes in the development of ADAs, patients will be carefully 
monitored for development of such ADA or ADA-related reactions during the study.
As LLG783 is a monoclonal antibody, no specific drug-drug interactions are anticipated.
Women of child bearing potential must be informed that taking the study treatment 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 requirements outlined 
in Section 4.2 (Exclusion Criteria). If there is any question that the patient will not reliably 
comply, they should not be entered or continue in the study.
For those patients participating in the lower extremity assessment of microvascular blood flow 
and skeletal muscle perfusion, there is minimal risk associated with the NIRS procedure. 
Specifically, discomfort from inflation from the blood pressure cuff during the NIRS 
assessment protocol may occur. Discomfort would be anticipated to be transient and resolve 
following deflation of the cuff.
3.7.1
Blood sample volumes
A maximum of 500 mL of blood is planned to be collected over a period of approximately 
35 weeks, from each patient as part of the study. Additional samples may be required for 
safety monitoring.
Timings of blood sample collection are outlined in the Assessment Schedule (Section 8.1).
A summary blood log is provided in the SOM. Instructions for sample collection, processing, 
storage and shipment information is available in the Central Laboratory Manual.
4
Population
Approximately 40 patients with PAD and intermittent claudication will be randomized into 
the study to be treated with 4 i.v. doses of study medication vs. placebo.
Replacement patients will be enrolled to replace those patients who discontinue the study for 
reasons other than safety before their 16-week 6MWT visit. This includes patients who, for 
clinical reasons, require an interventional procedure (e.g. angioplasty, stenting, or bypass 
surgery) after randomization, but before the 16 week (day 113) visit. 
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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 patients.
Patient selection is to be established by checking through all eligibility criteria at screening. 
This criteria should be re-reviewed at the time of their Day 1 visit prior to the administration 
of the first dose. A relevant record (e.g. checklist) of the eligibility criteria must be stored with 
the source documentation at the study site.
Deviation from any entry criterion excludes a patient from enrollment into the study.
4.1
Inclusion criteria
Patients eligible for inclusion in this study must fulfill all of the following criteria:
1. Written informed consent (IC) must be obtained before any study assessment is performed.
2. Male and female patients 40 to 85 years of age (inclusive) at screening with clinical
evidence of PAD and intermittent claudication (Fontaine stage II) (Hardman et al 2014).
Intermittent claudication, as defined by pain with exertion in either leg (this may include
atypical symptoms, e.g. fatigue, paresthesias, pallor, etc.) AND any one of the following:
a. resting ABI of 0.40-0.90 (inclusive) in at least one leg;
b. OR for patients with a resting ABI >0.90 but ≤ 1.0, a decrease in ABI of ≥20% with
exercise (to be measured immediately following completion of 6MWT at screening)
in at least one leg;
c. OR a decrease in ankle pressure ≥30 mmHg with exercise in at least one leg;
d. OR for patients with an ABI >0.90, an abnormal toe-brachial index (TBI) <0.70.
Note: documented values within 3 months of signing the informed consent are acceptable
provided that there has been no peripheral revascularization in the interim.
3. On stable medical therapy for PAD and PAD symptoms, which may include statins,
aspirin, and anti-platelet medications (as medically indicated) unless individually
contraindicated, for at least 4 weeks prior to the screening visit.
4. Vital signs must be within the following ranges:
a. body temperature between 35.0-37.5°C
b. systolic blood pressure, 90-159 mm Hg
c. diastolic blood pressure, 50-99 mm Hg
d. pulse rate, 50 - 90 bpm
Refer to the SOM for guidance on collecting vital signs and repeated vital sign 
assessments in case screening vital signs are out-of-range.
5. Moderately impaired ambulatory function judged by the investigator to be due primarily
to PAD and assessed by a maximum walk distance between 50 and 400 meters (inclusive
of these values) at the screening 6MWT.
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6. Able to communicate well with the investigator, to understand and comply with the
requirements of the study.
4.2
Exclusion criteria
Patients fulfilling any of the following criteria are not eligible for inclusion in this study:
1. Participation in any clinical investigation within four (4) weeks prior to enrollment or use
of other investigational drugs at the time of enrollment, or within 5 half-lives at the time of
enrollment, or until the expected PD effect has returned to baseline, whichever is longer;
or longer if required by local regulations. Patients previously enrolled in clinical trials of
stem cell therapy for PAD may be included if this therapy ended at least 6 months prior to
enrollment.
2. 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.
3. Patients who meet any of the following PAD related criteria:
a. Patients actively attending and participating in a supervised exercise rehabilitation
program (patients who have already completed such a program and remain
symptomatic may be included).
b. Patients with any condition other than PAD that limits walking ability.
c. Known inflammatory disease of the arteries (other than atherosclerosis; e.g.
Thromboangiitis obliterans).
d. Clinical evidence of critical limb ischemia including new or non-healing ulcers (felt
secondary to critical limb ischemia), new or recent onset of resting pain in the lower
extremities particularly at night (felt secondary to critical limb ischemia) and/or
gangrene of the lower extremities (Fontaine stage III-IV) .
4. 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 150 days after stopping of investigational drug.
Highly effective contraception methods include:

Total abstinence from heterosexual intercourse (when this is in line with the preferred
and usual lifestyle of the patient, and only in countries that accept “total abstinence”
as effective contraception). Periodic abstinence (e.g. calendar, ovulation,
symptothermal, post-ovulation methods) and withdrawal are NOT acceptable methods
of contraception.

Female sterilization (have had surgical bilateral oophorectomy with or without
hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking
investigational drug.  In case of oophorectomy alone, only when the reproductive
status of the woman has been confirmed by follow up hormone level assessment
(e.g. FSH).

Male sterilization (at least 6 months prior to screening). For female patients on the
study the vasectomized male partner should be the sole partner for that patient.


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
Use of oral (estrogen and progesterone), 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 be stable on the same pill for
≥3 months before taking investigational drug.
If local regulations deviate from the contraception methods listed above and require more 
extensive measures to prevent pregnancy, local regulations apply and will be described in 
the Informed Consent Form (ICF).
Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation
≥6 weeks prior to the screening visit. In the case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up hormone level 
assessment is she considered not of child bearing potential. 
5. Any of the following concomitant cardiovascular or metabolic conditions or diseases:
a. Myocardial infarction within 6 months of screening.
b. Stroke within 6 months of screening.
c. History of clinically significant ventricular arrhythmias, according to the discretion of
the investigator, within 6 months of screening.
d. Significant ECG abnormalities, according to the discretion of the investigator, at
screening.
e. History of sustained and clinically significant supraventricular arrhythmias
(e. g. associated with hemodynamic compromise) within 6 months of screening.
f.
Chronic heart failure New York Heart Association Class III or IV.
g. Known presence of aortic aneurysm > 5 cm.
h. Uncontrolled diabetes as defined by a random fasting glucose level of 13 mmol/L or
240 mg/dL or a HbA1c greater than 9% as measured at screening. Diabetes should be
treated as appropriate during the study.
6. Any of the following concomitant hepatic or renal conditions or diseases:
a. Patients with severe renal impairment defined as eGFR < 15 mL/min/1.73m2
[as calculated by the MDRD (Modification of Diet in Renal Disease) method] or
those receiving current or planned dialysis or ultrafiltration.
b. Known active or recurrent hepatic disorder (including cirrhosis, hepatitis B and
hepatitis C - including positive hepatitis B surface antigen or hepatitis C test), or
alanine aminotransferase/aspartate aminotransferase (ALT/AST) levels > 2.5 times
upper limits of normal (ULN) or total bilirubin > 2 times ULN at screening.
7. History of any of the following chronic conditions:
a. Malignancy of any organ system (other than localized basal or squamous cell
carcinoma of the skin), treated or untreated, within the past 3 years, regardless of
whether there is evidence of local recurrence or metastases.
b. Hemoglobin levels < 10.6 g/dL at screening.


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c. History of immunodeficiency diseases, including a positive HIV (ELISA and Western
blot) test result.
d. History of any hypercoagulable or bleeding disorders.
8. Major surgical procedure (such as coronary artery bypass grafting, carotid endarterectomy,
abdominal surgery) ≤6 months before screening (≤ 4 weeks before screening for coronary
stent placement or angioplasty) or planned coronary revascularization or any other major
surgical procedure planned to occur during the planned time frame of the study. Patients
who have undergone peripheral vascular interventions > 6 months prior to screening may
still be considered eligible, provided they meet all other inclusion/exclusion criteria.
Patients with actively planned/scheduled lower extremity peripheral vascular interventions
within the first 4 months after enrollment should not be enrolled. However, if clinically
indicated during the study, a patient may undergo peripheral vascular intervention.
9. Any surgical or medical condition that in the opinion of the Investigator may place the
patient at higher risk from his/her participation in the study.
10. History of significant and active drug or alcohol abuse that could interfere with conduct of
the trial within the 12 months prior to dosing. Note: Investigator may establish veracity of
patient history with drug or alcohol testing as deemed necessary.
11. History of multiple and clinically significant recurring drug allergies.
12. History of allergy to the investigational compound / compound class (e.g. allergic
reactions to other protein therapeutics) being used in this study.
13. History of any transplant with the exception of skin or cornea.
14. Patients unable to hold all narcotic pain relievers for 24 hours prior to performance of the
6MWT. (Instructions to this effect will be provided to enrolled patients).
15. Patients who are taking any other monoclonal antibody at screening are not necessarily
excluded from the study, but the site MUST contact the Novartis study safety monitor so
that the monoclonal antibody information can be reviewed before confirming whether or
not the patient can be enrolled.
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.
Refer to Section 8.3 (Patient Screening) for information regarding re-screening. 
5
Restrictions for Study Subjects
Patients should be informed and reminded of the restrictions outlined in this section at each 
visit for the duration of the study.
5.1
Contraception requirements
Women of child bearing potential must be informed that taking the study treatment 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 outlined 
in Section 4.2 (Exclusion Criteria). 
If there is any question that the patient will not reliably comply, they should not be entered or 
continue in the study.


