Conditions: Spinal Muscular Atrophy
Keywords: Type 1 Spinal Muscular Atrophy
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 40
Healthy volunteers: no

Brief summary:
An open-label, multi-part, first-in-human study of oral branaplam in infants with Type 1 spinal muscular atrophy. The purpose of this study was to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy after 13 weeks; and to estimate the Maximum Tolerated Dose (MTD) of orally administered branaplam; and to identify the dose that was safe for long term use as well as that can provide durable efficacy optimal dosing regimen in patients with Type 1 SMA.

Detailed description:
This was an open-label, multi-part, first-in-human, proof of concept study in infants with Type 1 spinal muscular atrophy who have exactly 2 copies of SMN2, to evaluate safety, tolerability, PK, PD and efficacy of oral branaplam after 13 weeks treatment.

Parts 1,2 and 3 were intended to be non-confirmatory.

In Part 1 of the study, patients were dosed once weekly with branaplam. The branaplam dose was escalated in subsequent cohorts until MTD was determined or when sufficient PK results confirmed that the MTD could not be reached due to a potential pharmacokinetic plateau at higher doses. A decision to dose escalate the next cohort was made after safety data was collected for 14 days following the first dose (14-day DLT window). PK was used to confirm that there was no accumulation of the compound. After 13 weeks treatment, participants in part 1 could enter an extension treatment phase until they discontinued from the study or were transferred into part 3.

Part 2 of the study enrolled new patients into one 2 dose cohorts with once weekly dosing for 52 weeks. The branaplam dose was escalated in subsequent cohorts after 6 patients were enrolled and at least 3 patients from the previous cohort completed 13 weeks of treatment. After 52 weeks, patients may have continued treatment in part 3 if it was in the best interest of the patient.

Part 3, participants from part 1 and 2 who have completed at least 52 weeks of banaplam treatment were elegible to continue receiving treatment as long as in the best interest of the patient. In all cases continuation of the treatment was done at a dose selected as optimum, considering existing safety as well as efficacy data.

Arms:
arm 1: branaplam Treatment

Interventions: intervention 1: branaplam
Intervention descriptions: intervention 1: None

Protocol document:
Prot_000.pdf: 
Novartis Research and Development
LMI070/Branaplam
Clinical Trial Protocol CLMI070X2201 / NCT02268552
An open-label multi-part first-in-human study of oral 
LMI070 in infants with Type 1 spinal muscular atrophy
Document type:
Amended Protocol Version
EUDRACT number:
2014-002053-19
Version number:
v11 (clean)
Clinical trial phase:
I/II 
Release date:
19-Jul-2021
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 (01-Aug-2018)


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Site Operations Manual (SOM) and Pharmacy Manual
A Site Operations Manual (SOM) accompanies this protocol, providing the operational details 
for study conduct. Pharmacy Manual will contain all important guidelines for site on how to 
store, dispense, maintain and return Investigational Medical Product (IMP).


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Table of contents
Table of contents .................................................................................................................3
List of tables ........................................................................................................................7
List of figures ......................................................................................................................8
List of abbreviations............................................................................................................9
Glossary of terms...............................................................................................................12
Amendments and rationale for amendments .....................................................................15
Protocol summary..............................................................................................................49
1
Introduction .......................................................................................................................56
1.1
Background............................................................................................................56
1.1.1
Relevant data summary.........................................................................57
1.2
Purpose ..................................................................................................................64
2
Objectives and endpoints...................................................................................................64
2.1
Primary objective(s)...............................................................................................64
2.2
Secondary objective(s)...........................................................................................64
65
3
Study design ......................................................................................................................65
3.1
Part 1 Study Design ...............................................................................................66
3.2
Part 2 Study Design ...............................................................................................70
3.3
Part 3 Study Design ...............................................................................................73
3.4
Rationale for study design .....................................................................................75
3.5
Rationale for dose/regimen and duration of treatment ..........................................77
3.5.1
Doses in Part 1 ......................................................................................77
3.5.2
Doses in Part 2 ......................................................................................78
3.5.3
Doses in Part 3 ......................................................................................79
3.5.4
Safety margins.......................................................................................80
3.5.5
Age effect..............................................................................................80
3.6
Rationale for choice of comparator .......................................................................80
3.7
Purpose and timing of interim analyses/design adaptations..................................81
3.8
Risks and benefits..................................................................................................82
3.9
Rationale for Public Health Emergency Mitigation Procedures............................86
4
Population..........................................................................................................................87
4.1
Inclusion criteria ....................................................................................................87
4.1.1
Part 1 .....................................................................................................87
4.1.2
Part 2 .....................................................................................................88
4.1.3
Part 3 .....................................................................................................89


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4.2
Exclusion criteria...................................................................................................89
4.2.1
Part 1 .....................................................................................................89
4.2.2
Part 2 .....................................................................................................91
4.2.3
Part 3 .....................................................................................................92
5
Treatment...........................................................................................................................92
5.1
Study treatment......................................................................................................92
5.1.1
Investigational treatment.......................................................................92
5.1.2
Treatment arms......................................................................................92
5.2
Treating the patient................................................................................................94
5.2.1
Preparation and dispensation.................................................................94
5.3
Other treatments.....................................................................................................95
5.3.1
Concomitant therapy.............................................................................95
5.3.2
Prohibited medication ...........................................................................96
5.3.3
Rescue medication ................................................................................97
5.3.4
Treatment blinding................................................................................97
5.4
Dose escalation and dose modification..................................................................97
5.4.1
Dose escalation guidelines....................................................................97
5.4.2
Definitions of dose limiting toxicities (DLTs)......................................97
5.4.3
Dose modifications................................................................................98
5.4.4
Implementation of dose escalation decisions........................................99
5.4.5
Intra-patient dose escalation................................................................100
5.4.6
Follow up for toxicities.......................................................................101
5.4.7
Within-patient dose escalation............................................................105
5.5
Treatment assignment..........................................................................................106
5.6
Additional treatment guidance.............................................................................106
5.6.1
Treatment exposure and compliance...................................................106
5.6.2
Recommended treatment of adverse events........................................107
5.6.3
Emergency breaking of assigned treatment code................................107
5.7
Restrictions for Study Patients.............................................................................107
5.7.1
Dietary restrictions..............................................................................107
5.7.2
General restrictions .............................................................................107
5.8
Preparation and dispensation...............................................................................107
6
Informed consent procedures ..........................................................................................107
7
Visit schedule and assessments .......................................................................................109
7.1
Screening .............................................................................................................127


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7.1.1
Information to be collected on screen failures ....................................127
7.2
Patient demographics/other baseline characteristics ...........................................127
7.2.1
Mandatory DNA for patient enrollment..............................................127
7.3
Efficacy................................................................................................................127
7.3.1
Children’s Hospital of Philadelphia Infant Test of Neuromuscular 
Disorders (CHOP INTEND)...............................................................127
7.3.2
Hammersmith Infant Neurological Examination (HINE Section 2)...127
7.3.3
Videotaping of the patient’s motor activities (optional) .....................128
7.4
Safety...................................................................................................................128
7.4.1
Laboratory evaluations........................................................................128
7.4.2
Physical examination ..........................................................................129
7.4.3
Vital signs............................................................................................129
7.4.4
Body length, weight and head circumference.....................................129
7.4.5
Electrocardiogram (ECG) ...................................................................129
7.4.6
Echocardiogram ..................................................................................129
7.4.7
Other safety evaluations......................................................................130
7.5
Additional assessments........................................................................................132
7.5.1
Pharmacokinetics ................................................................................132
133
7.5.3
RNA ....................................................................................................133
7.5.4
Acceptability and Palatability Questionnaire......................................133
7.5.5
Speech and motor performance (milestones)......................................133
7.5.6
Appropriateness of safety measurements............................................134
8
Discontinuation and completion......................................................................................134
8.1
Discontinuation from study treatment and from study........................................134
8.1.1
Discontinuation of study treatment (applicable for participants 
following the Extended Schedule of Assessment Part 1 and 
participants enrolled in Part 2 and in Part 3).......................................134
8.1.2
Discontinuation from study.................................................................135
8.1.3
Withdrawal of informed consent/Opposition to use data/biological 
samples................................................................................................135
8.1.4
Lost to follow-up.................................................................................136
8.1.5
Early study termination by the sponsor...............................................136
8.2
Study completion and post-study treatment ........................................................137
9
Safety monitoring, reporting and committees .................................................................137
9.1
Definition of adverse events and reporting requirements....................................137


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9.1.1
Adverse events ....................................................................................137
9.1.2
Serious adverse events ........................................................................139
9.1.3
SAE reporting......................................................................................140
9.1.4
Pregnancy reporting ............................................................................140
9.1.5
Reporting of study treatment errors including misuse/abuse..............141
9.2
Additional Safety Monitoring..............................................................................141
9.2.1
Early phase safety monitoring.............................................................141
9.2.2
Data Monitoring Committee ...............................................................142
9.2.3
Steering Committee.............................................................................142
9.2.4
Adjudication Committee.....................................................................142
10 Data collection and database management......................................................................142
10.1
Data collection.....................................................................................................142
10.2
Database management and quality control..........................................................143
11 Data analysis and statistical methods ..............................................................................143
11.1
Analysis sets ........................................................................................................143
11.2
Patient demographics and other baseline characteristics.....................................144
11.3
Treatments ...........................................................................................................144
11.4
Analysis supporting primary objectives ..............................................................144
11.4.1
Definition of primary endpoint(s).......................................................145
11.4.2
Statistical model, hypothesis, and method of analysis........................145
11.4.3
Handling of missing values/censoring/discontinuations.....................146
11.5
Analysis supporting secondary objectives...........................................................146
11.5.1
Efficacy and/or Pharmacodynamics endpoint(s) ................................146
11.5.2
Safety endpoints..................................................................................147
11.5.3
Pharmacokinetics ................................................................................147
11.5.4
DNA....................................................................................................148
11.5.5
Pharmacokinetic / Pharmacodynamic relationships............................148
148
11.7
Interim analyses...................................................................................................148
11.8
Sample size calculation........................................................................................149
11.8.1
Part 1 ...................................................................................................149
11.8.2
Part 2 ...................................................................................................149
11.8.3
Part 3 ...................................................................................................150
12 Ethical considerations and administrative procedures ....................................................150
12.1
Regulatory and ethical compliance......................................................................150


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12.2
Responsibilities of the investigator and IRB/IEC................................................150
12.3
Publication of study protocol and results.............................................................150
12.4
Quality Control and Quality Assurance...............................................................151
13 Protocol adherence ..........................................................................................................151
13.1
Protocol amendments...........................................................................................151
14 References .......................................................................................................................152
15 Appendices ......................................................................................................................154
15.1
Appendix 1 Prior calibration of the Bayesian logistic regression model ............154
15.2
Appendix 2 - Administration of branaplam by caregivers- Instruction for 
study site staff and caregivers..............................................................................156
List of tables
Table 1-1
Systemic exposure values of branaplam across all observation 
periods - Study CLMI070X2201 Part 1................................................62
Table 1-2
Systemic exposure values of branaplam across all observation 
periods - Study CLMI070X2201 Part 2................................................63
Table 3-1
Summary of Important Potential Risks.................................................83
Table 5-1
Provisional dose levels for Part 1 dose escalation ................................93
Table 5-2
Dose conversion between BSA and weight for patients in Part 1.........94
Table 5-3
Planned doses for Part 2........................................................................94
Table 5-4
Planned doses for Part 3........................................................................94
Table 5-5
Prohibited Chronic treatment for SMA.................................................96
Table 5-6
Criteria for defining dose-limiting toxicities during dose escalation 
– Part 1 ................................................................................................100
Table 5-7
Criteria for interruption and re-initiation of branaplam treatment 
for AE possibly related to study medication.......................................102
Table 7-1
Assessment Schedule – Part 1 – Initial treatment period (Day -14 to 
Day 85)................................................................................................110
Table 7-2
Assessment Schedule – Part 1 – Extended treatment period ..............112
Table 7-3
Assessment Schedule – Part 2.............................................................114
Table 7-4
Assessment Schedule – Part 3.............................................................122
Table 9-1
Guidance for capturing the study treatment errors including 
misuse/abuse .......................................................................................141
Table 11-1
Power to detect a difference in CHOP INTEND score between two 
adjacent dose groups (by one-sided t test at nominal significance 
level 5 percent)....................................................................................150


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Table 15-1
Prior parameters for bivariate normal distribution of model 
parameters ...........................................................................................154
Table 15-2
Summary of prior distribution of DLT rates derived from the prior 
in Table 15-1 .......................................................................................155
List of figures
Figure 1-1
Branaplam modulates survival motor neuron 2 (SMN2) gene 
splicing and increases generation of full length SMN2 mRNA, 
leading to increased functional SMN protein........................................57
Figure 3-1
Part 1 study design ................................................................................67
Figure 3-2
Part 2 study design ................................................................................71


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List of abbreviations
ADME
Absorption, distribution, metabolism and excretion
AE
Adverse Event
ALT
Alanine Aminotransferase
ALP
Alkaline Phosphatase
AST
Aspartate Aminotransferase
BLRM
Bayesian Logistic Regression Model
BSA
Body Surface Area
CDC
United States Centers for Disease Control and Prevention 
CD-ROM
Compact Disc – Read Only Memory
CFR
Code of Federal Regulation
CHOP INTEND
Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders
CMAP
Compound Motor Action Potential
CPAP
Continuous Positive Airway Pressure
CM
Concomitant Medication
CNS
Central Nervous System
CRF
CSF
Case Report/Record Form (paper or electronic)
Cerebral Spinal Fluid
CSR
Clinical Study Report
CTC
Common Terminology Criteria
CV
coefficient of variation
CYP
Cytochrome P450 metabolizing enzyme
DDS
Dose determining set (for dose escalation)
DLT
Dose Limiting Toxicity
DMC
Data Monitoring Committee
ECHO
Echocardiogram
ECG
Electrocardiogram
EDC
ENR
Electronic Data Capture
Enrolled set
EWOC
FAS
Escalation With Overdose Control
Full Analysis Set
FDA
Food and Drug Administration
FIH
First in Human
GCP
Good Clinical Practice
h
Hour
hERG
Human-ether-a-go-go-related gene
HINE
Hammersmith Infant Neurological Examination
HIV
Human Immunodeficiency Virus
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IMP
Investigational medicinal product
IN
Investigator Notification
IRB
Institutional Review Board


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IVSTd
Intraventricular Septum Thickness diastole
LLOQ
lower limit of quantification
LVEDV
LVEDI
LVEF
LVESV
LVESVI
LVFS
LVIDd
LVIDs
LVPWTd
MedDRA
Left Ventricular End Diastolic Volume
Left Ventricular End Diastolic Volume Index
Left Ventricular Ejection Fraction
Left Ventricular End Systolic Volume
Left Ventricular End Systolic Volume Index
Left Ventricular Fractional Shortening
Left Ventricular Internal Dimension Diastole
Left Ventricular Internal Dimension Systole
Left Ventricular Posterior Wall Thickness diastole
Medical dictionary for regulatory activities 
mg
milligram(s)
mL
milliliter(s)
mRNA
messenger RiboNucleic Acid
MTD
MMRM
Maximum Tolerated Dose
Mixed Model for Repeated Measurements
NCV
Nerve Conduction Velocities
NfL
NTproBNP
Neurofilament-light chain
N-Terminal pro B-type Natriuretic Peptide
PD
pEFD
Pharmacodynamic(s)
Preliminary Embryo  Fetal Development
PI
Principle Investigator
PIP
Pediatric Investigation Plan
PK
Pharmacokinetic(s)
PRO
Patient Reported Outcomes
PT
Preferred Term
QMS
Quality Management System
RAP
Report and Analysis Plan
RBC
red blood cell(s)
REB
Research Ethics Board
SAE
SAF
Serious Adverse Event
Safety Analysis Set
SBP
Systolic Blood Pressure
SD
standard deviation
SMA
SMN
Spinal Muscular Atrophy
Spinal Motor Neuron
SMN1 
Survival of Motor Neuron 1
SMN2 
Survival of Motor Neuron 2
SMQ
Standardized MedDRA Query
SNAPs
Sural Nerve Action Potentials
SOM
Site Operations Manual 
STD10
Severe Toxic Dose in 10% animals
SUSAR
Suspected Unexpected Serious Adverse Reaction
TEAE
TR
Treatment Related Adverse Event
Tricuspid Regurgitation


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ULN
upper limit of normal
WBC
white blood cell(s)
WHO
World Health Organization 
WoC
wt
Withdrawal of Consent
Wild type


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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
AUC0-168h
The area under the plasma (or serum or blood) concentration-time curve 
from time zero, which is equal to the dosing time to 168 h [mass x time / 
volume]
AUCinf
The area under the plasma (or serum or blood) concentration-time curve 
from time zero to infinity [mass x time / volume]
AUClast
The area under the plasma (or serum or blood) concentration-time curve 
from time zero to the time of the last quantifiable concentration [mass x 
time / volume]
AUCweek
The area under the plasma (or serum or blood) concentration-time curve 
for the time period of one week [mass x time / volume]
Biologic Samples
A biological specimen including, for example, blood (plasma, serum), 
saliva, tissue, urine, stool, etc. taken from a study participant 
CL/F
The apparent systemic (or total body) clearance from plasma (or serum or 
blood) following extravascular administration [volume / time]
Cmax
The observed maximum plasma (or serum or blood) concentration 
following drug administration [mass / volume]
Cohort
A group of individuals who share a common exposure, experience or 
characteristic, or a group of individuals followed-up or traced over time
same time
Cycles
Number and timing or recommended repetitions of therapy are usually 
expressed as number of days (e.g., q28 days)
Discontinuation from 
study
Point/time when the participant permanently stops receiving the study 
treatment and further protocol required assessments or follow-up, for any 
reason. No specific request is made to stop the use of their samples or 
data.
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
or at a later point in time as defined by the protocol 
Enrollment
Point/time of participant entry into the study at which informed consent 
must be obtained. The action of enrolling one or more participants
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


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Other treatment
Treatment that may be needed/allowed during the conduct of the study 
(i.e. concomitant or rescue therapy)
Part 
A sub-division of a study used to evaluate specific objectives or contain 
different populations. For example, one study could contain a single dose 
part and a multiple dose part, or a part in participants with established 
disease and in those with newly-diagnosed disease
Participant
A trial participant (can be a healthy volunteer or a patient). "Participant" 
terminology is used in the protocol whereas term "Subject" is used in data 
collection
Participant 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.
Patient
An individual with the condition of interest for the study
Period
The subdivisions of the trial design (e.g. Screening, Treatment, and 
Follow-up) which are described in the Protocol. Periods define the study 
phases and will be used in clinical trial database setup and eventually in 
analysis
Personal data
Participant information collected by the Investigator that is transferred to 
Novartis for the purpose of the clinical trial. This data includes patient 
identifier information, study information and biological samples. 
Remote
Describes any trial activities performed at a location that is not the 
investigative site where the investigator will conduct the trial, but is for 
example a home or another appropriate location
Screen Failure
A participant who did not meet one or more criteria that were required for 
participation in the study
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
Start of the clinical trial
The start of the clinical trial is defined as the signature of the informed 
consent by the first participant
Study treatment
Any single drug or combination of drugs or intervention administered to 
the participant as part of the required study procedures
Study treatment 
discontinuation
When the participant permanently stops taking any of the study drug(s) 
prior to the defined study treatment completion date (if any) for any 
reason; may or may not also be the point/time of study discontinuation 
Subject number
A unique number assigned to each subject upon signing the informed 
consent. This number is the definitive, unique identifier for the subject and 
should be used to identify the subject throughout the study for all data 
collected, sample labels, etc.
T1/2
The terminal elimination half-life [time]
Tele-visit
Procedures or communications conducted using technology such as 
telephone or video-conference, whereby the participant is not at the 
investigative site where the investigator will conduct the trial.
Tmax
The time to reach the maximum concentration after drug administration 
[time]


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Troponin
Complex of three regulatory proteins that is integral to muscle contraction 
in skeletal muscle and cardiac muscle
Variable (or endpoint)
The variable (or endpoint) to be obtained for each participant that is 
required to address the clinical question. The specification of the variable 
might include whether the participant experiences an intercurrent event.
Vz/F
The apparent volume of distribution during the terminal elimination phase 
following extravascular administration [volume]
Withdrawal of study 
consent (WoC) / 
Opposition to use of 
data /biological 
samples
Withdrawal of consent from the study occurs when the participant explicitly 
requests to stop use of their data and biological samples (opposition to 
use data and biological samples) AND no longer wishes to receive study 
treatment, AND does not agree to further protocol required assessments. 
This request should be in writing (depending on local regulations) and 
recorded in the source documentation.
Opposition to use data/biological samples occurs in the countries where 
collection and processing of personal data is justified by a different legal 
reason than consent.


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Amendments and rationale for amendments
Amendment 11 (19-Jul-2021)
Amendment rationale 
The main purpose of this amendment is to implement increased cardiac enzyme monitoring 
from every six months to every three months based on new cardiac microscopic findings 
(cardiomyocyte vacuolation) from a wild type RasH2 mouse study with 4-week daily dosing of 
branaplam at ≥10 mg/kg/day. It is not known whether this finding translates to humans. At a 
dose of 4 mg/kg/day, that did not induce cardiac lesions in the mouse, the area under the plasma 
(or serum or blood) concentration-time curve for the time period of one week [mass x time / 
volume] (AUCweek) based exposure multiple for the new findings is 2.2-fold for Type 1 SMA 
patients (mean of male and female). The observed maximum plasma (or serum or blood) 
concentration following drug administration [mass / volume] (Cmax)-based exposure multiple 
is 1.2-fold (mean of male and female).
Following cardiac safety consultation, it was agreed to increase cardiac enzyme monitoring to 
every three months; and, if any abnormalities are found, an unscheduled ECHO assessment 
should be performed. 
In addition: 

UFB112: The bioanalytical validation of UFB112 failed with initial sample collection 
and a new analysis method was not completed. To avoid unnecessary blood sample 
collection and to reduce the total blood volume collected, the determination of 
UFB112 in blood samples of patients enrolled into Part 3 has been removed from the 
protocol.
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.

List of abbreviations has been aligned with amendment 11

Glossary of terms has been updated to align with Protocol Amendment Template v 4.0

Protocol Summary has been updated to remove ‘Impossibility/inappropriateness of 
treatment with nusinersen’ as an inclusion criteria for Part 2 and to remove caloric intake 
as an additional assessment

Section 1.1.1 Relevant data summary: Updated to add new findings from ongoing 
preclinical studies

Section 2.2 Secondary objectives: Aligned and corrected Protocol Summary Section with 
the secondary objectives as follows:
1. Part 1, Part 2, Part 3: 
a.
Removed two endpoints namely ‘Discontinuation due to permanent ventilation 
(defined as more than 21 days for more than 16 hours/day of ventilation) or 
tracheostomy’ and ‘Removal of tracheostomy’ from the objective ‘To evaluate the 


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effect of branaplam on respiratory function’ due to the removal of the secondary 
objectives
b.
Clarified the timepoint of CHOP INTEND infant motor scale endpoint
2. For Part 2 and Part 3:
a.
Removed the objective related to UFB112 PK and its endpoint due to failed 
bioanalytical validation and to avoid unnecessary blood sample collection
b. Removed one endpoint namely ‘Change from baseline for Hammersmith Infant 
Neurologic Examination’ from the objective ‘To evaluate the efficacy of 
branaplam on motor and development milestones’ since this level of detail is not 
needed in this section
3. For Part 2: Changed the timepoint of ability to sit without support assessed by HINE-2 
from ‘at 12 months of Treatment’ to ‘over time’ since all patients have received more 
than 12 months of treatment at this point
 
 

Section 3.5.1 Doses in Part 1: Updated the link to the reference for the International 
Council for Harmonization (ICH) S9 guidelines 2010 and removed repetitive text

Section 3.5.3 Doses in Part 3: Updated the section to reflect the selection of the optimal 
dose

Section 3.5.4 Safety margins: Removed details around the calculations for exposures 
measured in animals, details can be found in the current IB

Section 3.8 Risks and benefits: Section was revised with new risks (ovarian and cardiac)
as identified from the latest preclinical studies and re-ordered according to the newly 
added Table 3-1. The methods to minimize the cardiac risks to the patients have been 
updated and the following details have been removed - the benefits and risks of approved 
therapy nusinersen, the comparison of long-term risks (potential/clinical) to patients 
receiving branaplam and nusinersen, and the comparison of exposure and number of 
patient of branaplam and nusinersen (and deleted corresponding tables)

Section 3.9 Rationale for Public Health Emergency Mitigation Procedures: Newly added 
regarding the Public Health Emergency Mitigation Procedures, in line with latest version 
of Protocol template (version 4.0, dated 15-Feb-2021). Section 7 has been updated with 
this related text

Section 4 Population: Clarification added that no new patients will be enrolled in Parts 2 
and 3

Section 5.1.2 Treatment arms: Updated the section to reflect the selection of the optimal 
dose

Section 5.4.3 Dose Modifications, Part 3: Updated the section to reflect the selection of 
the optimal dose and to update the wording to be consistent with Section 5.4.7

Table 5-7 Criteria for interruption and re-initiation of branaplam treatment for AE 
possibly related to study medication: Added a new row for clinically significant increase 
in cardiac enzymes


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
Section 5.4.7 Within-patient dose escalation: Updated the section to reflect the selection of 
the optimal dose

Section 6 Informed consent procedures: Updated to reflect latest template (v4.0, dated 
150Feb-2021) language as appropriate

Section 7 Visit schedule and assessments: Updated to reflect latest template language

Table 7-1 Additional instructions on Part 1 assessment schedule: Updated to clarify Part 1 
of the study

Table 7-2 Additional instructions on Part 1 Extended assessment schedule: Updated to 
clarify ‘Part 1 Extended’

Table 7-3 ‘Additional instructions’ for all table footers: Updated to clarify ‘Part  and 
Treatment Period’

Table 7-4 Assessment Schedule – Part 3: Increased the frequency of cardiac enzymes 
collection from every 6 months to every 3 months (also updated in Section 7.4.1), with the 
additional information to repeat the test within 1 week if there is a clinically significant 
increase and to perform echocardiogram and ECG and if not already done for the visit, 
corrected PK collection at EoS visit

Section 7.3 Efficacy: Added the subheading ‘Appropriateness of efficacy assessments for 
consistency with Protocol template (v4.0, dated 150Feb-2021)

Section 7.4.6 Echocardiogram: Section updated to add requirement of unscheduled 
assessment if there is a clinically significant increase in cardiac enzymes and to detail the 
standard parameters

Section 7.5.1 and Section 11.5.3: Text related to UFB112 PK sample collection and 
evaluation/analysis has been removed

Section 7.5.6 Appropriateness of safety measurements: Added section to align with the 
latest template version

Section 8 Discontinuation and completion: Updated heading to align with the latest 
template version

Section 8.1.1 Discontinuation of study treatment: Updated to align with the latest template 
version (version 4.0, dated 15-Feb-2021) and to include other approved SMA therapies as 
opposed to just nusinersen

Section 8.1.2 Discontinuation of study: Section added to align with the latest template 
version

Section 8.1.3 Withdrawal of informed consent/Opposition to use data/biological samples: 
Updated to align with latest template version

Section 8.1.4 Lost to follow up: Updated to align with the latest template version (version 
4.0, dated 15-Feb-2021)

Section 9 Safety monitoring, reporting and committees: Updated heading to align with the 
latest template version (version 4.0, dated 15-Feb-2021)

Section 9.1.3 SAE reporting: Updated to align with the latest template version (version 
4.0, dated 15-Feb-2021)


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
Section 9.2.2 Data Monitoring Committee: Revised to reflect possible changes in the 
members of the DMC

Section 10.1 Data collection: Removed the option of receiving paper copies of the patient
data after database lock (CD-ROM only) and updated section to align with the latest 
template version (version 4.0, dated 15-Feb-2021)

Section 10.2 Database management and quality control: Section added to align with the 
latest template version

Section 11.1 Analysis sets: added definition of ENR and updated definitions of FAS and 
SAF accordingly

Section 11.3 Treatments: Added that the data for treatments will be listed by part as well

Section 11.5 Analysis of secondary endpoints: mixed model for repeated measures 
specification updated; also for safety endpoints, some more detail added

Section 11.5.1 Efficacy and/or Pharmacodynamics endpoint(s): Analysis of secondary 
endpoints more clearly defined

Section 11.5.2 Safety endpoints: Analysis of endpoints more clearly defined
 

Section 14 References: Removed two references that are no longer applicable to the 
document

General changes made throughout document to reflect patients are in Part 3 only

General grammatical, spelling, linking and referencing corrections and updates were made 
throughout the document
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.


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Amendment 10 (13-Feb-2020)
Amendment rationale
The main purpose of this amendment is to clarify the frequency of ophthalmology assessments 
in Part 3 of the study. The ophthalmology assessment, dilated direct and indirect 
ophthalmoscopy, can be performed at each onsite visit if considered applicable by the 
investigator. However, if the patient does not have any ocular related complaints and if at the 
previous ophthalmology assessments there were no clinical findings which, potentially could
be attributed to branaplam, the examination will need to be performed every 12 months, from 
the date of the last ophthalmology assessment. (See Section 3.3 - Part 3 Study Design).
Further change to this protocol amendment is relevant for patients in Part 3. In Part 3, patients 
treated with 0.625 mg/kg dose, from Part 2, now have the possibility to have a dose increase to 
2.5 mg/kg, if no further improvement becomes evident, or in case of disease progression. This 
dose increase is at the discretion of investigator and after consultation with the sponsor. 
Likewise, in case of any safety concern, patients who are receiving 2.5 mg/kg could have their 
dose decreased to 0.625 mg/kg, at the discretion of the investigator and after consultation with 
the sponsor. See 3.3 Part 3 Study Design, 3.5.3 Doses in Part 3 and 5.4.3 Dose modifications.
In addition to the above, other changes were also implemented to this protocol amendment, 
mainly correcting discrepancies and providing additional explanations that were lacking in 
protocol amendment 9 for Part 3 of the study. 

Monthly safety testing panel during safety visits was corrected to full liver function panel. 
Full liver function panel includes: Alanine Aminotransferase (ALT), Aspartate 
Aminotransferase (AST), Alkaline Phosphatase (ALP), Total Bilirubin (Direct and 
Indirect if increase > 1.5 ULN), Albumin, Total Protein (Section 7.4.1).

Table 7-4 Assessment Schedule – Part 3: Correction to replace “Weeks” with “Days”

Table 7-4 Assessment Schedule – Part 3: Clarification that the assessments performed 
during the last visit of Part 1 or 2 do not need to be repeated on visit 1 of Part 3, if visit 1 
of Part 3 is performed within 14 days of last visit of Part 1 or 2.

Clarification that branaplam can be administered at home by the patient caregiver, 
however patients may visit the investigator site for dosing if preferable (Section 3.1)

Clarification on the nerve conduction study (Section 7.4.7). It is a test commonly used to 
evaluate the function, especially the ability of electrical conduction by the motor and 
sensory nerves of human body. It is evaluated by performing the following assessments:

Compound Muscle Action Potential (CMAP)

Sural Nerve Action Potential (SNAP) 

Nerve Conduction Velocity (NCV)

F wave

Clarification on the primary objectives based on the clarification on the nerve conduction 
study (Section 2.1)


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
Addition of a new PK parameter (Section 1.1.1 Relevant data summary, Table 7-3 
Assessment Schedule – Part 2, Table 7-4 Assessment Schedule – Part 3, Section 7.5.1): 

Beside the measurement of branaplam (LMI070) in plasma, the determination of its
major metabolite UFB112 (M18) in plasma will be included into the bioanalytical 
analysis. PK parameters of UFB112 will be estimated if possible (Section 
1.1.1).Update of subsection “Human pharmacokinetic data” with new findings on PK 
and UFB112

Collection of UFB112 added in the core protocol and on schedule of assessments for 
Part 2 (starting week 40) and Part 3. Blood volume sampling increases by 0.7 ml per 
PK sample to account for an additional tube in order to test UFB112 metabolite. 
Increased volume will be required in Part 2 Week 40 visit and for all PK samples in 
Part 3 (Table 7-3 Assessment Schedule – Part 2 and Table 7-4 Assessment Schedule –
Part 3, Section 7.5.1).

Addition of UFB112 in secondary objectives (Section 2.2)

Section 3.8 Risks and Benefits updated with new information available


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Amendment 09 (25-Apr-2019)
Amendment rationale
The main purpose of this amendment is to provide to patients from Part 1 and Part 2 of this 
protocol the possibility for continuous treatment and long term safety and efficacy follow up in 
the newly added Part 3 of the study. Once all patients have transitioned into part 3, the parts 1 
and 2 will be closed. 
All patients treated in Part 1 and Part 2 of this protocol after completing at least 52 weeks of 
treatment, will be offered the possibility to further extend the treatment, for as long as 
branaplam treatment is in the best interest of the patient. If continued branaplam treatment is 
not in the best interest of the patient, investigator to discuss standard of care of the study site 
with the parents/caregivers.
Part 3 study duration will be as long as the branaplam treatment is in the best interest of the 
patient or other treatment options will be offered to the patients. 
Patients who have completed at least 52 weeks of treatment either in Part 1 or Part 2 study are 
eligible to continue treatment under Part 3 of this protocol.
In addition to the above, other changes were also implemented to this protocol amendment, 
mainly correcting discrepancies and providing additional explanations that were lacking in 
protocol amendment 8 for Part 1 and 2 of the study. 
Study description for Part 3 is also provided, in order to clarify the following points:

Eliminate assessments that were present in Parts 1 and 2 and which are not necessary for 
part 3 (Three day food record, Survival of Motor Neuron Protein (SMN Protein), Survival 
of Motor Neuron2 mRNAs (SMN2 mRNAs) blood collections)

Revise efficacy endpoints (CHOP-INTEND to be collected up to 3 years of age, i.e. 36 
months)

Change in schedule of assessments to reflect the reduced visit frequency

Clarify and simplify the process of branaplam administration at home

Extend the list of assessments which can be performed by Home Nurse, when applicable

Reformatting and renaming sections of protocol amendment 9 to have them displayed in a 
more logical and sequential order for the ease of use
Additionally following clarification were made for Part 1 and Part 2:

Consequently to Part 3 updates Eliminate Three day food record assessment

Consequently to Part 3 updates: Clarify and simplify the process of branaplam 
administration at home


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Amendment 08 (October 2018)
Amendment rationale
The main purpose and rationale for this from three to two, in order to better ensure that the 
studied doses are clinically distinguishable, and to more efficiently investigate the branaplam 
dose-response relationship in conjunction with the data generated in Part 1. In addition, several 
modifications were made to the inclusion and exclusion criteria to reflect evolving knowledge 
and practice in the diagnosis and treatment of Type 1 spinal muscular atrophy (e.g. allowing 
patients diagnosed before the onset of symptoms to be eligible for the study).
The data from Part 1, which utilized a within-patient dose escalation design, suggest that 
systemic exposure to branaplam is proportional to the dose across the full-range of doses studied 
(6 mg/m2 [0.3125 mg/kg] to 60 mg/m2 [3.125 mg/kg]). The originally selected three doses for 
Part 2 spanned a range of only 4-fold (0.625, 1.25, 2.5 mg/kg). The preliminary PK results of 
this study showed that Cmax and AUC values were not clearly separated between the middle 
dose and either the lower dose or the higher dose leading to difficulties in the interpretation of 
the dose-response. Since all three doses were associated with increases in CHOP-INTEND in 
Part 1, continuing the clinical characterization of the dose-response for branaplam with two 
doses separated by 4-fold (0.625 and 2.5 mg/kg) represents a more efficient study design and 
avoids exposing patients to unnecessary research. Due to the design of Part 1, which mandated 
within-patient dose escalation, it is not clear if continuous dosing with 12 mg/m2 (0.625 mg/kg) 
may yet be effective and durable. In the event that the response to 12 mg/m2 (0.625 mg/kg) 
appears inadequate and in order to ensure patient safety, Part 2 has a rescue provision that allows 
within-patient dose escalation. The lower dose cohort may be closed early and the higher dose 
cohort opened if three patients experience unacceptable responses to 12 mg/m2 (0.625 mg/kg) 
as defined in Section 5.4.
The Part 2 study design and sample size were modified accordingly throughout the protocol. 
Other changes include clarifications and harmonization throughout the protocol of: 

Relevant sections updated to reflect the latest edition of the Investigators’ Brochure (IB) 

Definition of permanent ventilation

Toxicity management and dose interruption guidance 

Inclusion criteria modified per comments from the Italian Health Authority (Istituto 
Superiore di Sanità, ISS) during their review of the protocol amendment 7

Clarification that Part 1 patients following the Extended treatment Schedule of 
Assessment and patients enrolled in Part 2 may continue receiving study treatment in a 
separate branaplam protocol 
The following Assessments have been modified: 

The nerve conduction studies and compound motor action potential (CMAP) assessments 
were modified. Novartis consulted external experts in the area of neurophysiology, who 
advised that the prolongation of the neurophysiology current protocol may increase the 
stress for patients and bear the risks of low quality results, missing parameters and/or 
withdrawal from the study. The recommended modifications address the safety concern to 


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detect potential neuropathy due to the study drug, as well as the feasibility in the study 
population

The possibility for administration of the study drug at home by caregivers was added and 
an Instructions for administration of the study drug at home by caregivers developed

Monitoring of patient dietary intake, per data monitoring committee (DMC) request, using 
a 3-day caloric intake record, has been added
Changes to the protocol: 

List of abbreviations updated 

Protocol synopsis updated to reflect the changes to the protocol described below 

Preclinical Data: has been updated with most recent pre-clinical Pharmacokinetic data

Human safety and tolerability data updated to reflect the most recent data available

Human pharmacokinetic data updated to reflect the IB Edition 7.0 and 

Table 1-1 added 

Study purpose updated to clarify the rationale for Part 1 and Part 2

Primary Objective (s):
-
Objective of Part 2 was rephrased as evaluation of two doses of branaplam administered 
weekly
-
Endpoint Part 1 and Part 2: Nerve conduction studies and ulnar nerve compound motor 
action potential assessments have been described and moved under safety endpoints 

Secondary Objective(s): Part 1and Part 2 
-
Objective: To evaluate the effect of branaplam on respiratory function. The 
corresponding endpoint has been updated with the definition of permanent ventilation 
and removal of tracheostomy endpoint has been added to reflect the change in exclusion 
criterion number 8 
-
Compound motor action amplitude potential endpoints moved to primary 
 
 objectives - ulnar nerves assessments are suitable to address safety concerns 
and peroneal nerve assessments changed to optional

Study design: 
-
Text referring to Part 2 updated with two doses
-
Text referring to the possibility for the Patient in Part 1 and Part 2 to continue receiving 
study medication under a separate branaplam protocol if in the best interest of the patient
and assessed by the investigator has been added 
-
Part 2 Study Design: Section updated to reflect the dose change and the cohort 1 dose 
escalation option after 3 patients treated for at least 13 weeks
-
Figure 3-2, cohort 2 and footnote removed 
-
Screening paragraph: first sentence has been removed as unclear


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-
End of Study: The option for the patient to continue receiving treatment under a separate 
branaplam protocol added

Rationale for study design: updated with references 

Rationale for dose/regimen, duration of treatment 
-
Doses in Part 1: the maximum dose text was moved under this section. No change to the 
content
-
Doses in Part 2: Second dose level rational paragraph has been added to describe the 
choice of the 2.5mg/kg 
-
Dose escalation: text removed since it was not applicable 
-
Safety margins: text was updated to reflect the IB Edition 7.0
-
Age effect was updated per IB Edition 7.0

Table 3-3 Comparison of long-term potential risks of branaplam and nusinersen added with 
number of cases and duration of treatment per Italian Health Authority request

Inclusion criteria Part 2: 
-
Criterion # 2 modified to allow inclusion of symptomatic SMA Type 1 patient. Based 
on the current data, the Sponsor has determined that symptomatic patients could also 
benefit from branaplam
-
Criterion # 3 added per Italian Health Authority request 
-
Criterion # 4: “as assessed by investigator” added. This addresses the differences of 
supportive care in countries and upon patient clinical status
-
Criterion # 5: the age was changed to include patients up to 180 days of age to reflect 
new practices in diagnosis such as newborn screening
-
Criterion # 9 reworded to help clarity 
-
Criterion # 10 removed since local standard of care and compliance is already evaluated 
during site selection.
-
Criterion # 11 removed since difficult to assess and restricts both caregivers and 
physicians choice 

Exclusion criteria Part 2
-
Criterion # 4: Anemia grade 1 has been changed to Anemia grade 2. Mild anemia is 
frequent in this population with low weight. The cumulative part 1 data have not shown 
increase risks of anemia worsening. 
-
Criterion # 8: presence of tracheostomy removed. The cumulated safety data from Part 
1 support that patients could benefit from branaplam even with a tracheostomy

Prohibited chronic treatment: new data related to some potential drug-drug interaction has 
been added and caution warning. 

General restrictions: reference to Pharmacy Manual corrected and replaced by the most 
recent version of the Instruction for administration of branaplam for phase I/II 
investigational human use.

Treatment arms and Table 7-3 Treating the patient Part 2 updated with two doses

Treating the Patient: the option to administer branaplam the patient’s home by legal 
representative caregivers and reference to Appendix 2 –Administration of branaplam by 
caregivers - Instruction for site staff and caregivers added


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
Dose cohort modification - Part 2: The text was updated with definition and time-point of 
potential intra-cohort 1 dose escalation in the event that the response to 0.625 mg/kg appears 
ineffective. The evaluation of a potential loss of positive effect is described

Within-patient dose escalation - Part 2: The text was updated to clarify the possibility that 
a patient enrolled in cohort 1 may be escalated to the cohort 2 dose in the event of loss of 
durable positive effect

Adverse events: reference to CTCAE vs 4 modified as “the most recent version” of the 
CTCAE

Permitted dose adjustment and interruptions of study treatment: This section has been 
updated to reflect the Part 2 design and patients under Part 1 Extended treatment schedule. 
The references to dose-level decrease have been removed

Concomitant treatment: “including vaccinations” has been added

Discontinuation of study treatment: This section has been updated to reflect the Part 2 design 
and to be applicable for patients following the Extended schedule of assessment Part 1: 
“Patient has unresolved adverse events that require two dose de-escalations” removed and 
“Patients who never improve and decline in CHOP-INTEND by 5 or more points or lose 
one or more previously attained motor milestones” added

Withdrawal of consent has been updated to reflect Novartis most recent protocol template

Study Stopping rules updated to reflect status of the trial

Table 7-2 Assessment Schedule – Part 1 – Extended treatment period and Table 7-3 
Assessment Schedule – Part 2 has been updated :
-
with visits that study drug administration may be done in the patient's home by a 
qualified clinician or by the assigned and trained caregivers
-
add 3-day food record assessment 
-
add footnotes to clarify optional peroneal CMAP, ophthalmologic assessment (to 
address errors and align with amendment 3), CHOP-INTEND assessment not 
required after patient/s have reached three years of age, and assessments that may 
be performed at a subsequent visit at the discretion of the investigator if patient/s 
experience an acute illness episode
-
Echocardiogram Part 1: 2 planned visit changed and echocardiogram Part 2:1 visit 
in period 2, 3 and 4 changed to reduce the burden of extra visits for the patient  
 

(CHOP-INTEND): The collection of the assessment will be terminated once patient reaches 
3 years of age

Laboratory evaluation: urine analysis: microscopic analysis replaced by bacterial analysis

CMAP and Nerve conduction velocities (NCV). The list and order of the assessments and 
tests have been added

Three –Day diary record added 

Pharmacokinetics: Total blood volumes have been added. EMA Good Clinical Practice and 
FDA Code for Federal regulation specify that blood volume should be minimized and 
justified in protocols

CMAP and NCV Optional has been added. The section describes the optional CMAP 
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
Data Monitoring Committee: Last paragraph has been removed. The study is open label. 
Data to the DMC are not generated by an Independent Statistical Team statistician.

Analysis of the primary, secondary 
 variables. The sections have been 
updated to reflect the most recent Statistical Analysis Plan

Sample size calculation Part 1 and Part 2. The section has been updated to reflect the actual 
total number of patients enrolled in Part 1, and the revised total number of patients in Part 
2 considering the removal of the cohort 1.25mg/kg 

References has been updated 

Appendix 2 Administration of branaplam by caregivers- Instruction for study site staff and 
caregivers has been added 


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Amendment 7 (December 2017)
Amendment rationale
The main purpose of this amendment is to implement in all countries where the study is being 
conducted or being submitted to the Health Authorities the changes made based on the request 
of the German Health Authority during their review of the Amended Protocol version v06. 
These changes had so far been implemented in a local protocol amendment (Amendment 6 
DE0.1) submitted and approved exclusively in Germany.
In addition the criteria used to decide interrupting and re-initiating treatment with branaplam in 
the event of thrombocytosis were added based on a commitment done to a Health Authority.
At the time of this amendment 8 patients are ongoing in Part 1 of the study and no new patients 
have been recruited in Part 2 of the study.
Changes to the protocol

All changes listed in the Amendment 6 DE0.1

Notification of serious adverse events: the name of the Novartis department where serious 
adverse events (SAEs) need to be sent has been changed. 

Table 6-2 has been updated to include the dose conversion from BSA to weight for doses 
in Part 1 of the study since the previous amendment of the protocol did only specify the 
conversion for planned doses in Part 2 of the study.

Table 6-5 Criteria for interruption and re-initiation of branaplam treatment has been 
updated to include specific recommendations for dose modifications in the event of 
thrombocytosis.
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. The changes described 
in this amended protocol require IRB/IEC approval prior to implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.


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Amendment 6 DE0.1 (August 2017)
Amendment rationale
The main purpose of this amendment is to implement changes based on the request of the 
German Health Authority during their review of the Amended Protocol version v06 to better 
reflect that Spinraza® (nusinersen) is now approved in many countries for the treatment of 5q 
SMA and is considered standard of care. The impacts of this approval for study eligibility, study 
execution, study comparator and long term potential risks between an approved agent and 
branaplam have been added.
In addition in the Amended Protocol v06 (see corresponding Amendment rationale) it is 
foreseen to have the dose calculation for branaplam done based on the patient’s weight instead 
of the body surface area. The rationale for the conversion of the dose administered from a body 
surface area calculation to a weight-based calculation has also been clarified.
Changes to the protocol

The List of abbreviations has been updated.

Protocol synopsis: Changes were made in the synopsis to reflect all changes throughout 
the protocol as outlined below.

Section 3.2 Rationale for study design and Section 3.4 Rationale for choice of comparator: 
these sections have been updated to indicate that Spinraza® (nusinersen) has now been 
approved in both the US and in the EU.

Section 3.2 Rationale for study design: The section had been updated to clarify a sentence 
which was unclear about the initial study design and why the study had been designed to 
start directly in infants with Type I SMA

Section 3.6 Risks and benefits: This section has been updated to specify the known 
benefits and risks of the approved therapy for 5q SMA. Table 3-1 and Table 3-2 had been 
added comparing potential risks observed in preclinical studies and of long-term 
administration of branaplam and nusinersen.

