Clinical trial NCT04066244
Conditions: Amyotrophic Lateral Sclerosis
Keywords: PET ALS Microglia CSF
Sponsor: Novartis Pharmaceuticals
Start date: 2019-12-30; Completion date: 2024-02-01
Enrollment: 28 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
It was an open label study to evaluate safety, tolerability and brain microglia response in participants with Amyotrophic Lateral Sclerosis (ALS) following multiple doses of BLZ945.

Detailed description:
The purpose of the study was to identify a dose (or doses) of BLZ945, that measurably decrease(s) 18 KDa Translocator Protein (TSPO) binding in the brain of participants with ALS. The study also aimed to evaluate the safety and tolerability of BLZ945 in participants with ALS at different doses and dosing regimens, and safety related effects on extracellular matrix (ECM) accumulation.

This was an exploratory, adaptive , open label study of approximately 16 participants in cohorts of 4 participants per cohort at increasing doses of BLZ945 with the last dose determined after the completion of cohorts 1 to 3.

Each cohort received treatment for 4 days and continued with a 32 day follow up period with an end of study visit at day 36.

After completion of the 4 initial cohorts a fifth cohort was initiated with two parallel arms receiving BLZ945 for up to 12 weeks at two different treatment regimens, either once weekly or 4 days of treatment followed by 10 days off drug.

Arms: arm 1: BLZ945 300mg arm 2: BLZ945 600mg arm 3: BLZ945 1200mg arm 4: BLZ945 800mg arm 5: BLZ945 800mg (4 days treatment + 10 days off) arm 6: BLZ945 800mg (once weekly)
Interventions: intervention 1: BLZ945
Intervention descriptions: intervention 1: Investigational drug capsules taken orally or via enteral infusion

Protocol documents:
Prot_000.pdf: 
Novartis Research and Development
BLZ945
Clinical Trial Protocol Title: CBLZ945C12201 / NCT04066244
An open-label, adaptive design study in patients with 
amyotrophic lateral sclerosis (ALS) to characterize safety, 
tolerability and brain microglia response, as measured by 
TSPO binding, following multiple doses of BLZ945, using 
positron emission tomography (PET) with the radioligand 
[11C]-PBR28
Document Type:
Amended Protocol Version
EUDRACT number:
2019-000826-22
Version number:
v07 (Clean)
Clinical Trial Phase
II
Release date:
05-Oct-2023
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 2.0 dated 01-Aug-2018


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Site Operations Manual (SOM)
A Site Operations Manual (SOM) accompanies this protocol, providing the operational details 
for study procedures. Note: The SOM will not be a part of the Clinical Study Report.


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Table of contents
Site Operations Manual (SOM) ...........................................................................................2
Table of contents..................................................................................................................3
List of tables.........................................................................................................................7
List of figures.......................................................................................................................8
List of abbreviations ............................................................................................................9
Glossary of terms...............................................................................................................12
Protocol summary..............................................................................................................37
1
Introduction........................................................................................................................44
1.1
Background............................................................................................................44
1.2
Purpose...................................................................................................................45
2
Objectives and endpoints...................................................................................................45
3
Study design.......................................................................................................................48
3.1
Cohorts 1-4.............................................................................................................48
3.2
Cohort 5..................................................................................................................52
4
Rationale ............................................................................................................................56
4.1
Rationale for study design......................................................................................56
4.1.1
Rationale for study design for Cohorts 1-4 ...........................................56
4.1.2
Rationale for study design for Cohort 5 ................................................57
4.1.3
Rationale for choice of background therapy .........................................58
4.2
Rationale for dose/regimen and duration of treatment...........................................59
4.2.1
Dosing rationale for the first four cohorts (Cohort 1 - 4)......................59
4.2.2
Dosing rationale for Cohort 5................................................................61
4.3
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs.......................................................................................................................62
4.4
Purpose and timing of interim analyses/design adaptations ..................................62
4.5
Risks and benefits ..................................................................................................62
4.5.1
Potential risk associated with the COVID-19 Pandemic.......................65
4.5.2
Potential risks associated with exposure to ionizing radiation..............65
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4.5.3
Potential risks associated with arterial cannulation (Participants 
undergoing PET examinations).............................................................66
4.5.5
Blood sample volume............................................................................66
4.6
Rationale for Public Health Emergency mitigation procedures.............................66
4.7
End of study definition...........................................................................................67
5
Population ..........................................................................................................................67
5.1
Inclusion criteria ....................................................................................................67
5.2
Exclusion criteria ...................................................................................................68
6
Treatment...........................................................................................................................71
6.1
Study treatment ......................................................................................................71
6.1.1
Investigational and control drugs ..........................................................72
6.1.2
Additional study treatments...................................................................72
6.1.3
Treatment arms/group ...........................................................................74
6.2
Other treatment(s) ..................................................................................................75
6.2.1
Concomitant therapy .............................................................................75
6.2.2
Prohibited medication............................................................................76
6.2.3
Rescue medication.................................................................................78
6.2.4
Restriction for study participants...........................................................78
6.3
Participant numbering, treatment assignment, randomization...............................78
6.3.1
Participant numbering ...........................................................................78
6.3.2
Treatment assignment, randomization...................................................78
6.4
Treatment blinding.................................................................................................79
6.5
Dose escalation and dose modification..................................................................79
6.5.1
Dose escalation guidelines for Cohorts 1-4...........................................79
6.5.2
Dose reductions/interruptions (Cohort 5)..............................................80
6.6
Additional treatment guidance...............................................................................81
6.6.1
Treatment compliance ...........................................................................81
6.6.2
Recommended treatment of adverse events ..........................................81
6.6.3
Emergency breaking of assigned treatment code ..................................81
6.7
Preparation and dispensation .................................................................................81
7
Informed consent procedures.............................................................................................82
8
Visit schedule and assessments..........................................................................................84
8.1
Screening..............................................................................................................107
8.1.1
Eligibility screening.............................................................................107
8.1.2
Information to be collected on screening failures ...............................107
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8.2
Participant demographics/other baseline characteristics......................................107
8.3
Efficacy................................................................................................................107
8.3.1
Efficacy assessment.............................................................................107
8.3.2
Appropriateness of efficacy assessments ............................................108
8.4
Safety and tolerability..........................................................................................109
8.4.1
Laboratory evaluations........................................................................109
8.4.2
Electrocardiogram (ECG)....................................................................111
8.4.3
Pregnancy and assessments of fertility................................................112
8.4.4
Cardiac imaging – echocardiogram.....................................................112
8.4.5
Esophageal computed tomography (CT) scan.....................................112
8.4.6
Markers of inflammation.....................................................................113
8.4.7
Appropriateness of safety measurements ............................................113
8.4.8
COVID-19 contingency plan...............................................................113
8.5
Additional assessments ........................................................................................114
8.5.1
Pharmacokinetics.................................................................................114
9
Study discontinuation and completion.............................................................................120
9.1
Discontinuation and completion ..........................................................................120
9.1.1
Study treatment discontinuation and study discontinuation................120
9.1.2
Withdrawal of informed consent.........................................................122
9.1.3
Lost to follow-up.................................................................................123
9.1.4
Study stopping rules ............................................................................123
9.1.5
Cohort 5 stopping rules for one treatment arm:...................................124
9.1.6
Early study termination by the sponsor...............................................124
9.2
Study completion and post-study treatment.........................................................125
10 Safety monitoring and reporting......................................................................................125
10.1
Adverse events (AEs), serious adverse events (SAEs), and other safety 
reporting...............................................................................................................125
10.1.1
Definition and recording of adverse events.........................................125
10.1.2
Definition and recording of serious adverse events ............................127
10.1.3
SAE reporting......................................................................................127
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10.1.4
Pregnancy reporting.............................................................................129
10.1.5
Reporting of study treatment errors including misuse/abuse ..............130
10.2
Additional Safety Monitoring..............................................................................130
10.2.1
Liver safety monitoring.......................................................................130
10.2.2
Renal safety monitoring ......................................................................130
10.2.3
Vasculitis safety monitoring................................................................130
10.2.4
Monitoring for ECM accumulation.....................................................131
10.2.5
Prospective suicidality assessment......................................................132
11 Data Collection and Database management ....................................................................132
11.1
Data collection .....................................................................................................132
11.2
Database management and quality control ..........................................................133
11.3
Site monitoring.....................................................................................................133
11.4
Data Monitoring Committee................................................................................134
12 Data analysis and statistical methods...............................................................................134
12.1
Analysis sets.........................................................................................................134
12.2
Subject demographics and other baseline characteristics ....................................134
12.3
Treatments............................................................................................................135
12.4
Analysis of the primary endpoint(s).....................................................................135
12.4.1
Definition of primary endpoint(s) .......................................................136
12.4.2
Statistical model, hypothesis, and method of analysis ........................136
12.4.3
Handling of missing values/censoring/discontinuations .....................136
12.4.4
Sensitivity and Supportive analyses....................................................137
12.5
Analysis of secondary endpoints..........................................................................137
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s) ..................................137
12.5.2
Safety endpoints ..................................................................................137
12.5.3
Pharmacokinetics.................................................................................137
12.6
Analysis of exploratory endpoints .......................................................................138
12.7
Interim analyses ...................................................................................................140
12.8
Sample size calculation........................................................................................140
12.8.1
Primary endpoint(s).............................................................................140
13 Ethical considerations and administrative procedures.....................................................144
13.1
Regulatory and ethical compliance......................................................................144
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13.2
Responsibilities of the investigator and IRB/IEC................................................144
13.3
Data protection.....................................................................................................144
13.4
Publication of study protocol and results.............................................................144
13.5
Quality Control and Quality Assurance...............................................................145
14 Protocol adherence...........................................................................................................145
14.1
Protocol amendments...........................................................................................145
15 References........................................................................................................................147
16 Appendices.......................................................................................................................150
16.1
Appendix1: Liver safety monitoring....................................................................150
16.2
Appendix 2: Specific Renal Alert Criteria and Actions and Event Follow-up....155
16.3
Appendix 3: Guidance for the identification of potential cases of vasculitis 
and their follow-up...............................................................................................157
16.3.1
Identification of potential cases of vasculitis ......................................157
16.3.2
Clinical management of potential cases of vasculitis..........................159
List of tables
Table 2-1
Objectives and related endpoints...........................................................45
Table 6-1
Investigational drug...............................................................................72
Table 6-2
Additional study treatment ....................................................................73
Table 6-3
Treatment Arm(s)..................................................................................74
Table 6-4
Prohibited medication/procedure...........................................................76
Table 6-5
Provisional dose levels ..........................................................................80
Table 8-1
Assessment Schedule, 4 Days dosing cohorts.......................................84
Table 8-2
Details for highly repetitive assessments ..............................................89
Table 8-3
Assessment Schedule, 7 Days dosing cohorts.......................................91
Table 8-4
Details for highly repetitive assessments ..............................................96
Table 8-5
Assessment Schedule Cohort 5 .............................................................98
Table 8-6
Details for highly repetitive assessments in Cohort 5 .........................103
Table 8-7
Assessment schedule for Cohort 5 extended treatment period............104
Table 8-8
Assessments and specifications...........................................................109
Table 8-9
Laboratory evaluations........................................................................110
Table 8-10
Non-compartmental pharmacokinetic parameters of BLZ945............114
Table 9-1
Additional procedures at EoT 1 in case of premature 
discontinuation of treatment................................................................121
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Table 9-2
Adverse events that will be considered DLTs Cohorts 1-4.................124
Table 12-1
Percent CV estimate for ED-50 parameter..........................................140
Table 12-2
Probability to observe different outcomes for microglia Vt percent 
change from baseline to Week 12 assuming a true mean reduction 
of 21 percent........................................................................................141
Table 12-3
Precision of estimation for esophagus wall thickness change from 
baseline to Week 12 and LVEF change from baseline to Week 12 ....142
Table 12-4
Precision of estimation for cardiac valve thickness and cardiac 
valve function (stenosis and regurgitation) – any worsening from 
baseline to Week 12.............................................................................143
Table 12-5
Probability of observing at least 1 participant with AEs of ECM 
accumulation during the first 12 weeks of treatment ..........................143
Table 16-1
Liver event and laboratory trigger definitions.....................................150
Table 16-2
Follow up requirements for liver events and laboratory triggers ........151
Table 16-3
Alternative causes of liver disease and related assessments ...............154
Table 16-4
Specific Renal Alert Criteria and Actions...........................................155
Table 16-5
Renal Event Follow Up .......................................................................156
Table 16-6
Clinical manifestations of vasculitis....................................................157
Table 16-7
Laboratory triggers for additional assessment.....................................158
List of figures
Figure 3-1
Study design Cohorts 1-4 ......................................................................49
Figure 3-2
The different cohorts in the adaptive design (Cohorts 1-4)...................50
Figure 3-3
Decision algorithm for the timing of the third PET scan in 
subsequent cohorts up to Cohort 4 (for dosing cohorts above 
300 mg / day).........................................................................................52
Figure 3-4
Study design Cohort 5 ...........................................................................53
Figure 3-5
Study design Cohort 5 including the 24-week extended treatment 
period.....................................................................................................54


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List of abbreviations
AE
adverse event
ALP
alkaline phosphatase
ALS
Amyotrophic Lateral Sclerosis
ALT
alanine aminotransferase
ANCA
anti-neutrophil cytoplasm antibodies
AST
aspartate aminotransferase
AxMP
Auxiliary Medicinal Product
BCRP
Breast Cancer Resistance Protein
BLRM
Bayesian Logistics Regression Model
BMI
Body Mass Index
BUN
blood urea nitrogen
C-SSRS
Columbia - Suicide Severity Rating Scale
CK
creatine kinase
CK-MB
creatine kinase myocardial band
CLR
Renal clearance
CNS
Central Nervous System
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CRP
C-reactive protein
CSF-1R
Colony-stimulating factor 1 receptor
CSR
Clinical study report
CT
Computed Tomography
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
CTX-I
C-terminal telopeptide of type I collagen
CV
coefficient of variation
DDI
Drug drug interaction
DLT
Dose Limiting Toxicity
ECG
Electrocardiogram
ECM
Extracellular Matrix
EDC
Electronic Data Capture
ELISA
Enzyme-linked immunosorbent assay
eSource
Electronic Source
ESR
Erythrocyte Sedimentation Rate
EWOC
Escalation With Overdose Control
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
GFAP
Glial fibrillary acidic protein
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GGT
Gamma-glutamyl transferase
GI
Gastrointestinal
GPMNB
Osteoactivin / transmembrane glycoprotein NMB
h
hour
HAB
High affinity binder
HIV
human immunodeficiency virus
HNV
home nursing visit
HRRT
High Resolution Research Tomography
i.v.
intravenous
IB
Investigator's Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IgG
Immunoglobulin-G
IgM
Immunoglobulin-M
IL-1β
Interleukin 1β
IMP
Investigational Medicinal Product
irAE
Immune related adverse event
IRB
Institutional Review Board
IRT
Interactive Response Technology
LAB
Low affinity binder
LDH
lactate dehydrogenase
LFT
Liver function test
LLOQ
lower limit of quantification
LVEF
Left Ventricular Ejection Fraction
MAB
Mixed-affinity binder
MATE
Multi-drug and toxin extrusion transporter
MBq
megaBecquerel
MCV
Mean Corpuscular Volume
MedDRA
Medical dictionary for regulatory activities
mg
milligram(s)
mL
milliliter(s)
mrem
Milli roentgen equivalent man
MRI
Magnetic Resonance Imaging
mSv
millisievert
MTD
Maximum Tolerated Dose
NFL
Neurofilament Light
NSAIDs
Nonsteroidal Anti-inflammatory Drugs
NYHA
New York Heart Association
p75 ECD
Extracellular domain of p75
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p.o.
oral
PBMC
Peripheral blood mononuclear cell
PBPK
Physiologically based pharmacokinetic
PCR
Polymerase Chain Reaction
PD
pharmacodynamic(s)
PET
Positron Emission Tomography
P-gp
P-glycoprotein
PINP
Procollagen type I N-propeptide
PK
pharmacokinetic(s)
PT
prothrombin time
OAT
Organic Anion Transporter
OATP
Organic Anion Transporting Polypeptide
OCT
Organic Cation Transporter
QMS
Quality Management System
QTcF
QT interval corrected by Fridericia’s formula
RA
Rheumatoid arthritis
ROI
Region of interest
SAE
serious adverse event
sCR
serum creatinine
SD
standard deviation
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SLE
Systemic lupus erythematosus
SOC 
Standard of care
SOM
Site Operations Manual
sTREM2
Soluble fragments of Triggering Receptor Expressed on Myeloid Cells 2
SUSAR
Suspected Unexpected Serious Adverse Reactions
SUVR
Standardized Uptake Value Ratio
TD
Study Treatment Discontinuation
Trap-5b
Tartrate-resistant acid phosphatase 5b
TREM-2
Triggering Receptor Expressed on Myeloid Cells 2
TSPO
18 kDa Translocator Protein
ULN
upper limit of normal
ULOQ
Upper Limit Of Quantification
UMNB scale
Upper Motor Neuron Burden scale
vs
versus
Vt
Volume of Distribution
WBC
white blood cell(s)
WoC
Withdrawal of Consent
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Glossary of terms
Additional 
treatment
Medicinal products that may be used during the clinical trial as described in 
the protocol, but not as an investigational medicinal product (e.g. any 
background therapy)
Assessment
A procedure used to generate data required by the study
Auxiliary 
Medicinal Product 
(AxMP)
Medicinal product used for the needs of a clinical trial as described in the 
protocol, but not as an investigational medicinal product (e.g., rescue 
medication, challenge agents, background treatment or medicinal products used 
to assess endpoints in the clinical trial). Concomitant therapy is not considered 
as AxMP. 
Biologic Samples
A biological specimen including, for example, blood (plasma, serum), saliva, 
tissue, urine, stool, etc. taken from a study participant
Cohort
A specific group of participants fulfilling certain criteria
Control drug
A study drug (active or placebo) used as a comparator to reduce assessment 
bias, preserve blinding of investigational drug, assess internal study validity, 
and/or evaluate comparative effects of the investigational drug
Cycles
Number and timing or recommended repetitions of therapy are usually 
expressed as number of days (e.g., q28 days)
Dosage
Dose of the study treatment given to the participant 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.
End of the 
Clinical Trial
The end of the clinical trial is defined as the last visit of the last participant.
Enrollment
Point/time of participant entry into the study at which informed consent must be 
obtained (i.e. prior to starting any of the procedures described in the protocol).
eSource
eSource Direct Data Entry (DDE) refers to the capture of clinical study data 
electronically, at the point of care. eSource combines source documents and 
case report forms (eCRFs) into one application, allowing for the real time 
collection of clinical trial information to sponsors and other oversight authorities, 
as appropriate.
Healthy volunteer
A person with no known significant health problems who volunteers to be a study 
participant 
Investigational 
drug/treatment
The drug whose properties are being tested in the study
Investigational 
Product/ 
Investigational 
Medicinal product
A pharmaceutical form of an active ingredient or placebo being tested or used as 
a reference (such as an active comparator) in a clinical trial, including a product 
with a marketing authorization when used or assembled (formulated or 
packaged) in a way different from the approved form, or when used for an 
unapproved indication, or when used to gain further information about an 
approved use.
Medication pack 
number
A unique identifier on the label of each drug package in studies that dispense 
study treatment using an IRT system
Part
A single component of a study which contains different objectives or populations 
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a multiple dose part, or a part in participants with established disease and in 
those with newly-diagnosed disease.
Patient
An individual with the condition of interest.
Personal Data
Participant information collected by the Investigator that is transferred to Novartis 
for the purpose of the clinical trial. This data includes participant identifier 
information, study information and biological samples.
Randomization 
number
A unique identifier assigned to each randomized participant, corresponding to 
a specific treatment arm assignment
Run in Failure
A participant who is screened but not randomized/treated after the run-in period 
(where run-in period requires adjustment to participant’s medications or other 
intervention)
Screen Failure
A participant 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 participant permanently stops taking study treatment prior to 
the defined study treatment completion date
Subject
A trial participant (can be a healthy volunteer or a patient)
Subject number
A unique number assigned to each participant upon signing the informed 
consent. This number is the definitive, unique identifier for the participant and 
should be used to identify the participant throughout the study for all data 
collected, sample labels, etc.
Treatment 
number
A unique identifier assigned in non-randomized studies to each dosed 
participant, corresponding to a specific treatment arm 
Variable
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being tested in 
the study
Withdrawal of 
Consent (WoC)
Withdrawal of consent from the study occurs only when a participant does not 
want to participate in the study any longer and does not allow any further 
collection of personal data


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Protocol summary
Protocol 
number
BLZ945C12201
Full Title
An open-label, adaptive design study in patients with amyotrophic lateral 
sclerosis (ALS) to characterize safety, tolerability and brain microglia response, 
as measured by TSPO binding, following multiple doses of BLZ945 using 
positron emission tomography (PET) with the radioligand [11C]-PBR28
Brief title
Study of safety and proof of the mechanism of BLZ945 in ALS patients
Sponsor and 
Clinical Phase
Novartis / Phase II
Investigation 
type
Oral Drug
Study type
Interventional
Purpose and 
rationale
The purpose of the study is to identify a dose (or doses) of BLZ945, that 
measurably decreases microglia in the brains of participants with amyotrophic 
lateral sclerosis (ALS), and to evaluate the safety and tolerability of BLZ945 in 
ALS participants at these doses and dosing regimens. Cohort 5 will evaluate 
the safety, microglia reduction (PET sub-study) 
after repeated cycles of 
BLZ945 using two dose regimens over 12 weeks. PET imaging using 
[11C]-PBR28, a PET ligand selective for the 18 kDa translocator protein (TSPO), 
is widely used as a biomarker of microglial numbers and activation. 
Following microglia reduction, the repopulation of microglia in ALS participants 
will be assessed.
In addition to the demonstration of proof of mechanism (PoM), the results of 
this Phase 2 study with PET imaging will be used for PK/PD modelling to guide 
dose selection for subsequent Phase 2 (PoC) and Phase 3 clinical studies.
The purpose of Cohort 5 is to evaluate two planned dosing regimens in order to 
inform future clinical studies in participants with ALS. The 24-week extended 
treatment aims to evaluate safety and tolerability of BLZ945 and maintenance of 
its pharmacodynamic effects with prolonged treatment.
Primary 
Objective(s) 
•
Cohorts 1-4 and Cohort 5 (PET Sub-study): To evaluate brain microglial
reduction, as measured by reduction in TSPO binding, following treatment
with BLZ945 in ALS participants by using PET imaging with [11C]-PBR28.
•
Cohort 5: To assess safety-related effects on ECM accumulation under
BLZ945 treatment
Secondary 
Objectives
•
Cohorts 1-5: To characterize the pharmacokinetics (PK) of BLZ945 in ALS
participants
•
Cohorts 1-5: To evaluate safety and tolerability of BLZ945 in ALS
participants at the planned doses and dosing regimen(s)
•
Cohorts 1-5: To assess the CYP2C8 pharmacogenomic-pharmacokinetic
relationship
Study design
Cohorts 1-4
This is an exploratory, adaptive, open-label study of approximately 16 ALS 
participants in cohorts of 4 participants per cohort. Dosing at 300 mg, 600 mg 
and 1200 mg as well as two additional cohorts are planned at doses to be 
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determined, within the range of 150 to 1200 mg for the 4 days dosing regimen 
or at 300 mg for the 7 days dosing regimen. The follow-up period will continue 
until Day 19 (4 days dosing) or Day 22 (7 days dosing) with an End of Study 
visit on Day 36 (4 days dosing) or Day 40 (7 days dosing). The maximum study 
duration for each participant including the 42-day screening visit is 80 (4-day 
dosing) and 84 days (7-day dosing).
After each dosing cohort and prior to proceeding with dosing of the next cohort, 
a review of all available data will be conducted, including PD (% microglia 
reduction), and safety/tolerability (continuous review of adverse events, 
laboratory assessments, blood pressure and ECG data) data. PK data from 
the first three dosing cohorts (planned as 300 mg, 600 mg, 1200 mg) will be 
reviewed after the third dosing cohort prior to proceeding to the fourth dosing 
cohort. The PK review will be done to assist with the determination of the 
appropriate next dose(s). The PK data may be reviewed prior to the initiation of 
any dosing cohort should this information be determined by the Investigators 
and/or Sponsor as necessary for decision-making purposes. The decision to 
proceed to the next dose cohort will be made jointly between the Sponsor and 
the Investigator. If notable adverse events or safety concerns are found at one 
of the planned dose levels, the next planned dosing levels may be modified 
based on the available data from previous cohorts. The participants will be 
domiciled during the treatment period.
Cohort 5
Cohort 5 will include an open-label, randomized, 2 arm administration of 
repeated oral doses of BLZ945. Approximately 30 adult participants will be 
enrolled in this cohort. The cohort includes a screening period (up to 6 weeks), 
a 12-week open-label treatment period with two dosing regimens, followed by a 
4-week safety follow-up in participants with a confirmed diagnosis of ALS.
Participants will be randomized in a 1:1 ratio across two dosing regimens:
600 mg BLZ945 the first 4 days of a two-week period in repeated cycles i.e.
4 days on and 10 days off (4/10) or 400 mg BLZ945 once a week (QW). A PET
sub-study will enroll approximately 4 participants in each arm at specific study
sites. 
 Participants may have 
the option for selected study visits to occur on an outpatient basis in conjunction 
with home nursing on four visit days during the treatment period.
After the completion of the Follow up period (Week 16 visit), eligible participants 
will be offered to continue treatment with BLZ945 for an additional 24 weeks.
Population
The study population will be comprised of adults at least 18 years of age with 
clinically probable laboratory supported, or definite ALS according to the World 
Federation of Neurology Revised El Escorial criteria (Ludolph et al 2015).
Key Inclusion 
criteria
1.
Able to communicate well with the investigator, to understand and comply
with the visits and procedures of the study.
2.
Written informed consent must be obtained before any assessment is
performed.
3.
Male and female participants of at least 18 years of age, who are diagnosed
with familial or sporadic ALS according to the World Federation of
Neurology Revised El Escorial criteria of either bulbar or limb onset.
4a. Cohort 1-4: Able to swallow medication capsules, in the opinion of 
the investigator.
5.
Disease duration from symptoms onset no longer than 48 months at
the screening visit.
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6.
Participants undergoing PET assessments: Having a SVC (slow vital
capacity) equal to or more than 60% predicted normal value per local
standards for gender, height, and age at the screening visit.
7a. Females of childbearing potential must have a negative pregnancy test at 
screening and/or baseline.
8a. Participants undergoing PET assessments: High-affinity binders (HAB) to 
TSPO, as evaluated by genotyping for the rs6971 polymorphism in the 
TSPO gene at the screening visit.
9.
Participants undergoing PET assessments: Baseline PET scan of sufficient
image quality, as determined by the PET experts, for the measurement of
[11C]-PBR28 volume of distribution (Vt) in the relevant CNS regions.
10b. Treatment with currently approved therapies is allowed, but participants 
need to be on a stable dose and regimen for at least 30 days prior to 
baseline. In case of riluzole, participants need to be on a stable dose and 
regimen for at least 90 days prior to baseline.  In case for edaravone, the 
participant can be included if the initial BLZ945 dosing days can be 
scheduled off period of the edaravone treatment regimen.
11. Participants undergoing PET assessments: An Upper Motor Neuron Burden
(UMNB) scale level ≥25 at the screening visit.
12. Participants undergoing PET assessments: BMI between 18 – 35 kg/m2 at
the screening visit.
13. Cohort 5 extended treatment period: Written informed consent for
the extended treatment must be obtained before any assessment in
the extended treatment period is performed.
14. Cohort 5 extended treatment period: Having completed the 12-week
treatment period and the 4-week follow-up.
15. Cohort 5 extended treatment period: Females of childbearing potential must
have a negative pregnancy test at Week 16 and agree to continue
the contraception methods used in the treatment period.
Key Exclusion 
criteria
1a. A history of clinically significant ECG abnormalities, or any of the following 
ECG abnormalities at screening and/or baseline
•
QTcF > 450 msec (males)
•
QTcF > 460 msec (females)
2.
Active hematologic, hepatic, or respiratory disorders that are clinically
significant and may jeopardize the participant's safety if participating in
the study or limit his/her participation in the study, including ability to tolerate
the imaging studies.
3.
Active dementia, neurologic diseases other than ALS, or psychiatric illness,
that in the opinion of the investigator would limit their participation in
the current study.
4.
Use of other investigational drugs within 5 half-lives of screening, or until the
expected PD effect has returned to baseline, whichever is longer; or longer
if required by local regulations.
5.
History of hypersensitivity to any of the study treatments or excipients or to
drugs of similar chemical classes.
6.
Presence of human immunodeficiency virus (HIV) infection based on
screening lab results.
7.
Evidence of active or latent tuberculosis as assessed by Quantiferon or
similar testing as per local practice at screening.
8.
Positive serology for hepatitis B surface antigen, or hepatitis C antibodies
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9a. Signs or symptoms, in the judgement of the investigator, of a clinically 
significant systemic viral, bacterial or fungal infection within 30 days prior to 
the screening visit.
COVID-19 specifically: COVID-19 testing as per local practice will be 
completed within 3 days prior to first dosing. Positive COVID-19 results 
would exclude participants from being enrolled into this study. 
10a. Cardiac disorders, such as recent cardiac history (within 6 months) of 
acute coronary syndrome, acute heart failure, or significant ventricular 
arrhythmia at the screening visit or participants with a history of severe 
pulmonary hypertension, or cardiac failure class 3 or 4 of the NYHA 
classification, or history of reduced LVEF (<45%), or individuals with 
implanted cardiac pacemaker, or defibrillator.
11. Any of the following abnormal laboratory values at the screening visit:
•
Total white blood cell count (WBC) outside the range of 1,500-
15,000/mm3 (1.5-15.0 x 109/L)
•
Platelets< 100,000/mm3 (100 x 109/L)
•
Hemoglobin (Hgb) < 8.0 g/dL (<0.5 mmol / L)
•
Lymphocyte count <500/mm3 (<0.5 X 109 / L)
12. Clinical evidence of liver disease or liver injury or any of the following
hepatic conditions at the screening visit:
•
Active chronic liver or biliary disease
•
Direct bilirubin greater than the 1.5 x ULN
•
Alkaline phosphatase (AP) greater than 3 x ULN
•
AST (SGOT), ALT (SGPT) greater than 3 x ULN
•
Gamma-glutamyl-transferase (GGT) > than 3 x ULN
13. 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 14 days after last dose of
BLZ945. Highly effective contraception methods include:
•
Total abstinence (when this is in line with the preferred and usual
lifestyle of the participant). Periodic abstinence (e.g., calendar,
ovulation, symptom-thermal, 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 study treatment. In case of oophorectomy alone,
only when the reproductive status of the woman has been confirmed by
follow up hormone level assessment.
•
Male sterilization (at least 6 months prior to screening). For female
participants on the study, the vasectomized male partner should be
the sole partner for that participant.
•
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 have been stable on 
the same pill for a minimum of 3 months before taking study treatment.
14. Pregnant or nursing female participants.
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taking the drug during treatment, for 14 days after stopping BLZ945 and should 
not father a child in this period. A condom is required to be used also by 
vasectomized men in order to prevent delivery of the drug via semen.
16. Intentionally left blank; removed in amendment 02
17. Participants undergoing PET assessments: Any contraindications to MRI,
including but not limited to the following:
•
Brain Aneurysm Clip
•
Implanted cardiac pacemaker, pacemaker wires or defibrillator
•
Prosthetic heart valves
•
Cochlear implant
•
Ocular foreign body (e.g. metal shavings)
•
Implanted insulin pump
•
Tattoos (as determined by radiologist)
•
Known claustrophobia
18. Taking medications prohibited by the protocol (see Section 6.2.2 (Prohibited
medication) or Table 6-4 (Prohibited medication/procedure)).
19a. Participants undergoing PET assessments: Any contraindications to 
the line sampling, including but not limited to the following:
•
Thromboangiitis obliterans (Buerger disease)
•
Full-thickness burns over the cannulation site
•
Inadequate circulation to the extremity
•
Raynaud syndrome
•
Coagulopathy
•
Inadequate collateral flow
•
Infection at the cannulation site
•
Partial-thickness burn at the cannulation site
•
Previous surgery in the area
•
Synthetic vascular graft in the area
20. History or presence of impaired renal function as indicated by clinically
significantly abnormal creatinine or BUN and/or urea values, or abnormal
urinary constituents (e.g., albuminuria) at the screening visit.
21. Active suicidal ideation as measured by a response of “yes” on item 4 or
item 5 of the Suicidal Ideation section of the C-SSRS, if this ideation
occurred in the past 6 months; or “yes” on any item of the Suicidal Behavior
section, except for the “Non-Suicidal Self-Injurious Behavior” question of
that section of the C-SSRS, if this behavior occurred in the past 2 years. A
response of "Yes" to these questions is considered exclusionary at
screening.
22a.History of drug abuse or harmful alcohol use within the 12 months prior to 
dosing within the judgement of the investigator and the below definition, or 
evidence of such abuse as indicated by the laboratory assays conducted 
during screening. Harmful alcohol use is defined as a history of, or current 
alcohol misuse/abuse, defined as “Five or more standard drinks on 
the same occasion on each of 5 or more days in the past 30 days prior to 
screening."
23. Inability or unwillingness to undergo repeated venipuncture or arterial
cannulation, or in the opinion of the investigator, participant would be at an
increased risk for adverse events related to these procedures.
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24. Active GI conditions such as Barrett’s esophagus, achalasia, esophageal
varices and active or history of esophageal cancer, pre-existing pancreatic
disease
25. History of active vasculitis or history of autoimmune disease associated with
vasculitis (eg. RA, SLE, Sjögrens disease, scleroderma)
26. History or current cardiac valve disorder, such as clinically significant
stenosis or regurgitation (CTCAE grade ≥2), congenital valve disease, or
other clinical condition that might affect cardiac valve function (excluding
hemodynamically insignificant mitral valve prolapse)
27. Use of systemic anticoagulation that cannot be temporarily paused before
study procedures (LP arterial line placement for PET scan)
28. Cohort 5 extended treatment period: Participants who are planning to
initiate treatment with an additional approved ALS therapy in the next
24 weeks
29a. Cohort 5 extended treatment period:  Clinically relevant changes on CT 
scan or echocardiography, signs of vasculitis, or evidence of a significant 
medical condition meeting treatment discontinuation criteria at EoT1 or 
EoS1 visits even if finding has resolved at EoS1
Study treatment
BLZ945 (sotuletinib)
Efficacy 
assessments
•
Cohorts 1-5: PET imaging of [11C]-PBR28 binding as a measure of
the pharmacodynamic effect of BLZ945 on brain microglia.
Key safety 
assessments
•
Cohorts 1-5: Adverse event monitoring, Physical examinations, monitoring
of laboratory markers in blood and urine, ECG.
•
Cohort 5:  Echocardiogram, CT scan
Other 
assessments 
Data analysis
Analysis of the primary objective:
1.
Cohorts 1-4: Change of Vt in different brain regions as assessed by
[11C]-PBR28 PET imaging, from baseline after BLZ945 treatment
2.
Cohort 5: The percent change from baseline to Week 12 in Vt measured via
PET scan.
3.
Cohort 5: The changes from baseline to Week 12 in: esophagus wall
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thickness (mm) and LVEF (%)
4.
Cohort 5: Any worsening from baseline to Week 12 in cardiac valve
thickness and cardiac valve function (stenosis and regurgitation).
5.
Cohort 5: Adverse events of ECM accumulation during the first 12 weeks of
treatment.
Analysis of the secondary objective:
1.
Cohorts 1-5: Frequency of relevant findings on physical examination,
neurological examination, vital signs, hematology, chemistry, urinalysis,
ECG evaluation, AE and SAE recordings
2.
Cohorts 1-4: Relative change from baseline in % in Vt of [11C]-PBR-28 after
BLZ945 treatment depending on the pharmacokinetic exposure of BLZ945
PK assessment
3.
Cohorts 1-4: Relative change from baseline in % in Vt of [11C]-PBR28 after
BLZ945 treatment versus other PD markers
4.
Cohorts 1-4: Relative change from baseline in % in Vt [11C]-PBR28, at 4 or
10 or 15 days post treatment cessation
5.
6.
Cohort 5: BLZ945 plasma PK parameters  on Day 4 (Arm #1) or on Day 1
(Arm #2)
Key words
Phase II, BLZ945, CSF-1R, Safety, [11C]-PBR28
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1
Introduction
1.1
Background
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by 
progressive loss of motoneurons (MNs) in the motor cortex, brainstem and spinal cord. 
It manifests with skeletal muscle weakness, spasticity and progressive paralysis, leading to the 
death of subjects by respiratory failure 3 to 5 years after diagnosis (Kiernan et al 2011). 
Although some drugs are currently approved for the treatment of ALS, none offer a 
significant improvement in survival of individuals with ALS. Thus, there is a significant 
unmet medical need for the treatment of ALS. Neuroinflammation plays a key role in many 
neurodegenerative diseases including ALS (Rodríguez, Mahy 2016). Indeed, an important 
pathophysiological mechanism in ALS is microglial activation, that is associated with 
degenerative motor neurons. Further, recent evidence links macrophage colony-stimulating 
factor 1 receptor (CSF-1R)-dependent microgliosis with ALS disease progression 
(Martínez-Muriana et al 2016).
Upon activation, microglial cells demonstrate increased expression of the 18 kDa translocator 
protein (TSPO). [11C]-PBR28 is a positron emission tomography (PET) radiotracer for TSPO 
that is used to image neuroinflammation in vivo (Albrecht et al 2018, Zürcher et al 2015, 
Alshikho et al 2016, Alshikho et al 2018). Further references in the protocol to measures of 
change in microglia refer to TSPO binding, which is a measure of microglial content.
BLZ945 (sotuletinib) is a potent and selective low molecular weight tyrosine kinase inhibitor 
of the receptor CSF-1R. It shows functional activity in in vitro assays with normal human 
donor peripheral blood mononuclear cells as well as in transgenic mouse models. In animal 
models of ALS (SOD1G93A mice) BLZ945 showed dose-dependent microglia clearance as 
well as dose-dependent beneficial effects on weight maintenance and reductions in decline of 
grip strength. For additional information on BLZ945, please refer to the Investigator Brochure. 
Novartis is developing BLZ945 as a potential disease-modifying oral treatment for ALS by 
targeting microglia cells.
The planned study will evaluate the effect of BLZ945 on neuroinflammation in participants 
with ALS as measured by [11C]-PBR28 PET imaging. Preliminary results from Cohorts 1-4, 
suggest that microglia reduction following BLZ945 dosing may persist for up to 10 days off 
drug, suggesting that there could be a cumulative effect with repeated dosing cycles. 
The planned Cohort 5 will evaluate the safety and tolerability of BLZ945 with 
the administration of repeated dosing cycles, as well as evaluate the effect on 
neuroinflammation as measured by [11C]-PBR28 PET imaging (PET Sub-study) 
 