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Women who become pregnant during the study should NOT be administered any further 
doses of study drug. Refer to Section 9.6 for Pregnancy Reporting requirements.
5.2
Prohibited treatment
Use of the treatments displayed in Table 5-1 is NOT allowed throughout the prohibited period 
noted in the table.
Table 5-1
Prohibited medication
Medication
Prohibited 
period
Action to be taken
Monoclonal antibody use must be 
reported to the Novartis study 
safety monitor to be reviewed 
before a patient can be enrolled or 
continued in this study.
Within 6 months 
of screening 
through to the end 
of the study
Novartis safety monitor may exclude patient 
from study or require discontinuation of 
study treatment in cases where highly 
similar classes/types of antibodies are 
prescribed (and replacement of patient in 
study)
Change in type or dosage of 
narcotic pain relievers; OR
Change in type or dosage of PAD 
specific symptom-relief drugs 
(specifically: cilostazol, 
pentoxifylline, or naftidrofuryl)
4 weeks prior to 
screening through 
week 16
Notify Novartis study team as it may be 
determined that it is necessary to 
discontinue study treatment and replace the
patient
5.3
Dietary restrictions and smoking
Not applicable.
Smoking and alcohol history will be collected and documented in the CRF at screening.
5.4
Other restrictions
Not applicable.
6
Treatment
6.1
Study treatment
Details on the requirements for storage and management of study treatment, and instructions 
to be followed for subject numbering, prescribing/dispensing and taking study treatment are 
outlined in the Pharmacy Manual.
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6.1.2
Additional study treatment
No additional treatment beyond investigational drug and control drug are included in this trial.
6.2
Treatment arms
Patients will be assigned to one of the following 2 treatment arms in a ratio of 1:1:

LLG783 (
)

Placebo (0 mg/vial)
6.3
Treatment assignment and randomization
At the randomization visit, all eligible patients will be randomized via Interactive Response
Technology (IRT) to one of the treatment arms. The investigator or delegate will contact the
IRT after confirming that the patient fulfills all the eligibility criteria. The IRT will assign a
randomization number to the patient, which will be used to link the patient to a treatment- arm.
The randomization number will not be communicated to the caller.
The randomization number is only used to identify which treatment the patients have been 
randomized to receive. The Subject number assigned to a patient at screening remains the 
unique identifier for the patient throughout the study. For information on subject numbering, 
please see ‘Subject numbering’ section in the SOM.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from subjects and investigator staff. A patient 
randomization list will be produced by the IRT provider, or by a delegate under their 
supervision, using a validated system that automates the random assignment of subject 
numbers to randomization numbers. These randomization numbers are linked to the different 
treatment arms.
The randomization scheme for patients will be reviewed and approved by a member of the 
Novartis Randomization Office.
Follow the details outlined in the SOM regarding the process and timing of treatment 
assignment and randomization of patients.
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6.4
Treatment blinding
Table 6-2
Blinding and un-blinding plan
Time or Event
Role
Randomization 
list generated
Treatment
allocation & 
dosing
Safety event 
(single subject 
unblinded)
IA & dose 
escalation
Subjects
B
B
UI
B
Site staff e.g. investigator and 
study nurse
B
B
UI
B
Unblinded 
site 
staff 
(*) 
e.g. 
pharmacy staff
B
UI
UI
UI
Drug Supply and 
Randomization 
Office
UI
UI
UI
UI
Unblinded sponsor staff (**) e.g. 
for 
drug 
re-supply, 
unblinded 
monitor, sample analytics
B
UI
UI
UI
Statistician/statistical 
programmer/biomarker expert
B
B
UI
UI
Independent 
committees 
(e.g. 
DMC) used for assessing interim 
results
NA
NA
NA
NA
All 
other 
sponsor 
staff 
not 
identified above (trial team, project 
team, management & decision 
boards, support functions)
B
B
UI
UI
IA Interim analyses
UI Allowed to be unblinded on individual patient level 
B
Remains blinded
At Database lock all roles can be unblinded
This is a patient and investigator-blinded study: patients and investigator will remain blinded 
to study treatment throughout the study (except in the case of a safety event necessitating 
unblinding). The identity of the treatments will be concealed by the use of study drugs that are 
all identical in packaging, labeling, schedule of administration, appearance, and odor.
With the exception of unblinded site staff identified below, all site staff (including study 
investigator and study nurse) will be blinded to study treatment during treatment allocation 
and at the point of subject dosing but may be unblinded to the treatment assignment of an 
individual subject in case of a safety event necessitating unblinding.
Unblinding a single subject for safety reasons (necessary for subject management) will occur 
via an emergency system in place at the site. 


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* Unblinded site staff: Drug product will be supplied in bulk, so an unblinded pharmacist, or
appropriately designated study site staff, who is independent of the study team will be
required in order to maintain the blind. This unblinded associate at the site will be notified by
the IRT system that a patient is randomized and to which treatment arm, which will then
enable them to prepare the study drug.
** Unblinded sponsor staff: The following unblinded sponsor roles are required for this 
study:
Unblinded monitor
Unblinded sample analyst(s) (for example, PK, biomarker, and IG blood)
The unblinded monitor is required to review drug accountability and allocation at site. 
The unblinded monitor is not provided with a randomization list directly but will be unblinded 
through review of source documentation compiled by the unblinded pharmacist, which details 
treatment allocation to individual subjects. 
The sample analysts will receive a copy of the randomization schedule (via request to the 
Randomization Office) to facilitate analysis of the samples. The sample analysts will provide 
the sample data to the team under blinded conditions. Both the pharmacist and bioanalyst will 
keep this information confidential until clinical database lock.
The study statistician will be able to access the randomization list for IAs and is allowed to 
share unblinded information with the rest of the clinical team as appropriate for internal 
decision purposes, as outlined in the blinding table above. For example, unblinded summaries 
and unblinded individual data can be shared with the team for planned and unplanned IAs. 
Study programmers and other personnel involved in study data analysis (e.g. biomarker 
expert) are allowed to access treatment assignment information for the purpose of conducting 
planned and unplanned IAs. 
The clinical trial team is allowed to share unblinded results with other sponsor staff 
(e.g. decision boards) as required for internal decision making on the study or the project 
while the study is ongoing. 
Following final database lock all roles may be considered un-blinded.
6.5
Treating the patient
LLG783 will be administered via i.v. 
Sponsor qualified medical personnel will be readily available to advise on trial related 
medical questions or problems.
Refer to the Pharmacy Manual for does preparation and administration instructions.
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6.6
Permitted dose adjustments and interruptions of study treatment
Planned study drug dose adjustments and/or interruptions are not permitted for this study. 
In the case of a suspected serious infusion reaction, the infusion must be stopped and the 
sponsor notified.
Short interruptions of the i.v. infusion may be tolerated, for example, to re-insert a cannula for 
i.v. drug administration.
Any changes must be recorded on the Dosage Administration Record case report form (CRF).
6.7
Emergency breaking of assigned treatment code
Emergency code breaks must occur only when it is required to treat the patient safely. Most 
often, study treatment discontinuation and knowledge of the possible treatment assignments 
are sufficient to treat a study patient who presents with an emergency condition. Emergency 
treatment code breaks are performed using IRT. When the investigator contacts the system to 
break a treatment code for a patient, he/she must provide the requested patient identifying 
information and confirm the necessity to break the treatment code for the patient. 
The investigator will then receive details of the investigational drug treatment for 
the specified 
patient
and 
a 
fax 
or 
email 
confirming 
this 
information. 
The system will automatically inform the Novartis study monitor for the site and the Study 
Team that the code has been broken.
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to IRT in case of an emergency.   The investigator will need to provide:

protocol number
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
study drug name (if available)

subject number
In addition, the investigator must provide oral and written information to inform the patient
how to contact the investigator's backup in case of emergency when he/she is unavailable to 
ensure that un-blinding can be performed at any time.
An assessment will be done by the appropriate site personnel and sponsor after an emergency 
un-blinding to assess whether or not study treatment should be discontinued for a given 
patient. 
6.8
Treatment exposure and compliance
Pharmacokinetic parameters (measures of treatment exposure) will be determined in all 
subjects treated with LLG783, as detailed in Section 8.7.
All study treatment will be administered at the clinical center, by qualified site staff, under the 
supervision of the investigator or qualified designee.
All study treatment dispensed must be recorded in the Drug Accountability Log.
6.9
Recommended treatment of AEs
The investigator and site staff must carefully observe the patients for any AE. In principle, 
any AE should be treated according to clinical practice.
Specific AEs, which can occur following i.v. or s.c. administration of monoclonal antibodies 
such as LLG783, are hypersensitivity reactions. The clinical symptoms of hypersensitivity 
reactions can be very variable. Typical manifestations are itching, flushing, headache, 
nausea/vomiting, hypotension, urticaria, bronchospasm, or angioedema. In the event of a 
hypersensitivity reaction, the infusion has to be stopped, if it is ongoing. Next, assessment and 
treatment should be done for anaphylaxis/ anaphylactoid reaction if indicated, and supportive 
care be initiated. Fluids, vasopressors, corticosteroids, antihistamines, bronchodilators, 
epinephrine and oxygen should be on hand. Specifically, in the case of an SAE suggestive of 
anaphylaxis or anaphylactoid reaction, acute cytokine release syndrome, or vasculitis-like 
reaction, the investigator should strongly consider prompt administration of epinephrine, 
corticosteroids, antihistamines, and/or plasmapheresis as therapeutic options. Treatment with 
plasmapheresis may be helpful in situations in which decreasing the systemic concentration of 
LLG783 may be of clinical benefit, based on the capacity of plasmapheresis to remove IgG 
antibody, such as the IgG monoclonal antibody LLG783, from the intra-and extra-vascular 
compartments.
If any other signs and symptoms of potential immune-related reactions are detected, 
appropriate intervention should be instituted, including full supportive care and consideration 
of discontinuation of further LLG783 treatment, which may mitigate more serious reactions.  
For further details see Risk / Benefit section of the IB.
Medication used to treat AEs must be recorded on the Concomitant medications/Significant 
non-drug therapies CRF.


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6.10
Rescue medication
There is currently no specific recommendation for rescue medication for this compound, but 
standard-of-care medications for AEs should be administered at PI discretion. See Section 6.9
for recommended treatment of AEs.
If clinically indicated during the study, a patient may undergo peripheral vascular intervention
for treatment of their underlying PAD (see details for exclusion criteria related to
interventions in Section 4.2).
Use of concomitant medication or therapy must be recorded on the Concomitant 
medications/Significant non-drug therapies CRF.
6.11
Concomitant treatment
In principle, it is allowed that all patients participating in the study can continue their regular 
medication, unless the concomitant medication is not allowed per exclusion criteria as 
described in the prohibited treatment section. Medication intake should occur at the same time 
throughout the study; morning medication should be taken early enough so that it does not 
interfere with the dosing on dosing days. Accordingly, the regular intake time should be 
adapted if needed.
All prescription medications, over-the-counter drugs and significant non-drug therapies 
(including physical therapy and blood transfusions) administered or taken within the 
timeframe defined in the entry criteria prior to the start of the study and during the study, must 
be recorded on the Concomitant medications/ Significant non-drug therapies CRF.
Medication entries should be specific to trade name, the single dose and unit, the frequency 
and route of administration, the start and discontinuation date and the reason for therapy.
The investigator must instruct the patient to notify the study site about any new medications 
he/she takes after being enrolled into the study.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact Novartis before randomizing a patient
or, if the patient is already enrolled, to determine if the patient should continue participation in 
the study.
7
Study completion and discontinuation
7.1
Study completion and post-study treatment
Each patient will be required to complete the study in its entirety and thereafter no further 
study treatment will be made available to them.