Section 4.2.2 Part 2 Exclusion criteria: the use of nusinersen has been removed from the 
exclusion criterion #1 since nusinersen is an approved therapy and not an investigational 
drug and is now treated as a separate exclusion criterion. The need to check exclusion 
criterion #10 at baseline had been removed since Electrocardiogram (ECG) and 
echocardiogram (ECHO) are only performed at the screening visit. 

Section 5.2 Prohibited Chronic Treatment: nusinersen has been removed from Table 5-1
and listed separately to make a clear distinction between experimental therapies and 
approved therapies for the treatment of SMA.

Section 6.3 Treatment arms: the explanation of how the dose conversion between BSA 
and weight was performed has been added. Data from PK samples collected in Part 1 of 
the study enabling this conversion have been added in Table 6-2. Table 6-3 has been 


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added to clarify the dose conversion from BSA to weight for provisional doses to be tested 
in Part 2 of the study.

Section 5 Discontinuation of study treatment: the use of nusinersen during the study has 
been added as a reason to discontinue branaplam treatment, in agreement with Section 5.2
since this could interfere with the assessment of study endpoints.

Section 7 Procedures and assessments: minor discrepancies have been corrected in the 
following assessment schedules:

Table 7-2: the nerve conduction velocities are planned to be performed every 3 months 
and not only at the end of study visit as previously indicated for Part 1 of the study in 
the clean version of the Amended Protocol v06. 

Table 7-3: the number of the footnote specifying the frequency at which detailed 
neurologic examination needs to be performed has been corrected. 

Section 7.4 Physical examination: the wording defining the frequency of detailed physical 
examination has been corrected to match the Assessment Schedule.

Section 14 References: the EMA report for Spinraza® had been added as a reference 
because it is mentioned in Section 3.6.
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.


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Amendment 6 (April 2017)
Amendment rationale
The enrollment of the ongoing clinical study had been voluntarily and temporarily suspended 
following the implementation of a Urgent Safety Measure after preclinical findings in the 
52-week, daily dosing toxicity study in juvenile Beagle dogs (see Amendment 5).The main 
purpose of this sixth amendment is to allow resumption of enrollment in the ongoing study as 
agreed by the independent Data Monitoring Committee (DMC). The DMC agreed that the 
benefit-risk was positive for new patients as well as for ongoing patients. This DMC 
recommendation was based on review of the available clinical data for the patients ongoing in 
the study as well as the results of the preclinical investigations as part of the chronic dog 
toxicology study. An independent benefit-risk assessment by Prof. 
 at Catholic 
University in Rome also found evidence of a continued positive benefit-risk for patients 
enrolled in the study. Following the DMC recommendation one of the safety monitoring 
measures put in place at the time of the third Urgent Safety Measure (USM), namely the 
expanded neurophysiologic examination will be modified to include the measurement of both 
median and sural nerve action potentials (SNAPs) to assess sensory as well as motor nerves in 
the monitoring plan.
 
 
LMI070 now has a recommended International Nonproprietary Name (INN): branaplam which 
has passed the objection period and will thus be used in place of LMI070.
The study was initially designed as a multi-part study with Part 2 planning to evaluate the safety 
and efficacy of multiple dose regimens of branaplam. However in view of the available data 
collected in this ongoing clinical study as well as the preclinical findings reported in the 52-
week, daily dosing toxicity study in juvenile Beagle dogs, and a dosing regimen more frequent 
than weekly administration was not supported. Part 2 of the study will thus be modified to obtain 
additional safety and efficacy data with oral administration of up to 3 dose levels of branaplam, 
already tested in Part 1, to identify the dose that is safe for long term use as well as that can 
provide durable efficacy. Part 2 will enroll up to approximately 30 patients (a minimum of 6 
patients and a maximum of 10 patients will be enrolled in each cohort). Unlike in Part 1, no 
planned within-patient dose escalation will occur in Part 2, although rescue is allowed if 
response does not prove durable. No new patients will be enrolled in Part 1 of the study. The 
total number of patients planned to be enrolled is slightly increased, i.e. up to 45 patients 
(previously a maximum of 42 patients were planned to be enrolled). 
The following inclusion and exclusion criteria for Part 2 have been modified or added compared 
to the ones for Part 1: 

the age of patients at screening is now expressed in days instead of months and restricted to 
180 days of age (upper limit) because of the higher likelihood of motor response in younger 
patients, based upon Part 1 data from this study as well as responder age from other therapies 
in development 

A minimum CHOP INTEND score of 15 is required at baseline and patients must be able 
to feed orally for all nutritional needs and be greater than the 2nd percentile for weight on 


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the standard growth curves for the country of origin. This is undertaken to avoid inclusion 
of patients whose disease state is already too severe to expect clinical benefit 
Since the relationship between weight and BSA is nearly linear in infants and individuals less 
than 50 kg the dose calculation will now be done based on the patient’s weight only instead of 
the body surface area. This change will reduce burden in the study and simplify the dose 
calculation, and will apply to patients in both parts of the study. A conversion table based upon 
the linear relationship found for patients in part 1 of this study is included in Section 6.3. 
Finally, where possible the number of assessments to be conducted has been reduced in order 
to lower burden on the patients.
Changes to the protocol

The List of abbreviations has been updated.

Protocol synopsis: changes were made in the synopsis to reflect all changes throughout the 
protocol as outlined below.

Section 1.1 – Figure 1-1 the figure describing the mode of action of branaplam has been 
modified to increase clarity.

Section 1.1.1.4 has been updated to include the available information from all patients 
enrolled in the study at time of this amendment.

Section 2.1 – Primary Objectives: the objective has been revised to reflect the dosing 
regimen and duration of treatment in Part 2 of the study.

Section 2.2 – Secondary Objectives: 

The endpoint corresponding to the pharmacokinetic objective has been re-written to be 
accurate.

The cry vital capacity which was an optional assessment foreseen to be conducted in 
Part 2 has been removed.

The discontinuation due to permanent ventilation or tracheostomy has been added as an 
endpoint to evaluate the effect of branaplam on respiratory function

The Hammersmith Infant Neurologic Examination has been added as an endpoint to 
evaluate the efficacy of branaplam on motor and developmental milestones for 
comparability to other molecules in development in SMA type I.

The percentage of infants who are sitting without support at 12-months of Treatment has 
been added as a secondary objective for Part 2 of the study

Peroneal compound motor action amplitude potential (CMAP) has been included in 
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
Section 3.1.1 Part 1 Study Design:

The actual number of patients enrolled in the study has been indicated since no more 
patients will be enrolled in Part 1 of the study. 

The amount of time patients need to stay on site after administration has been removed 
and the decision is left to the investigator’s decision. This is supported by safety data 
collected until now in the study.

Section 3.1.2 Part 2 Study Design and Section 3.2 Rationale for study design: this section 
has been entirely adapted to reflect the 3 cohorts to be evaluated, the duration of treatment 
and the dose escalation. 

Section 3.3 Rationale for dose/regimen, duration of treatment: the choice of the starting 
dose for Part 2 has been described as well as the duration of treatment (52 weeks).

Section 3.4 Rationale for choice of comparator: the section has been updated to take into 
account the recent approval of Spinraza® (nusinersen) for SMA in the United States.

Section 3.5 Purpose and timing of interim analyses/design adaptations: the section has 
been updated to describe the actual interim analysis performed during Part 1 of the study 
and to specify that intra-patient dose escalation is not planned for patients enrolled in 
Part 2 of the study unless specific criteria are met.

Section 3.6 Risks and benefits: the text has been updated with the most recent preclinical 
information on the effects of branaplam on peripheral nerve system.

Section 4 Population: this section has been divided in 2 subsections for Part 1 and Part 2 
since the eligibility criteria are different in each part of the study.

Section 4.1. Inclusion criteria Part 2: Inclusion criterion #4 has been modified and 
inclusion criteria #7 and #8 have been added as described in the amendment rationale

Section 4.2 Exclusion criteria Part 2: 

Criterion #1 has been modified to take into account the availability of Spinraza®
(Nusinersen) in some countries and the ongoing clinical trial with gene therapy.

Criterion #7 “Intractable seizure disorder” has been changed to “Intractable epilepsy” 
to clarify that infants with intractable epilepsy should be excluded from the study. 
Indeed these patients would not be expected to achieve motor milestones due to severe 
underlying brain disease and would interfere with secondary objectives of the study.

Criterion #8 has been modified to remove oral suctioning as a potential factor to 
determine eligibility in the study since this does not inform on the patient’s 
respiratory function

Criterion #10 has been modified to specify that an echocardiogram needs to be 
performed at screening to exclude any clinical significant cardiac findings.

Section 5.2 Prohibited chronic treatment: Spinraza® (nusinersen) and other non-approved 
experimental therapy for the treatment of SMA have been added in Table 5-1.

Section 6.3 – Treatment Arms:

A conversion table from body surface area to weight is included for Part 1 and 2

The dose levels for Part 2 have been added


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
Section 6.4 Treating the Patient: the text has been modified to include the details on the 
route of administration in Part 2. The possibility to have the administration performed in 
the patient’s home once reviewed and agreed by the Investigator, Novartis and the DMC 
has been added.

Section 6.5.2 Dose cohort modification: the details of the composition of cohorts in Part 2 
as well as the dose escalation criteria have been included.

Section 6.5.4 and Section 6.7.2 Intra-patient dose escalation and permitted dose 
adjustments and interruptions: sub-sections have been added for Part 2 to specify the rules 
to follow in order to decide when an intra-patient dose escalation could take place.

Section 7.1 Discontinuation of study treatment: the criteria used to define the disease 
progression have been revised following discussion with the DMC.

Table 7-2 Assessment Schedule – Extended treatment periods:

Speech and motor milestones and Hammersmith Infant Neurological Examination
(HINE) have been added at the end of each treatment cycle and V777. The 
information on these milestones was previously collected but the frequency was left 
to the investigator’s discretion. 

Nerve conduction studies have been added based as per DMC feedback following the 
implementation of the third USM. 

Physical examination, vital signs and body measurements, respiratory function 
assessments: the frequency of these assessments was reduced to monthly instead of 
weekly as previously scheduled. In view of the data collected so far in the ongoing 
study this reduced frequency is deemed sufficient and allows to reduce burden on 
patients.

The possibility to have drug administration performed in the patient’s home has been 
added to reduce burden on the patients.

Table 7-3 Assessment Schedule – Part 2: the schedule has been completely revised to 
match study Part 2 design. The schedule of assessments has been divided in 4 treatment 
periods of 13 weeks for readability. The possibility to have drug administration performed 
in the patient’s home has also been added.

Section 8.3.1 ulnar nerve compound motor action potential (CMAP) (expanded 
assessment) has been moved to the section describing safety assessments and to include 
peroneal nerves in the description of the assessment (Section 8.4.9)

Section 8.3.2 Hammersmith Infant Neurologic Examination (HINE): this section has been 
added since this is a new assessment.

Section 8.4.3 Body length, weight and head circumference: the calculation of the body 
surface area (BSA) has been removed since dose calculation will be performed based on 
weight only.

Section 8.4.7 Respiratory function: the cry vital capacity has been removed.

Section 8.4.8 GI function: the section has been deleted. Indeed the diary previously given 
to parents/caregivers Parents/Care-givers to record any adverse events when patients are 


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not in the clinic was focused only on the GI adverse events. As per the sites feedback the 
diary was too specific and not used. AEs are recorded as per standard practice.

Section 8.4.10: Nerve conduction velocities (NCV): the section has been added since this 
is a new assessment.

Section 11: The entire section has been adapted to reflect the changes in design in Part 2

Minor spelling and administrative changes were made throughout the protocol to improve 
clarity.
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
A copy of this amended protocol will be sent to the Institutional Review Board
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.


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Amendment 05 (August 2016)
Amendment rationale
The main purpose of this amendment is to implement additional safety monitoring following a 
third urgent safety measure (USM), based on new non-clinical findings and dose lowering that 
was implemented, and later on reversed with a fourth urgent safety measure (USM) following 
serious clinical adverse events associated with a lower dose.  
The new non-clinical findings that were considered adverse, potentially serious and unexpected 
and led to the third urgent safety measure (USM) have been reported to health authorities, ethics 
committees, and investigators. Histopathology data in the 52-week, daily dosing toxicity study 
in juvenile Beagle dogs, became available and identified three new target organs of toxicity: the 
nervous system, kidney and testes. In the ongoing CLMI070X2201 clinical study, where 
patients are dosed on a weekly basis, LMI070 continues to be well tolerated with signs of 
clinical benefit. However, following consultation with an external pediatric SMA expert, 
internal safety experts and in agreement with the external safety Data Monitoring Committee, 
Novartis had decided to take the following urgent safety measures which have been notified to 
all clinical sites and submitted to the Health Authorities: 

Reduction of the weekly dose of LMI070 administered to all patients having completed the 
initial 13 weeks of treatment to 6 mg/m2. The dose of 6 mg/m2 was selected as the dose for 
continued treatment of enrolled patients because it represented the lowest dose which 
exhibited clinical response (CHOP INTEND improvements) with a small safety margin 
over the lowest dose tested in dogs, based on systemic drug exposure. 

An expanded neurophysiologic examination to be conducted every 3 months to address the 
risk of nerve degeneration as identified in the 52-week chronic toxicology dog study. 

A detailed, serial neurologic examination focusing on both motor and sensory findings 
conducted monthly to document the patient’s clinical status. 

A new benefit: risk determination by an independent physician for each patient enrolled in 
the study. Subsequent treatment for each enrolled patient would be conducted only if the 
benefit: risk assessment for this patient continued to be positive. 
Also following recommendations from the independent Data Monitoring Committee (DMC) in 
response to the new non-clinical findings, the enrollment of new patients in the study has been 
voluntarily and temporarily suspended until data are available that allow for a better 
understanding of the pathophysiological mechanisms that may explain the observations in the 
chronic dog toxicology study. 
However within 6-7 weeks following implementation of the lower dose of LMI070 as part of 
the third USM, new safety events, including serious adverse events indicating decrease of motor 
skills, generalized motor weakness and increased respiratory muscle weakness, occurred in 7 
of 10 patients in the ongoing study whose dose was lowered to 6 mg/m2. After consultation with 
Investigators and following recommendations from the internal safety board and as agreed to 
by the independent DMC, Novartis has decided to institute a fourth USM in response to these 
clinical events: to re-instate the weekly dose of LMI070 (either 48 mg/m2 or 60 mg/m2) that 
was administered prior to the dose reduction to 6 mg/m2 for each patient. The evaluations 


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implemented in the third USM (additional neurologic and neurophysiologic examinations, 
risk/benefit determination by independent physician) remain implemented in the study. Also, 
as implemented in the third USM, enrollment of new patients remains suspended.
In addition, the following changes have been made to reduce the burden for patients already 
enrolled in the study: 

Option for safe oral administration of LMI070 to patients who have completed the initial 13 
weeks of treatment has been introduced.

The optional infant cry vital capacity assessment has been removed from Part 1 of the study. 

The number of PK samples taken and their frequency has also been reduced where possible.
At the time this amendment was written thirteen patients have been treated with LMI070 in Part 
1 of the study. New information concerning the safety and pharmacokinetics in these patients 
is provided as part of this amendment.
Changes to the protocol

Protocol synopsis: changes were made in the synopsis to reflect all changes throughout the 
protocol as outlined below.

Figure 1-1: The figure was replaced to reflect a more accurate number of mRNA splicing 
in SMN2.

Section 1.1.1.1 has been updated with additional available preclinical information, mainly 
from the 52-week toxicology study in juvenile dogs.

Section 1.1.1.4 and Section 1.1.1.5 have been updated to include the available 
information from all patients enrolled in Part 1 of the study at time of this amendment.

Section 2.1 – Primary Objective: addition of two following safety endpoints: neurologic 
examination and neurophysiologic examination following preclinical safety findings in the 
52-week toxicology study in juvenile dogs and subsequent implementation of an USM.

Section 2.2 – Secondary Objectives: 

Correction of a discrepancy which indicated that LMI070 pharmacokinetics are 
evaluated in serum whereas it is actually performed in plasma samples only. 

The compound motor action potential (CMAP) which used to be optional is now 
mandatory for all patients enrolled in the study as an additional safety monitoring 
assessment and thus the text has been adapted accordingly throughout the protocol.

Section 3.1.1 – Part 1 Study design: Clarification that the dose escalation of LMI070 in Part 
1 of the study could stop depending on PK results even if the MTD could not be reached.

Section 3.1.2 – Study design: clarification on the data to be used for the determination of 
the dose regimen to be tested in Part 2.


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
Section 3.3 – Rationale for dose/regimen, duration of treatment: 

A typo has been corrected in the section explaining the calculation of the starting 
dose in patients.

The sub-section on the Maximum dose has been updated in view of the newly 
available preclinical data from the 52-week toxicology study in juvenile dogs.

The sub-section on age effect has been updated with the available information from 
the ongoing clinical study.

Section 3.6: the benefit/risk assessment has been updated to reflect that with current 
information it does not justify enrollment of new patients (based upon new pre-clinical tox 
findings) but that the risk/benefit justifies continued dosing for currently enrolled patients 
(based on clinical data thus far).

Section 4.1- Inclusion criteria: the inclusion criterion #6 has been updated to indicate that 
placement of a feeding tube for the administration of LMI070 in Part 1 should be applied 
only in patients who cannot be administered orally.

Section 6.4 – Treating the Patient: this new section has been added to clarify when and 
under which conditions oral administration could be performed during the study.

Table 8-1 and Table 8-3: the time points when the detailed neurologic examination should 
be performed and the fact that the expanded neurophysiologic examination is now 
mandatory for all patients have been added.

Table 8-2: in addition to the changes listed above for Table 8-1 and Table 8-3 the following 
changes have been done: the Acceptability and palatability questionnaire has been added 
since in the extended treatment periods LMI070 can be administered orally; the frequency 
at which PK samples need to be drawn and their number have been reduced to take into 
account the patient’s burden.

Section 8.3.1 – Ulnar Nerve Compound Motor Action Potential (CMAP): this section has 
been updated since this examination becomes mandatory for all patients in the study.

Section 8.4.1 – Physical Examination: this section has been updated to indicate when the 
detailed neurologic examination should be performed.

Section 8.6.3 Acceptability and Palatability Questionnaire: this new section has been added 
since a new questionnaire has been introduced to evaluate the acceptability of LMI070 by 
patients when administered orally.

Section 11.5 – Analysis of secondary 
 variables: this section was updated to 
remove the analysis of ultrasound data as this assessment is no longer performed

Section 11.5.2 – Safety has been updated to take into account the additional safety findings 
reported in the different Urgent Safety Measures.

Minor spelling and administrative changes were made throughout the protocol to improve 
clarity
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.


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A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. Please note that the additional safety monitoring measures as described are 
already in effect as communicated by the Urgent Safety Measure notification. 


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Amendment 04 (March 2016)
Amendment rationale
The main purpose of this amendment is to implement additional cardiac monitoring following 
a second urgent safety measure (USM) based on two separate and distinct serious cardiac events 
that were reported in 2 patients enrolled in the study within the first 6 – 8 weeks following 
LMI070 treatment. While it is unlikely that the cardiac events were caused by LMI070, 
additional cardiac monitoring was implemented for every patient enrolled in the study as safety 
precaution. Measures were based on recommendations from both internal Novartis and external 
consulting cardiologists. Exclusion criterion #10 has been expanded to exclude a broader range 
of cardiac disease. Additionally, dose modification rules have been added for cardiac disorders 
and hypertension. The two higher dose levels (120 mg/m2 and 240 mg/m2), which exceed the 
available preclinical toxicology exposure, are removed in this amendment, based on the request 
of a Health Authority during their review of the Amended Protocol version v03. The highest 
dose level evaluated in the study will thus remain 60 mg/m2 as initially foreseen. In addition, 
the measurement of quadriceps muscle thickness by ultrasound 
 
 are removed. The data collected so far in the study 
do not support the continuation of these assessments, and this will allow reducing the burden 
on patients in the study.
At the time this amendment was written twelve patients have been treated with LMI070 in Part 
1 of the study. New information concerning the safety and pharmacokinetics in these patients 
is provided as part of this amendment.
Changes to the protocol

Protocol synopsis: changes were made in the synopsis to reflect all changes throughout the 
protocol as outlined below.

Introduction-Section 1.1.1.1 has been updated with additional available preclinical
information.

Introduction-Section 1.1.1.4 and Section 1.1.1.5 have been updated to include preliminary 
information from the 12 patients enrolled in Part 1 of the study at time of this amendment.

Section 2.1: addition of echocardiographic evaluation as an endpoint for Primary 
Objectives

Section 2.2: Removal of the secondary objective meant to evaluate the effect of LMI070 
on muscle by ultrasound.
 
 
 


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
Study design – Figure 3-1 Part 1 study design: the 2 highest dose levels of 120 mg/m2 and 
240 mg/m2 have been removed based upon the request of a Health Authority during their 
review of the Amended Protocol version v03. Subsequent sections of the protocol have been 
updated to remove reference to these two higher dose levels (e.g. Table 6-1), and the 
protocol now refers to ‘up to 5 cohorts’ instead of ‘up to 7 cohorts’.

Section 3.6: the benefit/risk assessment has been updated with the most recent information 
from non-clinical chronic toxicology studies and from the CLMI070X2201 clinical study.

Section 4.2: exclusion criterion #10 was clarified in order to exclude patients with cardiac 
and/or vascular abnormalities. This modification is done based on the request from a Health 
Authority following their review of the USM.

Section 6.7 - Table 6-5 Criteria for interruption and re-initiation of LMI070 treatment has 
been updated to include specific recommendations for dose modifications in the event of 
cardiac disorders or hypertension. This modification is done based on the request from a 
Health Authority following their review of the USM.

Table 8-1 and Table 8-3: addition of echocardiographic examination at 1 and 2 months 
during the initial treatment period, in order to reflect the measures described in the USM. 
Removal of the ultrasound assessment 

Table 8-2: addition of monthly echocardiographic examination in the event of a Grade 2 
systolic function Adverse Event (AE). The assessments not performed during the extended 
treatment period have been removed, the footnotes updated accordingly and a mistake in 
the visit numbers has been corrected. Removal of the ultrasound assessment 
 

Section 8.3.1: Removal the section describing the determination of muscle thickness by 
ultrasound.

Section 8.4.5: addition of the QTcB in the list of parameters to be collected when an ECG 
is performed. The QTcB, which is more accurate at high heart rates will be used from now 
on for clinical decision instead of QTcF.


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
Section 14: references listed in the Risks and Benefits section have been added and the 
references mentioned in the section describing the ultrasound assessment have been 
removed.
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. Please note that the cardiac monitoring changes as described are already in 
effect as communicated by the Urgent Safety Measure notification. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.


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Amendment 03 (November 2015)
Amendment rationale
The main purpose of this amendment is to implement additional safety measures. First, 
ophthalmologic monitoring was added as part of the safety monitoring plan. This measure was 
already implemented at clinical sites in all countries, due to an immediate implementation 
request generated by a Health Authority following their review of newly available preclinical 
data. In addition, this amendment is also implementing requests for modification from the 
independent Data Monitoring Committee (DMC) following their review of the clinical safety 
data so far. Furthermore, based on feedback from site investigators and patient guardians, the 
measure of infant respiratory function (cry vital capacity) is considered too burdensome for 
many patients and therefore is no longer a required evaluation of the study and becomes an 
optional assessment. A different and much less burdensome assessment to evaluate respiratory 
function, measurement of chest circumference during quiet breathing, has been added. Also the 
requirement for parents/guardians to wear gloves during 48h after each administration has been 
removed since a toxicological safety assessment on accidental dermal exposure indicated that 
the calculated maximum systemic exposure following an accidental spill of LMI070 solution 
onto the skin is not considered to present an undue health risk to the caregiver. Finally, two 
dose levels are added since at the time of this amendment the MTD has not yet been reached. 
Moreover preliminary PK results obtained up to the 48 mg/m2 dose level indicate the need to 
further evaluate the dose proportionality. This amendment thus plans to increase the total 
number of patients to be enrolled in Part 1 of the study up to approximately 30 in order to also 
include additional patients who may present in order not to delay their treatment.
At the time this amendment was written nine patients have been treated with LMI070 in Part 1 
of the study. New information concerning the safety and pharmacokinetics in these patients is 
provided as part of this amendment.
Changes to the protocol

List of abbreviations: The list was updated and some abbreviations were added. 

Protocol synopsis

Introduction – Section 1.1: the genetic background of SMA patients has been re-worded to 
increase clarity and the mechanism of action of LMI070 has been specified since it has been 
elucidated and published. 

Introduction – Section 1.1.1.1: the effect of LMI070 on the SMN protein level observed in 
mice has been re-worded to increase clarity. The preliminary observations from the ongoing 
26-week juvenile rat including ophthalmologic examination findings have been added as 
well.

Introduction – Section 1.1.1.4 and Section 1.1.1.5 have been updated to include preliminary 
information from the 10 patients enrolled as of today in Part 1 of the study.

Section 2.1. Addition of ophthalmologic monitoring as an endpoint for Primary Objectives 

Section 2.2 Secondary objectives: the respiratory function endpoints have been modified to 
indicate that the cry vital capacity is now an optional assessment and to include the 


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measurement of chest circumference during quiet breathing instead since this is a 
non-invasive and another way to quantify the degree of respiratory muscle impairment. 
These changes are also reflected in Section 8.4.7 and in the different assessment schedules 
(Table 8-1 Assessment Schedule – Part 1 – Initial treatment period (Day -14 to Day 85) ; 
Table 8-2 Assessment Schedule –
Part 1 –
Extended treatment period
; 
Table 8-3 Assessment Schedule – Part 2)

Section 3.1, Section 4 and Section 8.2.1: clarification on the number of SMN2 gene copies 
needed for eligibility in the study, which must be exactly 2.

Section 3.1.1 and Section 4: the number of patients to be enrolled in study Part 1 had been 
increased and the study design figure has been updated with the 2 additional provisional 
dose levels.

Section 3.1.1, Section 3.1.2 and Section 5.3: clarification on the guidance to be followed for 
the implementation of reflux precautions post-dosing.

Section 3.1.1 – A recommendation for patients to stay within less than 120 minutes by 
ground transportation of the site for the time interval between signing the Informed Consent 
Form (ICF) and the end of the DLT (Dose Limiting Toxicity) period has been added.

Section 3.1.2: clarification that data from chronic juvenile toxicity studies available at the 
time of initiation of Part 2 will be taken into account for determination of the dosing 
regimens to be tested in Part 2.

Section 3.2 the sentence explaining the rationale for including infants between 1 and 
7 months has been re-written to increase clarity. Also the description of Part 2 dosing 
regimen has been corrected. Finally clarification has been added on the possibility for 
patients to continue receiving treatment beyond the initial treatment period.

Section 3.3 and Table 6-1: Clarification that the dose escalation is guided by the Bayesian 
logistic regression model (BLRM) with escalation with overdose control (EWOC) principle. 
The maximum dose level has been increased and the rationale for this change has been 
indicated.

Section 3.5: clarification of the conditions for enabling or not to proceed to Part 2 as well 
as the criteria to stop dose escalation.  

Section 3.6: removal of a sentence repeated twice, addition of preclinical retinal findings 
and the rationale for the ophthalmologic monitoring.

Section 4.1: re-wording of inclusion criterion #2 and criterion #8 to clarify the language


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
Section 4.2: Re-wording of exclusion criterion #2 to clarify the language. 

Laboratory measurement values to define anemia, leukopenia and thrombocytopenia have 
been added in exclusion criterion #3 to have cut-off for these parameters adapted to the 
values observed in the pediatric population. In addition neutropenia has been added to 
exclusion criterion #3. Likewise numeric values for defining hepatic dysfunction have been 
added in exclusion criterion #4. These changes were requested by the independent Data 
Monitoring Committee.

The formula to be used for the calculation of the renal function in infants has been specified 
in exclusion criterion #5 to ensure homogeneity of this evaluation at sites in a multi-center 
setting. The supportive reference has been added in Section 14. The Heilbronn formula 
initially indicated for the calculation of the body surface area has been removed since it is 
widely known and to increase clarity.

Clarification of exclusion criterion #8 to indicate that either persistent hypoxemia or 
presence of a tracheostomy would lead to ineligibility of a patient as they are considered 
too advanced in their disease to participate in the study.

Addition of changes in hematologic parameters or gastrointestinal dysfunction not 
otherwise specified in exclusion criterion #13 that may also pose a safety risk since LMI070 
has cell cycle arrest properties that would increase the risk of such events.

Section 5.4: Removed requirements for the use of gloves during handling of bodily fluids 
after dosing.

Section 6.2: Clarification that only one strength of LMI070 is provided as well as 
modification of the storage temperature of the variant to be used from now on.

Section 6.3–Table 6-1 had been updated with the 2 additional provisional dose levels to be 
evaluated in Part 1.

Section 6.5.2: the number of patients per cohort for dose levels ≥ 48 mg/m2 has been 
increased and a clarification on inclusion of additional patients has been included.

Section 6.5.4: language corrected to increase clarity in the event of intra-patient dose 
escalation.

Table 6-4: update of some criteria for defining dose-limiting toxicities during dose 
escalation to account for differences in typical management of these events in infants 

Section 7.1: clarification of the study treatment discontinuation rules to specify time interval 
for measurement and define extent of disease progression.

The original Assessment Schedule has been sub-divided in Table 8-1 and Table 8-2 to 
distinguish the assessments to be conducted during the initial treatment period (Day -14 up 
to Day 85) or during the extended treatment period since the number of evaluations have slightly 
decreased for the extended treatment period. Where reference was made to the Assessment 
Schedule it has been changed to the appropriate table throughout the document.

Table 8-1, Table 8-2, Table 8-3: Addition of a time point for the 
 
 and mRNA blood collection at the end of each 
treatment period.

Table 8-2: Removal of blood samples for PK analysis on Day 3 and Day 5 during the 
extended treatment period since a lighter PK profile is acceptable. As a consequence Day 5 


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visit could be removed as well to reduce burden for the patients while keeping a close safety 
monitoring in place.

Section 8.3.1: clarification that the CHOP INTEND test allows measurement of the strength 
as well.
.

Section 8.4.2: clarification of the Blood Pressure measurements to be done by an 
oscillometric method. The supporting reference has been added in Section 14.

Section 8.4.4: the reticulocyte count has been added to the existing measurements performed 
for the hematology sample to monitor for cell cycle arrest. The absolute neutrophil count 
calculation to be done has been added as well. Platelet volume has been added to better 
understand the impact of elevated platelet counts seen in the study on blood SMN 
pharmacodynamics measures as described in Section 1.1.1.4. Bicarbonate and high 
sensitivity C - reactive protein (CRP) are added to the existing measurements performed for 
the chemistry sample. No extra blood draw is necessary for any of these measurements.

Section 8.4.5: clarification added regarding the calculation of the QTcF. 

Section 8.4.6: has been created to add echocardiogram as a new safety monitoring required 
following occurrence of a SUSAR in one patient enrolled in the study.

Section 8.4.8: has been created to describe the ophthalmologic monitoring required by a 
Health Authority and previously implemented as an Urgent Safety Measure submitted to 
Health Authorities. This monitoring has also been added as an endpoint in Section 2.1
Primary Objective as well as in the different assessment schedules (Table 8-1 Assessment 
Schedule – Part 1 - Initial treatment period; Table 8-2 Assessment Schedule – Part 1 –
Extended treatment period; Table 8-3 Assessment Schedule – Part 2).
 
 
 

Section 11.6.1: the number of patients to be included in each upcoming cohort of study Part 
1 has been clarified.

The Blood Logs (previously in the Appendix 2) have been removed from the Protocol since 
they are already present in the Site Operations Manual document. 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. Please note that the ophthalmologic monitoring as described are changes 
already in effect triggered by requirements from a Health Authority, as communicated by the 
Urgent Safety Measure notification. 


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The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 
Amendment 02 (February 2015)
Amendment rationale
The purpose of this amendment is to address the requests from the European health authorities 
during their review for clinical trial authorization in Europe. The amendment provides 
clarification about the exclusion criteria, the dose limiting toxicities and the provisional dose 
levels. This amendment also corrects minor errors that are considered non-substantial. At the 
time this amendment was written the study was not open for enrollment.
Changes to the protocol

Protocol synopsis and Section 4.2: Clarification of exclusion criteria #3 and #4 to change 
the excluded values to grades from CTCAE.

Protocol synopsis and Section 4.2: Clarification of exclusion criterion #5 to revise the 
excluded eGFR ranges to be appropriate for the pediatric target population as well as to 
specify which formula to use for the eGFR calculation. 

Protocol synopsis and Section 4.1; Clarification of inclusion criterion #6 to indicate that the 
tube should be placed for dosing LMI070 but could be removed between doses.

Replacement of the assessment schedule in Section 3.1.1 with a study design figure to better 
explain the study flow. Moreover the assessment schedule is already present in Table 8-1. 

Indication of the days on which the study visits are scheduled both for Part 1 in Section 3.1.1
and for Part 2 in Section 3.1.2.

Clarification in Section 3.1.2 of the different study visits and the assessments scheduled. 
Update of the provisional dose levels in Table 6-1 to show one possible dose escalation 
trajectory where the highest dose level equals the top dose 60 mg/ m2.Revision of the dose 
limiting toxicity (DLT) criteria (Table 6-4) based on the patient population and on 
observations in preclinical data and based on recommendations from the external 
Data Monitoring Committee. These changes were based on realization that the earlier 
criteria were extremely unlikely to occur with present day standard of care (platelet and red 
blood cell transfusion, use of rescue growth factors, etc.) These changes were also made to 
standardize the DLT criteria across this multi-centre study as there are some small 
differences between countries and centres in their approach.

Revision of the criteria for interruption and re-initiation of LMI070 treatment (Table 6-5) 
based on the revision of the DLT criteria and removal of the values to standardize the criteria.

Clarification of when the End of study visit should be conducted in Section 3.1, in the study 
design 
figure 
(Figure 
3-2-Section 
3.1.2), 
in 
Section 
7.2, 
in 
the 
Table 8-1 Assessment Schedule-Part 1 and Table 8-3 Assessment Schedule-Part 2.


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
Correction of the Visit Numbers, clarification of the inclusion/exclusion criteria check that 
needs to be done at Baseline, and removal of the optional DNA collection in the 
Table 8-3 Assessment Schedule-Part 2 and in Appendix 2-Blood Logs Part 2.

Removal of the reference made to the therapeutic misconduct in Section 8.1 since not 
relevant as part of the protocol.

For the Bayesian analysis plan, changes to the reference dose from 14 mg/ m2 to 40 mg/ m2
in Section 11.4.2, and to one statistical prior parameter in Table 15-1 to update the non-
informative prior that will be used. The new prior suits the dose range 6 mg/ m2 to 60 mg/ 
m2 better while it remains non-informative and conservative. Table 15-2 was updated to 
reflect the new prior. 

Addition of a new reference in Section 14 to support the use of the formula for the 
calculation of the eGFR. Changes to specific sections of the protocol are shown in the track 
changes version of the protocol using strike through red font for deletions and red underlined 
for insertions.
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.


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Amendment 01 (November 2014)
Amendment rationale
The purpose of this amendment is to address the requests from a European health authority 
during the request for clinical trial authorization in Europe. The amendment provides 
clarification about the phases of the study, the sequential enrollment of patients into the cohorts 
and the safety monitoring of the patients after they receive their first dose of study drug. This 
amendment also corrects minor typographical errors that are considered non-substantial. At the 
time this amendment was written the study was not open.
Changes to the protocol
Correction of the study phase from Phase II to Phase I/II. Phase I for part 1 of the study and 
Phase II for part 2 of the study which has been corrected through-out the document.
Additional information provided on the relationship between aneuploidy and carcinogenesis in 
Section 1.1.1.2
Clarification that continued observation in the study unit beyond 24 hours after the first dose is 
at the discretion of the investigator given the nature and severity of the disease. This has been 
corrected throughout the document.
 
Clarification that patient treatment will be sequential and will allow at least 24 hours between 
the treatment of 2 patients at any one dose level for the first dose. This has been corrected 
throughout the document.
Clarification that more than 2 patients could be enrolled into a cohort to prevent a patient
waiting for the next cohort due to the life threatening nature of the disease.
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.


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Protocol summary
Protocol number
CLMI070X2201
Full Title
An open-label multi-part first-in-human study of oral LMI070 in infants with 
Type 1 spinal muscular atrophy
Brief title
An open-label study of branaplam (LMI070) in Type 1 spinal muscular 
atrophy (SMA)
Sponsor and Clinical 
Phase
Novartis 
Phase I (Part 1)/ Phase II (Part 2)/ Phase II (Part 3)
Investigation type
Drug
Study type
Interventional
Purpose and 
rationale
The purpose of this study is to evaluate the safety, tolerability, 
pharmacokinetics (PK), pharmacodynamics (PD) and efficacy; and to 
estimate the Maximum Tolerated Dose (MTD) and optimal dosing regimen 
of orally administered branaplam in patients with Type 1 SMA.
Primary Objective(s)
Part 1
To determine the safety and tolerability of ascending weekly doses and 
estimate the MTD of oral/enteral branaplam in infants with Type 1 SMA
Part 2
To evaluate the long-term safety and tolerability of 2 doses of oral/enteral 
branaplam administered weekly for 52 weeks in patients with Type 1 SMA
Part 3
To assess long term safety and tolerability of extended oral/enteral, once a 
week branaplam treatment in patients with type 1 SMA who have had at 
least 52 weeks of treatment in either Part 1 or 2 study of this protocol
Secondary 
Objectives
Part 1, Part 2, Part 3

To evaluate branaplam pharmacokinetics in plasma after single 
and repeated doses of branaplam

To evaluate the effect of branaplam on growth parameters

To evaluate the effect of branaplam on respiratory function

To evaluate the effect of branaplam on infant motor development
Part 2 (in addition to the above)

To evaluate the efficacy of branaplam on motor and developmental 
milestones

To evaluate the efficacy of branaplam on the ability to sit without 
support 
Part 3 (in addition to the above)

To assess the proportion of infants who are alive and are without 
permanent ventilation over time  

To assess the impact of treatment with branaplam on time-to-event 
(death, permanent ventilation)
Study design
This is a phase I/II, open-label, multi-part, first-in-human proof of concept 
study in infants with Type 1 spinal muscular atrophy, to evaluate safety, 
tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of 
orally administered branaplam.
Enrollment to this study is restricted to patients with Type 1 SMA with 2 
copies of the survival of motor neuron 2 (SMN2) gene. 


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In Part 1 of the study patients will be dosed once weekly with branaplam 
until MTD is determined or when sufficient PK results confirm that the MTD 
cannot be reached due to a potential pharmacokinetic exposure plateau at 
higher doses. A Bayesian logistic regression model (BLRM) with escalation 
overdose control (EWOC) will be used to determine the dose levels used 
for each dose escalation. The decision to dose escalate the next cohort will 
be made after safety data have been collected for 14 days following the first 
dose (14-day DLT window). PK will be used to confirm wash-out of 
branaplam to avoid accumulation of the compound and to improve 
understanding of the metabolic pathways of degradation and clearance of 
branaplam due to maturation of the CYP system. The data will be used to 
further develop the PK model. If PK data show the potential for 
accumulation, the dosing frequency may be decreased; For Part 1, patients 
completing 13 weeks of treatment (12 doses) will be considered to have 
completed the study. Patients who completed at least 52 weeks of 
treatment may continue treatment in Part 3 if in the best interests of the 
patient, as assessed by the investigator.
In Part 2 of the study, new patients will be enrolled and will participate for 
52 weeks to assess efficacy and safety of branaplam. Patients will be 
dosed once weekly with branaplam. The decision for starting the next dose 
level cohort will be made after safety and efficacy data have been collected 
for at least 3 patients treated for 13 weeks following the first dose. Patients 
completing 52 weeks of treatment will be considered to have completed the 
study. However, they may continue treatment in part 3 of the protocol, if 
further treatment is in the best interest of the patient.
Part 3 of the study is long term safety and efficacy follow up of extended 
oral/enteral, once a week branaplam treatment. All patients who 
participated in Part 1 and Part 2 of the study and have completed at least 
52 weeks of treatment, or more can continue receiving treatment with 
branaplam in Part 3 of the study.  
Population
The study population will be comprised of infants with Type 1 SMA with 2 
SMN2 gene copy numbers, aged approximately 1 to 7 months in Part 1 and 
up to 180 days of age at screening in Part 2. A total of 13 patients have 
been treated in Part 1 and 25 patients have been treated in Part 2. All 
patients from Part 1 and Part 2 of the study who completed at least 52 
weeks of treatment or more are continuing receiving treatment in the Part 3 
of the study
Inclusion criteria
Part 1
1.
Written informed consent must be obtained from the parent / 
guardian before any assessment is performed.
2.
Type 1 SMA, diagnosed clinically, with symptom onset <6 months 
of age and genetic confirmation of mutations in both alleles of the 
survival of motor neuron 1 (SMN1) gene, and with SMN2 copy 
number of 2.
3.
Best supportive care in place and stable for at least 14 days before 
screening.
4.
Age at screening between 1 and 7 months.
5.
Must be able to demonstrate antigravity strength in both biceps.
6.
Must have or agree to have placement of feeding tube for enteral 
access via nasogastric (NG), nasojejunal (NJ), percutaneous 
gastrostomy (PEG), or percutaneous jejunostomy (PEJ) tube for 


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dosing LMI070 (Part 1 only and for patients who cannot be 
administered orally; tube may be removed between doses).
7.
Medical care meets and is expected to continue to meet guidelines 
set out in the Consensus Statement for Standard of Care in SMA 
(Wang et al 2007), in the opinion of the Site Investigator
8.
At birth gestational age >32 weeks and body weight at birth >2 kg
9.
Must live within 2 hours drive of study center. Clearance should be 
obtained from the site investigator and sponsor if the patient 
resides more than 2 hours ground travel from the study center.
10. Able to complete all study procedures, measurements and visits; 
and parent or guardian/patient has adequately supportive 
psychosocial circumstances, in the opinion of the Site Investigator.
Part 2
1.
Written informed consent must be obtained from the parent / 
guardian before any assessment is performed.
2.
Type 1 SMA, diagnosed with genetic confirmation of mutations in 
both alleles of the SMN1 gene, and with SMN2 copy number of 2.
3.
Best supportive care in place and stable for at least 14 days before 
screening as assessed by the investigator.
4.
Age at screening up to 180 days of age.
5.
Must be able to demonstrate antigravity strength in both biceps.
6.
Must have or agree to have placement of feeding tube for enteral 
access via nasogastric (NG), nasojejunal (NJ), percutaneous 
gastrostomy (PEG), or percutaneous jejunostomy (PEJ) tube for 
dosing branaplam (required for the first administration only, and 
subsequently only for patients who cannot be dosed orally; tube 
may be removed between doses).
7.
Minimum CHOP INTEND score of 15 at baseline
8.
Must be able to swallow solid and liquid even if tube feeding is 
used to support nutrition intake and must be the 5th percentile for 
length or weight on the international growth curves and must be 
proportional in height and weight  
9.
At birth gestational age >32 weeks and body weight at birth >2 kg
10. Able to complete all study procedures, measurements and visits; 
and parent or guardian/patient has adequately supportive 
psychosocial circumstances, in the opinion of the Site Investigator.
Part 3
1.
Written informed consent must be obtained from the parent / 
guardian
2.
Current participation in Part 1 or Part 2 of the study protocol and 
completion of at least 52 weeks of treatment with branaplam
3.
Further treatment with branaplam is in the best interest of the 
patient as assessed by the Site Investigator
4.
Able to complete all study procedures, measurements and visits; 
and parent or guardian/patient has adequately supportive 
psychosocial circumstances, in the opinion of the Site Investigator
Exclusion criteria
Part 1
1.
Use of other investigational drugs within 14 days
2.
Neurologic or neuromuscular conditions other than SMA.
3.
Anemia (Hgb < 9.5 gm/dl ; <5.9 mmol/L), leukopenia (CTCAE 
Grade 2 or higher, <3000 /mm3; <3.0 x109/L), neutropenia (Grade 2 
or higher, <1,500/mm3; < 1.5 X 109/L) or thrombocytopenia 
(CTCAE Grade 2 or higher, ≤ 75,000/mm3), ≤75 X 109/L 


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4.
Hepatic dysfunction (AST or ALT CTCAE Grade 1 or higher, ≥ 
Upper Limit of Normal (ULN)); total bilirubin CTCAE Grade 1 or 
higher, ≥ ULN).
5.
Age adjusted renal dysfunction with eGFR calculated using the 
following formula:
eGFR (in mL/min/1.73 m2) = 0.45 X Length (cm) ÷ serum creatinine 
(mg/dl) (Schwartz and Work 2009), 
-
≤ 26 mL/min/1.73 m2 up to age 28 days of age
-
≤ 30 mL/min/1.73 m2 for 1 to 3 months of age
-
≤ 40 mL/min/1.73 m2 for 3 to 6 months of age
-
≤ 50 mL/min/1.73 m2 for 6 to 12 months of age
6.
Clinically significant abnormalities in hematology or clinical 
chemistry parameters, as assessed by the Site Investigator, at 
screening that would render the patient unsuitable for inclusion
7.
Intractable seizure disorder (other than inactive febrile seizures).
8.
Persistent (in the opinion of the Investigator) hypoxemia (O2 
saturation awake <92% or O2 saturation asleep <91%, without 
ventilation support) or requiring oral suctioning >2 per day, or 
presence of a tracheostomy.
9.
Presence of an untreated or inadequately treated active infection 
requiring systemic antiviral or antimicrobial therapy at any time 
during the screening period.
10. Current diagnosis of cardiac and/or vascular abnormalities 
including uncontrolled hypertension, intolerance of blood pressure 
and pulse assessment techniques such that consistent normal 
values cannot be measured, echocardiographic abnormalities (both 
structural and function) or ECG abnormalities (such as long QT, 
heart block or Torsade’s) indicating significant risk of safety for 
infant patients participating in the study such as: Concomitant 
clinically significant pediatric cardiac arrhythmias, e.g. sustained 
ventricular tachycardia, and clinically significant second or third 
degree AV block
11. Prohibited Concomitant Medications used to treat SMA, including 
but not exclusively: oral albuterol or oral salbutamol, hydroxurea, 
riluzole, valproate, carnitine, creatine, sodium phenylbutyrate within 
14 days prior to enrollment or during the study
12. Excluding SMA, any medically unstable condition including 
cardiomyopathy, hepatic dysfunction, kidney disorder, endocrine 
disorder, GI disorders, metabolic disorders, severe respiratory 
compromise and significant brain abnormalities or injuries including 
hypoxic-ischemic encephalopathy.
13. Acute or ongoing medical condition that, according to the Site 
Investigator and discussed with sponsor, would interfere with the 
conduct and assessments of the study. Examples are medical 
disability other than SMA that would interfere with the assessment 
of safety or would compromise the ability of the patient to undergo 
study procedures including be assessed by CHOP INTEND infant 
motor scale, changes in hematologic parameters or gastrointestinal 
dysfunction that would compromise the ability of adequate 
assessment of safety
Part 2
1.
Use of gene transfer at any time or other investigational drugs 
within 14 days