Data on microglia reduction and safety will be assessed to demonstrate proof of mechanism 
and to select potential doses of BLZ945 for future studies in ALS participants. Expected 
adverse events include elevation of transaminases (AST/ALT) and creatine kinase (CK) due 
to reduction in hepatic Kupffer cells, which share a macrophage lineage with microglia and 
are responsible for liver transaminase and CK clearance. 
 
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 Periorbital, orbital, 
eyelid, and face swelling has been observed in a study of BLZ945 in patients with advanced 
solid tumors (CBLZ945X2101) after treatment with BLZ945 and have been reported in 
studies with other CSF-1 and CSF-1R inhibitors (Pognan et al 2019). 
1.2
Purpose
The purpose of Cohorts 1-4 of this study is to identify a dose (or doses) of BLZ945, that 
decrease(s) TSPO binding by at least 20% in the brain of ALS participants, and to evaluate 
the safety and tolerability of BLZ945 in ALS participants at these doses and dosing regimen. 
PET imaging with a ligand selective for TSPO is widely used as a marker for microglial 
activation. Following microglia reduction, the repopulation of microglia in ALS participants 
will be assessed at different times post dosing. 
Since there is no established clinically meaningful threshold for reduction of activated 
microglia, a threshold of a decrease of 20% has been chosen since this exceeds the published 
variability of the [11C]-PBR28 PET imaging biomarker (5-10%) and would therefore be of 
sufficient magnitude to be unlikely to be the result of chance.
The purpose of Cohort 5 is to evaluate the safety, microglia reduction (PET sub-study) and the 
changes in blood 
 after repeated cycles of BLZ945 
using two dosing regimens over 12 weeks. The 24-week extended treatment to Cohort 5 aims 
to evaluate safety and tolerability of BLZ945 and maintenance of its pharmacodynamic 
effects with prolonged treatment.
2
Objectives and endpoints
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)
•
Cohorts 1-4 and Cohort 5 (PET Sub-
study): To evaluate brain microglial
reduction, as measured by reduction in
TSPO binding, following treatment with
BLZ945 in ALS participants by using
PET imaging with [11C]-PBR28
•
Volume of distribution (Vt) in different brain regions
for each [11C]-PBR28 PET scan, and change after
BLZ945 treatment
•
Cohorts 1-4: at Day 5 (or 8) following 4 (or 7)
oral doses of BLZ945 compared to baseline
•
Cohort 5 (PET sub-study): at Week 12
following repeated cycles of BLZ945 compared to
baseline
•
Cohort 5: To assess safety-related
effects on ECM accumulation under
BLZ945 treatment
•
Cohort 5: Changes in esophageal wall thickness
(based on CT-scans) at Week 12 compared to
baseline
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Objective(s)
Endpoint(s)
•
Cohort 5: Cardiac valve thickness, cardiac valve
function (stenosis and regurgitation based on
echocardiography) and Left Ventricular Ejection
Fraction (LVEF) as indicator of cardiac function
(based on echocardiography) at Week 12compared
to baseline
•
Incidence of AEs related to ECM accumulation
during the first 12 weeks of treatment
Secondary objective(s)
Endpoint(s) for secondary objective(s)
•
Cohorts 1-5: To characterize the
pharmacokinetics (PK) of BLZ945 in
participants with ALS.
•
Cohort 1-4:
•
Plasma: PK parameters on Day 1 and Day of
last treatment (Day 4 or Day 7) (e.g. Cmax,
Tmax, AUC, T1/2).Urine: renal clearance
(CLR) on Day 1 and Day of last treatment
(Day 4 or Day 7)
•
Cohort 5: BLZ945 plasma concentrations and
selected PK parameters (Cmax, Tmax, AUClast,
Tlast) on Day 1 (Arm #2) and Day 4 (Arm #1) as
feasible
•
Cohorts 1-5: To evaluate safety and
tolerability of BLZ945 in participants with
ALS at the planned doses and dosing
regimen.
•
Cohorts 1-5: Relevant clinical findings - as per
assessment schedule - on physical
examination, neurological examination, vital signs,
hematology, chemistry, urinalysis, ECG evaluation,
AE and SAE recordings during the entire duration
of the study (including extended treatment period)
•
Cohorts 1-5: To assess the CYP2C8
pharmacogenomic-pharmacokinetic
relationship
•
CYP2C8 genotypes and BLZ945 plasma PK
parameters
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3
Study design
3.1
Cohorts 1-4
This study is an exploratory, adaptive, open-label study of a single treatment cycle of multiple 
oral doses of BLZ945 in ALS participants, administered using either a 4 days on / 10 days off 
or a 7 days on 7 days off treatment regimen.
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The first four cohorts in the study consist of an up to 42-day screening and baseline period, 
a treatment period of a minimum of 4 days and a maximum of 7 days, a follow-up period until 
day 36 (for 4 day cohorts) or day 40 (for 7 day cohorts) (during this period repopulation of 
microglia will be assessed); see Figure 3-1. The maximum study duration for each participant, 
including the 42-day screening visit, is 80 days for the 4-day cohorts and 84 days for the 
7-day cohort.
Figure 3-1
Study design Cohorts 1-4
This is a multiple ascending dose study with the starting dose of 300 mg daily for four days. 
After each dosing cohort and before proceeding to the next cohort, a review of all available 
data will be conducted, including pharmacodynamic (PD) (% microglial reduction), and 
safety/tolerability (continued review of adverse events, laboratory assessments, blood pressure 
and ECG data) data. PK data from the first three dosing cohorts (planned as 300 mg, 600 mg, 
1200 mg) will be reviewed after the third dosing cohort prior to proceeding to the fourth 
dosing cohort. The PK review will be done to assist with the determination of the appropriate 
next dose(s). The PK data may be reviewed prior to the initiation of any dosing cohort should 
this information be determined by the Investigators and/or Sponsor as necessary for decision-
making purposes. The decision to proceed to the next dose cohort will be made jointly 
between the Sponsor and the Investigator.
Dosing will continue according to the dose escalation schedule shown in Figure 3-2. 
If a decision is made not to proceed to the next (higher) planned dose, according to the dose 
escalation criteria outlined in Section 6.5.1 then dosing may be resumed at 300 mg and 
the dosing regimen may be extended to 7 days of BLZ945, as indicated in Figure 3-2. 
Alternatively, following a review of the available data and discussion between the Sponsor 
and the Investigator, if notable adverse events or safety concerns are found at one of 
the planned dose levels, the next planned 4-day dosing level may be modified (within the 
range of 150 mg to 1200 mg) based on the available data from previous cohorts.
The first dosing cohort will receive a dose of 300 mg per day. A total of five cohorts are 
planned (300 mg, 600 mg, 1200 mg, plus two additional cohorts at doses to be determined 
between 150 mg and 1200 mg, inclusive). The dose for the two additional cohorts will be 
determined by a decision algorithm. The recommended dose and dose regimen for the next 
cohort of participants (as per Figure 3-2) will be guided by the BLRM (Bayesian Logistic 
Regression Model) with EWOC (Escalation with overdose control) principle. The general 


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approach will be to fit an Emax model to TSPO binding as a measure of microglial reduction 
data at Day 5. An informative prior distribution for the parameters will be derived from 
available animal data (See Table 4-1). Prior distributions will be determined before study start, 
and documented in the Statistical Analysis Plan. After each cohort of 4 participants, the 
posterior distributions of the efficacy curve will be updated, and the next dose and number of 
doses chosen. Clinical judgement will always be used in combination with the 
recommendation of the dose-finding algorithm when the next cohort is to be dosed. Dose and 
dose duration modification decisions will be made by Investigators and Novartis study 
personnel. Decisions will be based on a synthesis of all relevant data available from all dose 
levels evaluated in the ongoing study including safety information, DLTs, all CTCAE 
Grade ≥ 2 toxicity data, PK, and PD data from evaluable participants.
For further details on the decision to dose escalate, see Section 6.5.
Figure 3-2
The different cohorts in the adaptive design (Cohorts 1-4)
Note: a 800 mg dose was selected for Cohort 4
Each participant will undergo:
•
The screening and baseline visit to assess eligibility.
•
An MRI at the end of screening period (after rs6971 genotype is known, and eligibility is
confirmed from the other screening visit assessments) for delineation of the brain regions
of interest (ROIs), through either stand-alone MRI or during PET/MRI scanning if
PET/MRI is used. Safety assessments during screening/baseline, treatment and EOS
periods will be performed according to the assessment schedule and PK samples will be
collected prior to dosing and at the time points after dosing as indicated in the assessment
schedule (Table 8-1, Table 8-2, Table 8-3, Table 8-4).
•
A maximum of three PET scans are scheduled (maximum total effective radiation dose of
approx. 6.93 mSv per participant). These will include the baseline PET scan and up to two
additional PET scans, which will be performed following the multiple dose administration
of BLZ945. The 2nd PET scan will be performed one day after last dosing, and the 3rd PET
scan as per Figure 3-3. Refer to Table 8-1 and Table 8-3 for accepted visit windows.


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A transmission scan for attenuation correction will be acquired before each PET scan 
using an appropriate method [example: a 137Cs point source or a low dose CT scan 
depending on the PET system used, i.e. High Resolution Research Tomography (HRRT) 
or PET/CT (maximum total effective radiation dose of approx. 8.1 mSv per participant if 
CT is used for attenuation correction)].
•
1st PET Scan
•
In order for the participant to be eligible for the study and be dosed with BLZ945,
the baseline PET scan (which is taken during screening period and at latest at
baseline) must be of sufficient image quality to enable the measurement of Vt in
the relevant brain regions.
•
2nd and 3rd PET Scan
•
The 4 participants in the first cohort (300 mg) will have a 2nd PET scan with
[11C]-PBR28 one day after the last BLZ945 administration (Day 5) to assess
microglial reduction.
•
The repopulation of microglia will be assessed during the 3rd PET scan.
Because the TSPO binding is anticipated to only minimally decrease at the
300 mg dose, no 3rd PET scan will be acquired in the first cohort. For subsequent
cohorts, a 3rd PET scan will be acquired to evaluate repopulation of microglia.
The 3rd PET scan will be performed 10 days after last dose (Day 14 or Day 17) in
the second cohort. The timing of the 3rd PET scan for the next cohort(s) will be
determined after review of the results of the previous cohort(s).
If the TSPO binding signal in the motor cortex in the 3rd PET scan has already
returned to at least 80% of the baseline level by 10 days after treatment cessation,
then the 3rd PET scan may be performed earlier (relative to treatment cessation)
for the next cohort(s).
If the TSPO binding signal in the motor cortex has not returned to 80% of
the baseline signal by 10 days after treatment cessation, then the 3rd PET scan
may be performed later (relative to treatment cessation) in the next cohort(s)
(See Figure 3-3).
The decision regarding the timing of the 3rd PET scan will be made jointly
between the Sponsor and the Investigator during the dose escalation decision
meeting.
If the data suggest that the pre-defined time points for the 2nd and 3rd PET scans
are not properly timed to capture either the maximal effect on microglial
reduction or repopulation, then the 2nd and 3rd PET scan time points may be
further revised, as described in the SOM.
If the 2nd or 3rd PET scan cannot be performed on the planned day for any reason,
the assessment can be scheduled per the visit windows stated in the assessment
schedule.
•
Participants in the subsequent cohorts (Cohorts 2 to 4) will undergo identical
assessments with the exception of the BLZ945 dose (and possibly dosing duration) and
the timing of the post-dose PET scans.


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For Cohorts 1-3, the 3rd PET scan was conducted on Day 14. Following a review of the data 
from Cohorts 1-3, which showed that the TSPO PET signal had not returned to at least 80% of 
the baseline, the 3rd PET scan in Cohort 4 was performed at Day 19.
Figure 3-3
Decision algorithm for the timing of the third PET scan in subsequent 
cohorts up to Cohort 4 (for dosing cohorts above 300 mg / day)
At the time of amendment 5, Cohorts 1-4 have been completed. In each cohort, 4 participants 
received 300 mg (Cohort 1), 600 mg (Cohort 2), 1200 mg (Cohort 3) or 800 mg (Cohort 4) 
BLZ945 over 4 days. Following review of the data from the first three cohorts, supported by 
PK modeling, 800 mg over 4 days of dosing was selected as the dose level for Cohort 4. 
The planned 7 days dosing cohort was not conducted and will not be considered further.
3.2
Cohort 5
Cohort 5 will consist of an open-label, randomized, two-arms study investigating two BLZ945 
dosing regimens. Participants with confirmed diagnosis of ALS will receive repeated 
treatment cycles of BLZ945 either 4 days on followed by 10 days off or once weekly. 
 Approximately, a total of 40 participants are planned to 
be enrolled in Cohort 5 (also see replacement policy Section 9.1.1.2).
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The cohort includes a screening period (up to 6 weeks), a 12-week treatment period, followed 
by a 4-week safety follow-up (Figure 3-4). Participants who completed the 12-week treatment 
period as per assessment schedule (Table 8-5) consent and are eligible, may continue to an 
additional 24-week extended treatment period on the same regimen (Figure 3-5).
Participants will be randomized in a 1:1 ratio across two dosing regimens: Arm #1: 600 mg 
BLZ945 in repeated cycles of 4 days on treatment followed by 10 days off treatment (4/10) or 
Arm #2: 400 mg BLZ945 once a week (QW). 
Participants previously screened or dosed in Cohorts 1 to 4 may be enrolled in Cohort 5 if 
they meet eligibility criteria. 
A PET sub-study will enroll approximately 8 participants at specific study sites. 
Figure 3-4
Study design Cohort 5
x = drug administration
W = week of treatment
* 4 weeks follow up in all participants + 8 weeks for recovery in participants with findings
# Cohort 5 
 PET sub-study will recruit approximately 8 participants at 
selected sites
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Figure 3-5
Study design Cohort 5 including the 24-week extended treatment period
* 4 weeks follow up in all participants + 8 weeks for recovery in participants with findings
Each participant in Cohort 5 will undergo:
•
The screening and baseline visit to assess eligibility
•
The treatment period of 12 weeks
The follow-up period without treatment for 4 weeks (and up to 12 weeks), including
the end of study visit (EoS 1).
Participants who are eligible and willing to continue in the 24-week extended treatment period 
will receive additional treatment for 24 weeks and will be followed up for one year via phone 
calls.
All participants will undergo a CT-scan of the esophagus and an echocardiogram at screening 
after eligibility is confirmed from other screening visit assessments, and at Week 12 (End of 
Treatment 1). If a participant discontinues treatment before Week 4, the subsequent CT-scan 
and echocardiography planned at EoT1 visit (Week 12) do not need to be performed.
An additional safety follow-up visit with the corresponding procedure (CT scan or 
echocardiography or both) will be done at Week 24 in participants showing clinically relevant 
changes at Week 12. The additional safety follow-up visit at Week 24 will also be done in 
case of unresolved diagnosed vasculitis; during this visit, safety laboratory tests will be 
performed locally and blood for inflammatory markers of vasculitis will be collected.
The maximum study duration for each participant enrolled in Cohort 5, including the 6-week 
screening period, is 22 weeks, or 30 weeks if an additional safety follow-up visit has to be 
performed.
After the completion of the Follow up period (Week 16 visit), eligible participants will be 
offered to continue treatment with BLZ945 for an additional 24 weeks. The assessments 
conducted at Day 113 will be considered as the baseline assessment for the extended 
treatment period of 24 weeks, ie. up to Week 40. Participants will continue on the same 
dosing regimen during the extended treatment period. Participants who consent to enroll in 
the extended treatment period will be asked to return for safety, tolerability, 
and functional assessments at regular visits as indicated in Table 8-7.
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Participants who discontinue treatment during the extended treatment period will be asked if 
they agree to continue attending the study visits for assessments of safety and clinical function. 
After the end of the treatment period, quarterly telephone contacts for one year will be 
implemented to collect vital status information including survival, initiation of permanent 
assisted ventilation, and feeding tube utilization.
PET sub-study
Participants in the PET sub-study will receive:
•
An MRI at the end of screening period (after rs6971 genotype is known, and eligibility is
confirmed from the other screening visit assessments) for delineation of the brain regions
of interest (ROIs), through either stand-alone MRI or during PET/MRI scanning if
PET/MRI is used. A maximum of three PET scans. These will include the baseline PET
scan and two additional PET scans, which will be performed following repeated dose
administration of BLZ945. The 2nd PET scan will be performed on Week 12 and the 3rd
PET scan on Week 16. Refer to Table 8-5 for accepted visit windows.
A transmission scan for attenuation correction will be acquired before each PET scan
using an appropriate method [example: a 137Cs point source or a low dose CT scan
depending on the PET system used, i.e., High Resolution Research Tomography (HRRT)
or PET/CT ].
•
1st PET Scan
•
In order for the participant to be eligible for the PET sub-study, the baseline PET
scan (which is taken during screening period and at latest at baseline visit) must
be of sufficient image quality to enable the measurement of Vt in the relevant
brain regions.
•
2nd and 3rd PET Scan
•
The participants will have a 2nd PET scan with [11C]-PBR28 at Week 12 to assess
microglial reduction.
•
The repopulation of microglia will be assessed during the 3rd PET scan at
Week 16.
If the 2nd or 3rd PET scan cannot be performed on the planned day for any reason, the 
assessment can be scheduled per the visit windows stated in the assessment schedule.
Remote Procedures
Cohorts 1-4: Participants may have the option for their study visits to occur on an outpatient 
basis in conjunction with home nursing on the visit days between PET scan 1 and 2. 
The remote procedures will be offered in certain countries and sites as determined by Novartis 
based on national and local regulations.
Cohort 5: Participants may have the option for selected study visits to occur on an outpatient 
basis in conjunction with home nursing during treatment period as per Table 8-5.
Home nursing will be implemented at the investigator's discretion and based on risk-benefit 
considerations of the participant's clinical condition.


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Procedures will be performed remotely under the oversight of the Investigator, who retains 
accountability for the oversight and all efficacy and safety decisions with delegation of tasks 
to an off-site healthcare professional. The off-site nurses will be provided by a third-party 
vendor sourced by Novartis. Where a site wishes to use off-site nurses that are not provided 
by Novartis this must be agreed with Novartis before use.
4
Rationale
4.1
Rationale for study design
4.1.1 Rationale for study design for Cohorts 1-4
The study fits an Emax model to the TSPO binding reduction (as a measure of microglia 
reduction) data from all participants at Day 5 and it uses an informative prior derived from 
allometric scaling of mouse data. Further references to measures of change in microglia, in 
this protocol, refer to TSPO binding, which is considered a measure of microglial volume.
For this planned study, which is designed to evaluate changes in activated microglia pre- and 
post-treatment within an individual, a control arm is not needed and an open-label study 
design is appropriate. The dose levels and treatment duration of BLZ945 inducing microglial 
reduction are not known for humans, thus the testing of a range of possible dose levels and / 
or dosing durations may be required.
TSPO is expressed at low levels by glial cells and other cells in the healthy brain. However, 
its 
expression 
is 
highly 
upregulated 
during 
microglial 
activation 
(Banati 2002; 
Cagnin et al 2007; Chen, Guilarte 2008; Tronel et al 2017). TSPO PET imaging is the current 
gold standard technique for in vivo assessment of neuroinflammation and is widely recognized 
as a useful biomarker of activated microglia involvement in CNS disorders. Increased TSPO 
expression has been observed in brain regions of ALS subjects, such as motor cortex, 
compared to healthy controls (Turner et al 2004; Corcia et al 2012; Zürcher et al 2015). 
The PET tracer [11C]-PBR28 is a second generation TSPO radioligand that has been used 
widely to measure microglial activation in neurodegenerative diseases, including ALS. 
It shows higher affinity, superior signal-to-background ratios and more favorable 
pharmacokinetics than the first generation radioligand ([11C]-PK-11195). It is sensitive to the 
rs6971 polymorphism in the TSPO gene and, therefore, genetic stratification is required to 
exclude low-affinity binders (LAB), which would correspond to less than 10% of the 
population (Owen et al 2012; Kreisl et al 2013; Turkheimer et al 2015).
In human studies using PET, both the total number of participants and the number of scans 
per participant are limited. For this study, the number of participants is limited to 
approximately 20 and the number of PET scans is limited to up to 3 for each participant. 
The study will be conducted using an adaptive design to best characterize the exposure–time–
PD relationship. Adaptive-optimal designs can provide an efficient experimental design for 
studies using PET, by minimizing the number of participants and maximizing the information 
obtained.


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For Cohorts 1 to 4 of this study, 16 participants with ALS were enrolled to achieve the 
primary objective of the study. The screening/baseline PET scan is needed to assess binding 
of [11C]-PBR28 to the TSPO receptor, which enables quantification of activated microglia 
before treatment with BLZ945. During the subsequent scans, changes in the binding of 
[11C]-PBR28 in the brain will allow for an indirect measurement of the changes in the amount 
of activated microglia. Arterial blood samples will be drawn during the PET scanning 
procedures to define the metabolite-corrected arterial plasma input function that will be used 
for quantification of the PET data. Quantitative analysis with tracer kinetic modelling and 
arterial input function is the gold standard.
Due to the requirement of frequent blood sampling for PK evaluations during the dosing 
period, participants should be domiciled from Day -1 until the day after last dosing. However, 
participants may have the option for their visits to occur on an outpatient basis in conjunction 
with home nursing. In this situation, home nurses may be able to carry out study activities on 
the visit days between PET scan 1 and 2. Having participants domiciled at the study center or 
allowing them to be at their residence along with home-nursing will facilitate the timely 
collection of these samples and decrease the travel requirements of study participants. If no 
clinically significant AEs are observed at Day 5 in case of a 4-day dosing (or Day 8 for 7 days 
dosing), participants will be allowed to leave the center.
4.1.2
Rationale for study design for Cohort 5
In the previous cohorts, study participants received a single cycle of BLZ945 using a 
4/10 dosing regimen. TSPO PET imaging data from Cohorts 2 to 4 indicated a decline, 
compared to pre-dose, in TSPO PET signal following dosing with BLZ945 in the majority of 
study participants and was still observed at 10 to 15 days off drug. In contrast, peripheral 
monocyte counts returned to baseline by 10 days off drug. This suggests that repeated cycles 
could result in additional TSPO PET signal changes, reflective of brain microglial reduction, 
while allowing for the recovery of peripheral monocyte macrophage lineage cells. Since the 
depletion of peripheral monocyte macrophage lineage cells is an undesirable on-target effect 
of BLZ945, a longer effect centrally could result in a more favorable treatment profile. 
Cohort 5 will therefore extend the duration of treatment to 12 weeks to evaluate the safety and 
preliminary efficacy of repeated cycles of BLZ945, using two dosing regimens. Additional 
safety monitoring assessments based on preclinical data, as well as new clinical and PD 
outcome measures have been added in order to evaluate the safety and efficacy of BLZ945 
administered in these repeated cycles.
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 Participants will 
receive a maximum of 72 doses (for the treatment arm #1, 4/10) and 36 doses (for the 
treatment arm #2, QW) during the entire treatment period of 40 weeks. 
The metabolism of riluzole is mostly hepatic and consists of cytochrome P450-dependent 
hydroxylation 
(phase 
I 
reaction) 
and 
glucuronoconjugation 
(phase 
II 
reaction) 
(Sanderink et al 1997). The primary metabolic pathways of riluzole biotransformation in 
humans may involve direct glucuronidation of riluzole (involving the glucurotransferase 
isoform UGT-HP4) and oxidation of riluzole to N-hydroxyriluzole by CYP1A2 and CYP1A1, 
followed by rapid glucuronidation. Furthermore, riluzole was shown to be a substrate for 
breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp) (Milane et al 2009). 
BLZ945 was identified in vitro as an inhibitor of CYP1A1 and of transporters P-gp and BCRP. 
Phenylbutyrate/taurursodiol is available as oral therapy. It is a fixed combination of sodium 
phenylbutyrate and taurursodiol. No mass balance studies of sodium phenylbutyrate and 
taurursodiol have been conducted in humans to confirm the metabolic pathways and 
elimination routes. Sodium phenylbutyrate/taurursodiol is a substrate of OATP1B3. Sodium 
phenylbutyrate/taurursodiol inhibits CYP2C8 and induces CYP3A4 based on in vitro data 
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4.1.3 
Rationale for choice of background therapy
With the exception of the prohibited medications described in Section 6.2.2, the participants 
can continue on their usual care treatment, according to the treating physician and local 
guidelines.
To date there are three approved drugs in the US for the treatment of ALS, riluzole, edaravone 
and sodium phenylbutyrate/taurursodiol. These three drugs are not approved globally. 
Only riluzole is currently approved in the EU and is therefore considered an AxMP per EU 
Clinical Trial Regulation 536/2014. It is expected that a large proportion of the 
participants enrolled in the study will be under one of these ALS treatments. 