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Study completion is defined as when the last patient completes their Study Completion visit, 
and any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the investigator, or in the event of an early study termination decision, the 
date of that decision.
All patients who receive at least one dose of study medication should have a safety follow-up
phone call conducted approximately 140 days after last administration of study treatment IF 
they fail to return to the site for scheduled site visits prior to 140 days following the 
administration their last dose. The information collected from the follow-up phone call will be
kept as source documentation.  
All SAEs reported during this time period must be reported as described in Section 9.2 and 
the SOM.  Documentation of attempts to contact the patient should be recorded in the source 
documentation.
7.2
Discontinuation of study treatment
Patients may voluntarily discontinue study treatment for any reason at any time.
The investigator should discontinue study treatment for a given patient if, on balance, they 
believe that continuation would be detrimental to the patient’s well-being. 
Study treatment MUST BE discontinued for a given patient under the following 
circumstances:

Patient withdraws consent

Pregnancy

Severe hypersensitivity reaction occurs, including any of the following: anaphylaxis, fever,
chills, urticaria, dyspnea, headache, myalgia, hypotension. Immediate interruption of the
infusion to administer study treatment is required in such cases if the reaction occurs
during infusion.

Circumstances where the Sponsor or investigator determine that continuation of treatment
puts the patient’s safety at significant risk.
There may also be situations where the patient’s safety is not considered to be at risk, but 
where study treatment may be temporarily suspended at the discretion of the investigator, 
such as:

A protocol deviation (missed assessment, use of prohibited medication)

Lab value for individual patient is outside the normal range
Under these circumstances, the Investigator may choose to hold study drug pending further 
investigation and collection of additional data, or discussion with the Sponsor. If after such 
deliberation, the Investigator deems the study drug safe to be restarted at a time point which is  
outside the treatment window for that dose, the patient should skip the interrupted dose and 
restart dosing at the next dose (unless this is the final dose, in which case, no further doses 
should be given). This missed dose should be reported in the CRF by the investigator. 
No replacement dose should be given (i.e. there should be no dosing beyond the scheduled
month dosing window) to avoid exposure longer than that study in the 13-week GLP 
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All visits, including dosing visits, should be scheduled as per the study assessment table (see 
the SOM for visit windows).
In case of an unavoidable delay in dosing visits, the site may still dose a patient if the visit is 
≤7 days later than the scheduled timepoint. Dosing visits which exceed a 7-day delay should 
be considered as missed doses. All other scheduled assessments should still take place as per 
the protocol assessment table for that visit, despite the duration of the delay.
The subsequent visit should, as much as possible, continue to be scheduled as per the original 
planned visit schedule (i.e. the subsequent visit should NOT be delayed by the same number 
of days as the delayed dosing visit). 
The exception to this request is for the fourth dose. If the fourth (final) dose is delayed, then 
the week 16 visit should also be delayed by approximately the same number of days to ensure 
approximately one month between final dose and the week 16 assessments.
Patients who miss more than 1 dose should be discontinued from the study, but should 
continue to return for safety assessments.
The appropriate personnel from the site and Novartis will assess whether study treatment 
should be discontinued for any patient whose treatment code has been broken inadvertently 
for any reason.
If discontinuation of study treatment occurs, the investigator must determine the primary 
reason for the patient’s premature discontinuation of study treatment and record this 
information on the Dosage Administration CRF.
Patients who discontinue study treatment should NOT be considered withdrawn from the 
study UNLESS they withdraw their consent (see Section 7.3, Withdraw of Informed Consent). 
Where possible, they should return for the assessments indicated by an asterisk (*) in the 
Assessment Schedule. 
If they fail to return for these assessments for unknown reasons, every effort (e.g. telephone, 
e-mail, letter) should be made to contact the patient/pre-designated contact as specified in
Section 7.4 (Lost to follow-up). This contact should preferably be done according to the study
visit schedule.
The investigator must also contact the IRT to register the patient’s discontinuation from study 
treatment.
7.3
Withdrawal of informed consent
Patients may voluntarily withdraw consent to participate in the study for any reason at any 
time.
Withdrawal of consent from the study is defined as when a patient:

Does not want to participate in the study anymore and

Does not want any further visits or assessments and

Does not want any further study related contacts and

Does not allow analysis of already obtained biologic material.


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In this situation, the investigator must make every effort (e.g. telephone, e-mail, letter) to 
determine the primary reason for the patient’s decision to withdraw his/her consent and record 
this information.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the patient are not allowed unless safety findings require 
communicating or follow-up.
7.4
Lost to follow-up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator should show "due diligence" by 
documenting in the source documents steps taken to contact the patient, e.g. dates of 
telephone calls, registered letters, etc. A patient cannot be formally considered lost to follow-
up until his/her scheduled end of study visit would have occurred.
7.5
Study Stopping rules
The study will be paused and safety data will be reviewed if any of the following criteria are 
met, and no further dosing or enrollment will take place pending a full safety review 
conducted by the sponsor:

One or more patients experience an SAE potentially considered study drug-related.

If two or more patients experience an AE that is similar, of severe grade (including
hypersensitivity reactions or injection site reactions) and potentially considered to be
study-drug related.

The sponsor considers that the aggregate number, severity and/or relatedness of AEs
justify postponing or discontinuing the study. This assessment will be made based on
periodic review of AEs by the investigator and the sponsor.

The sponsor requests it.
The study may resume following the safety review if it is deemed safe to proceed.
The study may be stopped early by the Sponsor based on results of IAs. For a detailed 
example, refer to statistical Section 11.8.
7.6
Early study termination by the sponsor
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit/ risk assessment of participating in the study, practical reasons (including 
slow enrollment), or for regulatory or medical reasons. Should this be necessary, patients must 
be seen as soon as possible and treated as prematurely discontinued patients. The investigator 
may be informed of additional procedures to be followed in order to ensure that adequate 
consideration is given to the protection of the patient’s interests. The investigator will be 
responsible for informing IRBs/IECs of the early termination of the trial.


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8
Procedures and assessments
8.1
Assessment Schedule
Patients should be seen for all visits/assessments as outlined in the Assessment Schedule or as 
close to the designated day/time as possible.
Missed or rescheduled visits should not lead to automatic discontinuation. Patients who 
prematurely discontinue the study for any reason should be scheduled for a visit as soon as 
possible, at which time all of the assessments listed for the final visit will be performed. 
At this final visit, all dispensed investigational product should be reconciled, and the AE and
concomitant medications recorded on the CRF.
Unscheduled visits are permitted throughout the study upon request from the investigator or 
the study participant. 


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Table 8-1
Assessment Schedule
Epoch Screening1
Treatment
Visit Number 
(internal use)
1
101
102 103
104
104.100
105
105.100
106
107
108
109
110
199
Visit Name Screening
Treatment
Follow-Up
EOS
Days
-21 to -21
1
4
15
29
43
57
71
85
95
113
156
169
225 10, 11
Time (post-dose)
-
-1h2 0h 1h3 2h 4h
-
-
0h2 1h3 4h
-
0h2 1h3
4h
-
0h2 1h3 2h
4h
-
-
-
-
-
Informed consent
X
X
Inclusion / 
Exclusion criteria
S
S
Demography
X
Smoking and 
Alcohol history
X
Relevant medical 
history/current 
medical 
conditions
As appropriate throughout study
Concomitant 
medications
As appropriate throughout study
Body height
X
X*
Body weight
X
X
X
X
X
X
X
X
X
X
X*
Vital Signs:
Temperature, 
Blood Pressure, 
Pulse Rate and 
Respiratory Rate
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X*
Physical 
examination
S
S
S
S
S
S
S
S
S
S
S*
ECG evaluation
X
X
X
X
X
X
X
X
X
X 
X*
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Epoch Screening1
Treatment
Visit Number 
(internal use)
1
101
102 103
104
104.100
105
105.100
106
107
108
109
110
199
Visit Name Screening
Treatment
Follow-Up
EOS
Days
-21 to -21
1
4
15
29
43
57
71
85
95
113
156
169
225 10, 11
Time (post-dose)
-
-1h2 0h 1h3 2h 4h
-
-
0h2 1h3 4h
-
0h2 1h3
4h
-
0h2 1h3 2h
4h
-
-
-
-
-
Randomization
X4
Study drug 
administration
X
X
X
X
Pregnancy test
X5
X6
X6
X6
X6
X*
Hepatitis and HIV 
screen
S
Standard Safety 
Labs 
(hematology, 
chemistry, 
urinalysis)
X
X
X
X
X
X
X
X
X
X
X*
Fasting Serum 
Lipid Panel
X
X
X*
X
X
X
X
X
X
X
X
X*
PK blood 
collection
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
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
X
X
X
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Epoch Screening1
Treatment
Visit Number 
(internal use)
1
101
102 103
104
104.100
105
105.100
106
107
108
109
110
199
Visit Name Screening
Treatment
Follow-Up
EOS
Days
-21 to -21
1
4
15
29
43
57
71
85
95
113
156
169
225 10, 11
Time (post-dose)
-
-1h2 0h 1h3 2h 4h
-
-
0h2 1h3 4h
-
0h2 1h3
4h
-
0h2 1h3 2h
4h
-
-
-
-
-
Markers
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
6-Minute Walk
Test
X
X
X
X 
X
i
X
X
X
X
X
X
X
Once assigned, the device should be worn throughout the study; see SOM for details
X
X
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Epoch Screening1
Treatment
Visit Number 
(internal use)
1
101
102 103
104
104.100
105
105.100
106
107
108
109
110
199
Visit Name Screening
Treatment
Follow-Up
EOS
Days
-21 to -21
1
4
15
29
43
57
71
85
95
113
156
169
225 10, 11
Time (post-dose)
-
-1h2 0h 1h3 2h 4h
-
-
0h2 1h3 4h
-
0h2 1h3
4h
-
0h2 1h3 2h
4h
-
-
-
-
-
AEs/SAEs
As Required
Comments
As Required
Epoch completion 
information
X
Key:
X = assessment to be recorded on clinical database
S = There is no CRF page created with the same name as these assessments, however results of these collections will be included in source documents and all pertinent 
information will also be included in the clinical database for all screened patients, either by means of CRF entries (i.e. AEs noted during physical examinations) or through 
data transfers (i.e. HIV/Hepatitis results) from the central lab.  
* = assessment should be collected even if patient is prematurely discontinued from the study.
1 Screening activities may occur over more than 1 visit; Results of screening assessments MUST be available prior to treating a patient.
2 Assessments, including blood work, to be performed PRIOR TO DOSING.
3 The “1 hour” time point refers to the estimated completion of the infusion of study drug (i.e. at the end of the infusion). The “1 hour” blood collection at visits 101 and 106
should be collected within 5 minutes post COMPLETION of the infusion. The “1 hour” vital signs assessment at all 4 dosing visits should be within 20 minutes of the 
COMPLETION of the infusion (see SOM for more details).
4 Randomization scheduled on Day 1, prior to dosing, but may take place 24 hours in advance to accommodate preparation of study drug.
5 FSH will be analyzed by the central lab for female study participants who have had oophorectomy in absence of a hysterectomy.
6 All female study participants will have serum pregnancy testing as part of the central lab tests at all visits where pregnancy is assessed. IN ADDITION, a local urine 
sample will be collected on dosing days - prior to dosing -and analyzed at the site. Urine results collected on dosing days MUST BE available and confirmed as negative 
prior to dose administration. 
9 Measurements will only be conducted at a subset of trained investigational sites. These assessments may be performed during the screening period if the patient has 
already passed the inclusion and exclusion criteria, including ABI and 6MWT. See SOM for time windows and details for these assessments.
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10 The site will contact patients who do not return for their end of study visit, but have not withdrawn consent, approximately 140 days after their last dose of study 
medication, to capture any AEs or SAEs which occurred since their last visit. This contact should be documented in the source documents, and any AEs noted should be 
captured in the AE CRF.
11 The end-of-study visit may be prolonged for any patient who has positive ADA values at the day 225 visit. See Section 8.8.1 for details.