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2.
Patients who have received nusinersen at any time prior to 
screening
3.
Neurologic or neuromuscular conditions other than SMA. 
4.
Anemia (CTCAE grade 2 of higher Hgb < 1.0 g/dl ; <6.2 mmol/L); 
leukopenia (CTCAE Grade 2 or higher, <3000 /mm3 ; <3.0 x109/L), 
neutropenia (Grade 2 or higher, <1,500/mm3; < 1.5 X 109/L) or 
thrombocytopenia (CTCAE Grade 2 or higher, ≤ 75,000/mm3), ≤75 
X 109/L
5.
Hepatic dysfunction (AST or ALT CTCAE Grade 1 or higher, ≥ 
ULN); total bilirubin CTCAE Grade 1 or higher, ≥ ULN).
6.
Age adjusted renal dysfunction with eGFR calculated using the 
following formula: eGFR (in mL/min/1.73 m2) = 0.45 X Length (cm) 
÷ serum creatinine (mg/dl) (Schwartz and Work 2009), ≤ 26 
mL/min/1.73 m2 up to age 28 days of age ≤ 30 mL/min/1.73 m2 for 
1 to 3 months of age ≤ 40 mL/min/1.73 m2 for 3 to 6 months of age 
≤ 50 mL/min/1.73 m2 for 6 to12 months of age
7.
Clinically significant abnormalities in hematology or clinical 
chemistry parameters, as assessed by the Site Investigator, at 
screening that would render the patient unsuitable for inclusion
8.
Intractable epilepsy
9.
Persistent (in the opinion of the Investigator) hypoxemia 
(O2 saturation awake <92% or O2 saturation asleep <91%, without 
ventilation support).
10. Presence of an untreated or inadequately treated active infection 
requiring systemic antiviral or antimicrobial therapy at any time 
during the screening period.
11. Current diagnosis of cardiac and/or vascular abnormalities 
including uncontrolled hypertension, intolerance of blood pressure 
and pulse assessment techniques such that consistent normal 
values cannot be measured, echocardiographic abnormalities (both 
structural and function) or ECG abnormalities (such as long QT, heart 
block or Torsade’s) indicating significant risk of safety for infant patients 
participating in the study such as: Concomitant clinically significant 
pediatric cardiac arrhythmias, e.g. sustained ventricular tachycardia, and 
clinically significant second or third degree AV block. Clinically significant 
findings identified by an echocardiogram performed at screening
12. Prohibited Concomitant Medications used to treat SMA: oral 
albuterol or oral salbutamol, hydroxyurea, riluzole, valproate, 
carnitine, creatine, sodium phenylbutyrate within 14 days prior to 
enrollment or during the study
13. Excluding SMA, any medically unstable condition including 
cardiomyopathy, hepatic dysfunction, kidney disorder, endocrine 
disorder, GI disorders, prematurity of <32 weeks gestation, 
metabolic disorders, severe respiratory compromise and significant 
brain abnormalities or injuries including hypoxic-ischemic 
encephalopathy.
14. Acute or ongoing medical condition that, according to the Site 
Investigator and discussed with sponsor, would interfere with the 
conduct and assessments of the study. Examples are medical 
disability other than SMA that would interfere with the assessment 
of safety or would compromise the ability of the patient to undergo 
study procedures including be assessed by CHOP INTEND infant 
motor scale, changes in hematologic parameters or gastrointestinal 


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dysfunction that would compromise the ability of adequate 
assessment of safety
Part 3
There are no specific exclusion criteria for part 3 study
Study treatment
Branaplam
Efficacy assessments

CHOP INTEND infant motor scale (only for patients up to an age of 
36 months)

Physical examination including assessment of oral feeding, head 
control, rolling, sitting up, respiratory function

Hammersmith Infant Neurologic Examination (HINE) (Including 
Independent sitting, standing and walking)

Time to death or permanent ventilation from enrollment 
Safety assessments

Physical exam

Vital signs

Body length, weight, head circumference and respiratory function

ECG and echocardiographic evaluation

Safety laboratory parameters

Neurologic examination

Nerve conduction study (CMAP, SNAP, NCV)

Ophthalmologic examination

Adverse events (AE) 
Other assessments
 
PK, and speech and motor 
performance
Data analysis
The Safety Analysis Set (SAF) will consist of all patients in the Enrolled Set 
who received at least one dose of study drug and have at least one valid 
post-baseline safety assessment.
Part 1 only: The dose determining set (DDS) consists of all patients from 
the safety set who have sufficient safety evaluations to provide DLT 
information 2 weeks after the first dosing or discontinue earlier due to DLT. 
Patients who do not experience DLT during the first 2 weeks after the first 
dose are considered to have sufficient safety evaluations if they are 
considered by both the Sponsor and Investigators to have sufficient safety 
data to conclude that a DLT did not occur. An adaptive Bayesian logistic 
regression model (BLRM) guided by the escalation with overdose control 
principle (EWOC) will be used to determine MTD during the dose 
escalation phase of the study.
Part 1 and Part 2: the PK analysis set will include all patients who received 
at least one dose of LMI070 with available PK data and no protocol 
deviations with relevant impact on PK data.
The PD analysis set will include all patients who received at least one dose 
of LMI070 with available PD data and no protocol deviations with relevant 
impact on PD data.
The sample size for Part 1 is driven by feasibility. In Part 1, cohorts of at 
least 2 patients will be dosed until a decision is made for MTD. However, 
adjustment of cohort size might be considered due to enrollment and safety 
consideration. At least 2 patients are required for cohort 1 at the starting 
dose. Size of later cohorts maybe adjusted based on feasibility. In Part 2,


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25 patients were enrolled to evaluate up to 2 different dose cohorts with at 
a minimum of 6 patients and a maximum of 10 patients per cohort. 
The driver of the sample size in part 2 is the primary objective, safety. With 
the current sample size, we are able with 95% confidence to rule out that 
the true incidence rate exceeds 50% of any class of adverse events if none 
in that class are observed in 6 patients, 
An interim analysis was performed after MTD determination in Part 1 to 
evaluate PD effects of the treatment. Data on growth measurements, 
respiratory function assessments and CHOP INTEND infant motor scale 
will be summarized at different time points and compared to baseline. 
Additional interim analyses may be conducted to support decision making 
concerning the current clinical study, the sponsor’s clinical development 
projects in general or in case of any safety concerns.
Part 3
Sample size of part 3 will depend on the number of ongoing patients in Part 
1 and Part 2 of the study protocol. Only patients who have participated in at 
least 52 weeks of treatment in either Part 1 or Part 2 are eligible to enroll in 
Part 3 Period. Additional interim analyses may be conducted to support 
decision making concerning the current clinical study, the sponsor’s clinical 
development projects in general or in case of any safety concerns. Internal 
analysis of Part 2 will be conducted once all Part 2 patients completed 52 
weeks of treatment. After all patients have transitioned from Part 1 and 2 of 
the study in the Part 3, additional interim analysis might be conducted 
Key words
Type 1 Spinal Muscular Atrophy


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1
Introduction
1.1
Background
Type I SMA (Spinal Muscular Atrophy) is a fatal disease of infants who are deficient in SMN 
(Survival Motor Neuron), a key survival protein for alpha motor neurons in the spinal cord. 
Oral branaplam has been shown to systemically increase SMN production in animal models 
and prolongs survival of a most severe mouse model bearing the SMA mutation. In addition, 
an oral single dose of branaplam in preclinical models has shown upregulation of SMN protein 
in the spinal cord for up to 7 days. However, because it has potential toxicity (aneuploidy and 
cell cycle arrest) at high doses, it is being introduced into human use in infant patients who may 
benefit most from it despite the risks. The known risks (marrow suppression and GI 
disturbances) are monitorable, manageable and reversible; based on preclinical studies, toxicity 
can be controlled or can be mitigated by intermittent dosing. 
In patients with spinal muscular atrophy (SMA), bi-allelic loss of function mutations of the 
SMN1 (Survival Motor Neuron 1) gene, leads to all SMN protein being produced by the 
inefficiently spliced SMN2 gene with loss of exon 7 (Figure 1-1). Up to 90% of the protein 
resulting from the SMN2 gene is truncated and unstable, resulting in a marked deficiency of 
SMN protein which in turn leads to premature cell death (apoptosis) of alpha motor neurons in 
the spinal cord. In type I SMA, the onset of symptoms for affected infants is in the first 6 months 
of life. This inappropriate and accelerated motor neuron cell death leads to muscle weakness 
and ultimately respiratory failure, paralysis, and death. The majority of patients with Type 1 
SMA die by age of 22 months unless they receive mechanical feeding and ventilation supportive 
care, which can prolong life but does not reverse the loss of skeletal muscle function. Thus, 
infants with Type 1 SMA have the most to gain by a potential SMN splice modulator such as 
branaplam. As the neuromuscular system develops from birth throughout infancy, the survival 
of alpha-motor neurons of the spinal cord is crucial for the normal development of infants’ 
motor skills. 
Branaplam modulates SMN2 splicing and increases generation of full length SMN2 mRNA and 
functional SMN protein by stabilization of the transient double-strand RNA structure formed 
by the SMN2 pre-mRNA and the U1 small nuclear ribonucleic protein (snRNP) complex due 
to sequence selective increased binding affinity of U1 snRNP to the 5′ splice site of SMN2 
(Palacino et al 2015). In humans it is postulated that splice modulation of SMN2 by branaplam 
will result in more full length SMN protein, leading to improved motor neuron survival, 
neuromuscular junction formation and motor unit development, which will facilitate muscle 
growth, motor gains and motor milestones, and lead to improved respiratory function and longer 
survival without ventilator dependence in SMA patients. 


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Figure 1-1
Branaplam modulates survival motor neuron 2 (SMN2) gene splicing 
and increases generation of full length SMN2 mRNA, leading to 
increased functional SMN protein
1.1.1
Relevant data summary
Preclinical data
Preclinical pharmacodynamics and efficacy
The pharmacodynamics of branaplam were assessed in in vitro and in vivo studies with 2 SMA 
mouse models, a severe neonatal efficacy model called the SMNDelta7 or hereon referred to as 
Delta7 mouse model (that phenotypically resembles clinical picture of Type I SMA) and a 
Pharmacodynamic (PD) model called the C/+ SMA mouse model. The C/+ model is a mild 
SMA mouse model in adult mouse which harbors a humanized exon 7 and 8 and a 42 kb 
fragment of human SMN2. These mice do not display an overt phenotype and show life 
expectancy matching that seen in normal wild type mice. This model offers an in vivo model to 
elucidate PK/PD effects of SMN2 splicing modulators. In all in vivo efficacy and PD studies, 
branaplam was administered orally, which is the clinical route of administration. The data 
generated support the potential for branaplam to elevate spinal cord SMN protein levels and 
based on the data, branaplam may be able to halt or slow down the debilitating disease 
progression of SMA in patients. 

Branaplam increases full length (FL)-SMN transcript and SMN protein in the brain and 
spinal cord of two SMA mouse models.

A single dose of branaplam (30 mg/kg) in the adult C/+ model results in sustained 
elevation of SMN protein levels in the spinal cord for over 160 hrs. In parallel with 
elevated brain branaplam levels above the EC50. It is unknown if the elevated protein 


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levels represent prolonged SMN half-life or new synthesis from continued splice 
modulation.

Studies 
with 
the 
Delta7 
mouse 
models 
show 
that 
subcutaneous 
plus 
intracerebroventricular (ICV) delivery of SMN2 splice modulating antisense 
oligonucleotides, achieves superior life-extension effects over ICV delivery alone 
(Hua et al 2011). Branaplam can increase SMN protein in both peripheral and CNS 
tissues in mice.

Branaplam elicits a dose-dependent (0.03-3 mg/kg) survival extension in the most 
severe neonate Delta7 mouse model. Additionally, enduring weight gain and survival 
extension were observed for up to two weeks after branaplam treatment was 
discontinued.

Data published in peer reviewed literature show that early treatments which cause an 
increase in full length SMN protein (transgenic inducible promoters, antisense 
oligonucleotides) confer the greatest survival benefit in the Delta7 mouse (Le et al 2011, 
Hua et al 2011), underscoring the importance of early treatment in SMA.
Preclinical pharmacokinetics
In adult rats and dogs, branaplam was moderately or completely absorbed. In rats there was 
some indication of first-pass elimination. Upon daily administration there was no accumulation 
of branaplam in adult animals. 
In juvenile rats, an age-related change in PK was observed, with a ~3-5 fold decrease in 
branaplam plasma AUC on postnatal day 41 compared to postnatal day 7. After continued daily 
treatment (postnatal days 97 and 186) exposure levels increased but were comparable to day 7 
values, i.e. 2-3 fold lower than the expected value if accumulation is taken into account. 
A reduction in systemic exposure with progressing age of the animals may be related to 
maturation of metabolizing enzymes and other physiological processes (e.g. hepatic blood flow). 
In juvenile dogs a similar but less pronounced decrease was observed in plasma exposure 
between postnatal day 28 and 56 (20-40% decline in AUC). These changes may be attributed 
to the maturation of drug metabolizing enzymes and/or transporters as well as tissue perfusion 
and permeability changes during growth and development in juvenile animals. Similar effects 
can be expected in humans over the first year to two years of life.
In juvenile mice and dogs, the brain to plasma exposure ratio was about 10, indicating that 
branaplam penetrated well into the brain. This is expected to decrease as a consequence of 
maturation of the blood brain barrier. As such, good central exposure is also anticipated in 
human infants, while a similar decrease in brain exposure may occur as infants grow.
The elimination of branaplam in rats occurred mainly via glucuronidation with subsequent 
excretion into feces. In vitro experiments indicated that UGT1A4, UGT1A7, and UGT1A9 were 
capable of branaplam direct glucuronidation. Experiments in human liver microsomes showed 
that CYP3A4 is the major enzyme involved in human hepatic metabolism of branaplam. 
Branaplam was also found to be a substrate of P-gp. Other transporters seem not to be involved 
in cross-membrane transport of branaplam. 


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Branaplam showed weak inhibition of CYP2C19, CYP2D6, and CYP3A4/5 (unbound IC50
values of 9.9, 19, and 21 µM, respectively) and did not inhibit transporters (BCRP, P-gp, 
OATP1B1, OATP1B3). Overall, it is thus thought that the drug-drug interaction potential with 
branaplam is low and infants with SMA type I are not expected to be on chronic polypharmacy.
Branaplam showed some inhibition of MATE1 (IC50: 5.47 μM), MATE2-K (IC50: 0.183 μM), 
OCT1 (IC50: 0.299 μM) and OCT2 (IC50: 8.92 μM). Preliminary assessment on the drug-drug 
interaction potential of branaplam indicated a potential risk for MATE2-K and OCT1 inhibition. 
At the time of the amendment 8 this information is not available in the current IB and will be 
included in the next version. 
PK/PD modeling based on animal data (C/+ mouse model) was performed to support the 
selection of the starting dose. As a PD effect, brain SMN protein levels in C/+ mice treated with 
branaplam were used. The results of the modeling suggested that the selected starting dose may 
also show minimal efficacy. 
Preclinical safety
The safety profile of branaplam was assessed in Safety Pharmacology, General Toxicity, 
Genotoxicity, Phototoxicity, and Reproductive studies. The data generated thus far support 
clinical safety and tolerability studies in SMA Type 1 patients. 

Cardiovascular safety pharmacology studies in vitro, CNS safety and respiratory safety 
studies in vivo do not raise a concern for patient safety.

Repeat dose toxicity studies in adult and juvenile rats and dogs showed that weekly dosing 
is better tolerated compared to daily dosing. In all animal species effects on the 
hematopoietic system and gastrointestinal tract were observed when daily and high dose 
levels of branaplam were administered. The exposure at the highest dose Part 1 of the 
proposed study will dose patients on a weekly basis for this reason, as well as because the 
prolonged PD effect seen in animals suggests that intermittent dosing may be efficacious in 
infants.

Observations from the 26-week juvenile rat study (daily dosing), showed findings of corneal 
opacities and retinal/choroid atrophy. The histological assessment showed minimal and 
focal atrophy of the retina near the ora serrata (the very periphery of the neurosensory retina 
where it meets the ciliary body) at all dose levels and the vehicle control. The incidence in 
rats given a high dose of branaplam was higher than in control animals. Focal retinal atrophy 
is not an uncommon microscopic observation in albino rats and is described as a congenital 
or age-related finding. No retinal changes were observed in any other toxicology studies 
conducted in mice, rats or dogs or monkeys. Liver microscopic findings were additionally 
observed in the 26-week rat study and consisted of hepatocellular necrosis and 
biliary hyperplasia. No safety margins could be established in the rat. 

Daily administration of branaplam to juvenile dogs for resulted in a minimal to mild axonal 
degeneration in the spinal cord and nerves (sciatic, peroneal, tibial and/or ulnar nerves), 
vascular proliferation and glomerulopathy in the kidney and testicular atrophy and 
degenerative changes in seminiferous tubules. No safety margin could be established in the 
dog.


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
New findings were observed in the heart and ovary in a 4-week dose range finding study in 
the wild type RasH2 mouse strain and consisted of vacuolation of cardiomyocytes and 
decrease in corpora lutea and follicles in the ovary. The pathogenesis of the cardiomyocytes 
in the wild type RasH2 mice is unknown and is currently explored in-vivo and in-vitro. The 
heart was not identified as a target organ in previous chronic animal safety studies in 
rat or dog with daily administration of branaplam. No heart findings were observed in a 6-
week monkey study with twice weekly branaplam dosing up to 6 mg/kg/dose. The exposure 
multiples for the AUCweek of the new mouse findings in the heart and ovary is 2.2-fold for 
Type 1 SMA patients (mean of male and female mice). The Cmax-based exposure multiple 
is 1.2-fold (mean of male and female mice).
Genotoxicity
Branaplam was not genotoxic in a bacterial mutagenicity assay. Micronucleus (MN) tests in 
vitro and in vivo showed an induction of increased MN frequencies. An in vitro study in human 
lymphocytes demonstrated that increased MN frequencies were a consequence of aneugenic 
(i.e., chromosome maldistribution to daughter cells) but not clastogenic (i.e., DNA breaking) 
activity of branaplam. The aneugenic effect of branaplam is likely secondary to the cellcycle
inhibiting properties of the compound and does not indicate a mutagenic potential because 
aneugenicity, unlike clastogenicity, does not damage DNA and is not propagated to subsequent 
daughter cells. In-vitro data show that branaplam can stabilize microtubulin polymerization.
The relationship between aneuploidy and carcinogenesis is complex and poorly understood. 
Moreover, it is confounded by the difference between aneuploidy and chromosomal instability, 
which is a feature of cancers caused by mutations in checkpoint genes that are known to be 
carcinogenic (Ricke and van Deursen 2013). Thus, although aneuploidy is a common 
characteristic of tumor cells, it is generally considered a consequence rather than a cause of 
tumorigenesis. Aneugenicity may be able to drive tumor growth by amplifying oncogene 
dosage or removing tumor suppressor activity. However, it is widely accepted that the 
occurrence of aneugenic cells is the consequence of cell selection during tumor growth rather 
than a causal event. A causal event may be a mutation in cell cycle checkpoint factors or other 
genes responsible for maintaining genomic integrity. The ability of aneuploidy-inducing agents 
to drive tumorigenesis remains unproven and is considered to be unrelated to tumor initiation 
(Marx 2002). 
The aneugenic effects are expected based on the stabilization of microtubulin polymerization 
and consequently, cell cycle inhibition properties of branaplam. In this context it is important 
to note that an European Center for Ecotoxicology and Toxicology of Chemicals (ECETOC) 
task force concluded that, although there is clear evidence of chemically induced aneuploidy in 
experimental systems, to date there are insufficient data to determine with certainty if 
chemically induced aneuploidy contributes to human disease (Aardema et al 1998). 
Therefore, the results of the micronucleus tests indicate that the aneugenic effect of branaplam 
is unlikely to pose a genetic or neoplastic threat to patients at therapeutic dose levels. 


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Teratogenicity and reproductive toxicity data
Embryofetal toxicity studies have been conducted with branaplam in rats and rabbits. No 
teratogenic or embryo-toxic potential was observed in the rat (NOAEL 2.5 mg/kg, estimated 
AUCweek: 5838 h*ng/mL). The safety margins are 1.4-fold or 1.7-fold (AUC-based) higher 
compared to the highest dose used Type 1 SMA patients or recently selected dose for Part 3 of 
this study (3.125 mg/kg, Table 1-1, and 2.5 mg/kg, Table 1-2, respectively). Maternal toxicity 
and embryo-fetal toxicity were observed in the rabbit preliminary Embryo Fetal Development 
(pEFD) study at high dose levels (NOAEL 1.5 mg/kg, estimated AUCweek: 9380 h*ng/mL). 
The safety margin is approximately 2.2-fold (AUC-based) higher compared to the highest dose 
in Type 1 SMA patients (nominal dose: 3.125 mg/kg, Table 1-1). 
Testicular findings (degenerative changes involving seminiferous tubules of testes and 
testicular atrophy) were observed in a 52-week (juvenile) dog study with daily dosing of 
branaplam and in a 4-week wild type RasH2 mouse study with daily dosing of branaplam. 
Testicular findings in the mouse consisted of minimal to severe atrophy/degeneration of testis 
seminiferous tubules, including germ cells. Testes findings are likely related to the known cell-
cycle effects of branaplam.
Ovary findings (decrease of corpora lutea and follicles) were also observed in the wild type 
RasH2 mouse study with daily dosing of branaplam. Ovary findings are likely related to the 
known cell-cycle effects of branaplam.
Human safety and tolerability data
At the time this protocol amendment is written 14 patients have been enrolled and 13 treated in 
the Part 1 of the study, and 25 patients have been enrolled and treated in the Part 2 of the study. 
In addition, patients from Part 1 and Part 2 of the study have all transferred to Part 3 of the 
study.
Thirteen patients aged 2-7 months were randomized to escalating weekly doses of branaplam 
(6, 12, 24, 48 and 60 mg/m2) for 13 weeks followed by an extension period, currently up to 190 
weeks in part 1 of the study. First patient was dosed in April 2015. No dose limiting toxicity 
was found at the different doses. Improvements in motor function were seen as determined by 
the CHOP-INTEND score. Discovery of axonal degeneration in dogs led to an Urgent Safety 
Measure to reduce the dose in all patients to the lowest level (6 mg/m2). Following the dose 
reduction, the patients in the study experienced a clinically apparent worsening of symptoms.
The clinical worsening associated with the dose reduction either led to or contributed to a fatal 
outcome in 5 patients. Surviving patients did not fully regain function (by CHOP-INTEND) 
despite resumption of the original dosing at 6 mg/m2.. 
In Part 1 and 3, the most commonly reported AEs were pyrexia and pneumonia followed by 
vomiting, upper respiratory tract infection and diarrhea. In Part 2 and 3, the most commonly 
reported AEs were pneumonia, followed by pyrexia and bronchitis, constipation and 
thrombocytosis.
The most common serious adverse events (SAEs) in Part 1 and 3 as seen in more than 30% of 
patients were pneumonia, atelectasis, respiratory distress, respiratory failure, and femur fracture.


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Continuation to Part 2 of the study was warranted to evaluate the longer-term safety and 
tolerability of 2 doses of 0.625 mg/kg and 2.5 mg/kg without forced escalation or reduction. Up 
to 10 patients were planned for each cohort. In total, 25 patients aged 0-6 months have been 
enrolled. The most common SAEs in Part 2 and 3 in more than 10% of patients were pneumonia, 
respiratory failure, and bronchitis.
Suspected Unexpected Serious Adverse Reactions (SUSARs) were reported in 4 patients, 2 
each in Part 1 and Part 2 of the study. There were no SUSARs reported in Part 3. The events 
consisted of PTs: left ventricular hypertrophy, sinus tachycardia, ejection fraction decreased
(reported term: decreased systolic function of left ventricle EF45%), and hypertension, 
pericardial effusion, and laryngospasm.
There continues to be no evidence of dose-limiting toxicities of branaplam. 
More detailed review of the safety events in this study are presented in the most recent 
Investigator Brochure.
Human pharmacokinetic data
In Part 1 of present study, PK parameters were investigated across all observation periods at 
actual mean doses of 0.299, 0.644, 1.30, 2.51, and 2.99 mg/kg (respective nominal doses: 6, 12, 
24, 48, and 60 mg/m2, Table 1-1). Following oral branaplam administration across all 
observation periods, median Tmax values of branaplam in plasma ranged between 2.97 to 4.00 
h. AUC and Cmax values increased with increasing dose after a single dose or across all 
observation periods. Both exposure parameters were considered to increase in an apparent dose 
proportional manner across all observation periods with a slight deviation from the upper 90% 
confidence interval for Cmax, which was considered to be clinically not relevant. Considering 
plasma profiles across all observation periods, mean apparent systemic clearance (CL/F) and 
volume of distribution (Vz/F) values were comparable across the dose levels and ranged 
between 735 and 1050 mL/h/kg and between 45600 and 63400 mL/kg, respectively. Branaplam 
concentrations decreased in plasma with mean apparent terminal elimination T1/2 values 
ranging between 37.4 h and 59.3 h. No obvious accumulation was observed in a subset of 
patients comparing exposure parameters of treatment cycle 1 and 2 after administration of same 
dose at both cycles.
Table 1-1
Systemic exposure values of branaplam across all observation 
periods - Study CLMI070X2201 Part 1
Nominal dose
Actual dose a
Arithmetic mean ± SD (%CV)
(mg/m2)
(mg/kg)
n b
Cmax (ng/mL)
n b
AUC (h·ng/mL) c
6 mg/m2
0.299 ± 0.0240
11
8.84 ± 3.58 (40.5)
10
413 ± 98.3 (23.8)
12 mg/m2
0.644 ± 0.0341
4
15.3 ± 4.10 (26.8)
4
761 ± 170 (22.3)
24 mg/m2
1.30 ± 0.0858
6
37.8 ± 12.8 (33.8)
6
1340 ± 381 (28.5)
48 mg/m2
2.51 ± 0.186
16
69.1 ± 15.7 (22.8)
11
3310 ± 850 (25.7)
60 mg/m2
2.99 ± 0.159
52
96.5 ± 32.7 (33.9)
41
4280 ± 1030 (24.2)
All values were rounded to 3 significant digits;


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a: mean ± Standard Deviation (SD); b number of PK profiles considered; please note, that a patient
provides several PK profiles to the analysis; c: AUC corresponds to the area under the plasma (or 
serum or blood) concentration-time curve from time zero to infinity [mass x time / volume] (AUCinf)
after the first dose and the area under the plasma (or serum or blood) concentration-time curve from 
time zero, which is equal to the dosing time to 168 h  [mass x time / volume] (0AUC0-168h) after 
multiple doses
Dose-normalized AUC and Cmax values across the age range from 2.5 to 58.5 months ranged 
from 595 to 2360 (h*ng/mL)/(mg/kg) and from 10.3 to 57.0 (ng/mL)/(mg/kg), respectively, and 
seemed to be comparable across the age range investigated. Linear regression analysis, which 
considered all dose-normalized exposure values, indicated a minor age-dependent increase with 
a maximum of 1.2 (AUC) and 1.4-fold (Cmax) increase across the observed age range. Similar 
assessment has been executed across the body weight range (5.11 kg to 16.3 kg). Comparable
observations were made when dose-normalized AUC and Cmax values were correlated with 
the body weight range from 5.11 to 16.3 kg. Exposure values seemed to be comparable across 
the body weight range investigated. Linear regression analysis indicated a minor body weight-
dependent increase of dose-normalized AUC and Cmax by 1.4 and 1.3-fold, respectively, 
considering the minimum and maximum observed body weight. No obvious impact of the 
administration method (feeding tube versus oral) was observed on both plasma exposure 
parameters, AUC and Cmax.
In Part 2 of present study, PK parameters were investigated across all observation periods at 
actual mean doses of 0.625 and 2.5 mg/kg, Table 1-2). Following oral branaplam administration 
across all observation periods, median Tmax values of branaplam in plasma ranged between 
3.75 and 4 h at all observation periods (after 1 dosing, at month 3 and months 9). Thereafter, 
branaplam decreased slowly from plasma with mean apparent terminal elimination T1/2 values 
of 42.2 h and 46.0 h at the low and high dose level, respectively. AUC and Cmax values 
increased approximately with increasing dose in a dose-proportional manner. Mean apparent 
systemic clearance (CL/F) were 660 and 781 mL/h/kg and volume of distribution (Vz/F) values 
40000 and 52400 mL/kg for 0.625 mg/kg and 2.5 mg/kg, respectively. Overall, all PK 
parameters were comparable to those observed in Part 1 (see above).
Table 1-2
Systemic exposure values of branaplam across all observation 
periods - Study CLMI070X2201 Part 2
Actual dose 
Arithmetic mean ± SD (%CV)
(mg/kg)
n a
Cmax (ng/mL)
n a
AUC (h·ng/mL) b
0.625
29
21.7 ± 5.71 (26.3)
28
1020 ± 278 (27.4)
2.5
38
77.4 ± 27.5 (35.6)
29
3470 ± 909 (26.2)
All values were rounded to 3 significant digits
a: number of PK profiles considered; please note, that a patient provides several PK profiles to the 
analysis; b AUC corresponds to AUCinf after the first dose and AUC0-168h after multiple doses
Human Pharmacodynamic data
Preliminary data on SMN protein and SMN2 mRNA splicing as well as efficacy data are 
presented in the Investigator Brochure.


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1.2
Purpose
The purpose of Part 1 of the study was to evaluate the safety, tolerability, pharmacokinetics 
(PK), pharmacodynamics (PD) and efficacy; and to estimate the Maximum Tolerated Dose 
(MTD) of branaplam.
The purpose of Part 2 of the study is to characterize dose-exposure-response to inform dose 
selection of orally administered branaplam in patients with Type 1 SMA. 
The purpose of Part 3 of the study is to provide continuous treatment with branaplam to patients 
who have participated in Part 1 or 2 of the study and have completed at least 52 weeks of 
treatment. In addition, part 3 allows to provide long term safety and efficacy follow up for 
patients treated with branaplam for more than 52 weeks. 
2
Objectives and endpoints
2.1
Primary objective(s)
Objective
Endpoint
Part 1: Determine the safety and tolerability of 
ascending weekly doses and estimate the MTD 
of branaplam in infants with Type 1 SMA.
For all parts:

Physical exam

Vital signs

ECG and echocardiographic evaluation

Safety laboratory parameters

Ophthalmologic examination

Neurologic examination

Nerve conduction study: sensory nerve 
action potential (SNAP), nerve 
conduction velocity (NCV) for sensory 
and motor nerves and ulnar nerve 
compound motor action potential 
(CMAP)

Adverse events
Part 2: Evaluate the safety and tolerability of 2 
doses of branaplam administered weekly for 52 
weeks in patients with Type 1 SMA.
Part 3: Assess long term safety and tolerability 
of extended oral/enteral, once a week 
branaplam treatment in patients with type 1 
SMA who have had at least 52 weeks of 
treatment in either Part 1 or 2 study of this 
protocol.
2.2
Secondary objective(s)
Objective
Endpoint
Part 1, Part 2, Part 3:
Part 1, Part 2, Part 3:

To evaluate branaplam pharmacokinetics in 
plasma after single and repeated doses of 
branaplam.

AUC and Cmax of branaplam

To evaluate the effect of branaplam on 
growth parameters 

Growth measurements (body weight, head 
circumference, length and chest 
circumference)

To evaluate the effect of branaplam on 
respiratory function 

Pulse oximetry, respiratory rate, paradoxical 
breathing assessment, chest circumference 
during quiet breathing.


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Objective
Endpoint

To evaluate the effect of branaplam on infant 
motor development.

CHOP INTEND infant motor scale up to age 
of 36 months

Hammersmith Infant Neurologic Examination

In addition to the above for Part 2:

In addition to the above for Part 2:

To evaluate the efficacy of branaplam on 
motor and developmental milestones

Preservation of oral feeding


To evaluate the efficacy of branaplam on the 
ability to sit without support.

Ability to sit without support over time as 
assessed by HINE-2 

In addition to the above for Part 3:

In addition to the above for Part 3:

To evaluate the efficacy of branaplam on 
motor and developmental milestones

Preservation of oral feeding

To evaluate the efficacy of branaplam on the 
ability to sit without support.

Ability to sit without support, stand or walk 
over time as assessed by HINE-2

To assess the proportion of infants who are 
alive and are without permanent ventilation 
over time

Adverse Events and deaths over time

To assess the impact of treatment with 
branaplam on time-to-event (death, 
permanent ventilation)

Adverse Events and deaths over time
3
Study design
This is an open-label, multi-part, first-in-human proof of concept study in infants with Type 1 
spinal muscular atrophy, to evaluate safety, tolerability, PK, PD and efficacy of oral branaplam. 
Parts 1, 2 and 3 are intended to be non-confirmatory.
All patients must have confirmed SMA type 1 and 2 copies of the SMN2 gene.
In Part 1 of the study, patients will be dosed once weekly with branaplam. The branaplam dose 
will be escalated in subsequent cohorts until MTD was determined or when sufficient PK results 
would not confirm that the MTD could not be reached due to a potential pharmacokinetic 
exposure plateau at higher doses. Patients will be dosed at least 24 hours apart for the first dose 


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of each dose level to ensure patient safety. A decision to dose escalate the next cohort will be 
made after safety data have been collected for 14 days following the first dose (14-day DLT 
window). PK will be used to confirm that there is no accumulation of the compound. If PK data 
show the potential for accumulation, the dosing frequency may be decreased. For Part 1, 
patients completing 13 weeks of treatment will be considered to have completed the study. 
Patients who are continuing to receive study medication follow the Assessment schedule-part1-
Extended treatment period. The assessment schedule repeats until the patient discontinues the 
study or transfers to Part 3 the investigator agree that this is in the best interest of the patient.
Part 2 of the study did enroll new patients into one of 2 dose cohorts of 0.625 mg/kg and 
2.5 mg/kg with once weekly dosing for 52 weeks. The branaplam dose was escalated in 
subsequent cohorts after 6 patients have been enrolled or at least 3 patients from the initial 
cohort have completed 13 weeks of treatment. After 52 weeks, patients may continue treatment 
in Part 3 of the study if in the best interests of the patient, as assessed by the investigator.
Part 3 of the study is long term safety and efficacy follow up of extended oral/enteral, once a 
week branaplam treatment. All patients who participated in Part 1 and Part 2 of the study and 
have completed at least 52 weeks of treatment, or more can continue receiving treatment with 
branaplam in Part 3 of the study.
Continuation of the treatment will be done at the dose assigned while in Part 1 or Part 2 of the 
study. However, if at any later time an interim analysis of Part 1 or Part 2 study data suggest 
one optimal dose considering existing safety as well as efficacy data, the dose patients are 
receiving might be adjusted while participating in Part 3 of the study protocol. 
3.1
Part 1 Study Design
14 patients have been enrolled and 13 patients treated in Part 1 (at least 2 patients planned in 
each of 5 cohorts). No new patients will be enrolled in Part 1.


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Figure 3-1
Part 1 study design


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Screening
Visit 1 – Day -14 to -8
Patients will be required to attend the investigator center for the screening visit (for logistical 
reasons more than 1 visit may be planned) where suitability for the study will be assessed by 
the investigator. Patients should stay within 120 minutes ground travel after signing the ICF 
through the end of the DLT period (Visit 9) and any longer travel should be discussed with and 
agreed to by the Sponsor.
Screening assessments will be completed per the Assessment Schedule.
To assess eligibility and confirm the diagnosis of SMA, SMN2 copy number will be determined 
in all patients in whom this has not been previously confirmed. As part of the inclusion and 
exclusion criteria, hepatitis and HIV screens will also be assessed at this visit. Similarly, general 
demographics and relevant and current medical history will be recorded.
Monitoring of concomitant medications, adverse events, and serious adverse events will be 
initiated during this visit. 
Only patients who meet the inclusion/exclusion criteria at screening will be eligible to proceed 
to the baseline visit. 
For a full list of assessments, please refer to Table 7-1.
Baseline
Visit 2 (Day -7 to -3) and Visit 3 (Day -2 to -1)
Due to the limited blood volumes available in infants, the baseline assessments have been split 
across two visits. The baseline visit may be combined into one day if appropriate.
All baseline eligibility assessment results must be available and confirmed by the investigator 
prior to progression into the treatment period.
First dose – Visit 4 (Day 1)
Patients will attend the investigator site in the morning. They will remain at the site for at least 
24 hours for safety monitoring, after which they will be discharged locally at the discretion of 
the investigator. Patients who do not live within 60 minutes travel from the site should be 
housed locally until the day 8 visit (Visit 8) either at family/friends, or in a hotel. After visit 8 
they may return home until their next scheduled study visit. 
Pre-dose assessments will be conducted according to Table 7-1.
Time of dosing will be collected in the eCRF and appropriate documentation of the patient
specific dispensing process must be maintained. Dose administration should occur at 
approximately the same time of day at each dosing visit (morning or afternoon). 
The investigator should be in contact with the Sponsor before dosing to confirm that there is a 
24 hour gap between patients receiving their first dose of study drug across all study sites. If two 
sites have patients scheduled for Visit 4 in the same week, they must be scheduled 24 hours 
apart, allowing for time zone variations.


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Following study drug administration blood samples will be drawn for PK analysis at specified 
time points throughout the day. 
Reflux precautions must be implemented post-dosing per local institutional standards. 
For a complete list of assessments, please refer to Table 7-1 for the initial treatment period and 
to Table 7-2 for the extended treatment period.
PK collections – Visits 5, 6, 7 and 8 (Day 2, 3, 5 and 8)
PK blood collections and safety assessments will be performed per Table 7-1 during the initial 
treatment period and per Table 7-2 during the extended treatment period and after the transfer 
into Part 3 per Table 7-4.
Safety Review – Visit 8 (Day 8)
Safety assessments and respiratory function will be performed per Assessment Schedule.
 a blood sample for PK will be obtained.
Dosing Visits 9 (End of DLT review period) - 19 (Day 15 – Day 85)
If the first dose has been well tolerated during the 14-day DLT review period, patients will 
continue to be dosed on a weekly basis until end of study, or as long as it is in the best interest 
of the patient.
Patients will attend the investigator site in the morning. They will be discharged at the discretion 
of the investigator.
Safety and respiratory function assessments will be performed prior to dose administration per 
Table 7-1 during the initial treatment period and as per Table 7-2 during the extended treatment 
period.
Time of dosing will be collected in the eCRF and appropriate documentation of the patient
specific dispensing process must be maintained. Dose administration should occur at 
approximately the same time of day at each dosing visit (morning or afternoon).
Reflux precautions must be implemented post-dosing per local institutional standards.
Patients entering treatment extension will undergo assessments as described in Table 7-2.
End of Study – Visit 777
The End of Study visit will be performed 30 days after the last treatment.
End of study visit will become applicable only when further branaplam treatment is 
discontinued.
Study completion information is mandatory for this visit and must be completed regardless of 
the patient’s completion / discontinuation status.
All other assessments within this visit should be completed wherever possible, depending on 
the patient’s status and ability to tolerate assessments.


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For a complete list of assessments, please refer to the Assessment Schedule.
Patients who are continuing to receive study medication follow the Assessment Schedule - Part 
1 - Extended treatment period. The assessment schedule repeats until the patient discontinues 
the study or transfers to Part 3 of the study. 
For patients who completed at least 52 weeks of treatment and who will continue treatment in 
Part 3, no end of study visit needs to be done.
3.2
Part 2 Study Design
In Part 2 of the study there are 2 different dose cohorts the patients will be enrolled to: cohort 1 
at 0.625 mg/kg and cohort 2 at 2.5 mg/kg. 
Those selected dose levels are based on previously obtained safety data from Part 1, as well as 
all data from preclinical chronic juvenile toxicity studies available at the time of initiation of 
Part 2. The rationale is described in Section 3.2.
A minimum of 6 and up to approximately 10 patients will be enrolled in each cohort. 
Patients will be receiving the same dose of branaplam once weekly, as allocated at enrollment 
throughout the initial 52 weeks, no intra-cohort escalation is planned. Exceptionally in case of 
lack of efficacy/progressive disease, as assessed by investigator, patient(s) from cohort 1 (0.625 
mg/kg) may receive next level dose (2.5 mg/kg).
In general, the loss of positive benefit of the cohort 1 dose of branaplam will be assessed on a 
patient by patient level. If positive benefit cannot be confirmed for majority of the patients, the 
cohort 1 might be closed and ongoing patient will be escalated to 2.5 mg/kg.
After completing 52 weeks of treatment, patients will have the possibility to continue receiving 
further branaplam treatment under Part 3 of this protocol. 
However, in order to ensure patient safety, a dose escalation within cohort 1 will be allowed in 
case there is no benefit at the 0.625 mg/kg dose or if there is evidence of loss of benefit (non-
durable effect). Efficacy and safety data will be reviewed after three patients have completed at 
least 13 weeks of treatment. In the event of no positive effect, or a loss of positive effect of 
0.625 mg/kg as defined in Section 5.4.7, the protocol will allow patients to receive the next 
higher dose.
Part 2 patients who have completed at least 52 weeks of branaplam treatment will be eligible to 
continue receiving branaplam treatment, as long as this is in the best interest of the patient, as 
assessed by the investigator will be enrolled to Part 3. For patients who will not be eligible to 
enter Part 3, End of Study of Part 2 will be performed.


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Figure 3-2
Part 2 study design
Screening
Visit 1 – Day -14 to -8
Patients will be required to attend the investigator center for the screening visit 
Screening assessments will be completed per the Assessment Schedule.
To assess eligibility and confirm the diagnosis of SMA, SMN2 copy number will be determined 
in all patients in whom this has not been previously confirmed. As part of the inclusion and 
exclusion criteria, hepatitis and HIV screens will also be assessed at this visit. Similarly, general 
demographics and relevant and current medical history will be recorded.
Monitoring of concomitant medications, adverse events, and serious adverse events will be 
initiated during this visit. 
Only patients who meet all of the inclusion and none of the exclusion criteria at screening will 
be eligible to proceed to the baseline visit. 
For a full list of assessments, please refer to the Assessment Schedule. 
Baseline/Randomization
Visit 2 (Day -7 to -3) and Visit 3 (Day -2 to -1)
Due to the limited blood volumes available in infants, the baseline assessments have been split 
across two visits. The baseline visit may be combined into one day if appropriate.
All baseline eligibility assessment results must be available and confirmed by the investigator 
prior to progression into the treatment period.
First dose – Visit 4 (Day 1)
Patients will attend the investigator site in the morning.
Pre-dose assessments will be conducted according to the Assessment Schedule.
Time of dosing will be collected in the eCRF and appropriate documentation of the patient
specific dispensing process must be maintained. Dose administration should occur at 
approximately the same time of day at each dosing visit (morning or afternoon).


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Following study drug administration blood samples will be drawn for PK analysis at specified
timepoints throughout the day. 
Reflux precautions must be implemented post-dosing per local institutional standards. 
For a complete list of assessments, please refer to the Assessment Schedule.
Dosing Visits 8-67 (Day 8 - 358)
Patients will attend the investigator site in the morning.
Safety and respiratory function assessments will be performed prior to dose administration per 
the Assessment Schedule.
Time of dosing will be collected in the eCRF and appropriate documentation of the patient
specific dispensing process must be maintained. Dose administration should occur at 
approximately the same time of day at each dosing visit (morning or afternoon).
Reflux precautions must be implemented post-dosing per local institutional standards.
Home Visits
Home Visit can be performed at patient’s home by Home Nurse professionals, if this service is 
available at the study site. The following activities can be performed at patient home depending 
on local regulations: Vital Signs (i.e. body temperature, blood pressure and pulse), Blood and 
urine draws for safety 
, blood draws for PK, ECG/Echocardiogram (ECHO), 
support with patients specific documents, study drug delivery, administration and return, 
Adverse Events and Concomitant Medication check
End of Study – Visit 777
The End of Study visit will be performed 30 days after the last treatment. For patients from Part 
2, after completing at least 52 weeks of treatment, who will continue treatment in Part 3, no end 
of study visit needs to be done.
End of study visit will become applicable only when further branaplam treatment is 
discontinued. 
When end of study visit is applicable, study completion information is mandatory for this visit 
and must be completed regardless of the patient’s completion / discontinuation status.
All other assessments within this visit should be completed wherever possible, depending on 
the patient’s status and ability to tolerate assessments. For a complete list of assessments, please 
refer to the Assessment Schedule.
Patients will have the possibility to continue receiving branaplam treatment in Part 3 of the 
study if in the best interest of the patient, as assessed by the investigator. 


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3.3
Part 3 Study Design
Patients from Part 1 and Part 2 of the study who have completed at least 52 weeks of branaplam 
treatment will be eligible to continue receiving branaplam treatment, as long as this is in the 
best interest of the patient, as assessed by the investigator.
Part 3 of the study will have long-term safety follow up and monitoring as well as long term 
efficacy evaluation. 
Part 3 Visit 1 (14- to 1)
After completion of at least 52 weeks of branaplam treatment in Part 1 or Part 2 of the study, 
the investigator will assess whether continued branaplam treatment is in the best interest of the 
patient. When this is confirmed, a consent from parents/guardians will be collected and patient
will transition to Part 3 of the study. Date of transition to Part 3 of the study will be collected in 
the eCRF and first dosing in Part 3 will ideally be done at site.
Visit 1 in Part 3 can be combined with last visit of either Part 1 or Part 2.
The assessments performed during last visit of either Part 1 or Part 2 do not need to be 
repeated at the first visit of Part 3, if the last visit of Part 1 or Part 2 occurred within the 
previous 14 days of the patient entering Part 3. 
At Visit 1 of Part 3, investigator should always collect samples for PK, Troponin and N-
terminal pro-brain natriuretic peptide (NTproBNP).
The ophthalmology assessments can be performed at Visit 1 if considered applicable by the 
investigator. However, if the patient does not have any ocular related complaints and if at the 
previous ophthalmology assessments there were no clinical findings which, potentially could 
be attributed to branaplam, the examination will be performed every 12 months from the date 
of the last ophthalmology assessment.
All consecutive doses in Part 3 can be administered at home, except if the dosing and site visit 
as per Assessment Schedule are overlapping, then patient will be dosed at the site. 
If, in the opinion of the investigator, a patient receiving 0.625 mg/kg experiences no further 
clinical improvement of the condition or progression of disease, the dose may be increased to 
2.5 mg/kg after consultation with the Sponsor. Similarly, if the investigator has any safety 
concerns for a patient receiving 2.5 mg/kg, the dose may be decreased to 0.625 mg/kg after 
consultation with the Sponsor.
If the caregivers do not wish to administer the IMP at home, the patient can visit the site for 
dosing anytime. 
Treatment and Long term follow up Period
The onsite visits will be performed as Regular (R) onsite visits every 3 months which will 
include all study assessments and Safety (S) onsite visits which will be done every month.
During Safety visits only Clinical Chemistry will be taken, weight of the patient collected and 
Adverse Events and Concomitant Medication checks done. Safety visits should be done on 


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site or at patient home performed by Home Nurse. If neither onsite visit nor home nurse visit 
is possible, investigator will perform a telephone call to caregivers. It is acceptable the patient
will perform Clinical Chemistry locally and the results will be provided to investigator.
During Regular visits (R) following safety evaluations will be done:

Blood samples for Hematology and Clinical Chemistry

Urine Analysis

Physical Examination

Vital Signs

Body Weight, Length and head and chest circumference

Respiratory rate

Electrocardiogram (ECG)

Echocardiogram (ECHO)

Respiratory Function

Ophthalmology Examination

Nerve Conduction Study (CMAP, SNAP, NCV)

Adverse Events and Concomitant Therapies
All safety evaluations are described in Section 7.4.
Patient will follow the schedule of assessment of Part 3 as presented on Table 7-4.
Telephone call interviews
In case patient is not able to visit the site for Safety Visit, site will perform telephone call 
interviews of the caregiver/legal guardians to assess the condition of the patient as well as verify 
patient’s weight and study drug volume taken. The site will do all effort to reach the 
parents/caregivers. The contact will be reported in source documents. In case of adverse events 
and new concomitant medication, or patient’s weight change these will be captured in 
applicable CRF pages.
Unscheduled Visits
Unscheduled Visit can be performed by site at any time of the study under discretion of 
investigator. The site can perform some or all assessments listed in Assessment Schedule. 
Home Visits
Home Visit can be performed at patient’s home by Home Nurse professionals, if this service is 
available at the study site. The following activities can be performed at patient home depending 
on local regulations: Vital Signs, Blood and urine draws for safety 
, blood draws 
for PK, ECG/ECHO, support with patients specific documents, study drug delivery, 
administration and return, Adverse Events and Concomitant Medication check.