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(Relyvrio US product information). BLZ945 is an inhibitor of OATP1B3 but static modeling 
showed no DDI risk at 800 mg dose of BLZ945. 
 
Edaravone is available as intravenous or oral therapy. Glucuronide conjugation is the primary 
pathway for edaravone metabolism and eight UGTs (UGT1A1, UGT1A6, UGT1A7, 
UGT1A8, UGT1A9, UGT1A10, UGT2B7, and UGT2B17) were found to contribute to the 
production of a significant amount of glucuronide metabolites (Dash et al 2018). The findings 
from in vitro studies demonstrated that, at a clinical dose, edaravone and its metabolites are 
not expected to potentially inhibit CYP enzymes, UGTs and transporters in humans. 
The pharmacokinetics of edaravone are not expected to be significantly affected by inhibitors 
of CYP enzymes, UGTs, or major transporters (Radicava US product information).
In case of approval of new ALS treatments, the same restrictions as defined for eligibility will 
be applied (see Section 5.1). Such therapies are expected to be maintained throughout the 
study duration unless discontinued for medical reasons. Initiation of additional ALS treatment 
during the study is prohibited.
Treatment-naive participants should only be enrolled if, in the opinion of the investigator, 
they can refrain from initiation of an additional approved ALS treatment throughout the 
course of the study.
4.2
Rationale for dose/regimen and duration of treatment
4.2.1
Dosing rationale for the first four cohorts (Cohort 1 - 4)
The starting dose for BLZ945, for participants enrolled in this trial, is set at 300 mg p.o. 
administered once daily for 4 days.
The first in human study with BLZ945 (CBLZ945X2101), is currently ongoing in adult 
participants with advanced solid tumors. The Investigator's Brochure (IB) contains a 
description of the relevant clinical experience from study CBLZ945X2101 with dosing up to 
1200 mg per day with a 4 days on/10 days off dosing regimen. The current study will employ 
similar doses and dosing regimens as used in the ongoing study CBLZ945X2101 and 
described in the IB.
This dosing regimen of 4 days on/10 days off (4/10) has been established to control 
asymptomatic AST/ALT increase, which is believed to be an on target effect due to reduced 
clearance of these circulating transaminases resulting from a drug-induced decrease in 
Kupffer cells, which are also reduced by CSF-1R inhibition. The safety data from the FIH 
study (CBLZ945X2101) has been carefully reviewed to identify a safe starting dose for 
administration to ALS participants. In the ongoing CBLZ945X2101 study, eight participants 
were enrolled and treated at the planned starting dose for this study in ALS participants, 
(300 mg, 4 days on/10 days off, BLZ945). None of the treated participants experienced any 
dose limiting toxicity (DLT).
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The BLZ945 PK in ALS participants was predicted based on 
preliminary PK data in study CBLZ945X2101 (assumes similar PK in ALS participants to 
that in oncology participants). 
The results of the PK/PD modeling 
indicate that 4 days of treatment with the selected starting dose of 300 mg BLZ945 once daily 
is predicted to result in a reduction of 10-12% in brain microglia. In the FIH study 
(CBLZ945X2101), preliminary PK data indicated that BLZ945 AUC0-24h and Cmax 
following a 300 mg once daily administration for 4 days, were between 3.42- and 7.4-fold and 
between 2.7- and 6.7-fold lower, respectively, 
 
 A starting dose of 300 mg has been chosen, since it is lower than 
the current dose being evaluated in the FIH study, CBLZ945X2101. The first cohort will be 
dosed for 4 days to follow the FIH dosing schedule. Dosing will continue according to 
the dose escalation schedule shown in Figure 3-2.
The radiotracer [11C]-PBR28 will be injected as a bolus of approximately 350 MBq i.v. PET 
radiotracers are administered in very low concentrations, which allow for detection of 
ligand-target interactions without prompting a pharmacological effect. According to published 
data, [11C]-PBR28 can be prepared at a sufficiently high specific activity and an injection of 
350 
MBq 
will 
permit 
determination 
of 
activated 
microglia 
(Scott et al 2018; 
Zürcher et al 2015; Alshikho et al 2016).
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4.2.2
Dosing rationale for Cohort 5
Several BLZ945 dosing regimens were explored in a previous oncology study in patients with 
advanced solid tumors, including glioblastoma (CBLZ945X2101). In the CBLZ945X2101 
Phase I/II study conducted in adult participants with advanced solid tumors, 192 patients have 
been exposed to BLZ945 as single agent or in combination with PDR001. In patients exposed 
to BLZ945 single agent, the median duration of treatment was 8.0 weeks (range: 1.0-161 
weeks) in Phase 1 (n=80) and 9.9 weeks (range: 2.0-68 weeks) in Phase 2 (n=22). In patients 
exposed to BLZ945 in combination with PDR001, the median duration of treatment was 
8.0 weeks (range: 2.1-212 weeks) in Phase 1 (n=69) and 8.0 weeks (range: 1.9-27 weeks) in 
Phase 2 (n=21). In the CBLZ945X2101 study a maximal dose of 1600 mg was used with 
a QW regimen and a dose of 1200 mg in cycles of 4/10 was selected for further studies. 
The most frequently observed adverse events (≥ 10 %) that were suspected to be related to 
study drug were enzyme elevations (AST, ALT, CPK, amylase and lipase), nausea, vomiting, 
fatigue, and decreased appetite. For further details on study CBLZ945X2101, please see the 
IB.
Although dosing with 1600 mg/day with a QW regimen and 1200 mg/day with a 4/10 
regimen, was tolerated in patients with advanced solid tumors, in patients with ALS, treated in 
Cohorts 1-4 of study CBLZ945C12201, an increased number of adverse events was seen at 
daily doses of 1200 mg, while dosing at 800 mg per day was generally well tolerated. 
Therefore, the 800 mg dose has been identified as the highest well-tolerated dose in patients 
with ALS. In Cohort 5, two dose-regimens (continuing repeated cycles of 4/10 vs QW dosing 
of BLZ945) will be used to evaluate the PD effects of BLZ945 up to end of treatment.
The 800 mg/day dose level was originally selected for both treatment arms in this Cohort. Of 
the first 12 participants enrolled in Cohort 5, 3 out of 6 who were randomized to the QW 
dosing regimen experienced adverse events of liver transaminase elevations >5 x ULN, one of 
whom was reported as serious. In an effort to reduce the likelihood of further liver enzyme 
elevations, for the remainder of the study, the dose will be reduced to 400 mg in the QW 
dosing arm. The 400 mg dose level closely corresponds to the lowest dose that has been 
previously administered to participants with ALS (300 mg) in Cohort 1 of this study.
Although similar adverse events of transaminase elevations were not seen in the 4/10 dosing 
arm, the observed tolerability with repeated dosing cycles of 4/10 at 800 mg was worse than 
had been seen with a single dosing cycle in Cohort 4. In Cohort 5, two of the six initial 
participants either discontinued treatment or required dose reductions due to poor tolerability. 
Therefore, in an effort to improve tolerability, the dose for the 4/10 regimen will be reduced to 
600 mg. Fewer adverse events were observed at the 600 mg dose level than at the 800 mg 
dose in Cohorts 1-4. 
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The two dose regimens were selected in order to account for the expected accumulation of 
microglia reduction in the CNS with administration of repeated dosing cycles, while allowing 
for the recovery of the peripheral (non-CNS) monocyte macrophage lineage cells between 
dosing intervals, in order to reduce the risk of the undesired peripheral PD effects over 
repeated treatment cycles, such as liver enzyme elevation. In both regimens, the BLZ945 
plasma levels are expected to decrease below the limit of quantification by the end of their 
respective “off” periods, in line with an apparent elimination T1/2 of about 24h.
Although the overall treatment 
duration in Cohort 5 of 36 weeks (12 weeks of treatment followed by 24 weeks extension) 
will formally exceed that of the 13-week repeat dose toxicity studies, treatment over this 
period will result in a maximum of 72 administrations of BLZ945 for the 4 days on/10 days 
off (4/10) dosing regimen and 36 administrations of BLZ945 for the 1 day on/6 days off (QW) 
dosing regimen. Therefore, the total number of administrations to participants will remain 
below the ≥91 administrations (consecutive daily dosing for 13 weeks) that were administered 
to the nonclinical species.
4.3
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
Not applicable.
4.4
Purpose and timing of interim analyses/design adaptations
4.5
Risks and benefits
Because the potential therapeutic effects of BLZ945 are unknown, no clinical benefit to study 
participants is expected.
Potential Risks Related to BLZ945
The study inclusion/exclusion criteria and prohibited medications have been chosen to 
exclude potential participants who are at a greater likelihood to suffer an adverse effect of 
BLZ945; safety monitoring measures have been implemented to mitigate risks to trial 
participants. In addition, an independent DMC will be reviewing individual and aggregated 
data from Cohort 5 throughout the 40 weeks of extended treatment on a regular basis for 
safety oversight.
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Effects on liver enzymes and creatine phosphokinase (CK)
Reversible AST, ALT, and CK elevations may be expected with administration of BLZ945. 
In preclinical studies in rats and monkeys, increased serum ALT, AST and CK activities were 
observed at all doses. The transaminase elevations were reversible upon discontinuation of 
BLZ945 administration and were not associated with tissue damage on histological 
examination. Investigative studies showed that inhibition of the CSF-1 pathway reduces 
clearance of AST, ALT and CK without increased production or evidence of cellular damage, 
and that  this change in clearance correlates with reduction in Kupffer cell numbers 
(Radi et al 2011, Pognan et al 2022). In the study conducted in adult participants with 
advanced solid tumors (CBLZ945X2101), asymptomatic increases in AST, ALT and CK 
were reported with BLZ945 monotherapy in the absence of liver or muscle injury.
In Cohort 5 of study CBLZ945C12201, to date, three participants have experienced 
significant elevations of AST / ALT (grades 3 and 4) in the weekly dosing regimen with 800 
mg, including one potential case of Hy’s Law.  These events resolved approximately 1 month 
after the treatment cessation. Following the observation of these AST / ALT elevations, the 
study protocol was amended to reduce the dose of BLZ945 for future participants.
Participants with liver disease or abnormal liver chemistry will be excluded from the study 
(see details in Section 5.2). Safety monitoring for liver function, close observation and 
follow-up of liver abnormalities and stopping rules have been implemented to mitigate this 
risk. 
Effects on the GI tract
GI events such as nausea, vomiting and diarrhea have been observed in the clinical study 
CBLZ945X2101.
In cohorts 1-4 of study CBLZ945C12201, commonly reported GI events included nausea, 
vomiting, diarrhea, abdominal pain; most of these events were observed in the 1200 mg dose 
group. A lower dose was selected for Cohort 5 to improve GI tolerability.
Effects on bone
In nonclinical studies, findings in bones consisted of thickened and/or dysplastic primary 
growth plate in rats and increased thickness of the physis in monkeys. They were reversible 
and are consistent with inhibition of osteoclasts (Dai et al 2002, Dobbins et al 2002). 
The impact of this potential risk in adults who no longer have active growth plates is currently 
unknown.
Accumulation of extracellular matrix (ECM)
In addition, in the study conducted 
in adult participants with advanced solid tumors (CBLZ945X2101), while periorbital, orbital, 
eyelid, and face swelling has been observed after treatment with BLZ945, clinically 
significant adverse events related to ECM accumulation were not observed and 
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echocardiography measurements did not show changes in cardiac function associated with 
BLZ945 administration.
Participants with active GI conditions that could adversely affect esophageal function, cardiac 
and cardiac valve disorders will be excluded from this study (see details in Section 5.2). 
The planned Cohort 5 of this study includes an assessment of the potential for ECM 
accumulation on heart and cardiac valves (echocardiography) and on the esophagus (CT scan). 
In addition to the follow-up period will be extended up to Week 24 in the event of 
abnormalities on echocardiography or CT scan at Week 12. Participants with safety findings 
at Week 12 that prolong follow-up to Week 24 will not be eligible for entering the extension 
study.
Vasculitis
Furthermore, no specific events indicating an impact 
on blood vessels were observed in the clinical study CBLZ945X2101. This suggests that 
vascular inflammation would be unlikely to occur in the current study using the planned 
doses and intermittent dosing regimens.
Participants with history of active vasculitis or autoimmune disease associated with vasculitis 
will be excluded from this study (see details in Section 5.2). Safety monitoring for vascular 
inflammation will include a detailed assessment of signs and symptoms of vasculitis 
(including guidance in the adverse event diary for the identification of signs and symptoms by 
the patient), detailed physical examination by the investigator or qualified delegate, laboratory 
assessments including markers of general inflammation (i.e., erythrocyte sedimentation rate 
and C-reactive protein), complete blood count, liver function tests, renal function tests (serum 
creatinine, blood urea nitrogen) and urinalysis for hematuria, proteinuria and cell casts. 
A detailed guidance for the identification of potential cases of vasculitis, clinical 
monitoring and management of suspected cases of vasculitis is provided in Section 16.3. 
Stopping rules for participants with confirmed vasculitis have been implemented and 
participants with signs of vasculitis will not be eligible to enter the extension study. 
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4.5.1
Potential risk associated with the COVID-19 Pandemic
Novartis is committed to supporting the safety and well-being of our study participants, 
investigators, and site staff. All local regulations and site requirements are being applied in 
the countries that are affected by the COVID-19 pandemic, including COVID-19 testing of 
participants. The Novartis clinical trial team will review the situation in each participating 
country and work with investigators to continue to ensure the safety of participants during 
the conduct of the trial. BLZ945 may have immunosuppressive effects; the required 
COVID-19 testing prior to dosing, and where home nursing is considered feasible, the risk for 
COVID-19 may be further reduced through the implementation of this option. These factors 
suggest there will be no additional risks related to COVID-19 for participants who enroll in 
this study. As the COVID-19 situation evolves, investigators must use their best judgement to 
minimize risk to participants during the conduct of the study. If participants (Cohorts 1-4) are 
diagnosed with COVID-19 during the treatment period, these participants should be 
discontinued and monitored accordingly. For participants enrolled in Cohort 5, refer to 
Section 6.5.2.
4.5.2
Potential risks associated with exposure to ionizing radiation
This clinical study involves exposure to radiation from the CT and PET examinations. 
These assessments are intended for research purposes only.
Radiation dose for participants from Cohorts 1-4:
•
According to published dosimetry for [11C]-PBR28 (Brown et al 2007), the total radiation
from the PET scans will be approximately 6.93 mSv (693 mrem). This amount of
radiation is equivalent to 2.3 years of exposure to background radiation (average yearly
background dose is approx. 3 mSv in the US).
•
If a low dose CT scan (PET/CT) is acquired for attenuation correction purposes, the total
radiation exposure will be approximately 8.1 mSv (810 mrem), equivalent to 2.8 years of
exposure to background radiation.
The carrier PBR28 mass that will be administered to each participant and each PET 
radiotracer injection is expected to be less than 1 µg and should not exceed 10 µg. Based on 
the literature (Brown et al 2007), i.v. injection of 650 MBq [11C]PBR28 (carrier PBR mass of 
approx. 1.5 μg) produced no clinically observable effects.
Radiation dose for participants from Cohort 5:
•
The total radiation dose from the esophagus CT scans will be approximately 8 mSv
(800 mrem), equivalent to 2.7 years of exposure to background radiation.
•
Those participants who will also be part of the PET sub-study will receive a total radiation
dose of approximately 16 mSv (5.3 years of exposure to background radiation) from
the esophagus CT and the PET assessments.
For effective radiation doses between 3 mSv (300 mrem) and 50 mSv (5000 mrem), the risk is 
considered to be minimal (Stabin 2022) or moderate (ICRP 1991). The radiation exposure in 
this study involves low to moderate risk. This is necessary to obtain the research information 
desired and is balanced against the substantial societal benefit gained from the trial.


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4.5.3
Potential risks associated with arterial cannulation (Participants 
undergoing PET examinations)
Arterial line placement is considered a safe procedure, with a low rate of major complications. 
However, it is not entirely without risk. Arterial cannulation may cause mild-to-moderate pain, 
hematoma, inflammation, bleeding or bruising at the puncture site. It may also cause spasm or 
clotting of the artery with a temporary decrease in blood flow. In rare instances, blocking of 
the artery, tearing of the artery, arterial leakage, poor healing or infection at the site of 
the catheter insertion may occur.
Risks are minimized by having the procedure performed by an experienced physician. Pain is 
minimized by using a local anesthetic. Infection can be avoided by cleansing of the skin prior 
to catheter insertion.
4.5.5
Blood sample volume
A volume smaller than a typical blood donation is planned to be collected over a period of up 
to 8 weeks in Cohorts 1-4, up to 22 weeks for Cohort 5 and up to 40 weeks for extended 
treatment period of Cohort 5, from each participant as part of the study. Additional samples 
may be required for safety monitoring.
Timings of blood sample collection are outlined in the assessment schedule (Table 8-1, 
Table 8-2, Table 8-3, Table 8-4, Table 8-5, Table 8-6 and Table 8-7).
A summary blood log is provided in the Site Operations Manual (SOM). Instructions for all 
sample collection, processing, storage and shipment information is also available in the SOM.
See the section on the potential use of residual samples (Section 8.5.2.2).
4.6
Rationale for Public Health Emergency mitigation procedures
During a public health emergency as declared by local or regional authorities e.g., pandemic, 
epidemic, or natural disaster, mitigation procedures to ensure participant safety and trial 
integrity may be implemented. Notification of the public health emergency as declared by 
local or regional authorities should be discussed among investigators and Novartis. 
All procedures adapted to the situation must be submitted, if required as per local regulations, 
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through a protocol amendment for approval by local or regional Health Authorities and Ethics 
Committees prior to implementation of mitigation procedures.
4.7
End of study definition
Study completion is defined when the last participant finishes their last study visit and any 
repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator.
5
Population
The study population will be comprised of adults who are at least 18 years old with clinically 
probable laboratory supported, or definite ALS according to the World Federation of 
Neurology Revised El Escorial criteria of either bulbar or limb onset (Ludolph et al 2015). 
A total of 16 participants were recruited in Cohorts 1-4. Cohort 5 
 
 PET sub-study will recruit approximately 8 participants.
5.1
Inclusion criteria
Participants eligible for inclusion in this study must meet all of the following criteria:
1. Cohorts 1-5: Able to communicate well with the investigator, to understand and comply
with the study visits and procedures of the study.
2. Cohorts 1-5: Written informed consent must be obtained before any assessment is
performed.
3. Cohorts 1-5: Male and female participants who are ≥ 18 years at screening, and who are
diagnosed with familial or sporadic ALS according to the World Federation of Neurology
Revised El Escorial criteria of either bulbar or limb onset.
4a. Cohorts 1-4: Able to swallow medication capsules, in the opinion of the investigator.
5. Cohorts 1-5: Disease duration from symptoms onset no longer than 48 months at
the screening visit.
6. Cohorts 1-4 and Cohort 5 (PET sub-study): Having a SVC (slow vital capacity) equal to or
more than 60% predicted normal value per local standards for gender, height, and age at
the screening visit.
7a. Cohorts 1-5: Females of childbearing potential must have a negative pregnancy test at 
screening and/or baseline.
8a. Cohorts 1-4 and Cohort 5 (PET sub-study): High-affinity binders (HAB) to TSPO as 
evaluated by genotyping for the rs6971 polymorphism in the TSPO gene at the screening 
visit.
9. Cohorts 1-4 and Cohort 5 (PET sub-study): Baseline PET scan of sufficient image quality,
as determined locally by the PET experts, to enable the measurement of [11C]-PBR28
volume of distribution (Vt) in the relevant CNS regions.
10b. Cohorts 1-5: Treatment with approved ALS therapies is allowed, but participants need to 
be on a stable dose and regimen for at least 30 days prior to baseline. In case of riluzole, 
participants need to be on a stable dose and regimen for at least 90 days prior to baseline. 
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In case for edaravone, the participant can be included if the initial BLZ945 dosing days 
can be scheduled in the off period of the edaravone treatment regimen.
11. Cohorts 1-4 and Cohort 5 (PET sub-study): An Upper Motor Neuron Burden (UMNB)
scale ≥25 at the screening visit
12. Cohorts 1-4 and Cohort 5 (PET sub-study): BMI between 18-35 kg/m2 at the screening
visit.
13. Cohort 5 extended treatment period: Written informed consent for the extended treatment
must be obtained before any assessment in the extended treatment period is performed.
14. Cohort 5 extended treatment period: Having completed the 12-week treatment period and
the 4-week follow-up
15. Cohort 5 extended treatment period: Females of childbearing potential must have
a negative pregnancy test at Week 16 and agree to continue the contraception methods
used in the treatment period.
5.2
Exclusion criteria
Participants meeting any of the following criteria are not eligible for inclusion in this study.
1a. Cohorts 1-5: A history of clinically significant ECG abnormalities, or any of 
the following ECG abnormalities at screening or baseline
•
QTcF > 450 msec (males)
•
QTcF > 460 msec (females)
2. Cohorts 1-5: Active hematologic, hepatic, respiratory disorders that are clinically
significant and may jeopardize the participant's safety if participating in the study or limit
his/her participation in the study, including ability to tolerate the imaging studies.
3. Cohorts 1-5: Active dementia, neurologic diseases other than ALS, or psychiatric illness
that in the opinion of the investigator would limit their participation in the current study.
4. Cohorts 1-5: Use of other investigational drugs within 5 half-lives of screening, or until
the expected PD effect has returned to baseline, whichever is longer; or longer if required
by local regulations.
5. Cohorts 1-5: History of hypersensitivity to any of the study treatments or excipients or to
drugs of similar chemical classes.
6. Cohorts 1-5: Presence of human immunodeficiency virus (HIV) infection based on
screening lab results.
7a. Cohorts 1-5: Evidence of active or latent tuberculosis as assessed by Quantiferon or 
similar testing as per local practice at the screening visit.
8. Cohorts 1-5: Positive serology for hepatitis B surface antigen, or hepatitis C antibodies
confirmed by an appropriate licensed test at screening.
9a. Cohorts 1-5: Signs or symptoms, in the judgement of the investigator, of a clinically 
significant systemic viral, bacterial or fungal infection within 30 days prior to 
the screening visit. COVID-19 specifically: testing as per local practice for COVID-19 
will be completed within 3 days prior to first dosing. Positive COVID-19 test results 
would exclude participants from being enrolled into this study.
10a.Cohorts 1-5: Cardiac disorders, such as recent cardiac history (within 6 months of 
screening) of acute coronary syndrome, acute heart failure, or significant ventricular 


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arrhythmia at the screening visit or participants with a history of severe pulmonary 
hypertension, or cardiac failure class 3 or 4 of the NYHA classification, or history of 
reduced LVEF (<45%), or individuals with implanted cardiac pacemaker, or defibrillator.
11. Cohorts 1-5: Any of the following abnormal laboratory values at the screening visit:
•
Total white blood cell count (WBC) outside the range of 1,500-15,000/mm3
(1.5 - 15.0 x 109/L)
•
Platelets < 100,000/mm3 (100 x 109/L)
•
Hemoglobin (Hgb) < 8.0 g/dL (<0.5 mmol / L)
•
Lymphocyte count <500/mm3 (<0.5 X 109 / L)
12. Cohorts 1-5: Clinical evidence of liver disease or liver injury or any of the following
hepatic conditions at the screening visit:
•
Active chronic liver or biliary disease
•
Direct bilirubin greater than the 1.5 x ULN
•
Alkaline phosphatase (AP) greater than 3 x ULN
•
AST (SGOT), ALT (SGPT) greater than 3 x ULN
•
Gamma-glutamyl-transferase (GGT) > than 3 x ULN
13. Cohorts 1-5: 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 14 days after last dose of BLZ945. Highly effective
contraception methods include:
•
Total abstinence (when this is in line with the preferred and usual lifestyle of
the participant). Periodic abstinence (e.g., calendar, ovulation, symptom-thermal,
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
study treatment. In case of oophorectomy alone, only when the reproductive status of
the woman has been confirmed by follow up hormone level assessment.
•
Male sterilization (at least 6 months prior to screening). For female participants on
the study, the vasectomized male partner should be the sole partner for that participant.
•
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 have been stable on the same pill for 
a minimum of 3 months before taking study treatment.
14. Cohorts 1-5: Pregnant or nursing female participants
15. Cohorts 1-5: Sexually active males unless they use a condom during intercourse while
taking the drug during treatment, for 14 days after stopping BLZ945 and should not father
a child in this period. A condom is required to be used also by vasectomized men in order
to prevent delivery of the drug via semen.
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17. Cohorts 1-4 and Cohort 5 (PET sub-study): Any contraindications to MRI, including but
not limited to the following:
•
Brain Aneurysm Clip
•
Implanted cardiac pacemaker, pacemaker wires or defibrillator
•
Prosthetic heart valves
•
Cochlear implant
•
Ocular foreign body (e.g., metal shavings)
•
Implanted insulin pump
•
Tattoos (as determined by radiologist)
•
Known claustrophobia
18. Cohorts 1-5: Taking medications prohibited by the protocol (see Section 6.2.2 (Prohibited
medication) or Table 6-4 (Prohibited medication/procedure))
19a.Cohorts 1-4 and Cohort 5 (PET sub-study): Any contraindications to the arterial line 
sampling, including but not limited to the following:
•
Thromboangiitis obliterans (Buerger disease)
•
Full or partial thickness burns over the cannulation site
•
Inadequate circulation to the extremity
•
Raynaud syndrome
•
Coagulopathy
•
Inadequate collateral flow
•
Infection at the cannulation site
•
Previous surgery in the area
•
Synthetic vascular graft in the area
20. Cohorts 1-5: History or presence of impaired renal function as indicated by clinically
significantly abnormal creatinine or BUN and/or urea values, or abnormal urinary
constituents (e.g. albuminuria) at the screening visit.
21a.Cohorts 1-5: Active suicidal ideation as measured by a response of “yes” on item 4 or 
item 5 of the Suicidal Ideation section of the C-SSRS at screening, if this ideation 
occurred in the past 6 months; or “yes” on any item of the Suicidal Behavior section, 
except for the “Non-Suicidal Self-Injurious Behavior” question of that section if 
this behavior occurred in the past 2 years. A response of "Yes" to these questions is 
considered exclusionary at screening.
22a.Cohorts 1-5: History of drug abuse or harmful alcohol use within the 12 months prior to 
dosing within the judgement of the investigator and the below definition, or evidence of 
such abuse as indicated by the laboratory assays conducted during screening. Harmful 
alcohol use is defined as a history of, or current alcohol misuse/abuse, defined as “Five or 
more standard drinks on the same occasion on each of 5 or more days in the past 30 days 
prior to screening."
23. Cohorts 1-5: Inability or unwillingness to undergo repeated venipuncture or arterial
cannulation, or in the opinion of the investigator, participant would be at an increased risk
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24. Cohort 5: Active GI conditions such as Barrett’s esophagus, achalasia, esophageal varices
and active or history of esophageal cancer, pre-existing pancreatic disease at screening
visit.
25. Cohort 5: History of active vasculitis or history of autoimmune disease autoimmune
disease associated with vasculitis (e.g., RA, SLE, Sjögrens disease, scleroderma).
26. Cohort 5: History or active cardiac valve disorder, such as clinically significant stenosis
or regurgitation (CTCAE grade ≥2), congenital valve disease, or other clinical condition
that might affect cardiac valve function (excluding hemodynamically insignificant mitral
valve prolapse).
27. Cohort 5: Use of systemic anticoagulation that cannot be temporarily paused before study
procedures (LP, arterial line placement for PET scan)
28. Cohort 5 extended treatment period: Participants who are planning to initiate treatment
with an additional approved ALS therapy in the next 24 weeks
29a. Cohort 5 extended treatment period: Clinically relevant changes* on CT scan or 
echocardiography, signs of vasculitis, or evidence of a significant medical condition meeting 
treatment discontinuation criteria at EoT1 or EoS1 visits even if finding has resolved at EoS1.
* Participants with ≤3mm mean increase in esophageal wall thickness compared to the
baseline (pre-BLZ945 dose), as measured by CT scan who completed EoT1 under the
previous protocol versions are eligible to the extended treatment period.
6
Treatment
6.1
Study treatment
The study drug is defined as single agent BLZ945. The study drug will be provided by 
Novartis.
All dosages prescribed and dispensed to participants and all dose changes during the study must 
be recorded on the Dosage Administration Record electronic Case Report Form (eCRF).
Details on the requirements for storage and management of study treatment, and instructions 
to be followed for participant numbering, prescribing/dispensing, and taking study treatment 
are outlined in the SOM.
In Cohorts 1-4 for the 4-day dosing schedule, participants should take BLZ945 daily for 
4 days at approximately the same time each day in the morning. On days that PK samples are 
obtained, the participants should take BLZ945 during the clinic visit, or in the presence of the home 
nurse, after the pre-dose PK samples and prior to post-dose PK samples, when instructed by the 
study staff and/or home nurse.
In Cohort 5, participants should take BLZ945 in accordance with the regimen to which they 
were assigned upon randomization, at approximately the same time each day in the morning. 
On Day 1 for Arm #2 and Day 4 for Arm #1, participants should take BLZ945 as well as their 
additional ALS treatment(s) (e.g. riluzole or sodium phenylbutyrate/taurursodiol) during the 
clinic visit or in presence of the home nurse. The exact time of the BLZ945 and additional 
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Participants should take BLZ945 on an empty stomach (i.e., fast from food and drink, except 
water) at least 1 hour before or 2 hours after a meal.  Also see Section 6.2.4.1 for dietary 
restrictions.
If vomiting occurs during the course of treatment or after the daily dose, participants should 
not take the study drug BLZ945 again before the next scheduled dose. If the participant 
vomits an intact dose immediately after dose administration, the Sponsor should be contacted 
for determination about repeat dosing.
In Cohort 5, participants are allowed to take BLZ945 via gastric feeding tube. 
Participants will receive instructions on how to prepare and administer BLZ945 from the 
study site staff. The route of BLZ945 administration will be recorded in the CRF. 
6.1.1
Investigational and control drugs
Table 6-1
Investigational drug
Treatment Title
BLZ945
BLZ945
BLZ945
BLZ945
Treatment 
Description
Cohorts 1-4
300 mg, 600 mg, 
800 mg, 1200 mg
daily
Cohorts 1-4
300 mg, 600 mg, 
800 mg, 1200 mg
daily
Cohort 5
400 mg
weekly
Cohort 5
600 mg
4 days on/10 
days off
Type 
drug 
drug 
drug
drug
Dose 
Formulation
capsule
capsule
capsule
capsule
Unit Dose 
Strength(s)
50 mg
200 mg
200 mg
200 mg
Dosage Level(s)
300 mg, 600 mg, 
800 mg, 1200 mg
daily
300 mg, 600 mg, 
800 mg, 1200 mg
daily
400 mg
weekly
600 mg
4 days on/10 
days off
Route of 
Administration
oral
oral
oral/enteral infusion
oral/enteral 
infusion
Use
experimental
experimental
experimental
experimental
IMP
Yes
Yes
Yes
Yes
6.1.1.1
Decentralized Clinical Trial Model (US sites only)
The study medication and all required clinical study supplies may be distributed via direct-to-
participant shipment, if needed to accommodate home nursing.
6.1.2
Additional study treatments
Background treatment with approved ALS therapies is allowed (see Table 6-2), but 
participants need to be on a stable dose and regimen for at least 30 days prior to baseline for 
sodium phenylbutyrate/taurursodiol and at least 90 days prior to baseline for riluzole. 
Background regimens have to be captured in the eCRF accordingly. For Cohort 5, the riluzole 
and sodium phenylbutyrate/taurursodiol background dose and regimen must remain 