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8.2
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent.
If applicable, in cases where the patient’s representative gives consent (if allowed according 
to local requirements), the patient must be informed about the study to the extent possible,
given his/her understanding. If the patient is capable of doing so, he/she must indicate assent 
by personally signing and dating the written informed consent document or a separate assent 
form.
Informed consent must be obtained before conducting any study-specific procedures (e.g. all 
of the procedures described in the protocol). The process of obtaining informed consent must 
be documented in the patient source documents.
Novartis will provide to investigators a proposed informed consent form that complies with 
the ICHE6 GCP guideline and regulatory requirements and is considered appropriate for this 
study. The informed consent form will also include a section related to optional future 
research which will require a separate signature if the patient agrees to future research.  
The procedures set out in the main consent form concerning the storage, maintenance of 
privacy, and release of the data or specimens for the main study will also be adhered to for 
any future research. Any changes to the proposed consent form suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC.
Information about common side effects already known about the investigational drug can be 
found in the IB. This information will be included in the patient informed consent and should 
be discussed with the patient during the study as needed. Any new information regarding the 
safety profile of the investigational drug that is identified between IB updates will be 
communicated as appropriate, for example, via an Investigator Notification or an Aggregate 
Safety Finding. New information might require an update to the informed consent and then 
must be discussed with the patient.
Ensure patients are informed of the contraception requirements outlined in the Section 4.2
(Exclusion criteria) and in Section 5.1 (Contraception requirements).
A copy of the approved version of all consent forms must be provided to the Novartis monitor 
after IRB/IEC approval.
Refer to the SOM for a complete list of ICFs included in this study.
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8.3
Patient screening
It is permissible to re-screen a patient if s/he fails the initial screening or falls outside of the 
screening window; however, each case must be discussed and agreed with the Sponsor on a 
case-by-case basis.
Information on what data should be collected for screening failures is outlined in the SOM.
8.4
Patient demographics/other baseline characteristics
Patient demographic and baseline characteristic data will be collected on all patients.  
Relevant medical history/current medical conditions data will also be collected until signature 
of informed consent.  Details are outlined in the SOM.
Investigators have the discretion to record abnormal test findings on the medical history CRF, 
if in their judgment, the test abnormality occurred prior to the informed consent signature.
8.5
Efficacy / Pharmacodynamics
Pharmacodynamic measurements will be assessed at the timepoints defined in the 
Assessment Schedule.
8.5.1
6-minute walk test
Maximum walking distance as assessed by the 6MWT will be used to evaluate functional 
capacity of PAD patients participating in this study.
In addition to the PD assessment of maximum walking distance, data generated from the 
6MWT will also be used to evaluate pain-free walking distance.
Details of the 6MWT will be provided in the SOM, and sites will be provided additional 
training videos and manuals specific to the conduct and data collection of the 6MWT.
8.6
Safety
Safety assessments are specified below; methods for assessment and recording are specified in 
the SOM, with the Assessment Schedule (Section 8.1) detailing when each assessment is to be 
performed.
8.6.1
Physical examination
See the SOM for details.
8.6.2
Vital signs

Body temperature

Blood pressure

Pulse rate

Respiratory rate
See the SOM for details.


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8.6.3
Height and weight

Height

Body weight

BMI will be calculated as (Body weight (kg) / [Height (m)]2)
See the SOM for details.
8.6.4
Laboratory evaluations
Clinically relevant deviations of laboratory test results occurring during or at completion of 
the study must be reported and discussed with Novartis personnel. The results should be 
evaluated for criteria defining an AE 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 be contacted.
Patients should be instructed to fast for at least 8 hours prior to scheduled serum lipid panel 
collections. Fasting is not required prior to other scheduled lab collections.
Details regarding collection methods and processing are outlined in the Central Laboratory 
Manual.
Hematology
Hemoglobin, hematocrit, PTT, PT/INR, red blood cell (RBC) count, white blood cell (WBC) 
count with differentials and platelet count will be measured.
Urinalysis
Dipstick measurements for specific gravity, protein, glucose and blood will be performed. 
Microscopy, WBC, RBC and sediments will also be assessed in case of an abnormal dipstick 
test.
Coagulation panel
D-dimer, fibrinogen, PTT, PT/INR will be measured as part of the safety labs conducted at the
central lab.
. 
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8.6.5
Electrocardiogram
Full details of all procedures relating to the ECG collection and reporting are contained in the 
SOM.
PR interval, QRS duration, and QT intervals will be assessed.
The Fridericia QT correction formula (QTcF) should be used for clinical decisions.
Clinically significant abnormalities must be reported in the AE CRF.
8.7
Pharmacokinetics
8.7.1
Pharmacokinetics
PK samples will be collected at the timepoints defined in the Assessment Schedule
(Section 8.1). Follow instructions outlined in the SOM and Central Laboratory Manual
regarding sample collection, numbering, processing and shipment. See Section 8.9 regarding 
the potential use of residual samples.
In order to better define the PK profile, the timing of the PK sample collection may be altered 
based on emergent data. The number of samples/blood draws and total blood volume 
collected will not exceed those stated in the protocol. The changes will be communicated to 
participating sites in a protocol or SOM amendment.
PK samples will be obtained and evaluated in all patients at all dose levels except the placebo 
group.
Concentrations will be expressed in mass per volume units.
Concentrations below the LLOQ will be reported as “zero” and missing data will be labeled 
as such in the Bioanalytical Data Report.
For standard PK abbreviations and definitions see the list provided at the beginning of this 
protocol.
The following PK parameters will be determined using the actual recorded sampling times 
and non-compartmental method(s) with Phoenix WinNonlin (Version 6.4 or higher): 
Cmax, Tmax, AUClast, AUCtau, T1/2, Vz/F and CL/F from the serum concentration-time 
data. Some of these PK parameters are exploratory in this study.
The linear trapezoidal rule will be used for AUC calculation. Regression analysis of the 
terminal serum elimination phase for the determination of T1/2 will include at least 3 data 
points after Cmax. If the adjusted R2 value of the regression analysis of the terminal phase 
will be less than 0.75, no values will be reported for T1/2, AUCinf and CL/F.
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9
Safety monitoring
9.1
Adverse events
An AE is any untoward medical occurrence (i.e., any unfavorable and unintended sign,
including abnormal laboratory findings, symptom or disease) in a patient after providing 
written informed consent for participation in the study until the end of study visit. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
In addition, all reports of intentional misuse and abuse of the study treatment are also 
considered an AE irrespective if a clinical event has occurred. See Section 9.5 for an overview 
of the reporting requirements.
The occurrence of AEs must be sought by non-directive questioning of the patient at each 
visit during the study. Adverse events also may be detected when they are volunteered by the 
patient during or between visits or through physical examination finding, laboratory test 
finding, or other assessments.
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Abnormal laboratory values or test results constitute AEs 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 should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from
screening or the previous visit, or values which are considered to be non-typical in patients 
with underlying disease. Investigators have the responsibility for managing the safety of 
individual patient and identifying adverse events. Alert ranges for liver and kidney related 
events are included in Appendix 1 and Appendix 2, respectively.
Adverse events should be recorded on the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, and accompanied by the following information:
1. The severity grade

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities
2. its relationship to the study treatment

Yes or

No
3. its duration (start and end dates) or if the event is ongoing an outcome of not
recovered/not resolved must be reported.
4. whether it constitutes a SAE (see Section 9.2 for definition of SAE) and which seriousness
criteria have been met
5. Action taken regarding investigational treatment.
All AEs must be treated appropriately. Treatment may include one or more of the
following:

no action taken (e.g. further observation only)

investigational treatment interrupted/withdrawn

concomitant medication or non-drug therapy given

hospitalization/prolonged hospitalization (see Section 9.2 for definition of SAE)
6. its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving,
recovered/resolved with sequelae; fatal; or unknown).
Information about common side effects already known about the investigational drug can be 
found in the IB or will be communicated between IB updates in the form of Investigator 
Notifications.  Once an AE is detected, it must be followed until its resolution or until it is 
judged to be permanent, and assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the investigational drug, 
the interventions required to treat it, and the outcome.