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End of Study 
End of study visit will be performed in case of patient discontinuation/early withdrawal. The 
End of Study visit will have to be performed 30 days after the last treatment.
Part 3 of the study currently does not have a study end defined, taking into account the lethal 
nature of the SMA Type 1 disease if left untreated. In case the study is discontinued for reasons 
other than branaplam related patient’s safety, patient will continue treatment according to local 
standard of care, or if not available Novartis will offer available alternative treatment.
Study completion information is mandatory for this visit and must be completed regardless of 
the patient’s completion / discontinuation status.
All other assessments within this visit should be completed, depending on the patient’s status 
and ability to tolerate assessments. For a complete list of assessments, please refer to the 
Assessment Schedule as presented on Table 7-4.
PK 
 collections
Blood collection for 
 PK will be performed every 6 months. Blood 
collection will require 2 time points for sample collection, pre dose (Cthrough
) and post 
dose (C4h), therefore the study drug administration should be done onsite, at the day when PK 
is scheduled. Actual PK sampling times must be documented in the eCRF. 
Actual date and the time of dosing for the preceding last dose, and the dosing date and time on 
the day of PK sampling, must be documented in the eCRF.
3.4
Rationale for study design
Due to the life-threatening severity of the disease, rapid clinical decline of these patients and 
the presence of effective therapy, that is also available in some European countries, it would be 
unethical to include a placebo treatment as part of the study design. Therefore, the proposed 
study design is an open label study with all patients on active treatment for the duration of the 
study. At the time of initiation of Part 1 based on the natural history over 13 weeks (about 3 
months) in infants with type I SMA who have 2 copies of SMN2 and who are greater than 1 
and less than 8 months of age, the following was agreed as a consensus: if symptomatic, no 
infant will hold their head up independently, or roll, sit, crawl, stand, or show antigravity leg 
strength. In addition, all infants will essentially lose proximal motor strength in all 4 limbs by 
12 months of age (depends on how old they are when they enroll).
At the time of initiation of Part 2 additional sham control data are available: in symptomatic 
SMA Type 1 infants with onset of signs less than 6 months of age who have exactly 2 copies 
of SMN2 and who are at least 30 days and less than 180 days old, approximately 75% will be 
unable to maintain their head upright or kick horizontally, and almost all will be unable to 
complete any motor tasks in the HINE for rolling or sitting. No patients are expected to be able 
to crawl, stand or walk, and no acquisition of these skills is anticipated. 
Type 1 SMA infants have severely impaired motor milestones indicating their motor neurons 
are dysfunctional and likely dying by the time of diagnosis, usually after 3 months of age. Thus, 
early treatment is vital if SMN protein elevation from splice modulation is to have any benefit. 


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Based on the available information to date, Novartis assumes that SMN2 splice modulation will 
not lead to generating new motor neurons, but it should enable the survival and recovery of 
existing dysfunctional ones. 
The study population (Type 1 SMA) was initially selected because, given the cell cycle arrest 
liability of branaplam and thus narrow therapeutic window, it was not considered appropriate 
to expose healthy adult volunteers who could not benefit from the study drug. An additional 
consideration was the inability of an adult first-in-human study to adequately predict 
bioavailability of the drug in a young infant population in this Type 1 SMA infant study. 
The diagnosis of SMA is usually prompted by referral for evaluation between 1 and 4 months 
of age (range: birth to 8 months). The diagnosis of Type 1 SMA is traditionally made on clinical 
grounds, ultimately dependent upon the demonstration that independent sitting is not achieved 
after a period of observation (EMA 2016). The patients in Part 1 of the study were aged between 
1-7 months. Since newborn pre-screening is already in place in some countries, the age of the 
study patients in Part 2 will be defined as up to 180 days of age at screening.
Branaplam distributes to the brain in both rat and dog, both juvenile and adult animals, so 
significant brain penetration in infants is anticipated. If branaplam is to offer benefit, it is most 
likely to be in preserving motor neurons before they die off and thus age of patient at entry into 
study is crucial. The mechanism of action of branaplam is via increasing SMN protein in key 
cell types such as the alpha-motor neurons. Therefore, it is likely that branaplam will offer the 
maximal benefit if the target population of motor neurons are not irreversibly diminished, so 
recruitment for this study must be built around enrolling infants with SMA at the earliest stages 
of the disease process as possible.
Studies should be conducted in the patient population where there is the potential for benefit of 
the treatment. Novartis proposes that branaplam be tested in SMA patients with SMA Type I, 
because they suffer the most life-threatening form of SMA and have the greatest medical need 
for effective therapies and the highest prospect for direct benefit from participating in the 
planned study. By selection of 2 copy SMN2 SMA Type I patients, the study population is 
generally more homogeneous than other SMA types, which is anticipated to increase the 
probability to see treatment benefit in an open label study.
Patients with milder SMA Type II, III or IV have more slowly progressive disease, often 
characterized as a stable disease course. They typically survive to adulthood.
The study design has adopted a dose escalation design method to originally identify the MTD 
in Part 1 similar to that used in oncology studies. Branaplam has known reversible cell-cycle 
arrest effects at high doses so the study design is planned to monitor and manage such effects 
(marrow or GI tissue) as delineated from standard pediatric oncology experience. The AE 
profile anticipated from potential cell-cycle arrest effects are considered to be clinically 
differential to the type I SMA clinical phenotype. Since Type 1 SMA is fatal, the prospect for 
direct clinical benefit is a fundamental mandate. In an adult Pharmacodynamic SMA mouse 
model, it has been demonstrated that a single oral dose of branaplam can drive up SMN protein 
in the brain and spinal cord and remains elevated for nearly a week. Weekly dosing is 
implemented after the initial 14-day safety review window, as this is expected to allow for a 
complete washout between doses. While more frequent dosing may be possible even in Part 1, 


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our approach is to avoid accumulation until we can be sure that branaplam does not harm 
patients. Patients will initially be dosed for 13 weeks, however dosing may be extended if 
recommended by the independent DMC.
PK will be analyzed to complement the safety data acquired. Similar FIH studies have been 
carried out in infants with fatal illnesses before (Kishnani et al 2007; Worgall et al 2008). It is 
not practical or ethical to enroll patients into a traditional single dose study and then have them 
wait potentially 3-6 months until a full cohort is treated at one dose before dose escalation, even 
with retreatment of the same patients. In that period, a great majority of their vulnerable motor 
neurons could die off and they would no longer be able to receive potential benefit from 
branaplam, though they would still be vulnerable to any AE’s the drug may cause. We 
hypothesize that branaplam will rescue alpha-motor neurons from dying, but it is probably not 
capable of restoring or regenerating lost alpha-motor neurons; thus timing is key for patient
entry at early stages of disease for receiving a potentially efficacious dose.
Part 2 is designed to assess safety and tolerability of 0.625 mg/kg and 2.5 mg/kg of weekly oral 
branaplam for 52 weeks. Additionally, it will be investigated whether a change over time in 
infant growth and motor parameters can be detected and interpreted as an effect of branaplam 
treatment. Patients will initially be dosed for 52 weeks. After this initial 52 weeks, patients may 
continue receiving continuous treatment in Part 3 if the investigator confirms that this is in the 
best interest of the patient. 
Part 3 is designed to assess long term safety and tolerability and some long term efficacy of 
weekly oral branaplam treatment. Based on the interim analysis of Part 1 patients an 
improvement in motor function was seen as determined by the CHOP-INTEND score. Based 
on this improvement, and overall survival in Part 1, there is a strong rationale to extend 
treatment in participating patients and further assess efficacy and safety.
3.5
Rationale for dose/regimen and duration of treatment
3.5.1
Doses in Part 1 
Starting dose: Due to the life-threatening nature of the Type I SMA disease, a starting dose 
must be selected which is intended to be safe but has the potential to show pharmacologically 
active effects e.g., SMN2 splice modulation. Therefore, an oncology approach was used to 
calculate the starting dose (14 References, International Council for Harmonization (ICH) S9
guidelines 2010)  Doses were adjusted for body surface area since the toxicological reference 
studies in rats and dogs were done in juvenile animals.
In juvenile rats the highest dose evaluated was 10 mg/kg/day (60 mg/m2/day), and neither 
lethality nor severe toxicity were observed at this dose; therefore, this dose is considered the rat 
STD10 (severely toxic dose in 10% animals). The Highest Non-Severely Toxic Dose (HNSTD) 
in juvenile dogs is considered to be 10 mg/kg/day (200 mg/m2/day). Since 1/10th the rat STD10 
scaled for body surface area is not severely toxic in dogs, which is the most sensitive species, 
the rat data are considered most appropriate for calculating the human starting dose.
The starting dose in patients is 1/10th of the rat STD10 (60 mg/m2/day) = 6 mg/m2/day. 
Assuming that a pediatric patient of 6.5 kg body weight and 62 cm has a body surface of 0.32 m2, 


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(using the DuBois formula of BSA= 0.007184*W0.425*H0.725) (DuBois and DuBois 1916), the 
starting dose for the first-in-human patient should be 6 mg/m2/day x 0.32 m2 ≈ 1.9 mg/day or 
approximately 0.3 mg/kg. The actual dose of each patient will be adjusted based on weight and length. 
Similarly, the dose in the extension may be adjusted based all available exposure data.
To uphold pediatric clinical trial guidance, the prospect for direct clinical benefit is built into 
this study design for all enrolled patients. Thus, the study design has a starting dose that is 
projected to be minimally efficacious and allows for dose escalation that is not limited by the 
enrollment pace of a sizeable cohort of patients with a rare disease. Once a patient has been 
treated for 13 weeks (end of part 1) and enters extended treatment, a patient may be switched 
to a higher dose once this higher dose has been deemed safe in other patients.
Maximum dose: At the highest tested dose of 60 mg/m2 (corresponding to 3.125 mg/kg), the 
preliminary AUC0-24h value was 1470 ng.h/mL after single and repeated branaplam 
administration (Section 1.1.1). This exposure was about 6-fold higher than the projected 
efficacious AUC exposure based on nonclinical animal models. Due to the preliminary efficacy 
data of Part 1 of this study described in the current IB, no further increase of the dose is 
considered, although no dose limiting adverse event have been observed. Additionally, the 
available data from the 52-week toxicology study in juvenile dogs suggested not to exceed 
60 mg/m2 (corresponding to 3.125 mg/kg).
3.5.2
Doses in Part 2
Starting dose: The dose of 0.625 mg/kg was chosen as a starting dose in Part 2 based on safety 
and preliminary efficacy data collected in Part 1 of the study (see Table 7-1 and Table 7-2). 
Indeed, following an urgent safety measure (USM) in Part 1, treatment with branaplam 
continued but at a reduced dose of 6 mg/m2 (0.3125 mg/kg) for all patients who had completed 
the initial 13 weeks of treatment. This dose was predicted to be efficacious based upon the 
preliminary clinical (CHOP INTEND) response of patients in Cohort 1. However, following 
the branaplam dose reduction to 6 mg/m2 (0.3125 mg/kg) , safety events including decrease of 
motor skills, generalized motor weakness and increased respiratory muscle weakness have been 
reported (see also Section 1.1.1). While a mechanistic relation between these clinical 
observations and the preclinical nerve fiber degeneration following branaplam treatment cannot 
be completely excluded, due to the almost synchronous temporal association of the events with 
the decrease in dose and the similar course of the events in the 7 patients, it is most likely that 
branaplam was benefitting the patients and that the lower dose of branaplam is less effective. 
For that reason and also given the preliminary efficacy data collected in patients treated with 
branaplam 12 mg/m2 (0.625 mg/kg)it was decided to take this dose as a starting dose in Part 2.
Second dose level: The dose of 2.5 mg/kg (48 mg/m2) was selected as second dose in Part 2 
being 4-fold higher than the starting dose of 0.625 mg/kg. Considering the preliminary PK 
exposure values and their variability determined in Part 1 (Section 1.1.1), the difference 
between 0,625 mg/kg and 2.5 mg/kg was considered to be sufficient to ensure appropriate 
separation in terms of systemic branaplam exposure and potentially also of efficacy endpoints. 
In addition, the magnitude of the dose difference would be sufficient to guide the dose-response. 
An increase of the selected second dose of 48 mg/m2 to 60 mg/m2 was not further considered 
as the dose difference is only 1.25-fold and exposure overlap was clearly observed in Part 1.


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3.5.3
Doses in Part 3
In Part 3 patients will be treated at doses that have already be assigned in Part 1 and Part 2 of 
the study until an optimal selected dose has been determined. However, if in the opinion of the 
investigator, a patient from Part 2, receiving 0.625 mg/kg experiences no further clinical 
improvement of the condition or even progression of disease, the dose may be increased to 2.5 
mg/kg after consultation with the Sponsor. Similarly, if the investigator has any safety concerns 
for a patient receiving 2.5 mg/kg, the dose may be decreased to 0.625 mg/kg after consultation 
with the Sponsor.
Following the Part 2 (52 weeks) analysis, a comparison of the two doses showed 2.5 mg/kg to 
have numerically better changes in HINE-2 scores compared to 0.625 mg/kg following one year 
of treatment, and comparable safety profiles. The SMN mRNA analysis also noted a greater 
target engagement favoring the higher dose as well (see Section 1.1.1).  Thus, it is expected that 
this higher dose will maximize the potential long-term benefit for patients. Therefore, the dose 
of 2.5 mg/kg was selected as the optimal dose in Part 3 and the investigators from study sites 
were prompted to have all patients transition to this new dose, unless there are safety concerns 
or this change in dose is not in the best interest of the patient.
Dose escalation
In Part 1 dose escalation is guided by the Bayesian logistic regression model (BLRM) with 
escalation with overdose control (EWOC) principle. Based on modeling and simulation 
projections from preclinical toxicology and the most relevant mouse models for efficacy studies, 
the doses planned/anticipated after dose level 1 are no more than 100% increases of the previous 
dose level rather than the typical ½-log (3-fold) increase in order to be careful with these 
symptomatic infants. 
The initial duration of treatment in Part 1 (13 weeks) and Part 2 (52 weeks) are designated to 
allow adequate time for SMN upregulation to not only rescue motor neurons from dying but 
also enable neuromuscular development to manifest observable gains in motor and respiratory 
function. Based on the safety and efficacy data analyzed so far, a benefit for the patients has 
been demonstrated and is justifying to continue with long term treatment. 
Part 2 is designed to have two separate dose cohorts and no in-patient dose escalation from 
0.625 mg/kg to 2.5 mg/kg is planned. However, in case of no improvement or progressive 
disease individual patients might be escalated from lower to higher dose.
In Part 3 patients will continue receiving doses that they have been receiving at time of transition 
into Part 3. If, in the opinion of the investigator a patient receiving 0.625 mg/kg experiences no 
further clinical improvement of the condition or even disease progression, the dose may be 
increased to 2.5 mg/kg. Similarly, if the investigator has any safety concerns for a patient 
receiving 2.5 mg/kg, the dose may be decreased to 0.625 mg/kg after consultation with the 
Sponsor.
After analysis of Part 2 data, if new information on the optimal dose of branaplam becomes 
available, dosing of all patients in Part 3 might be adjusted.PK/PD relationship


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PK/PD modeling based on PK and brain SMN protein levels in mice suggested that 0.3 mg/kg 
(projected plasma AUC0-24h ~239 ng.h/mL in infants) could be a minimally efficacious dose. 
Since the SMN protein elevation observed at this dose corresponded to approximately a 35% 
increase above baseline brain SMN levels in these animals, it is anticipated that elevating SMN 
protein levels in Type I SMA patients to about 35% of the SMN levels in normal, unaffected 
individuals may elicit clinically meaningful effects. Given that peripheral (blood) SMN protein 
levels will be monitored as a surrogate for central SMN elevation and that the range of SMN 
protein levels in Type I individuals is ≤ 5-20% of normal levels, it is anticipated that a dose of 
branaplam that provides a 15-30% increase (over baseline levels of a given patient) in peripheral 
SMN levels is expected to be within an efficacious dose range. 
3.5.4
Safety margins
In order to estimate multiples of animal exposures relative to human exposures, the exposures 
at dose levels not associated with severe toxicity were compared to preliminary exposures in 
human at the projected minimum efficacious dose level (6 mg/m2, corresponding to 
0.3125 mg/kg) and at the maximum dose levels tested in humans so far (60 mg/m2
corresponding to 3.125 mg/kg). Details of the safety margin calculations are presented in the 
most current IB.
The estimated exposure at the No-observable-effect-level for genotoxicity (specifically, 
aneugenicity) in the rat (227 ng.h/mL) is similar to the projected efficacious exposure resulting 
in an exposure multiple of 1. For the maximum anticipated exposure, the exposure multiple 
would be 0.1 (for further details see the Investigator’s Brochure). Since the aneugenic effect is 
considered secondary to the cell-cycle effects of branaplam the projected efficacious and 
maximum foreseen exposures are considered justified. 
3.5.5
Age effect
Branaplam PK is expected to change with age as a consequence of maturation of metabolizing 
enzymes (UGTs and CYP3A4) and transporters (Pgp). This may reduce the bioavailability, 
impact the distribution to the brain (Pgp) and/or increase the clearance, leading to a reduction 
of exposure. Therefore, the doses in both parts have to be adjusted either to the BSA (Part 1) or 
body weight (Part 1 extension, Part 2) as described in Section 5.1.2. Since BSA and body weight 
increases with age in infants, the effect of age on the PK will, at least partially, be compensated 
by the BSA/body weight adjustment. However, this may not completely compensate for the 
changes in metabolic and absorption/distribution processes. Therefore, PK samples have been 
and will be collected in all study parts every 3 to 6 months for assessment of PK exposure 
parameters (Part 1 and Part 2) and of steady state concentrations (Part 3). Results of all of these 
assessments will be evaluated for potential dose adjustments even on an individual basis to 
maintain the same exposure (AUC) as observed after the first dose.
3.6
Rationale for choice of comparator
Because of the lethal and progressive nature of SMA Type I, no placebo control will be offered. 
No active comparator is proposed despite of the approval of nusinersen for SMA in the US and 
EU because this is an exploratory study to determine safety and initial efficacy of branaplam.


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Nusinersen is not yet available in some countries where this study may be run. Supportive care 
will be used as background treatment throughout the study. Comparison to natural history 
studies may be used as well. 
3.7
Purpose and timing of interim analyses/design adaptations
In Part 1, prior to dose escalation, a review of all safety/tolerability (continued review of 
physical examination, vital signs, safety laboratory assessments and adverse events), 
dose-limiting toxicity (DLT) and available PK data up to 14 days post-dose for at least 1 patient
in the dose cohort will be performed and must be assessed as satisfactory to proceed. See 
Section 5.4 for definitions of dose limiting toxicities.
The decision for dose escalation will be based on a review of all relevant data available from 
all dose levels evaluated in the ongoing study and will be made jointly between the Sponsor 
and the Site Investigators. The recommended dose for the next cohort of patients will be guided 
by the Bayesian logistic regression model (BLRM) with escalation with overdose control 
(EWOC) principle.
Dose escalation will continue in Part 1 until a Maximum Tolerated Dose (MTD) is adequately 
defined for the weekly dosing regimen or when sufficient PK results confirm that the MTD 
cannot be reached due to a potential pharmacokinetic exposure plateau at higher doses.
When MTD or a pharmacokinetic exposure plateau is reached, PD as measured by either blood 
SMN protein upregulation from baseline or blood cell SMN2 mRNA splicing in Part 1 will 
confirm branaplam’s mechanism of action occurring in human periphery. This is expected to 
be similar to the effect in brain stem and spinal cord motor neurons. If clinical efficacy is seen 
in Part 1 with positive PD whole blood SMN protein upregulation or other PD markers, and 
MTD is not determined, sponsor may not pursue establishing the MTD and may go into Part 2 
with efficacious doses only.
Final analysis will be performed at the end of Part 3 which will evaluate PK/PD (blood SMN 
protein upregulation) and evaluate the change over time in clinical endpoints related to infant 
growth and motor function. 
Patients enrolled in Part 1 who tolerate the assigned doses of branaplam may receive extended 
treatment beyond the initial treatment period if Novartis, the investigator and the DMC agree 
that this is in the best interest of the patient. Under this regimen, a patient may continue to 
receive weekly dosing at the originally assigned dose level, or they may be escalated to a higher 
dose (Part 1 only) once this higher dose has been deemed safe in other patients. Additional 
adjustment for age may also be required, as discussed earlier. However, for each patient, DLTs 
observed while taking doses subsequent to the initial 14-day safety review will not influence 
dose escalation decisions, in order to avoid bias of increased tolerance or toxicity to branaplam. 
In Part 2 patients will be assigned to one of the two cohorts, 0.625 mg/kg or 2.5 mg/kg and 
patients from lower dose cohort will not be escalated to a higher dose than their originally 
assigned dose level unless there is a potential lack of efficacy/disease progression. 
 
 


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Additional information is presented in Section 11.7.
3.8
Risks and benefits
Overall, the benefit-risk of branaplam for newly diagnosed infants with type I spinal muscular 
atrophy appears to be favorable. The inclusion of new patients in Part 1 of the study was 
withheld in 2017 until data were available that allowed for a better understanding of the 
pathophysiological mechanisms that may explain the observations in the chronic dog toxicology 
study. For patients already enrolled in the Part 1 of the study at that time, the benefit-risk, the 
additional survival and functional data, and the new benefit-risk determination for each patient
in the study by an independent physician support a continued positive benefit-risk ratio. In 
addition, an autopsy from a patient who died shortly following dose reduction showed no 
evidence of axonal degeneration. Clinical neurophysiologic 
monitoring has been added to address this risk identified in the chronic dog toxicology study.
A total of 38 patients have been treated with branaplam to date in CLMI070X2201 study. 
Treatment has been well tolerated with few safety events. Investigators have reported seeing 
improvements in some patients that exceed the expected natural history of SMA type I disease, 
and assessment of the CHOP INTEND motor function measure after interim analyses in Part 1 
are showing increases of CHOP INTEND over time at serial evaluations in most patients. Seven 
patients have reached a CHOP INTEND score of > 36, exceeding the results seen in historical 
control studies with infants with symptomatic Type I SMA (Finkel et al 2014; Kolb et al 2016). 
Similar changes have been seen in  data in part 2. In result of these changes seen, branaplam 
may be beneficial to patients, enabling motor neurons to survive and indeed leading to 
acquisition of motor skills as hypothesized. The survival of motor neurons in this critical 
window of infancy requires sufficient amounts of functional SMN protein so that the muscle 
fibers remain innervated and function. The potential benefit of branaplam is to rescue motor 
neurons from dying out and enable neuromuscular development to occur which is required for 
muscle functions such as motor development e.g. rolling, sitting and walking in addition to 
independent respiratory function and eating/swallowing. Thus, the potential for benefit to 
patients from branaplam is motor skills acquisition, prolonged survival in this fatal disease with 
improved respiratory function, plus enhanced growth with better nutritional intake by improved 
feeding. 
Since the initiation of the CLMI070X2201 study, the therapeutic landscape has changed with 
new therapies for treating SMA type 1. The following are approved therapies for SMA:
Spinraza (nusinersen), an antisense oligonucleotide, Zolgensma (onasemnogene abeparvovec-
xioi), an SMN1 gene replacing gene therapy, and Evrysdi (risdiplam), an SMN splice modulator.
For full details please review product labels. 
For detailed information on safety, including the number of SUSAR, please refer to the 
investigator brochure.


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The table below summarizes the important potential risks from pre-clinical studies as well as 
human experience from this ongoing trial (CLMI070X2201) as well as recently completed 
Single Ascending Dose study and human absorption, distribution, metabolism and excretion
(ADME) study in healthy volunteers.
Table 3-1
Summary of Important Potential Risks
Class/Compound
Risk 
Classification
Risk Name
Compound
Potential
Cell 
cycle 
effects
Bone marrow effects
Gastrointestinal effects
Nerve fiber degeneration
Retinal atrophy
Gonadal effects: Testicular/ovarian
Reproductive toxicity: Pregnancy in Women of 
Childbearing Potential
Genotoxicity (aneuploidy*)
Potential
Liver function effects
Potential
Cardiovascular effects
Potential
Renal toxicity
Potential
Drug-drug interactions
Missing 
Information
Effects of Breastfeeding
Class
None
None
*Branaplam was not mutagenic in a bacterial mutagenicity (Ames) test. Branaplam is aneugenic but not clastogenic. A 
neoplastic risk of branaplam as a consequence of the aneugenic effect is considered unlikely but cannot be excluded.
The risk to patients in this trial will be minimized by adherence to the eligibility criteria with 
experienced SMA pediatric clinical experts, close clinical monitoring, and close adherence to 
the stopping rules.
Bone Marrow Effects
In this ongoing study some events of cytopenias consisting of neutropenia, anemia and 
thrombocytopenia were reported. However, these events were mild to moderate and reversible. 
Additionally, events of increased platelet counts were also reported which were also mild to 
moderate in severity and resolved spontaneously while on treatment. In the Single Ascending 
Dose (SAD) study in healthy volunteers, five participants dosed with 420 mg or placebo showed 
platelet count increases above the ULN (max increase up to 2x ULN) which were most 
pronounced in the 3 participants with liver events, which have not been observed at lower dose 
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Gastrointestinal Effects
In this ongoing study in Type 1 SMA patients the majority of gastrointestinal events were Grade 
1 and 2, were not related to study drug and resolved while on treatment.
In the healthy volunteer study in healthy adult participants 7 out of 8 participants in this Cohort 
4 (420 mg branaplam) reported diarrhea (5 branaplam and 2 placebo-treated) on Day 1 with a 
spontaneous recovery by Day 2.
Nerve Fiber Degeneration
Nerve fiber degeneration (axonal degeneration) in peripheral nerves and spinal cord was found 
in one species (dogs) after 17 weeks of daily administration of branaplam. The onset of axonal 
degeneration preceded or coincided with an increased in Neurofilament light chain (NfL)
concentration in serum and cerebral spinal fluid (CSF). A dose-dependent increase of NfL levels 
was observed in the serum and CSF of monkeys treated twice weekly with branaplam for a 
duration of 6 weeks in the absence of microscopic findings in the brain, spinal cord or peripheral 
nerves. 
Furthermore, weekly dosing is expected to potentially mitigate this risk.
 
 So far there are no recorded 
adverse events indicative of neurotoxicity and the nerve conduction studies have not shown a 
clear indication of neurotoxicity.
In the SAD study in healthy adult volunteers, NfL levels in serum were monitored at several 
timepoints in the study. Individual serum NfL results showed overall no trend of increase within 
each cohort or across the investigated exposure range across the 4 cohorts and were not 
suggestive of any effects of branaplam on this variable.
The risk to patients in this trial will be minimized by adherence to the eligibility criteria with 
experienced SMA pediatric clinical experts, close clinical monitoring, and close adherence to 
the stopping rules.
Renal Atrophy
Corneal opacities and retinal/choroid atrophy were observed in the 26-week study in juvenile 
albino rats which was considered rat specific.
In the current ongoing study in Type 1 SMA CLMI070X2201 no ocular events pertaining to 
retinal atrophy have been reported.  
This risk will be monitored by ophthalmoscopic examinations.
Testicular Effects
Degenerative changes involving seminiferous tubules of testes were observed after daily dosing 
with branaplam in a 4-week adult mouse study and 52-week juvenile dog study. This risk is 
considered unmonitorable in the sexually immature patients enrolled in this trial.


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Ovarian Effects
Ovary findings (decrease of corpora lutea and follicles) were observed in the adult mouse (wild 
type (wt) RasH2 strain)  with daily dosing of branaplam. No ovarian findings in any other 
toxicological studies conducted in the rat and dog. This risk is considered unmonitorable in the 
sexually immature patients enrolled in this trial.
Genotocicity (Aneuploidy)
A neoplastic risk of branaplam as a consequence of the aneugenic effect is considered to be 
unlikely but cannot be excluded. This potential risk may not present in the duration of this study.
Liver Function Effects
Liver findings were observed in animals after daily dosing with high dose levels (mouse, rat 
and dog) or after chronic dosing in the rat.
In this ongoing study in Type 1 SMA patients there were some reported events of transient 
increases in aminotransferases.   In the SAD study in healthy subjects all 6 subjects receiving 
single doses of 420 mg branaplam showed increases in AST and/or ALT with an onset on Day 
8, which in of which 3 subjects were classified as “liver events” as per protocol defined criteria 
(ALT or AST increase >5x ULN or ALT increase >3x ULN accompanied by clinical symptoms) 
and were recorded as adverse events. A trend of ALT and AST increase within the normal range 
was already observed at doses of 210 mg (SAD study) and 140 mg (human ADME study).This 
risk is considered monitorable by history, physical exam, and liver function tests.
Renal Effects
Kidney findings were observed after chronic daily dosing only in the dog. Blood pressure 
monitoring, serum chemistry measurements of electrolytes and renal function and urinalysis are 
included in the ongoing clinical study CLMI070X2201 as well as in the planned Clinical 
Pharmacology studies. In the current ongoing CLMI070X2201 study no relevant renal adverse 
events have been identified. In the SAD and humanADME study in healthy participants there 
have been no relevant abnormalities or changes in blood pressure, serum electrolyte levels or 
renal function variables or in the urinalysis assessments.  
The risk to patients in this trial will be minimized by adherence to the eligibility criteria with 
experienced SMA pediatric clinical experts, close clinical monitoring, and close adherence to 
the stopping rules.
Cardiac effects
Vacuolation of cardiomyocytes was observed with daily dosing of branaplam in the mouse
study (wt RasH2 mouse strain). No heart functional changes were observed in the dog safety 
study and in the 6 weeks monkey study with twice-weekly dosing. The exposure at the highest 
dose in the monkey were 7.5-fold higher compared to exposures observed in Type 1 SMA 
patients. The safety margin for human-ether-a-go-go-related gene (hERG) channel inhibition is 
37.8-fold higher than the highest Cmax observed in humans to date. Although these preclinical 


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findings are new findings, cardiac effects are already listed as a risk in the current Investigator’s 
Brochure (IB).
At the time this protocol amendment is written, three cases of cardiac SUSARs have been 
reported in the CLMI070X2201 study (see Section 1.1.1). The events consisted of PTs: left 
ventricular hypertrophy, sinus tachycardia, ejection fraction decreased(reported term: decreased 
systolic function of left ventricle EF45%), and hypertension, and pericardial effusion.
The SMN protein is expressed in moderate levels in skeletal as well as cardiac muscle
(Coovert et al 1997). Multiple preclinical in vivo studies and emerging clinical findings in SMA 
patients suggest that partial deficiency state of SMN in SMA may have an adverse effect on 
cardiac embryogenesis and function. Cardiac deficits, including bradycardia, arrhythmias and 
impaired blood flow have been described in several mouse models of SMA and are often the 
cause of death of these mice (Heier et al 2010). Drug treatments that elevate SMN levels have 
been shown to improve heart function in the same models. (Heier and DiDonato 2015). 
In patients, severe forms of SMA, including Type I SMA, have been associated with autonomic 
dysfunction, congenital heart block, ASD, VSD, aortic stenosis, hypoplastic aortic arch, severe 
aortic coarctation, partial atrioventricular canal, tricuspid atresia, a single ventricle and 
hypoplastic left heart syndrome
(Bach 2007; Bach et al 2007; Menke et al 2008; 
Rudnik Schöneborn et al 2008; for review see also Shababi et al 2014). 
In summary, there appears to be an association of structural cardiac disease and autonomic 
findings, presenting as bradycardia and heart rate variability abnormality, with severe SMA that 
could potentially cause, or contribute to, the findings seen in study CLMI070X2201. 
The risk to patients will be minimized by safety monitoring for cardiovascular function 
including monitoring of blood pressure at regular visits, cardiac biomarkers, such as troponin 
and NTproBNP every 3 months, ECGs every 3 months and echocardiography performed every 
6 months or when clinically significant elevation in troponin and or NTproBNP levels are 
identified by the investigators. It is important that investigators ensure these protocol required 
investigations and get early pediatric cardiology consult if any abnormalities are identified.
Additional risks
An additional risk to patients in this trial is that despite branaplam exposure and its toxicity 
risks, the SMA type I disease course may progress without evidence of stabilization or 
improvement or there may be loss of effect as patients age. In other words, there could be a lack 
of clinical efficacy despite participation in this trial.
There may also be unknown risks of branaplam that may be serious and unforeseen.
Please also refer to the current Investigator’s Brochure.
3.9
Rationale for Public Health Emergency Mitigation Procedures
During a Public Health emergency as declared by Local or Regional authorities i.e. pandemic, 
epidemic or natural disaster, mitigation procedures to ensure patient safety and trial integrity 
are listed in relevant sections. Notification of the Public health emergency should be discussed


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with Novartis prior to implementation of mitigation procedures, and permitted/approved by 
Local or Regional Health Authorities and Ethics Committees as appropriate.
4
Population
Part 1
The study population will be comprised of infants with Type 1 SMA with SMN2 copy 
number of 2, aged approx. 1 month to 7 months. Fourteen patients have been enrolled (amongst 
them, 13 were treated) in Part 1 of the study. No new patients will be enrolled in Part 1.
Part 2
Twenty-five additional patients have been enrolled in Part 2. The study population will be 
comprised of infants with Type 1 SMA with SMN2 copy number of 2, aged up to 180 days of 
age at screening. The investigator must ensure that all patients being considered for the study 
meet the following eligibility criteria. No additional criteria should be applied by the 
investigator
Patient selection is to be established by checking through all eligibility criteria at screening and
baseline. A relevant record (e.g. checklist) of the eligibility criteria must be stored with the 
source documentation at the study site.
Deviation from any entry criterion excludes a patient from enrollment into the study. No new 
patients will be enrolled in Part 2.
Part 3
Patients treated currently with branaplam, who participated in Part 1 or Part 2 of this protocol 
and have completed at least 52 weeks of treatment with branaplam will be eligible to continue 
the study in Part 3. Except for previous participation in Part 1 or Part 2 of the study and 
completion at least 52 weeks of treatment, no further eligibility criteria will be implemented for 
Part 3. Patients will continue treatment as long as they are benefiting from it and it is in the best 
interest of the patients, or other treatment option(s) will be considered more appropriate. No 
new patients will be enrolled in Part 3.
4.1
Inclusion criteria
4.1.1
Part 1
Screening
Baseline 
Criteria
X
1. Written informed consent must be obtained from the parent / guardian before any 
assessment is performed.


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Screening
Baseline 
Criteria
X
2. Type 1 SMA, diagnosed clinically, with symptom onset <6 months of age and genetic 
confirmation of mutations in both alleles of the SMN1 gene, and with SMN2 copy 
number of 2. 
X
3. Best supportive care in place and stable for at least 14 days before screening.
X
4. Age at screening between 1 and 7 months 
X
X
5. Must be able to demonstrate antigravity strength in both biceps.
X
X
6. Must have or agree to have placement of feeding tube for enteral access via 
nasogastric (NG), nasojejunal (NJ), percutaneous gastrostomy (PEG), or 
percutaneous jejunostomy (PEJ) tube for dosing LMI070 (Part 1 only and for 
patients who cannot be administered orally; tube may be removed between doses)
X
X
7. Medical care meets and is expected to continue to meet guidelines set out in the 
Consensus Statement for Standard of Care in SMA (Wang et al 2007), in the 
opinion of the Site Investigator.
X
8. At birth gestational age >32 weeks and body weight at birth >2 kg.
X
X
9. Must live within 2 hours drive of study center. Clearance should be obtained from the 
site investigator and sponsor if the patient resides more than 2 hours ground travel 
from the study center.
X
X
10. Able to complete all study procedures, measurements and visits; and parent or 
guardian/patient has adequately supportive psychosocial circumstances, in the 
opinion of the Site Investigator.
4.1.2
Part 2
Screening
Baseline 
Criteria
X
1. Written informed consent must be obtained from the parent / guardian before any 
assessment is performed.
X
2. Type 1 SMA, diagnosed with genetic confirmation of mutations in both alleles of the 
SMN1 gene, and with SMN2 copy number of 2. 
X
3. Best supportive care in place and stable for at least 14 days before screening as 
assessed by the investigator.
X
4. Age at screening up to 180 days of age
X
X
5. Must be able to demonstrate antigravity strength in both biceps.
X
X
6. Must have or agree to have placement of feeding tube for enteral access via 
nasogastric (NG), nasojejunal (NJ), percutaneous gastrostomy (PEG), or 
percutaneous jejunostomy (PEJ) tube for dosing branaplam (for the first 
administration only and for patients who cannot be administered orally; tube may 
be removed between doses)
X
7.
Minimum CHOP INTEND score of 15 at baseline


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Screening
Baseline 
Criteria
X
X
8. Must be able to swallow solid and liquid even if feeding is used to support nutrition 
intake and must be in the 5th percentile for length or weight on the international 
growth curves and must be proportional in height and weight.
X
9. At birth gestational age >32 weeks and body weight at birth >2 kg.
X
X
10. Able to complete all study procedures, measurements and visits; and parent or 
guardian/patient has adequately supportive psychosocial circumstances, in the 
opinion of the Site Investigator.
4.1.3
Part 3
Baseline
Criteria
X
1. Written informed consent must be obtained from the parent / guardian
X
2. Current participation in Part 1 or Part 2 study and completion of at least 52 weeks of 
treatment with branaplam
X
3. Further branaplam treatment is in the best interest of the patient as assessed by the Site 
Investigator 
X
4. Able to complete all study procedures, measurements and visits; and parent or 
guardian/patient has adequately supportive psychosocial circumstances, in the opinion of the 
Investigator.
4.2
Exclusion criteria
Patients fulfilling any of the following criteria are not eligible for inclusion in this study. 
4.2.1
Part 1
Screening
Baseline 
Criteria
X
1. Use of other investigational drugs within 14 days.
X
2. Neurologic or neuromuscular conditions other than SMA.
X
3. Anemia (Hgb < 9.5 gm/dl ; <5.9 mmol/L), leukopenia (CTCAE Grade 2 or higher, 
<3000 /mm3; <3.0 x109/L), neutropenia (Grade 2 or higher, <1,500/mm3; < 1.5 X 
109/L) or thrombocytopenia (CTCAE Grade 2 or higher, ≤ 75,000/mm3), ≤75 X 109/L 
X
4. Hepatic dysfunction (e.g. AST or ALT CTCAE Grade 1 or higher, ≥ ULN if considered 
to be consequence of hepatic dysfunction); total bilirubin CTCAE Grade 1 or higher, 
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Screening
Baseline 
Criteria
X
5. Age adjusted renal dysfunction with eGFR calculated using the following formula:
eGFR (in mL/min/1.73 m2) = 0.45 X Length (cm) ÷ serum creatinine (mg/dl)
(Schwartz and Work 2009).
≤ 26 mL/min/1.73 m2 up to age 28 days of age
≤ 30 mL/min/1.73 m2 for 1 to 3 months of age
≤ 40 mL/min/1.73 m2 for 3 to 6 months of age
≤ 50 mL/min/1.73 m2 for 6 to 12 months of age
X
6. Clinically significant abnormalities in hematology or clinical chemistry parameters, as 
assessed by the investigator, at screening that would render the patient unsuitable for 
inclusion
X
7. Intractable seizure disorder (other than inactive febrile seizures).
X
X
8. Persistent (in the opinion of the investigator) hypoxemia (O2 saturation awake <92% 
or O2 saturation asleep <91%, without ventilation support) or requiring oral 
suctioning >2 per day
X
X
9. Presence of an untreated or inadequately treated active infection requiring systemic 
antiviral or antimicrobial therapy at any time during the screening period.
X
X
10. Current diagnosis of cardiac and/or vascular abnormalities including uncontrolled 
hypertension, intolerance of blood pressure and pulse assessment techniques such 
that consistent normal values cannot be measured, echocardiographic abnormalities 
(both structural and function) or ECG abnormalities (such as long QT, heart block or 
Torsade’s) indicating significant risk of safety for infant patients participating in the 
study such as: Concomitant clinically significant pediatric cardiac arrhythmias, e.g. 
sustained ventricular tachycardia, and clinically significant second or third degree AV 
block.
X
X
11. Prohibited Concomitant Medications used to treat SMA, including but not exclusively: 
oral albuterol or oral salbutamol, hydroxurea, riluzole, valproate, carnitine, creatine, 
sodium phenylbutyrate within 14 days prior to enrollment or during the study.
X
12. Excluding SMA, any medically unstable condition including cardiomyopathy, hepatic 
dysfunction, kidney disorder, endocrine disorder, GI disorders, prematurity of <32 
weeks gestation, metabolic disorders, severe respiratory compromise and significant 
brain abnormalities or injuries including hypoxic-ischemic encephalopathy.
X
13. Acute or ongoing medical condition that, according to the Site Investigator and 
discussed with sponsor, would interfere with the conduct and assessments of the 
study. Examples are medical disability other than SMA that would interfere with the 
assessment of safety or would compromise the ability of the patient to undergo study 
procedures including be assessed by CHOP INTEND infant motor scale, changes in 
hematologic parameters or gastrointestinal dysfunction that would compromise the 
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4.2.2
Part 2
Screening
Baseline 
Criteria
X
Use of gene transfer at any time or other investigational drugs within 14 days.
X
Patients who have received nusinersen at any time prior to screening
X
Neurologic or neuromuscular conditions other than SMA.
X
Anemia ( CTCAE Grade 2 or higher Hgb < 10 gm/dl ; <6.2 mmol/L ),Leukopenia 
(CTCAE Grade 2 or higher, <3000 /mm3; <3.0 x109/L), neutropenia (Grade 2 or higher, 
<1,500/mm3; < 1.5 X 109/L) or thrombocytopenia (CTCAE Grade 2 or higher, ≤ 
75,000/mm3), ≤75 X 109/L 
X
Hepatic dysfunction (e.g. AST or ALT CTCAE Grade 1 or higher, ≥ ULN, if considered to 
be consequence of hepatic dysfunction); total bilirubin CTCAE Grade 1 or higher, ≥ 
ULN).
X
Age adjusted renal dysfunction with eGFR calculated using the following formula:
eGFR (in mL/min/1.73 m2) = 0.45 X Length (cm) ÷ serum creatinine (mg/dl)
(Schwartz and Work 2009).
≤ 26 mL/min/1.73 m2 up to age 28 days of age
≤ 30 mL/min/1.73 m2 for 1 to 3 months of age
≤ 40 mL/min/1.73 m2 for 3 to 6 months of age
≤ 50 mL/min/1.73 m2 for 6 to12 months of age
X
Clinically significant abnormalities in hematology or clinical chemistry parameters, as 
assessed by the Site Investigator, at screening that would render the patient unsuitable 
for inclusion
X
Intractable epilepsy 
X
X
Persistent (in the opinion of the Investigator) hypoxemia (O2 saturation awake <92% or 
O2 saturation asleep <91%, without ventilation support), 
X
X
Presence of an untreated or inadequately treated active infection requiring systemic 
antiviral or antimicrobial therapy at any time during the screening period.
X
Current diagnosis of cardiac and/or vascular abnormalities including uncontrolled 
hypertension, intolerance of blood pressure and pulse assessment techniques such that 
consistent normal values cannot be measured, echocardiographic abnormalities (both 
structural and function) or ECG abnormalities (such as long QT, heart block or 
Torsade’s) indicating significant risk of safety for infant patients participating in the study 
such as: Concomitant clinically significant pediatric cardiac arrhythmias, e.g. sustained 
ventricular tachycardia, and clinically significant second or third degree AV block. Clinically 
significant findings identified by an echocardiogram performed at screening
X
X
Prohibited Concomitant Medications used to treat SMA: oral albuterol or oral 
salbutamol, hydroxurea, riluzole, valproate, carnitine, creatine, sodium phenylbutyrate 
within 14 days prior to enrollment or during the study.
X
Excluding SMA, any medically unstable condition including cardiomyopathy, hepatic 
dysfunction, kidney disorder, endocrine disorder, GI disorders, metabolic disorders, 
severe respiratory compromise and significant brain abnormalities or injuries including 
hypoxic-ischemic encephalopathy.


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Screening
Baseline 
Criteria
X
Acute or ongoing medical condition that, according to the Site Investigator and 
discussed with sponsor, would interfere with the conduct and assessments of the study. 
Examples are medical disability other than SMA that would interfere with the 
assessment of safety or would compromise the ability of the patient to undergo study 
procedures including be assessed by CHOP INTEND infant motor scale, changes in 
hematologic parameters or gastrointestinal dysfunction that would compromise the 
ability of adequate assessment of safety
Note: In the case where a safety laboratory assessment at screening is outside of the range 
specified above, the assessment may be repeated once prior to dosing. If the repeat value 
remains outside of the specified ranges, the patient should not be dosed and may be excluded 
from the study after discussion between the principal investigator and the sponsor. In borderline 
situations, where the clinical relevance of the result is unclear, additional repetition of the 
assessment over a limited time frame may be considered.
4.2.3
Part 3
There are no specific exclusion criteria. 
5
Treatment
5.1
Study treatment
5.1.1
Investigational treatment
Details on the storage and management of study medication, instructions for dispensing, 
administering and return study treatment are outlined in the Pharmacy Manual. The 
investigational drug, branaplam, will be prepared by Novartis and supplied to the Investigator.
Storage
Branaplam is an oral solution and is provided in one dose strength: 3.5 mg/mL in 6 mL 
borosilicated glass, class 1, single use vials with a rubber stopper. Vials should be stored below 
25°C, kept protected from light and not be frozen.
5.1.2
Treatment arms
Part 1:
14 patients have been enrolled into Part 1 in order to establish the MTD or determine with 
certainty that the MTD cannot be reached. All patients will be treated with branaplam with a 
weekly single dose. No new patients will be enrolled in Part 1.