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unchanged at least until Day 1 (Arm #2) or Day 4 (Arm #1) included. The riluzole and sodium 
phenylbutyrate/taurursodiol dose administration must be captured in the eCRF (and on the 
patient diary when applicable) on the day of, and on the day before PK samples are collected 
(see Table 8-6).
Initiation of new or additional ALS treatment during the entire treatment duration is 
prohibited.
Participants who are on a stable dose and regimen of an approved treatment for ALS should 
continue throughout the extended treatment period unless they need to discontinue for medical 
reasons. Participants who elect to initiate an additional approved ALS treatment during the 
4-week follow up period, will not be eligible to participate in the extended treatment period.
Table 6-2
Additional study treatment
Treatment Title
riluzole
edaravone
edaravone
sodium 
phenylbutyrate/
taurursodiol
Treatment 
Description
50 mg, Q 12 
hours
60 mg, daily, 
Initial cycle: 14 
days on, 14 days 
off
Subsequent 
cycles: 10 days 
out of 14-day 
periods, followed 
by 14 days drug 
free period
105 mg, daily,
Initial cycle: 14 
days on, 14 days 
off 
Subsequent 
cycles: 10 days 
out of 14-day 
periods, followed 
by 14 days drug 
free period
Initial dose: 3 g 
sodium 
phenylbutyrate 
and 1 g 
taurursodiol, 
daily for 3 weeks
Maintenance: 3 g 
sodium 
phenylbutyrate/ 
1 g taurursodiol, 
Q 12 hours
Type
drug
drug
drug
drug
Dose 
Formulation
tablet
solution
oral suspension
oral suspension
Unit Dose 
Strength(s)
50 mg
30 mg /100 mL
105 mg/5 mL 
3 g sodium 
phenylbutyrate 
and 1 g 
taurursodiol
Dosage Level(s)
100 mg, daily
60 mg, daily
105 mg, daily
Initial dose: 3 g 
sodium 
phenylbutyrate 
and 1 g 
taurursodiol,
Maintenance: 6 g 
sodium 
phenylbutyrate/ 
2 g taurursodiol 
Q 12 hours
Route of 
Administration
oral
intravenous 
infusion
oral/ enteral 
infusion 
oral/ enteral 
infusion
Use
background 
intervention
background 
intervention
background 
intervention
background 
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Treatment Title
riluzole
edaravone
edaravone
sodium 
phenylbutyrate/
taurursodiol
Authorization 
status of the 
AxMP in EEA
Yes
No 
No
No
Participants from European Economic Area (EEA) countries may receive only riluzole and participants 
from non-EEA countries may receive any ALS therapies approved in their country (riluzole, edaravone 
and/or sodium phenylbutyrate/ taurursodiol).
6.1.3
Treatment arms/group
Participants within a treatment cohort in Cohorts 1-4 all receive the same dose of BLZ945.
Participants in Cohort 5 will be randomized to receive either one or the other of the following 
treatment regimens:
•
Treatment Arm #1 – 600 mg 4/10 dosing
•
Treatment Arm #2 – 400 mg QW dosing
Table 6-3
Treatment Arm(s)
Arm Title
Cohort 1-4
Cohort 5
Treatment Arm 
#1
Cohort 5
Treatment Arm 
#2
Cohort 5
Treatment 
extension
Arm Type
Experimental
Experimental
Experimental
Experimental
Arm 
Description
Participants 
received BLZ945 
300 mg (Cohort 
1), BLZ945 
600 mg (Cohort 
2), BLZ945 1200 
mg (Cohort 3), 
BLZ945 800 mg 
(Cohort 4) daily, 
for 4 days.
Participants will 
receive BLZ945 
600 mg in 
repeated cycles of 
4 days on 
treatment 
followed by 10 
days off treatment 
(4/10) during 12 
weeks, followed 
by a 4 week 
period off 
treatment.
Participants will 
receive BLZ945 
400 mg once a 
week (QW) during 
12 weeks, 
followed by a 4 
week period off 
treatment.
Patients on 
Arm#1 and Arm#2 
can enter an 
optional treatment 
extension period if 
eligible and will 
continue 
treatment at the 
same dosing 
regimen during 24 
weeks.
Associated 
Treatment 
Labels
BLZ945
BLZ945
BLZ945
BLZ945


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6.2
Other treatment(s)
6.2.1
Concomitant therapy
The participant must be instructed to notify the investigational site about any new medications, 
herbal remedies and dietary supplements he/she takes after the start of the study treatment.
The participant may need concomitant medication(s) to tolerate the PET and/or MRI scans. 
Any concomitant medications used for this purpose must be documented accordingly.
All medications, procedures, and significant non-drug therapies (including physical therapy 
and blood transfusions) administered after the participant is enrolled into the study must be 
recorded on the appropriate Case Report Forms. Medication entries should be specific to trade 
name, the single dose and unit, the frequency and route of administration, the start and 
discontinuation date and the reason for therapy.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact the Novartis medical monitor before 
enrolling a participant or allowing a new medication to be started. If the participant is already 
enrolled, contact Novartis to determine if the participant should continue participation in the 
study.
6.2.1.1 Permitted concomitant therapy requiring caution and/or action
The following medications are to be used with caution in this study and only after discussion 
and alignment with the study sponsor:
1. Concomitant medications, which are known to be moderate inhibitors or inducers of
CYP3A4/5 or CYP2C8, are permitted to be used with caution but not in combination.
Refer to the SOM for permitted medications that require caution when concomitantly used
with study drug.
2. Concomitant medications which are known to be narrow therapeutic index substrates of
CYP3A4 and/or CYP2C8, are permitted to be used with caution. Refer to the SOM for
permitted medications that require caution when concomitantly used with study drug.
3. Concomitant medications which are known to be substrates of OATP1B1, OATP1B3,
P-gp, BCRP, OCT1, OCT2, OAT3, MATE1, or MATE2-K (with the exception of the
narrow therapeutic index substrates of P-gp and BCRP which are prohibited - see
Table 6-4), are permitted to be used with caution. Refer to the SOM for permitted
medications that require caution when concomitantly used with study drug.
4. Drugs that alter the pH of the upper GI tract (e.g., H2-receptor antagonists, antacids) may
alter the solubility of BLZ945 and reduce its bioavailability. Short-acting gastric acid
modulators containing aluminum hydroxide and magnesium hydroxide, (e.g., Maalox®) or
calcium carbonate (e.g., TUMS®) can be taken. However, it is recommended to take
these drugs at least 1 hour before or 2 hours after administration of BLZ945. H2 receptor
antagonists should be avoided. If participants are using H2 receptor antagonists
(e.g., ranitidine or famotidine) during the course of this study, participants should take
BLZ945 at least 3 hours before H2 receptor antagonists. In addition, next dose schedule of
BLZ945 administration should be at least 6 hours after taking H2 receptor antagonists.


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If any of these medications were taken without prior sponsor consultation, the sponsor 
needs to be consulted before the next dose.
5. Anti-platelet therapies are permitted to be used following discussion and approval by
sponsor.
6.2.2 Prohibited medication
Use of the treatments displayed in the below table are not allowed during the indicated period.
Table 6-4
Prohibited medication/procedure
Medication
Prohibition period
Action to take in 
case prohibited 
medication taken
•
Proton pump inhibitors. Examples include:
omeprazole, pantoprazole, and lansoprazole
1 week before 
treatment start until 4 
days after last BLZ945 
dosing, inclusive.
Discontinue study 
treatment and inform 
immediately sponsor
•
Narrow therapeutic index substrates of PgP
and/or BCRP transporters
From the day of first 
BLZ945 dosing until 4 
days after last BLZ945 
dosing, inclusive
Discontinue study 
treatment and inform 
immediately sponsor
•
Sensitive dual substrate of both BCRP and
OATP1B
From the day of first 
BLZ945 dosing until 4 
days after last BLZ945 
dosing, inclusive
Discontinue study 
treatment and inform 
immediately sponsor
•
Concomitant medications with known risk of
QT prolongation*
•
Hepatotoxic agent (e.g., allopurinol,
methyldopa, sulfasalazine)
•
Any investigational treatment related or not to
ALS
•
Hematopoietic colony-stimulating growth
factors (e.g. G-CSF, GM-CSF, M-CSF) and
thrombopoietin mimetics
•
Therapeutic monoclonal antibodies and
immunosuppressive medication
•
Systemic steroid therapy and other
immunosuppressives
•
Live vaccines
From screening until 
4 days after last dosing, 
inclusive.
Discontinue study 
treatment and inform 
immediately sponsor
•
Study drugs, devices, chemotherapy, or any
other therapies that may modulate immune
responses, including inhibitors colony
Depends on 
immunomodulatory 
treatment
To discuss with the 
Sponsor
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Medication
Prohibition period
Action to take in 
case prohibited 
medication taken
stimulation factor 1 Receptor (CSF-1R)
•
Anticoagulants
Cohorts 1-4: At least 5 
half-lives before the first 
PET scan until after the 
last PET scan has been 
performed
Cohort 5: Anticoagulant 
therapies can be 
permitted for use 
following discussion 
and prior approval by 
sponsor
To discuss with the 
Sponsor
•
Anti-platelet agents including acetylsalicylic
acid (ASA)
Cohorts 1-4: 1 week 
before the first PET 
scan until after the last 
PET scan has been 
performed
Anti-platelet therapies 
can be permitted for 
use following 
discussion and prior 
approval by sponsor
Cohort 5: Can be used 
with caution if permitted 
by local practice, or 
following discussion 
with the sponsor, prior 
to the placement of the 
arterial line required for 
the TSPO PET 
procedure, and prior to 
the LP procedure in the 
other participants.
To discuss with the 
Sponsor
•
Initiation/addition of approved ALS treatment
From screening until 
End of Study.
To discuss with the 
Sponsor
•
Procedure: gastrojejunostomy or jejunostomy
tube
From screening until 
End of Study.
Discontinue study 
treatment and inform 
immediately sponsor
If the participant cannot discontinue a prohibited concomitant medication, the participant may be 
eligible if the participant has been on a stable dose for 3 months, AND Sponsor approval has been 
confirmed.
.
See the SOM for a list of generic names of strong and moderate inducers or inhibitors of 
CYP3A4/5 and CYP2C8, and substrates of transporters OATP1B1/1B3, PgP and BCRP, as 
well as medications with known risk of QT prolongation.
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6.2.3
Rescue medication
There is no known rescue medication. However, in the event of a hypersensitivity reaction, 
treat with appropriate therapy as outlined in the Site Operations Manual.
6.2.4
Restriction for study participants
For the duration of the study, participants should be informed and reminded of the restrictions 
outlined in this section.
6.2.4.1
Dietary restrictions
•
Cohorts 1-5: Participants must avoid consumption of Seville orange (bitter orange) (and
juice), grapefruit or grapefruit juice, grapefruit hybrids, pomelos and star citrus fruits at
least 7 days prior to the first dose of study treatment and until 4 or 7 days included after
last dosing due to potential CYP3A interaction.
•
Cohorts 1-4: In order to avoid wide variations in urine volumes on PK collection days,
participants should be encouraged to have a fluid intake of approximately 240 mL every
4 hours during their waking hours, in addition to the fluid taken with meals and
medication on Days 1 and 4 (in case of 4 days dosing) or Days 1 and 7 (in case of 7 days
dosing).
6.2.4.2
Other restrictions
Not applicable.
6.3
Participant numbering, treatment assignment, randomization
6.3.1
Participant numbering
The subject number assigned to a participant at screening remains the unique identifier for 
the participant throughout the study. For information on subject numbering, please see 
‘subject numbering’ section in the Site Operations Manual.
6.3.2
Treatment assignment, randomization
No randomization will be performed in the first four cohorts of this study. The assignment of 
a participant to a particular cohort will be coordinated between the sponsor and sites.
In Cohort 5, participants will be randomized across the two study arms with a randomization 
ratio of 1:1.
Upon signing the informed consent form by the participant, the investigator or his/her staff 
will contact the IRT and provide the requested identifying information to register a subject 
into the IRT. If participant is eligible for the PET sub-study, results from the genotyping for 
rs6971 polymorphism in the TSPO gene high-affinity binders (HAB) to TSPO will need to be 
available prior to randomization.
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 randomization list will be produced by or under the responsibility of Novartis Global 


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Clinical Supply using a validated system that automates the random assignment of treatment 
arms to randomization numbers in the specified ratio.
The randomization scheme for subjects will be reviewed and approved by a member of 
the Randomization Office.
Follow the details outlined in the Site Operations Manual regarding the process and timing of 
treatment assignment and randomization of participants.
6.4
Treatment blinding
Not applicable.
6.5
Dose escalation and dose modification
6.5.1
Dose escalation guidelines for Cohorts 1-4
Prior to dose changes or dose regimen changes, data review of all safety/tolerability, PK data 
(as applicable) and PD up to 10 days after last treatment for all participants in the dose cohort 
will be performed, and must be assessed as satisfactory to proceed. The decision to proceed to 
the next dose or dose regimen will be made jointly between the Sponsor and the 
Investigator(s).
Data to be reviewed for modification of dose or dose regimen
The dataset that will be evaluated for dose escalation/de-escalation or dose regimen extension 
decisions, in between cohorts, will include the following data up until 10 days after last 
treatment: adverse events, safety laboratory assessments, vital signs, relevant findings on 
physical and neurological examinations, C-SSRS, ECG data, urine analysis, PK (as applicable. 
Refer to Section 3 for more information), PET imaging data.
Criteria for dose escalation
The sponsor and site investigators will perform a joint data review of safety data to assess 
the nature of any adverse events and decide upon study continuation with the next cohort.
In this study, after a minimum of 3 participants have completed Day 5 in the 4-day cohort or 
Day 8 in the 7-day cohort, safety must be reviewed and assessed as satisfactory to proceed to 
the next cohort.
Dose escalation decisions will be made by Investigators and Novartis study personnel. 
Decisions will be based on a synthesis of all relevant data available from all dose levels 
evaluated in the ongoing study including safety information, and all PK (as applicable. Refer 
to Section 3 for more information), and PD data from evaluable participants.
Dose escalation or dose regimen modification will proceed according to the schema illustrated 
in Figure 3-2. Refer to Section 3 for more information. Dosing will continue until the 
maximum planned dose is reached unless a cohort or study stopping rule is met 
(see Section 9.1.4).


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6.5.1.1
Starting dose
The starting doses for BLZ945 will be 300 mg/day for 4 days for Cohort 1.
6.5.1.2
Provisional dose levels
Table 6-5 describes the starting dose and the dose levels that are planned for Cohorts 1 to 4 in 
this trial. A total of five cohorts are planned (300 mg, 600 mg, 1200 mg daily for four 
consecutive days plus two additional cohorts at doses to be determined). Refer to Section 3 for 
more information regarding selection of dosing regimen for cohorts.
Table 6-5
Provisional dose levels
Dose level
Proposed daily dose*
Increment from previous dose
-1**
150 mg
-50%
1
300 mg
(starting dose)
2
600 mg
100%
3
1200 mg
100%
4
800 mg
-33%
5
400 mg
-50%
6
200 mg
-50%
*It is possible for additional and/or intermediate dose levels to be added during the course of the study.
Cohorts may be added at any dose level below the MTD in order to better understand safety, PK, or
PD.
**Dose level -1 represents treatment doses for participants requiring a dose reduction from the starting 
dose level. No dose reduction below dose level -1 is permitted for this study.
6.5.2
Dose reductions/interruptions (Cohort 5)
Safety or tolerability issues
In case of safety or tolerability issues, the BLZ945 dose can be lowered in steps of 200 mg (1 
capsule) per day. BLZ945 dosing may be interrupted for a maximum of four weeks for 
tolerability issues. Dosing can be restarted at the discretion of the investigator upon resolution, 
at the next lower dosing level (for example 400 mg or 200 mg). Once lowered for tolerability 
reasons, the dose should not be increased again. 
Please see Section 16.1 for drug interruption and discontinuation rules in case of liver enzyme 
elevations. 
COVID and other significant infections
A participant who develops clinical symptoms of COVID-19 or other significant infection 
should temporarily interrupt dosing until resolution of symptoms.


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6.6
Additional treatment guidance
6.6.1
Treatment compliance
Cohorts 1-4: The administration of BLZ945 will be conducted on site and witnessed by study 
personnel, or at the participant’s home and witnessed by the home nurse.
Cohort 5: The administration of BLZ945 will be performed on site during Day 1 or Day 4 if 
on-site visits or in the presence of home nurse at the participant`s home if this visit is a home 
nursing visit. Participants will be provided with a diary to capture date and time of study 
treatment intake and riluzole and/or sodium phenylbutyrate/taurursodiol administration 
(Section 8.5.6).
The data on study drug and any other potential therapy will be collected, in order to provide 
information about exposure and compliance. These data should correspond to the information 
requested on the standard CRFs. PK parameters will be determined in participants treated 
with BLZ945 as feasible, as detailed in pharmacokinetics section (Section 8.5.1).
6.6.2
Recommended treatment of adverse events
At present there is insufficient information to provide specific recommendations regarding 
treatment of adverse events (AEs).
The emergence of immune-related AE (irAE) may be anticipated based on general experience 
in clinical studies with similar class of compounds that block the negative immune regulators 
or interfere with immune cell compartments.
An irAE is a clinically important AE of unknown etiology associated with the study drug 
exposure. irAEs are typically low grade and self-limited, often occurring after multiple doses, 
and most frequently involving the GI tract (diarrhea/colitis), skin (rashes), liver (hepatitis), 
and endocrine systems (a variety of endocrinopathies). Serologic and immunological 
assessments should be performed as deemed appropriate by the Investigator, to verify the 
immune-related nature of the AE, and exclude an infectious or metabolic origin of the AE.
Medication used to treat AEs must be recorded on the appropriate CRF.
6.6.3
Emergency breaking of assigned treatment code
This section is not applicable since there is no blinding involved.
6.7
Preparation and dispensation
Each study site will be supplied with study drug in packaging as described under the 
investigational and control drugs section (Section 6.1.1).
BLZ945 will be administered orally to the participant. See the Site Operations Manual for 
further details.


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7
Informed consent procedures
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent. A separate informed 
consent will be signed for continuation in the Cohort 5 24-week extended treatment period.
If applicable, in cases where the participant's representative(s) gives consent (if allowed 
according to local requirements), the participant must be informed about the study to 
the extent possible given his/her understanding. If the participant is capable of doing so, 
he/she must indicate agreement by personally signing and dating the written informed consent 
document.
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 participant source documents.
Novartis will provide to investigators in a separate document a proposed informed consent 
form that complies with the ICH GCP guidelines and regulatory requirements and is 
considered appropriate for this study. Any changes to the proposed consent form suggested by 
the investigator must be agreed 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 participant informed consent and 
should be discussed with the participant 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 participant.
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.
Male participants must be informed that if a female partner becomes pregnant while he is 
enrolled in the study, contact with the female partner will be attempted to request her consent 
to collect pregnancy outcome information.
During the COVID-19 pandemic that may challenge the ability to obtain a standard written 
informed consent due to limits that prevent an on-site visit, the Investigator may conduct the 
informed consent discussion remotely (e.g. telephone, videoconference). Guidance issued by 
local regulatory bodies on this aspect prevail and must be implemented and appropriately 
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documented (e.g. the presence of an impartial witness, sign/dating separate ICFs by trial 
participant and person obtaining informed consent, etc.).
The study includes the option for the participant (at some sites) to have certain study 
procedures performed off-site by an off-site healthcare professional instead of at the study site. 
A separate home nursing document may be used in addition to the main ICF if a patient opts 
for home nursing. It is required as part of this protocol that the Investigator presents this 
option to the participant, as permitted by national and local governing regulations. 
The process for obtaining consent should be exactly the same as described above for the main 
informed consent.
A copy of the approved version of all consent forms must be provided to Novartis/sponsor 
after IRB/IEC approval.
Refer to the Site Operations Manual for a complete list of ICFs included in this study.


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8
Visit schedule and assessments
Assessment schedules (Table 8-1 for 4 days dosing, Table 8-3 for 7 days dosing, Table 8-5 for Cohort 5 and Table 8-7 for the Cohort 5 
extended treatment period) lists all of the assessments when they are performed. All data obtained from these assessments must be supported 
in the participant’s source documentation.
Participants should be seen for all visits/assessments as outlined in the assessment schedule (Table 8-1 for 4 days dosing, Table 8-3 for 
7 days dosing, Table 8-5 for Cohort 5 and Table 8-7 for Cohort 5 extended treatment period) or as close to the designated day/time as 
possible. Refer to timing and preferred order of assessments in the SOM. Missed or rescheduled visits should not lead to automatic 
discontinuation.
Table 8-1
Assessment Schedule, 4 Days dosing cohorts
Period
Screening
Treatment
Follow-up 
EOS
Visit Name
Screening
Baseline22
Treatment24
Follow-up
EOS
Visit Numbers1
1
20
100
110
120
130
140
15023
16023
17023
1999
Days
-42 to -2
-1
1
2
3
4
5
+1
8
±2
14
±2
19
±2
36
±2
Time (post-dose)
-
-
-
Pre-dose
-
-
-
-
-
-
-
-
Informed consent
X
Inclusion / Exclusion criteria
S
S
S
Study completion information
X
Demography
X
Detailed Medical History / 
Current Medical Condition2
X
Hepatitis screen3
S
Alcohol Test and Drug Screen 
3
S
HIV screen3
S
Quantiferon testing 3
S
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Period
Screening
Treatment
Follow-up 
EOS
Visit Name
Screening
Baseline22
Treatment24
Follow-up
EOS
Visit Numbers1
1
20
100
110
120
130
140
15023
16023
17023
1999
Days
-42 to -2
-1
1
2
3
4
5
+1
8
±2
14
±2
19
±2
36
±2
Time (post-dose)
-
-
-
Pre-dose
-
-
-
-
-
-
-
-
Covid-19 PCR testing25
S
S
Pulse rate
X
X
X
Blood Pressure
X
X
X
Body Temperature
X
X
X
Body Height
X
Body Weight
X
Physical Examination
S
S
Fertility assessment4
S
Targeted Neurological 
Examination2
S
S
ALS Functional Rating Scale 
Revised (ALS-FRS-R)
X
X
Slow Vital Capacity (SVC)5
S
Upper Motor Neuron Burden 
Scale (UMNB)
X
X
Columbia-Suicide Severity 
Rating Scale (C-SSRS) 6
X
X
X7
X7
X7
X
Hematology
X
X
X
X
X
X
X7
X7
X7
X
Clinical Chemistry
X
X
X
X
X
X
X7
X7
X7
X
Urinalysis
X
X
X7
X7
X7
X
Thyroid Function Test: T3, T4, 
TSH
S
Coagulation Panel
X
Electrocardiogram (ECG)8
X
X
 X
X
 X
X
X7
 X7
X7 
X
Pregnancy test9
S
S10
S
S7,10
S7,10
S7,10
S


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Period
Screening
Treatment
Follow-up 
EOS
Visit Name
Screening
Baseline22
Treatment24
Follow-up
EOS
Visit Numbers1
1
20
100
110
120
130
140
15023
16023
17023
1999
Days
-42 to -2
-1
1
2
3
4
5
+1
8
±2
14
±2
19
±2
36
±2
Time (post-dose)
-
-
-
Pre-dose
-
-
-
-
-
-
-
-
Study drug administration
X
X
X
X
Participants domiciled11,12
X
X
 X
X
X
X
X21
PK blood collection (BLZ945)
See table below
PK urine collection (BLZ945)
X14
X14
Polymorphism rs6971 
Genotyping
X
CYP2C8 Genotyping
X15
X15
PET scan
X17
X17
X18
X19
X19
X19
Arterial Blood Collection
X17
X17
X
X7
X7
X7
Brain MRI20
X
Adverse Events
X
Concomitant medications
X
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X Assessment to be recorded in the clinical database or received electronically from a vendor
S Assessment to be recorded in the source documentation only
1 Visit structure given for internal programming purpose only
2 Please refer to the SOM for more details.
3 Screening test is done in local lab only.
4 Only for women - Historical documentation is also acceptable; see section Pregnancy and assessments of fertility (in Section 8.4.3).
5 Historical documentation of max 3 months old is also acceptable.
6 The Columbia-Suicide Severity Rating Scale (C-SSRS) also needs to be performed at any unscheduled visit. 
7 For 300 mg cohort, participants should return for Day 14 assessments with the exception of the 3rd PET scan. For other cohorts, this assessment is only to be performed 
at the time of the 3rd PET scan.
8 During the study, 12-lead ECGs should be conducted prior to blood collection.
9 Serum pregnancy test result needs to be available and negative before dosing of the PBR28 tracer for the PET scan and the first BLZ945 dosing.
10 The serum pregnancy test is preferred prior to each planned PET scan. Site can perform PET scan if result of urine pregnancy test within 24 hours of PET scan is 
negative, and local practice allows.
11 Participants may have the option of home nursing during study days 1-4.
12 Percent consumption of meals need to be recorded during the domiciliation period or during the period that the participants are having home nursing visits.
13
14 Five samples will be collected: predose, 0-4, 4-8, 8-12 and 12-24 h post dose
15 CYP2C8 genotyping screening test is needed at only one time point during screening or baseline. If not done at screening and Day -1 and Day 1 visits are combined, 
the sample should be collected pre-dose on Day 1.
16
.
17 Only one Baseline PET scan will be done during the screening period or at latest at Day -1. The PET scan should always be conducted after all other assessments are 
done and participant fulfills all other inclusion criteria (PET scan can proceed if a local result for rs6971 genotyping is available, but enrollment cannot occur until the 
central lab result is available). Baseline PET scan cannot occur on Day 1 if Day -1 and Day 1 visits are combined. If the visits are combined, the PET scan and arterial 
blood collection should be done in the screening period.
18 The 2nd PET scan needs to be of sufficient quality allowing analysis for the participant to be considered for the PD analysis.
19 A 3rd PET scan will be performed either on Day 8 OR Day 14 OR Day 19.  A 3rd PET scan will only be performed for cohorts at higher doses than 300mg. 
The participants of the 600mg cohort, will receive a PET scan at 10 days after last dose. For the following cohorts it may be decided to perform the 3rd PET scan on the 
best timing based on the outcomes of the earlier cohorts (either 4, 10 or 15 days post last dose), which will be decided at the dose escalation meetings.
20 The MRI assessment can be conducted at any time during the screening period once eligibility of the participant is confirmed on all other eligibility assessments (MRI 
can proceed if a local result is available for rs6971 genotyping is available). The assessment will be performed before the PET scan and can be conducted independently 
of the screening visit. This assessment will be done during the PET acquisition if a PET/MRI scanner is used. Historical MRIs within the past year may be used, pending 
central imaging reader approval.
21 Participant is discharged on this day after assessments unless otherwise determined by the investigator.
22 Day -1 visit can be combined with Day 1 visit per the discretion of the investigator. If combined, Day -1 assessments not previously done at screening need to be done 
on Day 1 prior to dose administration.
23 Day 8 OR Day 14 OR Day 19 will be conducted, but not all three. The visit to be conducted depends on the cohort, and is decided at the dose escalation meeting.
24 Participants may have the option to complete study activities in conjunction with home nursing during these study days.
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25 To be completed within 3 days prior to dosing.
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Table 8-2
Details for highly repetitive assessments
Period
Visit Name
Visit Numbers
Days
Time (post-dose)
PK blood collection (BLZ945)
Screening
1
-42 to -2
-
Screening
Baseline
20
-1
-
Pre-dose
X
0.5h
X
1h
X
2h
X
4h
X
6h
X
8h
X
100
1
12h
X6
110
2
24 h (Pre-dose)
X
120
3
Pre-dose
X
Pre-dose
X
0.5h
X
1h
X
2h
X
4h
X
6h
X
8h
X
Treatment
Treatment
130
4
12h
X6
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Period
Visit Name
Visit Numbers
Days
Time (post-dose)
PK blood collection (BLZ945)
140
5
+1
24h
X
150
8
±2
96h
X3,4
160
14
±2
240h
X3,4
Follow-up 
Follow-up
170
19
±2
-
EOS
EOS
1999
36
±2
-
X Assessment to be recorded in the clinical database or received electronically from a vendor
1
2
3 Sample to be collected at approximately the same time of the day as previously collected BLZ945 pre-dose samples. 
4 For the 300 mg 4-day cohort, participants will have Day 14 sample collected. For subsequent cohorts, this sample is only collected at the time point of the 3rd PET scan.
5
6 This assessment is optional for participants who choose to have home nursing during the course of this study.
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Table 8-3
Assessment Schedule, 7 Days dosing cohorts
Period
Screening
Treatment
Follow-up 
EOS
Visit Name
Screening
Baseline23
Treatment25
Follow-up
EOS
Visit Numbers1
1
20
100
110
120
130
145
146
147
150
18024
19024
20024
1999
Days
-42 to -2
-1
1
2
3
4
5
6
7
8
+1
11
±2
17
±2
22
±2
40
±2
Time (post-dose)
-
-
-
Pre-dose
-
-
-
-
-
-
-
-
-
-
-
Informed consent
X
Inclusion / Exclusion 
criteria
S
S
S
Study completion 
information
X
Demography
X
Detailed Medical History / 
Current Medical 
Condition2
X
Hepatitis screen3
S
Alcohol Test and Drug 
Screen 3
S
HIV screen3
S
Quantiferon testing 3
S
Covid-19 PCR testing26
S
S
Pulse rate
X
X
X
Blood Pressure
X
X
X
Body Temperature
X
X
X
Body Height
X
Body Weight
X
Physical examination
S
S
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Period
Screening
Treatment
Follow-up 
EOS
Visit Name
Screening
Baseline23
Treatment25
Follow-up
EOS
Visit Numbers1
1
20
100
110
120
130
145
146
147
150
18024
19024
20024
1999
Days
-42 to -2
-1
1
2
3
4
5
6
7
8
+1
11
±2
17
±2
22
±2
40
±2
Time (post-dose)
-
-
-
Pre-dose
-
-
-
-
-
-
-
-
-
-
-
Fertility assessment4
S
Targeted Neurological 
Examination2
S
 S
Slow Vital Capacity 
(SVC)6
S
ALS Functional Rating 
Scale Revised (ALS-FRS-
R)
X
X
Upper Motor Neuron 
Burden Scale (UMNB)
X
X
Columbia-Suicide 
Severity Rating Scale (C-
SSRS) 7
X
X
X8
X8
X8
X
Hematology
X
X 
X
X
X
X
X
X
X
X8
X8
X8
X
Clinical Chemistry
X
 X
X
X
X
X
X
X
X
X8
X8
X8
X
Urinalysis
X
X
X8
X8
X8
X
Thyroid Function Test: T3, 
T4, TSH3
S
Coagulation Panel3
X
Electrocardiogram (ECG)9
X
X
X
X
X
X
X
X
X
X8
X8
X8
X
Pregnancy test10
S
S11
S
S8,11
S8,11
S8,11
S
Study drug administration
X
X
X
X
X
X
X
Participants domiciled12,13
X
X
X 
X
X
X
X
X
X
X22
PK blood collection 
(BLZ945)
See table below