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The investigator must also instruct each patient to report any new adverse event (beyond the 
protocol observation period) that the patient, or the patient’s personal physician, believes 
might reasonably be related to study treatment. This information must be recorded in the 
investigator’s source documents; however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis.
*Refer to the SOM for data capture methodology regarding AE collection for patients that fail
screening.
9.2
Serious adverse event reporting
9.2.1
Definition of SAE
An SAE is defined as any AE [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 in offspring

requires inpatient hospitalization or prolongation of existing hospitalization, UNLESS the
hospitalization is for:

routine treatment or monitoring of the studied indication, not associated with any
deterioration in condition (e.g. critical limb ischemia)

elective or pre-planned treatment for a pre-existing condition (that is unrelated to the
indication under study  and has not worsened since the start of study drug;

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, e.g. defined as an event that jeopardizes the patient or may require
medical or surgical intervention.
NOTE that all malignant neoplasms will be assessed as serious under “medically significant” 
if other seriousness criteria are not met.
Life-threatening in the context of a SAE refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to ICH-E2D Guideline 2004).
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 
development of dependency or abuse (please refer to ICH-E2D Guideline 2004).
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
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All AEs (serious and non-serious) are captured on the CRF; SAEs also require individual 
reporting to Novartis Chief Medical Office and Patient Safety (CMO & PS) as per 
Section 9.2.2.
9.2.2
SAE reporting
Screen Failures 
Details collected about Screen Failures is outlined in the SOM.
SAEs occurring after the patient has provided informed consent until the time the patient is 
deemed a Screen Failure must be reported to Novartis.
Randomized / Treated Patients
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 140 days after the last administration of study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence as described below.
Any SAEs experienced after this period should only be reported to Novartis if the investigator 
suspects a causal relationship to study treatment.
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at 
a different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.
Follow- up information provided must describe whether the event has resolved or continues, if 
and how it was treated, whether the blind was broken or not (if applicable) and whether the 
patient continued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event must be reported as a follow-up to that event regardless of 
when it occurs.
If the SAE is not previously documented in the IB and is thought to be related to the study 
treatment, a CMO&PS Department associate may urgently require further information from 
the investigator for Health Authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same study 
treatment that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions 
(SUSARs) will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with EU Guidance 2011/C 172/01 or as per national regulatory 
requirements in participating countries.
Follow the detailed instructions outlined in the SOM regarding the submission process for 
reporting SAEs to Novartis.   Note:  SAEs must be reported to Novartis within 24 hours of the 
investigator learning of its occurrence/receiving follow-up information.


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9.3
Liver safety monitoring
To ensure patient safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed.
Please refer to Table 15-1-Appendix 1 for complete definitions of liver events.
Follow-up of liver events
Every liver event defined in Table 15-1-Appendix 1should be followed up by the investigator 
or designated personnel at the trial site, as summarized below. Additional details on actions 
required in case of liver events are outlined in Table 15-1-Appendix 1.

Repeating liver chemistry tests (ALT, AST, TBL, PT/INR, ALP and G-GT) to confirm
elevation within 48-72 hours.
These liver chemistry repeats should always be performed using the central laboratory, with 
the results provided via the standard electronic transfer.  If results will not be available from 
the central laboratory within 24 hours, then the repeats can also be performed at a local 
laboratory to monitor the safety of the patient. If a liver event is subsequently reported, any 
local liver chemistry tests previously conducted that are associated with this event should 
have results reported on the unscheduled local laboratory CRF.

If the initial elevation is confirmed, close observation of the patient will be initiated,
including consideration of treatment interruption if deemed appropriate.

Discontinuation of the investigational drug [refer to Section 7.2 (Discontinuation of study
treatment), if appropriate

Hospitalization of the patient if appropriate

Causality assessment of the liver event

Thorough follow-up of the liver event should include

Repeating liver chemistry tests two or three times weekly. Testing should include ALT,
AST, ALP, PT/INR, and GGT. If total bilirubin is elevated > 2 x ULN, fractionation into
direct and indirect bilirubin is required. To rule out muscular origin of transaminase
elevations, CPK should be measured along with liver chemistry tests. Frequency of
retesting can decrease to once a week or less if abnormalities stabilize or the study drug
has been discontinued and the patient is asymptomatic. Retesting should be continued up
to resolution.

Obtaining a more detailed history of symptoms and prior or concurrent diseases.

Obtaining a history of concomitant drug use (including nonprescription medications and
herbal and dietary supplement preparations), alcohol use, recreational drug use, and
special diets.

Exclusion of underlying liver disease, as specified in Table 15-3.

Imaging such as abdominal US, CT or MRI, as appropriate

Obtaining a history of exposure to environmental chemical agents.

Considering gastroenterology or hepatology consultations.
All follow-up information, and the procedures performed must be recorded as appropriate in 
the CRF. Refer to the Site Operations Manual for additional details. 


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9.4
Renal safety monitoring
Every renal laboratory trigger or renal event must be followed up by the investigator or 
designated personnel at the trial site. Recommended follow-up assessments are listed in 
Appendix 2.
All follow-up information, and the procedures performed must be recorded as appropriate in 
the CRF. Refer to the Site Operations Manual for additional details.
9.5
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient/subject 
or consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately 
used not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects.
All study treatment errors and uses outside of what is foreseen in the protocol will be 
collected in the dose administration record CRF. Study treatment errors are only to be 
reported to CMO&PS department if the treatment error is associated with an SAE.
All instances of misuse or abuse must be documented in the AE CRF irrespective of the 
misuse/abuse being associated with an AE/SAE. In addition, all instances of misuse or abuse 
must be reported to Novartis CMO&PS. As such, instances of misuse or abuse are also to be 
reported using the SAE form/CRF. Table 9-1 summarizes the reporting requirements.
Table 9-1
Guidance for capturing study treatment errors
Treatment error type
Document in Dose
Administration (DAR) CRF 
Document in AE 
CRF
Complete SAE 
form/CRF 
Unintentional study 
treatment error
Yes
Only if associated 
with an AE
Only if associated with 
an SAE
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a SAE
For more information on AE and SAE definition and reporting requirements, please see 
Section 9.1 and Section 9.2, respectively.


CCI


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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 data capture requirements (i.e. electronic CRFs) 
with the investigators and their staff. During the study Novartis employs several methods of 
ensuring protocol and GCP compliance and the quality/integrity of the sites’ data. 
The monitor will visit the site to check the completeness of patient records, the accuracy of 
data capture / data entry, the adherence to the protocol and to Good Clinical Practice, the 
progress of enrollment, and 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 or a CRO 
working on behalf of Novartis. Additionally, a central analytics organization may analyze data 
and identify risks & trends for site operational parameters, and provide reports to Novartis 
Clinical Teams to assist with trial oversight.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
patient's file. The investigator must also keep the original informed consent form signed by 
the patient (a signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the data capture and/or data entry. Novartis monitoring standards 
require full verification for the presence of informed consent, adherence to the 
inclusion/exclusion criteria, 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 patients will be disclosed.
10.2
Data collection
Designated investigator staff will enter the data required by the protocol into the electronic 
CRFs 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. The Investigator must certify that the data 
entered into the electronic CRFs are complete and accurate. After database lock, the 
investigator will receive copies of the patient data for archiving at the investigational site.
Data not requiring a separate written record will be defined in the SOM
and 
Assessment schedule (Section 8.1) and can be recorded directly on the CRFs. All other data 
captured for this study will have an external originating source (either written or electronic) 
with the CRF not being considered as source.


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All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
10.3
Database management and quality control
Novartis staff or CRO working on behalf of Novartis review the data entered into the CRFs by 
investigational staff for completeness and accuracy and instruct the site personnel to make any 
required corrections or additions. Queries are sent to the investigational site using an 
electronic data query. Designated investigator site staff is required to respond to the query and 
confirm or correct the data. If the electronic query system is not used, a paper Data Query 
Form will be faxed to the site. Site personnel will complete and sign the faxed copy and fax it 
back to Novartis staff or CRO working on behalf of Novartis, who will make the correction to 
the database. The signed copy of the Data Query Form is kept at the investigator site.
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
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.
Randomization codes and data about all study drug(s) dispensed to the patient and all dosage 
changes will be tracked using an IRT. The system will be supplied by a vendor, who will also 
manage the database. The database will be sent electronically to Novartis (or a designated 
CRO).
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. 
The code break functionality will remain available until study shut down or upon request of 
Novartis.
The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked and the treatment codes will be unblinded and made available for data analysis. 
Any changes to the database after that time can only be made after written agreement by 
Novartis management.
10.4
Data Monitoring Committee
Not required.
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10.5
Adjudication Committee
Not required.
11
Data analysis
The analysis will be conducted on all patient data at the time the trial ends. Any data analysis 
carried out independently by the investigator should be submitted to Novartis before 
publication or presentation.
11.1
Analysis sets
For all analysis sets, patients will be analyzed according to the study treatment(s) received.
The safety analysis set will include all patients that received any study drug.
The PK analysis set will include all patients with at least one available valid (i.e. not flagged 
for exclusion) PK concentration measurement, who received any study drug and with no 
protocol deviations that impact on PK data.
The PD analysis set will include all patients with available PD data and no protocol deviations 
with relevant impact on PD data.
11.2
Patient demographics 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.
11.3
Treatments
Data for study drug administration and concomitant therapies will be listed by treatment 
group and patient.
11.4
Analysis of the primary variable(s)
11.4.1
Primary Variable(s)
The primary efficacy endpoint is maximum walking distance (MWD) from the 6-minute walk 
test. 
11.4.2
Statistical model, hypothesis, and method of analysis
The change from baseline in MWD will be analyzed in a repeated measures mixed effects 
model with treatment, day (as a categorical variable), and the treatment-by-day interaction as 
fixed effects and baseline MWD as a covariate. The day-by-baseline MWD interaction may
be included in the model as an additional covariate. An unstructured covariance structure will 
be used. Baseline will be taken from the screening 6-minute walk test.


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The least-square mean change from baseline in MWD for each day will be estimated from the
model for each treatment along with the treatment difference and the associated p-value and 
two-sided 80% confidence interval (CI). 
From the Week 16 quantities, the following criteria will be assessed:
1. The lower confidence limit of the 80% CI for the treatment difference (LLG783 –
placebo) is greater than 0.
2. The estimated treatment difference is greater than or equal to 50 meters.
The first criterion will address whether, with high certainty, LLG783 is superior to placebo in 
improvement in MWD. The second criterion will address whether the observed mean 
improvement in MWD over placebo is at least 50 meters, a threshold that is considered to 
represent highly competitive efficacy in this patient population. 
11.4.3
Handling of missing values/censoring/discontinuations
The primary analysis will be based on all patients with a baseline MWD and at least one post-
baseline MWD. Patients who undergo any lower extremity vascular interventions (angioplasty, 
stenting, or bypass surgery) before the Week 16 efficacy assessment or patients who drop out 
for other reasons before this assessment may be replaced to ensure 40 patients complete this 
primary endpoint assessment. Data from such patients will be included in the model for the 
primary analysis until the time of dropout or intervention; no imputation of the missing data 
will be performed for the primary analysis.
11.4.4
Summary statistics of safety
Vital signs
All vital signs data will be listed by treatment group, patient, and visit/time and if ranges are 
available abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics 
will be provided by treatment and visit/time.
ECG evaluations
All ECG data will be listed by treatment group, patient and visit/time, abnormalities will be 
flagged. Summary statistics will be provided by treatment and visit/time.
Clinical laboratory evaluations
All laboratory data will be listed by treatment group, patient, and visit/time and if normal 
ranges are available abnormalities will be flagged. Summary statistics will be provided by 
treatment and visit/time.
Adverse events
All information obtained on AEs will be displayed by treatment group and patient.
The number and percentage of patients with AEs will be tabulated by body system and 
preferred term with a breakdown by treatment. A patient with multiple AEs within a body 
system is only counted once towards the total of this body system.