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Table 5-1
Provisional dose levels for Part 1 dose escalation
a Dose level -1, and -2 may be used if appropriate (e.g. if the starting dose level is not well tolerated)
b The dose increase will be guided by BLRM. Up to 100% dose increase is permitted per dose level if 
the recommended dose increment is higher than 100%.
* This weekly dose level 5 would convert into a 2.95 mg/kg dose of branaplam for a 6.5 kg, 62 cm 
patient with BSA of approximately 0.32 m2.
This table is intended as an example for guidance for the dose escalation part only. Intermediate 
dose levels may be used and some dose levels may be skipped if the dose-escalation rules presented 
in this protocol are followed. Actual dose levels will be confirmed in writing by Novartis and provided to 
all participating study sites before treatment of patients in a new cohort.
Part 2:
A total of 25 patients have been enrolled into Part 2 and assigned to either of the two doses, 
0.625 mg/kg or 2.5 mg/kg, previously tested in Part 1 to further evaluate safety and tolerability 
and change over time in infant growth and motor parameters. All patients will be treated with 
branaplam.
Part 2 dose levels and regimens were decided from the data generated in Part 1. Actual dose 
levels and regimens will be confirmed in writing by Novartis and provided to all participating 
study sites before treatment of patients in Part 2.
In Part 2, dosing will be changed from dosing per m2 of body surface to per weight based dosing 
(mg/kg) in order to simplify study conduct by following a more common outpatient care 
practice while achieving in vivo exposures to branaplam that are similar to those associated with 
clinical response in Part 1. The doses administered in Part 1 were originally normalized to BSA. 
The equivalent mg/kg doses were calculated for a selection of dosing events (all events with 
PK sampling, 119 in total) and the results are shown in Table 6-2. The calculations were based 
on 13 patients who ranged in age from 2 to 17 months, in weight from 5 to 11 kg, and in length 
from 60 to 88 cm. As can be seen from Table 6-2, the calculated mg/kg doses were strongly 
correlated and increased linearly with the BSA normalized doses. Plasma exposure measured 
by AUC was dose-proportional up to 48 mg/m2 with no additional increase in exposure at 
60 mg/m2. Thus, the 48 mg/m2 value was chosen as the dose to anchor all dose calculations for 
Part 2. The planned weight-based doses for Part 2 were calculated as factors of 2.5 mg/kg 
(corresponding to 48 mg/m2 in Part 1) as shown in Table 5-3.
Dose level
Provisional weekly dose
Increment from previous doseb
-2a
1 mg/m2
67% reduction
-1a
3 mg/m2
50% reduction
1
6 mg/m2
Starting dose
2
12 mg/m2
100% increase
3
24 mg/m2
100% increase
4
48 mg/m2
100% increase
5*
60 mg/m2
25% increase


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Table 5-2
Dose conversion between BSA and weight for patients in Part 1
N=number of data points used for dose conversion
Table 5-3
Planned doses for Part 2
Dose level
Planned weekly dose by 
weight
Approximate equivalent 
weekly dose by BSA
1
2
0.625 mg/kg
2.5 mg/kg
12 mg/m2
48 mg/m2
Part 3
In Part 3 subjects will be treated at doses that have already be assigned in Part 1 and Part 2 of 
the study until an optimal selected dose has been determined. However, if in the opinion of the 
investigator, a patient from Part 2, receiving 0.625 mg/kg experiences no further clinical 
improvement of the condition or even progression of disease, the dose may be increased to 2.5 
mg/kg after consultation with the Sponsor. Similarly, if the investigator has any safety concerns 
for a patient receiving 2.5 mg/kg, the dose may be decreased to 0.625 mg/kg after consultation 
with the Sponsor. 
Table 5-4
Planned doses for Part 3
5.2
Treating the patient
5.2.1
Preparation and dispensation
Branaplam will be administered to the patient via the following route of administration:
Part 1:

Enteral (via a feeding tube) during the initial treatment period of 13 weeks 
Dose level
Weekly dose by 
BSA
N
Calculated weekly dose by 
weight
CV 
(%)
Planned weekly 
dose by weight
1
6 mg/m2
28
0.302 mg/kg
8.7
0.3125 mg/kg
2
12 mg/m2
12
0.640 mg/kg
5.0
0.625 mg/kg
3
24 mg/m2
22
1.27 mg/kg
7.6
1.25 mg/kg
4
48 mg/m2
27
2.51 mg/kg
8.3
2.5 mg/kg 
5
60 mg/m2
30
2.89 mg/kg
5.3
3.125 mg/kg
Dose level
Weekly dose by BSA
Planned weekly dose by weight
1
6 mg/m2
0.3125 mg/kg
2
12 mg/m2
0.625 mg/kg
3
24 mg/m2
1.25 mg/kg
4
5
48 mg/m2
60 mg/m2
2.5 mg/kg 
3.125 mg/kg


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
Either oral or enteral during the following extended treatment periods. The decision of the 
route of administration will be performed by the Investigator depending on the patient’s 
ability to swallow. 
Detailed information on how the transition from enteral to oral administration should be 
performed are given in the Site Operations Manual.
Part 2:

Enteral (via a feeding tube) for the first administration on Day 1 

Either oral or enteral for the rest of the study. The decision of the route of administration 
will be performed by the Investigator depending on the patient’s ability to swallow.
The option to administer branaplam orally may be reconsidered based on emerging PK data or 
if oral administration of the investigational drug is not tolerated by the patient following 2 
consecutive attempts and as documented by the Acceptability and Palatability Questionnaire 
(see Table 7-3 and Section 7.5.1).
In Part 1 and Part 2 of the study branaplam may be administered at the study site, or at the 
patient’s home by a qualified clinician or parent / legal guardian. 
See the Site Operations Manual for further details. Sponsor qualified medical personnel will be 
readily available to advise on trial related medical questions or problems.
Part 3:

Similarly to Part 1 and Part 2 of the study, in Part 3 branaplam can be administered by oral 
or enteral application. The decision of the route of administration will be performed by the 
Investigator depending on the patient’s ability to swallow.

Patient will receive first dose at Visit 1 and continue weekly drug administration at home 
administrated by parents/caregivers or qualified personnel. 

At all of the visits where PK is collected the study drug administration should be 
performed at the site.

Dispensation and return of study drug is described in Site Operations Manual
5.3
Other treatments 
5.3.1
Concomitant therapy
All prescription medications including vaccinations, over-the-counter drugs and significant 
non-drug therapies (including physical therapy and blood transfusions) administered or taken 
within the timeframe defined in the entry criteria prior to the start of the study and during the 
study, must be recorded on the Concomitant medications/ Significant non-drug therapies section of 
the CRF.
Medication entries should be specific to trade name, the single dose and unit, the frequency and 
route of administration, the start and discontinuation date and the reason for therapy.


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5.3.2
Prohibited medication
Except for medication which may be required to treat adverse events, and continuation of 
standard of care medications prescribed for SMA, no medication other than study drugs will be 
allowed from the first dosing until all of the Study Completion evaluations have been conducted.
Should a patient have an incidental and limited need for a medication to be taken within the 
restricted pre-dose timeframe (e.g. acetaminophen or ibuprofen, antibiotics, etc.), the sponsor 
should be advised, as administration of any concomitant medication may require the patient to 
be withdrawn. Administration of paracetamol/acetaminophen is acceptable, but must be 
documented
Uses of the treatments displayed in Table 5-5 is NOT allowed after screening:
Table 5-5
Prohibited Chronic treatment for SMA
Medication
Other non-approved experimental therapy for the treatment of SMA
Oral albuterol or salbutamol (inhaled form is not prohibited)
Hydroxyurea
Riluzole
Valproate
Carnitine
Creatine
Sodium phenylbutyrate
Such prohibited medications are postulated in some in-vitro studies as offering low levels of 
SMN splice modulation or alpha motor neuron cell survival benefits and could be considered 
confounding to this study; therefore, these drugs could interfere with assessment of study 
endpoints. The sponsor may consider removing the patient from study if prohibited medications 
are taken during the study. None of these are considered standard of care and are typically only 
used in experimental off-label use since none have been approved for SMA use.  Note: Only if 
valproate is being used for a seizure disorder independently of treatment for SMA, this would 
not be considered prohibited. 
As mentioned in Section 1.1, in vitro experiments showed that branaplam can be metabolized 
via CYP3A4 and glucuronidation. Therefore, there is a potential for inhibitors or inducers of 
CYP3A4 to alter the clearance of branaplam in vivo if oxidative metabolism is the major 
clearance pathway of branaplam. Branaplam should not be administered together with strong 
systemic inhibitors of CYP3A4 such as systemic boceprevir, clarithromycin, conivaptan, 
indinavir, itroconazole, ketoconazole, ritonavir, mibefradil, nefazodone, nelfinavir, 
posaconazole, saquinavir, telaprevir, telithromycin, voriconazole or with strong systemic 
inducers such as carbamazepine, rifampin, phenytoin, St. John’s Wort. Use of weak to moderate 
inhibitors of CYP3A4 should be avoided unless absolutely necessary.
Recent results indicated that branaplam showed a potential perpetrator risk on MATE2-K and 
OCT1 transporters (Section 1.1), which might alter the disposition of MATE2-K and OCT1 
substrates. Therefore, co-administration should be avoided unless absolutely necessary or at 


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least caution should be taken when substrates of MATE2-K (evidence shown in clinics: 
fexofenadine, glycopyrronium, metformin) and OCT1 (clinical known substrates: cephalexin, 
dofetilde, pilsicainide, pindolol, procainamide, ranitidine, varenicline, umeclidinium, 
zidovudine) are co-administered. 
The sponsor will remove the patient from study treatment if nusinersen is taken during the study 
as it would interfere with assessment of study endpoints.
5.3.3
Rescue medication
In general, medications used to treat specific signs and symptoms of SMA are acceptable as 
long as they are part of the standard of care and not listed in Table 5-1. Experimental treatments 
other than branaplam are not allowed. Use of rescue medication must be recorded on the 
Concomitant medications/Significant non-drug therapies CRF after start of study drug.
5.3.4
Treatment blinding
This is an open-label study.
5.4
Dose escalation and dose modification
5.4.1
Dose escalation guidelines
The MTD is the highest drug dosage that is unlikely (<25% posterior probability) to cause DLT 
in more than 25% of the treated patients in the first 2 weeks of the LMI070 treatment. 
A two-parameter Bayesian logistic regression model (BLRM) employing the escalation with 
overdose control (EWOC) principle (Neuenschwander et al 2008; Babb et al 1998) will be used 
during the dose escalation to guide dose level selection and to estimate the MTD. 
Dose escalation will continue until the MTD is reached or until Novartis and Investigators reach 
consensus that, based on a review of the totality of the clinical data (e.g., DLT, lower grade AE, 
PK, PD, etc.) there is no benefit to continue escalation.
Estimation of the MTD during the escalation part of the study will be based upon the estimation 
of the probability of DLT in the first 2 weeks in patients in the Dose-Determining Set (DDS). 
The corresponding statistical methodology is described in Section 11.4.2.
5.4.2
Definitions of dose limiting toxicities (DLTs)
A DLT is defined as an adverse event or abnormal laboratory value assessed as unrelated to 
disease, disease progression, inter-current illness, or concomitant therapies that occurs within 
the first 14 days of treatment with LMI070 and meets any of the criteria listed in Table 5-6.
The National Cancer Institute Common Terminology Criteria for Adverse events (NCI CTCAE) 
most recent version will be used for all grading. For the purpose of dose-escalation decisions, 
DLTs will be considered and included in the BLRM.
The investigator must notify Novartis immediately of any unexpected CTCAE grade > 3 
adverse events or laboratory abnormalities. Prior to enrolling patients into a higher dose level, 
CTCAE grade > 2 adverse events will be reviewed for all patients at the current dose level.


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5.4.3
Dose modifications
Part 1
For the purposes of dose escalation decisions, each cohort will consist of at least 2 newly 
enrolled patients who will be treated at the specified dose level, at least 24 hours apart. The first 
cohort will be treated with the starting dose of 6 mg/m2. In cohorts being treated with doses ≥
48 mg/m2 up to a total of 5 patients will be initially treated. If more than five patients present at 
the same time, additional patients may be treated at the highest dose level deemed safe by 
Novartis and the DMC, in order to avoid unnecessary delays in treatment of this life-threatening 
disease.
Patients must complete the minimum safety evaluation at 2 weeks after the first dose or have 
had a DLT within the first 2 weeks after the first dose to be considered evaluable for dose 
escalation decisions. Dose escalation decisions will occur when the cohort of patients has met 
these criteria.
Dose escalation decisions will be made jointly 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 during the 14 day DLT window and available PK data from evaluable patients. 
The recommended dose for the next cohort of patients will be guided by the Bayesian logistic 
regression model (BLRM) with escalation with overdose control (EWOC) principle.
The adaptive Bayesian methodology provides an estimate of all dose levels of LMI070 that do 
not exceed the MTD and incorporates all DLT information at all tested dose levels for this 
estimation. In general, the next dose will have the highest chance that the DLT rate will fall in 
the target interval [10%, 25%) and will always satisfy the escalation with overdose control 
(EWOC) principle see (Section 11.4.2). In all cases, the dose for the next cohort will not exceed 
a 100% increase from the previous dose. Smaller increases in dose may be recommended by 
the Investigators and Novartis upon consideration of all of the available clinical data. If needed 
to better define the dose-toxicity relationship additional patients may be enrolled to the current 
dose level, to a preceding dose level, or to an intermediate dose level before proceeding with 
further dose escalation.
If the first patient in previously untested dose level experiences a DLT during the first 2 weeks, 
enrollment to that cohort will stop, the BLRM will be updated and the next cohort will be 
opened at the next lower level or an intermediate dose level that is recommended and satisfied 
the EWOC criteria. 
Enrollment will continue until at least 8 evaluable patients in Part 1 have provided DLT 
information during the first 2 weeks after the first dose. MTD will be identified based on 
recommendation of the model and review of all clinical data by Novartis and Investigators in a 
dose-escalation teleconference. MTD will not be declared as higher than the maximum dose 
level tested in Part 1 patients.
If a decision is made to escalate to a higher dose level but one or more additional patient(s) 
treated at the preceding dose level experiences a DLT during the first 2 weeks after the first 


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dose, then the BLRM will be updated with this new information before any additional patients 
are treated at that higher dose level. Patients ongoing will continue treatment at their assigned 
dose levels.
Part 2
In order to ensure patient safety, a dose increase for cohort 1 patients to the next level dose (2.5 
mg/kg) will be allowed if there is lack of efficacy/progressive disease at the 0.625 mg/kg dose.
The following criteria will be applied to define lack of efficacy/progressive disease:
Loss of previously obtained motor skills after baseline of at least two points on the HINE 
Section 2, excluding voluntary grasp and/or more of five points on the CHOP-INTEND scales 
for two consecutive assessments. On the other hand, if decline of assessment occurred during 
an acute illness episode this would not be considered a loss of effect. Pulmonary events or loss 
of feeding will not be considered as loss of effect since these will not be distinguishable for 
normal disease progression without efficacy.
Decision to increase the dose for individual cohort 1 patients will be made jointly by 
Investigators, Novartis study personnel and DMC. Decisions will be based on a synthesis of all 
relevant data available from all dose levels evaluated in the ongoing study, including safety 
information, available PK data from evaluable patients, CHOP INTEND and HINE scores.
Part 3
In Part 3 patients will be treated at doses that have already be assigned in Part 1 and Part 2 of 
the study. However, if a patient from Part 2, receiving 0.625 mg/kg experiences no further 
clinical improvement of the condition or even disease progression, the dose might be increased 
to 2.5 mg/kg. This dose increase is at the discretion of investigator and after consultation with 
the sponsor. Likewise, in case of any safety concern, patients who are receiving 2.5 mg/kg could 
have their dose decreased to 0.625 mg/kg, at the discretion of the investigator and after 
consultation with the sponsor. After the 52-weeks analysis for Part 2, a comparison of the two 
doses showed 2.5 mg/kg to have numerically better changes in HINE-2 scores compared to 
0.625 mg/kg following one year of treatment, and with comparable safety profiles. In addition, 
SMN mRNA analysis shows a trend for dose-dependent effects, with more target engagement 
favoring the 2.5 mg/kg dose. Thus, it is expected that the higher dose will maximize the 
potential long-term benefit which participating patients may be switched to as a selected optimal 
dose. After dose of 2.5 mg/kg was selected to be used as the treatment dose in Part 3, 
investigators from study sites were prompted to have all patients transition to this new dose, 
unless there are safety concerns or this change in dose is not in the best interest of the patient.  
5.4.4
Implementation of dose escalation decisions
To implement dose escalation decisions, the available toxicity information (including adverse 
events and laboratory abnormalities that are not DLTs), the recommendations from the BLRM 
(Part 1 only), and the available PK and PD information will all be evaluated by the Investigators 
and Novartis study personnel (including the study physician and statistician) during a dose 
decision meeting by teleconference. The meeting will, at least, be composed of all investigators 


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who have included patients in the cohort for evaluation and a representative of the sponsor. The 
final dose escalation decisions will be made between the sponsor and the study investigators. 
Drug administration at the next higher dose level may not proceed until the investigator receives 
written confirmation from Novartis indicating that the results of the previous dose level were 
evaluated and that it is permissible to proceed to a higher dose level.
5.4.5
Intra-patient dose escalation
Part 1
Enrolled patients who tolerate the assigned doses of branaplam and continue to extended 
treatment may be escalated to a higher dose once this higher dose has been deemed safe in other 
patients as determined by BLRM with EWOC. This decision will be made on a patient by 
patient basis based on PK accumulation data from that patient, review of all available safety 
data, and PD response. Each time the dose will be escalated for a patient, a new cycle will have 
to be started again as described in Table 7-2.
Data at the new dose level will not be formally included in the statistical model describing the 
relationship between dose and occurrence of DLT. However, these data will be incorporated 
into the clinical assessment of safety when escalation to a new dose level is considered for the study.
Whenever a patient experiences a DLT, treatment with the study drug will be interrupted and 
the toxicity will be followed up as described in Section 5.4.6.
Table 5-6
Criteria for defining dose-limiting toxicities during dose escalation –
Part 1 
TOXICITY
DLT CRITERIA
Blood and lymphatic 
system disorders
Anemia CTCAE Grade ≥ 3
Neutrophil count CTCAE Grade ≥ 4  
Febrile neutropenia CTCAE Grade ≥ 3
Platelet count CTCAE Grade 3 or Grade 2 accompanied by clinically 
significant bleeding
Platelet count CTCAE Grade ≥ 4
Gastrointestinal disorders 
Diarrhea CTCAE Grade 3 ≥ 72 hrs., or dehydration > 5% requiring 
therapy
Diarrhea CTCAE Grade 4, 
Vomiting CTCAE Grade 3 ≥ 72 hrs., despite the use of anti-emetic 
therapy
Vomiting CTCAE Grade 4, despite the use of anti-emetic therapy
Evidence of oral, peri-anal or gastric mucositis characterized by the 
presence of ≥ 2 of the following within 1 week;
Diarrhea CTCAE Grade 3 ≥ 48 hrs.
Vomiting CTCAE Grade 3 ≥ 48 hrs., despite the use of anti-emetic 
therapy
Ulceration CTCAE Grade 2 ≥ 48 hours
Haemorrhaging CTCAE Grade 2 ≥ 48 hours


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TOXICITY
DLT CRITERIA
Investigations
Bilirubina CTCAE Grade 2 for > 7 consecutive days
Bilirubina CTCAE Grade ≥ 3
AST or ALT ≥3 ULN in conjunction with blood bilirubin ≥ 2 x ULN of any 
duration
AST or ALT ≥ 5 x ULN in conjunction with blood bilirubin ≥ 2 x ULN of 
any duration, for patients with elevated AST, ALT, or blood bilirubin at 
baseline
AST or ALT CTCAE Grade 3 for > 7 consecutive days
AST or ALT CTCAE Grade 4
Serum alkaline phosphatase CTCAE Grade 4 > 7 consecutive days
Serum Creatinine Grade 2 for more than 7 days
Serum Creatinine Grade ≥3
Serum lipase and/or serum amylase CTCAE Grade 3 > 7 consecutive 
days with clinical signs or symptoms of pancreatitis
Serum lipase and/or serum amylase (symptomatic and asymptomatic) 
CTCAE Grade 4
Other toxicities
Any other CTCAE Grade ≥ 3 toxicity except:
An AE must be clinically significant to be defined as DLT: lymphopenia, 
study drug-related fever and electrolyte abnormalities (including K, Na, 
Cl, HCO3, Mg, Ca, PO4) that are ≤ CTCAE grade 3 abnormalities will 
not be considered a DLT unless clinically significant. Single incident of 
allergy to study drug will not be defined as DLT
Any adverse event or serious adverse event that is suspected to be 
related to the study drug per investigator assessment and which leads 
to a temporary interruption of treatment with study drug for more than 
14 consecutive days from the day of the first missed dose.
aAn increase of indirect (unconjugated) bilirubin indicative of M. Meulengracht/Gilbert’s syndrome is 
not considered a DLT
Patients may receive supportive care as per local institutional guidelines. Optimal therapy for 
vomiting or diarrhea will be based on institutional guidelines, with consideration of the 
prohibited medications listed in this protocol.
When there is ambiguity about whether an AE is related to the underlying disease as opposed 
to the study drug, the most conservative approach will be taken and the AE will be considered 
as study drug related.
5.4.6
Follow up for toxicities 
For patients who do not tolerate the protocol-specified dosing schedule due to drug related 
toxicities, temporary dose interruptions are permitted. 
If the patient has experienced evidence of clinical benefit and in the opinion of the investigator 
it is in the best interest of the patient to remain on study, then following discussion and 
agreement with the sponsor, the patient may continue on study treatment.
The guidelines in Table 5-5 should be applied. Novartis study team can at all times during the 
study ask the investigator to discontinue the treatment, also for reasons not specified in the 


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Table 5-5. For example, in case emerging PK data for an individual patient is showing higher 
exposure than anticipated, the investigator could be asked by Novartis study team to lower the 
dose, even if no toxicity has been observed. Any dose modification must be recorded on the 
Dosage Administration Record CRF.
The below guidance for interruption of study treatment is applicable when there is no clear 
clinical explanation for the toxicity other than possibly due to study treatment. It may not 
necessarily apply to abnormalities assessed by the Investigator as associated predominantly 
with the underlying disease or intercurrent illness. Such cases should be discussed with the 
Novartis medical team. 
Table 5-7
Criteria for interruption and re-initiation of branaplam treatment for AE 
possibly related to study medication
Worst toxicity
CTCAE Gradea
7 days post dose administration (including day of administration)
Blood and lymphatic system disorders
Anaemia
Grade 1 
Maintain dose
Grade 2 or higher 
Suspend dose until resolved to Grade ≤ 1 or baseline 
If not resolved after 14 days then discontinue of study treatment
Neutropenia (ANC)
Grade 1 
Maintain dose
Grade 2 
Maintain dose
Grade 3 and Grade 4 
Suspend dose until resolved to Grade ≤ 1 or baseline 
If not resolved after 14 days then discontinue of study treatment
Febrile neutropenia
Grade 3 
Suspend dose until resolved
If not resolved after 14 days then permanently discontinue of study 
treatment 
Grade 4
Suspend dose and discontinue of study treatment
Thrombocytopenia
Grade 1 
Maintain dose
Grade 2 or higher 
Suspend dose until resolved to Grade ≤1 or baseline
If not resolved after 21 days , then permanently discontinue of study 
treatment 
Thrombocytosis
Grade 1, no evidence of 
clinical thrombosis and 
platelet counts < 1,000K
Maintain dose and current monitoring plan


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Grade 2, no evidence of 
clinical thrombosis and 
platelet count ≥ 1,000K
Suspend dose until resolved to Grade ≤1 or baseline
If not resolved by 14 days, then obtain hematology consultation
If not resolved after 21 days, then permanently discontinue study 
treatment 
Grade 3 or Grade 4, 
evidence of clinical 
thrombosis event
Suspend dose and permanently discontinue patient from study 
treatment
Investigations
Serum creatinine
Grade 1 
Maintain dose
Grade 2 
Suspend dose until resolved to Grade ≤1 or baseline
If not resolved after 21 days, this discontinue of study treatment 
Grade 3 or Grade 4 
Suspend dose and permanently discontinue patient from study 
treatment
Bilirubinb
Grade 1 
Maintain dose
Grade 2 
Suspend dose until resolved to Grade ≤ 1 or baseline
If not resolved after 21 days then discontinue of study treatment
Grade 3 
Suspend dose until resolved to Grade ≤ 1 or baseline, then:
Grade 4 
Suspend dose and discontinue patient from study treatment
AST or ALT
Grade 1 
Maintain dose
Grade 2 and bilirubin < 
CTCAE grade 2
Maintain dose
Grade 2 and bilirubin ≥ 
CTCAE grade 2
Suspend dose until resolved to Grade ≤ 1 or baseline
If not resolved after 21 days , then discontinue of study treatment
Grade 3 
Suspend dose until resolved to Grade ≤ 1 or baseline
If not resolved after 21 days, then discontinue of study treatment
Grade 4 
Suspend dose and discontinue patient from study treatment
Amylase and/or lipase elevation
Grade 1 
Maintain dose 
Grade 2 
Maintain dose 
Grade 3 with clinical 
signs or symptoms of 
pancreatitis
Suspend dose until resolved to ≤ Grade 2, then:
Grade 4 
Suspend dose and discontinue patient from study treatment
Gastro intestinal disorders
Vomiting 
Grade 1
Maintain dose 
Grade 2 
Maintain dose 


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Grade 3
Suspend dose (only if vomiting cannot be controlled with optimal anti-
emetic treatments) until resolved to Grade ≤ 1
If not resolved after 14 days, then discontinue of study treatment
Grade 4
Suspend dose and discontinue patient from study treatment
Diarrhea
Grade 1 or 2 
Maintain dose 
Grade 2
Suspend dose (only if diarrhea cannot be controlled with optimal anti-
diarrhea treatments) until resolved to ≤ Grade 1
If not resolved after 14 days, then discontinue of study treatment 
Grade 3
Suspend dose (only if diarrhea cannot be controlled with optimal anti-
diarrhea therapy) until resolved to Grade ≤ 1
If not resolved after 14 days, then discontinue of study treatment 
Grade 4
Suspend dose and discontinue patient from study treatment
Ulceration
Grade 1
Maintain dose 
Grade 2
Suspend dose until resolved to Grade ≤ 1, then
If not resolved after 21 days , then discontinue of study treatment
Grade 3 or Grade 4
Suspend dose and permanently discontinue patient from study 
treatment
Hemorrhage
Grade 1
Maintain dose 
Grade 2
Suspend dose until resolved to Grade ≤ 1
If not resolved after 21 days , then permanently discontinue of study 
treatment
Grade 3 or Grade 4
Suspend dose and permanently discontinue patient from study 
treatment
Cardiac Disorders
Clinically significant 
increase in cardiac 
enzymes (Troponin and 
NTproBNP)
Recommendation: Repeat test within 1 week. If it remains elevated get 
pediatric cardiology consult, perform echocardiogram and ECG if not 
already done. Continuing study treatment should be done in 
consultation with a pediatric cardiologist. Manage per standard of care.
Continue checking Troponin/NTproBNP levels at a frequency 
determined by the cardiologist and investigator until resolution.
Grade 1
Maintain dose 
Asymptomatic Grade 2  
Maintain dose 
Symptomatic Grade 2 
Suspend dose until resolved to Grade ≤ 1 or baseline
If not resolved after 21 days, then permanently discontinue of study 
treatment
Symptomatic Grade 3 
with history of 
asymptomatic grade 2 
Suspend dose until resolved to ≤ Grade 1 or baseline 
If not resolved after 21 days, then permanently discontinue of study 
treatment


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Grade 3 – if Grade 2 was 
symptomatic
Suspend dose and permanently discontinue patient from study 
treatment
Grade 4 
Suspend dose and discontinue permanently patient from study 
treatment
Hypertension
Grade 1
Maintain dose 
Grade 2
Suspend dose until resolved to Grade ≤ 1 or baseline (with or without 
HTN monotherapy)
If not resolved with 21 days, then permanently discontinue of study 
treatment
Grade 3
Suspend dose until resolved to ≤ Grade 2, (with or without HTN 
monotherapy),
If two agents required for control, Suspend dose and discontinue 
patient from study treatment
Grade 4
Suspend dose and permanently discontinue patient from study 
treatment
Other adverse events
Grade 1 or 2
Maintain dose 
Grade 3
Suspend dose until resolved to Grade ≤ 1 or baseline, then↓ 1 dose 
level
Grade 4
Suspend dose and discontinue permanently patient from study drug 
treatment
a Common Toxicity Criteria for Adverse Events ( most current version of the CTCAE dictionnary.0)
b An increase of indirect (unconjugated) bilirubin in the absence of transaminase increase, indicative 
of M. Meulengracht/Gilbert’s syndrome, is considered a reason to permanently discontinue the 
study medication.
In the event of several organs being affected with any grade of AE, and with the AE being 
possibly drug related, then the study medication should be either discontinued until resolution 
to baseline or permanently discontinued. The decision must be made by the site investigator, in 
consultation with the Sponsor and independent DMC. 
All grade 4 AEs regardless of causality will result in the study medication being permanently 
discontinued.
For all grade 1 to 3 AEs that are non-related to the study medication, the decision to discontinue 
the study treatment is at the discretion of the investigator. 
5.4.7
Within-patient dose escalation 
In Part 2 and Part 3 of the study no intra-patient dose escalation was planned. However, the 
potential loss of a positive effect over time of the starting dose may occur. Loss of effect is 
defined as loss of previously obtained motor skills from baseline, independent of ventilation of 
at least 2 points on the HINE Section 2, excluding voluntary grasp and/or more of five points 
on the CHOP-INTEND scale for two consecutive assessments. On the other hand, if decline of 
assessment occurred during an acute illness episode this would not be considered a loss of effect.


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Pulmonary events or loss of feeding will not be considered as loss of effect since these will not 
be distinguishable for normal disease progression without efficacy.
After the 52-weeks analysis for Part 2, a comparison of the two doses showed 2.5 mg/kg to have 
numerically better changes in HINE-2 scores compared to 0.625 mg/kg following one year of 
treatment, and with comparable safety profiles. It is expected that the higher dose (2.5mg/kg) 
will maximize the potential long-term benefit which participating patients may be switched to 
as a selected optimal dose in Part 3 of the study. 
The decisions will be made jointly by the investigator and Sponsor, with consultation by the
independent DMC.
5.5
Treatment assignment
Part 1
In Part 1, treatment numbers will be assigned in ascending, sequential order to eligible patients 
(see Site Operations Manual for details). The investigator will enter the treatment number on 
the eCRF.
Part 2
In Part 2, treatment numbers will be assigned in ascending, sequential order to eligible patients 
(see Site Operations Manual for details). The investigator will enter the treatment number on 
the eCRF. Once assigned to a patient, a treatment number will not be reused.
The treatment number becomes the definitive patient number as soon as a patient receives the 
first dose of the respective dosing regimen.
There should be a source document maintained at the site which links the screening number to 
the treatment number (once assigned). This source document should be provided to all 
appropriate parties (i.e. Central Laboratory, ECG Laboratory) as soon as this is available.
Patients who are withdrawn from the study before having completed the first 13 weeks of 
treatment for reasons unrelated to branaplam may be replaced by an equal number of newly 
enrolled patients.
Part 3
In part 3, patients will remain with study numbers already assigned in Part 1 and Part 2 of the 
study. 
5.6
Additional treatment guidance
5.6.1
Treatment exposure and compliance
Pharmacokinetic parameters (measures of treatment exposure) will be determined in all patients 
treated with branaplam.
Compliance will be inherent as patients will be dosed by medical staff in the clinic.


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5.6.2
Recommended treatment of adverse events
All complications of SMA should be treated by the attending physician according to local 
standard of care and treatment guidelines. Medication used to treat AEs must be recorded on 
the Concomitant medications/Significant non-drug therapies CRF.
5.6.3
Emergency breaking of assigned treatment code
Not applicable.
5.7
Restrictions for Study Patients
During recruitment, screening/informed consent review, and baseline visit, the patient’s parent 
or guardian must be informed and reminded of the following restrictions:
5.7.1
Dietary restrictions
Patients will be treated with typical age-appropriate nutrition, each patient will be fed per 
direction of pediatric standards of care. Feeding tube or gastrostomy tube may also be used to 
provide supplemental nutrition.

In order to ensure hydration for urine collection, patients should be encouraged to have 
adequate fluid intake throughout the day. 
A normal feeding schedule should be followed for patients. However, at least one hour should 
be allowed between dosing with branaplam and feeding (before and after dosing), in order to 
avoid complications such as gastroesophageal reflux, which could interfere with the dose 
administration. Reflux precautions must be implemented post-dosing and post-feeding per local 
institutional standards.
5.7.2
General restrictions 
Special handling instructions are required for branaplam as described in the most recent 
Instruction for administration of LMI/branaplam for phase I/II investigational human use. 
5.8
Preparation and dispensation
Preparation, dispensation and return of study drug was described in Section 5.1 and Section 5.2
of the protocol. 
6
Informed consent procedures
Eligible participants may only be included in the study after a legally acceptable 
representative(s) or parent of the participant has provided (witnessed, where required by law or 
regulation), IRB/IEC-approved informed consent.
Site investigators will have detailed discussions about the purpose of this clinical trial to ensure 
there are realistic expectations from participating in this study.


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Informed consent must be obtained before conducting any study-specific procedures (i.e. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the patient source documents. 
Novartis will provide to investigators a proposed informed consent form that complies with the 
ICH GCP guideline and regulatory requirements and is considered appropriate for this study. 
Any changes to the proposed consent form suggested by the investigator must be agreed to by 
Novartis before submission to the IRB/IEC.
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval.


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7
Visit schedule and assessments
The Assessment Schedules below list all of the assessments for each part of the study 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 schedules or as close to the designated day/time as possible. 
Missed or rescheduled visits should not lead to automatic discontinuation.
Participants who discontinue from study treatment are to return for the end of treatment visit as soon as possible, as indicated in the Assessment 
Schedules.
Participants who discontinue from study or withdraw their consent/oppose the use of their data/biological samples should be scheduled for a 
final evaluation visit if they agree, as soon as possible, at which time all of the assessments listed for the final visit will be performed. At this 
final visit, all dispensed investigational product should be reconciled, and the adverse event and concomitant medications not previously 
reported must be recorded on the CRF.
The “X” in the table denotes the assessments to be recorded in the clinical database or received electronically from a vendor. The “S” in the 
table denotes the assessments that are only in the participant’s source documentation and do not need to be recorded in the clinical database.
As per Section 3.9, 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, alternative methods of providing continuing care may be implemented by the investigator as the 
situation dictates. If allowable by a local Health Authority and depending on operational capabilities, phone calls, virtual contacts (e.g. tele 
consult) or visits by site staff/ home nursing staff to the patient´s home, can replace on-site study visits, for the duration of the disruption until 
it is safe for the patient to visit the site again.


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Table 7-1
Assessment Schedule – Part 1 – Initial treatment period (Day -14 to Day 85)
Screening
Baseline Baseline 
Cont.
EOS6,7
Visit Numbers (internal use only) 1
1
2
3
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
777
Day
D -14 to -8 D -7 to -3 D-2 to -1
2
3
5
8
15
22
29
36
43
50
57
64
71
78
85
-
Week
-
-
-
2
3
4
5
6
7
8
9
10
11
12
13
-
Time (h)
-
-
-
0
1
2
4
8
24
48
96
168
-
-
-
-
-
-
-
-
-
-
-
-
Obtain informed consent
X
Inclusion /Exclusion criteria 
X
X
Relevant med history / current medical conditions
X
SMN2 copy number3
X3
Demography
X
Physical examination
X
X
X
X
X
X4
X
X
X
X4
X
X
X
X4
X2
Hepatitis and HIV screen
X
Drug administration 
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs and body measurements
    Body weight/ Body length/ BSA
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X2
   Head & Chest Circumference
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X2
   Body temperature
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X2
   Blood pressure / Pulse rate/ Respiratory rate
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X2
ECG evaluation
X
X
X
X
X2
Echocardiogram
X
X
X
X
X2
Hematology, Blood chemistry, Urinalysis
X
X
X
X
X
X
X
X
X
X
X2
Ophthalmologic examination
X
X
X2
CHOP-INTEND (SMA type I infant motor scale)
X
X
X
X2
Respiratory function
Pulse Oximetry
X
X
X
X
X
X
X
X
X
X
X
X
X
X2
Paradoxical Breathing
X
X
X
X
X
X
X
X
X
X
X
X
X
X2
Breathing pattern: chest circumference during quiet 
breathing (sleep)
X
X
X
X
X
X
X
X
X
X
X
X
X
X2
Ulnar compound motor action amplitude potential 
(CMAP)
X
X
X2
mRNA blood collection
X
X
X2
PK blood collection
X
X
X
X
X
X
X
X
X
X
X
Videotaping of motor activities5
 Adverse Events
Concomitant meds/Therapies
Study completion information
X2
As required8
As required
As required
Treatment Period 1
Treatment Period 2
4
1
1
This document (090095a8948fe802 in docbase CREDI_BS) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/29/2021 9:33:02 AM, signing status at this time:  Completed (1 of 1 signatures) 
Approved for report publication 
at Thu, 29 Jul 2021 05:32:26 AM EDT


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Additional instructions on Part 1 assessment schedule: 
1 Visit structure given for internal programming purposes only
2 To be completed where possible based on completion/discontinuation status
3 Unless already obtained at point of diagnosis. Must be clearly documented in source notes
4 Detailed neurologic examination must be performed at least monthly (and more often if deemed necessary by the investigator)
5 Optional - Informed Consent must be obtained before this assessment
6 For all patients, the end of Study must be completed 30 days after last study drug administration.
7 if patients continue in the extended treatment period then assessment schedule as per Table 8-2 should be followed.
8 up to the discretion of the investigator or parents/guardians


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Table 7-2
Assessment Schedule – Part 1 – Extended treatment period


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Additional instructions on Part 1 Extended assessment schedule: 


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Table 7-3
Assessment Schedule – Part 2
Treatment period 1


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Additional instructions on Part 2, Treatment Period 1 assessment schedule: 


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Treatment period 2


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Additional instructions on Part 2, Treatment Period 2 assessment schedule: 


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Treatment period 3


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Additional instructions on Part 2, Treatment Period 3 assessment schedule: 


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Treatment Period 4


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Additional instructions on Part 2, Treatment Period 4 assessment schedule: 


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Table 7-4
Assessment Schedule – Part 3
Part 3
Visit 1 Treatment and long term follow up (after study month 12 visit the cycle should be 
repeated every year)
Unscheduled 
Visit
End Of Study
Study Month
0
1
2
3
4
5
6
7
8
9
10
11
12
Any time 
Investigator 
considers as 
necessary
30 days after 
last dose
Days
0
28
56
84
112
140
168
196
224
252
280
308
336
Some or all 
assessments 
can be 
performed as 
required
30 days after 
last dose
Visit Window (days)
-14-to 1 +/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
Visit types: R-Regular, S-Safety
R
S
S
R
S
S
R
S
S
R
S
S
R
R/S
R
Obtain informed consent
X
Inclusion /Exclusion criteria 
X
Current medical conditions
X
Drug dispensation/Return
X
X
X
X
X
X
X
Acceptability and Palatability 
Questionnaire
X
X
X
X
X
X
X
Safety
   Physical examination
X
X
X
X
X
X
X
Body weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Body length
X
X
X
X
X
X
X
   Head & Chest Circumference
X
X
X
X
X
X
X


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Part 3
Visit 1 Treatment and long term follow up (after study month 12 visit the cycle should be 
repeated every year)
Unscheduled 
Visit
End Of Study
Study Month
0
1
2
3
4
5
6
7
8
9
10
11
12
Any time 
Investigator 
considers as 
necessary
30 days after 
last dose
Days
0
28
56
84
112
140
168
196
224
252
280
308
336
Some or all 
assessments 
can be 
performed as 
required
30 days after 
last dose
Visit Window (days)
-14-to 1 +/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
Visit types: R-Regular, S-Safety
R
S
S
R
S
S
R
S
S
R
S
S
R
R/S
R
   Body temperature
X
X
X
X
X
X
X
   Blood pressure / Pulse rate
X
X
X
X
X
X
X
   ECG evaluation
X
X
X
X
X
X
X
   Echocardiogram
X
X
X
X
X
   Hematology, Urine analysis
X
X
X
X
X
X
X
   Clinical chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
  Nerve conduction study
X
X
X
X
X
X
X
   Ophthalmologic examination
(X)
(X)
(X)
(X)
(X)
(X)
X
   Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
   Concomitant Medications/Therapies
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Part 3
Visit 1 Treatment and long term follow up (after study month 12 visit the cycle should be 
repeated every year)
Unscheduled 
Visit
End Of Study
Study Month
0
1
2
3
4
5
6
7
8
9
10
11
12
Any time 
Investigator 
considers as 
necessary
30 days after 
last dose
Days
0
28
56
84
112
140
168
196
224
252
280
308
336
Some or all 
assessments 
can be 
performed as 
required
30 days after 
last dose
Visit Window (days)
-14-to 1 +/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
Visit types: R-Regular, S-Safety
R
S
S
R
S
S
R
S
S
R
S
S
R
R/S
R
Motor Scales
   CHOP INTEND (SMA type I infant motor 
scale) 
X
X
X
X
X
X
X
   Speech and motor milestones
X
X
X
X
X
X
X
   HINE (Hammersmith Infant Neurological 
Examination)
X
X
X
X
X
X
X
   Videotaping of motor activities
Optional
Respiratory function
   Pulse Oximetry / Respiratory rate
X
X
X
X
X
X
X
   Paradoxical Breathing
X
X
X
X
X
X
X
   Breathing pattern: chest circumference 
during quiet breathing (sleep)
X
X
X
X
X
X
X


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Part 3
Visit 1 Treatment and long term follow up (after study month 12 visit the cycle should be 
repeated every year)
Unscheduled 
Visit
End Of Study
Study Month
0
1
2
3
4
5
6
7
8
9
10
11
12
Any time 
Investigator 
considers as 
necessary
30 days after 
last dose
Days
0
28
56
84
112
140
168
196
224
252
280
308
336
Some or all 
assessments 
can be 
performed as 
required
30 days after 
last dose
Visit Window (days)
-14-to 1 +/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
Visit types: R-Regular, S-Safety
R
S
S
R
S
S
R
S
S
R
S
S
R
R/S
R
Other assessments
   PK blood collection (Before dosing and 4 
hours post dose)
X
X
X
X
PK blood collection (single blood draw)
X
   Troponin / NTproBNP
X
X
X
X
X
X
X


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Additional instructions on the assessments to be performed in Part 3

Visit 1 can be combined with last visit of Part 1 or Part 2. Visit 1 of Part 3 can be 
combined with last visit of Part 1 or Part 2. It means that assessments of Visit 1 in Part 3
do not need to be repeated if they already were performed in Part 1 or Part 2 within 14 
days before entering Part 3. PK, Troponin and NTproBNP should always be collected on 
Visit 1 of Part 3.

Investigational Medicine Product (IMP) will be administered at site at Visit 1 and then can 
be administered either weekly at home by parent / legal guardian or qualified medical 
personnel, or at study site by qualified medical personnel.

Physical examination will include neurological examination by an experienced pediatric 
physician, neurologist or neuromuscular specialist.

Safety Visits (S) – will be performed every month in between Regular visits (R). Safety 
Visits should be performed on site or at patients’ home by Home Nurse. If neither onsite 
visit nor home nurse visit is possible, investigator will perform a telephone call to 
caregivers. In case none of above is possible, it is acceptable the patient will perform 
Clinical Chemistry locally and the results will be provided to the investigator.

Clinical Chemistry at Safety Visits will include total bilirubin (direct and indirect should 
be differentiated in case of increase > 1.5 ULN), AST, ALT, ALP, total protein and 
albumin.

Home Visits: According to local regulations following procedures can be done at patient 
home by Home Nurse professionals: Vital Signs, Blood draws and urine for safety, blood 
draws for PK 
, IMP delivery, support with patients specific documents, 
administration and return of IMP, ECG/ECHO, AE and Concomitant Medication check.

End of study visit will be performed in case of patient discontinuation/early withdrawal. 
The End of Study visit will have to be performed 30 days after the last treatment. Part 3 of 
the study currently does not have a study end defined, taking into account the lethal nature 
of the SMA Type 1 disease if left untreated. In case the study is discontinued for reasons 
other than branaplam related patient’s safety, Novartis will offer to ongoing patient
alternative treatment.

CHOP INTEND will be collected until 36 months of age.

Ophthalmology assessments: The ophthalmology assessments can be performed at each 
onsite visit. However, if the patient does not have any ocular related complaints and if at 
the previous ophthalmology assessments there were no clinical findings which, potentially 
could be attributed to branaplam, the examination will need to be performed every 12 
months, from the date of the last ophthalmology assessment. This is marked in the 
schedule of assessments as “(X)”.

Every PK assessment includes two blood draws: one blood draw just before dosing the 
patient, and another one 4 hours after dosing, except for a single PK blood draw at EoS.

For any clinically significant increase in cardiac enzymes (Troponin / NTproBNP), repeat 
test within 1 week, if enzymes remain elevated, obtain pediatric cardiology consult, 
perform unscheduled echocardiogram and ECG if not already done for the visit. 


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Continuance of study treatment should be done in consultation with a pediatric 
cardiologist. Please refer to Table 5-7 for more details.
7.1
Screening
7.1.1
Information to be collected on screen failures
For Part 1 and Part 2 patients a following information may be collected as minimum:
Demographics, Informed Consent sign off date and/or withdrawal, adverse events. Full 
description is Screen Failures process data collection is described in eCRF Completion Guide. 
For Part 3 is not applicable.
7.2
Patient demographics/other baseline characteristics
Patient demographic and baseline characteristic data will be collected on all patients.
Relevant medical history/current medical conditions data includes data until signature of 
informed consent. Where possible, diagnoses and not symptoms will be recorded.
Investigators have the discretion to record abnormal test findings on the medical history CRF 
whenever in their judgement, the test abnormality occurred prior to the informed consent 
signature.
7.2.1
Mandatory DNA for patient enrollment
As a mandatory condition of participation all patients will be genotyped at Visit 1 (screening) 
to determine their SMN2 copy number, if not already determined at diagnosis. Only patients 
with exactly 2 copies (alleles) of the SMN2 gene will be included. SMN2 copy number will be 
determined in a validated reference laboratory using a mandatory blood sample.
7.3
Efficacy 
7.3.1
Children’s Hospital of Philadelphia Infant Test of Neuromuscular 
Disorders (CHOP INTEND)
The CHOP INTEND is a reliable, easily administered and well tolerated motor test measure for 
SMA Type 1 and similarly weak infants with neuromuscular disease. The CHOP INTEND can 
provide a useful measure of motor skills and strength in this population.
The assessment will be stopped for patients older than 36 months of age.
7.3.2
Hammersmith Infant Neurological Examination (HINE Section 2)
The HINE is a simple and scorable method for assessing infants between 2 and 36 months of 
age, including different aspects of neurological examinations as cranial nerves, posture, 
movements, tone and reflexes. It provides a summary of motor developmental milestones 
giving not only the opportunity to record the age at which the various milestones were achieved 
but also allowing one to quantify intermediate steps leading to the full achievement of the 
milestone (HINE Section 2).