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Period
Screening
Treatment
Follow-up 
EOS
Visit Name
Screening
Baseline23
Treatment25
Follow-up
EOS
Visit Numbers1
1
20
100
110
120
130
145
146
147
150
18024
19024
20024
1999
Days
-42 to -2
-1
1
2
3
4
5
6
7
8
+1
11
±2
17
±2
22
±2
40
±2
Time (post-dose)
-
-
-
Pre-dose
-
-
-
-
-
-
-
-
-
-
-
PK urine collection 
(BLZ945)
X15
X15
Polymorphism rs6971 
Genotyping
X
CYP2C8 Genotyping
X16
X16
PET scan
X18
X18
X19
X20
X20
X20
Arterial Blood Collection
X18
X18
X
X8
X8
X8
Brain MRI21
X
Adverse Events
X
Concomitant medications
X
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X Assessment to be recorded in the clinical database or received electronically from a vendor
S Assessment to be recorded in the source documentation only
1 Visit structure given for internal programming purpose only
2 Please refer to the SOM for more details.
3 Screening test is done in local lab only.
4 Only for women - medical documentation of fertility; see section Pregnancy and assessments of fertility (in Section 8.4.3).
5 This footnote has been intentionally deleted in amendment 03 of the protocol.
6 Historical documentation of up to 3 months old is also acceptable.
7 The Columbia-Suicide Severity Rating Scale (C-SSRS) also needs to be performed at any unscheduled visit. 
8 To be performed only if the 3rd PET scan is taking place at this time point.
9 During the study, 12-lead ECGs should be conducted prior to blood collection.
10 Serum pregnancy test result needs to be available and negative before dosing of the PBR28 tracer for the PET scan and the first BLZ945 dosing.
11 The serum pregnancy test result is preferred prior to each planned PET scan. Site can perform PET scan if result of urine pregnancy test within 24 hours of PET scan is 
negative, and local practice allows. 12 Participants may have the option of home nursing during study days 1-7
13 Percent consumption of meals need to be recorded during the domiciliation period or during the period that the participants are having home nursing visits.
14
15 Five samples will be collected: predose, 0-4, 4-8, 8-12 and 12-24 h post dose
16 CYP2C8 genotyping screening test is needed at only one time point during screening or baseline. If not done at screening and Day -1 and Day 1 visits are combined, 
the sample should be collected pre-dose on Day 1. 
17
18 Only one Baseline PET scan will be done and this during the screening period or at latest at Day -1. The PET scan should always be conducted after all other 
assessments are done and participant fulfills all other inclusion criteria (PET scan can proceed if a local result for rs6971 genotyping is available, but enrollment cannot 
occur until the central lab result is available). Only a Baseline PET scan of sufficient quality allowing analysis will be considered for eligibility. Baseline PET scan cannot 
occur on Day 1 if Day -1 and Day 1 visits are combined. If the visits are combined, the PET scan and arterial blood collection should be done in the screening period.  
19 The 2nd PET scan needs to be of sufficient quality allowing analysis for the participant to be considered for the PD analysis.
20 A 3rd PET scan will be performed either on Day 8 OR Day 14 OR Day 19.  A 3rd PET scan will only be performed for cohorts at higher doses than 300mg. For the 
following cohorts it may be decided to perform the 3rd PET scan on the best timing based on the outcomes of the earlier cohorts (either 4, 10 or 15 days post last dose), 
which will be decided at the dose escalation meetings.
21 The MRI assessment can be conducted at any time during the screening period once eligibility of the participant is confirmed on all other eligibility assessments (MRI 
can proceed if a local result for rs6971 genotyping is available). The assessment will be performed before the PET scan can be conducted independently of the screening 
visit. This assessment will be done during the PET acquisition if a PET/MRI scanner is used. Historical MRIs within the past year may be used, pending central imaging 
reader approval.
22Participant is discharged on this day after assessments unless otherwise determined by the investigator
23 Day -1 visit can be combined with Day 1 visit per the discretion of the investigator. If combined, Day -1 assessments not previously done at screening need to be done 
on Day 1 prior to dose administration.
24 Day 11 OR Day 17 OR Day 22 will be conducted, but not all three. The visit to be conducted depends on the cohort, and is decided at the dose escalation meeting.
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25 Participants may have the option to complete study activities in conjunction with home nursing during these study days
26 To be completed within 3 days prior to dosing


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Table 8-4
Details for highly repetitive assessments
Period
Visit Name
Visit Numbers
Days
Time (post-dose)
PK blood collection (BLZ945)
Screening
1
-42 to -2
-
Screening
Baseline
20
-1
-
Pre-dose
X
0.5h
X
1h
X
2h
X
4h
X
6h
X
8h
X
100
1
12h
X6
110
2
24 h (Pre-dose)
X
120
3
Pre-dose
X
130
4
-
145
5
-
X
146
6
-
Pre-dose
X
0.5h
X
1h
X
2h
X
4h
X
6h
X
8h
X
Treatment
Treatment
147
7
12h
X6
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Period
Visit Name
Visit Numbers
Days
Time (post-dose)
PK blood collection (BLZ945)
150
8
+1
24h
X
180
11
±1
96h
X3,4
190
17
±1
240h
X3,4
Follow-up 
Follow-up
200
22
±1
-
EOS
EOS
1999
40
±2
-
X Assessment to be recorded in the clinical database or received electronically from a vendor
1
2
3 Sample to be collected at approximately the same time of the day as previously collected BLZ945 pre-dose samples. 
4 To be collected at the time point of the 3rd PET scan.
5
6 This assessment is optional for participants who choose to have home nursing during the course of this study
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Table 8-5
Assessment Schedule Cohort 5
Period
Screening
Treatment
Follow up
Visit name
Screening 
Baseline
Treatment
EoT 1
EoS 1
Days
-42 to -1
-15 to 1
(pre-dose)
113,19
414,19
1519
±2
29
±3
4319
±3
57
±3
74
±3
8520
±3
11320
±7
Weeks of 
treatment 
HNV
Week 0
HNV
Week 0
HNV
Week 2
Week 4
HNV
Week 6
Week 8 Week 10
Week 12
Week 16
Informed consent
X
Inclusion / Exclusion 
criteria
S
S
Demography
X
Medical History / 
Current Conditions1
X
ALS history
X
Screening 
laboratory 
assessments, 
Thyroid function2
S
Coagulation panel 
X
COVID-19 testing
S7
Vital signs3
X
 X
X
X
X 
X 
 X
X
X 
X
X
Physical 
Examination
S
S
S
S
S
Fertility 
assessment4
S
Targeted 
Neurological 
Examination
S
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Period
Screening
Treatment
Follow up
Visit name
Screening 
Baseline
Treatment
EoT 1
EoS 1
Days
-42 to -1
-15 to 1
(pre-dose)
113,19
414,19
1519
±2
29
±3
4319
±3
57
±3
74
±3
8520
±3
11320
±7
Weeks of 
treatment 
HNV
Week 0
HNV
Week 0
HNV
Week 2
Week 4
HNV
Week 6
Week 8 Week 10
Week 12
Week 16
(SVC)
Upper Motor Neuron 
Burden Scale 
(UMNB)12
X
Columbia-Suicide 
Severity Rating 
Scale (C-SSRS)6
X
X
X
X
X
Clinical chemistry
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
Electrocardiogram 
(ECG)8
X
X 
X
X
X
X
X
X 
Ventilation
X
Cardiac 
echocardiography10
X
X
Esophagus CT 
scan10,11
X
X
Feeding tube 
placement 
X
Pregnancy test9
S
S
S
S
S
Polymorphism 
rs6971 Genotyping12
X
Randomization
X21
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Period
Screening
Treatment
Follow up
Visit name
Screening 
Baseline
Treatment
EoT 1
EoS 1
Days
-42 to -1
-15 to 1
(pre-dose)
113,19
414,19
1519
±2
29
±3
4319
±3
57
±3
74
±3
8520
±3
11320
±7
Weeks of 
treatment 
HNV
Week 0
HNV
Week 0
HNV
Week 2
Week 4
HNV
Week 6
Week 8 Week 10
Week 12
Week 16
Study drug 
dispensing
 X21
X
 X
Study drug 
administration
Repeated cycles of 4/10 in Arm #1, QW in Arm #2
Patient diary
X
Training for study 
drug administration 
via feeding tube
As required
Study completion 
information 
X
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Period
Screening
Treatment
Follow up
Visit name
Screening 
Baseline
Treatment
EoT 1
EoS 1
Days
-42 to -1
-15 to 1
(pre-dose)
113,19
414,19
1519
±2
29
±3
4319
±3
57
±3
74
±3
8520
±3
11320
±7
Weeks of 
treatment 
HNV
Week 0
HNV
Week 0
HNV
Week 2
Week 4
HNV
Week 6
Week 8 Week 10
Week 12
Week 16
Adverse Events
X
Concomitant 
medications
X
HNV: Home Nursing Visits
SAssessment to be recorded in the source documentation only.
1 Please refer to the SOM for more details.
2 Screening tests are analysed by the local laboratory only. Screening tests consist of hepatitis, HIV, quantiferon or similar test, and drug screen
3 Vital signs: Pulse rate, Blood Pressure, Body Temperature. In addition: Body Height at Screening and Body Weight at Screening and EoT 1
4 Only for women - Historical documentation is also acceptable; see section Pregnancy and assessments of fertility (in Section 8.4.3).
6 The Columbia-Suicide Severity Rating Scale (C-SSRS) also needs to be performed at any unscheduled visit. 
7 To be completed within 3 days prior to dosing
8 During the study, triplicate 12-lead ECGs should be conducted, 2 hours post-dose (+/- 2h) during treatment period and prior to blood collection during screening and 
follow-up periods.
9 Serum pregnancy tests. 
 serum pregnancy test only at baseline. PET Sub-study: During screening period, the serum pregnancy test result needs to be 
available and negative before dosing of the PBR28 tracer for the PET scan. If PET scan is performed during screening visit, an additional urine pregnancy test to be 
performed during baseline visit.
10 Additional ad hoc in case of moderate or severe AE of facial swelling or unexpected dysphagia, also see footnote #20
11 These assessments should be performed only after all other eligibility criteria are met. ALS SOC refers to riluzole and/or sodium phenylbutyrate/taurursodiol.
12 PET sub-study only.
13 Only applicable for participants on Arm #2, 4 hours post-dose
14 Only applicable for participants on Arm #1, 4 hours post-dose
16 The Baseline PET scan should always be conducted after all other assessments are done and participant fulfills all other inclusion criteria (PET scan can proceed if a 
local result for rs6971 genotyping is available, but dosing cannot occur until the central lab result is available).
17 The MRI assessment can be conducted at any time during the screening period once eligibility of the participant is confirmed on all other eligibility assessments (MRI 
can proceed if a local result is available for rs6971 genotyping is available). The assessment will be performed before the PET scan and can be conducted independently 
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Period
Screening
Treatment
Follow up
Visit name
Screening 
Baseline
Treatment
EoT 1
EoS 1
Days
-42 to -1
-15 to 1
(pre-dose)
113,19
414,19
1519
±2
29
±3
4319
±3
57
±3
74
±3
8520
±3
11320
±7
Weeks of 
treatment 
HNV
Week 0
HNV
Week 0
HNV
Week 2
Week 4
HNV
Week 6
Week 8 Week 10
Week 12
Week 16
of the screening visit. This assessment will be done during the PET acquisition if a PET/MRI scanner is used. Historical MRIs within the past year may be used, pending 
central imaging reader approval.
18 Genetic ICF must be obtained before the optional DNA sampling. This optional sample can be collected anytime on Day 1 or thereafter.
19 Participants have the option to complete study activities during home visits.
20 Patients with safety findings at Week 12 (i.e., clinically relevant changes on CT scan or echocardiography, unresolved vasculitis) will perform the Extended safety follow 
up visit/EoS 1 on Week 24 and cannot continue with the 24 weeks extended treatment.
21After eligibility was confirmed
22In case of early discontinuation
23 Additional ad-hoc samples may be required. See Table 16-2
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Table 8-6
Details for highly repetitive assessments in Cohort 5
Period
Visit Name
Days
Time 
(BLZ945 
post-dose) 
PK blood 
collection4 
(BLZ945)
Arm #1 (4/10)
PK blood 
collection4 (ALS 
SOC)
Arm #1 (4/10)
PK blood 
collection4 
(BLZ945)
Arm #2 (QW)
Pre-dose
X
1h
X
2h
X
11
4h
X
Pre-dose
X
X
1h
X
X
2h
X
X
42
4h
X
X
Treatment
Treatment
74 ±35
X
X
X
X Assessment to be recorded in the clinical database
1 Treatment arm #2
2 Treatment arm #1
3The PK sampling time points are defined with respect to the BLZ945 dose administration
4 Percent consumption of meals need to be recorded on the days when PK samples are collected. 
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Table 8-7
Assessment schedule for Cohort 5 extended treatment period
Period
Follow up
Extended treatment
End of the 
study
Visit name
EoS 12
/Baseline3
Extended treatment 
EoT 2
EoS 2
Days
113
±7
141
±3
169
±3
197
±3
225
±3
253
±3
281
±3
365, 449, 533, 
617
±7
Weeks of treatment
Week 16
Week 20
Week 24
Week 28
Week 32
Week 36
Week 40
Week 52, 64, 
76, 88
Informed consent
X
Inclusion/Exclusion criteria
X
COVID-19 testing
X
Vital signs
X
X
X
X
X
Physical Examination
S
S
S
S
S
ALS vital status
X
X
X
X
X
X
X
X1
Ventilation 
X
Feeding tube placement
X
Columbia-Suicide Severity 
Rating Scale (C-SSRS)
X
X
X
X
X
Clinical chemistry
X
X
X
X
X
Hematology
X
X
X
X
X
Urinalysis
X
X
X
X
X
Electrocardiogram (ECG)
X
X
X
X
X
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Period
Follow up
Extended treatment
End of the 
study
Visit name
EoS 12
/Baseline3
Extended treatment 
EoT 2
EoS 2
Days
113
±7
141
±3
169
±3
197
±3
225
±3
253
±3
281
±3
365, 449, 533, 
617
±7
Weeks of treatment
Week 16
Week 20
Week 24
Week 28
Week 32
Week 36
Week 40
Week 52, 64, 
76, 88
Cardiac echocardiography
X
X
Esophagus CT scan
X
X
Serum pregnancy test
S
S
S
S
S
S
S
Study drug dispensing
X
X
X
X
X
X
Study drug administration 
X
Training for study drug 
administration via feeding 
tube
As required
Patient diary
X
Concomitant medications
X
Adverse events
X
Study completion 
information 
X
XAssessment to be recorded in the clinical database
1Phone calls
2 3rd PET scan for the PET sub-study in addition
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3 Extension Baseline visit may not coincide with Day 113/Week 16 visit for participants who completed the 12 week treatment period under previous protocol amendment 
versions
4 Additional ad-hoc samples may be required. See Table 16-2
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8.1
Screening
8.1.1
Eligibility screening
It is permissible to re-screen a participant if she/he fails the initial screening and the reason for 
failure is anticipated to be transient (e.g., positive COVID-19 test, abnormal laboratory values, 
temporary conditions e.g., flu symptoms or urinary tract infections).
Re-screening may be allowed under other circumstances, however, each case must be 
discussed and agreed with the Sponsor on a case-by-case basis. The details of the re-screening 
process can be found in the SOM.
8.1.2
Information to be collected on screening failures
Information on what data must be collected for screening failures and further information on 
re-screening is outlined in the SOM.
8.2
Participant demographics/other baseline characteristics
Participant demographic and baseline characteristic data are to be collected on all participants.
Relevant medical history/current medical condition present before signing the informed 
consent will be recorded. Investigators will have the discretion to record abnormal test 
findings on the appropriate CRF whenever, in their judgment, the test abnormality occurred 
prior to the informed consent signature. Details are outlined in the Site Operations Manual.
Selected laboratory parameters will be assessed to determine patient eligibility. Please refer to 
Table 8-9.
The Upper Motor Neuron Burden Scale (UMNB) is a scale that measures deep tendon 
reflexes and pathological reflexes. UMNB scale scores have been found to be positively 
associated with glial activation as measured by [11C]-PBR28 uptake on PET imaging 
(Zürcher et al 2015, Alshikho et al 2016, Alshikho et al 2018). In Cohorts 1-4, the 
 
and the UMNB scale will be collected from all study participants at baseline and at end of 
study. In Cohort 5, UMNB will be collected at Screening from all participants.
The slow vital capacity (SVC) will be measured during the screening period for participants 
enrolled in Cohorts 1 to 4, and during the entire study duration in Cohort 5 as per Table 8-5 
and extended treatment period as per Table 8-7.
8.3
Efficacy
8.3.1
Efficacy assessment
Efficacy will be assessed by PET imaging of [11C]-PBR28 binding as a measure of 
the pharmacodynamic effect of BLZ945 on brain microglia.
To avoid unnecessary radiation to the participants, all screening activities except imaging 
need to be completed prior to PET scan. PET scan can proceed if a local rs6971 genotyping 
result is available, but enrollment cannot happen until the central lab result is available.
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Each participant will have a 3-D structural MRI scan to provide an anatomical image that will 
help for delineation of the brain regions of interest (ROIs). If a combined PET/MRI scanner is 
used, which allows simultaneous acquisition of the MRI and PET data, the anatomical MRI 
scan will be acquired at the beginning of the PET examination.
Refer to Section 3 for more information about PET scan timing, and decision-making 
processes regarding the timing.
On each day of PET scanning, a cannula will be inserted into the left or right antecubital vein 
for radioligand administration and another cannula into the radial artery of the contralateral 
arm for blood sampling.
All participants will undergo brain [11C]-PBR28 PET imaging on state-of-the-art, 3D PET 
scanners. For consistency, the same PET scanner should be used at screening and follow up 
scans.
The participants will be positioned in the PET scanner. If HRRT PET or PET/CT systems are 
used, a transmission scan will be acquired to generate the attenuation correction for the 
emission PET sinograms. If a PET/MRI scanner is used, an MRI scan will be acquired and 
used for anatomical localization and generation of the attenuation correction maps. After this 
scan, [11C]-PBR28 (approx. 350 MBq) will be injected as a bolus for about 30-60 (depending 
on the volume) sec via the venous cannula. The dynamic emission scan will be started 
simultaneously to the radioligand administration. PET examination will have a total duration 
of approx. 90 minutes. Arterial blood samples will also be collected during the course of the 
PET scan to determine the metabolite corrected arterial plasma input function that will be 
used in the quantification of the PET data. Further details on the arterial blood collection will 
be available in the SOM.
The MRI image for each participant will be co-registered to his PET image and the different 
ROIs will be defined. Arterial input fraction based compartmental models are considered the 
gold standard of PET image quantification. and estimation of the volume of distribution (Vt). 
Vt will be utilized for estimation of [11C]-PBR28 binding to TSPO. Analysis of the scan will 
be centralized. The results of the post-treatment scans will be compared to baseline. 
Detailed information will be provided in a separate imaging manual.
The relationship between the TSPO binding and BLZ945 exposure will be calculated graphically.
8.3.2
Appropriateness of efficacy assessments
This study will use [11C]PBR28 imaging to provide evidence for microglia reduction in ALS 
participant on BLZ945 treatment. PET is a noninvasive molecular imaging technique that 
enables quantification of neuropathological markers and pharmacodynamic properties of new 
drug candidates. In vivo functional imaging of activated microglia has been widely explored 
by PET. TSPO is minimally expressed in resting (homeostatic) microglia in the healthy brain 
but its expression is upregulated during the microglial activation process in several 
neurodegenerative and neuroinflammatory diseases including ALS. TSPO is widely 
recognized as a reference molecular biomarker for PET imaging of activated microglia. 
The TSPO PET tracer [11C-PBR28] has been used in different clinical trials to image 
microglial 
activation 
in 
ALS 
participants 
(Zürcher et al 2015; 
Alshikho et al 2018; 
Albrecht et al 2018).


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8.4
Safety and tolerability
Safety and tolerability assessments are specified below with the assessment schedule detailing 
when each assessment is to be performed.
For details on AE collection and reporting, refer to AE section (Section 10.1).
The methods, assessment, specification, and recording for each assessment will be detailed in 
the SOM.
Table 8-8
Assessments and specifications
Assessment
Specification
Physical Examination
The examination of general appearance, skin (e.g., purpura; 
see guidance in Section 16.3), neck (including thyroid), head, 
eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph 
nodes, extremities, vascular and neurological (e.g. new onset 
of paresthesia or dysesthesia). If indicated based on medical 
history and/or symptoms, rectal, external genitalia, breast, 
and/or pelvic exams may be performed.
Targeted Neurological Examination
Assessment of muscle strength, deep tendon reflexes, and 
the presence of pathologic reflexes (Hoffman, Babinski, and 
jaw jerk). UMNB is scored based on results from the 
neurological examination.
Medical History
Detailed medical history should be collected.
Vital signs
Vital signs include body temperature, blood pressure and 
pulse measurements.
Height and weight
Height in centimeters (cm) and body weight (to the nearest 
0.1 kilogram (kg) in indoor clothing, but without shoes).
8.4.1
Laboratory evaluations
Clinically significant abnormalities must be recorded as either medical history/current medical 
conditions or adverse events as appropriate.
All laboratory parameters assessed for safety purposes will be evaluated locally while 
primarily the liver enzymes and related lab tests will also be assessed centrally. Refer to 
Table 8-9 for a summary of the parameters and where these are to be evaluated.
More frequent evaluations may be performed at the investigator’s discretion if medically 
indicated; results should be recorded as unscheduled laboratory assessments.
Novartis will be provided with a copy of the laboratory certification and tabulation of the 
normal ranges for each parameter required. In addition, if at any time a participant has 
laboratory parameters obtained from a different outside laboratory, Novartis must be provided 
with a copy of the certification and a tabulation of the normal ranges for that laboratory.
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All abnormal lab results must be evaluated for criteria defining an adverse event and reported 
as such if the criteria are met.
Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, 
require therapy (e.g., hematologic abnormality that requires transfusion).
Safety samples that can be collected remotely during home nursing visits will be collected and 
analyzed in line with the study laboratory manual. If participants cannot visit the site for 
safety laboratory assessments conducted through central laboratories, local laboratory 
collection may be used during a Public Health emergency as declared by Local or Regional 
authorities i.e., pandemic, epidemic or natural disaster, that limits or prevents on-site study 
visits.
For those laboratory adverse events, repeated evaluations are mandatory until normalization 
of the result(s) or until the result is no longer considered to be clinically significant.
Table 8-9
Laboratory evaluations
Test Category*
Test Name
Central or Local 
laboratory
Hematology
Cohorts 1-5: Hematocrit, Hemoglobin, MCV, 
Platelets, Red blood cells, White blood cells, 
Differential (Basophils, Eosinophils, 
Lymphocytes, Monocytes, Neutrophils)
Cohort 5: Erythrocyte sedimentation rate
Local
Chemistry
Cohorts 1-5: Albumin, Bicarbonate, Calcium, 
Magnesium, Phosphorus, Chloride, Sodium, 
Potassium, Creatinine, Blood Urea Nitrogen 
(BUN) or Urea, Uric Acid, Glucose, Total 
Protein
Local
Chemistry
Cohorts 1-5: Amylase, Lipase, Alkaline 
phosphatase, ALT, AST, Creatine kinase 
(CK), CK-MB, Troponin, GGT, Total Bilirubin 
(also measure direct and indirect bilirubin if 
total bilirubin is > grade 1, i.e., increased 
above 1.5 x ULN)
Cohort 5: C-reactive protein
Local and Central*,**
Screening
Cohorts 1-5: Tuberculosis, Hepatitis B and 
C, HIV (ELISA and Western Blot), Alcohol 
test (Cohorts 1-4) and drug screen, Direct 
Bilirubin, COVID-19 test
Local
Urinalysis
Cohorts 1-5: Microscopic Panel (Red Blood 
Cells, White Blood Cells, Casts, Crystals, 
Bacteria, Epithelial cells)
Cohorts 1-5: Macroscopic Panel (Dipstick) 
(Color, Bilirubin, Blood, Glucose, Ketones, 
Leukocytes esterase, Nitrite, pH, Protein, 
Specific Gravity, Urobilinogen)
Local
Coagulation
Cohorts 1-5: Prothrombin time (PT), 
International normalized ratio ([INR]), Partial 
thromboplastin time (PTT) or Activated 
Local


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Test Category*
Test Name
Central or Local 
laboratory
partial thromboplastin time (APTT)
Thyroid
Cohorts 1-5: T3 [free], T4 [free], TSH
Local
Pregnancy Test
Cohorts 1-4: Serum / Urine pregnancy test 
only for women of child-bearing potential
Cohort 5: Serum pregnancy test only for 
women of child-bearing potential
Local
Genotyping rs6971 
polymorphism
Cohorts 1-5: Genotyping rs6971 
polymorphism
Central* or Local***
Genotyping CYP2C8
Cohorts 1-5: Genotyping CYP2C8
Central*
* Details will be provided in the laboratory manual.
** For eligibility, the local laboratory results will be used and for the dose escalation reviews,
the central laboratory results will be used.
***If CLIA certification available
8.4.2
Electrocardiogram (ECG)
Full details of all procedures relating to the ECG collection and reporting are contained in 
the Site Operations Manual.
A standard 12-lead ECG will be performed as per the assessment schedule in Table 8-1, 
Table 8-5 and Table 8-7. Blood samples scheduled at the same clock time point should be 
taken after the ECGs are completed. The ECGs must be performed in triplicate in supine 
position.
PR interval, QRS duration, heart rate, RR interval, QT interval, QTcF will be recorded.
The Fridericia QT correction formula (QTcF) must be used for clinical decisions.
As applicable, QTcF may be calculated in-house. Unless auto-calculated by the ECG machine, 
the investigator must calculate QTcF at the Screening and/or Baseline visit(s) (as applicable) 
to assess eligibility. Since the ECGs are done in triplicate, the average of the three QTcF 
values should be used to determine eligibility.
Interpretation of the tracing must be made by a qualified physician and documented on the 
ECG. Each ECG tracing should be labeled with the study number, participant initials (where 
regulations permit), participant number, and date, and kept in the source documents at the 
study site. Clinically significant abnormalities present at screening should be reported on the 
Medical History eCRF. Clinically significant findings must be discussed with Novartis prior 
to enrolling the participant in the study. New or worsened clinically significant findings 
occurring after informed consent must be recorded on the Adverse Events eCRF. 
All eligibility and participant management decisions should be made based on the local 
reading of the ECG. An ECG may be replaced if, in the opinion of the qualified physician, the 
tracing is not representative of the participant’s baseline.
See the SOM for additional details.
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8.4.3
Pregnancy and assessments of fertility
A condom is required for all sexually active male participants to prevent them from fathering 
a child AND to prevent delivery of study drug via seminal fluid to their partner. In addition, 
male participants should not donate sperm for the period from dosing start till EOS visit.
All pre-menopausal women who are not surgically sterile will have pregnancy testing. 
Additional pregnancy testing might be performed if requested by local requirements.
Any woman of child bearing potential with a positive pregnancy test will be excluded from the 
study.
Refer to Table 8-1, Table 8-3, Table 8-5 and Table 8-7 for more guidance about pregnancy 
testing timing and accepted test methods.
Assessments of fertility
Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source documents. Subsequent hormone level assessment to confirm the woman is not of 
child-bearing potential must also be available as source documentation in the following cases:
1. Surgical bilateral oophorectomy without a hysterectomy
2. Reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical
profile.
In the absence of the above medical documentation, FSH testing is required of any female 
participant regardless of reported reproductive/menopausal status at screening/baseline.
8.4.4
Cardiac imaging – echocardiogram
Echocardiograms will be performed at the visits defined in the assessment schedule 
(Table 8-5 and Table 8-7). A subset of a standard echocardiographic two-dimensional and 
doppler examination will be performed. The images will be sent to a central reading vendor 
for independent review and analysis. Echocardiographic assessments may include but are not 
limited to:
•
Left ventricular ejection fraction (LVEF)
•
Left ventricular diastolic/systolic volumes
•
Left ventricular dimensions
•
Cardiac valve thickness, stenosis, and regurgitation
Please refer to Section 9.1.1 for end of treatment echocardiogram in case of premature 
discontinuation and to Section 10.2.4 for monitoring in case of abnormalities at EoT 1 visit 
(Week 12).
8.4.5
Esophageal computed tomography (CT) scan
Esophageal CT-scans will be performed at the visits defined in the assessment schedule to 
evaluate esophageal wall thickness (EWT).
Esophagus CT scans will be acquired in the supine position. In all participants, the baseline 
and follow-up CT scans should be performed where possible on the same scanner. The EWT 


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will be evaluated at three anatomic landmarks: at the level of the carina, a few centimeters 
above the gastroesophageal junction, and some centimeters below the cricopharyngeus to 
measure the upper, mid and lower thoracic esophagus with consistency. The images will be 
sent to a central reading vendor for independent review and analysis. Protocol specific 
requirements of the CT and machine settings will be provided to the sites as part of a separate 
Imaging Manual.
Please refer to Section 9.1.1 for end of treatment CT scan in case of premature discontinuation. 
In the event of the report of unexpected worsening of swallowing, or if onset of facial or 
periorbital swelling of moderate or severe intensity is detected, an ad hoc CT scan of the chest 
must be performed to evaluate for possible esophageal thickening within 2 weeks of the event. 
Please refer to Section 10.2.4 for monitoring in case of abnormalities at EoT 1 visit (Week 12). 
Note: The coded medical images will be used primarily for analysis as described in this 
protocol; however, the images may also be used for the development and evaluation of new 
analysis methods directly related to the area of research that this study covers.
8.4.6
Markers of inflammation
In the absence of clinically validated markers for the assessment of BLZ945-induced vascular 
inflammation, markers of general inflammation (erythrocyte sedimentation rate (ESR) and 
C-reactive protein (CRP)) will be measured at the times indicated in the assessment schedule.
Additional diagnostic work will be performed, in the event of signs and symptoms of vascular 
inflammation or in the event of elevations in ESR and CRP (refer to Table 16-6 for ESR and 
CRP values triggering additional evaluation).
Please refer to Section 10.2.3 for monitoring of vasculitis.
8.4.7
Appropriateness of safety measurements
The selected safety assessments will take advantage of the clinical expertise of the 
investigators who are familiar with the standard care of ALS patients. A full battery of 
standard clinical laboratory measurements will be collected for safety purposes. In addition, 
effects of ECM accumulation on target organs (i.e., heart and esophagus) will be assessed via 
echocardiography and CT scan. Echocardiography is the most commonly used imaging 
technique to monitor cardiac valve and cardiac function (Lang et al 2015, Vahanian et al 2022) 
and CT scan is the most commonly used method for assessing esophageal wall thickness 
(Reinig et al 1983, Berkovich et al 2000). Physical examination and laboratory measurements, 
such as markers of general inflammation (i.e., ESR and CRP), complete blood count, liver and 
renal function tests (creatinine, BUN, electrolytes and urinalysis), cardiac enzymes, will be 
analyzed for assessing potential cases of vasculitis.
8.4.8
COVID-19 contingency plan
The sponsor recommends that subjects in the study are screened for symptomatic or 
asymptomatic carriage of SARS-CoV-2 at any time during the entire study duration as 
deemed necessary by the investigator taking in consideration the study site specific 
procedures and/or local and national regulatory requirements or guidelines.