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11.4.5
Sensitivity analyses
As sensitivity analyses, the same analysis described for the primary analysis will be 
performed using the last observation carried forward (LOCF) and worst observation carried 
forward (WOCF) approaches of imputation for missing MWD data. 
Baseline maximum walk distance will be summarized separately for patients who complete 
the 6MWT at week 16 and those who drop out of the study prior to this assessment. 
Summary statistics will include N, mean, SD, minimum, median, and maximum. The p-value 
from a two-sample t-test comparing the baseline maximum walk distance between the two 
groups will be reported together with the summary.
The relationship between the maximum change in maximum walk distance and baseline 
maximum walk distance will be explored using a graphical and modeling approach. A simple 
linear regression line and the Pearson correlation, both for each treatment, will be overlaid 
onto a scatterplot. Additionally, a linear regression model for the maximum change in 
maximum walk distance with effects of treatment, baseline, and the treatment-by-baseline 
interaction will be fit, and the p-value for the test of the interaction effect will be reported. 
The relationship between change in maximum walk distance and change in ABI at week 16
will be explored in a similar fashion.
11.5
Analysis of secondary variable(s)
11.5.1
Pharmacokinetics
LLG783 serum concentrations will be listed by treatment, patient, and visit/sampling time 
point. Descriptive summary statistics will be provided by treatment and visit/sampling time 
point, including the frequency (n, %) of concentrations below the LLOQ and reported as zero.
Pharmacokinetic parameters will be calculated as described in Section 8.7.1 and will be listed 
by treatment and patient and summarized by treatment and visit. Summary statistics will 
include mean (arithmetic and geometric), SD, CV (arithmetic and geometric), median, 
minimum and maximum. An exception to this is Tmax where median, minimum and 
maximum will be presented. 
Concentrations below LLOQ will be treated as zero in summary statistics and for 
PK parameter calculations. A geometric mean will not be reported if the dataset includes zero 
values. 
11.5.3
Pain-free walk distance
The change from baseline in pain-free walking distance will be analyzed in a similar way to 
MWD as described in Section 11.4.2 and Section 11.4.3.
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12
Ethical considerations
12.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed 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 Title 21, and Japanese Ministry of Health, Labor, and Welfare), and with the 
ethical principles laid down in the Declaration of Helsinki.
12.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial 
protocol, written informed consent form, consent form updates, patient recruitment 
procedures (e.g. advertisements) and any other written information to be provided to patients. 
Prior to study start, the investigator is required to sign a protocol signature page confirming 
his/her agreement to conduct the study in accordance with these documents and all of the 
instructions and procedures found in this protocol and to give access to all relevant data and 
records to Novartis monitors, auditors, Novartis Quality Assurance representatives, designated 
agents of Novartis, IRBs/IECs, 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 by the time of 
Last Patient Last Visit to be a reviewer and signatory for the clinical study report. 
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12.3
Publication of study protocol and results
The key design elements of this protocol will be posted in a publicly accessible database such 
as clinicaltrials.gov. In addition, upon study completion and finalization of the study report 
the results of this trial will be either submitted for publication and/or posted in a publicly 
accessible database of clinical trial results.
12.4
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management (QM) system that includes all activities 
involved in quality assurance and quality control, including the assignment of roles and 
responsibilities, the reporting of results, and the documentation of actions and escalation of 
issues identified during the review of quality metrics, incidents, audits and inspections.
Audits of investigator sites, vendors, and Novartis systems are performed or overseen by 
Novartis Pharma Auditing and Compliance Quality Assurance (or CRO working on behalf of 
Novartis), a group independent from those involved in conducting, monitoring or performing 
quality control of the clinical trial. The clinical audit process uses a knowledge/risk based 
approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes.
13
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected 
on study participants. Additional assessments required to ensure safety of patients should be 
administered as deemed necessary on a case by case basis. Under no circumstances is an 
investigator allowed to collect additional data or conduct any additional procedures for any 
research related purpose involving any investigational drugs under the protocol.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be 
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13.1
Protocol Amendments
Any change to the protocol can only be made in a written protocol amendment that must be 
approved by Novartis, Health Authorities where required, and the IRB/IEC prior to 
implementation.
Amendments that are intended to eliminate an apparent immediate hazard to patients may be 
implemented immediately, provided the Health Authorities are subsequently notified by 
protocol amendment and the reviewing IRB/IEC is notified.
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 9 (Safety Monitoring) must be followed and the Study Lead 
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References
References are available upon request.
Brass EP, Cooper LT, Morgan RE, et al (2012) A phase II dose-ranging study of the 
phosphodiesterase inhibitor K-134 in patients with peripheral artery disease and claudication. 
J Vasc Surg, 55, 381-389 e1.
Committee for proprietary medical products, European Agency for the Evaluation of
Medicinal Products (2002) Note for Guidance on clinical investigation of medicinal products 
for the treatment of peripheral arterial occlusive disease. London, UK, 1-16.
Fowkes FG, Aboyans V, Fowkes, FJ, et al (2017) Peripheral artery disease: epidemiology and 
global perspectives. Nat Rev Cardiol, 14, 156-170.
Gerhard-Herman MD, Gorink HL, Barrett C, et al (2017) 2016 AHA/ACC Guideline on the 
Management of Patients With Lower Extremity Peripheral Artery Disease: Executive 
Summary: A Report of the American College of Cardiology/American Heart Association 
Task Force on Clinical Practice Guidelines. Circulation, 135, e686-e725.
Go A, Mozaffarian D, Roger VL, et al (2014) Heart disease and stroke statistics - 2014 update: 
a report from the American Heart Association. Circulation; 129: e28-e292.
Hardman RL, Jazaeri O, YI J, et al (2014) Overview of classification systems in peripheral 
artery disease. Semin Intervent Radiol, 31, 378-88.
Hirsch AT, Duval S (2013) The global pandemic of peripheral artery disease. Lancet; 382: 
1312-1314.
ICH E2D (2004) Clinical Safety Data Management: Definitions and Standards for expedited 
reporting. Accessed from: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC5
00002807.pdf  Accessed on: 02Dec2016. 
International Conference on Harmonisation (1997) General Considerations for Clinical Trials, 
8:1-13.
Kieffer E, Bahnini A, Mouren X, et al (2001) A new study demonstrates the efficacy of 
naftidrofuryl in the treatment of intermittent claudication. Findings of the Naftidrofuryl 
Clinical Ischemia Study (NCIS). Int Angiol, 20, 58-65.
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Money SR, Herd JA, Isaachohn JL, et al (1998) Effect of cilostazol on walking distances in 
patients with intermittent claudication caused by peripheral vascular disease. J Vasc Surg, 27, 
267-74; discussion 274-5.
Rup B, Pallardy M, Sikkema D, et al (2015) Standardizing terms, definitions and concepts for 
describing 
and 
interpreting 
unwanted 
immunogenicity 
of 
biopharmaceuticals: 
recommendations of the Innovative Medicines Initiative ABIRISK consortium, Clin. Exp. 
Immunol.; 181: 385-400.


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Appendix 1: Liver Event Definitions and Follow-up 
Requirements
Table 15-1
Liver Event Definitions
Definition
Thresholds
Potential Hy’s law cases

ALT or AST > 3 × ULN and TBL > 2 × ULN without initial increase
in ALP to > 2 × ULN
ALT or AST elevation with 
coagulopathy

ALT or AST > 3 × ULN and INR > 1.5 (in the absence of
anticoagulation)
ALT or AST elevation 
accompanied by symptoms

ALT or AST > 3 × ULN accompanied by (general) malaise, fatigue,
abdominal pain, nausea, or vomiting, or rash, or eosinophilia
Isolated ALT or AST 
elevation

ALT or AST > 8 × ULN

5 x ULN < ALT/AST ≤ 8 x ULN

3 x ULN < ALT/AST ≤ 5 x ULN
Isolated ALP elevation

ALP > 2 × ULN (in the absence of known bone pathology)
Others

Any clinical event of jaundice (or equivalent term)

Any adverse event potentially indicative of liver toxicity
Table 15-2
Actions required for Liver Events
Criteria
Actions required
Potential Hy’s Law case

Discontinue the study treatment immediately
Hospitalize, if clinically appropriate

Establish causality

Complete CRFs per liver event guidance*
ALT or AST elevation with coagulopathy
ALT or AST elevation accompanied by 
symptoms
Isolated ALT or AST elevation > 8 × ULN
Jaundice
Isolated ALT or AST elevation > 5 to ≤ 8 
× ULN

If confirmed, consider interruption or discontinuation
of study drug

If elevation persists for more than 2 weeks,
discontinue the study drug

Establish causality

Complete CRFs per liver event guidance*
Isolated ALT or AST elevation > 3 to ≤ 5 
× ULN (patient is asymptomatic)

Monitor liver chemistry tests two or three times weekly
Isolated ALP elevation

Repeat liver chemistry tests within 48-72 hours

If elevation is confirmed, measure fractionated ALP; if
>50% is of liver origin, establish hepatic causality

Complete CRFs per liver event guidance*
Any AE potentially indicative of liver 
toxicity

Consider study treatment interruption or
discontinuation

Hospitalize if clinically appropriate

Complete CRFs per liver event guidance*
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Note: In exceptional cases when a hepatologist considers a liver biopsy, it is strongly 
recommended to make specimen slides available for evaluation by Novartis to potentially 
identify project-wide patterns of hepatotoxicity.
Table 15-3
Exclusion of underlying liver disease
Disease
Assessment
Hepatitis A, B, C, E

IgM anti-HAV; HBSAg, IgM anti-HBc, HBV DNA; anti-HCV, HCV RNA,
IgM & IgG anti-HEV, HEV RNA
CMV, HSV, EBV 
infection

IgM & IgG anti-CMV, IgM & IgG anti-HSV; IgM & IgG anti-EBV
Autoimmune hepatitis

ANA & ASMA titers, total IgM, IgG, IgE, IgA
Alcoholic hepatitis

Ethanol history, GGT, MCV, CD-transferrin
Nonalcoholic 
steatohepatitis

Ultrasound or MRI
Hypoxic/ischemic 
hepatopathy

Medical history: acute or chronic CHF, hypotension, hypoxia, hepatic
venous occlusion. Ultrasound or MRI.
Biliary tract disease

Ultrasound or MRI, ERCP as appropriate.
Wilson disease

Caeruloplasmin
Hemochromatosis

Ferritin, transferrin
Alpha-1-antitrypsin 
deficiency

Alpha-1-antitrypsin


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


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Amended Protocol Version v02 (Clean)
Protocol No. CLLG783X2201
Whenever a renal event is identified, a detailed patient history and examination are indicated
to identify, document and potentially eliminate risk factors that may have initiated or 
contributed to the event:

Blood pressure assessment (after 5 min rest, with an appropriate cuff size)

Signs and symptoms such as fever, headache, shortness of breath, back or abdominal pain,
dysuria, hematuria, dependent or periorbital edema

Changes in blood pressure, body weight, fluid intake, voiding pattern, or urine output

Concomitant events or procedures such as trauma, surgical procedures, cardiac or hepatic
failure, contrast media or other known nephrotoxin administration, or other potential
causes of renal dysfunction, e.g., dehydration, hemorrhage, tumor lysis
Table 16-1
Follow-up of renal events
Action
Follow up
Assess*, document and record in the Case Report Form 
(CRF) or via electronic data load. Review and record 
possible contributing factors to the renal event (co-
medications, other co-morbid conditions) and additional 
diagnostic procedures (MRI etc) in the CRF.