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The HINE section 2 will be performed as specified in the Assessment Schedule. Methods for 
assessment and recording are specified in the Site Operations Manual.
7.3.3
Videotaping of the patient’s motor activities (optional)
Videotaping is to explore the potential effect of LMI070 on motor activities. Videotaping will 
be up to the discretion of the investigator and parents/guardians, if it is deemed desirable to 
capture any significant changes in the patient’s motor activities that are not already captured by 
the CHOP INTEND. Methods for this assessment are described in the Site Operations Manual. 
7.4
Safety
Safety assessments are specified below; methods for assessment and recording are specified in 
the Site Operations Manual, with the Assessment Schedule detailing when each assessment is 
to be performed.
7.4.1
Laboratory evaluations
Clinically relevant deviations of laboratory test results occurring during or at completion of the 
study must be reported and discussed with Novartis personnel. The results should be evaluated 
for criteria defining an adverse event and reported as such if the criteria are met. Repeated 
evaluations are mandatory until normalization of the result(s) or until the change is no longer 
clinically relevant. In case of doubt, Novartis personnel should again be contacted.
Hematology
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential and 
platelet count, platelet volume, reticulocyte count will be measured. Absolute neutrophil count 
will be calculated. 
Clinical chemistry
Following routine clinical chemistry will need to be done according to Assessment Schedule:
Sodium, potassium, creatinine, urea, chloride, bicarbonate, high sensitivity CRP, albumin, 
calcium, alkaline phosphatase, total bilirubin, AST, ALT, TSH (if abnormal, T4 should be 
assessed), glucose. 
In Part 3, routine clinical chemistry will be done at 3-month interval visits. In addition, liver
function tests will be done at 1-month interval safety visits; albumin, total protein, ALT, AST, 
ALP, and total bilirubin. If the total bilirubin concentration is increased above 1.5 times the 
upper limit of normal, direct and indirect reacting bilirubin should be differentiated.
Additionally, in Part 3, troponin and NTproBNP levels will be assessed at 3-months interval
visits.
Urine analysis
Urine test by dipstick e.g. Combur9: leucocytes, nitrite, pH, protein, glucose, ketones, 
urobilinogen, bilirubin, blood/ hemoglobin


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If the dipstick result is positive for a combination of nitrite, leucocytes and/or blood and protein, 
it is recommended that the sample is sent for bacteriological culture. Investigators may use 
clinical judgement for this additional assessment.
7.4.2
Physical examination
A full physical examination (PE) that evaluates all major organ systems will be performed at 
time points indicated in the Assessment Schedule. This should include a physical and 
neurological examination by an experienced pediatric physician, neurologist or neuromuscular 
specialist. Detailed instructions for the neurologic examination are specified in the Site 
Operations Manual, with the Assessment Schedule detailing when this examination should be 
performed.
Other PEs should be focused on clinical signs and symptoms including evidence of potential 
cell cycle arrest impact on the GI system such as stomatitis, mucositis or lesions of the peri-
anal area. 
Significant findings that were present prior to the signing of ICF must be included in the 
Relevant Medical History/Current Medical Conditions page on the patient’s eCRF. Significant 
new findings that begin or worsen after informed consent must be recorded on the Adverse 
Event page of the patient’s eCRF.
7.4.3
Vital signs

Body temperature in degrees Celsius (°C)

Blood pressure (BP) will be measured at by an oscillometric method at the times indicated 
in the different Assessment Schedules and further described in the Site Operations Manual

Pulse 
7.4.4
Body length, weight and head circumference

Length (measured from the top of the head to the sole of the foot) in cm

Body weight in kg

Head circumference in cm

Chest circumference across nipple line in cm
7.4.5
Electrocardiogram (ECG)

Age-appropriate PR interval, QRS duration, heart rate, RR, QT, QTc, QTcB

The Bazette QT correction formula (QTcB), calculated with the RR interval expressed in 
seconds, should be used for clinical decisions
7.4.6
Echocardiogram
An echocardiogram will be performed at the timepoints defined in the Assessment Schedule or 
if clinically significant elevation of Troponin and/or elevated NTproBNP (as unscheduled)in 
consultation with pediatric cardiologist (refer toTable5-7). The following standard parameters 
will be obtained during the study:


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
Biplane four and two chamber Left Ventricular End Diastolic Volume(LVEDV) 

Biplane four and two chamber Left Ventricular End Systolic Volume(LVESV) 

Left Ventricular Ejection Fraction from LVEDV and LVESV(LVEF) 

Left Ventricular Internal Dimension Diastole) 2-D guided M-mode measurements from 
parasternal long axis (LVIDd)

Left Ventricular Internal Dimension Systole (LVIDs) 2-D guided M-mode measurements 
from parasternal long axis 

Left Ventricular Fractional Shortening (LVFS) 

Intraventricular Septum Thickness diastole (IVSTd) 2-D guided M-mode measurements 
from parasternal long axis 

Left Ventricular Posterior Wall Thickness diastole (LVPWTd) 2-D guided M-mode 
measurements from parasternal long axis 

tricuspid regurgitation(TR) peak velocity (continuous wave Doppler) 

Left Ventricular End Diastolic Volume Index(LVEDVI) = LVEDV/ BSA 

Left Ventricular End Systolic Volume Index(LVESVI) = LVESV/ BSA 
7.4.7
Other safety evaluations
Respiratory function

Respiratory rate

Pulse oximetry

Paradoxical breathing

Breathing pattern: chest circumference measured during quiet breathing or sleep
Ophthalmologic examination
An ophthalmologic examination without sedation using dilated direct and indirect 
ophthalmoscopy will be performed at the time points defined in the Assessment Schedule. Any 
ocular change, compared to baseline or previous assessment that is considered clinically 
significant will need to be documented and reported as a new AE. 
In addition, where feasible, hand-held Optical Coherence Tomography (OCT) will be 
performed as well at the same time points as the routine ophthalmologic examination, as 
described in Table 7-1 for the initial treatment period, Table 7-2 for the extended treatment 
period in Part 1. Please refer to Table 7-3 for Part 2 and Table 7-4 for Part 3. Further details can 
be found in the Site Operations Manual.
Any ocular change, compared to baseline or previous assessment that is considered clinically 
significant will need to be documented and reported as a new AE.
Nerve Conduction Studies
Nerve conduction study is a test commonly used to evaluate the function, especially the ability 
of electrical conduction by the motor and sensory nerves of human body. Nerve conduction 


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velocity (NCV) and F wave are common measurements made during this test. A NCV test 
measures how quickly electrical impulses move along a nerve. Velocities will be assessed in 
upper and lower limbs. The Compound Motor Action Potential (CMAP) is recorded by 
electrical stimulation of a motor nerve and measured in millivolts. 
The Sensory Motor Action Potential (SNAP) is obtained by electrically stimulating sensory 
fibers and is measured in microvolts.  
The same order should be followed at all centers, starting from (1) and going as far as patient
can tolerate. Numbers with a/b refer to the fact that these measurements are yielded from one 
and the same stimulation.
The following tests will be assessed as safety parameters:
Nerve conduction study safety parameters
A maximum of 3 measurements are performed per nerves.
1a
Sural SNAP
Measurement #1 #2 #3
Safety (+)
1b
Sural sensory NCV
Measurement #1 #2 #3
Safety (+)
2a
Ulnar CMAP 
Measurement #1 #2 #3
Efficacy
2b
Ulnar motor NCV
Measurement #1 #2 #3
Efficacy
(+) If an investigator is unable to detect a reliable sural SNAP at the first neurophysiological 
assessment, he/she should switch to the median SNAP and use this in that individual patient further 
on. In these cases, (1a) would turn to “median SNAP”, (1b) to “median NCV”.
The following tests will be assessed as optional parameters:
Nerve conduction study optional parameters
1
Ulnar F-wave latency, wrist
Measurement #1 (*)
Efficacy
2
Peroneal CMAP (EDB muscle)
Measurement #1 #2 #3
Efficacy
3(b)
Peroneal motor NCV (EDB 
muscle)
Measurement #1 #2 #3
Efficacy
4
Peroneal F-wave latency, 
ankle
Measurement #1 (*)
Efficacy
(*) refers to the minimum latency out of 10 F-waves - One measurement, comprising 10 stimuli, is 
sufficient.
Detailed instructions are described in the Site Operations Manual. The Assessment Schedule
does specify the frequency at which this expanded neurophysiologic examination should be 
performed.


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7.5
Additional assessments
7.5.1
Pharmacokinetics
PK samples will be collected at the timepoints defined in the Assessment Schedule.
In order to better define the PK profile, the timing of the PK sample collection may be altered 
based on emergent data. The total blood volume drawn including safety, PK 
 
assessments will not exceed 10 ml per visit over 13 weeks treatment period in Part 2 and 8.2 ml 
per visit over a 13 week period in an Extended treatment period in Part 1. In Part 3, the sample 
volume will not exceed 10 mL per visit over 13 weeks. 
Further details on sample collection, numbering, processing and shipment can be found in the 
Site Operations Manual and Laboratory Manual.
Pharmacokinetics (PK) of branaplam will be evaluated in all patients at all dose levels in Parts 
1, 2, and 3. PK plasma samples for branaplam analysis from venous blood or capillary blood 
(approximately 75 – 200 µL blood per sample). Further details of PK plasma sample collection 
method and associated procedure can be found in the Site Operations Manual.
Branaplam will be determined by a validated LC-MS/MS method; the anticipated Lower Limit 
of Quantification (LLOQ) is 0.500 ng/mL for both analytes. Concentrations will be expressed 
in mass per volume units and will refer to the free base. Concentrations below the LLOQ will 
be reported as “zero” and missing data will be labeled as such in the Bioanalytical Data Report.
Part 1 and 2
The following pharmacokinetic parameters will be determined for branaplam using the actual 
recorded sampling times and non-compartmental method(s) with Phoenix WinNonlin (Version 
8 or higher): Cmax, Tmax, AUClast, AUCinf, T1/2, Vz/F and CL/F from the plasma concentration-
time data.
The linear trapezoidal rule will be used for AUC calculation. 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, Vz/F, and CL/F.
Part 3
The following pharmacokinetic parameters will be determined for branaplam using the actual 
recorded sampling times with Phoenix WinNonlin (Version 8 or higher): Ctrough and C4h.
Summary statistics will be calculated for these parameters.


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7.5.3
RNA
The intermediate products of gene expression, such as mRNA and miRNA will be used to 
examine expression in whole blood using concurrent nucleic acid analytical technologies, such 
as expression microarrays, PCR, Nanostring, Next Generation Sequencing techniques, or others. 
 
 
7.5.4
Acceptability and Palatability Questionnaire
The Acceptability and Palatability Questionnaire should be completed at time points specified 
in Table 7-2 and in Table 7-3. This questionnaire will assess the investigational drug with 
respect to: 

Ease of administration/ acceptability/ tolerability

Palatability (taste)
7.5.5
Speech and motor performance (milestones)
Speech and motor performance (milestones) that are not captured with the CHOP INTEND nor 
the HINE-2 will be captured in the eCRF page called Motor and Speech Domains. The 
following domains including the date of the assessment can be entered into the database:

Voluntary Grasp

Upper extremity function

Hip strength

Speech


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The assessment has to be performed as specified in the assessment schedules in Section 7.
Further details are provided in the study operation manual (SOM).
7.5.6
Appropriateness of safety measurements
The safety assessments selected are standard for this indication/participant population.
8
Discontinuation and completion
8.1
Discontinuation from study treatment and from study
8.1.1
Discontinuation of study treatment (applicable for participants 
following the Extended Schedule of Assessment Part 1 and 
participants enrolled in Part 2 and in Part 3) 
A patient’s parent or guardian may request discontinuation of study treatment for any reason at 
any time.
The investigator must discontinue study treatment for a given participant if he/she believes that 
continuation would negatively impact the participant’s well-being.
Discontinuation from study treatment is required under the following circumstances:

Participant’s parent/guardian withdraws consent

Clinical judgement of site investigator in consultation with Sponsor and independent 
DMC that incurred risks outweigh any potential clinical benefits

Any adverse event, toxicity and laboratory abnormality as per Table 5-7

Participant has unresolved adverse events that require 2 dose de-escalations

Use of prohibited treatment as per Section 5.3 if the potential risk associated with the use 
of the medication outweighs any potential clinical benefits. If a prohibited medication is 
inadvertently administered to a participant, the investigator should contact Novartis 
providing as many details as possible on the co-administered drug (dose and dose 
regimen, duration of treatment, PK data if available) to discuss further steps.

Use of other approved SMA therapies as per Section 5.3

Participants SMA disease course progresses without clear evidence of improvement or 
stabilization of motor function over 6 months. 

Participants SMA disease trajectory is unfavorable and tracking towards late- or end-stage 
of type I SMA e.g. impaired respiratory function requiring a tracheostomy or permanent 
ventilation defined as > 21 days for > 16 hours/day of ventilation as adjudicated by the 
independent DMC.

Any protocol deviation that results in a significant risk to the participant’s safety

If there is perceived clinical benefit, after discussion with Novartis, the investigator and 
the independent DMC, continuation of study treatment may be considered
Patients 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 


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withdraw their consent (see Section 8.1.3). Where possible, they should return for the 
assessments indicated in the Assessment table. If they fail to return for these assessments for 
unknown reasons, every effort (e.g. telephone, e-mail, and letter) should be made to contact 
them as specified in Section 8.2.
If discontinuation from study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the participant’s discontinuation from study treatment and 
record this information.
Participants who discontinue from study treatment agree to return for the end of treatment and 
follow-up visits indicated in the Assessment Schedule (refer to Section 7).
If the participant cannot or is unwilling to attend any visit(s), the site staff should maintain 
regular telephone contact with the participant’s parent/guardian. This telephone contact should 
preferably be done according to the study visit schedule.
8.1.2
Discontinuation from study
Discontinuation from study is when the participant permanently stops receiving the study 
treatment, and further protocol-required assessments or follow-up, for any reason.
If the participant’s parent/guardian agrees, a final evaluation at the time of the participant’s 
study discontinuation should be made as detailed in the assessment table (refer to Section 7).
8.1.3
Withdrawal of informed consent/Opposition to use data/biological 
samples
A patient’s parent or guardian may voluntarily withdraw consent for their child to participate 
in the study for any reason at any time. Withdrawal of consent/opposition to use data/biological 
samples occurs when a participant:

Explicitly requests to stop use of their biological samples and/or data (opposition to use 
participant’s data and biological samples)
and

No longer wishes to receive study treatment
and

Does not want any further visits or assessments (including further study-related contacts)
This request should be in writing (depending on local regulations) and recorded in the source 
documentation.
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/opposition to use data/biological samples 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.


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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 Schedule (Section 7).
Novartis will continue to retain and use all research results (data) that have already been 
collected for the study evaluation, including processing of biological samples that has already 
started at time of consent withdrawal/opposition. No new Personal Data (including biological 
samples) will be collected following withdrawal of consent/opposition.
For US: 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.
8.1.4
Lost to follow-up
For participants whose status is unclear because they fail to appear for study visits without 
stating an intention to from study treatment or discontinue from study or withdraw 
consent/oppose to the use of their data/biological samples, the investigator should 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 formally considered 
lost to follow-up until due diligence has been completed or until the end of the study.
8.1.5
Early study termination by the sponsor 
The study will be reviewed on an on-going basis by the sponsor, the study investigators, and 
the independent DMC. 
The study can be terminated by Novartis at any time. 
Reasons for early termination:

Unexpected, significant, or unacceptable safety risk to patients enrolled in the study

Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data

Discontinuation of study drug development
In taking the decision to terminate, Novartis will always consider patient welfare and safety. 
Should early termination be necessary, patients must be seen as soon as possible and treated as 
a prematurely withdrawn patient. The investigator may be informed of additional procedures to 
be followed in order to ensure that adequate consideration is given to the protection of the 
patient’s interests. The investigator or sponsor depending on local regulation will be responsible 
for informing IRBs/IECs of the early termination of the trial.


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8.2
Study completion and post-study treatment
Study completion is defined as when the last patient 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 patient enrolled into the study will be followed up until disease progression, death, lost to 
follow up, withdrawal or until end of the study. Study completion is defined as when the last 
patient completes their End of Study visit, and any repeat assessments associated with this visit 
have been documented and followed-up appropriately by the Investigator, or in the event of an 
early study termination decision, the date of that decision.
End of Study visit will happen 30 days after the last administration.
If patient is discontinued early, the investigator must provide standard follow-up medical care, 
or must refer them for appropriate ongoing care. If Novartis decides to terminate the study for 
reasons other than safety, the ongoing patients will be offered alternative treatment.
9
Safety monitoring, reporting and committees
9.1
Definition of adverse events and reporting requirements
9.1.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or 
clinical investigation patient 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 a 
medicinal (investigational) product.
The occurrence of adverse events should be sought by non-directive questioning of the patient
parent(s)/guardian(s) at each visit during the study. Adverse events also may be detected when 
they are volunteered by the patient during or between visits or through physical examination, 
laboratory test, or other assessments.
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms, 

they are considered clinically significant, 

they require therapy. 
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patients with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
patient and identifying adverse events. Alert ranges for liver related events are included in Table 
5-6 and Table 5-7.


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Adverse events must be recorded on the Adverse Events CRF for patients that pass screening 
and enter into the study. The adverse events should be reported according to the signs, 
symptoms or diagnosis associated with them, and accompanied by the following information:
1. The Common Toxicity Criteria (CTC) AE grade (most current version)
If CTC-AE grading does not exist for an adverse event, use: 

1=mild, 

2=moderate, 

3=severe 

4=life threatening. 
CTC-AE grade 5 (death) is not used, but is collected in other CRFs (e.g. Study 
Completion, Death/Survival).
2. Its relationship to the study treatment (no/yes), or
investigational treatment (no/yes), or other study treatment (non-investigational) (no/yes), 
or both or indistinguishable,
3. Its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved should be reported.
4. Whether it constitutes a serious adverse event (SAE). See Section 9.1 for definition of 
SAE.
5. Action taken regarding [study/investigational] treatment (select as appropriate). 
All adverse events should be treated appropriately. Treatment may include one or more of 
the following: 

no action taken (i.e. further observation only) 

study treatment dosage adjusted/temporarily interrupted 

study treatment permanently discontinued due to this adverse event 

concomitant medication given 

non-drug therapy given 

patient hospitalized/patient’s hospitalization prolonged 
6. Its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown)
Once an adverse event is detected, it should be followed until its resolution or until it is judged 
to be permanent, and assessment should be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study drug, the interventions 
required to treat it, and the outcome.
Information about expected side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB) or will be communicated between IB updates in the 
form of Investigator Notifications. This information will be included in the patient informed 
consent and should be discussed with the patient parents/guardians during the study as needed.
The investigator should also instruct each patient parent/guardian to report any new adverse 
event (beyond the protocol observation period) that the patient, or the patient’s personal 
physician, believes might reasonably be related to study treatment. This information should be 


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recorded in the investigator’s source documents; however, if the AE meets the criteria of an 
SAE, it must be reported to Novartis.
9.1.2
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:

is fatal or life-threatening 

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:

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 the start of study drug

treatment on an emergency out-patient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 

social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

is medically significant, i.e. defined as an event that jeopardizes the patient or may require 
medical or surgical intervention
Life-threatening in the context of a SAE refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if more severe.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
Medical and scientific judgement should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse (please refer to the ICH-E2D Guidelines).
If all AEs (serious and non-serious) are captured on the CRF, SAEs are monitored continuously 
and have also special reporting requirements; see section below.


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9.1.3
SAE reporting
To ensure patient safety, every SAE, regardless of causality, occurring after the patients 
parents/guardians have provided informed consent and until 30 days after the last study visit 
must be reported to Novartis safety immediately, without undue delay, under no circumstances 
later than 24 hours of learning of its occurrence as described below. Any SAEs experienced 
after this should only be reported to Novartis if the investigator suspects a causal relationship 
to study treatment. 
Recurrent episodes, complications, or progression of the initial SAE must be reported as follow-
up to the original episode, regardless of when the event occurs. This report must be submitted 
within 24 hours of the investigator receiving the follow-up information. An SAE that is 
considered completely unrelated to a previously reported one should be reported separately as 
a new event.
Information about all SAEs (either initial or follow up information) is collected and recorded 
on the paper Serious Adverse Event Report Form. The investigator must assess the relationship 
to each specific component of study treatment (if study treatment consists of several drugs)
complete the SAE Report Form in English, and send the completed, signed form by fax within 
24 hours after awareness of the SAE to the local Novartis Drug Safety and Epidemiology 
Department, notifying the Clinical Trial Leader. Contact information is listed in the Site 
Operations Manual. 
The original copy of the SAE Report Form and the fax confirmation sheet must be kept with 
the source documentation at the study site. Follow-up information should be provided using a 
new paper SAE Report Form stating that this is a follow-up to a previously reported SAE.
Follow- up information provided should describe whether the event has resolved or continues, 
if and how it was treated, whether the treatment code was broken or not and whether the patient
continued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the investigational treatment a Drug Safety and 
Epidemiology Department associate may urgently require further information from the 
investigator for Health Authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same investigational 
treatment that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions 
(SUSARs) will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with EU Guidance 2011/C 172/01 or as per national regulatory 
requirements in participating countries.
9.1.4
Pregnancy reporting
Not required for this patient population. 


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9.1.5
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient or 
consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects.
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE and reported to 
Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
Investigator’s awareness.
Table 9-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in Dosing 
CRF (Yes/No)
Document in AE 
eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated 
with an AE
Only if associated with 
an SAE
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a SAE
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections.
9.2
Additional Safety Monitoring
9.2.1
Early phase safety monitoring
The Investigator will monitor adverse events in an ongoing manner and inform the Sponsor of 
any clinically relevant observations. Any required safety reviews will be made jointly between 
medically qualified personnel representing the Sponsor and Investigator. Such evaluations may 
occur verbally, but the outcome and key discussion points will be summarized in writing (e-
mail) and made available to both Sponsor and all Investigator(s). Criteria pertaining to stopping 
the study/treatment or adapting the study design are presented above.
When two or more clinical site(s) are participating in the clinical study, the Sponsor will advise 
the Investigator(s) at all sites in writing (e-mail) (and by telephone if possible) of any new, 
clinically relevant safety information reported from another site during the conduct of the study 
in a timely manner.


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9.2.2
Data Monitoring Committee
An independent DMC is instituted for this open label study with focus on safety. The DMC will 
periodically review the safety information throughout the study to monitor for unexpected 
toxicity. 
The mission of the DMC will be to independently review and evaluate the safety, PD and 
efficacy data generated during the study as defined in this protocol. The DMC must also ensure 
that study patients are not exposed to unnecessary or unreasonable risks and that the study is 
conducted with high scientific and ethical standards. Finally, the DMC must make 
recommendations to the Sponsor on the actions to be taken on the study, which may include but 
not limited to the following:

Continuation of individual patient treatment based on demonstrated tolerability and 
clinical benefit with agreement with the sponsor and investigator

Initiation of Part 2 of study based on data collected in Part 1

Discontinuation of the study

Suggested modifications to the study protocol and/or the informed consent document

Continuation of the study according to the protocol and the relevant amendments
The DMC is accountable to the Sponsor for appropriate monitoring of the study data.
Although the DMC may make recommendations to the Sponsor about changes in the conduct 
of the study, final decisions will be made by Novartis. In the case of early termination, 
consultation with Health Authorities may be required.
The frequency of the DMC meetings will be determined by the members and ratified in the 
DMC Charter.
9.2.3
Steering Committee
Not applicable to this study
9.2.4
Adjudication Committee
Not applicable to this study
10
Data collection and database management
10.1
Data collection
Data not requiring a separate written record will be defined in the Site Operations Manual and 
Assessment Schedule and can be recorded directly on the CRFs. All other data captured for this 
study will have an independent originating source (either written or electronic) with the CRF 
not being considered as source.
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.


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Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms using fully validated software that conforms to 21 CFR Part 11 
requirements. Designated investigator site staff will not be given access to the EDC system until 
they have been trained. Automatic validation programs check for data discrepancies and, by 
generating appropriate error messages, allow the data to be confirmed or corrected before 
transfer of the data EDC. The Investigator must certify that the data entered into the Electronic 
Case Report Forms are complete and accurate. After database lock, the investigator will receive 
a CD-ROM of the patient data for archiving at the investigational site.
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.
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification.
10.2
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.
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and made available for data analysis/moved to 
restricted area to be accessed by independent programmer and statistician. Any changes to the 
database after that time can only be made after written agreement by Novartis development 
management.
11
Data analysis and statistical methods
11.1
Analysis sets
As a general principle, all tabulations and analyses will be done by the treatment received in the 
initial treatment period. For some inferential analyses on patients who receive multiple different 
doses over time, the actual dose received may be used. In the text below “treatment group” 
refers to the dose administered in the initial treatment period.
The following populations will be used for the statistical analyses:


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The Enrolled Set (ENR) will consist of all patients who signed informed consent and were 
assigned to a treatment arm.
The Full Analysis Set (FAS) will consist of all patients in the Enrolled Set who received at least 
one dose of study drug. 
The Safety Analysis Set (SAF) will consist of all patients in the Enrolled Set who received at 
least one dose of study drug. The safety population will be used for the analyses of safety 
variables
For Part 1 only: The Dose Determining Set (DDS) consists of all patients from the safety set 
who have sufficient safety evaluations to provide DLT information 2 weeks after the first dosing 
or discontinue earlier due to DLT. Patients who do not experience DLT during the first 2 weeks 
after the first dose are considered to have sufficient safety evaluations if they are considered by 
both the Sponsor and Investigators to have sufficient safety data to conclude that a DLT did not 
occur. 
For Parts 1 and 2, the PK analysis set will include all patients that received at least one dose of 
branaplam with available PK data and no protocol deviations with relevant impact on PK data.
The PD analysis set will include all patients that received at least one dose of branaplam with 
available PD data and no protocol deviations with relevant impact on PD data.
11.2
Patient demographics and other baseline characteristics
All data for background and demographic variables will be listed by treatment group and patient. 
Summary statistics will be provided by treatment group. Relevant medical history, current 
medical conditions, results of laboratory screens, drug tests and any other relevant information 
will be listed by treatment group and patient.
11.3
Treatments 
Data for study drug administration (rescue medication) and concomitant therapies will be listed
by part, treatment group, and patient.
11.4
Analysis supporting primary objectives
The primary objective of Part 1 is to estimate the Maximum Tolerated Dose (MTD) of 
branaplam when administered orally on a once weekly schedule to patients with Type 1 spinal 
muscular atrophy. The primary analysis method is an adaptive Bayesian logistic regression 
model (BLRM) guided by the escalation with overdose control (EWOC) principle 
(Neuenschwander et al 2008).
The primary objective of Part 2 is to evaluate the safety and tolerability of multiple dose 
regimens of branaplam for 52 weeks in patients with Type 1 SMA.
The primary objective of Part 3 is to assess long term safety and tolerability of extended 
oral/enteral, once a week branaplam treatment in patients with Type 1 SMA who have had at 
least 52 weeks of treatment in either Part 1 or 2 study of this protocol.


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All information obtained on adverse events will be displayed by initial and administered dose 
and patient. Additional interim analyses may be conducted to support decision making 
concerning the current clinical study, the sponsor’s clinical development projects in general or 
in case of any safety concerns. Internal analysis of Part 2 will be conducted once all Part 2 
patients completed 52 weeks of treatment. After all patients have transitioned from Part 1 and 
2 of the study in the Part 3, additional interim analysis might be conducted.
11.4.1
Definition of primary endpoint(s) 
The primary endpoint is the incidence of dose limiting toxicity (DLTs) in the first 2 weeks after 
the first dose in Part 1. Estimation of the MTD of LMI070 will be based upon the estimation of 
the probability of DLT in the first 2 weeks after the first dose in the DDS. This probability is 
estimated by the model in Section 11.4.2.
11.4.2
Statistical model, hypothesis, and method of analysis
11.4.2.1 Rules for Dose escalation in Part 1
An adaptive, 2 parameter Bayesian logistic regression model (BLRM) guided by the escalation
with overdose control (EWOC) principle, will be used to make dose recommendations and 
estimate the MTD during the escalation part of the study. The dose-toxicity (DLT) relationship 
in each dose escalation will be described by the following logistic regression model:
logit (π(d)) = log(α) + β log(d/d*), α>0, β>0
where logit(π(d))= ln (π(d)/(1- π(d))), and π(d) is the probability of a DLT at dose d, where d 
represents the total weekly dose in Part I. Doses are rescaled as d/d* with reference dose of d* = 
40 mg/m2. As a consequence α is equal to the odds of toxicity at d*. Note that for a dose equal 
to zero, the probability of toxicity is zero. The Bayesian approach requires the specification of 
prior distributions for the model parameters. The prior distributions and the process of their 
derivation are provided in the statistical appendix (Appendix 1).
11.4.2.2 Dose recommendation
After each cohort is completed the posterior distributions for the probabilities of DLT at 
different dose levels are obtained. The results of this analysis are summarized in terms of the 
estimated probabilities that the true rate of DLT at each dose-level will lie within each of the 
following intervals:

[0, 10%) under-dosing.

[10%, 25%) targeted toxicity.

[25%, 100%] excessive toxicity.
Following the principle of escalation with overdose control (EWOC), after each cohort of 
patients the recommended dose is the one with the highest posterior probability of the DLT rate 
falling in the target interval [10%, 25%) among the doses fulfilling escalation with overdose 
control (EWOC), i.e. it is unlikely (< 25% posterior probability) that the DLT rate at the dose 
falls in the excessive toxicity interval i.e. P(DLT) is 25% or higher. In addition, the maximum 
dose escalation is limited to 100% of the previous dose.


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Note that the dose that maximizes the posterior probability of targeted toxicity is the best 
estimate of the MTD, but it may not be an admissible dose according to the overdose criterion 
if the amount of data is insufficient. If vague prior information is used for the probabilities of 
DLT, in the early stages of the study this escalation procedure will reflect a cautious strategy. 
The dose recommended by the adaptive Bayesian logistic model may be regarded as guidance 
and information to be integrated with a clinical assessment of the toxicity profiles observed at 
the time of the analysis in determining the next dose level to be investigated.
Details of the criteria for dose escalation and the determination of the MTD are provided in 
Section 5.4.
11.4.2.3 Analysis of the primary variable
All information obtained on adverse events will be displayed by initial and administered dose 
and patient.
11.4.2.4 Listing/summary of DLTs
DLTs will be listed and their incidence summarized by primary system organ class, worst grade 
based on the CTCAE version 5.0, type of adverse event, and by treatment. The DDS will be 
used for these summaries.
11.4.3
Handling of missing values/censoring/discontinuations
In Part 1, patients who are ineligible for the dose-determining set (DDS) may be replaced if 
necessary. In Part 2, patients lost to follow up and are unable to provide week 12 data due to 
non-treatment related reason may be replaced if necessary.
In the inferential analyses of secondary 
 variables, missing observations will be 
assumed to be missing at random (MAR).
11.5
Analysis supporting secondary objectives
11.5.1
Efficacy and/or Pharmacodynamics endpoint(s)
Secondary endpoints including growth measurements, respiratory function assessments, and 
CHOP INTEND infant motor scale, as well as their difference from baseline where a baseline 
is present, will be summarized at different time points for Parts 1&3 and Parts 2&3 separately.
Measurements which fall on a close to continuous scale (such as CHOP-INTEND and), the 
change from baseline will be analyzed by a mixed model for repeated measurements (MMRM) 
for study parts 2 and 3, with terms for treatment group, baseline value, baseline age category 
(<= 4 months/> 4 months), visit, treatment group*visit interaction, and baseline value*visit 
interaction.
Kaplan Meier plots for time to death or permanent ventilation will be provided with 95% 
confidence intervals.


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11.5.2
Safety endpoints
Adverse events
All information obtained on adverse events will be displayed by initial and administered dose 
and patient. For reporting purposes, the main focus will be on treatment emergent adverse 
events (TEAEs). Treatment emergent AEs are defined as events starting on or after the first 
dose of study drug that were absent pre-treatment, or events present prior to the first dose but 
increased in severity after the first dose. TEAEs will be summarized in appropriate summary 
tables and in Parts 2 & 3, also displayed in stacked bar charts. All adverse events will be 
presented in listings.
Vital signs
All vital signs data will be listed by treatment, patient, and visit/time and if ranges are available 
abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics will be 
provided by scheduled visit, part, and treatment where appropriate. Individual blood pressure 
and pulse will be displayed in panel plots, while individual length and weight data will be 
displayed in spaghetti plots with US Center for Disease Control and Prevention (CDC)
percentiles relative to age at evaluations (in months).
ECG evaluations
All ECG data will be listed by treatment, patient and visit/time, abnormalities will be flagged. 
Summary statistics will be provided by scheduled visit, part, and treatment where appropriate.
Individual ECG data will be displayed in panel plots.
Clinical laboratory evaluations
All laboratory data will be listed by treatment, patient, and visit/time and if normal ranges are 
available abnormalities will be flagged. Summary statistics will be provided by scheduled visit, 
part and treatment where appropriate.
In addition, shift tables will be provided for all parameters to compare a patient’s baseline 
laboratory evaluation relative to the post-baseline values. Liver enzyme data will be 
summarized according to newly occurring abnormality criteria, as well as some standard graphs 
for this data.
11.5.3
Pharmacokinetics
Branaplam plasma concentration data will be listed by protocol part, dose, patient, and sampling 
time point. Descriptive summary statistics will be provided by dose and sampling time point, 
including concentrations below the LLOQ reported as zero. 
Summary statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and 
geometric), median, minimum and maximum. An exception to this is Tmax where median, 
minimum and maximum will be presented. Concentrations below LLOQ will be treated as zero 
in summary statistics and for PK parameter calculations. A geometric mean will not be reported 


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if the dataset includes zero values. Pharmacokinetic parameters will be calculated as described 
in Section 7.5.1 and will be listed by protocol part, dose and patient.
11.5.4
DNA
SMN2 copy number could be listed by patient.
11.5.5
Pharmacokinetic / Pharmacodynamic relationships
If possible and depending on the data a PK/PD model will be developed relating PK to SMN 
blood protein levels. The model may be used for guiding the dose frequency decision in Part 2 
of the protocol.
11.7
Interim analyses
After each cohort of patients finish first dosing and contribute safety data at week 2, an interim 
analysis (without requirement for database lock) will be conducted for dose escalation decisions. 
The analysis will be comprised of fitting a Bayesian logistic regression model (BLRM) based 
on the dose limiting toxicity (DLT) information. From this model, the posterior probability of 
DLT rate at different dose levels will be estimated and a dose will be recommended to guide 
dose selection for the next cohort or declaration of MTD. In general, the next dose will have the 
highest chance that the DLT rate will fall in the target interval [10%, 25%) and will always 
satisfy the escalation with overdose control (EWOC) principle that the posterior probability of 
DLT rate falling in overdosing interval (>25%) is below 25%. In all cases, the dose for the next 
cohort will not exceed a 100% increase from the previous dose. Final dose escalation decisions 
will be made by Investigators and Novartis study personnel. Decision will be based on a 
synthesis of all relevant data available from all dose levels evaluated in the ongoing study, 
including safety information, DLTs, and available PK data from evaluable patients. Dose 
escalation will continue until identification of the MTD. 
An interim analysis is planned after MTD determination in Part 1 to evaluate PD effects of the 
treatment and assist with decision making for Part 2. Data on muscle thickness, ratio of muscle 
thickness to subcutaneous tissue thickness and muscle echo intensity, growth measurements, 


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respiratory function assessments and CHOP INTEND infant motor scale will be summarized at 
different time points and compared to baseline.
Additional interim analyses may be conducted to support decision making concerning the 
current clinical study, the sponsor’s clinical development projects in general or in case of any 
safety concerns. Internal analysis of Part 2 will be conducted once all Part 2 patients completed 
52 weeks of treatment. After all patients have transitioned from Part 1 and 2 of the study in the 
Part 3, additional interim analysis might be conducted.
Additional interim analyses may be conducted to support decision making concerning the 
current clinical study, the sponsor’s clinical development projects in general or in case of any 
safety concerns.
The Interim Analysis Team may communicate interim results (e.g. evaluation of PoC criteria 
or information needed for planning/modifying another study) to relevant Novartis teams for 
information, consulting and/or decision purposes.
11.8
Sample size calculation
11.8.1
Part 1
The sample size for Part 1 is driven by feasibility. In part 1, cohorts of at least 2 patients are 
planned to be dosed until a decision is made for MTD, however adjustment of cohort size might 
be considered due to enrollment and safety consideration.  Thirteen patients were enrolled and
treated, to test 5 dose levels. At least 2 patients are required for cohort 1 at the starting dose. 
Size of later cohorts may be adjusted based on feasibility. As noted earlier, if more than two 
patients present simultaneously for the study, additional patient(s) may be dosed in a cohort to 
avoid unnecessary delays in treatment of this life-threatening disease. 
11.8.2
Part 2
In Part 2, 25 patients were enrolled to evaluate up to 2 different dose cohorts with at least 6 
patients and up to approximately 10 patients per cohort. 
The driver of the sample size in Part 2 is the primary objective, safety. We are able with 95% 
confidence to rule out that the true incidence rate exceeds 50% of any class of adverse events if 
none in that class are observed in 6 patients.
Furthermore, in an interim analysis of CHOP INTEND data from Part 1, CHOP INTEND scores 
were analyzed by a mixed linear model with covariates for dose, baseline CHOP INTEND, and 
calendar age. A compound symmetric covariance structure was assumed for observations 
within the same individual. This analysis pointed to a total estimated variability of 7 on a CHOP 
INTEND scale (sum of between and within patient’s variance components). The table below 
(Table 11-1) shows the power to detect a difference in CHOP INTEND score between two 
adjacent dose groups (by one-sided t test at nominal significance level 5%). It seems likely that 
differences exceeding 10 points on a CHOP INTEND scale will be identifiable with the planned 
sample size 


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11.8.3
Part 3
The sample size of Part 3 depends on the number of patients enrolled in Parts 1 and 2. All 
patients who complete at least 52 weeks of treatment in either Part 1 or Part 2 are eligible to 
enroll in Part 3.
Table 11-1
Power to detect a difference in CHOP INTEND score between two 
adjacent dose groups (by one-sided t test at nominal significance 
level 5 percent)
N=6
N=7
N=8
N=9
N=10
Effect size 8 points
56%
64%
70%
74%
78%
Effect size 10 points
74%
80%
85%
89%
92%
12 points
86%
91%
94%
96%
98%
12
Ethical considerations and administrative procedures
12.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC, US Code of Federal Regulations Title 
21, and Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid 
down in the Declaration of Helsinki.
12.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution should obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial 
protocol, written informed consent form, consent form updates, patient recruitment procedures 
(e.g. advertisements) and any other written information to be provided to patients. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made.
For multi-center trials, a Coordinating Investigator will be selected by Novartis around the time 
of Last Patient Last Visit to be a reviewer and signatory for the clinical study report. 
12.3
Publication of study protocol and results
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this trial will be either submitted for publication 
and/or posted in a publicly accessible database of clinical trial results.


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12.4
Quality Control and Quality Assurance
Novartis/sponsor 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
13
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study patients. Additional assessments required to ensure safety of patients should be 
administered as deemed necessary on a case by case basis. Under no circumstances should an 
investigator collect additional data or conduct any additional procedures for any research related 
purpose involving any investigational drugs.
Investigators must apply due diligence to avoid protocol deviations. If the investigator feels a 
protocol deviation would improve the conduct of the study this must be considered a protocol 
amendment, and unless such an amendment is agreed upon by Novartis and approved by the 
IRB/IEC/REB it cannot be implemented. All significant protocol deviations will be recorded 
and reported in the clinical study report (CSR).
13.1
Protocol amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC prior to 
implementation. 
Only amendments that are intended to eliminate an apparent immediate hazard to patients may 
be implemented, provided the Health Authorities and the reviewing IRB/IEC are subsequently 
notified by protocol amendment. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, the CTL should 
be informed and (serious) adverse event reporting requirements (Section 9) followed as 
appropriate.


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14
References
Available upon request.
Aardema MJ, Albertini S, Arni P et al. (1998) Aneuploidy: a report of an ECETOC task force. 
Mutation Res 410:3-79. 
Babb, J, Rogatko, A and Zacks, S (1998) Cancer phase I clinical trials: Efficient dose escalation 
with overdose control. Stat. Med., 17:1103-20.
Bach JR, Saltstein K, Sinquee D, et al (2007) Long-term survival in Werdnig-Hoffmann disease. 
Am J Phys Med Rehabil 86:339-45.
Bach JR (2007) Medical considerations of long-term survival of Werdnig-Hoffmann disease. 
Am J Phys Med Rehabil 86:349-55.
Coovert DD, Le TT, McAndrew PE, et al (1997) The Survival Motor Neuron protein in spinal 
muscular atrophy. Hum Mol Gene. 6: 1205-14.
Dubois D; Dubois EF (1916) A formula to estimate the approximate surface area if height and 
weight be known. Arch Int Med 17:863-871. 
EMEA guideline on small populations (2006)
EMA (2016): Briefing Document to the Clinical Trial Readiness in Spinal Muscular Atrophy 
(SMA) SMA Europe, TREAT-NMD and European Medicines Agency meeting.
FDA (2006) “General Guide for Starting Dose Selection for a Cytotoxic Agent in Cancer 
Patients”.
Finkel RS, McDermott MP, Kaufmann P, et al (2014) Observational study of spinal muscular 
atrophy type I and implications for clinical trials. Neurology; 83: 810-7.
Glanzman AM, Mazzone E, Main M et al. (2010) The Children’s Hospital of Philadelphia 
Infant Test of Neuromuscular Disorders (CHOP-INTEND): test development and reliability. 
Neuromuscular disorders: NMD; 20:155-61.
Heier C R, Satta R, Lutz C, et al (2010) Arrhythmia and cardiac defects are a feature of spinal 
muscular atrophy model mice. Hum Mol Genet 19(20): 3906-18.
Heier CR, DiDonato CJ (2015) ECG in neonate mice with spinal muscular atrophy allows 
assessment of drug efficacy. Front Biosci (Elite Ed). 7:107-16.
Heilbron DC, Malcolm AH, Al-Dahwi A, et al (1991) Expressing glomerular filtration rate in 
children. Pediatr Nephrol 5:5-11.
Holt TR, Withington DE, Mitchell E (2011) Which pressure to believe? A comparison of direct 
arterial with indirect blood pressure measurement techniques in the pediatric intensive care unit. 
Pediatr Crit Care Med; 12(6): e391-394.
Hua Y, Sahashi K, Rigo F, et al (2011) Peripheral SMN restoration is essential for long-term 
rescue of a severe SMA mouse model. Nature 478(7367): 123–6.


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International Council for Harmonization (ICH) S9 guidelines (2010)
Kishnani PS, Corzo D, Nicolino M (2007) Recombinant human acid α-glucosidase: Major 
clinical benefits in infantile-onset Pompe disease. Neurology 68:99-109.
Kolb SJ, Coffey CS, Yankey JW, et al (2016) Baseline results of the NeuroNEXT spinal 
muscular atrophy infant biomarker study. Annals of Clinical and Translational Neurology 3(2): 
132-145.
Le TT, McGovern VL, Alwine IE (2011) Temporal requirement for high SMN expression in 
SMA mice. Hum Mol Genet 20(18):3578-91.
Marx J (2002) Debate surges over the origins of genomic defects in cancer. Science 26; 
297(5581):544-46
Menke LA, Poll-The BT, Clur SA, et al (2008) Congenital heart defects in spinal muscular 
atrophy type I: a clinical report of two siblings and a review of the literature. Am J Med Genet 
A 146:740–44.
Neuenschwander B, Branson M, Gsponer T (2008) Critical aspects of the Bayesian approach 
to phase I clinical trials. Statist. Med. 27(13):2420-243.
Palacino J, Swalley SE, Song C, et al (2015). SMN2 splice modulators enhance U1-pre-mRNA 
association and rescue SMA mice. Nat Chem Biol; 11: 511-7
Pillen S, Scholten RR, Verrips A (2003a) Quantitative ultrasonography of skeletal muscles in 
children: normal values. Muscle Nerve. Jun;27(6):693-8.
Pillen S, Scholten RR, Zwarts MJ (2003b) Quantitative skeletal muscle ultrasonography in 
children with suspected neuromuscular disease. Muscle Nerve. Jun;27(6):699-705.
Rick RM, van Deursen JM (2013) Aneuploidy in health, disease, and aging.  J Cell Biol 201 
(1): 11-21
Rogatko A, Tighiouart M (2007) Novel and efficient translational clinical trial designs in 
advanced prostate cancer in Prostate Cancer, L. Chung, W. Isaacs, and J. W. Simons, Eds., pp. 
487–495, Humana Press, New Jersey, NJ, USA,.
Rudnik-Schöneborn S, Heller R, Berg C, et al (2008) Congenital heart disease is a feature of 
severe infantile spinal muscular atrophy. J Med Genet 45:635–38.
Schwartz GJ, Work DF (2009) Clin J Am Soc Nephrol; 4(11):1832-43.
Shababi M, Lorson CL, Rudnik-Schöneborn SS (2014) Spinal muscular atrophy: a motor 
neuron disorder or a multi-organ disease? J Anat. 224:15-28.
Wang CS, Finkel RS, Bertini ES (2007) Consensus statement of standard of care in Spinal 
Muscular Atrophy. J Child Neurol. 22:1027-49.
Worgall S, Sondhi D, Hackett NR (2008) Treatment of late infantile neuronal ceroid 
lipofuscinosis by CNS administration of a serotype 2 adeno-associated virus expressing CLN2 
cDNA. Hum Gene Ther. 19:463-74.