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Moreover, as part of the clinical study procedures, participants will be closely monitored for 
signs and symptoms of COVID-19 during the entire study duration.
Any subject that, in the opinion of the investigator, presents COVID-19-related symptoms 
and/or has a positive SARS-CoV-2 viral test, will be assessed on a case by case basis by 
the investigator (after consultation with Novartis, as applicable) to determine if the enrollment 
or further participation in the study is impacted.
8.5
Additional assessments
8.5.1
Pharmacokinetics
Urine (Cohorts 1-4), plasma (Cohorts 1-5) 
 PK samples will be collected 
at the visits defined in the assessment schedule. Follow instructions outlined in the Site 
Operations Manual regarding sample collection, numbering, processing, and shipment. 
See the potential use of residual samples for more information in Section 8.5.2.2.
In order to better define the PK profile, the timing of the PK sample collection may be altered 
based on emergent data.
The details of the assays will be documented in the Bioanalytical Data Report.
Plasma PK samples will be obtained and evaluated in all participants at all dose levels.
For standard pharmacokinetic abbreviations and definitions see the list provided at 
the beginning of this protocol.
For Cohorts 1-4: The following pharmacokinetic parameters will be determined for BLZ945 
using the actual recorded sampling times and non-compartmental method(s) with Phoenix 
WinNonlin (Version 8.0 or higher):
Table 8-10
Non-compartmental pharmacokinetic parameters of BLZ945
Plasma
AUClast
The AUC from time zero to the last measurable concentration sampling time (tlast) 
(mass x time x volume-1)
AUCinf
The AUC from time zero to infinity (mass x time x volume-1)
AUC0-24h
The AUC calculated to the end of a dosing interval (tau) (amount x time x volume-1)
Cmax
The maximum (peak) observed plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (mass x volume-1)
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Plasma
Tmax
The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (time)
Lambda_z
Smallest (slowest) disposition (hybrid) rate constant (time-1) may also be used for 
terminal elimination rate constant (time-1)
T1/2
The elimination half-life associated with the terminal slope (λz) of a semi logarithmic 
concentration-time curve (time). Use qualifier for other half-lives
CL/F
The total body clearance of drug from the plasma (volume x time-1)
Vz/F
The apparent volume of distribution during terminal phase (associated with λz) 
(volume)
Racc
Accumulation Ratio = Cmax (multiple Dose)/Cmax (single dose) and AUC0-24h 
(multiple Dose)/AUC0-24h (single dose)
Urine
Ae(0-t)
Amount of drug excreted into the urine from time zero to time ‘t’ [mass units]
CLR
The renal clearance of drug [volume x time-1]
For Cohort 5: selected PK parameters of BLZ945, 
 in plasma (Cmax, Tmax, AUClast, Tlast) on Day 1 (Arm 2) and 
Day 4 (Arm 1) will be determined using the actual recorded sampling times and 
non-compartmental method(s) with Phoenix WinNonlin (Version 8.0 or higher), as feasible. 
The linear trapezoidal rule will be used for AUC calculation. In cases where the percent 
extrapolated AUC is greater than 20%, AUCinf values will be indicated as missing values and 
only AUClast will be reported. Regression analysis of the terminal plasma 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.
BLZ945 renal clearance (CLR) will be estimated from the ratio of the amount of unchanged 
drug excreted in urine (Ae 0-t) to the corresponding AUC in plasma.
In Cohort 5: 
 plasma PK samples will be 
collected together with BLZ945 at the visits defined in the assessment schedule. The pre-dose 
PK sample may also be used as a reference of 
 prior to BLZ945 treatment. If participants experience an SAE or an AE of liver enzyme 
elevations leading to discontinuation of study treatment, an unscheduled PK blood sample of 
BLZ945 
should be 
taken as soon as possible. The date of time of the last dose and the time of PK blood draw 
must be recorded. 
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9
Study discontinuation and completion
9.1
Discontinuation and completion
9.1.1
Study treatment discontinuation and study discontinuation
Discontinuation of study treatment for a participant occurs when study treatment is stopped 
earlier than the protocol planned duration and can be initiated by either the participant or 
the investigator.
The investigator must discontinue study treatment for a given participant if, he/she believes 
that continuation would negatively impact the participant's well-being.
Study treatment must be discontinued under the following circumstances:
•
Participant/guardian decision
•
Pregnancy
•
Use of prohibited treatment as per recommendations in Section 6.2.2.
•
Any situation in which study participation might result in a safety risk to the participant
•
Any laboratory abnormalities that in the judgment of the investigator, prevents 
the participant from continuing participation in the study
•
Severe hypersensitivity reaction occurs, including any of the following: anaphylaxis, fever, 
chills, urticaria, dyspnea, headache, myalgia, hypotension.
•
QTcF on ECG ≥501 ms or a >60 ms change from baseline.
•
Development of symptomatic conduction abnormalities requiring urgent intervention.
•
Development of symptomatic cardiac arrhythmia requiring urgent intervention.
•
For liver events, please see Section 10.2.1 and consult the Hepatotoxicity Clinical Safety 
Standard Guideline. For renal events, please see Section 10.2.2.
•
If a liver or renal event occurs, follow guidelines outlined in Section 16.1 and Section 16.2.
•
Unexpected worsening of swallowing associated to abnormal thickening of 
the oesophagus on ad hoc CT scan.
•
Increased thickness of cardiac valve on echocardiography accompanied by clinically 
meaningful change in valve function (regurgitation or stenosis) or cardiac function 
(LVEF).
•
In case of confirmed vasculitis. For identification of potential cases of vasculitis and 
their follow-up, follow guidelines outlined in Section 16.3.
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If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the participant’s premature discontinuation of study 
treatment and record this information.
9.1.1.1
Premature discontinuation of study treatment in Cohort 5
In case of premature discontinuation of study treatment, participants will perform the 
assessments planned at EoT 1 visit as close as possible to the last dose. In addition to the 
assessments scheduled at the EoT 1 visit (see Table 8-5), the procedures be performed are 
listed in Table 9-1. 
Table 9-1
Additional procedures at EoT 1 in case of premature discontinuation 
of treatment
Discontinuation 
before Week 4 
Discontinuation 
between Week 4 
and Week 8
Discontinuation 
between Week 
8 and Week 10
Timing from last dose
LP and blood PK 
sample or PET
no
no 
yes
within 6 days (+/- 1) 
day
CT-scan, 
echocardiogram
no
yes 
yes
within 2 weeks (and at 
EoS 1)
Participants who discontinue study treatment or who decide they do not wish to participate in 
the study further should NOT be considered withdrawn from the study UNLESS they 
withdraw their consent (see Section 9.1.2 Withdrawal of Informed Consent). Where possible, 
they should return for the assessments indicated in the Assessment Schedule as soon as 
possible. At this final visit, all dispensed investigational product should be reconciled, and the 
adverse event and concomitant medications recorded on the CRF. 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 participant/pre-designated contact as specified in the lost to follow-up 
section (Section 9.1.3).
This contact should preferably be done according to the study visit schedule. If the participant 
cannot or is unwilling to attend any visit(s), the site staff should maintain regular telephone 
contact with the participant, or with a person pre-designated by the participant. This telephone 
contact should preferably be done according to the study visit schedule.
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should be collected at clinic visits or via telephone/email contact:
•
New / concomitant treatments
•
Adverse Events / Serious Adverse Events
In case of premature treatment discontinuation prior to Week 40 in the extended treatment 
period, participants will perform the assessments from the Week 40 visit as close as possible 
to the last dose (ideally within 2 weeks). Study site should nevertheless continue with 
the quarterly contacts over 1 year to collect the vitality status. 


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9.1.1.2
Replacement policy
Participants will not be replaced on study in the first four cohorts. However, if a participant is 
considered as non-evaluable for the dose escalation decision, enrollment of a new participant 
to the current cohort will be considered until at least the minimum number (3) of evaluable 
participants is achieved within the cohort. If the evaluation of the second PET scan is not 
possible then the participant may be discontinued and enrollment of a new participant into 
the current cohort may be considered until at least the minimum number of evaluable 
participants is achieved within the cohort.
9.1.2
Withdrawal of informed consent
Participants may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a participant:
•
Does not want to participate in the study anymore, and
•
Does not allow further collection of personal data
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the participant’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 participant are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the participant’s study withdrawal should be made as detailed in 
the assessment table.
Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a participant’s samples until the time of withdrawal) according to applicable 
law.
For US and Japan: All biological samples not yet analyzed at the time of withdrawal may still 
be used for further testing/analysis in accordance with the terms of this protocol and of 
the informed consent form.
For EU and RoW: All biological samples not yet analyzed at the time of withdrawal will no 
longer be used, unless permitted by applicable law. They will be stored according to 
applicable legal requirements.
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9.1.3
Lost to follow-up
For participants whose status is unclear because they fail to appear for study visits without 
stating an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the participant, e.g. dates of 
telephone calls, registered letters, etc. A participant should not be considered as lost to 
follow-up until due diligence has been completed or until the end of the study.
9.1.4
Study stopping rules
The study may resume following the safety review, if the Investigator and Sponsor agree it is 
safe to proceed.
9.1.4.1
Cohort 1-4 stopping rules:
Following dosing for each cohort, dosing of the next cohort will be paused until the 
Investigator and Sponsor's Medical Monitor discuss the safety and tolerability data from that 
cohort. Drug administration of subsequent cohorts will only be triggered if an adequate safety 
and tolerability profile has been confirmed through 10 days after the last treatment from 
the preceding cohort. A cohort will be stopped if two or more study participants experience 
dose limiting toxicities (DLTs) as described in Table 9-2 below. No further dosing / dose 
escalation decisions will be taken pending a full safety review.
Enrollment will be placed on hold and a safety review undertaken if any of the following 
occurs cumulatively across Cohorts 1-4:
•
One study drug related SAE
•
Two participants experience SAEs related to dose limiting toxicities, regardless of
suspected relatedness to drug
•
At least 2 or more participants experience a similar AE which was assessed as severe in
intensity (≥CTCAE grade 3), and are considered as potentially related to the study drug;
The Sponsor considers that the number and/or severity of AEs, abnormal safety monitoring 
tests or abnormal laboratory findings justify putting the study on hold.
A DLT is defined as an adverse event or abnormal laboratory value assessed as unrelated to 
disease, disease progression, inter-current illness, or concomitant medications that occurs by 
study day 14 (or day 17 for 7-day dosing).
The DLTs will be assessed according to the standardized grading scale, the NCI (National 
Cancer Institute) CTCAE version 5. For the purpose of dose- and dosing schedule 
modification decisions, DLTs will be considered and included in the BLRM.
The investigator must notify the Sponsor immediately of any unexpected CTCAE grade 
≥ 3 adverse events or laboratory abnormalities. Prior to enrolling participants into a higher 
dose level or prior to extending the dosing period, CTCAE grade ≥ 2 adverse events will be 
reviewed for all participants at the current dose level.
•
Following the occurrence of an AE by day 14 (or day 17 for 7-day dosing) for Cohorts 1-4,
the observation period to determine whether an AE is considered to be a DLT is through
the end of study visit, or longer if deemed necessary by the site investigator or Sponsor.


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Table 9-2
Adverse events that will be considered DLTs Cohorts 1-4
•
≥ CTCAE grade 3 neutropenia
•
≥ CTCAE grade 3 thrombocytopenia
•
≥ CTCAE grade 3 serum creatinine
•
Serum creatinine 2 x ULN for > 7 consecutive days
•
Total bilirubin 2 x ULN for > 7 consecutive days
•
Total bilirubin 2 x ULN and CTCAE grade 2 AST or ALT
•
≥ CTCAE grade 3 total bilirubin
•
≥ CTCAE grade 3 AST or ALT, unless it resolves to ≤ grade 1 within 7 days
•
≥ CTCAE grade 3 cardiac events
•
≥CTCAE grade 3 ECG QT corrected interval prolongation
•
≥CTCAE grade 3 ECG cardiac conduction disorder
•
≥ CTCAE grade 3 rash
•
Other clinically significant toxicities, including a single event or multiple occurrences of the same
event that lead to a dosing delay of > 7 days
9.1.5
Cohort 5 stopping rules for one treatment arm:
Enrollment in a treatment arm will be placed on hold and a safety review undertaken if any of 
the following occurs in that specific treatment arm of Cohort 5:
•
Two out of the first 6 participants experience SAEs suspected to be related to study drug,
or 4 participants overall experience SAEs suspected to be related to the study drug in each
treatment arm.
•
The Sponsor considers that the number and/or severity of AEs, abnormal safety
monitoring tests or abnormal laboratory findings justify putting the study on hold.
Enrollment in that treatment arm may resume following the safety review, if the Sponsor, the 
DMC, and investigators judge it safe to proceed. In case of safety and/or tolerability concerns 
resulting from the safety review, a dose reduction in one or both treatment arms may be 
considered by the Sponsor in consultation with the DMC to resume enrollment.
A treatment arm may be terminated for safety reasons and all ongoing participants switched to 
the other arm. The study will continue with a single arm design to achieve the target overall 
sample size.
9.1.6
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. In taking the decision to 
terminate, Novartis will always consider the participant welfare and safety. Should early 
termination be necessary, participants must be seen as soon as possible and treated as a 
prematurely withdrawn participant. 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 participant’s interests. The investigator or sponsor depending on the local 
regulation will be responsible for informing IRBs/IECs of the early termination of the trial.


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9.2
Study completion and post-study treatment
Study completion is defined as when the last participant finishes 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. Each participant will be required to complete the study in its entirety 
and thereafter no further study treatment will be made available to them.
10
Safety monitoring and reporting
Safety and adverse event monitoring should be continued for at least 30 days following 
the last dose of study treatment.
10.1
Adverse events (AEs), serious adverse events (SAEs), and other 
safety reporting
10.1.1
Definition and recording of adverse events
Definition of AEs
An adverse event (AE) is any untoward medical occurrence (e.g., any occurrence of 
unfavorable and unintended sign(s), symptom(s) or medical condition, including abnormal 
laboratory findings, or worsening of any pre-existing sign(s), symptom(s) or medical 
condition) in a participant after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of 
any treatment used in this study. This includes events reported by the participant (or, when 
appropriate, by a caregiver, surrogate, or the participant’s legally authorized representative).
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 must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values considered to be non-typical in participant with the 
underlying disease. 
Collecting and assessing AEs
The occurrence of AEs must be sought by non-directive questioning of the participant at each 
visit during the study. AEs also may be detected when they are volunteered by the participant 
during or between visits or through physical examination findings, laboratory test findings, or 
other assessments (patient diaries, C-SSRS).
The investigator will attempt to establish a diagnosis of the event (including lab abnormalities 
that constitute AEs) based on signs, symptoms, and/or other clinical information. 


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Whenever possible, the diagnosis (not the individual signs/symptoms) will be documented as 
the AE.
For each AE, the investigator must assess:
1.
The Common Terminology Criteria for Adverse Events (CTCAE) version.
2. The causality
The investigator is obligated to assess the relationship between any treatment used in the 
study (study treatment, AxMP(s)) and each occurrence of each AE. The investigator will use 
clinical judgment to determine the relationship. A reasonable possibility of a relationship 
conveys that there are facts, evidence, and/or arguments to suggest a causal relationship, 
rather than a relationship cannot be ruled out. Alternative causes, such as underlying 
disease(s), concomitant therapy, and other risk factors, as well as the temporal relationship of 
the event to study intervention administration, will be considered and investigated. 
For causality assessment, the investigator will also consult the IB and/or product information, 
for marketed products.
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
Handling of AEs
All adverse events must be treated appropriately. More information about how to manage AEs 
can be found in the IB. Information about adverse drug reactions can also be found in product 
information for marketed products.
Once an AE is detected, the Investigator must pro-actively followed up the participant, until 
resolution of the AE, or until it is judged to be not recovered/not resolved (e.g., continuing at 
the end of the study), or until stabilization, or until the participant is lost to follow-up. 
Any change in severity or suspected relationship to study treatment must be assessed at each 
visit (or more frequently, if necessary).
Timeframe of recording of AEs
AE recording for each participant should be continued for at least 30 days following the last 
dose of study treatment.
Reporting of AEs related to AxMP(s)
All AEs related to authorized auxiliary medicinal product used in this study must be reported 
to Novartis.
In assessing causality, the investigators will use the points above.
If a suspicion that medical occurrence could be related to study treatment (and/or interaction 
with study treatment) cannot be ruled out, the reporting rules for study treatment apply.


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10.1.2
Definition and recording of serious adverse events
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s), or medical conditions(s) which meets any one of the 
following criteria:
•
fatal
•
life-threatening
Life-threatening in the context of a SAE refers to a medical occurrence in which the 
participant was at risk of death at the time of the reaction; it does not refer to a medical 
occurrence that hypothetically might have caused death if it were more severe (please refer to 
the ICH-E2D Guidelines).
•
results in persistent or significant disability/incapacity
•
constitutes a congenital anomaly/birth defect, fetal death or a congenital abnormality or
birth defect
•
requires inpatient hospitalization or prolongation of existing hospitalization, unless
hospitalization is for:
•
routine treatment or monitoring of the studied indication, not associated with any
deterioration in condition
•
elective or pre-planned treatment for a pre-existing condition that is unrelated to the
indication under study and has not worsened since signing the informed consent
•
social reasons and respite care in the absence of any deterioration in the participant’s
general condition
•
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
•
is medically significant, e.g. defined as an event that jeopardizes the participant or may
require medical or surgical intervention to prevent one of the outcomes listed above
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 
participant or might require intervention to prevent one of the other outcomes listed above. 
Such events should be considered as “medically significant.” 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. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All new malignant neoplasms and confirmed cases of vasculitis will be assessed as serious 
under “medically significant” even if other seriousness criteria are not met.
10.1.3
SAE reporting
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until 30 days after the last study visit must be reported to 
Novartis/safety immediately, without undue delay, but under no circumstances later than 


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within 24 hours of obtaining knowledge of the events (Note: If more stringent, local 
regulations regarding reporting timelines prevail). Detailed instructions regarding the 
submission process and requirements are to be found in the investigator folder provided to 
each site. Information about all SAEs is collected and recorded on the Serious Adverse Event 
Report Form. All applicable sections of the form must be completed in order to provide a 
clinically thorough report.
The investigator must review and provide an assessment of causality for each SAE. 
There may be situations in which an SAE has occurred, and the investigator has minimal 
information to include in the initial report to Novartis. However, it is very important that the 
investigator always makes an assessment of causality for every event before the initial 
transmission of the SAE data to Novartis. The investigator may change their opinion of 
causality in light of follow-up information and send an SAE follow-up report with the updated 
causality assessment.
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 
immediately, without undue delay, but under no circumstances later than within 24 hours of 
the Investigator receiving the follow-up information (Note: If more stringent, local regulations 
regarding reporting timelines prevail).
Any SAEs experienced after the 30-day period should only be reported to Novartis Safety if 
the Investigator suspects a causal relationship to study treatment, unless otherwise specified 
by local law/regulations.
Reporting of SAEs related to AxMP(s)
AxMP safety reporting requirements will only apply once the trial has been transitioned under 
EU Clinical Trial Regulation 536/2014. Once this is completed, all SAEs related to any 
AxMP (whether authorized or not) used in this study must be reported to Novartis within 24 
hours of the site becoming aware of it. In assessing causality, the investigators will use the 
points above. If a suspicion that the medical occurrence could be related to study treatment (or 
and interaction with study treatment) cannot be ruled out, the reporting rules for study 
treatment apply. 
SAE Reporting via an Electronic Data Collection Tool
The primary mechanism for reporting an SAE to Novartis will be the electronic data 
collection tool.
If the electronic system is unavailable, then the site will use the paper SAE data collection 
tool (see next section) to report the event within 24 hours.
The site will enter the SAE data into the electronic system as soon as it becomes available.
After the study is completed at a given site, the electronic data collection tool will be taken 
offline to prevent the entry of new data or changes to existing data.


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If a site receives a report of a new SAE from a study participant or receives updated data on a 
previously reported SAE after the electronic data collection tool has been taken offline, then 
the site can report this information on a paper SAE form (see next section) or by telephone.
Reporting of Suspected Unexpected Serious Adverse Reactions (SUSARs)
If an SAE is not previously documented in the IB or product information for marketed 
products and is thought to be related to any study treatment, Novartis may urgently require 
further information from the investigator for HA reporting. Novartis may need to issue an 
Investigator Notification (IN) to inform all investigators involved in any study with the same 
study treatment. SUSARs will be reported to the competent authorities and relevant ethics 
committees in accordance with national regulatory requirements in participating countries, 
including EU Clinical Trial Regulation 536/2014.
10.1.4
Pregnancy reporting
•
Details of all pregnancies in female participants and female partners of male participants
will be collected after the start of study treatment and until 14 days after the last dose.
•
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication
or elective termination of a pregnancy for medical reasons will be reported as an AE or
SAE.
•
Abnormal pregnancy outcomes (e.g. spontaneous abortion, fetal death, stillbirth,
congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported as
such.
•
Any post study pregnancy-related SAE considered reasonably related to the study
treatment by the Investigator will be reported Novartis as described in Section 10.1.3.
While the Investigator is not obligated to actively seek this information in former study
participants/pregnant female partner, he or she may learn of an SAE through spontaneous
reporting.
Pregnancies
If a female trial participant becomes pregnant, the study treatment should be stopped, and the 
pregnancy consent form should be presented to the trial participant. The participant must be 
given adequate time to read, review and sign the pregnancy consent form. This consent form 
is necessary to allow the Investigator to collect and report information regarding the 
pregnancy. To ensure participant safety, each pregnancy occurring after signing the informed 
consent must be reported to Novartis within 24 hours of learning of its occurrence. 
The pregnancy should be followed up to determine outcome, including spontaneous or 
voluntary termination, details of the birth, and the presence or absence of any birth defects, 
congenital abnormalities, or maternal and/or newborn complications.
Pregnancy should be recorded and reported by the Investigator to Novartis. Pregnancy follow-
up should be recorded on the same form and should include an assessment of the possible 
relationship to the study treatment any pregnancy outcome. Any SAE experienced during 
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If a female partner of a male trial participant who took study treatment in this study becomes 
pregnant, pregnancy outcomes should be collected. Consent to report information regarding 
these pregnancy outcomes should be obtained from the mother.
After consent is provided, the pregnancy reporting will occur up to one year after the 
estimated date of delivery.
10.1.5
Reporting of study treatment errors including misuse/abuse
Study treatment errors are unintentional errors in the prescribing, dispensing, and 
administration of study treatment. 
Study treatment misuse refers to situations where the study treatment is intentionally and 
inappropriately used not in accordance with the protocol.
Study treatment abuse corresponds to the persistent or sporadic, intentional excessive use of a 
study treatment, which is accompanied by harmful physical or psychological effects. 
Once the trial has transitioned under EU Clinical Trial Regulation 536/2014, study treatment 
errors and uses outside of what is foreseen in the protocol, including misuse or abuse, must be 
reported on the AE (or SAE, if the event meets the definition of an SAE) CRF.
10.2
Additional Safety Monitoring
10.2.1
Liver safety monitoring
To ensure participant 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. Once a participant is exposed to study treatment, every liver 
event should be followed up by the investigator or designated personnel at the trial site, as 
summarized in Section 16.1. 
10.2.2 Renal safety monitoring
Abnormal renal event findings must be confirmed within 24-48 hours after the first 
assessment.
Once a participant is exposed to the study treatment, renal laboratory alerts or renal safety 
events should be monitored and followed up by the investigator or designated trial staff as 
summarized in Section 16.2, Table 16-4.
Refer to the Site Operations Manual for additional details.
10.2.3 Vasculitis safety monitoring
Vasculitis includes a group of disorders characterized by non-specific systemic manifestations 
resulting from release of chemical mediators from inflamed blood vessels (e.g., fever, weight 
loss, arthralgia, and myalgia) and more specific manifestations resulting from involvement of 
various organ systems.
A list of clinical manifestations of vasculitis is provided in Section 16.3, Table 16-6.


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Safety monitoring for vascular inflammation will include physical examination at every post-
treatment visit (see Table 8-5 and Table 8-7) by the investigator or qualified delegate 
(including assessment of skin manifestations such as purpura and neurological manifestations 
such as paresthesia and dysesthesia), assessment of markers of general inflammation (i.e., 
ESR and CRP), electrocardiogram, and urinalysis in addition to assessment of laboratory 
parameters such as creatinine, electrolytes, and BUN for assessment of renal involvement.
Participants will be instructed to contact the investigator immediately in case of development 
of signs and symptoms potentially suggestive of vasculitis.
In the event of signs and symptoms of vascular inflammation or in the event of elevations in 
ESR and/or CRP (refer to Table 16-7 for ESR and CRP values triggering additional 
evaluation), further diagnostic work should be performed to identify the primary reason for 
such increase (e.g., other inflammatory conditions such as bacterial infections). 
Detailed guidance for the identification and follow-up of potential cases of vasculitis is 
provided in Section 16.3.
If a diagnosis of BLZ945-induced vasculitis is made, BLZ945 should be discontinued and 
a SAE be recorded as a medically significant event (Section 10.1.3) with information captured 
from clinical management of the case as specified in Appendix 3.
10.2.4 Monitoring for ECM accumulation
Signs or symptoms of ECM accumulation may include:
•
Macroscopic signs including eyelid / orbital / periorbital swelling
•
Cardiac function alterations resulting for example in worsening of dyspnea, chest pain,
fatigue, syncope
•
Worsening of dysphagia
Assessment of potential effects of BLZ945 on ECM accumulation in the heart (including 
heart valves) and esophagus will be performed by echocardiography and CT scan at baseline 
and week 12.
In the event of the report of unexpected worsening of swallowing, or in the event that 
the onset of facial or periorbital swelling of moderate or severe intensity is detected, an ad hoc 
CT scan of the chest must be performed to evaluate for possible clinically relevant changes in 
esophageal thickening within 2 weeks of the event.
In case of clinically relevant changes in esophageal thickness (>3mm increase in mean wall 
thickness compared to the baseline measurement) detected at week 12, the study participant 
should be followed for an additional 12 weeks off treatment. At the end of the additional 
follow-up period, a CT scan will be performed to evaluate the esophageal thickness.
In case of abnormal cardiac valves thickening and/or clinically relevant cardiac valve / cardiac 
function (stenosis, regurgitation, LVEF) abnormalities detected at week 12, the study 
participant should be followed for an additional 12 weeks off treatment. At the end of the 
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additional follow-up period, an echocardiogram should be performed to evaluate the status of 
the previously identified abnormality.
10.2.5
Prospective suicidality assessment
The Columbia-Suicide Severity Rating Scale (C-SSRS) is a questionnaire that prospectively 
assesses suicidal ideation and suicidal behavior. The C-SSRS must be administered at 
the visits indicated in Table 8-1, Table 8-3,Table 8-5 and Table 8-7, as well as at any 
unscheduled visit.
The C-SSRS, which uses a semi-structured interview to probe participant responses, will be 
administered by an individual who has received training and certification in its administration. 
At the first study visit, the “baseline/screening” version of the C-SSRS will be administered. 
This version assesses suicidal ideation and suicidal behavior during the participant’s lifetime 
and during a predefined period. At subsequent visits, the “since last visit” version will be 
administered.
If, at any time after screening and/or baseline, the score is “yes” on item 4 or item 5 of 
the suicidal ideation section of the C-SSRS or “yes” on any item of the suicidal behavior 
section, the participant must be referred to a mental health care professional for further 
assessment and/or treatment. The decision on whether the study treatment should be 
discontinued is to be taken by the investigator in consultation with the mental health 
professional to whom the participant is referred.
In addition, all life-threatening events must be reported as SAEs. For example, if a participant 
answers “yes” to one of the questions in the suicidal behavior section, an SAE must be 
reported if the event was life-threatening. All events of “Non-Suicidal Self-Injurious Behavior” 
(question also included in the suicidal behavior section) should be reported as AEs and 
assigned the appropriate severity grade.
11
Data Collection and Database management
11.1
Data collection
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification.
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements, Investigator site staff will 
not be given access to the EDC system until they have been trained. Automatic validation 
programs check for data discrepancies in the eCRFs, allow modification and/or verification of 
the entered data by the investigator staff.
The investigator/designee is responsible for assuring that the data (recorded on CRFs) 
(entered into eCRF) is complete, accurate, and that entry and updates are performed in a 
timely manner. The Investigator must certify that the data entered are complete and accurate.
After final database lock, the investigator will receive copies of the participant data for 
archiving at the investigational site.


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All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification.
11.2
Database management and quality control
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to 
the investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using 
the World Health Organization (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.
11.3
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, 
a Novartis/delegated CRO representative will review the protocol and data capture 
requirements (i.e. eSource DDE or eCRFs) with the investigators and their staff. 
During the study, Novartis employs several methods of ensuring protocol and GCP 
compliance and the quality/integrity of the sites’ data. The field monitor will visit the site to 
check the completeness of participant records, the accuracy of data capture / data entry, the 
adherence to the protocol and to Good Clinical Practice, the progress of enrollment, and to 
ensure that study treatment is being stored, dispensed, and accounted for according to 
specifications. Key study personnel must be available to assist the field monitor during these 
visits. Continuous remote monitoring of each site’s data may be performed by a centralized 
Novartis/delegated CRO/CRA organization. Additionally, a central analytics organization 
may analyze data & identify risks & trends for site operational parameters, and provide 
reports to Novartis clinical teams to assist with trial oversight.
The investigator must maintain source documents for each participant 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 
participant’s file. The investigator must also keep the original informed consent form signed 
by the participant (a signed copy is given to the participant).
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 of data that will be used for all 
primary variables. Additional checks of the consistency of the source data with the CRFs are 
performed according to the study-specific monitoring plan. No information in source 
documents about the identity of the participants will be disclosed.


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11.4
Data Monitoring Committee
An independent Data Monitoring Committee (DMC) will review individual and aggregated 
data from Cohort 5 on a regular basis for safety oversight along with any new information 
emerging from preclinical toxicity studies. DMC will review all safety and tolerability 
assessments, including ECGs, laboratory tests, vital signs, adverse events, suicidality, 
esophageal CT-scans and echocardiogram abnormalities. 
 