Urine dipstick and sediment
microscopy

Blood pressure and body weight

Serum creatinine, electrolytes
(sodium, potassium, phosphate,
calcium), bicarbonate and uric acid

Urine output
Monitor patient regularly (frequency at investigator’s 
discretion) until:

Event resolution: (sCr within 10%
of baseline or protein-creatinine
ratio within 50% of baseline)
or

Event stabilization: sCr level with
±10% variability over last 6 months
or protein-creatinine ratio
stabilization at a new level with
±50% variability over last 6 months.
* Urine osmolality: in the absence of diuretics or chronic kidney disease this can be a very sensitive
metric for integrated kidney function that requires excellent tubular function. A high urinary osmolality
in the setting of an increase in sCr will point toward a “pre-renal” cause rather than tubular toxicity.

SAP_001.pdf: 
Biostatistics & Statistical Programming / 
Novartis Institutes for BioMedical Research
LLG783
CLLG783X2201
A Patient and Investigator-blinded, randomized, placebo-
controlled study of LLG783 in subjects with peripheral 
artery disease (PAD) and intermittent claudication
Statistical Analysis Plan (SAP)
Author(s):
Document type:
SAP Documentation – NIBR 
Document status:
Amendment 1/Final
Release date:
08-Feb-2019
Number of pages:
22
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May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
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Table of contents
Table of contents .................................................................................................................3
List of tables ........................................................................................................................4
List of figures ......................................................................................................................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(s)................................................................................5
1.3.2
Secondary objective(s)............................................................................5
1.4
Study design and treatment......................................................................................7
2
First interpretable results (FIR) ...............................................................................8
3
Interim analyses.......................................................................................................8
4
Statistical methods: Analysis sets............................................................................9
5
Statistical methods for Pharmacokinetic (PK) parameters....................................10
5.1
Variables................................................................................................................11
5.2
Descriptive analyses ..............................................................................................11
6
Statistical methods for Efficacy/Pharmacodynamic (PD) parameters...................11
6.1
Primary objective...................................................................................................11
6.1.1
Variables ...............................................................................................12
6.1.2
Descriptive analyses..............................................................................12
6.1.3
Statistical model, assumptions and hypotheses.....................................12
6.2
Secondary objectives .............................................................................................13
6.2.1
Variables ...............................................................................................14
6.2.2
Descriptive analyses..............................................................................14
6.2.3
Statistical model, assumptions and hypotheses.....................................14
7
Statistical methods for safety and tolerability data................................................17
7.1
Variables................................................................................................................17
7.2
Descriptive analyses ..............................................................................................18
7.3
Graphical presentation...........................................................................................19
8
Pharmacokinetic / pharmacodynamic relationships ..............................................19
9
Statistical methods for biomarker data ..................................................................20
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10
Reference list .........................................................................................................22
List of tables
Table 4-1
Protocol deviation codes and analysis sets............................................10
List of figures
Figure 1-1 
Study design............................................................................................7


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1
Introduction 
1.1
Scope of document
The RAP documents contain detailed information to aid the production of Statistics & 
Programming input into the Clinical Study Report (CSR) for trial “CLLG783X2201”.
The Statistical analysis plan (SAP) describes the implementation of the statistical analysis 
planned in the protocol.
Tables, Figures, Listings (TFL) details the presentation of the data, including shells of summary 
tables, figures and listings, and Programming Datasets Specification (PDS) contains 
programming specifications e.g. for derived variables and derived datasets, to support the 
creation of CSR and IA outputs.
1.2
Study reference documentation
Final study protocol (version v00) is available at the time of finalization of Statistical Analysis 
Plan.
1.3
Study objectives
1.3.1
Primary objective(s)
Primary objective(s)
Endpoints related to primary objectives

To evaluate the safety and tolerability
of LLG783 in subjects with PAD and
intermittent claudication after 16 weeks
of exposure to LLG783.

AEs (including observations made
during 
physical 
examinations 
as
appropriate)

Incidence

Severity

Vital signs including:

Pulse rate

Blood pressure (BP)

Respiratory rate

Body temperature

Laboratory evaluations

Hematology

Clinical chemistry

Urinalysis

Electrocardiogram (ECG) intervals

To evaluate the effect of LLG783 on
functional capacity after 3 months of
treatment in subjects with PAD and
intermittent claudication.

Maximum walking distance assessed by
6-minute walk test (6MWT)
1.3.2
Secondary objective(s)
Secondary objective(s)
Endpoints related to secondary objectives


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
To investigate the PK of LLG783 in
subjects with PAD and intermittent
claudication.

PK parameters will be determined,
including: AUCinf, AUClast, AUC0-t,
AUC0tau, Cmax and Tmax

To evaluate the effect of LLG783 on
symptomatic functional capacity after 3
months of treatment in subjects with
PAD and intermittent claudication.

Pain-free walking distance assessed by
6MWT
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1.4
Study design and treatment
This is a non-confirmatory, randomized, subject and investigator-blinded, placebo-controlled, 
parallel-group study in subjects with PAD and intermittent claudication. 
Approximately 40 randomized subjects will be treated in a 1:1 ratio to receive LLG783 or 
placebo as an i.v. infusion of 
 i.v. dosing once every 4 weeks for a total of 4 doses over 
a period of 12 weeks/3 months. 
The dose may be altered based on review of data from the 1st interim analysis (IA). 
. 
Figure 1-1
Study design
It is intended that the s.c. study participants would maintain the same assessment visit schedule 
as the i.v. dosed study participants.
Subjects who discontinue the study for reasons other than safety prior to the week 16 visit may
be replaced to ensure ability to assess 40 subjects with a functional assessment after 16 weeks 
of exposure.
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CCI
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2
First interpretable results (FIR)
FIR 
 will focus on the following analyses:
1. Subject disposition
2. Demographics and baseline characteristics
3. Safety results
o
Number and percentage of subjects with adverse events by preferred term.
o
Overall incidence of AEs.
4. Efficacy results
o
Arithmetic mean (80% CI) of 6MWT parameters vs time profile by treatment.
o
MMRM model analysis of 6MWT parameters.
o
Model estimated means of 6MWT parameters over time.
5. Pharmacokinetic results for Plasma
o
Arithmetic mean (SD) concentration-time plot.
o
Summary statistics for PK parameters.
6. Immunogenicity Data
3
Interim analyses 
There are 2 planned IAs in this study. It is planned to conduct the first IA (IA1) once 
approximately 12 subjects reach 8 weeks following the first dose. The purpose of IA1 will be 
to assess the PK of LLG783 to make a dose adjustment should the exposure be significantly 
lower or higher than expected. 
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.
Unblinded IA results will be reviewed by the clinical team. The clinical team may communicate 
interim results (e.g. evaluation of efficacy criteria or information needed for 
planning/modifying another study) to relevant Novartis teams for information, consulting 
and/or decision purposes.
Additional interim analyses may be conducted to support decision making concerning the 
current clinical study, the sponsor’s clinical development projects in general or in case of any 
safety concerns. In this case, the analyses as described in the sections below are conducted for 
the relevant endpoints.
4
Statistical methods: Analysis sets
For subjects whose actual treatment received does not match the randomized treatment, the 
treatment actually received will be used for the analysis.
The safety analysis set will include all subjects that received any study drug.
The PK analysis set will include all subjects with at least one available valid (i.e. not flagged 
for exclusion) PK concentration measurement, who received any study drug and experienced 
no protocol deviations with relevant impact on PK data.
The PD analysis set will include all subjects with any available PD data, who received any study 
drug and experienced no protocol deviations with relevant impact on PD data.
The analysis sets and protocol deviation codes are related as follows:
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Table 4-1
Protocol deviation codes and analysis sets
Category
Deviation code
Text description of deviation
Data exclusion
Subjects are excluded from PD analysis in case of these PDs:
Exclude subject from PD
analysis set
COMD03
Change in type or dosage of narcotic pain 
relievers; OR Change in type or dosage of 
PAD specific symptom-relief drugs prior to 
week 16 of study.
Inc05
Deviation from inclusion criterion 5 –
Moderately impaired ambulatory function due 
primarily to PAD and maximum walk distance 
between 50 and 400 meters.
Exc02
Deviation from exclusion criterion 2 –
Pregnant or nursing (lactating) women.
Exc05b
Deviation from exclusion criterion 05b –
Chronic heart failure New York Heart 
Association Class III or IV.
Exc14
Deviation from exclusion criterion 14 –
Patients unable to hold all narcotic pain 
relievers for 24 hours prior to performance of 
the 6MWT.
Inc03
Deviation from inclusion criterion 3 - On stable 
medical therapy for at least 4 weeks prior to 
the screening visit.
Exc03
Deviation from exclusion criterion 3 – Patients 
who meet the specific PAD related exclusion 
criteria.
If updates to this table are needed, an amendment to the SAP needs to be implemented prior to
DBL.
Dose adjustment might occur as part of the IA1 safety and tolerability conclusions. In case of 
dose adjustment occurring during the study, subjects will be analyzed under first dose received, 
censoring any observations post dose adjustment (if any) in statistical models and descriptive 
summaries. Further updates on the SAP analysis strategy described below may be needed, 
depending on the findings of the IA1 and the proposed changes to the dosing strategy.
5
Statistical methods for Pharmacokinetic (PK) parameters
All subjects within the PK analysis set will be included in the PK data analysis.
In case of dose adjustment occurring during the study, subjects will be analyzed under first 
doses received, censoring any observations post dose adjustment (if any) in descriptive 
summaries. 


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5.1
Variables 
If data permit and as applicable, the following pharmacokinetic parameters for the parent 
LLG783 will be determined using the actual recorded sampling times and non-compartmental 
method(s) with Phoenix WinNonlin (Version 6.4 or higher) from the serum concentration data.