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15
Appendices
15.1
Appendix 1 Prior calibration of the Bayesian logistic regression 
model
Introduction
An adaptive Bayesian logistic regression model (with 2 parameters) guided by the escalation 
with overdose control principle will be used to make dose recommendations and estimate the 
MTD during Part 1 of the study. The use of Bayesian response adaptive models for Phase I 
studies has been advocated by the EMEA guideline on small populations (2006) and by 
Rogatko and Tighiouart (2007) and is one of the key elements of the FDA’s Critical Path 
Initiative.
The dose-toxicity (DLT) relationship in the escalation part of the study will be described by the 
following logistic regression model:
logit(π(d)) = log(α) + β log(d/d*), α>0, β>0
Where logit(π(d))= ln (π(d)/(1- π(d))), and π(d) is the probability of a DLT at dose d. Doses are 
rescaled as d/d* with reference dose d*= 40 mg/m2 of branaplam. As a consequence α is equal 
to the odds of toxicity at d*. Note that for a dose equal to zero, the probability of toxicity is zero.
Prior specification
A vague bivariate normal prior for the model parameters (log(α),log(β)) is derived by assuming 
that the median DLT rate at reference dose d*= 40 mg/m2 equals the targeted toxicity 25%, and 
that for the remaining doses, median DLT rates a priori are linear in logit-scale as a function of 
log-dose (Neuenschwander et al 2008).
The information to derive the prior distribution of model parameters is provided in Table 15-1. 
Table 15-2 summarizes the associated prior distribution of the DLT rates. The doses not 
meeting the overdose criteria under the prior are bold in the table, i.e. doses not eligible at the 
start of the study.
Table 15-1
Prior parameters for bivariate normal distribution of model parameters
Parameters
Means
Standard deviations
Correlation
log(α), log(β)
(-1.099, 0)
(3.2, 1)
0


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Table 15-2
Summary of prior distribution of DLT rates derived from the prior in 
Table 15-1
branaplam 
(mg/m2)
Prior probabilities that Pr(DLT) is 
in interval:
Mean
SD
Quantiles
[0, 0.1)
[0.1, 
0.25)
[0.25, 1]
2.5%
50%
97.5%
1
0.771
0.072
0.157
0.119
0.244
<0.001
0.004
0.927
3
0.705
0.089
0.206
0.156
0.274
<0.001
0.012
0.956
6
0.648
0.101
0.251
0.190
0.296
<0.001
0.026
0.970
12
0.570
0.117
0.313
0.236
0.320
<0.001
0.056
0.981
24
0.464
0.132
0.404
0.306
0.345
<0.001
0.130
0.989
40
0.367
0.134
0.499
0.381
0.363
0.001
0.248
0.994
48
0.333
0.132
0.535
0.413
0.370
0.001
0.308
0.996
60
0.299
0.125
0.576
0.451
0.376
0.001
0.385
0.998
Note: bold values indicate doses not meeting the overdosing criterion (more than 25% chance of 
excessive toxicity) with the prior information only.


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15.2
Appendix 2 - Administration of branaplam by caregivers-
Instruction for study site staff and caregivers
Only caregivers holding legal responsibilities of the patient will be allowed to administer the 
study medication to the patients at home. Branaplam (IMP) will be administrated weekly at 
home.
If any mild or moderate adverse events are ongoing at the time of the planned dose 
administration, the investigator will decide whether the patient must visit the study site and 
receive study medication at the study site.
Principles:
The investigator holds the responsibility to explain to the caregivers the procedure of IMP 
maintenance and administration at home, including IMP administration, handling, storage and 
accountability of the IMP at home. Two caregivers or legal representatives must be identified
and trained on IMP administration. The process of training for IMP maintenance and 
administration at home must be documented in medical records.
Before IMP is dispensed to caregivers investigator or delegate will:  

Explain to caregivers the Administration of branaplam for phase I/II by the caregivers 
document

Train caregivers basing on Instruction for administration of LMI/branaplam for phase I/II 
investigational human use 

Explain and dispense Administration of branaplam by caregivers at home- Drug 
accountability log (Patient Diary)

Explain and dispense Acceptability and palatability questionnaire 

If available demonstrate Study drug training kits containing water and ensure full 
understanding of the procedure, the risks and benefit and all the documents
Training and instruction for the first dose of administration of branaplam by 
caregivers at the study site: 

The Principal investigator will present, explain and dispense the Instruction for 
administration of LMI/branaplam for phase I/II investigational human use document-
including the safety instruction, disposal instruction and storage conditions, use 
instructions- important usage information.

The dose volume calculation will not be presented as the responsibility will remain with 
the PI. However the PI will explain that the dose is calculated based upon the weight of 
the child and must assure that caregivers are given the appropriate syringes size, according 
to Pharmacy Manual.

When available the dose/volume preparation, dose administration, disposal will be 
presented supported by training kits available at site. The training kits contains water. The 
nurse in presence of the principal investigator or delegate as documented in the delegation 
log at site will choose a volume and demonstrate the preparation of the syringe using a 
training kit. Each caregivers will be asked to prepare the same dose. The caregiver repeats 


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the test as many times as necessary or wished and all attempts are documented in the 
medical file. Once the study team decides that the caregivers are ready, the caregivers will 
be ask to prepare the actual dose of the visit and administer to their child under the study 
nurse supervision. All events must be documented in the source notes. In case training kits 
are not available the site can use local available materials to demonstrate how the accurate 
volume should be taken.

Caregivers will prepare the syringe and administer the medication at the site. This will 
serve as a control and enable the study team to identify issues or need for re-training. 
Instruction for administration of branaplam by caregivers at home:
The caregivers will be given Patient Diary prefilled with planned date for study medication 
administration, number of vials, syringes and extenders handed over, planned number of vials 
per visit, study medication kits number (6 digit number). 
For Part 1 and Part 2: Weight will be taken every month at the onsite visits. 
For Part 3: Weight will be measured every month at the onsite visit. In case patient will not be 
able to visit the site for the visit a home nurse visit can be performed or telephone call will be 
done by the site. If during Home Visit or Telephone Interview the weight change has been 
reported the site will calculate new volume, record in the source note and inform the caregiver 
of the new volume in mL to administer. The caregiver must report in the Patient's Diary the 
volume and the day of administration. The weight at home will be measured according to 
local standards. In special circumstances Sponsor can provide to the patients the balance 
device. Note: the branaplam dose will always be calculated by the site staff (study nurse, 
pharmacist investigator), reviewed and approved by principal investigator or delegate and 
communicated to caregiver by study nurse, principal investigator at the site or by phone. 
The caregiver completes on the same day as the dose administration the Acceptability and 
Palatability questionnaire when required. 
Instruction for administration of LMI/branaplam for phase I/II investigational human will be 
dispensed to patient.
What should the caregivers do in case of vomiting?
The administration of the dose should be immediately repeated in case if the child vomits or 
regurgitates within 10 minutes of dose administration. If vomiting or regurgitation occurs more 
than 10 minutes after dosing, no dose re-administration should occur. 
The caregivers will document this event in Patient’s Diary.
At which visits branaplam can be administered at home by the caregivers?
Home dosing can be implemented as soon as caregivers/legal representatives were trained by 
investigator according to Administration of branaplam by caregivers- Instruction for study site 
staff and caregivers. 
The IMP will be dispensed and returned according to Pharmacy Manual.


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What will the caregivers be provided with? 

IMP kits and syringes
Depending on the weight of the child 1 or more vials will be used. 1 package of study treatment 
contains 4 vials with the same drug ID number. 
The number of kits given to the caregivers, and syringes will depend upon the weight of the 
child and planned estimated volume and it will include back up kits. The number of dispensed 
kits will depend on the time till next onsite visit.
The investigator is responsible and must ensure that the medication expiry date won’t be 
exceeded during home dosing period before next site visit. In case caregivers spot the IMP has 
expired or is to expire shortly, he or she must immediately contact the site in order to return 
affected IMP kits and receive new ones. Expired IMP must not be administrated.

Patient Diary

Instruction for administration of LMI/branaplam for phase I/II investigational human

Acceptability and Palatability questionnaires
What the caregivers should do in case of dosage error? 
The caregivers must report immediately to the site staff any error in the preparation of the study 
medication leading to an under or over- dosage. This must also be documented in the Patient’s
Diary. 
What is a Patient’s Diary to complete? 
The document is used to document all the information related to the branaplam administration 
at home: date, dose, by who, kits number as well as patient’s weight change, new symptoms, 
new medications including supplements. The site staff must prefilled the Patient’s Diary with 
planned date for study medication administrations and study medication kits number (6 digit 
number), quantities of bottle, number of syringes and extender given to the caregivers. The 
caregivers must complete this document precisely, before and after each administration and 
bring it back to review and discuss with the principal investigator at the next planned visit at 
the study site. The caregivers must save all used vials and bring it back at the next planned visit 
at the study site.

SAP_001.pdf: 
Clinical Development
LMI070/Branaplam
LMI070X2201 / NCT02268552
An open-label multi-part first-in-human study of oral 
LMI070 in infants with Type 1 spinal muscular atrophy
Statistical Analysis Plan (SAP)
Author:
Study Statistician
Document type:
SAP Documentation
Document status:
Final CSR
Release date:
13-Mar-2023
Number of pages:
47
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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SAP Amendment 4
LMI070X2201
Document History – Changes compared to previous final version of SAP
Date
Time point
Reason for update
Outcome for update
Section 
and
title 
impacted 
(Current)
11-Dec-2014
Prior to DB 
lock
Finalization of the 
document
N/A
27-Jul-2018
Prior to DB 
lock
Protocol 
amendment v7
Changes to add clarity and 
statistical analyses based on
updated protocol amendment v7.
26-Oct-2018
Prior to IA3 
DB lock
Protocol 
amendment v8
Changes to add clarity and 
statistical analyses based on 
updated protocol amendment v8.
09-Apr-2020
Prior to DB 
lock
Update of Parts 1 & 
2 analysis
Additional analyses added, in 
particular graphical methods
26-Aug-20
Prior to IA4 
DB lock
Further update of 
Parts 1 & 2
Alignment with TFL
16-Dec-20
After IA4 
DB lock
Further update of 
Parts 1 & 2
Alignment with TFL shells and 
analysis specified in protocol
8-Dec-22
Prior to 
Final DB
Add Part 3
Incorporate Part 3 into analyses 
for Parts 1 & 2; adapt to reflect 
pruning of some analyses, add 
some neurophysiological 
spaghetti plots


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Table of contents
Table of contents .................................................................................................................3
List of tables ........................................................................................................................5
List of figures ......................................................................................................................5
List of abbreviations............................................................................................................6
1
Introduction .........................................................................................................................7
1.1
Study objectives and endpoints .............................................................................12
1.1.1
Primary objective(s)..............................................................................12
1.1.2
Secondary objective(s)..........................................................................12
13
2
Statistical methods.............................................................................................................13
2.1
Data analysis general information .........................................................................13
2.1.1
General definitions................................................................................14
2.1.2
Visit windows........................................................................................16
2.1.3
Multiple assessments within visit windows..........................................23
2.1.4
Issues resolved in the analysis datasets.................................................23
2.2
Analysis sets ..........................................................................................................24
2.2.1
Subgroups of interest.............................................................................24
2.3
Subject disposition, demographics and other baseline characteristics ..................24
2.3.1
Subject disposition ................................................................................25
2.3.2
Background and demographic characteristics.......................................25
2.3.3
Medical history......................................................................................26
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................26
2.4.1
Exposure to study treatment / compliance / time at risk for AE...........26
2.4.2
Prior, concomitant and post therapies ...................................................27
2.5
Analysis of the primary objective..........................................................................27
2.6
Analysis of the key secondary objective ...............................................................27
2.7
Analysis of secondary objectives...........................................................................27
2.7.1
Secondary endpoint...............................................................................27
2.7.2
Statistical hypothesis, model, and method of analysis..........................31
2.8
Safety Analyses .....................................................................................................31
2.8.1
Treatment exposure...............................................................................32
2.8.2
Adverse events (AEs)............................................................................32
2.8.3
Deaths....................................................................................................33
2.8.4
Laboratory data .....................................................................................33
2.8.5
ECG and echocardiographic data..........................................................34


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2.8.6
Vital signs..............................................................................................35
2.8.7
Ophthalmology Examination ................................................................36
2.8.8
Neurophysiological Examination..........................................................36
2.8.9
Neurologic examination questionnaire .................................................36
2.8.10
Acceptability and palatability questionnaire.........................................36
2.9
Pharmacokinetic endpoints....................................................................................36
37
2.9.2
Accumulation ratio................................................................................37
2.9.3
Age and weight dependency .................................................................38
2.9.4
Comparison of dosing methods.............................................................38
2.10
PD and PK/PD analyses.........................................................................................38
2.11
Subject-reported outcomes ....................................................................................38
.38
2.13
Interim analysis......................................................................................................39
3
Sample size calculation .....................................................................................................39
4
Change to protocol specified analyses ..............................................................................40
5
Appendix ...........................................................................................................................41
5.1
Imputation rules.....................................................................................................41
5.1.1
Study drug.............................................................................................41
5.1.2
AE and concomitant medication date imputation.................................41
5.1.3
Values outside limits of quantification .................................................42
5.2
AEs coding/grading ...............................................................................................42
5.3
Laboratory parameters derivations ........................................................................42
5.3.1
Laboratory test groups and subgroups ..................................................43
5.3.2
Newly occurring liver enzymes abnormalities......................................44
5.4
Analysis of the primary objective in Part 1 ...........................................................45
5.4.1
Primary endpoint in Part 1 ....................................................................45
5.4.2
Statistical hypothesis, model, and method of analysis in Part 1 ...........45
5.4.3
Interim analysis in Part 1.......................................................................46
6
References .........................................................................................................................47


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List of tables
Table 1-1
Provisional dose levels for Part 1 dose escalation .................................................. 8
Table 1-2
Dose conversion between BSA and weight for subjects in Part 1........................ 10
Table 1-3
Planned doses for Part 2 ....................................................................................... 10
Table 1-4
Planned doses for Part 3 ....................................................................................... 11
Table 2-1
Visit windows for CHOP INTEND...................................................................... 17
Table 2-2
Visit windows for HINE....................................................................................... 18
Table 2-4
Visit windows for Motor and Speech milestones ................................................. 18
Table 2-5
Visit windows for ECG evaluations ..................................................................... 19
Table 2-6
Visit windows for body temperature and blood pressure/pulse 
rate/respiratory rate............................................................................................... 19
20
Table 2-8
Visit windows for physical examination, respiratory function, body 
weight/body length/BSA, head and chest circumference ..................................... 20
Table 2-9
Visit-windows for Ulnar CMAP and mRNA blood collection............................. 20
Table 2-10
Visit-windows for ophthalmological evaluations................................................. 21
Table 2-11
Visits windows for Hematology, Blood chemistry, and Urine analysis ............... 21
21
Table 2-13
Monthly visit windows in Part 3........................................................................... 22
Table 2-14
Three-monthly visit windows in Part 3................................................................. 22
Table 2-15
Bin widths for HINE subscale stacked bar charts................................................. 22
Table 2-16
Worst case direction for each parameter............................................................... 23
Table 2-17
HINE-2 and the Motor and Speech Domains ....................................................... 28
Table 2-19
Reference ranges for vital sign parameters........................................................... 35
Table 3-1
Power to detect a difference in CHOP INTEND score between two adjacent 
dose groups (by one-sided t-test at nominal significance level of 5 percent)....... 39
Table 5-1
Imputation of start dates (AE, CM)...................................................................... 41
Table 5-2
Imputation of end dates (AE, CM) ....................................................................... 41
Table 5-3
Creatinine clearance calculation........................................................................... 43
Table 5-4
Laboratory tests .................................................................................................... 43
Table 5-5
Prior parameters for bivariate normal distribution of model parameters.............. 46
List of figures
Figure 1-1
Study design for Part 1............................................................................8
Figure 1-2
Study design for Part 2..........................................................................10
Figure 1-3
Study design for Part 3..........................................................................11


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LMI070X2201
List of abbreviations                 
AE
Adverse event
ATC
Anatomical Therapeutic Chemical class
AUC
Area Under the Curve
BSA
Body Surface Area
CMAP
Compound Motor Action Potential
CSR
Clinical Study report
CTCAE
Common Terminology Criteria for Adverse Events
DDS
Dose Determining Set
DLT
Dose Limiting Toxicity
DMC
Data Monitoring Committee 
eCRF
Electronic Case Report Form
FAS
Full Analysis Set
IA3
IA4
MAR
Interim Analysis 3
Interim Analysis 4
Missing at Random
MedDRA
Medical Dictionary for Drug Regulatory Affairs
Mos.
MTD
Months
Maximum Tolerated Dose
NCV
Nerve Conduction velocity
PD
Pharmacodynamics
PK
Pharmacokinetics
PT
Preferred Term
RAP
Report and Analysis Process
SAE
Serious Adverse Event
SAF
Safety Set
SAP
Statistical Analysis Plan
SD
Standard Deviation
SMA
Spinal muscular Atrophy
SMN2
Survival motor neuron 2
TEAE
Treatment Emergent Adverse Event
TFLs
Tables, Figures, Listings
WHO
World Health Organization


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LMI070X2201
1
Introduction
The Report Analysis Plan (RAP) documents contain detail information to aid the production of 
Statistics & Programming input into the Clinical Study Report (CSR) for study 
“LMI070X2201”.
The purpose of this Statistical Analysis Plan (SAP) is to describe the implementation of the 
statistical analysis planned in the protocol, including planned interim analysis (see Section 2.13) 
and the full analysis for Parts 1, 2, and 3 after the final database lock.
This document is consistent with the current study protocol amendment version 11, 19-Jul-2021.
Study design
This is an open-label, multi-part, first-in-human proof of concept study in infants with Type 1 
spinal muscular atrophy (SMA), to evaluate safety, tolerability, PK, PD and efficacy of oral 
branaplam. Parts 1, 2, and 3 are intended to be non-confirmatory.
All subjects must have confirmed SMA type 1 and 2 copies of the survival motor neuron 2 
(SMN2) gene.
Part 1
In Part 1 of the study, subjects will be dosed once weekly with branaplam. The branaplam dose 
will be escalated in subsequent cohorts until maximum tolerated dose (MTD) was determined
or when sufficient pharmacokinetics (PK) results would not confirm that the MTD could not be 
reached due to a potential pharmacokinetic exposure plateau at higher doses. Subjects will be
dosed at least 24 hours apart for the first dose of each dose level to ensure subject safety.
A decision to dose-escalate the next cohort will be made after safety data have been collected
for 14 days following the first dose (14-day DLT window). PK will be used to confirm that
there is no accumulation of the compound. If PK data show the potential for accumulation, the
dosing frequency may be decreased. For Part 1, subjects completing 13 weeks of treatment will 
be considered to have completed the study. Subject who are continuing to receive study drug
follow the Assessment schedule-part1- Extended treatment period. The assessment schedule 
repeats until the subject discontinues the study or transfers to Part 3 if the investigator agree 
that this is in the best interest of the subject.
Figure 1-1 depicts the study design for Part 1, where 13 subjects have been enrolled (at least 2 
subjects planned in each of 5 cohorts). No new subjects will be enrolled in Part 1.


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Figure 1-1
Study design for Part 1
Table 1-1
Provisional dose levels for Part 1 dose escalation
Dose level
Provisional weekly dose
Increment from previous doseb
-2a
1 mg/m2
67% reduction
-1a
3 mg/m2
50% reduction
1
6 mg/m2
Starting dose
2
12 mg/m2
100% increase
3
24 mg/m2
100% increase
4
48 mg/m2
100% increase
5*
60 mg/m2
25% increase
a Dose level -1 and -2 may be used if appropriate (e.g. if the starting dose level is not well 
tolerated)
b The dose increase will be guided by BLRM. Up to 100% dose increase is permitted per dose level 
if the recommended dose increment is higher than 100%
* This weekly dose level 5 would convert into a 2.95 mg/kg dose of branaplam for a 6.5 kg, 62 cm 
subject with BSA of approximately 0.32m2


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Table 1-1 is intended as an example for guidance for the dose escalation part only. Intermediate 
dose levels may be used, and some dose levels may be skipped if the dose-escalation rules 
presented in this protocol are followed. Actual dose levels will be confirmed in writing by 
Novartis and provided to all participating study sites before treatment of subjects in a new 
cohort.
In Part 1, the dose unit changed from a body surface-normalized unit (mg/m2) to a body weight-
normalized unit (mg/kg). The body weight-normalized doses will be used in all study reports.
These will be labelled “nominal dose”.
Part 2
Part 2 of the study enrolled new subjects into one of 2 different dose cohorts; cohort 1 at 0.625 
mg/kg and cohort 2 at 2.5 mg/kg with once weekly dosing for 52 weeks, as shown in Figure 1-
2 below. The branaplam dose was escalated in subsequent cohorts after 6 subjects have been 
enrolled or at least 3 subjects from the initial cohort have completed 13 weeks of treatment.
A total of 25 subjects have been enrolled into Part 2 and assigned to either of the two doses, 
previously tested in Part 1. It is designed to evaluate whether a change over time in infant and 
growth parameters can be detected and interpreted as an effect in branaplam treatment.
Subjects will be receiving the same dose of branaplam once weekly, as allocated at enrollment 
throughout the initial 52 weeks, no intra-cohort escalation is planned. Exceptionally in case of 
lack of efficacy/progressive disease, as assessed by investigator, subject(s) from cohort 1 (0.625 
mg/kg) may receive next level dose (2.5 mg/kg).
In general, the loss of positive benefit of the cohort 1 dose of branaplam will be assessed on a 
subject by subject level. If positive benefit cannot be confirmed for majority of the subjects, the 
cohort 1 might be closed and ongoing subject will be escalated to 2.5 mg/kg.
After completing 52 weeks of treatment, subjects will have the possibility to continue receiving 
further branaplam treatment under Part 3 (see below).
However, in order to ensure subject safety, a dose escalation within cohort 1 will be allowed in 
case there is no benefit at the 0.625 mg/kg dose or if there is evidence of loss of benefit 
(nondurable effect). Efficacy and safety data will be reviewed after three subjects have 
completed at least 13 weeks of treatment. In the event of no positive effect, or a loss of positive 
effect of 0.625 mg/kg will allow subjects to receive the next higher dose.
Part 2 subjects who have completed at least 52 weeks of branaplam treatment will be eligible 
to continue receiving branaplam treatment, as long as this is in the best interest of the subject, 
as assessed by the investigator and will be enrolled to Part 3. For subjects who will not be 
eligible to enter Part 3 or decide to discontinue, End of Study of Part 2 will be performed.


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Figure 1-2
Study design for Part 2
In Part 2, dosing will be changed from dosing per m2 of body surface to per weight based dosing 
(mg/kg) in order to simplify study conduct, by following a more common out subject care
practice while achieving in vivo exposures to branaplam that are similar to those associated with
clinical response in Part 1. The doses administered in Part 1 were originally normalized to body 
surface area (BSA). The equivalent mg/kg doses were calculated for a selection of dosing events 
(all events with PK sampling, 119 in total) and the results are shown in Table 1-2. The 
calculations were based on 13 subjects who ranged in age from 2 to 17 months, in weight from 
5 to 11 kg, and in length from 60 to 88 cm. As can be seen from Table 1-2, the calculated mg/kg 
doses were strongly correlated and increased linearly with the BSA normalized doses. Plasma 
exposure measured by AUC was approximately dose-proportional up to 60 mg/m2 with an 
exposure overlap at the two highest doses (48 and 60 mg/m2). The 48 mg/m2 dose was chosen 
as the dose to anchor all dose calculations for Part 2. The planned weight-based doses for Part 
2 were calculated as factors of 2.5 mg/kg (corresponding to 48 mg/m2 in Part 1) as shown in 
Table 1-3.
Table 1-2
Dose conversion between BSA and weight for subjects in Part 1
Dose level
Weekly dose by 
BSA
N
Calculated weekly 
dose by weight
CV
(%)
Planned weekly 
dose by weight
1
6 mg/m2
28
0.302 mg/kg
8.7
0.3125 mg/kg
2
12 mg/m2
12
0.640 mg/kg
5.0
0.625 mg/kg
3
24 mg/m2
22
1.27 mg/kg
7.6
1.25 mg/kg
4
48 mg/m2
27
2.51 mg/kg
8.3
2.5 mg/kg
5
60 mg/m2
30
2.89 mg/kg
5.3
3.125 mg/kg
N= number of data points used for dose conversion
Table 1-3
Planned doses for Part 2
Dose level
Planned weekly dose by weight
Approximate equivalent 
weekly dose by BSA
1
0.625 mg/kg
12 mg/m2
2
2.5 mg/kg
48 mg/m2


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Part 3
Part 3 of the study is long term safety and efficacy follow up of extended oral/enteral, once a 
week branaplam treatment, as shown in Figure 1-3. All subjects who participated in Part 1 and 
Part 2 of the study and have completed at least 52 weeks of treatment or more, can continue 
receiving treatment with branaplam in Part 3 of the study, as long as this is in the best interest 
of the subject, as assessed by the investigator.
Continuation of the treatment will be done at the dose assigned while in Part 1 or Part 2 of the 
study. However, if at any later time an interim analysis of Part 1 or Part 2 study data suggest 
one optimal dose considering existing safety as well as efficacy data, the dose subjects are 
receiving might be switched to the selected optimal dose. Details of the planned doses for Part 
3, are shown in Table 1-4.
Here is the rationale for selecting the higher dose in Part 3:
Figure 1-3
Study design for Part 3
Table 1-4
Planned doses for Part 3
Dose level
Planned weekly dose by weight
Approximate equivalent
weekly dose by BSA
1
0.3125 mg/kg
6 mg/m2
2
0.625 mg/kg
12 mg/m2
3
1.25 mg/kg
24 mg/m2
4
2.5 mg/kg
48 mg/m2
5
3.125 mg/kg
60 mg/m2
Here is the rationale for selecting the higher dose in Part 3:
There was a consensus 
 
, that the higher dose should be selected for future studies
a.
No apparent safety concerns, so maximize potential long-term benefit 
b. Anecdotal evidence that some kids on lower dose did better after switching to higher 
dose (part 2) and some kids did worse after switching to a lower dose (part 1)  
c.
Evidence of more target engagement with higher dose


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1.1
Study objectives and endpoints
The purpose of Part 1 of the study was to evaluate the safety, tolerability, pharmacokinetics 
(PK), pharmacodynamics (PD) and efficacy; and to estimate the Maximum Tolerated Dose 
(MTD) of branaplam.
The purpose of Part 2 of the study is to characterize dose-exposure-response to inform dose
selection of orally administered branaplam in subjects with Type 1 SMA.
The purpose of Part 3 of the study is to provide continuous treatment with branaplam to patients 
who have participated in Part 1 or 2 of the study and have completed at least 52 weeks of 
treatment. In addition, Part 3 provides long-term safety and efficacy follow-up for patients 
treated with branaplam for more than 52 weeks. 
1.1.1
Primary objective(s)
Objective
Endpoint
Part 1: Determine the safety and tolerability of 
ascending weekly doses and estimate the MTD 
of branaplam in infants with Type 1 SMA.
For all parts:

Physical exam

Vital signs

ECG and echocardiographic evaluation

Safety laboratory parameters

Ophthalmologic examination

Neurologic examination

Nerve conduction study: sensory nerve action 
potential (SNAP), nerve conduction velocity 
(NCV) for sensory and motor nerves and ulnar 
nerve compound motor action potential (CMAP)

Adverse events
Part 2: Evaluate the safety and tolerability of 2 
doses of branaplam administered for 52 weeks 
in subjects with Type 1 SMA.
Part 3: Assess long-term safety and tolerability 
of extended oral/enteral, once a week 
branaplam treatment in patients with type 1 
SMA who have had at least 52 weeks of 
treatment in either Part 1 or 2 study of this 
protocol.
1.1.2
Secondary objective(s)
Objective
Endpoint
Part 1, Part 2, Part 3:
Part 1, Part 2, Part 3:

To evaluate branaplam pharmacokinetics in 
plasma after single and repeated doses of 
branaplam

AUC and Cmax of branaplam

To evaluate the effect of branaplam on 
growth parameters

Growth measurements (body weight, head 
circumference, length and chest circumference)

To evaluate the effect of branaplam on 
respiratory function

Pulse oximetry*, respiratory rate, paradoxical 
breathing assessment, chest circumference during 
quiet breathing*.


To evaluate the effect of branaplam on infant 
motor development.

CHOP-INTEND infant motor scale up to the age 
of 36 months.

Hammersmith Infant Neurologic Examination
In addition to the above for Part 2:
In addition to the above for Part 2:


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
To evaluate the efficacy of branaplam on 
motor and developmental milestones

Preservation of oral feeding

To evaluate the efficacy of branaplam on the 
ability to sit without support.

Ability to sit without support over time as 
assessed by HINE-2 
In addition to the above for Part 3:
In addition to the above for Part 3:

To evaluate the efficacy of branaplam on
motor and developmental milestones

Preservation of oral feeding

To evaluate the efficacy of branaplam on 
the ability to sit without support.

Ability to sit without support, stand or walk
over time as assessed by HINE-2

To assess the proportion of infants who are
alive and are without permanent ventilation
over time

Adverse Events and deaths over time

To assess the impact of treatment with
branaplam on time-to-event (death,
permanent ventilation)

Adverse Events and deaths over time
Note: * these secondary endpoints will not be analysed in this analysis (see Section 4 for a rationale)
2
Statistical methods
2.1
Data analysis general information
A statistical vendor (CRO), 
 to which the statistical analysis is outsourced, will 
perform all planned analyses, i.e. IAs (Section 2.13) as well as the final analysis after the final 
database lock. Details of the analyses for Parts 1, 2, and 3 at the upcoming final database lock 
are outlined in this document.
Data will be analyzed using SAS® version 9.4 (or higher).
Descriptive summary statistics, unless otherwise specified, for continuous variables include 
number of non-missing observations (n), mean, median, standard deviation (SD), Q1 (25th
percentile), Q3 (75th percentile), minimum and maximum, while for categorical variables 
frequencies and relative percentages will be reported.


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Descriptive analyses will be stratified by part as follows:

For disposition, demographics, baseline characteristics, and medical history, and protocol 
deviations, by parts (Part 1, Part 2, Part 1 & 2, Part 3)

For all other summaries and figures: Part 1 & 3, Part 2 & 3, and Total (where applicable)
For analysis summaries, Part 1 will not be stratified by titration dose, while Part 2 will be 
stratified by the two treatment doses. For patients in Part 3 from Part 2, the fixed dose in Part 2 
will be used as a strata; thus transitions from a low dose to a higher dose in Part 3 will not be 
analysed separately.
Individual graphs, such as spaghetti plots by study part and treatment and panel plots by study 
part and subject (with actual dose displayed as background shading) relative to time from first 
dose (in months) will be provided for selected endpoints, as applicable. Individual graphs 
relative to calendar age (in months) such as growth curve plots of vital signs, etc. will also be 
presented.
Listings will be provided by study part, cohort and subject.
The following treatment labels will be used for all tables, listings and figures in the order 
provided here:

Part 1:
LMI070 0.3125 mg/kg, LMI070 0.625 mg/kg, LMI070 1.25 mg/kg, LMI070 2.5 mg/kg, 
LMI070 3.125 mg/kg

Part 2:
LMI070 0.625 mg/kg, LMI070 2.5 mg/kg

Part 3 (from Part 1):
LMI070 0.625 mg/kg, LMI070 2.5 mg/kg, LMI070 3.125 mg/kg

Part 3 (from Part 2):
LMI070 0.625 mg/kg, LMI070 2.5 mg/kg
2.1.1
General definitions
‘Actual dose’ will be derived as the current dose for each subject on a daily basis across the 
entire study; in the case of the day of a dose change, the new dose will used.
‘Treatment group’ in Parts 2 & 3 will refer to the treatment group combination (as mentioned 
above) for efficacy analyses, and to the actual treatment for safety analyses (see definition 
below). In Parts 1 & 3, this will be Overall.
‘Cohort’ will refer to the initial dose for baseline or demographic characteristics.
The term ‘Study Day’ in this document relates to the Analysis Relative Day, Relative Start Day 
or Relative End Day as applicable. ‘Study Day’ is defined relative to the analysis reference date, 
which is the date of treatment assignment; it is the number of days from the reference date to 
the analysis date. For all dates on or after the analysis reference date, the study day is the 
difference to the analysis reference date plus one day (i.e. for date ≥ reference date, study day 
= date - reference date + 1); for any dates prior to the analysis reference date, the study day is 


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simply the difference to the reference date (i.e. for date < reference date, study day = date -
reference date). Thus, the Subject Reference Start Date is designated as Study Day 1, while the 
date directly prior to the reference date is defined as Study Day -1 (there is no Study Day 0).
‘Baseline’ is the last non-missing assessment obtained prior to the first administration of study 
drug. That means that if the measurement at the baseline visit is missing, then the previous 
measurement preceding baseline will be used as the baseline measurement. For pulse and blood 
pressure vital sign values, the baseline is the last non-missing value taken prior to the first 
administration of study drug.
‘Treatment phase’ includes the time interval on treatment and post-treatment follow-up. Any 
measurements taken after baseline will be considered as post-baseline measurements.
‘Actual treatment’ is defined as the treatment group the patient has most exposure to in each 
Part (for Parts 2 & 3), leading to a treatment group combination; in the case of two treatments 
having identical exposure, the higher dose will be used. This will be used for safety analyses.
‘Calendar age’ is defined as the age at the date of evaluation.
In this study, ‘last contact with the subject’ will be the end of study visit, unless an SAE occurs. 
However, to ensure subject safety, every SAE must be reported to Novartis:

occurring until 30 days after the last study visit, regardless of causality

occurring after the 30 days period, if a causal relationship to study treatment is suspected
‘Nominal visits’ Nominal visits are defined as all scheduled visits as per the clinical study 
protocol including the EOS visits. The definition of nominal visit excludes unscheduled visits.
‘Safety cutoff’ Unless explicitly otherwise stated (e.g. SAEs and deaths), data up to and 
including the safety cutoff will be included in the analysis and data beyond this time point for 
a given subject will be excluded from the safety analysis. The safety cutoff is defined as the 
minimum of 

the study day the patient leaves study Parts 1, 2*, or 3

the database cutoff date (the Final Database Lock date)

30 days after permanent study drug discontinuation. 

day of first dose of alternate treatment for SMA
‘Efficacy cutoff’ Unless explicitly otherwise stated, data up to and including the efficacy
cutoff will be included in the analysis and data beyond this time point for a given subject will 
be excluded from the efficacy analysis. The efficacy cutoff is defined as the minimum of 

the study day the patient leaves study Parts 1, 2*, or 3

the database cutoff date (the Final Database Lock date) 

day of first dose of alternate treatment for SMA
The following rules will be applied to assign data to part 3:
a.
For datasets/endpoints that have planned visit numbers populated (e.g. HINE, CHOP-
INTEND, etc.), the visit number included in the IFC dataset under ’Consent for 


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additional follow-up study phase' which is the first visit of Part 3 (as confirmed by Cmed) 
will be used: 
i.e. assessments with visit numbers that are >= that IFC visit number will be assigned to 
Part 3.
b. For datasets/endpoints that do not have planned visit numbers populated (e.g. AEs, 
Feeding status, etc.), the visit date that corresponds to the above IFC visit number will 
be used:
i.e. assessment dates that are >= that IFC visit date will be assigned to Part 3. In 
particular, AEs or concomitant medication with start date time >= that IFC visit date 
will be assigned to Part 3.
In general, data collected at a visit during the Part 3 will be analysed together with the part the 
subject came from (i.e. ‘Parts 1 & 3’, ‘Parts 2 & 3’).
The safety cutoff applies to safety analyses only. The only exception to this are serious adverse 
events and deaths. Any SAEs occurring after the 30 days period, where a causal relationship to 
study treatment is suspected, will be reported. All deaths will be reported irrespective of safety 
cutoff.
In general, treatment emergent AEs are defined as events starting after the first dose of study 
drug that were absent pre-treatment, or events present prior to the first dose but increased in 
severity after the first dose. This assumes the same AE with increased severity is properly 
entered as a separate record in the database with start date being the date when severity increases 
and that a second AE with same severity won’t be entered before the same AE is resolved.
For any other safety analyses based on post-baseline abnormalities compared to baseline (i.e. 
ECGs, vital signs, etc.), where either of the results is not available, the ‘missing’ category will 
be included to avoid any abnormalities being overlooked.
When showing values over time, for subjects who prematurely discontinued the study, study 
completion visit assessments will be displayed as if they had occurred at the next scheduled 
visit.
The eGFR is calculated using the MDRD formula. eGFR [mL/min/1.73 m2]=175 × (serum
Creatinine [umol/L]/88.4)-1.154 × (age [years])-0.203 × (0.742 if female) × (1.212 if African 
American) (Levey et al. 2007).
2.1.2
Visit windows
Visit-windows will be used for both efficacy and safety data summaries by visit. Visit windows 
define a time period “around” the targeted visit date as defined in the evaluation schedule of the 
clinical study protocol. Visit-windows are non-overlapping and defined without gaps between 
consecutive visit windows. The width of visit windows may vary over the course of the study 
period.
The purpo-se of visit windows is to analyze data based on the actual study days (rather than 
"nominal" visits). E.g., if a subject’s Week 3 visit is delayed; it is possible that the Week 3 data 
be re-aligned to visit-window Week 5 and be summarized under Week 5.


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
For efficacy analyses all nominal visits (i.e. excluding unscheduled visits) will be mapped 
into one of the defined visit-windows.

For safety analyses all nominal visits (i.e. excluding unscheduled visits) will be mapped 
into one of the defined visit-windows. Data from unplanned visits and unscheduled visits 
will not be re-mapped to other visits for the purpose of displaying variables over time 
except for laboratory data. For laboratory data, a time window will be used to identify the 
assessment closest to the target day within the window over time. The unplanned and 
unscheduled visits will be used in the analysis of event endpoints, and will be counted 
towards shift tables or other analyses regarding the worst observed values for patients.
It is possible that more than one assessment of a subject fall into a particular visit-window. 
Section 2.1.3, deals with the statistical approaches to handle multiple visits in a given visit-
window.
Tables displaying summary statistics “by visit” will also use the term visit-window as column 
header; this is to remind the reviewer that multiple assessments of a subject might be 
summarized. Table 2-1 up to Table 2-12, provide visit-windows definitions for applicable 
parameters in Part 1 and Part 2.
In all scenarios, later visits in Part 1, Part 1 & 3 and/or visits in Parts 2 & 3, will be treated in a 
similar fashion to those displayed, so that days between visits are divided evenly, without any 
gaps. The target day is number of weeks * 7 – 6. For Part 1, after week 26 visit, the extended 
treatment period (as per protocol Table 7-2) is repeated. For example, for CHOP-INTEND, 
after week 26 visit, there are week 32 (+6 weeks) and week 39 (+7 weeks) visits.
Note: When deriving week 52 visit-window for Part 2 data, the upper bound of the week 52 
visit-window will be ignored in order to make sure we do not miss any week 52 Part 2 data.
Indeed, data collected by visit are assumed to be Part 3 assessments if visit numbers are >= IFC
(’Consent for additional follow-up study phase') visit number.
For the visit windows for monthly assessments in Part 3, Table 2-13 uses the following logic: 
planned day -13 days for the start of visit window and +14 days for the end of the visit windows.
Day 0 in Tables 2-13 and 2-14 corresponds to the date of informed consent ’Consent for 
additional follow-up study phase', which is the first visit of Part 3.
Note: some assessments were collected only every 3 months in Part 3 (e.g. CHOP-INTEND, 
HINE-2). For those endpoints, please display in summary statistics tables only planned visits
for Part 3 (as per protocol).
Part 3 visits will be appended to whichever part the subject came from (i.e. Parts 1 & 3 and 
Parts 2 & 3).
Table 2-1
Visit windows for CHOP INTEND
Part 1 Day
Part 2 Day
Visit-window
Start 
Target 
End 
Start 
Target 
End
Week 6
1
36
60
1
36
60
Week 13
61
85
106
61
85
106
Week 19
107
127
151
107
127
151
Week 26
152
176
200
152
176
197


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Week 32
201
218
242
198
218
242
Week 39
243
267
291
243
267
287
Week 45
292
309
333
288
309
333
Week 52
334
358
382
334
358 
382
Table 2-2
Visit windows for HINE
Part 1 Day
Part 2 Day
Visit-window
Start 
Target 
End 
Start 
Target 
End
Week 6
1
36
60
Week 13
61
85
106
Week 19
107
127
151
107
127
151
Week 26
152
176
200
152
176
197
Week 32
201
218
242
198
218
242
Week 39
243
267
291
243
267
287
Week 45
292
309
333
288
309
333
Week 52
334
358
382
334
358 
382
Table 2-3
Visit windows Acceptability and Palatability Questionnaire
Part 1 Day
Part 2 Day
Visit-window
Start 
Target 
End 
Start 
Target 
End
Week 2
1
8
11
Week 3
12
15
18
Week 4
19
22
57
Week 14
89
92
95
58
92
95
Week 15
96
99
102
96
99
102
Week 16
103
106
109
103
106
144
Week 27
110
183
186
145
183
186
Week 28
187
190
193
187
190
193
Week 29
194
197
200
194
197
235
Week 40
201
274
277
236
274
277
Week 41
278
281
284
278
281
284
Week 42
285
288
291
285
288
291
Table 2-4
Visit windows for Motor and Speech milestones
Part 1 Day
Part 2 Day
Visit-window
Start 
Target 
End 
Start 
Target 
End
Week 13
61
85
106
Week 19
103
127
151
107
127
151
Week 26
152
176
200
152
176
197
Week 32
201
218
242
198
218
242
Week 39
243
267
291
243
267
287
Week 45
292
309
333
288
309
333
Week 52
334
358
382
334
358 
382


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Table 2-5
Visit windows for ECG evaluations
Part 1 Day
Part 2 Day
Visit-window
Start 
Target 
End 
Start 
Target 
End
Day 1
1
1
1
1
1
1
Week 2
2
8
46
2
8
46
Week 13
47
85
130
47
85
99
Week 17
100
113
145
Week 26
131
176
221
146
176
190
Week 30
191
204
236
Week 39
222
267
312
237
267
281
Week 43
282
295
326
Week 52
313
358
403
327
358
389
Table 2-6
Visit windows for body temperature and blood pressure/pulse 
rate/respiratory rate
Part 1 Day
Part 2 Day
Visit-window
Start 
Target 
End 
Start 
Target 
End
Day 2
1
2
2
1
2
2
Day 3
3
3
3
3
3
5
Day 5
4
5
6
Week 2
7
8
11
6
8
18
Week 3
12
15
18
Week 4
19
22
25
Week 5
26
29
32
19
29
43
Week 6
33
36
39
Week 7
40
43
46
Week 8
47
50
53
Week 9
54
57
60
44
57
71
Week 10
61
64
67
Week 11
68
71
74
Week 12
75
78
81
Week 13
82
85
102
72
85
102
Week 18
103
120
134
103
120
134
Week 22
135
148
162
135
148
162
Week 26
163
176
190
163
176
193
Week 31
191
211
225
194
211
225
Week 35
226
239
253
226
239
253
Week 39
254
267
281
254
267
284
Week 44
282
302
316
285
302
316
Week 48
317
330
344
317
330
344
Week 52
345
358
372
345
358
372


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Table 2-8
Visit windows for physical examination, respiratory function, body 
weight/body length/BSA, head and chest circumference
Part 1 Day
Part 2 Day
Visit-window
Start 
Target 
End 
Start 
Target 
End
Week 2
1
8
11
1
8
18
Week 3
12
15
18
Week 4
19
22
25
Week 5
26
29
32
19
29
43
Week 6
33
36
39
Week 7
40
43
46
Week 8
47
50
53
Week 9
54
57
60
44
57
71
Week 10
61
64
67
Week 11
68
71
74
Week 12
75
78
81
Week 13
82
85
102
72
85
102
Week 18
103
120
134
103
120
134
Week 22
135
148
162
135
148
162
Week 26
163
176
190
163
176
193
Week 31
191
211
225
194
211
225
Week 35
226
239
253
226
239
253
Week 39
254
267
281
254
267
284
Week 44
282
302
316
285
302
316
Week 48
317
330
344
317
330
344
Week 52
345
358
372
345
358
372
Table 2-9
Visit-windows for Ulnar CMAP and mRNA blood collection
Part 1 Day
Part 2 Day
Visit-window
Start 
Target 
End 
Start 
Target 
End
Week 13
1
85
130
1
85
130
Week 26
131
176
221
131
176
221
Week 39
222
267
312
222
267
312
Week 52
313
358
403
313
358 
403


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Table 2-10
Visit-windows for ophthalmological evaluations
Part 1 Day
Part 2 Day
Visit-window
Start 
Target 
End 
Start 
Target 
End
Week 12
1
78
123
1
78
123
Week 25
124
169
214
124
169
214
Week 38
215
260
305
215
260
305
Week 51
306
351
396
306
351
396
Table 2-11
Visits windows for Hematology, Blood chemistry, and Urine analysis
Part 1 Day
Part 2 Day
Visit-window
Start 
Target 
End 
Start 
Target 
End
Day 3
1
3
5
1
3
5
Week 2
6
8
11
6
8
18
Week 3
12
15
22
Week 5
23
29
36
19
29
43
Week 7
37
43
50
Week 9
51
57
64
44
57
71
Week 11
65
71
78
Week 13 
79
85
102
72
85
102
Week 18
103
120
134
103
120
134
Week 22
135
148
162
135
148
162
Week 26
163
176
190
163
176
193
Week 31
191
211
225
194
211
225
Week 35
226
239
253
226
239
253
Week 39
254
267
281
254
267
284
Week 44
282
302
316
285
302
316
Week 48
317
330
344
317
330
344
Week 52
345
358
372
345
358
372


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Table 2-13
Monthly visit windows in Part 3
Visit-window
Part 3 Day
Start 
Target 
End 
P3 Month 0
0
0
14
P3 Month 1
15
28
42
P3 Month 2
43
56
70
P3 Month 3
71
84
98
P3 Month 4
99
112
126
P3 Month 5
127
140
154
P3 Month 6
155
168
182
P3 Month 7
183
196
210
P3 Month 8
211
224
238
P3 Month 9
239
252
266
P3 Month 10
267
280
294
P3 Month 11
295
308
322
P3 Month 12
323
336
350
P3 Month x
28*x-13
28*x
28*x+14
Table 2-14
Three-monthly visit windows in Part 3
Visit-window
Part 3 Day
Start 
Target 
End 
P3 Month 0
0
0
42
P3 Month 3
43
84
126
P3 Month 6
127
168
210
P3 Month 9
211
252
294
P3 Month 12
295
336
378
P3 Month x
28*x-41
28*x
28*x+42
* post-baseline values
Table 2-15
Bin widths for HINE subscale stacked bar charts
Study Day
Visit-window
Start 
End 
>0-3 months
1*
91
>3-6 months
92
182


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>6-9 months
183
273
>9-12 months
274
364
>x-x+3 months
(x/3)*91+1
((x+3)/3)*91
* post-baseline values
2.1.3
Multiple assessments within visit windows
It is possible that multiple assessments of a subject fall into the same visit-window (e.g. due to 
unscheduled visits). All results (scheduled and unscheduled) will be displayed in listings, but 
only one value (observed or derived) will be selected for summary statistics by visit-window.
For quantitative variables, the assessment closest to the target day will be selected. If more 
than one assessment is at the same distance to the target day, the worst case will be selected. 
For tables displaying the worst-case scenario, all assessments within a visit window will be 
used to identify the worst (e.g. the maximum or the minimum depending on parameter).
For qualitative variables, the worst record is selected; it is noted that in the relevant data 
subsection, worst case is always well defined.
Table 2-13
Worst case direction for each parameter
Assessment
Worst case
CHOP INTEND
The lower the value
HINE
The lower the value
ECGs
The higher the value
Vital Signs
The higher the value
Labs
Usually the higher the value; however for 
some labs, such as hemoglobin and platelets, 
both higher and lower values can be worst 
case direction
Neurophysiological evaluations (NCV, 
CMAP, etc.)
The lower the value
Growth measurements
The lower the value
Respiratory measurements
The lower the value
2.1.4
Issues resolved in the analysis datasets
2.1.4.1
ECG/ECHO data
For some patients, ECG/ECHO data was entered mistakenly as unscheduled visits instead of 
scheduled visits. The  algorithms for multiple assessments for quantitative variables will be 
applied (see Section 2.1.3). For descriptive analyses for these patients, all data within each 
scheduled visit window will be taken into account, and the value on the closest day followed 


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by the worst case will be used. For worst case analyses, the worst case within a time window 
will be used.
2.2
Analysis sets
The following populations will be used for the statistical analyses:
Enrolled Set (ENR) will consist of all subjects giving study informed consent and are assigned 
a treatment.
Full Analysis Set (FAS) will consist of all subjects in the Enrolled Set who received at least 
one dose of study drug. Patients will be analyzed according to the treatment group (as defined 
in Section 2.1.1).
Safety Set (SAF) will consist of all subjects in the Enrolled Set who received at least one dose 
of study drug. Patients will be analyzed according to the actual treatment received (as defined 
in Section 2.1.1). The Safety Set will be used for the analyses of safety variables.
Dose Determining Set (DDS) (Part 1 only) will consist of all subjects from the safety set who 
have sufficient safety evaluations to provide DLT information 2 weeks after the first dosing or 
discontinue earlier due to DLT. Subjects who do not experience DLT during the first 2 weeks 
after the first dose are considered to have sufficient safety evaluations if they are considered by 
both the Sponsor and Investigators to have sufficient safety data to conclude that a DLT did not 
occur.
PK Analysis Set will include all subjects that received at least one dose of branaplam with 
available PK data and no protocol deviations with relevant impact on PK data. The PK Analysis 
Set will be used for the analyses of PK variables.
2.2.1
Subgroups of interest
Subgroup analyses will be performed using descriptive statistics.
The following subgroups will be used for selected efficacy and safety analyses:

Sex (M/F)

Baseline Age Group (<= 4 months/> 4 months)
2.3
Subject disposition, demographics and other baseline 
characteristics
Analyses for subject disposition, demographic characteristics, other baseline characteristics, 
and medical history, will be summarized by study part for the FAS (and additionally by cohort
for Parts 2 & 3) using frequency distributions (for categorical variables) and descriptive 


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statistics of mean, standard deviation, minimum, median and maximum (for continuous 
variables). They will also be listed by study part, treatment, and subject. The numbers in each 
population with be tabulated. Frequencies of protocol deviations will be displayed stratified by 
deviation category and part.
2.3.1
Subject disposition
The number and percentage of subjects who completed each study part, who prematurely 
discontinued and the reason for discontinuation will be presented by study part.
2.3.2
Background and demographic characteristics
Summary of baseline demographic characteristics will include:

Age

Sex

Predominant race

Ethnicity

Weight

Length

Body surface area

Chest circumference

Head circumference
Summary of other baseline characteristics will include:

Mean supine SBP

Mean supine SBP categories

< 130 mmHg

>= 130 mmHg

Mean supine DBP

Mean supine DBP categories

< 80 mmHg

>= 80 mmHg

Mean supine pulse

Paradoxical breathing assessment,

eGFR per MDRD formula categories

< 30 mL/min/SA

>= 30 to < 60 mL/min/SA

>= 60 to < 90 mL/min/SA

> 90 mL/min/SA

QTcF


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2.3.3
Medical history
Medical history will be summarized by study part for the FAS (and additionally by cohort for 
Parts 2 & 3). Any condition entered on the Medical History (MH) CRF will be coded using the 
MedDRA dictionary. The medical history will be summarized by primary system organ class 
(SOC), preferred term (PT) and cohort.
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
The SAF set will be used for the analyses below.
2.4.1
Exposure to study treatment / compliance / time at risk for AE
Duration of treatment exposure in months = (minimum(study day of last non-missing dose 
(>0) + 6, end of study date, Database cutoff date) - study day of first dose + 1)/30.4375.  
Duration of exposure to study drug will be summarized descriptively on the safety set by parts, 
treatment group and duration category (≥ 1 mos., ≥ 3 mos., ≥ 6 mos., ≥ 9 mos., ≥ 12 mos., ≥ 18
mos., ≥ 24 mos., ≥ 30 mos., ≥ 36 mos., ≥ 42 mos., etc. till no longer any patients).
For each treatment group, the number of patient-years is calculated as (the sum of the number 
of days of exposure for all patients in the group)/365.25 and will be summarized by baseline 
age group and gender.
Time at risk for AE is defined as (in months)

(minimum(study day of permanent study drug discontinuation + 30, study day of end of 
study part, Database cutoff date, study day of first dose of alternate treatment for SMA) -
study day of first dose + 1)/30.4375 (as defined in Section 2.1.1). 
Time at risk for AEs will be summarized in a similar way to duration of exposure to study 
drug.
Compliance to the study drug administration schedule will be calculated as

(Number of doses received / number of expected doses up to treatment 
discontinuation)*100                               

Number of doses received = Doses with non-missing dates and a non-missing dose >0                                

Number of expected doses = round((study day of last treatment day-1)/7) + 1                                             

The last treatment date/day is taken from the CMP dataset.                                                              

If number of received doses exceeds the number of planned doses, then compliance = 
100% Premature discontinuation from study drug will not be considered non-compliance.                           
Last treatment day corresponds to the last record of the administration page for parts 1, 2 or 3
with non-missing date for the patient. A dose is received if dose is non-missing and >0.
This rule means that compliance will be measured during the time interval the patient took study 
drug: premature discontinuation from study drug will not be considered non-compliance. 
Compliance to study drug administration will be summarized descriptively on SAF by treatment 
group. In addition, compliance will be summarized with cumulative number and percentage of 
patients in each compliance category (i.e., ≥ 20%, ≥ 30%, ≥ 40%, ≥50%, ≥60%, ≥70%, ≥80%, 
≥90%, ≥95%, ≥98%, =100%).