Disposition of participants will include the duration of exposure in 
Cohort 5 over the 40 weeks of extended treatment and, if applicable, the reason for early 
treatment discontinuation. DMC may recommend discontinuing treatment in an individual 
participant, one of the treatment arms or the whole Cohort 5 (see Section 9.1.4).
12
Data analysis and statistical methods
Any data analysis carried out independently by the investigator should be submitted to 
Novartis before publication or presentation.
All primary, secondary 
endpoints listed below will be analyzed using 
the same statistical methodology for all cohorts unless explicitly detailed for Cohort 5.
For Cohort 5, participants will be analyzed by the starting dose and regimen (800mg 4/10, 
800mg QW, 600mg 4/10 and 400mg QW) to account for the dose reductions implemented in 
protocol amendment v07. Participants may be pooled across starting doses and regimens as 
applicable to assess the primary PET objective, 
 
.
For the Cohort 5 secondary 
 endpoints assessing changes from baseline to 
Week 40, the change from baseline to be summarized primarily refers to the change from 
the baseline prior to BLZ945 drug administration of the core period. Additional summaries for 
change from start of extended treatment (Week 16) will also be included as applicable.
12.1
Analysis sets
For all analysis sets, which is identical to the safety analysis set, participants will be analyzed 
according to the study treatment(s) received.
The full analysis set will include all participants that received any study drug.
The PK analysis set will include all participants with at least one available valid (i.e., not 
flagged for exclusion) PK concentration measurement, who received any study drug, and had 
no protocol deviations that impact on PK data.
The PD analysis set will include all participants with available PD data and no protocol 
deviations with relevant impact on PD data.
12.2
Subject demographics and other baseline characteristics
Demographic and other baseline data will be summarized descriptively by dose cohort for 
each dosing cohort.
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Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. Differences from 
baseline of continuous variables will be presented in the same way.
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term, and by dose cohort.
12.3
Treatments
The duration of exposure in time to BLZ945 will be summarized by means of descriptive 
statistics using the safety set. Numbers of participants exposed to the different daily doses of 
BLZ945 will be tabulated.
Concomitant medications and significant non-drug therapies prior to and after the start of 
the study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system, by dose cohort.
12.4
Analysis of the primary endpoint(s)
Cohorts 1- 4
The fraction of brain microglia reduction following four oral doses of BLZ945 will be 
analyzed by an Emax model with dose as the independent variable and reduction fraction as 
the dependent variable. Allometric scaling of a mouse PK/PD model makes it credible that 
4 doses at 600 mg for 4 days will lead to a 50% reduction in microglia 18 days past the 4th 
dose. The same model points to a Hill constant between 1 and 3.3. It hence seems reasonable 
to analyze all available microglia reduction data at the 5 day time point by a sigmoidal Hill 
constant model with prior distributions on the EC50 of 600 mg and Hill constant centered at 2. 
Such a model assumes that the microglia reduction after 4 doses is independently normally 
distributed among participants with a mean which can be expressed by a two-parameter Emax 
function. If the microglia depletion fraction at concentration c is denoted Y(c), then the model 
assumes that
Y(c) =ch /(ch+Dh)+error
Here, D and h are the two unknown parameters, the concentration giving a 50% response and 
the Hill constant.
For the purposes of this study, brain [11C]-PBR28 binding reduction of 20% or more has been 
chosen as sufficient evidence of target engagement to enable further development.
Cohort 5
Descriptive statistics will be provided by treatment and visit for the cohort 5 for efficacy and 
safety endpoints. No formal statistical comparison will be carried out between the two 
treatment arms. For continuous measures, such as percent change from baseline to week 12 in 
Vt measured via PET scan, esophagus wall thickness change from baseline to week 12 and 
LVEF change from baseline to week 12, the mean, SD and 95% CI will be provided by 
treatment arm. For measures such as cardiac valve function (stenosis and regurgitation based 
on echocardiography) and cardiac valve thickness, the number and frequency of participants 


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with any worsening between baseline and Week 12 will be presented by treatment arm, as 
well as the 95% CI for the rate based on the Wilson method. Number and percentages of 
participants with AEs of ECM accumulation will be summarized by treatment arm.
12.4.1
Definition of primary endpoint(s)
Cohorts 1-4
The percent change in Vt of the first scan 24 hours after last BLZ945 treatment relative to 
baseline will be considered as primary endpoint.
Cohort 5
The percent change from baseline to Week 12 in Vt measured via PET scan.
The changes from baseline to Week 12 in: esophagus wall thickness (mm), and LVEF (%).
Any worsening from baseline to Week 12 in cardiac valve thickness and cardiac valve 
function (stenosis and regurgitation).
Adverse events of ECM accumulation during the 12 weeks of treatment.
12.4.2
Statistical model, hypothesis, and method of analysis
Cohorts 1, 2, 3 and 4 will receive 4 daily doses of BLZ945, after which the decrease in 
microglia level will be assessed. Cohort 1 will be dosed at a low dose, and barring any safety 
concerns while cohorts 2 and 3 will be dosed at increasing dose levels. After four cohorts of 4 
participants have been dosed, the sigmoidal model described in Section 12.4 will be fitted to 
data. That is, a nonlinear regression model of the form
Y(c)=ch /(ch+Dh)+e
will be fitted to the microglia depletion ratio (ratio to baseline) where c denotes the dose level, 
D is the ED-50 dose, and h is the Hill constant model.
When data from the first 12 participants are available from the 4 day dosing cohorts, the ED-
50 and Hill constant parameters will be estimated. The remaining two 4 day dosing cohorts 
will be allocated to doses in the unexplored part of the dose-response curve; that is, between 
dose cohorts 1 and 2, and dose cohorts 2 and 3, unless it clear that adding extra design points 
here will not lead to a more accurate characterization of the dose-response relationship. 
This is, the predictive variability in the ED-50 estimate available from adding 8 participants at 
two new doses between 1,2 and 2,3 and if the reduction in variability is deemed substantive, 
the 8 additional participants will be added. 
The decision to proceed to the next dose cohort will be made jointly between the Sponsor and 
the Investigator, following a review of all available data.
In Cohort 5, statistical analyses will be descriptive, no formal statistical hypothesis testing 
will be applied.
12.4.3
Handling of missing values/censoring/discontinuations
No imputation of missing value will be considered for the primary analysis.


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12.4.4
Sensitivity and Supportive analyses
Sensitivity analyses
Cohorts 1-4: It will be assessed through residual plots whether the model of the primary 
analysis gives a credible description of data. Other models with transformed response, non-
constant error variance, and baseline covariates included may be attempted in order to see if 
the dose-response fit and conclusions hold up.
If substantial dropouts are seen prior to study day 4 (so that the primary end point is missing), 
the dose -response relationship will be reassessed under a model for informative drop out. 
This will be done in order to ensure that potential non-responders are not more likely to drop 
out.
12.5
Analysis of secondary endpoints
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)
Not applicable.
12.5.2
Safety endpoints
The safety and tolerability will be evaluated by the following standard safety assessments; 
relevant findings from physical and neurological examinations, vital signs, hematology, 
chemistry, urinalysis, ECG evaluation, AE and SAE recordings. AEs potentially related to 
ECM accumulation (Section 10.2.4) or vasculitis (Section 10.2.3) will be summarized. 
The evaluations will be mostly descriptive; should a dose-dependent incidence in AEs be 
present, it will be quantified by Cochran-Armitage test for trend.
12.5.3
Pharmacokinetics
Cohorts 1-4: All participants who have evaluable PK data will be included in the PK data 
analysis. BLZ945 plasma pharmacokinetic parameters listed in Table 8-10 will be determined 
when feasible.
Summary statistics of BLZ945 pharmacokinetic parameters 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. 
A geometric mean will not be reported if the dataset includes zero values. Descriptive 
graphical plots of individual plasma concentration versus time profiles and mean 
concentration versus time profiles will be generated. 
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Other plasma or urine PK parameters will be determined as appropriate.
Cohort 5: All participants who have evaluable PK data will be included in the PK analysis.
The following BLZ945, 
 plasma 
pharmacokinetic parameters will be estimated when feasible: Cmax, Tmax, AUClast, Tlast. 
Pharmacokinetic parameters will be listed by treatment and participant.
Summary statistics of BLZ945, 
pharmacokinetic parameters 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. A geometric mean will 
not be reported if the dataset includes zero values. With only 4 samples and only up to 4 hrs 
post dose, it may not be possible to derive the PK parameters above.
Cohorts 1-5: the relationship between CYP2C8 polymorphisms and BLZ945 PK parameters 
will be assessed graphically and descriptively.
12.6
Analysis of exploratory endpoints
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12.7
Interim analyses
12.8
Sample size calculation
12.8.1
Primary endpoint(s)
12.8.1.1 Cohorts 1-4
It is assumed that up to 20 participants will provide a microglia fraction readout after 4 doses 
of study drug.
The operational characteristics of the design can be approximated by calculating the expected 
value of the Information matrix under various assumptions in the Hill constant and ED-50. 
As a guideline, it can be shown that when 20 participants are equally dosed with 300 mg, 
450 mg, 600 mg, 900 mg and 1200 mg, and if a pure error variability in the model of 10% is 
assumed, then the expected coefficient of variation of the estimated ED-50 value is as 
displayed in Table 12-1. So, unless the ED-50 is below the range of concentrations tested then 
it will be estimated with a CV not exceeding 12%. The spacing between the concentrations 
considered is least 33% (from 900 to 1200 mg), so a precision of 12% must be considered 
good for anchoring the estimated ED-50 to one of the concentrations in the range. If at the 
extreme, the SD of the microglia reduction measurements is assumed to be the double, 20%, 
then the CV of the estimate will still be below 20% in most cases.
Table 12-1
Percent CV estimate for ED-50 parameter
Hill constant/ED50
200 mg
400 mg
600 mg
800 mg
1
26.8
12.1
9.5
10.5
2
 20.6
6.4
5.4
 5.7
3
 23.6
4.6
4.2
 4.3
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12.8.1.2 Cohort 5
Cohort 5 
PET sub-study will recruit approximately 8 
participants.
Sample size operating characteristics evaluations are based on a minimum of 24 participants 
(12 participants per treatment arm) contributing to the ECM accumulation assessments 
(esophagus wall thickness, LVEF, cardiac valve thickness and function and AEs of ECM 
accumulation); additional evaluations based on 30 participants (15 participants per treatment 
arm) are also provided. For the PET assessments, operating characteristics are evaluated using 
a maximum of 8 patients (4 participants per treatment arm).
Percent change from baseline to Week 12 in Vt measured via PET scan
Based on the extensive burden to participants with ALS, the sample size for PET sub-study 
has been set to n=4 per treatment arm. The operating characteristics of the proposed sample 
size were assessed based on the probabilities to 1) observe a decrease of at least 20% in 
the point estimate of percent change from baseline to Week 12 in Vt, 2) observe a decrease 
between 10% and 20% in the point estimate of percent change from baseline to Week 12 in Vt, 
and 3) observe a decrease of less than 10% in the point estimate of percent change from 
baseline to Week 12 in Vt (Table 12-2). A reduction between 10% and 20% is expected to 
represent a clinically relevant change. For example, with a sample size of n=4 per treatment 
arm, if the true mean for percent change from baseline to Week 12 in Vt was a 21% reduction 
and the standard deviation (SD) was 17%, the probability to observe a decrease of 10% or 
higher in the point estimate is 90%. Across the scenarios considered, the probability to 
observe a reduction of 10% or higher in the point estimate is more than 80%, which is 
considered acceptable. A smaller sample size of n=3 was also evaluated in case of missing 
data due to treatment discontinuations. The assumptions on standard deviation and true mean 
reduction in Table 12-2 were made based on Cohort 2 (600 mg) results for percent change in 
Vt of precentral gyrus (Novartis data on file).
Table 12-2
Probability to observe different outcomes for microglia Vt percent 
change from baseline to Week 12 assuming a true mean reduction of 
21 percent
n
Assumed 
standard deviation 
(SD)
Prob (decrease at 
least 20% in point 
estimate)
Prob (decrease 
between 10% and 
20% in point 
estimate)
Prob (decrease less 
than 10% in point 
estimate)
3
3
4
4
17
21
17
21
54%
53%
55%
54%
33%
29%
35%
31%
13%
18%
10%
15%
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Changes from baseline to Week 12 in esophagus wall thickness (mm) and 
LVEF (%)
The operating characteristics of the sample size (using n= 12 and n=15 per treatment arm) for 
the esophagus wall thickness change from baseline to Week 12 (continuous variable measured 
in mm based on the esophagus CT scan) and for LVEF change from baseline to Week 12 
(continuous variable measured for each patient in % based on the echocardiogram) were 
assessed via a precision approach within treatment arm (Table 12-3). Across the scenarios 
considered, the half width of the 95% CI for the esophagus wall thickness change from 
baseline to Week 12 is less than 1 mm, which is sufficient to assess clinically relevant 
changes. Similarly, the half width of the 95% CI for LVEF change from baseline to Week 12 
is less than 1.3%, which is also considered sufficient. The assumption of a standard deviation 
(SD) of 0.89 for esophagus wall thickness change from baseline to Week 12 was derived 
based on an assumed SD of 2 mm from for the absolute measurement at both baseline and 
Week 12 (Berkovich et al 2000) and an assumed correlation value of 0.9 between baseline and 
Week 12. The assumption on the standard deviation for LVEF change from baseline to Week 
12 was based on a SD of 4.9% fromKou et al 2014 for the absolute measurement at both 
baseline and Week 12 and an assumed correlation value of 0.9 between baseline and Week 12.
Table 12-3
Precision of estimation for esophagus wall thickness change from 
baseline to Week 12 and LVEF change from baseline to Week 12
Variable
Assumed
SD
n
Half-width of 95% 
CI
Esophagus wall thickness
(mm) - change from baseline
0.89
12
15
0.51
0.45
LVEF (%) - change from baseline
2.19
12
15
1.24
1.11
Any worsening from baseline to Week 12 in cardiac valve thickness and 
cardiac valve function (stenosis and regurgitation)
The operating characteristics of the sample size (using n=12 and n=15 per treatment arm) for 
cardiac valve function, i.e. stenosis and regurgitation and for cardiac valve thickness 
(variables capturing any degree of worsening from baseline to Week 12) were assessed via 
a precision approach within treatment arm as measured by the half width of the 95% CI using 
Wilson’s method (Table 12-4). For example, with n=12 per treatment arm, if the true event 
rate was 0.1, the half-width of the 95% CI is 0.18, which is considered acceptable.


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Table 12-4
Precision of estimation for cardiac valve thickness and cardiac valve 
function (stenosis and regurgitation) – any worsening from baseline to 
Week 12
Assumed true event rate
n
Half-width of 95% CI
0.05
0.1
0.2
0.3
0.4
0.5
12
12
12
12
12
12
0.15
0.18
0.21
0.23
0.24
0.25
0.05
0.1
0.2
0.3
0.4
0.5
15
15
15
15
15
15
0.13
0.16
0.19
0.21
0.22
0.23
Adverse events of ECM accumulation during the first 12 weeks of treatment
The operating characteristics of the sample size (using n=12 and n=15 per treatment arm) for 
AEs of ECM accumulation during the first 12 weeks of treatment were assessed based on 
the probability to observe at least 1 participant with AEs of ECAnd aM accumulation 
(Table 12-5). For example, with n=12 per treatment arm, if the true event rate was 10%, the 
probability of observing at least one patient with an AE of ECM accumulation is 72%, which 
is considered sufficient. The same calculations hold also for the probability to observe at least 
1 participant with an event of any worsening in the cardiac thickness or in the cardiac valve 
function.
Table 12-5
Probability of observing at least 1 participant with AEs of ECM 
accumulation during the first 12 weeks of treatment
Assumed true event rate
n
Probability
0.03
0.05
0.10
0.2
0.5
12
12
12
12
12
31%
46%
72%
93%
100%
0.03
0.05
0.10
0.2
0.5
15
15
15
15
15
37%
54%
79%
96%
100%


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13
Ethical considerations and administrative procedures
13.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in 
accordance with the International Conference on Harmonisation (ICH) Harmonized Tripartite 
Guidelines for Good Clinical Practice, with applicable local regulations (including European 
Directive 2001/20/EC, US CFR 21), and with the ethical principles laid down in the 
Declaration of Helsinki.
13.2
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, participant recruitment 
procedures (e.g. advertisements) and any other written information to be provided to 
participants. 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.
13.3
Data protection
Participants will be assigned a unique identifier. Any participant records or datasets that are 
transferred to Novartis will contain the identifier only; participant names or any information 
which would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by 
Novartis in accordance with local data protection law. The level of disclosure must also be 
explained to the participant who will be required to give consent for their data to be used as 
described in the informed consent. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by Novartis, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
Novartis has appropriate processes and policies in place to handle personal data breaches 
according to applicable privacy laws.
13.4
Publication of study protocol and results
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT / CTIS public website. In addition, after study completion and 
finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical 


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trial results website and all required Health Authority websites (e.g. Clinicaltrials.gov, 
EudraCT / CTIS public website etc.).
Summary results of primary and secondary endpoints will be disclosed based upon the global 
Last Participant Last Visit (LPLV) date, since multinational studies are locked and reported 
based upon the global LPLV.
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial 
investigator meetings or site initiation visits.
Any data analysis carried out independently by the Investigator must be submitted to Novartis 
before publication or presentation.
13.5
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines.
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
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.
14
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 participants should 
be administered as deemed necessary on a case by case basis. Under no circumstances 
including incidental collection is an investigator allowed to collect additional data or conduct 
any additional procedures for any purpose involving any investigational drugs under 
the protocol, other than the purpose of the study. If despite this interdiction prohibition, data, 
information, observation would be incidentally collected, the investigator shall immediately 
disclose it to Novartis and not use it for any purpose other than the study, except for the 
appropriate monitoring on study participants.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC and Health Authorities, where required, it cannot be 
implemented.
14.1
Protocol amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation.


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Only amendments that are required for participant safety 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 participant included in 
this study, even if this action represents a deviation from the protocol. In such cases, Novartis 
should be notified of this action and the IRB/IEC at the study site should be informed 
according to local regulations.


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15
References
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Appendices
16.1
Appendix1: Liver safety monitoring 
Table 16-1
Liver event and laboratory trigger definitions
Definition/ threshold
Liver laboratory triggers
•
ALT or AST > 5 × ULN
If ALT, AST, TBL normal 
at baseline:
•
ALP > 2 × ULN (in the absence of known bone pathology)
•
TBL > 3 × ULN (in the absence of known Gilbert syndrome)
•
ALT or AST > 3 × ULN and INR > 1.5 (in the absence of 
anticoagulation)
•
Potential Hy’s Law cases (defined as ALT or AST > 3 × ULN and 
TBL > 2 × ULN [mainly conjugated fraction] without notable increase in 
ALP to > 2 × ULN)
•
Any clinical event of jaundice (or equivalent term)
•
ALT or AST > 3 × ULN accompanied by (general) malaise, fatigue, 
abdominal pain, nausea, or vomiting, or rash with eosinophilia
•
Any adverse event potentially indicative of a liver toxicity*
If ALT or AST abnormal 
at baseline:
•
ALT or AST > 3 x baseline
ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; TBL: 
total bilirubin; ULN: upper limit of normal.
*These events cover the following: Hepatic failure, fibrosis and cirrhosis, and other liver damage-
related conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver neoplasms. 
Once a participant is exposed to study treatment, every liver event defined in Table 16-1 
should be followed up by the investigator or designated personnel at the trial site, as 
summarized below. 
Additional details on actions required in case of liver events are outlined in Table 16-2.
Repeat liver chemistry tests (i.e. ALT, AST, TBL, PT/INR, ALP and GGT) to confirm 
elevation.
•
These liver chemistry repeats will be performed using the central laboratory. If results will 
not be available from the central laboratory, then the repeats can also be performed at a 
local laboratory to monitor the safety of the participant. If a liver event is subsequently 
reported, any local liver chemistry tests previously conducted that are associated with this 
event should have results recorded on the appropriate CRF.
•
If the initial elevation is confirmed, close observation of the participant will be initiated, 
including consideration of treatment interruption if deemed appropriate.
•
Discontinuation of the investigational drug (refer to Section 9.1.1 Discontinuation of study 
treatment), if appropriate
•
Hospitalization of the participant if appropriate
•
Causality assessment of the liver event


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•
Thorough follow-up of the liver event should include 
•
These investigations can include based on investigator’s discretion: serology tests, 
imaging and pathology assessments, hepatologist’s consultancy; obtaining more 
detailed history of symptoms and prior or concurrent diseases, 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 16-3).
•
Imaging such as abdominal US, CT or MRI, as appropriate
All follow-up information and procedures performed must be recorded as appropriate in the 
CRF.
Refer to the SOM for additional details.
Table 16-2
Follow up requirements for liver events and laboratory triggers
ALT or AST
Total Bilirubin 
(TBL)
Liver Symptoms
Action taken
ALT or AST increase without bilirubin increase:
If normal at 
baseline:
ALT or AST >1.0- 
<3.0 x ULN
If elevated at 
baseline:
ALT or AST > 1.0 - 
<2.0 x baseline
Normal
For participants with 
Gilbert’s syndrome: 
No change in 
baseline TBL
None
•
No change to study 
treatment.
•
Monitor as considered 
appropriate by the 
investigator until recovery to 
previous baseline.
If normal at 
baseline:
ALT or AST > 3.0 x 
ULN
If elevated at 
baseline:
ALT or AST > 2.0 x 
baseline
Normal
For participants with 
Gilbert’s syndrome: 
No change in 
baseline TBL
None
•
No change to study 
treatment.
•
Measure ALT, AST, ALP, 
GGT, TBIL, INR, and 
albumin in 48-72 hours.
•
Monitor closely until 
recovery to < 3.0 ULN or 
baseline.
•
Follow-up for symptoms.
If normal at 
baseline:
ALT or AST > 5.0 x 
ULN
If elevated at 
baseline:
ALT or AST 3.0 x 
baseline AND 5 x 
ULN
Normal
For participants with 
Gilbert’s syndrome: 
No change in 
baseline TBL
None
•
Interrupt study drug
•
Measure ALT, AST, ALP, 
GGT, TBIL, INR, and 
albumin, in 48-72 hours. 
•
Obtain PK samples to 
determine exposure to 
BLZ945 and SoC. 
•
Collect an unscheduled 
blood sample for 
measurement of miR122.
•
Follow-up for symptoms.
•
Initiate close monitoring and 


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ALT or AST
Total Bilirubin 
(TBL)
Liver Symptoms
Action taken
workup for competing 
etiologies (see Table 16.3). 
Monitor closely (e.g., 
weekly, or as considered 
appropriate by the 
investigator) until recovery 
to < 3.0 ULN or baseline.
•
Study drug can be restarted
at a lower dose level if liver
enzymes return to < 3.0
ULN or baseline.
ALT or AST > 20.0 x 
ULN
Normal
For participants with 
Gilbert’s syndrome: 
No change in 
baseline TBL
None
•
Discontinue BLZ945
treatment. Consider
interrupting riluzole until
resolution of the liver event
(if applicable).
•
Obtain PK samples to
determine exposure to
BLZ945 and SoC.
•
Collect an unscheduled
blood sample for
measurement of miR122
•
Monitor closely LFTs until
resolution1 (ALT, AST, total
bilirubin, albumin, INR, ALP
and GGT, frequency at
investigator discretion).
ALT or AST increase with bilirubin increase and/or symptoms:
If normal at 
baseline:
ALT or AST > 3 x 
ULN
If elevated at 
baseline:
ALT or AST > 2 x 
baseline AND 3 x 
ULN
TBL > 2 x ULN (or 
INR > 1.5)
For participants with 
Gilbert’s syndrome: 
doubling of direct 
bilirubin
None
If normal at 
baseline:
ALT or AST > 3 x 
ULN
If elevated at 
baseline:
ALT or AST > 2 x 
baseline AND 3 x 
ULN
Normal or elevated
Severe fatigue, 
nausea, vomiting, 
right upper 
quadrant pain
•
Interrupt study drug
•
Measure ALT, AST, ALP,
GGT, TBIL, INR, and
albumin in 48-72 hours. If
TBIL is elevated > 1.5 x
ULN, direct and indirect
bilirubin should be
measured.
•
Collect an unscheduled
blood sample for
measurement of miR122.
•
Follow-up for symptoms.
•
Obtain PK samples to
determine exposure to
BLZ945 and SoC.
•
Initiate close monitoring and
workup for competing
etiologies (see Table 16-3).
Monitor closely (e.g., weekly
or as considered appropriate
by the investigator) until


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ALT or AST
Total Bilirubin 
(TBL)
Liver Symptoms
Action taken
recovery to < 3.0 ULN or 
baseline. 
•
Upon recovery, collect blood 
sample for additional liver 
injury assay.
•
Study drug can be restarted 
only if liver enzymes return 
to baseline and if another 
etiology is identified. 
Total Bilirubin (isolated)
Normal or no change 
from baseline
>1.5 – 3.0 ULN
None 
•
Maintain study treatment. 
•
Repeat LFTs within 48-72 
hours, including 
measurement of direct and 
indirect bilirubin.
•
Monitor LFTs closely (e.g., 
weekly, or as considered 
appropriate by the 
investigator) until resolution 
to ≤ 1.5 ULN or to baseline 
(ALT, AST, TBIL, albumin, 
PT/INR, ALP and GGT).
•
Test for hemolysis (e.g., 
reticulocytes, haptoglobin, 
unconjugated [indirect] 
bilirubin).
Normal or no change 
from baseline
> 3 - 10 × ULN (in 
the absence of 
known Gilbert 
syndrome)
None 
•
Interrupt treatment. 
•
Repeat LFTs within 48-72 
hours, including 
measurement of direct and 
indirect bilirubin.
•
Monitor LFTs closely (e.g., 
weekly, or as considered 
appropriate by the 
investigator) until resolution 
to ≤ 1.5 ULN or to baseline 
(ALT, AST, total bilirubin, 
albumin, PT/INR, ALP and 
GGT). 


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ALT or AST
Total Bilirubin 
(TBL)
Liver Symptoms
Action taken
Normal or no change 
from baseline
> 10 x ULN
None
•
Discontinue treatment 
immediately. 
•
Measure LFTs within 48-72 
hours, including 
measurement of direct and 
indirect bilirubin.
•
Continue to monitor LFTs 
closely until resolution1 
(ALT, AST, direct, indirect 
and total bilirubin, albumin, 
PT/INR, ALP and GGT, 
frequency at investigator 
discretion).
1 Resolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable 
values at three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level after 
a maximum of 6 months, (4) liver transplantation, and (5) death. 
Based on the investigator’s discretion, additional investigation(s) for contributing factors for 
the liver event can be performed. These investigations may include: serology tests, imaging 
and pathology assessments, consultation with a hepatologist; obtaining more detailed history 
of symptoms and prior or concurrent diseases, 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 (see Table 16-3).
Table 16-3
Alternative causes of liver disease and related assessments 
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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16.2
Appendix 2: Specific Renal Alert Criteria and Actions and Event 
Follow-up
Table 16-4
Specific Renal Alert Criteria and Actions
Renal Event
Actions
Confirmed serum creatinine increase 25 – 49% 
•
Consider causes and possible 
interventions
•
Follow up within 2-5 days
Serum creatinine increase ≥ 50 %
OR if <18 years old, eGFR ≤ 35 mL/min/1.73 m2
New onset dipstick proteinuria ≥ 3+ OR
Protein-creatinine ratio (PCR) ≥ 1g/g Cr (or 
mg/mmol equivalent as converted by the measuring 
laboratory)
•
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 participant hospitalization and 
specialized treatment
•
Consider causes and possible 
interventions
•
Assess serum albumin & serum total 
protein
•
Repeat assessment to confirm
•
Consider drug interruption or 
discontinuation unless other causes are 
diagnosed and corrected
New onset hematuria ≥ 3+ on urine dipstick
Assess & document
•
Repeat assessment to confirm
•
Distinguish hemoglobinuria from 
hematuria
•
Urine sediment microscopy
•
Assess sCr
•
Exclude infection, trauma, bleeding from 
the distal urinary tract/bladder, 
menstruation
•
Consider bleeding disorder
+ Corresponds to KDIGO criteria for Acute Kidney Injury


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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 recommended 
to make slide specimen available for evaluation by the RSG to potentially identify project- 
wide patterns of nephrotoxicity.)
Whenever a renal event is identified, a detailed participant history and examination are 
indicated to identify and potentially eliminate risk factors that may have initiated or 
contributed to the event:
•
Blood pressure assessment (after 5-minute rest, with an appropriate cuff size)
•
Signs and symptoms like fever, headache, shortness of breath, back or abdominal pain,
dysuria or 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 diseases or
causes, e.g., dehydration due to delirium, tumor lysis
Table 16-5
Renal Event Follow Up
Assess, document and record in CRF
•
Urine dipstick and sediment microscopy evidence of DIN: crystals, red blood cells
(dysmorphic/glomerular vs. non-dysmorphic/non-glomerular), white blood cells, tubular epithelial
cells
•
Blood pressure and body weight
•
Serum creatinine, BUN, electrolytes (sodium, potassium, phosphate, calcium), bicarbonate and
uric acid
•
Urine output
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
Monitor participant regularly (frequency at investigator’s discretion) until -
•
Event resolution: (sCr within 10% of baseline or PCR < 1 g/g Cr, or ACR <300 mg/g Cr) 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.
•
Analysis of urine markers in samples collected over the course of the DIN event


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16.3
Appendix 3: Guidance for the identification of potential cases of 
vasculitis and their follow-up
16.3.1
Identification of potential cases of vasculitis
The identification of potential cases of vasculitis should be based on the occurrence of signs 
and symptoms based on a detailed medical history and physical examination, along with 
supportive laboratory evidence.
A list of clinical manifestations of vasculitis is provided in Table 16-6.
Table 16-6
Clinical manifestations of vasculitis
System organ involved
Clinical manifestations
General
Myalgia, arthralgia / arthritis, fever, weight loss
Cutaneous
Infarct, purpura, ulcer, necrosis, rash
Mucous membranes / eyes
Mouth ulcers, genital ulcers, adnexal inflammation, significant 
proptosis, red-eye conjunctivitis / blepharitis / keratitis*, red-eye 
epi/scleritis*, blurred vision*, uveitis*, retinal involvement*
Ear Nose Throat
Bloody nasal discharge, nasal obstruction, nasal crusting, sinus 
involvement, hearing loss*, hoarseness / stridor (due to subglottic 
stenosis#)
Chest
Persistent cough, dyspnoea or wheeze, hemoptysis / hemorrhage, 
nodules or cavities#, pleural effusion#, infiltrate#
Cardiovascular
Valvular heart disease#, pericarditis, ischemic cardiac pain#, 
cardiomyopathy#, congestive cardiac failure 
Gastrointestinal
Bloody diarrhoea, severe abdominal pain due to ischemia# or 
peritonitis
Renal 
Hypertension, proteinuria, hematuria, red cell casts in urine, 
deterioration of renal function
Nervous system
Sensory peripheral neuropathy, motor mononeuritis multiplex
* Additional specialist consultation may be required for further evaluation and management;
# Use of imaging techniques required for the evaluation of these clinical manifestations
Patients will be instructed to contact the investigator immediately in the event that 
they experience any sign or symptom of vasculitis. If investigators suspect a case of vasculitis, 
it is recommended that BLZ945 administration is temporarily interrupted until further 
investigations confirm or refute the case.
A detailed history of signs and symptoms, including time to onset, severity and evolution of 
symptomatology should be documented in the patient’s charts as well as history of exposure 
to new medications (if applicable). Changes in severity of symptoms as well as resolution of 
symptoms upon drug discontinuation should also be recorded. If any lesions are noticed by 
the patient (e.g., skin or mucous membranes), photographs may be taken and showed to 
the investigator and/or specialist to facilitate clinical assessment.