PK parameters related to secondary objectives:
-
AUCinf, AUClast, AUC0-t, AUC0tau, Cmax, Tmax.
5.2
Descriptive analyses
LLG783 serum concentrations will be listed by treatment, subject, and visit/sampling time point. 
Descriptive summary statistics will be provided by treatment and visit/sampling time point, 
including the frequency (n, %) of concentrations below the LLOQ (and above the ULOQ) and 
reported as zero. Pharmacokinetic parameters will be listed by treatment and subject and 
summarized by treatment and visit. Summary statistics will include mean (arithmetic and 
geometric), SD, CV (arithmetic and geometric), median, minimum and maximum. An 
exception to this is Tmax where median, minimum and maximum will be presented.
Concentrations below LLOQ will be treated as zero in summary statistics and for PK parameter 
calculations. A geometric mean will not be reported if the dataset includes zero values.
Arithmetic mean (SD) serum concentration by time will be plotted on linear-linear and log-
linear scale (all treatment groups in the same graph).
Overlaying individual serum concentration by time profile, by treatment will be plotted (one 
graph per treatment group, all subjects in the same graph) on linear-linear and log-linear scale.
Individual serum concentration by time profile, by subject will be plotted on linear-linear and 
log-linear scale (one graph per treatment group and subject).
6
Statistical methods for Efficacy/Pharmacodynamic (PD) 
parameters
All subjects within the PD analysis set will be included in the PD data analysis.
In case of dose adjustment occurring during the study, subjects will be analyzed under first 
doses received, censoring any observations post dose adjustment (if any) in statistical models 
and descriptive summaries. 
6.1
Primary objective
To evaluate the effect of LLG783 on functional capacity after 3 months of treatment in subjects 
with PAD and intermittent claudication.
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6.1.1
Variables 
The primary efficacy endpoint is the Maximum walking distance (MWD) defined as the total 
distance walked in 6 minutes as assessed by the 6MWT and will be used to evaluate functional 
capacity of PAD subjects participating in this study.
Change from baseline in MWD will also be derived. Baseline will be taken from the screening 
6-minute walk test.
6MWT data will be excluded from primary and secondary analyses under below conditions:

within 24 hours after narcotic pain medication

the very first 6MWT after the adverse event of COPD exacerbation

all tests after post baseline stent or angioplasty procedures

Lap distance for the 6MWT significantly shorter than the recommended length of
50-70m
6.1.2
Descriptive analyses
Maximum walking distance (MWD) and change from baseline in MWD will be listed by 
treatment, subject and visit. Summary statistics will be provided for raw and change from 
baseline by treatment and visit/time and will include sample size, mean (arithmetic), SD,
median, minimum, maximum. 
6.1.2.1
Graphical presentation of results
Arithmetic mean (80% CI) of raw MWD and change from baseline in MWD will be plotted by 
visit and treatment. Spaghetti plots of raw MWD and change from baseline in MWD of all 
individuals will be given by treatment.  
6.1.3
Statistical model, assumptions and hypotheses
The change from baseline in MWD will be analyzed in a repeated measure mixed effects model 
with treatment, visit and the treatment-by-visit interaction as fixed effects and baseline MWD 
as a covariate. The visit-by-baseline MWD interaction may be included in the model as an 
additional covariate. An unstructured residual covariance structure will be used, if possible, 
otherwise if an unstructured covariance cannot be fitted, simpler structures will be explored. 
The Least-Squares Mean (LSM) change from baseline in MWD for each visit will be estimated 
from the model for each treatment along with the treatment difference and the associated p-
value and two-sided 80% confidence interval (CI).
From the Week 16 quantities, the following criteria will be assessed:
1. The lower confidence limit of the 80% CI for the treatment difference (LLG783 –
placebo) is greater than 0.
2. The estimated treatment difference is greater than or equal to 50 meters.
The first criterion will address whether, with high certainty, LLG783 is superior to placebo in
improvement in MWD. The second criterion will address whether the observed mean


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improvement in MWD over placebo is at least 50 meters, a threshold that is considered to
represent highly competitive efficacy in this subject population.
6.1.3.1
Model checking procedures
Handling of missing values/censoring/discontinuations
The primary analysis will be based on all subjects with a baseline MWD and at least one post 
baseline MWD. Subjects who undergo any lower extremity vascular interventions (angioplasty, 
stenting, or bypass surgery) before the Week 16 efficacy assessment or subjects who drop out 
for other reasons before this assessment may be replaced to ensure 40 subjects complete this 
primary endpoint assessment. Data from such subjects will be included in the model for the 
primary analysis until the time of dropout or intervention; no imputation of the missing data 
will be performed for the primary analysis.
6.1.3.2
Graphical presentation of results
Model estimated treatment means and difference in change from baseline in MWD will be 
plotted over time, by visit (all treatment groups in the same graph).
6.1.3.3
Sensitivity analyses
As sensitivity analyses, the same analysis described for the primary analysis will be performed 
using the last observation carried forward (LOCF) and worst observation carried forward 
(WOCF) approaches of imputation for missing MWD data.
Baseline maximum walk distance will be summarized separately for subjects who complete the 
6MWT at week 16 and those who drop out of the study prior to this assessment. Summary
statistics will include n, mean, SD, minimum, median, and maximum. The p-value from a two-
sample t-test comparing the baseline maximum walk distance between the two groups will be 
reported together with the summary.
The relationship between the maximum change in maximum walk distance and baseline
maximum walk distance will be explored using a graphical and modeling approach. A simple
linear regression line and the Pearson correlation, both for each treatment, will be overlaid onto 
a scatterplot. Additionally, a linear regression model for the maximum change in maximum 
walk distance with effects of treatment, baseline, and the treatment-by-baseline interaction will 
be fitted, and the p-value for the test of the interaction effect will be reported.
The relationship between change in maximum walk distance and change in ABI at week 16 will
be explored in a similar fashion.
Depending on the assessment of the PK profiles and dose response of subjects on different dose 
levels (if any after IA1), it might be reasonable to assume same mean response for both doses 
(providing similar AUC in the PAD population as observed in healthy volunteers). In that case 
different dose levels can be combined in one treatment arm regardless of different dose level.
6.2
Secondary objectives
To evaluate the effect of LLG783 on symptomatic functional capacity after 3 months of 
treatment in subjects with PAD and intermittent claudication.


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6.2.1
Variables 
The secondary efficacy endpoint is the pain-free walking distance defined as the distance 
walked up to the point of onset of claudication symptoms as assessed by the 6MWT and will 
be used to evaluate symptomatic functional capacity of PAD subjects participating in this study.  
Change from baseline in pain-free walking distance will also be derived. Baseline will be taken 
from the screening 6-minute walk test.
The exclusion rule of 6MWT defined in Section 6.1.1 will also apply to pain-free walking 
distance.
6.2.2
Descriptive analyses
Secondary endpoint will be listed and summarized in an equivalent way as described in Section 
6.1.2.
6.2.3
Statistical model, assumptions and hypotheses
Secondary endpoint will be analyzed in an equivalent way as described in Section 6.1.3.
6.2.3.1
Model checking procedures
Model checking procedures for pain-free walking distance will be the same as for primary 
analysis, refer to Section 6.1.3.1.
6.2.3.2
Graphical presentation of results
Graphical presentation of results for pain-free walking distance will be the same as for primary 
analysis, refer to Section 6.1.3.2.
6.2.3.3
Sensitivity analyses
As sensitivity analyses, the same analysis described for the secondary analysis in Section 6.2.3, 
will be performed using the last observation carried forward (LOCF) and worst observation 
carried forward (WOCF) approaches of imputation for missing pain-free walking distance. 
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7
Statistical methods for safety and tolerability data
All subjects within the Safety analysis set will be included in the safety data analysis.
In case of dose adjustment occurring during the study, safety analyses will be performed by two
analysis periods: pre-dose adjustment period and post-dose adjustment period. All subjects will 
be summarized by dose received during each period. 
7.1
Variables
Safety variables include adverse events, vital signs (body temperature, blood pressure, pulse 
rate, respiratory rate), height and weight, ECG intervals, laboratory measurements (hematology, 
clinical chemistry, urinalysis, coagulation panel), as well as subject demographics, baseline 
characteristics, and treatment information.
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7.2
Descriptive analyses
Subject demographics and other baseline characteristics
All data for background and 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 by treatment group and subject.
Treatment
Data for study drug administration and concomitant therapies will be listed by treatment group 
and subject.
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 treatment and visit/time.
Height and weight
All height and weight and BMI data will be listed by treatment, subject, and visit, as part of the 
vital signs panel.
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. A separate listing is provided presenting all parameters 
in a subject with any abnormal values. Summary statistics will be provided by treatment and 
visit/time.
Adverse events
All information obtained on adverse events will be displayed by treatment and subject.
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 the total of this body system and treatment.
The number and percentage of subjects with adverse events by maximum severity of adverse 
events will be tabulated by body system and preferred term with a breakdown by treatment.
The number and percentage of subjects with adverse events classified as related to study drug 
will be tabulated by body system and preferred term with a breakdown by treatment.


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ClinicalTrials.gov and EudraCT
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on treatment 
emergent adverse events which are not serious adverse events with an incidence greater than 
5% and on treatment emergent serious adverse events and SAE suspected to be related to study 
treatment will be provided by system organ class and preferred term on the safety set population
and prepared internally by Novartis.
If for a same subject, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is ≤ 1 day gap between the end date of the
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date
of the preceding AE and the start date of the consecutive AE.
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non-SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT. 
Other safety evaluations
Immunogenicity
All immunogenicity results will be listed by subject and visit/time. Summary statistics will be 
provided by treatment and visit/time.
7.3
Graphical presentation 
Boxplots to visualize trends in longitudinal safety data (vitals, ECG, lab parameter) will be 
created.
8
Pharmacokinetic / pharmacodynamic relationships
All subjects within the PK/PD analysis set will be included in the PK/PD data analysis.
In case of dose adjustment occurring during the study, PK/PD analyses may be performed by 
two analysis periods: pre-dose adjustment period and post-dose adjustment period. All subjects 
will be summarized by dose received during each period. 
In addition, relationship between LLG783 concentration or an appropriate PK parameter and 
MWD may be explored in a graphical and/or modeling approach.
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9
Statistical methods for biomarker data
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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.
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To ensure that biomarkers only have numerical values, censored values will be imputed as 
follows

Values below the LLOQ are replaced by LLOQ/2.

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 above the 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 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.
If the proportion of imputed data for a given biomarker, across all treatment groups and time 
points, is more than 30%, no inferential analysis will be performed.
10
Reference list
1. Clinical Trial Protocol, CLLG783X2201
2. Site Operations Manual for Protocol No. CLLG783X2201
3. Investigator’s Brochure for Protocol No. CLLG783X2201
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