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2.4.2
Prior, concomitant and post therapies
Data for study drug administration will be listed by study part, cohort and subject.
Concomitant medications will be summarized for the safety set in separate tabulations based on 
the coding dictionary used. Concomitant medications used during the treatment phase will be 
summarized by anatomical therapeutic chemical (ATC) class, and preferred term.
Concomitant medications and significant non-drug therapies will be summarized by study part, 
therapeutic class and preferred term for the SAF. Any medication given at least once between 
the day of first dose of actual study drug received and the last day of the study will be a 
concomitant medication, including those which were started pre-baseline and continued into 
the treatment period. Concomitant medication will be identified based on recorded or imputed 
start and end dates of medication taking.
Concomitant medication will be assigned to Part 3 if the start date of the medication is after/on 
the date of first visit for Part 3 (see section 2.1.1). 
2.5
Analysis of the primary objective
The primary objective of Part 1 was analyzed in the Interim 3 CSR. This analysis will not be 
repeated here. Details of the planned analysis can be found in Appendices 5.4.
The primary objective of Part 2 is to evaluate the safety and tolerability of multiple doses of 
branaplam for 52 weeks in subjects with Type 1 SMA. The primary objective for Part 3 is to 
assess long-term safety and tolerability of extended oral/enteral, once a week branaplam 
treatment in patients with type 1 SMA who have had at least 52 weeks of treatment in either 
Part 1 or 2 study of this protocol. The analyses are described below in the safety section. All 
information obtained on adverse events will be displayed by initial and administered dose and 
subject.
2.6
Analysis of the key secondary objective
There is no key secondary objective for this study.
2.7
Analysis of secondary objectives
All efficacy analyses will be conducted using the full analysis set (FAS).
2.7.1
Secondary endpoint
The following efficacy endpoints will be summarized with appropriate descriptive tables over 
time by study part and in Parts 2 & 3, additionally by treatment group:

CHOP INTEND infant motor total score

Respiratory function assessments (respiratory rate, pulse oximetry, paradoxical breathing, 
breathing pattern [chest circumference measured during quiet breathing (sleep)])

Growth measurements (body weight, head circumference, length and chest circumference)

Ventilation status

Preservation of oral feeding

HINE motor total score


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
Ability to sit without support at 12-months of treatment: This is part of the HINE, if a
subject has the ITEM=”Sitting” with Score 3 or 4 then they are considered as able to sit 
without support. See Table 2-14 below.
For all continuous secondary endpoints, summary statistics for raw and change from baseline 
(when baseline is available), will be provided.
For the categorical secondary endpoints, frequencies and relative percentages will be reported.
Other secondary endpoints

AUC and Cmax of branaplam
For PK analysis please refer to section 2.9.
A summary of the number of patients and relative frequencies of patients with and without 
tracheostomy at baseline, installed or removed during the study will be provided by part and 
cohort (for parts 2 & 3).
The number of patients who had a tracheostomy or permanent ventilation during the study and 
discontinued the study drug on/after the start of the event will be provided by part and cohort 
(for parts 2 & 3).
HINE-2 and the Motor and Speech Domains
The domains for the HINE-2 motor score are provided in Table 2-14 below. If all subscores are 
“Did Not Test” (DNT) then the HINE Motor Total Score is missing. If at least one subscore is 
available, then any other DNT will be imputed as 0 in the sum for the HINE Motor Total Score 
derivation.
Note: HINE motor score information is available in two source datasets, MOT and QUE. Data 
from both datasets will be combined and used in the HINE data analysis.
Table 2-14
HINE-2 and the Motor and Speech Domains
Functional definitions and score
Item
Score
0
1
2
3
4
5
6
Head
Control
Did 
Not 
Test
Unable to 
maintain 
upright
Wobbles
All the 
time 
upright
Sitting
DNT
Cannot sit
Sits with 
support at 
hips
Sits with 
support 
(props)
Stable 
independent sit
Pivots 
(rotates)
Ability to 
Kick (in 
supine)
DNT
Does not 
kick
Kicks 
horizontal, 
leg(s) do 
not lift
Upward 
(vertical)
Touches leg
Touches toes
Rolling
DNT
Does not roll
Rolls to 
side 
(supine)
Rolls to 
side 
(prone)
Rolls prone to 
supine
Rolls supine 
to prone


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Crawling 
(from 
supine)
DNT
Does not lift 
head
Props on 
elbow
Supports 
weight on 
hand
Crawls flat on 
abdomen 
(commando 
crawl)
Crawls on 
hands and 
knees
Standing
DNT
Does not 
support 
weight
Supports 
weight
Stands 
with 
support
Stands 
unaided
Walking
DNT
Makes no 
attempt at 
walking
Bounces
Cruises 
(holding 
on)
Takes a few 
steps
Walks 
independently 
(>10 steps)
Hip 
strength
DNT
Unable to 
flex hips
Briefly 
flexes hip 
against 
gravity
Maintains 
hip 
flexion 
against 
gravity
Speech
DNT/  
Can-
not 
assess
Weak cry 
(cannot be 
heard 
outside of 
room with 
closed door)
Loud cry 
(can be 
heard 
outside of 
room with 
closed 
door)
Coos
Babbles in a 
speech-like 
way and uses 
many different 
sounds, 
including 
sounds that 
begin with p, b, 
and m
Babbles 
using long 
and short 
groups of 
sounds (tata, 
upup, bibibi)
Imitates 
differ-
ent 
speech 
sounds
Says 
one 
word
Voluntary 
grasp
DNT
No grasp
Uses 
whole 
hand 
(rake)
Index 
finger 
and 
thumb 
but 
immature 
grasp
Pincer grasp
Upper 
extremity 
function
DNT
Spontaneous 
movement of 
arm(s)
Hand(s) 
to midline 
on chest
Arm(s) 
held
above 
head
Hand(s) to 
mouth
Arm(s) reach 
over body 
(supine)
Arm(s) 
reach 
over 
head 
(held 
upright)
Feeding Status
Feeding status over the course of each part will be categorized as follows:

Only exclusively tube fed

Only orally fed

Started on tube fed, switched to orally fed

Started on orally fed, switched to tube fed

Other (mixture of both tube and oral feeding)


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Ventilation status
Permanent ventilation is included in a composite endpoint with death, permanent ventilation or 
tracheostomy (see Sections 2.7.2 and 2.8.3). A timeline of ventilation status is described below.
A patient’s ventilation information might be recorded in several records (for e.g if the number 
of hours/day changes). Information should be combined. If two records are available for the 
same day with different number of hours per day, the maximum will be assumed.
Further Analyses
Additionally, the following analyses will be carried out:

CHOP INTEND

Spaghetti plots of Total Score and Total Score Change from Baseline (Parts 1 & 3)

Spaghetti plots of Total Score and Total Score Change from Baseline stratified by 
treatment group (Parts 2 & 3)

Panel plots of individual CHOP INTEND Total Score and Total Score Change from 
Baseline – in each panel a spaghetti plot of all subjects (Parts 1 & 3, and 2 & 3) 

Panel plots of individual Total Score Change from Baseline by time with dose as 
background shading – one panel per subject (Parts 1 & 3)

Stratified bar chart of subjects showing >= 4 improvement from baseline in Total 
Score by Baseline Age Group, and Time (Parts 1 & 3, and 2 & 3) 

Table of Median Change in Total Score from Baseline by Visit and Baseline Age 
Group (Parts 1 & 3, and 2 & 3) 

Table of subjects reaching Total Score >= 40 by Visit (Parts 1 & 3, and 2 & 3) 

Growth measurements

Spaghetti plots (growth curves) of length and weight versus age at evaluation by sex 
with CDC percentiles (Parts 1 & 3, and 2 & 3) 

Summaries of chest circumference measured at the end of both inspiration and 
expiration during quiet breathing (sleep) by treatment group and part   

Feeding and Ventilation Status

Time lines of feeding and ventilation status with dose as background shading (Parts 1
& 3, and 2 & 3)

HINE Motor Score and Items

HINE sub-scales Crawling, Head Control, Kicking, Rolling, Sitting, Standing, and 
Walking

Stacked bar chart by visit and part (Parts 1 & 3, and 2 & 3) 

Table of milestones reached
HINE sub-scale
Milestone
Head control
Wobbles or all the time upright
Kicking
Any kick
Rolling
Any roll


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Sitting
Stable independent sit or Pivots (rotates)
Crawling
Lifts head in any way (Props on elbow)
Standing
Supports weight
Walking
Makes any attempt (ie Bounces)

HINE Motor Total Score

Table of frequencies of the following change from baseline categories by visit 
(Parts 2 & 3):

1 = Worsening (<0)

2 = No change (=0)

3 = Improvement of 1 point

4 = Improvement of 2 points

5 = Improvement of > 2 points

Table of frequencies of subjects reaching a post-baseline score of >=3 by visit 
(Parts 1 & 3, and 2 & 3)

Panel plot of individual values by time with dose as background shading (Parts 1
& 3 and 2 & 3)

Panel plot of individual values – in each panel a spaghetti plot of all subjects 
(Parts 2 & 3)

Motor and Speech Performance

Hip Strength, Speech, Upper Extremity Function, and Voluntary Grasp

Stacked bar chart by visit (Parts 1 & 3, and 2 & 3) 
2.7.2
Statistical hypothesis, model, and method of analysis
A Kaplan Meier (KM) analysis by part will be carried out on time to death, permanent 
ventilation or tracheostomy; results will be displayed in a life table with respective KM 
estimates and 95% confidence intervals, along with appropriate plots. Permanent ventilation is 
defined as more than 21 consecutive days for more than 16 hours/day of non-invasive 
ventilation (BiPAP or CiPAP).
2.8
Safety Analyses
In general, data assigned to Part 3 (section 2.1.1) will be analysed together with the part the 
subject came from (i.e. ‘Parts 1 & 3’, ‘Parts 2 & 3’).
Safety analyses will be conducted using the safety set (SAF). In Parts 1 & 3, subjects will be 
analyzed overall, with some graphical methods including the current dose; in Parts 2 & 3, the 
analyses will be summarized by actual treatment group. Unless explicitly stated otherwise, only 
data up to the safety cutoff (as defined in Section 2.1.1) will be included in the analysis and data 
beyond this time point for a given subject will be excluded from the safety analysis.
The assessment of safety will be primarily based on the frequency of adverse events (including 
death and non-fatal serious adverse events), and adverse events of special interest. Additional 
safety assessments include laboratory tests, ECG evaluations, echocardiograms, vital signs, 
ophthalmology, physical and neurophysiological examinations. Clinically significant findings 


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in these additional safety assessments will be reported as adverse events and analyzed as such. 
In addition, all safety assessments will be summarized or listed as appropriate.
2.8.1
Treatment exposure
Treatment dosing will be investigated both descriptively and graphically:

Table of treatment duration in total (in months) and frequencies of each separate dose

Time line of each subject’s dosing (Parts 1 & 3 and Parts 2 & 3)
For the plots only: Doses collected in the CRF will be remapped to two variables, one for each 
unit (mg/m2 and mg/kg). Indeed, doses were first collected in mg/m2 and unit was changed 
during Part 1 (see section 1.1). If dose as per CRF is not among the planned doses or dose is 
missing, the remapped dose variables will be missing. If a visit was missed or (remapped) 
dose was missing then the last non-missing dose will be displayed. The same is applied for 
plots with dose as background shading.
2.8.2
Adverse events (AEs)
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or
clinical investigation of a subject after providing written informed consent for participation in
the study. That means that a subject can report AEs before having started study drug. For
reporting purposes, the main focus will be on treatment emergent adverse events (TEAEs).
Treatment emergent AEs are defined as events starting on or after the first dose of study drug
that were absent pre-treatment, or events present prior to the first dose but increased in severity 
after the first dose (based on the MedDRA lower level term (LLT).  TEAEs are included up to 
the safety cutoff (as defined in Section 2.1.1). Except for serious TEAEs and death, only TEAEs 
up to and including safety cutoff (as defined in Section 2.1.1) will be included in the analyses. 
For serious TEAEs a modified safety cutoff is used (as defined in Section 2.1.1). TEAEs will 
be assigned to Part 3 if the start date is on/after the first visit date of Part 3 (see section 2.1.1).  
All deaths will be included, regardless of safety cutoff.
AEs will be reported by primary system organ class (SOC) and preferred term (PT) according 
to the Medical Dictionary for Regulatory Activities (MedDRA). The MedDRA version used 
for reporting the study will be described in a footnote.
The number and percentage of subjects reporting any TEAEs will be summarized by primary 
SOC, preferred term, maximum CTCAE grade (individual, as well as Grade 3 and above 
combined) and treatment group (Parts 2 & 3). Missing CTCAE grade will not be imputed. 
Separate summaries will be provided for serious TEAEs, drug related TEAEs, TEAEs leading 
to permanent discontinuation of study drug and most common TEAEs (10% in any group). 
Furthermore, exposure-adjusted incidences will be reported in an AE overview table, for all 
AEs in a table by system organ class and preferred term by part, and similarly for serious AEs.
If a subject reported more than one adverse event within the same primary system organ class, 
the subject will be counted only once with the maximum CTCAE grade at the system organ
class level, where applicable.
All AEs will be presented in listings.


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The following graphs will be displayed:

Bar charts of MedDRA system organ classes - crude incidences

Bar charts of MedDRA preferred terms - crude incidences

Similar bar charts for serious TEAEs
2.8.2.1
Adverse events of special interest / grouping of AEs
Selected tables will be produced for Adverse Events of Special Interest (AESI) (i.e., risks) 
defined in the latest version of case retrieval sheet (eCRS) at the time of analysis 
implementation (i.e., study database lock).
The LMI070X2201 eCRS is available at http://go/ecrs by selecting either

CRS NAME: (LMI070 Spinal muscular atrophy) or

CRS ID: 3689

Within the document, select SP=”Y”
Specifically, incidence of TEAEs that fulfill the risk search terms as defined in eCRS will be 
summarized by risk name, level, study part and treatment group (for Parts 2 & 3 only) with
crude incidences and 95% confidence intervals presented. 
Similarly, separate summaries will be provided for serious TEAEs that fulfill the risk search 
terms as defined in eCRS. Additionally, incidence of any TEAEs that fulfill the search terms as 
defined in eCRS will also be summarized by risk name, level, and maximum CTCAE grade.
Bar charts of MedDRA preferred terms that fulfill the search terms as defined in eCRS will be 
produced for crude incidences by part.
2.8.3
Deaths
Deaths will be summarized by providing the number and percentage of subjects by study part. 
All deaths as recorded in the final database (i.e., up to database lock) will be included.
Additionally, time to death, permanent ventilation or tracheostomy will be displayed in a 
Kaplan-Meier plot along with the respective table (see Section 2.7.2).
2.8.4
Laboratory data
Data summaries will be provided in SI units. The summary of laboratory evaluations will be 
presented for three groups of laboratory tests: Hematology, Chemistry and Urinalysis. On 
presenting summary statistics, laboratory data will be grouped and displayed in an alphabetical 
order within each of the three groups.
Descriptive summary statistics (mean, median, standard deviation, Min and Max) of the change 
from baseline in the laboratory result to each study visit-window by treatment group will be 
presented for continuous variables. Change from baseline will only be summarized for subjects 
with both baseline and post baseline values and will be calculated as:
change from baseline = post baseline value – baseline value
In addition, shift tables will be provided for all parameters to compare a subject’s baseline 
laboratory evaluation relative to the post-baseline values. For the shift tables, the normal local 


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laboratory ranges will be used to evaluate whether a particular laboratory test value was normal, 
low, or high relative to whether or not the baseline value was normal, low, or high. These 
summaries will be presented by laboratory test overall in Parts 1 & 3, additionally by actual 
treatment group in Parts 2 & 3. Shift table will also be provided for urinalysis results to compare 
baseline to post-baseline extreme values (negative, +, 2+, 3+, or 4+).
Number of subjects with newly occurring liver enzymes abnormalities will be summarized
using the respective criteria. Newly occurring liver enzymes abnormalities are defined in 
Section 5.3.2.
For both shift tables and newly occurring liver enzymes abnormalities, all applicable post-
baseline values (including unscheduled or unplanned visits) will be checked against the 
respective criteria and the rules for handling multiple laboratory assessments within visit 
windows will not be applied.
For continuous variables databased as <lower limit, these will be imputed as being half of the 
lower limit.
The following graphs will be generated for liver enzymes:

Panel plot of individual subjects for alkaline phosphotase, total bilirubin, ALT and AST 
with dose as background shading – one panel per subject (Parts 1 &3 and Parts 2 & 3)

eDISH scatterplot of Total Biliburin and ALT on log-log axes (Parts 1 & 3); additionally 
stratified by treatment group (Parts 2 & 3)

Matrix plot of each of the parameters (ALT, AST, Total Bilirubin and Alkaline 
Phosphotase) maximum post-baseline/ULN normalized (Parts 1 & 3, and Parts 2 & 3)
All above summaries include only data up to and including safety cut off. If there is any value 
for a parameter outside of the normal range for a subject, then all data of this parameter for that 
subject will be listed.
2.8.5
ECG and echocardiographic data
Clinically significant findings from ECG evaluations will be reported as AEs and included in 
the analysis of AEs. ECG parameters include max heart rate, mean PR duration, mean QT 
duration, mean QRS duration, QTf (QT corrected using Fridericia’s correction formula), and 
QTb (corrected using Bazett’s correction formula) - all as collected on the ECG CRF.
Descriptive statistics of each ECG parameter will be provided overall (Parts 1 & 3) and by 
treatment group (Parts 2 & 3) for baseline and all relevant post-baseline visits.
The number and percentage of subjects meeting the criteria defined in Table 2-15 will be 
provided for each criterion by treatment group for baseline and the relevant post-baseline 
assessments.
Table 2-15
Criteria for relevant ECG absolute values
Absolute values criteria:
QT > 450 msec
QTc > 450 msec


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The number and percentage of subjects with echocardiography abnormality will be provided by 
treatment group for baseline and any time post-baseline.
All ECG data will be listed, and abnormalities will be flagged. For echocardiographic data, all 
patients with at least one abnormality will be listed.
2.8.6
Vital signs
Vital sign measurements include sitting systolic and diastolic blood pressures, sitting pulse, 
body temperature, height and body weight.
Derivation of baselines for blood pressure and pulse are provided in Section 2.1.1.
Height will be collected at screening visit only and will be summarized in the baseline 
characteristic summary only.
Analyses of vital sign measurements using descriptive summary statistics (mean, median, 
standard deviation, min, max) for the change from baseline for each post-baseline visit-window 
will be performed. These descriptive summaries will be presented by vital sign parameter and 
treatment group (Parts 2 & 3). Change from baseline will only be summarized for subjects with 
both baseline and post-baseline values and will be calculated as:
change from baseline = post-baseline value – baseline value
In addition, shift tables will be provided for all vital sign parameters to compare a subject’s 
baseline value relative to the post-baseline values. For the shift tables, the reference ranges in 
Table 2-16 will be used to evaluate whether a particular value was normal, low, or high relative 
to whether or not the baseline value was normal, low, or high.
Table 2-16
Reference ranges for vital sign parameters
Age window
Pulse rate
Systolic blood pressure
Diastolic blood pressure
0–<3 months
100-150
65-85
45-55
3-<6 months
90-120
70-90
50-65
6-<12 months
80-120
80-100
55-65
1-<3 years
70-110
90-105
55-70
3-<6 years
65-110
95-110
60-75
6-<12 years
60-95
100-120
60-75
Source: Nelsons textbook of Pediatrics 18th Edition
Apart from the growth measurement graphs mentioned in Section 2.7.1, the following graph 
will be generated for vital signs data:

Panel plot of individual vital signs over time – systolic and diastolic BP, and pulse
All above summaries include only data up to and including safety cut off. All vital signs data 
will be listed, and age-dependent abnormalities will be flagged


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2.8.7
Ophthalmology Examination
All ophthalmological abnormalities will be descriptively summarized and for patients with at 
least one abnormality, data will be listed.
2.8.8
Neurophysiological Examination
All neurophysiological evaluations [Ulnar compound motor action potential (CMAP), Ulnar 
nerve conduction velocity (NCV), Sural SNAP, Sural sensory NCV] will be descriptively 
summarized and listed.
Furthermore the following analyses will be carried out:

Spaghetti plot of raw neurophysiological parameters vs months from first dose over time 
with all raw data (Parts 2 & 3)

Spaghetti plot of raw neurophysiological parameters vs months from first dose over time 
excluding implausible post-baseline zero values (Parts 2 & 3)

Spaghetti plot on a log scale of raw neurophysiological parameters vs months from first 
dose over time excluding implausible post-baseline zero values (Parts 2 & 3)

Spaghetti plot on a log scale of normalised neurophysiological parameters vs months from 
first dose over time with all normalised data (Parts 2 & 3)

Spaghetti plot on a log scale of normalised neurophysiological parameters vs months from 
first dose over time excluding implausible post-baseline zero values (Parts 2 & 3)
2.8.9
Neurologic examination questionnaire
All data will summarized with appropriate descriptive statistics, and all data will belisted.
2.8.10
Acceptability and palatability questionnaire
All data will summarized with appropriate descriptive statistics.
2.9
Pharmacokinetic endpoints
Parts 1 & 3 and Parts 2 & 3
The following pharmacokinetic parameters will be analyzed: Cmax, Tmax, AUCtau or AUC0-
168h, AUClast, AUCinf, T1/2, Vz/F and CL/F from the plasma concentration-time data.
Descriptive analyses
Branaplam plasma concentration data will be listed by study part, administered dose, subject, 
and sampling time point. Descriptive summary statistics will be provided by dose level (see 
Table 1-2) and sampling time point. Summary statistics will include mean (arithmetic and 
geometric), SD, CV (arithmetic and geometric), median, minimum, maximum, and the 
frequency (n, %) of concentrations below the LLOQ. Concentrations below LLOQ will be 
treated as zero in summary statistics and for PK parameter calculations. A geometric mean will 
not be reported if the dataset includes zero values. For all doses, the unit is transferred from 
“mg/m2” to “mg/kg” for summary statistics calculation. The summary statistics table also 
include columns with treatment group in Parts 2 & 3. A geometric mean will not be reported if 


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the dataset includes zero values. Graphical methods will be employed to show mean and 
individual concentration-time profiles. Pharmacokinetic parameters will be listed by study part, 
administered dose and subject and summarized by dose with descriptive summary statistics as 
described above. An exception to this is Tmax where median, minimum and maximum will be 
presented.
2.9.2
Accumulation ratio
Part 1
In subjects, who received the same dose in the first two treatment cycles of 3 months each, the 
parameters AUC0-168h for both observations and Cmax will be log transformed and used in 
an ANCOVA model with day as a factor, log dose as a covariate and day by dose interaction 
and subject as random effect. The LSMeans and their mean difference between treatment cycle 
2 and Day 1 for each dose level, together with 90% confidence limit will be calculated from 
this model. These will be back-transformed to provide an estimate of the accumulation ratio 
with corresponding 90% CI.
Part 2
Accumulation ratio can be estimated as described for Part 1. Since no intra-individual dose 
escalation is planned, the accumulation will be estimated for each observation period versus 
first administration.


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2.9.3
Age and weight dependency
PK parameters will be generated for all subjects over the whole duration of the study. Since the 
physiological changes in Type 1 SMA subjects is very dynamic, the PK parameters AUC 
(AUCinf after first administration, AUCtau or AUC0-168h after all other administrations), 
Cmax, CL/F, Vz/F, and T1/2 will be correlated with both age and weight. For Parts 1 & 3, AUC 
and Cmax will be dose-normalized using unit mg/kg. For Parts 2 & 3, the age and weight 
dependency will be executed for each dose independently. Scatter plots of PK parameters versus 
both age and weight at the time of the dose when PK parameter was calculated, including a 
regression analysis, will be provided on the individual level.
The analysis will be carried for each study part separately.
2.9.4
Comparison of dosing methods
Branaplam can be administered either via tube administration or orally. To test the impact of 
the dosing method on the systemic exposure, the exposure parameters AUC (AUCtau or AUC0-
168h) and Cmax will be compared between both dosing methods. The comparison will be 
executed for each subject individually, who was treated with both methods. Since the number 
of oral administrations per subject is considered to be low, especially when compared to tube 
administration, proposed assessments might be not feasible for all subjects treated with both 
methods.
Two assessments will be executed (if feasible) for Parts 1 & 3:

Exposure parameters across the complete study duration will be dose-normalized using 
unit mg/kg and summary statistics for each method executed. Box plot comparing the two 
dosing methods will be prepared for each PK parameter.

Exposure parameters of two subsequent profiles, of which one was derived after tube 
administration and the other after oral administration, will be dose-normalized using unit 
mg/kg. The ratio will be calculated between tube administration and oral administration.
For Parts 2 & 3, the same will be executed (if feasible) but without dose-normalizing. Results 
will be computed and displayed for each dose individually.
2.10
PD and PK/PD analyses
Not applicable.
2.11
Subject-reported outcomes
Not applicable.


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2.13
Interim analysis
In the third interim analysis, no DLT’s in Part 1 were identified; this analysis will not be 
repeated in the upcoming fourth interim analysis of Parts 1 and 2 – details can be found in 
Appendix 5.4.3.
3
Sample size calculation
Part 1
The sample size for Part 1 is driven by feasibility. In Part 1, cohorts of at least 2 subjects are 
planned to be dosed until a decision is made for MTD, however adjustment of cohort size might 
be considered due to enrollment and safety consideration. 13 subjects were enrolled to test 5 
dose levels. At least 2 subjects are required for cohort 1 at the starting dose. Size of later cohorts 
may be adjusted based on feasibility. As noted earlier, if more than two subjects present 
simultaneously for the study, additional subject(s) may be dosed in a cohort to avoid 
unnecessary delays in treatment of this life-threatening disease.
Part 2
In Part 2, 25 subjects were enrolled to evaluate up to 2 different dose cohorts with at least 6 
subjects and up to approximately 10 subjects per cohort.
The driver of the sample size in Part 2 is the primary objective, safety. We are able with 95% 
confidence to rule out that the true incidence rate exceeds 50% of any class of adverse events if 
none in that class are observed in 6 subjects.
Furthermore, in an interim analysis of CHOP INTEND data from Part 1, CHOP INTEND scores 
were analyzed by a mixed linear model with covariates for dose, baseline CHOP INTEND, and 
calendar age. A compound symmetric covariance structure was assumed for observations 
within the same individual. This analysis pointed to a total estimated variability of 7 on a CHOP 
INTEND scale (sum of between and within subjects’ variance components). The table below 
(Table 3-1) shows the power to detect a difference in CHOP INTEND score between two 
adjacent dose groups (by one-sided t test at nominal significance level 5%). It seems likely that 
differences exceeding 10 points on a CHOP INTEND scale will be identifiable with the planned 
sample size.
Table 3-1
Power to detect a difference in CHOP INTEND score between two 
adjacent dose groups (by one-sided t-test at nominal significance 
level of 5 percent)
N=6
N=7
N=8
N=9
N=10
Effect size 8 points
56%
64%
70%
74%
78%


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Effect size 10 points
74%
80%
85%
89%
92%
12 points
86%
91%
94%
96%
98%
4
Change to protocol specified analyses
The following analyses were specified in the protocol but will not be performed or will be 
analysed differently:
-
 
 
 
 
-
The repeated measures analysis specified in section 11.5.1 (for part 1 and part 2 together, 
for continuous endpoint) was not performed. No repeated measures model was 
estimated. 
-
Listings for relevant medical history and current medical condition, concomitant 
therapies, 
 from the protocol will not be produced. 
Team assessed that tables with summary statistics are sufficient for the purpose of the 
CSR.
-
The listing for laboratory will not display all data. Instead, if there is any value outside 
normal range of a parameter for a subject then all records for that parameter and this 
subject are listed.
-
As time to death, permanent ventilation or tracheostomy is specified as efficacy 
assessment in the protocol summary, Kaplan Meier tables and plots for that endpoint 
will be provided, and not for time to death or permanent ventilation as specified in 
section 11.5.1 from protocol.


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5
Appendix
5.1
Imputation rules
In any analysis or evaluation, if the visit date(s) is missing, no imputation will be implemented.
5.1.1
Study drug
Start date and end date of study drug on the respective CRF panel are mandatory; thus, no date 
imputation will be applied.
5.1.2
AE and concomitant medication date imputation
Incomplete start date or end date of an adverse event or concomitant medication taken will be 
handled by following rules: 
Table 5-1
Imputation of start dates (AE, CM) 
Missing 
Element
Rule
day, month, 
and year

No imputation will be done for completely missing dates
day, month

If available year = year of study treatment start date then 
o
If end date contains a full date and end date is earlier than 
study treatment start date then set start date = 01JanYYYY 
o
Else set start date = study treatment start date. 

If available year > year of study treatment start date then 01JanYYYY

If available year < year of study treatment start date then 01JulYYYY
day

If available month and year = month and year of study treatment start 
date then 
o
If end date contains a full date and end date is earlier than 
study treatment start date then set start date= 01MONYYYY. 
o
Else set start date = study treatment start date.

If available month and year > month and year of study treatment start 
date then 01MONYYYY  

If available month and year < month year of study treatment start date 
then 15MONYYYY  
Table 5-2
Imputation of end dates (AE, CM) 
Missing 
Element
Rule 
(*=min(death date, safety cutoff date, withdrawal of consent date))
day, month, 
and year

Completely missing end dates (incl. ongoing events) will be imputed 
by the end date of the on-treatment period* 


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Missing 
Element
Rule 
(*=min(death date, safety cutoff date, withdrawal of consent date))
day, month

If partial end date contains year only, set end date = earliest of 
31DecYYYY or end date of the on-treatment period * 
day

If partial end date contains month and year, set end date = earliest of 
last day of the month or end date of the on-treatment period*
Notice if imputed end date is less than the start date (if complete), use the start date as the 
imputed end date.
Any AEs and ConMeds with partial/missing dates will be displayed as such in the data listings.
For adverse events and any prior or concomitant medication, to decide whether the event or 
medication was prior or post-dosing is carried out as follows:

If start date and time are not missing, then report as post-dosing if start date and time > 
dosing start date and time

If start date is available, but not start time, then report as post-dosing if start date > dosing 
start date. This means that all events occurring on the dosing start day (even if they 
occurred prior to it) will be considered as post-dosing – similarly for medications, will be 
considered as concomitant.

If both start date and time are missing, both adverse events and medications will be 
defined as being post-dosing.
5.1.3
Values outside limits of quantification
For descriptive analyses of laboratory parameters 
 the following values will 
be imputed:

LLOQ with 0.5 * LLOQ 

ULOQ with 1.5 * ULOQ
The frequency (n, %) of values either below the LLOQ or above the ULOQ will also be 
reported.
For PK analyses, other rules apply (see Section 2.9.1).
5.2
AEs coding/grading
Not applicable.
5.3
Laboratory parameters derivations
For each subject, the estimated creatinine clearance values (without collecting urine) will be 
calculated using the Cockcroft-Gault formula (as specified in Table 5-3). In these calculations, 
the body weight is the last measurement collected on or before the day when the subject takes 
the laboratory test and age should also be calculated based on the time when the subject takes 
the laboratory test.


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If the creatinine value is collected in the unit µmol/L (SI unit), it will be converted to mg/dL in 
order to use the formulas. The conversion is via the equation below:

mg/dL = 88.4 µmol/L (e.g., creatinine = 2.0 mg/dL = 176.8 µmol/L).
Table 5-3
Creatinine clearance calculation
Variable
Formula
Creatinine clearance [mL/min] 
using Cockcroft-Gault formula 
(Cockcroft and Gault 1976)
= (140 – A) W / (72 C) G
Where
A is age [years]
W is body weight [kg]
C is the serum concentration of creatinine [mg/dL]
G is a constant: G=1 for males and G=0.85 for females.
The estimated creatinine clearance will be included as one of the laboratory parameters.
5.3.1
Laboratory test groups and subgroups
On presenting lab results, grouping parameters by family will ease the review. Table 5-4 below 
shows a possible set of lab parameters and their corresponding classification.
Table 5-4
Laboratory tests
Order
Laboratory Group Subgroups
Tests [SI unit]
1
Hematology
Absolute Basophils [10E9/L]
Absolute Eosinophils [10E9/L]
Absolute Lymphocytes [10E9/L]
Absolute Monocytes [10E9/L]
Absolute Neutrophils [10E9/L]
Absolute other differentials [10E9/L]
Basophils [%]
Eosinophils [%]
Hematocrit [1]
Hemoglobin [g/L]
Lymphocytes [%]
Mean Platelet Volume [fL]
Monocytes [%]
Neutrophils [%]
Other differentials [%]
Platelet count direct [10E9/L]
RBC [10E12/L]
Reticulocytes [%]
WBC (Total) [10E9/L]
2
Chemistry
Albumin [g/L]
Alkaline Phosphatase [U/L]
ALT [U/L]
AST [U/L]
Bicarbonate [mmol/L]
Bilirubin (direct/conjugated) [umol/L]
Bilirubin (indirect/unconjugated) [umol/L]
Calcium [mmol/L]


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Order
Laboratory Group Subgroups
Tests [SI unit]
Chloride [mmol/L]
Creatinine [umol/L]
Free Thyoxine (FT4) [pmol/L]
Glucose [mmol/L]
hsCRP (high sensitive C-Reactive protein) [mmol/L]
Potassium [mmol/L]
Sodium [mmol/L]
Thyroid hormones T4 [nmol/L]
Thyroid stimulating hormone [mU/L]
Urea [mmol/L]
3
Urinalysis
Bilirubin Dipstick test
Blood Dipstick test
Glucose Dipstick test
Ketone Dipstick test
Leukocytes Dipstick test
Nitrite Dipstick test
Protein Dipstick test
Sediment - Casts
Sediment - RBC
Sediment - WBC
Specific Gravity
Urobilinogen
pH
5.3.2
Newly occurring liver enzymes abnormalities
Below lists the criteria for “events” of newly occurring liver enzymes abnormalities:

ALT > 3, 5, 10, 20x ULN

ALT or AST > 3, 5, 8, 10, 20x ULN

ALT or AST > 3x ULN & TBIL > 1.5x ULN

ALT or AST > 3x ULN & TBIL > 2x ULN

ALP > 1.5, 2, 5x ULN

TBIL > 1, 1.5, 2x ULN

ALP > 3, 5x ULN & TBL > 2x ULN

ALT or AST > 3x ULN & TBIL > 2x ULN & ALP ≤ 2x ULN

ALT or AST > 3x ULN & (nausea or vomiting or fatigue or general malaise or abdominal 
pain or (rash and eosinophilia))
When a criterion contains multiple laboratory parameters (e.g., ALT > 3xULN & 
TBL > 2xULN), unless otherwise requested by the project clinical team/Brand Safety Leader 
(BSL), the criterion should be only considered to be met when the elevation in both parameters 
occurs on the same sample day (as evidenced by the same date that the lab samples were taken).
The “events” are defined in the Novartis safety guideline on hepatotoxicity (Novartis: Philippe 
Close 2011), Section: Safety parameters for special liver event analyses.


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5.4
Analysis of the primary objective in Part 1
The primary objective of Part 1 is to estimate the Maximum Tolerated Dose (MTD) of 
branaplam, when administered orally on a once weekly schedule to subjects with Type 1 spinal 
muscular atrophy. The primary analysis method is an adaptive Bayesian logistic regression 
model (BLRM) guided by the escalation with overdose control (EWOC) principle 
(Neuenschwander et al 2008).
5.4.1
Primary endpoint in Part 1
The primary endpoint is the incidence of Dose Limiting Toxicity (DLTs) in the first two weeks 
after the first dose in Part 1. Estimation of the MTD of LMI070 will be based upon the 
estimation of the probability of DLT in the first 2 weeks after the first dose in the DDS. This 
probability is estimated by the model in Section 5.4.2.
For the analysis of the primary variables, the DDS analysis set will be used.
DLTs will be listed and their incidence summarized by primary system organ class, worst grade 
based on the CTCAE version 4.03, type of adverse event, and by treatment group. The DDS 
will be used for these summaries.
5.4.2
Statistical hypothesis, model, and method of analysis in Part 1
The dose-toxicity (DLT) relationship in each dose escalation will be described by the following 
logistic regression model:
logit(π(d)) = log(α) + β log(d/d*), α>0, β>0
where, logit(π(d)) = ln (π(d)/(1- π(d))), and π(d) is the probability of a DLT at dose d, where d 
represents the total weekly dose in Part I. Doses are rescaled as d/d* with reference dose of d*= 
40 mg/m2 of branaplam. As a consequence, α is equal to the odds of toxicity at d*. Note that 
for a dose equal to zero, the probability of toxicity is zero.
The following sub-sections provide details for dose recommendation and prior distribution for
the model parameters.
Dose recommendation
After each cohort is completed the posterior distributions for the probabilities of DLT at
different dose levels will be obtained. The results of this analysis will be summarized in terms 
of the estimated probabilities that the true rate of DLT at each dose-level will lie within each of 
the following intervals:

[0, 10%) under-dosing.

[10%, 25%) targeted toxicity.

[25%, 100%] excessive toxicity.
Following the principle of escalation with overdose control (EWOC), after each cohort of 
subjects the recommended dose will be the one with the highest posterior probability of the 
DLT rate falling in the target interval [10%, 25%) among the doses fulfilling escalation with 
overdose control (EWOC), i.e. it is unlikely (< 25% posterior probability) that the DLT rate at 


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the dose falls in the excessive toxicity interval i.e. P(DLT) is 0.25 or higher. In addition, the 
maximum dose escalation is limited to 100% of the previous dose.
Note that the dose that maximizes the posterior probability of targeted toxicity is the best 
estimate of the MTD, but it may not be an admissible dose according to the overdose criterion 
if the amount of data is insufficient. If vague prior information is used for the probabilities of 
DLT, in the early stages of the study this escalation procedure will reflect a cautious strategy. 
The dose recommended by the adaptive Bayesian logistic model may be regarded as guidance 
and information to be integrated with a clinical assessment of the toxicity profiles observed at 
the time of the analysis in determining the next dose level to be investigated.
Prior specification
A vague bivariate normal prior for the model parameters (log(α), log(β)) is derived by assuming 
that the median DLT rate at reference dose d*=40 mg/m2 equals the targeted toxicity 0.25, and 
that for the remaining doses, median DLT rates a priori are linear in logit scale as a function of 
log-dose.
The information to derive the prior distribution of model parameters is provided in Table 5-5.
Table 5-5
Prior parameters for bivariate normal distribution of model parameters
Parameters
Means
Standard deviations
Correlation
log(α), log(β)
(-1.099, 0)
(3.2, 1)
0
All information obtained on adverse events will be displayed by initial and administered dose 
and subject.
5.4.3
Interim analysis in Part 1
After each cohort of subjects finish first dosing and contribute safety data at week 2, an interim 
analysis (without requirement for database lock) will be conducted for dose escalation 
decisions. The analysis will be comprised of fitting a Bayesian logistic regression model 
(BLRM) based on the dose limiting toxicity (DLT) information. From this model, the posterior 
probability of DLT rate at different dose levels will be estimated and a dose will be 
recommended to guide dose selection for the next cohort or declaration of MTD. In general, the 
next dose will have the highest chance that the DLT rate will fall in the target interval [10%, 
25%) and will always satisfy the escalation with overdose control (EWOC) principle that the 
posterior probability of DLT rate falling in overdosing interval (>25%) is below 25%. In all 
cases, the dose for the next cohort will not exceed a 100% increase from the previous dose. 
Final dose escalation decisions will be made by Investigators and Novartis study personnel. 
Decision will be based on a synthesis of all relevant data available from all dose levels evaluated 
in the ongoing study, including safety information, DLTs, and available PK data from evaluable 
subjects. Dose escalation will continue until identification of the MTD.
An interim analysis is planned after MTD determination in Part 1 to evaluate PD effects of the 
treatment and assist with decision making for Part 2. Data on muscle thickness, ratio of muscle 
thickness to subcutaneous tissue thickness and muscle echo intensity, growth measurements, 
respiratory function assessments and CHOP INTEND infant motor scale will be summarized at 
different time points and compared to baseline.


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The Interim Analysis Team may communicate interim results (e.g. evaluation of PoC criteria 
or information needed for planning/modifying another study) to relevant Novartis teams for 
information, consulting and/or decision purposes.
6
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Neuenschwander B, Branson M, Gsponer T (2008) Critical aspects of the Bayesian approach 
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Sahai H, Khurshid A (1993). Conﬁdence intervals for the ratio of two Poisson means. The 
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