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Physical examination
Vital signs will be collected at all site visits and during home nursing visits in accordance with 
the assessment schedule described in Table 8-5.
A physical examination will be performed by the investigator or qualified delegate at all site 
visits as scheduled per Table 8-5 or, if necessary, at unscheduled visits. The examination will 
include general appearance, head, neck (including thyroid), eyes, ears, nose, throat, lungs, 
heart, abdomen, back, lymph nodes, skin (e.g., purpura), extremities, vascular and 
neurological (e.g., paresthesia and dysesthesia) assessments.
Laboratory assessments
Laboratory assessments will be performed at baseline and at the site and home nursing visits 
as scheduled per Table 8-5, or at unscheduled visits. These assessments will include complete 
blood count, liver function tests, renal parameters such as creatinine, BUN and urinalysis 
(macroscopic and microscopic panel), cardiac enzymes (CK-MB, troponins) and markers of 
inflammation (e.g., ESR and CRP). For a full list of laboratory assessments, please refer to 
Section 8.4.1.
In case of elevations in ESR and CRP above the thresholds defined below in Table 16-7, 
additional diagnostic work should be performed to look for signs of symptoms indicative of 
vasculitis (e.g., physical examination). Unscheduled laboratory assessments might also be 
performed in case of new onset of signs and symptoms, if required by the investigator.
Table 16-7
Laboratory triggers for additional assessment
Parameter
Threshold
CRP
•
CRP > 20 mg/L in participants with baseline CRP < 10 mg/L
•
Any increase of additional 10 mg/L in participants with baseline 
CRP > 10 mg/L 
ESR
•
ESR > 30 mm/hr in female participants with baseline 
ESR < 15 mm/hr
•
Any increase of additional 15 mm/hr in female participants with 
baseline ESR > 15 mm/hr
•
ESR > 20 mm/hr in male participants with baseline 
ESR < 10 mm/hr
•
Any increase of additional 10 mm/hr in in male participants with 
baseline ESR > 10 mm/hr
Expedited reporting in case of results above threshold
As constitutional symptoms such as fever, arthralgia, myalgia and weight loss, and laboratory 
features including elevations in ESR and CRP can be encountered in other conditions, it is 
important to exclude other diagnoses that might account for the presenting signs and 
symptoms (e.g., bacterial infections).


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16.3.2
Clinical management of potential cases of vasculitis
For any potential case of vasculitis, the extent and location of vasculitis involvement should 
be assessed. For this purpose, the evaluations listed above may be supplemented by other 
investigations (e.g., urinalysis, serum creatinine and BUN in case of suspected renal 
involvement).
Tissue biopsy may be performed to confirm the diagnosis of vasculitis, with the choice of 
the site for biopsy determined by the pattern of organ involvement.
For cases of suspected vasculitis, anti-histone antibody levels should be measured, and assays 
for anti-neutrophil cytoplasm antibodies (ANCA) should be performed using both 
immunofluorescence and enzyme-linked immunosorbent assay (ELISA).
Depending on the site of involvement, additional follow-up of potential cases of vasculitis 
should include:
•
Referral to a rheumatologist for a complete evaluation of the symptomatology and clinical
course of vasculitis
•
Additional referral to specialist consultation based on the anatomical location of tissue
involvement is required, e.g.:
•
Assessment of skin lesions and rashes by a dermatologist; the evaluation of skin
lesions should include a skin biopsy.
•
Referral to a nephrologist for further evaluation in the event of suspected renal
involvement (e.g., renal biopsy as appropriate per local practice)
•
Additional specialist consultation may be considered in case of involvement of other
anatomical sites (e.g., retinal involvement).

SAP_001.pdf: 
Biostatistics & Statistical Programming / 
Novartis Institutes for BioMedical Research
BLZ945
CBLZ945C12201 / NCT04066244
An open-label, adaptive design study in patients with 
amyotrophic lateral sclerosis (ALS) to characterize safety, 
tolerability and brain microglia response, as measured by 
TSPO binding, following multiple doses of BLZ945 using 
positron emission tomography (PET) with the radioligand 
[11C]-PBR28
Statistical Analysis Plan (SAP)
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Author(s):
Document type:
SAP Documentation – NIBR 
Document status:
Amendment 3
Release date:
7-Mar-2024
Number of pages:
24
Personal Protected Data (PPD)


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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......................................................................................8
1.4.1
Cohorts 1-4:.............................................................................................8
1.4.2
Cohort 5:..................................................................................................9
2
First interpretable results (FIR)..........................................................................................10
3
Interim analyses .................................................................................................................11
4
Statistical methods: Analysis sets......................................................................................11
5
Statistical methods for Pharmacokinetic (PK) parameters ................................................13
5.1
Variables ................................................................................................................13
5.2
Descriptive Analyses..............................................................................................13
6
Statistical methods for Pharmacodynamic (PD) parameters .............................................14
6.1
Primary objective(s)...............................................................................................14
6.1.1
Variables................................................................................................14
6.1.2
Descriptive analyses..............................................................................15
6.1.3
Statistical model, assumptions and hypotheses for Cohorts 1-4 ...........15
6.1.4
Sensitivity and Supportive analysis for Cohorts 1-4.............................16
6.2
Secondary objectives..............................................................................................16
6.2.1
Descriptive analyses..............................................................................16
7
Statistical methods for safety and tolerability data............................................................18
7.1
Variables ................................................................................................................18
7.2
Descriptive analyses...............................................................................................18
7.3
Graphical presentation ...........................................................................................20
8
Pharmacokinetic / pharmacodynamic relationships ..........................................................20
8.1
Variables ................................................................................................................20
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8.2
Descriptive analyses...............................................................................................20
9
Pharmacogenomic / pharmacokinetic relationships ..........................................................21
9.1
Variables ................................................................................................................21
9.1.1
Descriptive analyses..............................................................................21
11 Statistical methods for the Data Monitoring Committee (DMC) review of Cohort 5 
data.....................................................................................................................................22
List of tables
Table 4-1
Protocol deviation codes and analysis sets............................................12
List of figures
Figure 1-1:
Study Design Cohorts 1-4 .......................................................................9
Figure 1-2
Study design Cohort 5 ...........................................................................10
Figure 1-3
Study design Cohort 5 including the 24-week extended treatment 
period.....................................................................................................10
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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 “CBLZ945C12201”.
The Statistical analysis plan (SAP) describes the implementation of the statistical analysis 
planned in the protocol.
1.2
Study reference documentation
Study protocol (v06) 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 objective(s)
•
Cohorts 1-4 and Cohort 5 (PET Sub-
study): To evaluate brain microglial 
reduction, as measured by reduction in 
TSPO binding, following treatment 
with BLZ945 in ALS participants by 
using PET imaging with [11C]-PBR28
•
Volume of distribution (Vt) in different 
brain regions for each [11C]-PBR28 PET 
scan, and change after BLZ945 treatment
•
Cohorts 1-4: at Day 5 (or 8) 
following 4 (or 7) oral doses of 
BLZ945 compared to baseline
•
Cohort 5 (PET sub-study): at Week 
12 following repeated cycles of 
BLZ945 compared to baseline
•
Cohort 5: To assess safety-related 
effects on ECM accumulation under 
BLZ945 treatment
•
Cohort 5: Changes in esophageal wall 
thickness (based on CT-scans) at Week 12 
compared to baseline
•
Cohort 5: Cardiac valve thickness, cardiac 
valve function (stenosis and regurgitation 
based on echocardiography) and Left 
Ventricular Ejection Fraction (LVEF) as 
indicator of cardiac function (based on 
echocardiography) at Week 12 compared 
to baseline
•
Incidence of AEs related to ECM 
accumulation during the first 12 weeks of 
treatment
1.3.2
Secondary Objective(s)
Secondary objective(s)
Endpoints related to secondary objective(s)


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•
Cohorts 1-5: To characterize the 
pharmacokinetics (PK) of BLZ945 in 
participants with ALS.
•
Cohort 1-4:
•
Plasma: PK parameters on Day 1 and 
Day of last treatment (Day 4 or Day 7) 
(e.g. Cmax, Tmax, AUC, T1/2). 
Urine: renal clearance (CLR) on Day 1 
and Day of last treatment (Day 4 or 
Day 7)
•
Cohort 5: BLZ945 plasma concentrations and 
selected PK parameters (Cmax, Tmax, 
AUClast, Tlast) on Day 1 (Arm #2) and Day 4 
(Arm #1) as feasible
•
Cohorts 1-5: To evaluate safety and 
tolerability of BLZ945 in participants 
with ALS at the planned doses and 
dosing regimen.
•
Cohorts 1-5: Relevant clinical findings - as 
per assessment schedule - on physical 
examination, neurological examination, vital 
signs, hematology, chemistry, urinalysis, ECG 
evaluation, AE and SAE recordings during the 
entire duration of the study (including 
extended treatment period)
•
Cohorts 1-5: To assess the CYP2C8 
pharmacogenomic-pharmacokinetic 
relationship
•
CYP2C8 genotypes and BLZ945 plasma PK 
parameters
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1.4
Study design and treatment
1.4.1
Cohorts 1-4:
This study is an exploratory, adaptive, open-label study of a single treatment cycle of multiple 
oral doses of BLZ945 in ALS participants, administered using either a 4 days on / 10 days off 
or a 7 days on 7 days off treatment regimen.
The first four cohorts in the study consist of an up to 42-day screening and baseline period, 
a treatment period of a minimum of 4 days and a maximum of 7 days, a follow-up period until 
day 36 (for 4 day cohorts) or day 40 (for 7 day cohorts) (during this period repopulation of 
microglia will be assessed); see Figure 1-1. The maximum study duration for each participant, 
including the 42-day screening visit, is 80 days for the 4-day cohorts and 84 days for the 7-day 
cohort.
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Figure 1-1:
Study Design Cohorts 1-4  
This is a multiple ascending dose study with the starting dose of 300 mg daily for four days. 
After each dosing cohort and before proceeding to the next cohort, a review of all available data 
will be conducted, including pharmacodynamic (PD) (% microglial reduction), and 
safety/tolerability (continued review of adverse events, laboratory assessments, blood pressure 
and ECG data) data. PK data from the first three dosing cohorts (planned as 300 mg, 600 mg, 
1200 mg) will be reviewed after the third dosing cohort prior to proceeding to the fourth dosing 
cohort. The PK review will be done to assist with the determination of the appropriate next 
dose(s). The PK data may be reviewed prior to the initiation of any dosing cohort should 
this information be determined by the Investigators and/or Sponsor as necessary for decision-
making purposes. The decision to proceed to the next dose cohort will be made jointly between 
the Sponsor and the Investigator.
1.4.2
Cohort 5:
Cohort 5 will consist of an open-label, randomized, two-arms study investigating two BLZ945 
dosing regimens. Participants with confirmed diagnosis of ALS will receive repeated treatment 
cycles of BLZ945 either 4 days on followed by 10 days off or once weekly. Cohort 5
 
PET sub-study will recruit approximately 8 participants.  Enrollment may
 
continue up to a maximum of 40 participants overall. 
The cohort includes a screening period (up to 6 weeks), a 12-week open-label treatment period, 
followed by a 4-week safety follow-up (Figure 1-2). Participants who consent and are eligible 
may continue to an additional 24-week extended treatment period on the same regimen 
(Figure 1-3).
Participants will be randomized in a 1:1 ratio across two dosing regimens: Arm #1: 800 mg 
BLZ945 in repeated cycles of 4 days on treatment followed by 10 days off treatment (4/10) or 
Arm #2: 800 mg BLZ945 once a week (QW). 
Participants previously screened or dosed in Cohorts 1 to 4 may be enrolled in Cohort 5 if they 
meet eligibility criteria.
A PET sub-study will enroll approximately 8 participants at specific study sites.  
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Figure 1-2
Study design Cohort 5
x = drug administration
W = week of treatment
* 4 weeks follow up in all participants + 8 weeks for recovery in participants with findings
# Cohort 5 
Figure 1-3
Study design Cohort 5 including the 24-week extended treatment period
* 4 weeks follow up in all participants + 8 weeks for recovery in participants with findings
2
First interpretable results (FIR)
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3
Interim analyses 
4
Statistical methods: Analysis sets
For all analysis sets, which is identical to the safety analysis set, participants will be analyzed 
according to the study treatment(s) received.
The full analysis will include all participants who received any study drug.
The PK analysis set (PAS) will include all participants with at least one evaluable (i.e., not 
flagged for exclusion) PK concentration measurement.. For a BLZ945 plasma  concentration to 
be considered evaluable, a subject must:
•
Have received a protocol planned dose.
•
For pre-dose samples, do not vomit within 4 hours after the dosing of BLZ945 prior to
sampling.
•
For post-dose samples, do not vomit within 4 hours after the dosing of BLZ945.
•
For pre-dose sample, have the sample collected before the next dose administration and
18-30 hours after the last dose administration.
•
Administer BLZ945 under fasted state (at least one hour before or two hours after meal).
•
No protocol deviations that impact PK data.
Additionally for arm 1 day 4 BLZ945 plasma sample, the above conditions must also be met 
for all four doses from day 1 to day 4.  
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Any blood samples with missing collection date or time, or missing associated study drug 
dosing date or time will be excluded. Additionally, a PK sample can be considered not evaluable 
as per scientific judgment of the clinical pharmacology expert. In such case, the PK sample is 
excluded from the analyses and the reason for its exclusion will be documented.
The PD analysis set will include all participants with available PD data and no protocol 
deviations with relevant impact on PD data.
The analysis sets and protocol deviation codes are related as follows:
Table 4-1
Protocol deviation codes and analysis sets
Category   
   Deviation code
Text description of deviation
Data exclusion
Participants are excluded from PK analysis in case of these 
PDs: 
Exclude subject from PK 
analysis set 
INCL##
Xxxxxxx
EXCL##
Xxxxxxx
Participants are excluded from PD analysis in case of these 
PDs:
Exclude subject from PD 
analysis set
INCL##
Xxxxxxx
EXCL##
Xxxxxxx
Participants are excluded from PK and PD analysis in case of 
these PDs:
Exclude subject from PK 
and PD analysis sets
INCL##
Xxxxxxx
EXCL##
Xxxxxxx
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If updates to this table are needed, an amendment to the SAP needs to be implemented prior to 
DBL.
5
Statistical methods for Pharmacokinetic (PK) parameters
All participants within the PK analysis set will be included in the PK data analysis. 
5.1
Variables
Cohort 1-4: Plasma PK parameters on Day 1 and Day of last treatment (Day 4 or Day 7) (e.g. 
Cmax, Tmax, AUClast, AUC0-24, T1/2, Racc). Urine: renal clearance (CLR) on Day 1 and Day 
of last treatment (Day 4 or Day 7)
Cohort 5: BLZ945 plasma concentrations and selected PK parameters (Cmax, Tmax, AUClast, 
Tlast) on Day 1 (Arm #2) and Day 4 (Arm #1) as feasible.
Other plasma or urine PK parameters will be determined as appropriate.
5.2
Descriptive Analyses
Cohorts 1-4
Summary statistics of BLZ945 pharmacokinetic parameters 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. 
A geometric mean will not be reported if the dataset includes zero values. Descriptive graphical 
plots of individual plasma concentration versus time profiles and mean concentration versus 
time profiles will be generated. Further graphical exploratory analysis will be carried out if 
deemed appropriate.
Cohort 5
Summary statistics of BLZ945, 
pharmacokinetic parameters will include mean (arithmetic and geometric), SD, CV (arithmetic 
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and geometric), median, minimum, and maximum. An exception to this is Tmax where median, 
minimum, and maximum will be presented. A geometric mean will not be reported if the dataset 
includes zero values. With only 4 samples and only up to 4 hrs post dose, it may not be possible 
to derive the PK parameters above.
Cohorts 1-5
The relationship between CYP2C8 polymorphisms and BLZ945 PK parameters will be 
assessed graphically and descriptively.
6
Statistical methods for Pharmacodynamic (PD) parameters
All participants within the PD analysis set will be included in the PD data analysis.
All primary, secondary 
same statistical methodology for all cohorts unless explicitly detailed for Cohort 5.
For Cohort 5 secondary and exploratory PD endpoints assessing the change from baseline to 
Week 40, the change from baseline to be summarized primarily refers to the change from the 
baseline prior to BLZ945 drug administration of the core period. Additional summaries for the 
change from start of the extended treatment (Week 16) will also be included as applicable.
6.1
Primary objective(s)
Cohorts 1-4 and Cohort 5 (PET Sub-study): To evaluate brain microglial reduction, as measured 
by reduction in TSPO binding, following treatment with BLZ945 in ALS participants by using 
PET imaging with [11C]-PBR28
Cohort 5: To assess safety-related effects on ECM accumulation under BLZ945 treatment
6.1.1
Variables 
Cohorts 1-4
The percent change in Vt of the first scan 24 hours after last BLZ945 treatment relative to 
baseline will be considered as primary endpoint.
Cohort 5
The percent change from baseline to Week 12 in Vt measured via PET scan.
The changes from baseline to Week 12 in: esophageal wall thickness (mm), and LVEF (%)
Any worsening from baseline to Week 12 in cardiac valve thickness and cardiac valve function 
(stenosis and regurgitation).
Adverse events of ECM accumulation during the 12 weeks of treatment.
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6.1.2
Descriptive analyses
Cohorts 1-4
The microglia depletion (raw and % percent change from baseline) will be listed by dose cohort, 
subject and visit time. Descriptive summary statistics for raw and % percent change from 
baseline will be provided by dose cohort and visit/time.
Summary statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and 
geometric), median, minimum, and maximum. A geometric mean will not be reported if the 
dataset includes zero values.
Cohort 5
Descriptive statistics will be provided by treatment and visit for the Cohort 5 for efficacy and 
safety endpoints. No formal statistical comparison will be carried out between the two treatment 
arms. For continuous measures, such as percent change from baseline to week 12 in Vt 
measured via PET scan, esophageal wall thickness change from baseline to week 12 and LVEF 
change from baseline to week 12, the mean, SD and 95% CI will be provided by treatment arm. 
For measures such as cardiac valve function (stenosis and regurgitation based on 
echocardiography) and cardiac valve thickness, the number and frequency of participants with 
any worsening between baseline and Week 12 will be presented by treatment arm, as well as 
the 95% CI for the rate based on the Wilson method. Number and percentages of participants 
with AEs of ECM accumulation will be summarized by treatment arm.
6.1.3
Statistical model, assumptions and hypotheses for Cohorts 1-4
The fraction of brain microglia reduction following four oral doses of BLZ945 will be analyzed 
by an Emax model with dose as the independent variable and reduction fraction as 
the dependent variable. Allometric scaling of a mouse PK/PD model makes it credible that 
4 doses at 600 mg for 4 days will lead to a 50% reduction in microglia 18 days past the 4th 
dose. The same model points to a Hill constant between 1 and 3.3. It hence seems reasonable 
to analyze all available microglia reduction data at the 5 day time point by a sigmoidal Hill 
constant model with prior distributions on the EC50 of 600 mg and Hill constant centered at 2. 
Such a model assumes that the microglia reduction after 4 doses is independently normally 
distributed among participants with a mean which can be expressed by a two-parameter Emax 
function. If the microglia depletion fraction at concentration c is denoted Y(c), then the model 
assumes that
Y(c) =ch /(ch+Dh)+error
Here, D and h are the two unknown parameters, the concentration giving a 50% response and 
the Hill constant.
For the purposes of this study, brain [11C]-PBR28 binding reduction of 20% or more has been 
chosen as sufficient evidence of target engagement to enable further development.
6.1.3.1
Model checking procedures for Cohorts 1-4
No imputation of missing values will be considered for the primary analysis.


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6.1.3.2
Graphical presentation of results for Cohorts 1-4
The relationship between the microglia depletion ratio and BLZ945 dose level obtained from 
the model described in section 6.1.3 will be presented graphically.
6.1.4
Sensitivity and Supportive analysis for Cohorts 1-4
It will be assessed through residual plots whether the model of the primary analysis gives a 
credible description of data. Other models with transformed response, non-constant error 
variance, and baseline covariates included may be attempted in order to see if the dose-response 
fit and conclusions hold up.
If substantial dropouts are seen prior to study day 4 (so that the primary end point is missing), 
the dose-response relationship will be reassessed under a model for informative drop out. 
This will be done in order to ensure that potential non-responders are not more likely to drop 
out.
The log-ratio-to-baseline of Vt will be analyzed using a one sample t-test for each PET scan, 
specifically for PET2 and PET3 and by brain region. The results will be back- transformed 
where the estimated geometric mean ratio, 90% confidence interval of the mean ratio and 
corresponding 2-sided p-value will be reported.
6.2
Secondary objectives 
A secondary objective of this study is to evaluate the safety and the brain microglia reduction 
following multiple oral doses of BLZ945 in ALS participants. 
6.2.1
Descriptive analyses 
The safety and tolerability will be evaluated by the following standard safety assessments; 
relevant findings from physical and neurological examinations, vital signs, hematology, 
chemistry, urinalysis, ECG evaluation, AE and SAE recordings. For Cohort 5, AEs potentially 
related to ECM accumulation or vasculitis will be summarized. The evaluations will be mostly 
descriptive; should a dose-dependent incidence in AEs be present, it will be quantified by 
Cochran-Armitage test for trend.
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7
Statistical methods for safety and tolerability data 
All participants within the Full Analysis Set (FAS) will be included in the safety data analysis.
All primary, secondary and exploratory safety endpoints listed below will be analyzed using 
the same statistical methodology for all cohorts unless explicitly detailed for Cohort 5.
For Cohort 5 secondary and exploratory safety endpoints assessing the change from baseline to 
Week 40, the change from baseline to be summarized primarily refers to the change from the 
baseline prior to BLZ945 drug administration of the core period. Additional summaries for the 
change from start of the extended treatment (Week 16) will also be included as applicable.
7.1
Variables
Safety and tolerability assessments including adverse events, cardiovascular safety parameters 
(ECG, vital signs), Columbia Suicide Severity Rating Scale questionnaire (C-SSRS), and 
general safety parameters (blood and urine laboratory parameters, physical examination) will 
be collected. 
7.2
Descriptive analyses
Participant demographics and other baseline characteristics
For Cohorts 1-4, demographic and other baseline data will be summarized descriptively by dose 
cohort. For Cohort 5, demographic and other baseline data will be summarized by treatment 
arm.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. Differences from 
baseline of continuous variables will be presented in the same way.
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term, and by dose cohort.
Treatment
The duration of exposure to BLZ945 will be summarized by means of descriptive statistics 
using the safety set. For Cohorts 1-4, numbers of participants exposed to the different daily 
doses of BLZ945 will be tabulated. For Cohort 5, numbers of participants exposed to the 
different treatment arms will be tabulated.
Concomitant medications and significant non-drug therapies prior to and after the start of 
the study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system, by dose cohort.
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Vital signs
All vital signs i.e. body temperature, blood pressure and pulse measurement data will be listed 
by dose cohort, subject, and visit/time and if ranges are available abnormalities will be flagged. 
Summary statistics will be provided by dose cohort and visit/time.
ECG evaluation
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.
C-SSRS
Summary statistics showing the number of Patients with Suicidal Ideation, Suicidal Behavior, 
and Self Injurious Behavior without Suicidal Intent Based on the C-SSRS during treatment, will 
be produced by dose cohort. The C-SSRS during treatment data will be listed by dose cohort, 
subject, and visit/time.
Clinical laboratory evaluations
All laboratory data will be listed by dose cohort, 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 dose 
cohort and visit/time.
The liver lab parameters (ALT, AST, ALK, BILI) may also be summarized spaghetti plots 
where the observations are converted into multiples of ULN (e.g. observed value/ULN for the 
given lab parameter) and are plotted over time for each subject.
To identify potential Hy’s Law cases, the eDISH (evaluation of Drug-Induced Serious 
Hepatotoxicity) plot may be used. A log/log display of correlation between peak TBIL vs. peak 
ALT, both in multiples of ULN, with horizontal and vertical lines indcating Hy’s law thresholds 
e.g. ALT = 3 x ULN and TBIL = 2 x ULN. The eDISH plot makes immediately evident subjects
potentially matching Hy’s law laboratory criteria, all located in the upper right quadrant of the
graph. Observations may also be color coded by treatment or by subject.
Adverse events
All information obtained on adverse events will be displayed by dose cohort and subject.
The number (and percentage) of patients with treatment emergent adverse events (events 
started after the first dose of study medication or events present prior to start of treatment but 
increased in severity based on preferred term) will be summarized in the following ways:
•
by treatment, primary system organ class and preferred term.
•
by treatment, primary system organ class, preferred term and maximum severity.
Separate summaries will be provided for study medication related adverse events, death, 
serious adverse events, other significant adverse events leading to discontinuation, AEs  of 
special interest potentially related to risks resulting from BLZ945 treatment (e.g. ECM 
accumulation, vasculitis)  and adverse events leading to dose adjustment.


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A patient with multiple adverse events within a body system is only counted once towards the 
total of this body system and treatment.
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.
Should a dose dependent incidence in AEs be present, it will be qualified by Cochran-Armitage 
test for trend.
Adverse events of special interest / grouping of adverse events in Cohort 5: 
Gastrointestinal toxicity and skin toxicities are identified risks for BLZ945. Hepatic effects, 
muscle effects, accumulation of extracellular matrix, QT prolongation, vasculitis, pancreatitis, 
effects on lymphoid organs, drug-drug interactions, effects on endocrine organs and effects on 
bones are potential risks related to BLZ945. In addition, suicidal ideation and behaviour and 
reproductive and developmental toxicity are also adverse of interest for BLZ945. The search 
criterion for each of these risks and events of interest will be defined based on MedDRA and 
on the BLZ945 Case Retrieval Strategy (eCRS). 
The most recent eCRS at the time of database lock will be used to determine the MedDRA 
search criteria to identify events of special interest.
7.3
Graphical presentation 
Boxplots to visualize trends in longitudinal safety data (vitals, ECG, lab parameter) will be 
created.
8
Pharmacokinetic / pharmacodynamic relationships
All participants within the PK/PD analysis set will be included in the PK/PD data analysis.
To evaluate the relationship between systemic PK (i.e. Cmax, AUC0-24 and AUClast) and PD 
markers such as AST/ALT, and peripheral monocyte counts.
8.1
Variables
Cohorts 1-4: BLZ945 PK parameters on Day 1 and Day of last treatment (Day 4 or Day 7) 
versus other PD markers.
Cohort 5: Estimated individual BLZ945 PK levels or parameters on Day 4 (Arm #1) or on Day 
1 (Arm #2) and/or on Week 10 vs other PD markers.
8.2
Descriptive analyses
Cohorts 1-4: The relationship between (cumulative) daily doses (and/or systemic exposure) 
with the brain microglia reduction, based on the volume of distribution, on the standardized 
uptake values ratios (SUVR), and on the percent change after repeated BLZ945 oral 


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administration will be investigated. All generated data at all dose levels will be pooled to 
explore a dose exposure response relationship.
Cohort 5: The exposure-response relationship for PET 
 will be 
explored.
9
Pharmacogenomic / pharmacokinetic relationships
All participants who have undergone CYP2C8 genotyping screening test during screening or 
baseline will be included in the PG/PK data analysis.
To assess the CYP2C8 pharmacogenomic-pharmacokinetic relationship.  
9.1
Variables
For cohort 1-4: PK parameters (i.e. Cmax, AUC0-24 and AUClast) at Day 1 and Day of last 
treatment (Day 4 or Day 7) versus CYP2C8 genotyping data at screening or baseline- CYP2C8 
genotyping data will only be recorded at one time point per subject. For cohort 5: PK parameters 
(i.e. Cmax and AUClast) at Day 1 (arm 2) or Day 4 (arm 1) versus CYP2C8 genotyping data at 
screening or baseline- CYP2C8 genotyping data will only be recorded at one time point per 
subject.
9.1.1
Descriptive analyses
The genotyping CYP2C8 data will be listed by dose cohort and subject. Descriptive summary 
statistics for raw data will be provided by dose cohort.
Summary statistics will include frequency and proportion (n, %). Multiple comparisons 
between dose cohorts on log (PK) parameters at Day 1 and Day of last treatment (Day 4 or Day 
7) will be performed by ANOVA to compare the plasma PK parameters and the genotypes.
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11
Statistical methods for the Data Monitoring Committee 
(DMC) review of Cohort 5 data 
Population for analysis: 
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•
The Full Analysis Set (FAS) will include all participants that received any study drug for a
given study period
A cut-off date to produce the outputs for the DMC review will be determined prior to each 
DMC meeting. All data available up to the cut-off date will be included in the DMC analyses. 
Since the trial is ongoing, data cleaning may be incomplete at the cut-off for DMC interim 
analysis.
The outputs will be presented by treatment group based on FAS. For the Cohort 5 secondary 
and exploratory endpoints assessing changes from baseline to Week 40, the change from 
baseline to be summarized primarily refers to the change from the baseline prior to BLZ945 
drug administration of the initial 12-week treatment period. Additional summaries for change 
from start of extended treatment (Week 16) will also be included as applicable.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented by treatment arm and 
visit. Differences from baseline of continuous variables will be presented in the same way. 
Whenever a figure eases the readability and interpretation of the data compared to a table, the 
data should be presented using a figure. For example, instead of showing summary statistics of 
continuous data per timepoint in a table, the relevant summary measures (e.g., mean+/- standard 
deviation) will be plotted over time by visit and treatment arm. 
Participant safety narratives will be provided for SAEs, AEDO, and adverse events of special 
interest (AESI) as selected by Novartis safety team.
A validated R-shiny app may be used to display a subset of the summaries described below. 
The report for the regular monitoring will include presentation of the following data: 
•
Participant disposition
•
Demographics and baseline disease characteristics
•
Medical and ALS disease history
•
Exposure to study drug
•
Concomitant medications
•
Adverse events (AEs and SAEs) by System Organ Class (SOC), preferred term (PT), by
most frequent PT, and by severity as applicable, AEs leading to treatment discontinuations,
deaths and AEs potentially related to risks resulting from BLZ945 treatment (e.g., ECM
accumulation, vasculitis)
•
Longitudinal changes in lab results, vital signs, and ECG
•
Changes in esophageal wall thickness (based on CT scans) and cardiac valve thickness,
cardiac valve function and left ventricular ejection fraction (based on echocardiography)
•
Suicidality will be reported based on the Columbia Suicide Severity Rating Scale (C-SSRS).
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•
Time to permanent assisted ventilation or death, whichever occurs first and time to death* 
from baseline and start of extended treatment to Week 40
*Vitality will be complemented with information collected quarterly during the 1-year 
follow-up phone calls
•
eDISH (evaluation of drug induced serious hepatoxicity) plots
•
Spaghetti plots of liver enzymes plotted in units of ULN